Publications

Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor- reactive CD8+T cells and reprogramming macrophages

M. Tichet; S. Wullschleger; A. Chryplewicz; N. Fournier; R. Marcone et al. 

Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most pa-tients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1+ T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8+ T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogram-ming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1+ stem-like T cells.

Cancer hallmarks intersect with neuroscience in the tumor microenvironment

D. Hanahan; M. Monje 

The mechanisms underlying the multistep process of tumorigenesis can be distilled into a logical framework involving the acquisition of functional capabilities, the so-called hallmarks of cancer, which are collectively envisaged to be necessary for malignancy. These capabilities, embodied both in transformed cancer cells as well as in the heterotypic accessory cells that together constitute the tumor microenvironment (TME), are conveyed by certain abnormal characteristics of the cancerous phenotype. This perspective discusses the link between the nervous system and the induction of hallmark capabilities, revealing neurons and neuronal projections (axons) as hallmark-inducing constituents of the TME. We also discuss the autocrine and paracrine neuronal regulatory circuits aberrantly activated in cancer cells that may constitute a distinctive “enabling”characteristic contributing to the manifestation of hallmark functions and consequent cancer pathogenesis.

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

Q. Zeng; S. Saghafinia; A. A. Chryplewicz; N. Fournier; L. Christe et al. 

Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP’s immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators-interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP’s cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses.

Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity

A. Chryplewicz; J. Scotton; M. Tichet; A. Zomer; K. Shchors et al. 

Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via in-hibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mech-anism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8(+) T cells

L. C. Deak; V. Nicolini; M. Hashimoto; M. Karagianni; P. C. Schwalie et al. 

Expansion and differentiation of antigen-experienced PD-1(+)TCF-1(+) stem-like CD8(+) T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade(1-4). Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8(+) T cells similar to those generated in an acute infection(5). IL-2 binding to the IL-2 receptor alpha-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor beta- and gamma-chain (IL-2R beta gamma)-biased agonists are currently being developed(6-10). Here we show that IL-2R beta gamma-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2R beta gamma on the same cell recovers the ability to differentiate stem-like CD8(+) T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

Cancer Cells Retrace a Stepwise Differentiation Program during Malignant Progression

S. Saghafinia; K. Homicsko; A. Di Domenico; S. Wullschleger; A. Perren et al. 

SIGNIFICANCE: Dedifferentiation has long been observed as a histopathologic characteristic of many cancers, albeit inseparable from concurrent increases in cell proliferation. Herein, we demonstrate that dedifferentiation is a mechanistically and temporally separable step in the multistage tumorigenesis of pancreatic islet cells, retracing the developmental lineage of islet beta cells.

Roadmap for the Emerging Field of Cancer Neuroscience

M. Monje; J. C. Borniger; N. J. D’Silva; B. Deneen; P. B. Dirks et al. 

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of “cancer neuroscience” and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.

Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV+ Cancers

G. Galliverti; S. Wullschleger; M. Tichet; D. Murugan; N. Zangger et al. 

Cancers induced by human papillomaviruses (HPV) should be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7. However, advanced forms of cervical cancer, driven by HPV, are poorly responsive to immune response-enhancing treatments involving therapeutic vaccination against these viral neoantigens. Leveraging a transgenic mouse model of HPV-derived cancers, K14HPV16/H2b, we demonstrated that a potent nanoparticle-based E7 vaccine, but not a conventional “liquid” vaccine, induced E7 tumor antigen-specific CD8(+) T cells in cervical tumor-bearing mice. Vaccination alone or in combination with anti-PD-1/anti-CTLA4 did not elicit tumor regression nor increase CD8(+) T cells in the tumor microenvironment (TME), suggesting the presence of immune-suppressive barriers. Patients with cervical cancer have poor dendritic cell functions, have weak cytotoxic lymphocyte responses, and demonstrate an accumulation of myeloid cells in the periphery. Here, we illustrated that myeloid cells in K14HPV16/H2b mice possess potent immunosuppressive activity toward antigen-presenting cells and CD8(+) T cells, dampening antitumor immunity. These immune-inhibitory effects inhibited synergistic effects of combining our oncoprotein vaccine with immune checkpoint-blocking antibodies. Our data highlighted a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of myeloid cells on CD8(+) T-cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPV+ cancer-induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious antitumor immune responses.

Towards a Cancer Mission in Horizon Europe

A. Berns; U. Ringborg; A. Eggermont; M. Baumann; F. Calvo et al. 

A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

I. P. Michael; S. Saghafinia; D. Hanahan 

MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robot and P2ryl, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs-miRNA-130/301-that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.

Synaptic proximity enables NMDAR signalling to promote brain metastasis

Q. Zeng; I. P. Michael; P. Zhang; S. Saghafinia; G. Knott et al. 

Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.

ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis

I. P. Michael; S. Saghafinia; M. Tichet; N. Zangger; I. Marinoni et al. 

Herein, we report that the TGF beta superfamily receptor ALK7 is a suppressor of tumorigenesis and metastasis, as revealed by functional studies in mouse models of pancreatic neuroendocrine and lumina! breast cancer, complemented by experimental metastasis assays. Activation in neoplastic cells of the ALK7 signaling pathway by its principal ligand activin B induces apoptosis. During tumorigenesis, cancer cells use two different approaches to evade this barrier, either downregulating activin B and/or downregulating ALK7. Suppressing ALK7 expression additionally contributes to the capability for metastatic seeding. ALK7 is associated with shorter relapse-free survival of various human cancers and distant-metastasis-free survival of breast cancer patients. This study introduces mechanistic insights into primary and metastatic tumor development, in the form of a protective barrier that triggers apoptosis in cells that are not “authorized” to proliferate within a particular tissue, by virtue of those cells expressing ALK7 in a tissue microenvironment bathed in its ligand.

Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors

S. Domingos-Pereira; G. Galliverti; D. Hanahan; D. Nardelli-Haefliger 

High-risk human papillomavirus (HPV) are responsible for genital and oral cancers associated with the expression of the E6/E7 HPV oncogenes. Therapeutic vaccines targeting those oncogenes can only partially control tumor progression, highlighting the necessity to investigate different treatment strategies. Using the genital orthotopic HPV16 TC-1 model, herein we sequentially investigated in progressively more stringent settings the effects of systemic administration of carboplatin/paclitaxel (C + P) chemotherapy combined with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation with the synthetic toll-like-receptor-9 agonist CpG. Our data show that systemic delivery of C+ P prior to E7LP vaccination significantly increased mice survival. This survival benefit was associated with both reduced genital tumor growth at the time of vaccination, and a decreased infiltration of Ly6G myeloid cells and tumor-associated macrophages. Adding intravaginal CpG, which results in increased E7-specific CD8 T cells locally, to E7LP vaccination and the chemotherapy formed a tri-therapy, which significantly increased mice survival as compared to any of the dual treatments. When the tri-therapy was further refined by using a recently optimized nanoparticle-conjugated E7LP vaccine, even larger end-stage genital-TC-1 tumors responded, with 90% of mice showing a survival benefit as compared to 30% of mice with the tri-therapy involving the traditional E7LP ‘liquid’ vaccine. C + P is commonly used to treat cervical cancer patients and its combination with E7/E6 vaccination is currently being tested in a phase I/II trial (NCT02128126). Our data suggests that new vaccine formulations combined with local immunostimulation and standard-of-care chemotherapy have promise to further benefit patients with HPV-associated cancer.

Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors

S. Saghafinia; M. Mina; N. Riggi; D. Hanahan; G. Ciriello 

The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and promote oncogenic pathways. Here, we designed an algorithmic approach (RESET) to identify aberrant DNA methylation and associated cis-transcriptional changes across >6,000 human tumors. Tumors exhibiting mutations of chromatin remodeling factors and Wnt signaling displayed DNA methylation instability, characterized by numerous hyper- and hypo-methylated loci. Most silenced and enhanced genes coalesced in specific pathways including apoptosis, DNA repair, and cell metabolism. Cancer-germ line antigens (CG) were frequently epigenomically enhanced and their expression correlated with response to anti-PD-1, but not anti-CTLA4, in skin melanoma. Finally, we demonstrated the potential of our approach to explore DNA methylation changes in pediatric tumors, which frequently lack genetic drivers and exhibit epigenomic modifications. Our results provide a pan-cancer map of aberrant DNA methylation to inform functional and therapeutic studies.

Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice

G. Galliverti; M. Tichet; S. Domingos-Pereira; S. Hauert; D. Nardelli-Haefliger et al. 

Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long-peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NP) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV+ cancers. Immunization of TC-1 tumor-bearing mice with a single dose of NP-conjugated E7LP (NP-E7LP) generated a larger pool of E7-specific CD8(+) T cells with increased effector functions than unconjugated free E7LP. At the tumor site, NP-E7LP prompted a robust infiltration of CD8(+) T cells that was not accompanied by concomitant accumulation of regulatory T cells (Tregs), resulting in a higher CD8(+) T-cell to Treg ratio. Consequently, the amplified immune response elicited by the NP-E7LP formulation led to increased regression of large, well-established tumors, resulting in a significant percentage of complete responses that were not achievable by immunizing with the non-NP-conjugated long-peptide. The partial responses were characterized by distinct phases of regression, stable disease, and relapse to progressive growth, establishing a platform to investigate adaptive resistance mechanisms. The efficacy of NP- E7LP could be further improved by therapeutic activation of the costimulatory receptor 4-1BB. This NP-E7LP formulation illustrates a “solid-phase” antigen delivery strategy that is more effective than a conventional free-peptide (“liquid”) vaccine, further highlighting the potential of using such formulations for therapeutic vaccination against solid tumors. (C) 2018 AACR.

GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

L. Li; Q. Zeng; A. Bhutkar; J. Galvan; E. Karamitopoulou et al. 

A Subset of Cancer-Associated Fibroblasts Determines Therapy Resistance

J. Huelsken; D. Hanahan 

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

M. Fankhauser; M. A. S. Broggi; L. Potin; N. Bordry; L. Jeanbart et al. 

In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naive T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naive T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.

The consensus molecular subtypes of colorectal cancer

J. Guinney; R. Dienstmann; X. Wang; A. De Reynies; A. Schlicker et al. 

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-beta activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.

A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

A. Sadanandam; S. Wullschleger; C. A. Lyssiotis; C. Groetzinger; S. Barbi et al. 

Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation-enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE: This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. (C) 2015 AACR.

Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit

K. Shchors; A. Massaras; D. Hanahan 

The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and conveyed modest therapeutic benefit in tumor-bearing animals. Then we screened clinically approved agents suggested to affect autophagy for their ability to enhance imipramine-induced autophagy-associated cell death. The anticoagulant ticlopidine, which inhibits the purinergic receptor P2Y(12), potentiated imipramine, elevating cAMP, a modulator of autophagy, reducing cell viability in culture, and increasing survival in glioma-bearing mice. Efficacy of the combination was obviated by knockdown of the autophagic regulatory gene ATG7, implicating cell-lethal autophagy. This seemingly innocuous combination of TCAs and P2Y(12) inhibitors may have applicability for treating glioma.

Deficiency for the Cysteine Protease Cathepsin L Impairs Myc-Induced Tumorigenesis in a Mouse Model of Pancreatic Neuroendocrine Cancer

N. R. Brindle; J. A. Joyce; F. Rostker; E. R. Lawlor; L. Swigart-Brown et al. 

Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycER(TAM); Bcl-x(L) model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycER(TAM); Bcl-x(L) tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.

Colorectal cancer classification based on gene expression is not associated with FOLFIRI response Reply

A. Sadanandam; J. Gray; D. Hanahan 

Reconciliation of classification systems defining molecular subtypes of colorectal cancer

A. Sadanandam; X. Wang; F. De Sousa E Melo; J. W. Gray; L. Vermeulen et al. 

Recently we published two independent studies describing novel gene expression-based classifications of colorectal cancer (CRC). Notably, each study stratified CRC into a different number of subtypes: one reported 3 subtypes, whereas the second highlighted 5. Given that each ascribed clinical significance, distinctive biology, and therapeutic prognosis to the different subtypes, we sought to reconcile this apparent incongruity in subtype stratification of CRC, and to interrelate the results. To do so, we each evaluated the other’s data sets and analytical methods and discovered that the subtypes and their classifiers are, in fact, clearly related to each other; indeed, the 5 subtype outcomes can be coalesced into the same three. In addition to presenting this clarification, we briefly discuss how both classification methods can be viewed within the broader literature on CRC subtypes, and potentially applied.

Rethinking the war on cancer

D. Hanahan 

Some 40 years ago a metaphor was posed that cancer was such an insidious adversary that a declaration of war on the disease was justified. Although this statement was a useful inspiration for enlistment of resources, despite extraordinary progress in our understanding of disease pathogenesis, in most cases and for most forms of cancer this war has not been won. A second metaphor was about magic bullets-targeted therapies based on knowledge of mechanisms that were envisaged to strike with devastating consequences for the disease. The reality, however, is that targeted therapies are generally not curative or even enduringly effective, because of the adaptive and evasive resistance strategies developed by cancers under attack. In this Series paper, I suggest that, much like in modern warfare, the war on cancer needs to have a battlespace vision.

A New Twist on Radiation Oncology: Low-Dose Irradiation Elicits Immunostimulatory Macrophages that Unlock Barriers to Tumor Immunotherapy

M. De Palma; G. Coukos; D. Hanahan 

Tumor-infiltrating macrophages typically promote angiogenesis while suppressing antitumoral T cell responses. In this issue of Cancer Cell, Klug and colleagues report that clinically-feasible, low-dose irradiation redirects macrophage differentiation from a tumor-promoting/immunosuppressive state to one that enables cytotoxic T cells to infiltrate tumors and kill cancer cells, rendering immunotherapy successful in mice.

A colorectal cancer classification system that associates cellular phenotype and responses to therapy

A. Sadanandam; C. A. Lyssiotis; K. Homicsko; E. A. Collisson; W. J. Gibb et al. 

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor–targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of ‘stemness’ and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI1 in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.

Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion

L. Li; D. Hanahan 

Glutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer patients. Treatment of a tumor-derived cell line with NMDAR antagonists impaired cancer cell proliferation and invasion. Flow conditions mimicking interstitial fluid pressure induced autologous glutamate secretion, activating NMDAR and its downstream MEK-MAPK and CaMK effectors, thereby promoting invasiveness. Congruently, pharmacological inhibition of NMDAR in mice with PNET reduced tumor growth and invasiveness. Therefore, beyond its traditional role in neurons, NMDAR may be activated in human tumors by fluid flow consequent to higher interstitial pressure, inducing an autocrine glutamate signaling circuit with resultant stimulation of malignancy.

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

K. Shchors; A. I. Persson; F. Rostker; T. Tihan; N. Lyubynska et al. 

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

K. Shchors; H. Nozawa; J. Xu; F. Rostker; L. Swigart-Brown et al. 

Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1β-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumor-associated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.

Bioavailable copper modulates oxidative phosphorylation and growth of tumors

S. Ishida; P. Andreux; C. Poitry-Yamate; J. Auwerx; D. Hanahan 

Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment.

A Biocompatible in Vivo Ligation Reaction and Its Application for Noninvasive Bioluminescent Imaging of Protease Activity in Living Mice

A. Godinat; H. M. Park; S. C. Miller; K. Cheng; D. Hanahan et al. 

The discovery of biocompatible reactions had a tremendous impact on chemical biology, allowing the study of numerous biological processes directly in complex systems. However, despite the fact that multiple biocompatible reactions have been developed in the past decade, very few work well in living mice. Here we report that D-cysteine and 2-cyanobenzothiazoles can selectively react with each other in vivo to generate a luciferin, substrate for firefly luciferase. The success of this “split luciferin” ligation reaction has important implications for both in vivo imaging and biocompatible labeling strategies. First, the production of a luciferin substrate can be visualized in a live mouse by bioluminescence imaging (BLI) and furthermore allows interrogation of targeted tissues using a “caged” luciferin approach. We therefore applied this reaction to the real-time noninvasive imaging of apoptosis associated with caspase 3/7. Caspase-dependent release of free D-cysteine from the caspase 3/7 peptide substrate Asp-Glu-Val-Asp-D-Cys (DEVD-(D-Cys)) allowed selective reaction with 6-amino-2-cyanobenzothiazole (NH2-CBT) in vivo to form 6-amino-D-luciferin with subsequent light emission from luciferase. Importantly, this strategy was found to be superior to the commercially available DEVD-aminoluciferin substrate for imaging of caspase 3/7 activity. Moreover, the split luciferin approach enables the modular construction of bioluminogenic sensors, where either or both reaction partners could be caged to report on multiple biological events. Lastly, the luciferin ligation reaction is 3 orders of magnitude faster than Staudinger ligation, suggesting further applications for both bioluminescence and specific molecular targeting in vivo.

Identification and Characterization of Poorly Differentiated Invasive Carcinomas in a Mouse Model of Pancreatic Neuroendocrine Tumorigenesis

K. E. Hunter; M. L. Quick; A. Sadanandam; D. Hanahan; J. A. Joyce 

Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.

Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment

D. Hanahan; L. M. Coussens 

Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy.

Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma

P. Olson; G. C. Chu; S. R. Perry; O. Nolan-Stevaux; D. Hanahan 

Preclinical trials in mice represent a critical step in the evaluation of experimental therapeutics. Genetically engineered mouse models (GEMMs) represent a promising platform for the evaluation of drugs, particularly those targeting the tumor microenvironment. We evaluated sunitinib, an angiogenesis inhibitor that targets VEGF and PDGF receptor signaling, in two GEMMs of pancreatic cancer. Sunitinib did not reduce tumor burden in pancreatic ductal adenocarcinoma (PDAC), whereas tumor burden was reduced in the pancreatic neuroendocrine tumor (PNET) model, the latter results confirming and extending previous studies. To explore the basis for the lack of pathologic response in PDAC, we used noninvasive microbubble contrast-enhanced ultrasound imaging, which revealed that sunitinib reduced blood flow both in PDAC and in PNET, concomitant with a reduction in vessel density; nevertheless, PDAC tumors continued to grow, whereas PNET were growth impaired. These results parallel the response in humans, where sunitinib recently garnered FDA and European approval in PNET, whereas two antiangiogenic drugs failed to demonstrate efficacy in PDAC clinical trials. The demonstration of on-target activity but with discordant benefit in the PDAC and PNET GEMMs illustrates the potential value of linked preclinical and clinical trials.

TRANSLATIONAL MEDICINE Cancer lessons from mice to humans

D. Tuveson; D. Hanahan 

Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy

E. A. Collisson; A. Sadanandam; P. Olson; W. J. Gibb; M. Truitt et al. 

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis(1). Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast(2) and lung(3) cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.

Endogenous Myc maintains the tumor microenvironment

N. M. Sodir; L. B. Swigart; A. N. Karnezis; D. Hanahan; G. I. Evan et al. 

The ubiquitous deregulation of Myc in human cancers makes it an intriguing therapeutic target, a notion supported by recent studies in Ras-driven lung tumors showing that inhibiting endogenous Myc triggers ubiquitous tumor regression. However, neither the therapeutic mechanism nor the applicability of Myc inhibition to other tumor types driven by other oncogenic mechanisms is established. Here, we show that inhibition of endogenous Myc also triggers ubiquitous regression of tumors in a simian virus 40 (SV40)-driven pancreatic islet tumor model. Such regression is presaged by collapse of the tumor microenvironment and involution of tumor vasculature. Hence, in addition to its diverse intracellular roles, endogenous Myc serves an essential and nonredundant role in coupling diverse intracellular oncogenic pathways to the tumor microenvironment, further bolstering its credentials as a pharmacological target.

Brivanib, a Dual FGF/VEGF Inhibitor, Is Active Both First and Second Line against Mouse Pancreatic Neuroendocrine Tumors Developing Adaptive/Evasive Resistance to VEGF Inhibition

E. Allen; I. B. Walters; D. Hanahan 

Purpose: Preclinical trials of a mouse model of pancreatic neuroendocrine tumors (PNET) were conducted to determine whether dual FGF/VEGF pathway inhibition with brivanib can improve first-line efficacy in comparison with VEGF inhibitors lacking fibroblast growth factor (FGF)-inhibitory activity and to characterize second-line brivanib activity before and after the onset of evasive resistance to VEGF-selective therapy.

Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression

M. Franco; P. Roswall; E. Cortez; D. Hanahan; K. Pietras 

Endothelial cells (ECs) in blood vessels under formation are stabilized by the recruitment of pericytes, both in normal tissues and during angiogenesis in pathologic situations, including neoplasia. In the tumor vasculature, besides supporting the functionality of blood flow, pericytes protect ECs from antiangiogenic therapies, and have thus been implicated in clinical resistance to vascular targeting drugs. However, the molecular nature of the crosstalk between pericytes and ECs is largely unchartered. Herein, we identified pericyte-induced survival signals in ECs by isolation of vascular fragments derived from tumors that had been genetically or pharmacologically engineered to be either pericyte-rich or pericyte-poor. Pericytes induced the antiapoptotic protein Bcl-w in tumor ECs both in vivo and in vitro, thereby conveying protection from cytotoxic damage. The pericyte-dependent survival signaling in ECs was consequential to enforcement of an autocrine loop involving VEGF-A expression in ECs. Through molecular and functional studies, we delineated a signal transduction pathway in ECs downstream of integrin alpha(v) involving activation of NF-kappa B as the initiating event of the protective crosstalk from pericytes. Our elucidation of pericyte-derived pro-survival signaling in tumor ECs has potentially important implications for clinical development of antiangiogenic drugs, and suggests new therapeutic targets for rational multitargeting of cancer. (Blood. 2011; 118(10): 2906-2917)

Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappa B-Dependent Manner

N. Erez; M. Truitt; P. Olson; D. Hanahan 

Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin carcinogenesis, we found a proinflammatory gene signature in CAFs isolated from dysplastic skin. This signature was maintained in CAFs from subsequent skin carcinomas and was evident in mammary and pancreatic tumors in mice and in cognate human cancers. The inflammatory signature was already activated in CAFs isolated from the initial hyperplastic stage in multistep skin tumorigenesis. CAFs from this pathway promoted macrophage recruitment, neovascularization, and tumor growth, activities that are abolished when NF-kappa B signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be “educated” by carcinoma cells to express proinflammatory genes.

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

D. B. Ulanet; D. L. Ludwig; C. R. Kahn; D. Hanahan 

The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic beta cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti-IGF1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti-IGF-1R therapies.

Survival Benefit With Proapoptotic Molecular and Pathologic Responses From Dual Targeting of Mammalian Target of Rapamycin and Epidermal Growth Factor Receptor in a Preclinical Model of Pancreatic Neuroendocrine Carcinogenesis

C. W. Chiu; H. Nozawa; D. Hanahan 

Purpose Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET.

Genetic Deletion of the Desmosomal Component Desmoplakin Promotes Tumor Microinvasion in a Mouse Model of Pancreatic Neuroendocrine Carcinogenesis

M. G. H. Chun; D. Hanahan 

We used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to profile the transcriptome of pancreatic neuroendocrine tumors (PNET) that were either non-invasive or highly invasive, seeking to identify pro- and anti-invasive molecules. Expression of multiple components of desmosomes, structures that help maintain cellular adhesion, was significantly reduced in invasive carcinomas. Genetic deletion of one of these desmosomal components, desmoplakin, resulted in increased local tumor invasion without affecting tumor growth parameters in RT2 PNETs. Expression of cadherin 1, a component of the adherens junction adhesion complex, was maintained in these tumors despite the genetic deletion of desmoplakin. Our results demonstrate that loss of desmoplakin expression and resultant disruption of desmosomal adhesion can promote increased local tumor invasion independent of adherens junction status.

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

M. G. H. Chun; J-H. Mao; C. W. Chiu; A. Balmain; D. Hanahan 

Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both non-invasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.

MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer

P. Olson; J. Lu; H. Zhang; A. Shai; M. G. Chun et al. 

While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.

Increased expression of GAD65 and GABA in pancreatic beta-cells impairs first-phase insulin secretion

Y. Shi; J. Kanaani; V. Menard-Rose; Y. Ma; P. Chang et al. 

The functional role of glutamate decarboxylase (GAD) and its product GABA in pancreatic islets has remained elusive. Mouse β-cells express the larger isoform GAD67, whereas human islets express only the smaller isoform GAD65. We have generated two lines of transgenic mice expressing human GAD65 in pancreatic β-cells (RIP7-hGAD65, Lines 1 and 2) to study the effect that GABA generated by this isoform has on islet cell function. The ascending order of hGAD65 expression and/or activity in β-cells was Line 1 heterozygotes < Line 2 heterozygotes < Line 1 homozygotes. Line 1 heterozygotes have normal glucose tolerance, whereas Line 1 homozygotes and Line 2 heterozygotes exhibit impaired glucose tolerance and inhibition of insulin secretion in vivo in response to glucose. In addition, fasting levels of blood glucose are elevated and insulin is decreased in Line 1 homozygotes. Pancreas perfusion experiments suggest that GABA generated by GAD65 may function as a negative regulator of first-phase insulin secretion in response to glucose by affecting a step proximal to or at the KATP +channel.

Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase

S. Kash; R. Johnson; L. Tecott; J. Noebels; R. Mayfield et al. 

γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, is synthesized by two glutamate decarboxylase isoforms, GAD65 and GAD67. The separate role of the two isoforms is unknown, but differences in saturation with cofactor and subcellular localization suggest that GAD65 may provide reserve pools of GABA for regulation of inhibitory neurotransmission. We have disrupted the gene encoding GAD65 and backcrossed the mutation into the C57BL/6 strain of mice. In contrast to GAD67−/− animals, which are born with developmental abnormalities and die shortly after birth, GAD65−/− mice appear normal at birth. Basal GABA levels and holo-GAD activity are normal, but the pyridoxal 5′ phosphate-inducible apo-enzyme reservoir is significantly decreased. GAD65−/− mice develop spontaneous seizures that result in increased mortality. Seizures can be precipitated by fear or mild stress. Seizure susceptibility is dramatically increased in GAD65−/− mice backcrossed into a second genetic background, the nonobese diabetic (NOD/LtJ) strain of mice enabling electroencephalogram analysis of the seizures. The generally higher basal brain GABA levels in this backcross are significantly decreased by the GAD65−/− mutation, suggesting that the relative contribution of GABA synthesized by GAD65 to total brain GABA levels is genetically determined. Seizure-associated c-fos-like immunoreactivity reveals the involvement of limbic regions of the brain. These data suggest that GABA synthesized by GAD65 is important in the dynamic regulation of neural network excitability, implicate at least one modifier locus in the NOD/LtJ strain, and present GAD65−/− animals as a model of epilepsy involving GABA-ergic pathways.

Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction

S-M. Kang; D. B. Schneider; Z. Lin; D. Hanahan; D. A. Dichek et al. 

Fas ligand is believed to mediate immune privilege in a variety of tissues, including the eye, testis, and a subset of tumors. We tested whether expression of Fas ligand on pancreatic islets either following adenovirai or germline gene transfer could confer immune privilege after transplantation. Islets were infected with an adenovirai vector containing the murine Fas ligand cDNA (AdFasL), and were transplanted into allogenic diabetic hosts. Paradoxically, AdFasL-infected islets underwent accelerated neutrophilic rejection. The rejection was T cell and B cell independent and required Fas protein expression by host cells, but not on islets. Similarly, transgenic mice expressing Fas ligand in pancreatic beta cells developed massive neutrophilic infiltrates and diabetes at a young age. Thus, Fas ligand expression on pancreatic islets results in neutrophilic infiltration and islet destruction. These results have important implications for the development of Fas ligand-based immunotherapies.

Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines

F. Radvanyi; S. Christgau; S. Baekkeskov; C. Jolicoeur; D. Hanahan 

Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, in addition, present the opportunity to establish cell cultures more representative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenesis pathway can be cultured in vitro and show that they preserve distinctive characteristics of the normal cells from which they arose, pancreatic beta cells. In the RIP1-Tag2 line of transgenic mice, which express the simian virus 40 T antigen in insulin-producing beta cells, pancreatic islets develop into vascularized tumors in a multistage pathway. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated beta HC, release insulin at physiological concentrations of glucose. In contrast to tumor-derived lines (beta TC), which are not properly regulated, the ability of the beta HC lines to respond correctly to glucose correlated with maintenance of normally depressed levels of low-Km hexokinases. Glutamic acid decarboxylase (GAD), an early autoantigen in type I diabetes, was detected in most of the beta HC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly between the different cell lines, suggesting independent regulation. Class I major histocompatibility complex antigens were detected on the beta HC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cytotoxic T-cell killing assay. The beta HC lines will be of value for studies of beta-cell physiology, autoantigenicity, and tumor development. This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation and to provide a source of cells that maintain important qualities of their normal progenitors.

Co-targeting autophagy, macrophages and vasculature in glioma tumors triggers tumor immunity.

A. Chryplewicz; J. Scotton; M. Tichet; D. Hanahan 

Reprogramming immunosuppressive tumor-associated macrophages potentiates standard-of-care therapy in melanoma

M. Tichet; A. Chryplewicz; D. Hanahan 

The immunocytokine PD1-IL2v overcomes immune checkpoint resistance, and combination with an anti-PD-L1 antibody further enhances its anti-tumor activity.

S. Wullschleger; M. Tichet; L. Codarri-Deak; P. Umana; C. Klein et al. 

Co-targeting distinct hallmark capabilities for therapeutic benefit in pre-clinical GBM models

A. Chryplewicz; D. Hanahan 

A personalised approach for anti-GITR-based immunotherapy in preclinical models of pancreatic ductal adenocarcinoma

K. Desai; C. Ragulan; P. V. Lawrence; S. Wullschleger; M. L. Tichet et al. 

Unsorted single-cell RNA sequencing profiles of metastatic melanoma patients reveal the heterogeneity of melanoma-associated fibroblasts

K. Homicsko; D. Barras; V. A. Lopez; B. G. Moura; G. Berthod et al. 

Proton pump inhibitors negatively impact survival of PD-1 inhibitor based therapies in metastatic melanoma patients

K. Homicsko; G. Richtig; F. Tuchmann; Z. Tsourti; D. Hanahan et al. 

Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

A. J. O’Donoghue; S. L. Ivry; C. Chaudhury; D. R. Hostetter; D. Hanahan et al. 

The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only -procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

Hallmarks of cancer: applications to cancer medicine?

D. Hanahan 

Time-resolved imaging system for fluorescence-guided surgery with lifetime imaging capability

F. Powolny; K. Homicsko; R. Sinisi; C. Bruschini; E. Grigoriev et al. 

We present a single-photon camera for fluorescence imaging, with a time resolution better than 100ps, capable of providing both intensity and lifetime images. the camera was fabricated in standard CMOS technology. With this FluoCam we show the possibility to study sub-nanosecond fluorescence mechanisms. The FluoCam was used to characterize a near-infrared probe, indocyanine green, conjugated with multimeric cyclic pentapeptide ( cRGD). The fluorescent probe-conjugated was used to target and mark tumors with better specificity, in particular aiming at targeting the integrins alpha(v)beta(3) and alpha(v)beta(5). As a first step towards clinical studies, preliminary results obtained in-vivo are presented. The first envisioned clinical application would be image-guided surgical oncology to help the surgeon to remove tumor tissue by a better discrimination from normal tissues and also to improve the detection of metastatic lymph nodes. A further application could be the in-vivo determination of the alpha(v)beta(3) and alpha(v)beta(5) targets to select patients for therapy with RGD-chemotherapy conjugates.

Copper chelation therapy suppresses tumor growth by inhibiting mitochondrial ATP production in tumors.

S. Ishida; P. Andreux; J. Auwerx; D. Hanahan 

Hallmarks Of Cancer: A 2012 Perspective

D. Hanahan 

Hallmarks of Cancer: New Dimensions

D. Hanahan 

The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underl y-ing principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refi nements. Herein, the prospect is raised that phenotypic plasticity and dis-rupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogram-ming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. Significance: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computa-tional tools and technologies are providing an avalanche of “big data” about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimen-sions presented in this perspective may add value to that endeavor, to more fully understand mecha-nisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.

The biology of personalized cancer medicine: facing individual complexities underlying hallmark capabilities

M. De Palma; D. Hanahan 

It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism-based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient’s tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients’ cancers with a suite of parametric tools, the promise of mechanism-based therapy may truly be realized.

Hallmarks of Cancer: The Next Generation

D. Hanahan; R. A. Weinberg 

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the “tumor microenvironment.” Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

Roles of Epigenetic Dysregulation in Cancer Progression and Metastasis

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

NMDAR signaling in cancer

Improved microfluidic transcriptome based screening methods

H. Hu; C. Merten; X. Ma; L. Kolmar 

The invention provides microfluidic screening systems for the identification of compounds or compositions influencing cellular transcriptomes. The invention is predicated upon taking into account differences in newly synthesized mRNA in contrast to so called old mRNA and such differences compared to control cell assays. The invention is applicable for screening in particular candidate ligand molecules such as antibodies for an effect on target cells, and thereby provides new strategies for the identification of therapeutically active compounds.

Rapidly verifiable aggregate signatures

M. Camaioni; R. Guerraoui; M. Monti; P-L. Roman; M. Vidigueira et al. 

A method for aggregating digital signatures comprises the following steps carried out by a signature aggregator: receiving first data packages from signers, each first data package comprising a signer identifier, a payload, and a payload signature; verifying the payload signatures to determine whether or not the payloads are correctly signed; bundling correctly signed payloads into a batch; obtaining a batch digest, and proofs of inclusion of the payloads in the batch; sending second data packages comprising the batch digest and a respective proof of inclusion to the signers, the respective proof of inclusion proving that the payload of the respective signer is included in the batch; receiving third data packages from the signers, each third data package comprising the signer identifier, and a respective batch digest signature; verifying the batch digest signatures to determine whether or not the batch digests are correctly signed; aggregating correctly signed batch digest signatures to obtain an aggregated batch digest signature; and including the aggregated batch digest signature in the batch. The payload and batch digest signatures may be obtained by using different secret keys of the respective signer.

Water-permeation sensor and method for making the same

M. Mariello; K. Kim; Y. Leterrier; S. P. Lacour 

A water permeation sensor suitable for monitoring and quantitatively assessing ultra-low permeability of thin film encapsulations engineered for bioelectronic microdevices, its fabrication as well as device comprising the same are disclosed herein.

Multi-gas processing and transport system

F. Marechal 

A gas processing and transport system comprising a natural gas pipeline (1), a plurality of gas conditioning stations (4) connected to the natural gas pipeline between an upstream main natural gas supply and a downstream consumer end, the gas processing stations including carbon dioxide producers and carbon dioxide consumers, the carbon dioxide producers including natural gas consumers, at least one control system (10), and at least one sensor connected to the control system. At least one of the gas processing stations producing carbon dioxide is configured to inject produced CO2 into the natural gas pipeline, and at least the gas processing station(s) consuming natural gas comprise(s) a gas separating membrane (5) configured for separating at least CO2 from CH4.

Method and apparatus for non-invasively computing cardio-vasculature parameters using morphology of uncorrelated pressure wave signal

V. Bikia; N. Stergiopulos 

[0054] Methods are provided for estimating key reliably and accurately predicting cardiac output using a limited set of non-invasively monitored physiologic inputs, and a calibrated one- dimensional arterial tree model, a database of synthetic data generated from such a model, and an artificial intelligence module. Systems for estimating CO based on non-invasively measured physiologic inputs also are provided that may be implemented without the need for extensive real-time computing resources.

Customized modular multi-material mouthguard and method of making the same

M. Broome; D. Pioletti; N. Nasrollahzadeh Mamaghani 

There is described a mouthguard comprising an externally exposed impact protective region defined by a first material property and configured to cover a front tooth, an internally exposed occlusional cushioning region defined by a second material property and configured to cover a molar tooth, and an internally exposed intermediate region defined by a third material property and configured to be located between the occlusional cushioning region and the impact protective region, wherein said first, second and third material properties are different. A corresponding method of fabricating a mouthguard is also described.

Biobased surfactant

S. Bertella; A. Komarova; S. Sun; J. Luterbacher 

The present invention relates to a compound of the general formula (I), (II) and (III), more specifically of formula (Ia), (Ib), (Ic)wherein R11 and R12 or R21 and R22 or R31 and R32 are both hydrogen or form together with CHR50 a cyclic moiety or one of R11 and R12 or R21 and R22 or R31 and R32 is hydrogen and the other is – CH2R70 and/or wherein R13 and R14 or R23 and R24 or R33 and R34 are both hydrogen or form together with CHR60 a cyclic moiety, R50 and R60 are different form each other and are selected from the group consisting of -R70, -ZR70, -Z-OH, -Z-NH2, -Z-SH, -Z-OC(O)R70, -OC(O)R70, -COOH, -C(O)NH2, -C(O)NH-R70, -C(O)N-(R70)2, -COOR70, -Z-COOH, -Z-C(O)NH-R70, -Z-C(O)NH2, -Z-C(O)N-(R70)2, – Z-COOR70, -CH(COOH)2, -CH(COOR70)2, and -Z-SO3<->, wherein R70 is a linear or branched C1 to C20 alkyl, (C1 to C10)-alkyloxy-(C1 to C10)-alkyl, C2 to C10 alkenyl, C6 to C12 aryl, C3 to C10 cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl, wherein Z is a linear or branched C1 to C10 alkyl, linear or branched C3 to C10 cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl, a linear or branched C6 to C10 aryl or a (C1 to C10)-alkyloxy-(C1 to C10)-alkyl, with the proviso that not all of R11, R12, R13 and R14 or R21, R22, R23 and R24 or R31, R32, R33 and R34 are hydrogen and if one of R11 and R12 or R21 and R22 or R31 and R32 is hydrogen and the other is -CH2R70, R13 and R14 or R23 and R24 or R33 and R34 form together with -CHR60 a cyclic moiety, wherein R60 is R70.Those compounds are useful as as biobased surfactants.

Biobased surfactant

S. Bertella; A. Komarova; S. Sun; J. Luterbacher 

The present invention relates to a compound of the general formula (I), and (II)wherein one of R11 and R12 is hydrogen and the other is -CH2-R70, and one of R13 and R14 is hydrogen and the other is -CH2-R71, or wherein one of R11 and R12 is hydrogen and the other is -CH2-R70, and both of R13 and R14 are hydrogen, and wherein two of R21, R22 and R23 is hydrogen and the other is -CH2-R70, and one of R24 and R25 is hydrogen and the other is -CH2-R71, wherein R31, R32 and R33 are hydrogen and R34 is -CH2-R71, and R70 and R71 are independently form each other and are selected from the group consisting of a linear or branched C5 to C20 alkyl, a (C2 to C10)-alkyloxy-(C2 to C10)-alkyl, a C5 to C10 cycloalkyl and C6 to C12 aryl.

Fluorometer system, fluorescene analysis method, and use thereof

C. Merten; J. Panwar 

The invention relates to a fluorometer system for analyzing fluid samples comprising a plurality of particles capable of being labeled with at least two fluorescent labels, in particular two distinct fluorophores. The invention also relates to a fluorescene analysis method for analyzing a fluid sample. Furthermore, the invention relates to the use of such a fluorometer system or fluorescene analysis method.

Compliant vascular grafts and methods of use

G. Rovas; N. Stergiopulos 

Compliant vascular grafts for implantation in the vasculature are provided. The compliant vascular grafts are designed to expand longitudinally and radially within a blood vessel, such as an artery, and is expected to be particularly well suited for treating aneurysms in challenging anatomy such as the thoracic aorta. The compliant vascular grafts preferably have an outer frame layer and an inner graft layer with a plurality of pleats to permit expansion.

Gas generating membrane-less electrolyser

D. Psaltis; P. Koumoutsakos; P. Hadikhani; S. J. Reinauer; S. A. Schenk 

Electrolyser including a reactor (2) comprising a housing (4), fluidic channels (6a, 6b, 6c) within the housing, and electrodes (16a, 16c) comprising an anode (16a) and a cathode (16c). The fluidic channels include an inter-electrode channel (6b) arranged between the anode (16a) and cathode (16c) and connected to an anode channel inlet (8a) for injection of an electrolyte into the inter-electrode channel (6b), a cathode channel (6c) separated from the inter-electrode channel (6b) by a porous cathode side wall (14c) comprising a plurality of canals (20), and an anode channel (6a) separated from the inter-electrode channel (6b) by a porous anode side wall (14a) comprising a plurality of canals (20). Each canal has a tapered shape such that an inlet surface area (Si) of the canal is greater than an outlet surface area (So) of the canal, the inlet surface area being on a side of the porous walls bounding the inter-electrode channel (6b).

Electrostatic particle collector

N. Dudani; S. Takahama 

ESP particle collector (1) for collecting particles in a particle containing gas stream, comprising an inlet section (4), a collector section (6), and an electrode arrangement (8), the inlet section comprising a flow tube (10) defining a gas flow channel (12) therein bounded by a guide wall (24) extending between an entry end (14) and a collector end (16) that serves as an inlet to the collector section (6), the entry end comprising an inlet (28) for the particle gas stream and a sheath flow inlet portion (26) for generating a sheath flow around the particle gas stream, the collector section comprising a housing (18) coupled to the flow tube, and a collector plate (20) mounted therein having a particle collection surface (23). The ESP particle collector comprises an optical measuring instrument (9) configured to transmit light through the collector plate along a centre axis (A) orthogonal or substantially orthogonal to the particle collection surface for optical analysis of the collector plate particle collection surface to measure particles collected thereon, and wherein the flow tube has a bent portion (15) such that the entry end (14) is positioned out of the centre axis A to allow the light to be transmitted through the collector plate in the direction of the centre axis and to be picked up without interfering with the gas flow or the gas inlet.

Highly effective adoptive t cell therapy

L. Tang; Y. Guo; B. Feng 

The present invention relates generally to the field of anti-cancer therapy and autoimmune therapy, in particular to the use of adoptive T cell transfer therapy. More specifically, the present invention relates to compositions, pharmaceutical compositions or methods using IL-4, a fragment or variant thereof, fused to a moiety, to increase the efficacy of an anti-cancer immunotherapy or an autoimmune therapy.

Engineered progenitor cells and methods of use

M. De Palma; A. Ghasemi; A. Martinez Usatorre 

Disclosed herein are engineered progenitor cells and methods of using the same. Also disclosed herein are engineered cells differentiated from engineered progenitor cells of the present disclosure. Also disclosed herein are methods of treating a condition in a subject by administering an engineered progenitor cell or an engineered cell differentiated from an engineered progenitor cell of the present disclosure.

Diaryl ether compound and manufacturing method from lignin

M. Liu; P. J. Dyson 

Herein described are diaryl ether compounds having the structure (I) as well as a method for their manufacture from lignin.

Nanopore-based scanning system and method

A. Radenovic; G. Fantner; S. Mendes Leitão; V. Navikas 

Nanopore-based scanning system including a probe structure comprising a nanopore; suction means configured to draw an end of a (bio)molecule inside the nanopore and inside the probe structure, single or multiple times; and displacement means configured to mechanically displace the probe structure and the nanopore relative to the one (bio)molecule along a direction following a direction of extension of the (bio)molecule while the (bio)molecule is located inside the nanopore and inside the probe structure, or configured to mechanically displace at least one support holding the (bio)molecule relative to the nanopore along a direction following a direction of extension of the (bio)molecule while holding the at least one support and while the (bio)molecule is located inside the nanopore.

High-resolution scintillation detector for two-dimensional reconstruction

V. Leccese; M. Caldara; A. Bertsch; A. Mapelli; F. Carbone 

A scintillation device including a silicon plate having a rectangular shape and having a first side and a second side opposite the first side, wherein the first side includes a plurality of first channels arranged to be in parallel with each other extending in a first direction, wherein walls in the silicon plate that form the first channels are coated with an optically reflective or dielectric layer, and wherein the first channels are filled with a scintillation resin in a solid state forming a first waveguide.

Systems and methods for de novo design of protein interactions with learned surface fingerprints

P. Gainza Cirauqui; S. Wehrle; A. K. Van Hall-Beauvais; A. Marchand; A. Scheck et al. 

The present application relates to a computer-implemented systems and methods for protein interaction design using surface fingerprints. The method comprises predicting at least one target interface site with high binding propensity, wherein, optionally, the step of predicting at least one target buried interface site comprises generating at least one surface fingerprint associated with a protein interaction based on at least one protein interface, wherein the at least one surface fingerprint preferably embeds geometric and/or chemical features of molecular surfaces, identifying at least one binding seed that displays required features to engage the target site, and performing a binding seed transplantation to protein scaffolds to confer stability and additional contacts on the designed interface.

Electron spectrometer calibration method

T. La Grange; P. Cattaneo; F. Carbone; B. Weaver; A. Sapozhnik et al. 

The present invention concerns an energy dispersion calibration method for calibrating an electron spectrometer of an electron spectrometer system including at least one electron emission source, electron optics and the electron spectrometer. The method comprising:obtaining, providing or receiving at least one electron energy loss spectrum produced by electrons of the electron spectrometer system exchanging energy with at least one resonant optical mode of an optical resonator into which light at a resonant wavelength is coupled;calculating or providing a Fourier transform of the at least one electron energy loss spectrum or a part of the at least one electron energy loss spectrum;determining or providing an energy dispersion (ΔE) of the electron spectrometer according to the equationΔ⁢E=fE⁢hcλ⁢N⁢or⁢Δ⁢E=fE⁢EpN.

Method for manufacturing an active structure for a radiation detector and polymeric mold for the method

V. Leccese; M. Caldara; M. Pagano; A. Bertsch; L. Müller et al. 

A method for manufacturing a scintillation detector structure including the steps of forming a plurality of first structures into a surface of a substrate to form a patterned substrate, filling the plurality of first structures and covering the surface of the substrate with a polymeric material, hardening the polymeric material and first removing the hardened polymeric material from the substrate to obtain a polymeric mold with a patterned surface having a plurality of second structures, performing a surface cleaning treatment and a silanization of the patterned surface of the polymeric mold, filling the plurality of second structures and covering the patterned surface of the polymeric mold with a moldable scintillation material, polymerizing the scintillation material while exerting a pressure on the scintillation material, and second removing the polymerized scintillation material from the plurality of second structures of the polymeric mold to obtain scintillation detector active structures.

High temperature electrolysis system and method

D. Psaltis; S. A. Schenk; S. J. Reinauer; P. Hadikhani 

The present invention concerns an electrolysis system for high temperature electrolysis including a plurality of flow-based electrolysis units configured to receive an electrolyte solution and to perform electrolysis to provide a first output gas and a second output gas, the plurality of flow-based electrolysis units being membrane-less electrolysis units; at least one heating mechanism or means for heating the electrolyte solution to undergo electrolysis; a first gas separator and a second gas separator configured to remove the first output gas and the second output gas from the electrolyte solution; and an encasement or a cell enclosing the plurality of flow-based electrolysis units, the encasement or the cell being configured to support a pressure of the electrolyte solution permitting to increase a boiling point of the electrolyte solution to a temperature between 96°C and 350°C.

Variants of the gain domain of adhesion g protein-coupled receptors

M. Marfoglia; L. Dumas; P. Barth 

The present invention relates to variants of the GAIN domain (G-protein-coupled receptor autoproteolysis-inducing domain) of an adhesion G protein-coupled receptor (ADGRG), such as a GAIN domain variant comprising or consisting of the amino acid sequence of the GAIN domain of ADGRG1 (Adhesion G Protein-Coupled Receptor G1) of SEQ ID NO: 1, wherein (i) one of amino acid positions (3) to (5), preferably amino acid position (4) and one of amino acid positions (47) to (49), preferably amino acid position (48) of SEQ ID NO: 1 are replaced by cysteines, (ii) one of amino acid positions (35) to (37), preferably amino acid position (36) and one of amino acid positions 180 to (182), preferably amino acid position (181) of SEQ ID NO: 1 are replaced by cysteines, (iii) one of amino acid positions (19) to (21), preferably amino acid position 20 and one of amino acid positions (124) to (126), preferably amino acid position (125) of SEQ ID NO: 1 are replaced by cysteines, (iv) one of amino acid positions (56) to (58), preferably amino acid position (57) and one of amino acid positions (65) to (67), preferably amino acid position (66) of SEQ ID NO: 1 are replaced by cysteines, (v) one of amino acid positions (16) to (18), preferably amino acid position (17) and one of amino acid positions (60) to (62), preferably amino acid position (61) of SEQ ID NO: 1 are replaced by cysteines, (vi) the amino acid position at position (40) is replaced by glutamic acid, the amino acid position at position (43) is replaced by leucine and the amino acid position at position (181) is replaced by arginine, (vii) the amino acid position at position (40) is replaced by glutamic acid, the amino acid position at position (43) is replaced by leucine, the amino acid position at position (135) is replaced by arginine and the amino acid position at position (181) is replaced by arginine, (viii) the amino acid position at position (40) is replaced by glutamic acid, the amino acid position at position (43) is replaced by leucine, the amino acid position at position (135) is replaced by arginine, the amino acid position at position (146) is replaced by tyrosine, and the amino acid position at position (181) is replaced by arginine, (ix) the amino acid position at position (33) is replaced by tryptophane, the amino acid position at position (40) is replaced by glutamic acid, the amino acid position at position (43) is replaced by leucine, the amino acid position at position (135) is replaced by arginine, the amino acid position at position (146) is replaced by tyrosine, the amino acid position at position (178) is replaced by tyrosine, the amino acid position at position (181) is replaced by arginine, the amino acid position at position (184) is replaced by glycine, the amino acid position at position (186) is replaced by glutamine, and the amino acid position at position (187) is replaced by glycine, (x) the amino acid position at position (174) is replaced by isoleucine, (xi) the amino acid position at position (218) is replaced by alanine, or (xii) at least two of (i) to (xi) apply; or (B) comprising or consisting of an amino acid sequence sharing at least 80% sequence identity with the variant of (A), provided that the cysteines as defined in (A), item (i), (ii), (iii), (iv) and/or (v), or the amino acid replacement(s) as defined in (A), item (vi), (vii), (viii), (ix), (x) and/or (xi), or the cysteines and/or the amino acid replacement(s) as defined in (A), item (xii) are retained.

System for automated and dynamic cell culture

S. J. Maerkl; J. Tischler 

The present relates to a system for automated cell culture, the system comprising an inflow module, a cell culture plate and an outflow module, said inflow module being in fluid connection with the outflow module via the cell culture plate, the inflow module further comprising a microfluidic distribution module in fluid connection with the inflow module, the microfluidic distribution module being configured for controlling the distribution of a fluid flow from the inflow module to the cell culture plate, characterized in that the cell culture plate comprises at least one culture well configured for cell culture, and in that the system further comprises an adaptor coupled to the microfluidic distribution module, the adaptor being reversibly connectable to the cell culture plate so that when the adaptor is connected to the cell culture plate, the distribution of the fluid flow to said culture well is controlled by the microfluidic distribution module.

Designed biosensors for enhanced t cell therapy

C. Arber; P. Barth; J. A. Rath; L. Rudden 

This disclosure describes a method for de novo bottom-up assembly and rational design of allosteric biosensors with programmable input-output behaviors that respond to soluble factors selectively enriched in tumors and trigger co-stimulation and cytokine signals. The disclosed method of effective mechanical coupling and biosensor signaling potency correlates with anti-tumor function. This disclosure provides synthetic biosensors with custom-built sensing and responses for basic and translational cell engineering applications.

Computer-implemented design of peptide:receptor signaling complexes for enhanced chemotaxis

P. Barth; R. Jefferson 

The present invention relates to a computer-implemented method for engineering the interaction between a protein and a cognate peptide that are capable of forming a molecular complex, wherein the method comprises (a) preparing in silico a library of test peptides based on the cognate peptide, and the molecular complex of the protein and the cognate peptide; and/or (a’) preparing in silico a library of test protein scaffolds based at least on the parts of the protein that participate in forming the molecular complex with the cognate peptide; (b) docking in silico (i) the library of test peptides onto the library of protein scaffolds by modelling peptide-protein molecular complexes, or (ii) the cognate peptide on the library of protein scaffolds, or the library of test peptides onto the protein or the parts of the protein that participate in forming the molecular complex with the cognate peptide by modelling peptide-protein molecular complexes; (c) identifying the test peptides in the library and/or the protein scaffolds in the library for which low interface energy peptide-protein molecular complexes can be modelled, preferably by a combination of flexible peptide docking and/or de novo protein structure building; (d) identifying the interacting amino acids of the test peptides and/or the protein scaffolds in the ensemble of low interface energy modelled peptide-protein molecular complexes of step (c); (e) selecting and substituting in silico one or more of the interacting amino acids of the peptides and/or the protein scaffolds as identified in step (d) based on the ensemble of low interface energy peptide-protein molecular complexes as identified in step (c); and (f) generating in silico based on the peptides with substituted amino acid(s) and/or the protein scaffolds with substituted amino acid(s) of (e) an ensemble of peptides with substituted amino acid(s) and/or the protein scaffolds with substituted amino acid(s) for which the lowest interface energy peptide-protein molecular complexes can be modelled, thereby obtaining engineered peptides and/or proteins being capable of forming a molecular complex with engineered binding characteristics.

Construction of sequencing libraries from a ribonucleic acid (rna) using tailing and ligation of cdna (tlc)

C. Ernst; D. Trono 

The present invention provides a method for preparing a sequencing library from a ribonucleic acid (RNA) sample.

Non-volatile data storage medium and system

R. Ricca; Y. Bellouard; M. Vetterli 

A data storage medium (2) comprising a stacked plurality of layers (9), each layer composed of a layer material selected from a group comprising at least two different dielectric materials, adjacent layers being formed of different materials, and at least one of the layers, that is not a top layer, constituting an information layer (9i) configured to be modified locally by energy from an electromagnetic beam (7) having a specific beam wavelength and a propagation direction (Z) transverse to the layers. The stacked plurality of layers include an aperiodic layer arrangement including at least three stacked adjacent layers having different thicknesses with respect to each other.

Biobased surfactants

A. Komarova; S. Sun; S. Bertella; J. Luterbacher 

Compound of the general formula (Ia), (Ib) and (Ic) R50 and R60 are different form each other and are selected from the group consisting of -R70, -ZR70, -Z-OH, -Z-NH2, -Z-SH, -Z-OC(O)R70, -OC(O)R70, – COOH and its corresponding salts, -C(O)NH2, -C(O)NH-R70, -C(O)N-(R70)2, – COOR70, -Z-COOH and its corresponding salts, -Z-C(O)NH-R70, -Z-C(O)NH2, -Z- C(O)N-(R70)2, -Z-COOR70, -CH(COOH)2 and its corresponding salts, -CH(COOR70)2, and -Z-SO3- wherein R70 is selected from the group consisting of a linear or branched C1 to C20 alkyl, (C1 to C10)-alkyloxy-(C1 to C10)-alkyl, C2 to C10 alkenyl, C6 to C12 aryl, C3 to C10 cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl, wherein Z is a linear or branched C1 to C10 alkyl, linear or branched C3 to C10 cycloalkyl, a linear or branched C6 to C10 aryl or a (C1 to C10)-alkyloxy- (C1 to C10)-alkyl, cycloalkylalkyl and cycloalkylalkenyl.

High-dimensional parameter determination based on mr fingerprinting measurements

M. S. Widmaier; S. Lim; L. Xin 

The present invention concerns a method for determining an estimated value for different parameters on the basis of one or more acquired signals obtained during a Magnetic Resonance Fingerprinting measurement. The method includes using a correction model and/or an iterative approach for improving the accuracy of the obtained estimated values.

Methods and devices for cultivating coenocytic algae

E. Nicodeme; E. Zanchetta; C. Ludwig 

The present invention concerns methods and devices for cultivating coenocytic algae and for producing cellulose, in particular microfibrillated cellulose (MFC). In one embodiment, the algae are grown on a solid substrate immersed in liquid culture medium. The solid substrate preferably comprises a carbonite mineral. The invention also concerns a method for producing spores of said coenocytic algae and a device comprising two separate containers, a first container for growing said algae and a second container for growing larger algae and inducing the generation of spores.

Neuromodulation/neurostimulation system for mitigating locomotor deficits of parkinson’s disease, spinal cord injury (sci), stroke and/or other neurological disorders

J. Bloch; T. Milekovic; E. Martin Moraud; G. Courtine; C. Newton et al. 

The present invention relates to a combined neuromodulation and/or neurostimulation system (10) for mitigating locomotor deficits of/or neuronal disorders, especially Parkinson’s disease, said system (10) comprising: – at least one Deep Brain Stimulation (DBS) System for providing Deep Brain Stimulation to brain tissue of a subject (P), – at least one control unit, configured and adapted to provide stimulation data, – at least one stimulation unit (12), operatively connected to the at least one control unit, the at least one stimulation unit (12) being configured and adapted to deliver epidural electrical stimulation (EES) to the dorsal side of the spinal cord (S) of said subject (P), and – at least one implantable pulse generator (IPG) (13), wherein the at least one stimulation unit (12) includes one or more electrodes (14) configured to be implanted epidurally, the one or more electrodes (14) being operatively connected to the at least one IPG (13).

Device, system, and method for ion fragmentation by use of an ion mobility device and messenger tagging

S. Warnke; T. Rizzo; A. Ben Faleh 

A device for fragmenting ions by collision induced dissociation, the device intended to be used together with a planar ion mobility apparatus, the device including a first conductive grid having a plurality of first openings, the first conductive grid configured for electric interconnection to a first electric potential, and a second conductive grid having a plurality of second openings, the second conductive grid configured for electric interconnection to a second electric potential, the first and second conductive grids being electrically insulated from each other.

Tumescense monitoring system for diagnosing erectile dysfunction and methods of use

R. Araujo Fraga Da Silva; N. Stergiopulos; C. S. Braissant 

Systems and methods for monitoring penile tumescence are provided that overcome the drawbacks of previously known systems by providing a wearable formed of a flexible and elastic tube having a plurality of sensors disposed on or embedded within it, the wearable configured to be applied to a penis of a subject, and a spaced-apart controller operatively coupled to retrieve data regarding circumferential and axial dimensional changes and penile rigidity from the plurality of sensors and transmit that data to an external computer or smartphone for analysis and display. The plurality of sensors may be coupled to the spaced-apart controller via a flexible lead or wirelessly using a passive RFID system.

Automated music composition and generation system and method

F. Colombo 

An automated music composition and generation system for automatically harmonizing digital pieces of music using an automated music composition and generation engine for multi-voice music harmonization, including a system-user interface configured to input user parameters comprising at least an instrument designation, a composer style designation, an empty or partial input musical score to be automatically completed, whereby the instrument designation and the composer designation are any one of a predetermined list of instrument designations and composer designations, an automated music composition and generation engine configured to implement a generation strategy that produces playable and well-structured multi-voice music scores, operationally connected to the system-user interface, and a neural network module configured to implement a rhythm recurrent artificial neural network model, a melody recurrent artificial neural network model and a harmony feedforward neural network model that have been trained for combinations of the instrument designations and composer designations of the predetermined list.

Waveguide amplifier and waveguide amplifier fabrication method

T. Kippenberg; Y. Liu; Z. Qiu; X. Ji 

The present invention concerns a waveguide amplifier comprising: – at least one embedding cladding material or layer, and – at least one rare-earth ion implanted silicon nitride material or layer embedded in the at least one embedding cladding material or layer, the at least one rare-earth ion implanted silicon nitride material or layer defining a waveguide core enclosed by the at least one embedding cladding material or layer.

Methanobrevibacter smithii ( m. smithii) for use as a biomarker and in the diagnosis and the treatment of disorders associated with aberrant microbiota and/or archaea-deficiency

D. Sutherland 

The present invention generally relates to the field of intestinal health, disorders associated with aberrant microbiota and/or archaea-deficiency, and early-life immune system development. The present invention more specifically relates to M. smithii and components thereof for use as a biomarker, to methods for detecting M. smithii and/or for monitoring colonization status of M. smithii, biosensors and kits for detecting M. smithii or markers thereof, and M. smithii for promoting immune system homeostasis and intestinal health and for treating disorders associated with aberrant microbiota and/or archaea-deficiency.

Photovoltaic devices containing cyclobutane-based hole transport materials

V. Jitardis; C. Lakstis; M. Daszkiewicz; S. Daskiewechut-Goguzni; Y. Zhang et al. 

The teachings herein relate to hole transport compounds containing cyclobutyl moieties that can be made into organic hole conductors and hole transport materials. Furthermore, optoelectronic and photoelectrochemical devices, in particular photovoltaic devices, organic-inorganic perovskite films, layered photovoltaic devices, p-n heterojunctions, dye-sensitized solar cells, organic solar cells and solid state solar cells, comprising such hole transport materials or hole transport compounds are described. It is notable that a perovskite solar cell module manufactured using the disclosed HTM compound exhibits a recording efficiency of more than 19.0% and an effective area of 30.24 cm2.

A multichannel versatile brain activity classification and closed loop neuromodulation system, device and method using a highly multiplexed mixed-signal front-end

M. Shoaran; U. Shin; B. Zhu 

A closed-loop neuromodulation system, including an electrode array that is implantable to a brain of a subject, analog front-end device (AFD) for selectively selecting and reading a plurality of channels from electrode array, a finite impulse response (FIR) filter for selectively filtering signals from the AFD, a feature extraction engine (FEE) operatively connected to the FIR filter, configured to selectively extract features from signals provided by the FIR filter, a tree-structured hierarchical neural network classifier for detecting disease symptoms, and a multi-channel stimulator having high-voltage (HV) drivers operatively connectable to the electrode array.

Cgas super-enzymes for cancer immunotherapy

A. Ablasser; N. Samson; A. Keller 

The present invention relates to anti-tumor lymphocytes, and a variant cyclic GMP-AMP synthase (cGAS) carrying an amino acid substitution of one or both arginines at amino acid positions 255 and 236 and/or an amino acid substitution of one or both lysines at amino acid positions 254 and 258; or a nucleic acid molecule encoding said variant cGAS for use in the treatment of a tumor in a subject.

Method for hormone or drug screening in a tissue sample

Y. Zhang; C. Merten; C. Brisken 

The present invention relates to a method for analyzing cellular responsiveness to hormones or drags in a tissue sample based on an alginate-based 3D ex vivo culture system for normal and malignant tissue microstructures and uses thereof.

Device and system as human interactive surface

J. Paik; F. Zuliani 

A force-feedback surface that creates and modulates distinctive profile and stiffnessto interact with a user in contact thereto, the surface being functionally independentto be used as a single module but can be customized to extend the application indiverse fields by assembling in series, parallel, or any combinations to form amultimodular system.

Dimensionality reduction of time-series data, and systems and devices that use the resultant embeddings

S. Schneider; M. W. Mathis 

Methods, systems, and apparatus, including computer programs encoded on a computer storage medium, for dimensionality reduction of time-series using contrastive learning. A method can include receiving multidimensional input time series data that includes data from a session or sessions that span time, selecting positive samples and negative samples from the multidimensional input time series data for respective reference samples from the multidimensional input time series data, wherein the positive samples and negative samples are each selected with a respective predetermined distribution across the time of the session or sessions of the multidimensional input time series, and mapping the reference samples, the positive samples, and negative samples into a common embedding space.

Inhibitors of acyl protein thioesterases against microbial infections

G. Van Der Goot; F. Mesquita; L. Abrami; C. Tapparel Vu; V. Cagno 

The present invention relates inhibitors of acyl protein thioesterases and method of preparation thereof. It also relates to the use of inhibitors of acyl protein thioesterases in the treatment and/or prevention of a microbial infection such as viral or bacterial infections or coinfection by virus and bacteria.

A wearable to assess knee joint integrity using non-contact acoustic sensors

J. P. R. Thevenot; K. Aminian; D. Atienza Alonso 

A smart wearable (SW) for collecting data on an integrity of a joint of a wearer, the wearable including a first frame (1) configured to be attached in proximity of the joint of the wearer, the frame (1) including an elastic sensor frame (3) having an open cavity (21) configured to be attached to an area of interest of the joint, a kinematic sensor device (19) configured to measure kinematics of the joint, and acoustic sensor device (13) arranged in the cavity (21) configured to capture airborne acoustic emissions from the area of interest, and a data processor device (18) configured to receive and record data from the kinematic sensor device (19) and from the acoustic sensor device (13).

Micro- or nanostructured optical element

D. G. Herle; N. Quack 

A micro- or nanostructured optical element (1) is proposed comprising: a membrane (3) with an array of holes (5), the membrane (3) comprising a membrane light wave facing surface; an array of pillars (7) sized and shaped such that a respective pillar (7) is configured to be at least partially received in a respective hole (5), the respective pillar (7) defining a central pillar axis, and comprising a pillar light wave facing surface; a support (9) configured to support the pillars (7); and an actuation mechanism configured to selectively generate a relative displacement between the membrane (3) and the pillars (7) along the central pillar axes to thereby define a first optical element reflectance state, where the membrane (3) is in an elevated position with respect to the support (9), and a second, different optical element reflectance state, where the membrane (3) is in a lowered position with respect to the support (9) such that the respective pillar (7) extends through the respective hole (5). In the first optical element reflectance state, the membrane light wave facing surface is substantially flush with the pillar light wave facing surfaces, or the membrane light wave facing surface is placed beyond the pillar light wave facing surfaces.

A variable stiffness magnetic catheter made of a conductive shape memory polymer for minimally invasive surgery

Y. Piskarev; D. Floreano; J. Shintake 

A hollow variable stiffness thread including a flexible inner tube, a conductive shape memory polymer (CSMP) layer arranged around the inner tube forming a variable stiffness zone, a flexible encapsulation layer arranged around the CSMP layer, and a first electrode and a second electrode, at least a portion of the first and the second electrodes being in contact with the CSMP layer.

Ferroelectric device or structure and a method for producing ferroelectric devices or structures

T. Kippenberg; Z. Tan; R. Wang 

The present invention concerns a method for producing at least one ferroelectric device or structure comprising the steps of providing at least one ferroelectric material or layer, or providing at least one ferroelectric material or layer to be patterned or structured; depositing at least one adhesion layer on a first side of the at least one ferroelectric material or layer; and depositing at least one diamond-like carbon layer or material on the at least one adhesion layer.

Method and setup for light detection and ranging

A. Lukashchuk; J. Riemensberger; T. Kippenberg 

A method and a setup for light detection and ranging are disclosed. The setup is configured to carry out the following method: generating signal radiation (S) at multiple signal frequencies (fs) with an optical signal source (1), wherein the signal radiation (S) exhibits random signal modulations preferably at each of the multiple signal frequencies (fs), splitting the signal radiation (S) into a target radiation part (T) and a reference radiation part (R), directing the target radiation part (T) towards a target (2), detecting a target signal (IT), wherein the target signal is associated with a reflected portion (TR) of the target radiation part being reflected from the target (2), detecting a reference signal (IR), wherein the reference signal is associated with the reference radiation part (R), and deriving at least one ranging information parameter from the target signal (IT) and the reference signal (IR).

Optoelectronic or photovoltaic device with metal halide perovskite film treated by passivating agent

E. A. Alharbi; L. Pfeifer; A. Krishna; S. M. Zakeeruddin; M. Graetzel 

This invention relates to an optoelectronic or photovoltaic device comprising a perovskite or metal halide perovskite film treated by one or more compounds of formula (I): ((R1-NH(R2)-R3)+)nW (I), wherein n is an integer selected from 1, 2, or 3; R1, R2, R3 are independently selected from a hydrocarbyl group containing 1-40 carbon atoms said hydrocarbyl group, if said hydrocarbyl group comprises 3 or more carbons, may be linear or branched; and W is an anion.

Electronic metadevice

M. Samizadeh Nikoo; E. Matioli 

Electronic metadevice comprising a conductive channel; a metal layer superposed on the conductive channel; and a barrier layer located between the metal layer and the conductive channel. The metal layer includes at least one recess extending through the metal layer to define at least one metallic metastructure comprising at least one first metal layer portion adjacent to at least one second metal layer portion. The recess extends through the metal layer to define a micro-structured or a nano-structured first metal layer portion comprising at least one first metallic extension or finger extending away from a first support of the first metal layer portion towards the second metal layer portion; and a micro-structured or a nano-structured at least one second metal layer portion comprising at least one second metallic extension or finger extending away from a second support of the second metal layer portion towards the first metal layer portion.

Performance gap in the building sector and its impact on investment decisions for heating requirements

L. C. N. Bernath 

Between the ideal and reality lies the decisive world of the performance gap. This project is conducted within the framework of a Master Thesis at the Industrial Processes and Energy Systems Engineering (IPESE) laboratory of Ecole Polytechnique F´ed´erale de Lausanne (EPFL). The objective is to evaluate the energy performance gap, with a static approach, of the building sector and understand its impact on the global energy system in the context of energy transition. The challenge lies in the conservative assumptions regarding the thermal transmission coefficients and construction details of existing buildings in modelling tools. This study is based on two detailed surveys, one on swiss architectural elements and the other on new thermal transmission coefficient ranges. A methodology is designed and integrated to the existing optimization model: Renewable Energy Hub Optimizer (REHO) for different types of buildings, each having particular features. The idea is to integrate to the REHO model a static approach by varying the thermal transmission coefficients and develop a new method concerning the link between the thermal envelope and energy reference area. In result, the impact of the thermal envelope and the form factor of buildings on space heating requirements is researched. The investment and operation uncertainties resulting from the modelling gap are assessed. Finally, the static model developed in this study is compared with a regulatory approach and real on site data from a clustered neighbourhood in Geneva. The results show an improvement of 13,4 % with a change of method.

Mapping Bibliotheca Hertziana

H. L. Casey 

The project introduces an innovative visual method for analysing libraries and archives, with a focus on Bibliotheca Hertziana’s library collection. This collection, which dates back over a century, is examined by integrating user loan data with deep mapping techniques to reveal usage patterns and thematic clusters. To achieve this, dimensionality reduction is employed to visualise the catalogue, map- ping books based on their loans, and prompt engineering with large language models helps to identify loan clusters with detailed descriptions and titles. This approach not only paves the way for cultural analytics but also provides the basis for dynamic classification and developing a recommendation system. This project offers alternative insights into the art historical research conducted at Bibliotheca Hertziana, capturing the collection’s evolution and usage. The method established here provides a flexible framework for visually mapping cultural and academic collections in the digital humanities.

A computational comparison of open-source branch-and-price solvers

J. Schneuwly 

Stochastic on-demand electric vehicle routing and charge scheduling

M. Essayouti 

Solve the problem of the EPFL catnpus in MOBi

A-V. Preto 

Construction of an Itinerary Optimization Algorithm for a Trip Planning App

G. Veigas 

Gas storage Optimization

Antoine Michel Marie Christian Goupil De Bouille 

Comparison of different methodologies for interpolating traffic count data

M. Jamal Lahjouji 

Generating a synthetic population with health and COVID-19 information

A. Janvier 

Investigating latent behaviour in multiday activity scheduling

H. Shirai 

In practice, most operational activity-based models have focused on single-day analyses. This common simplifying assumption significantly limits the models’ behavioural realism, as they cannot adequately capture the dynamics and processes involved in the scheduling of activities over multiple days. Decisions taken daily are affected by both habits built over time and forward-looking behaviour, where individuals decide based on the expected outcomes of future decisions. A person’s activity/travel planning behaviour depends on their behaviour on other days of the week and that there are two main components to this dynamic behaviour: 1. same-day and next-day substitution effects for activities and trips, and 2. latent propensity to engage in some activities or choose a specific transportation mode. In this semester project, we investigate the existence of these components and how to integrate them into a multiday activity scheduler (OASIS). More specifically, we will attempt to model these unobserved influences in the context of a latent choice model.

Scala 3 syntax rewriting

M. Tropin 

We present syntax rewriting rules that translate Scala 2 code into Scala 3. Two major syntactic changes are introduced: new control structure syntax and significant indentation. We describe the design and the implementation of these rules and evaluate their performance on a large Scala project. Finally, we discuss strategies regarding how this project can be extended in further iterations.

Cloud computing et protection des données

A. de Aragao 

Predicting activity schedules of the population considering non-pharmaceutical interventions

A. Nussbaumer 

Targeting population to evaluate COVID-19 strategies based on activity-travel behaviour.

A. Goupil De Bouille 

Modeling Individual Activity Schedules and Behavior Changes in COVID-19 Using Metaheuristic Optimization

P. Heillich 

Capturing dynamics in synthetic population

S. Benchelabi 

Synthetic generation of activity motifs

Q. Bochud 

Power to H2 – Tank to Power

D. Vermeire 

The urgent imperative to curtail carbon emissions necessitates the extensive implementation of renewable technologies. However, the intermittent nature of renewables poses challenges to sustainable and efficient energy storage. This project focuses on exploring long-term energy storage systems, evaluating both their cost-effectiveness and efficiency. Utilizing the well-established concept of Power to X to Power, the project employs modeling techniques to analyze various technologies, enabling a comprehensive comparison of long-term energy storage systems based on efficiency and cost. The first candidate for energy storage is Power to Heat to Power, involving a model that calculates the cost and efficiency of a heat storage device. This model incorporates components such as a heat pump cycle and a thermal engine cycle, assessing different temperatures and technical properties. A second candidate involves storing excess electricity as hydrogen. The second model, Power to Hydrogen Tank to Power, focuses on the storage of excess electricity in the form of hydrogen. It examines the use of Solid Oxide Electrolyzer Cells (SOEC) and Solid Oxide Fuel Cells (SOFC) in both liquid and gaseous hydrogen storage systems, assessing their potential as effective energy storage technologies. The ultimate objective is to facilitate a comparative analysis of different Power to X to Power technologies in terms of efficiency and investment cost. This research contributes to understanding viable long-term energy storage solutions, informing strategic decisions for a sustainable and low-carbon future.

Multi-agent Reinforcement Learning for Assembly of a Spanning Structure

G. Vallat 

In this master thesis, multi-agent reinforcement learning is used to teach robots to build a self-supporting structure connecting two points. To accomplish this task, a physics simulator is first designed using linear programming. Then, the task of building a self-supporting structure is modeled as a Markov game, where the robot arms correspond to the agents of the game. This formalism is then used to design learning agents and train them using deep reinforcement learning. Two different types of deep neural network models, based on image analysis and graph theory, respectively, are used to develop their policy. The agents are then trained either centrally or distributively to compare their learning processes and weaknesses. In a final experiment, the efficiency of the learning algorithm Soft Actor-Critic, is compared to Advantage Actor-Critic, highlighting the effectiveness of using Shannon entropy to search through the policy space. Finally, the training procedure allows agents to successfully build a structure that spans ten times the width of the building blocks without the need to use any binding between them or a removable scaffold during assembly.

L’influence des choix de l’ingénieur dans la modélisation des structures

S. Wey 

Systematic Analysis of Mountain Road Capacity

C. Welt 

Development of an optimization tool for the electricity production of the Enguri power plant in Georgia

L. H. L. Vernet 

The ongoing global warming situation has bolstered interests in developing and reinforcing green energy. One of the most promising fields is hydropower (Ahmad and Hossain, 2020 and Yazdi and Moridi, 2018). Many existing reservoirs have untapped potential to be exploited, provided they are operated in an optimal way. To this end, many algorithms have been established, all dealing with different issues that are recurrent in optimization problems. This work aims at developing an algorithm to optimize the energy production of the Enguri power plant in Georgia, the most productive one of the country and therefore vital to Caucasus’ regional electricity system. Besides the main objective of the algorithm, one will have to be careful about the impacts the management of the reservoir will have downstream, and other operational constraints.

Advanced Interaction-aware Motion Models for Motorcycle Trajectory Prediction: Experiments on pNEUMA Datasets

J. Su 

Forecasting the motion of motorcycles is a critical task for an autonomous system deployed in complex traffic, considering its distinguished characteristics compared to other vehicles. Motion of motorcycles in a scene is governed by the traffic context, i.e., the motion and relative spatial configuration of neighboring vehicles. In this thesis, we propose to use two advanced interactionaware motion models encompassing the dynamic interaction of the vehicles and maneuver-based encoding, CS-LSTM and PiP, along with their variation models developed specifically for motorcycle trajectory prediction. We evaluate our model using the publicly available pNEUMA datasets. Our results demonstrate the feasibility and superiority of the motorcycle-specific models and their improvements during evaluation in terms of RMSE values.

Pont sur le Rhône à Fully: examen et projet d’intervention

V. Smajli 

Pont sur le Torrent d’Allèves : examen et projet d’intervention

J. Sanglard 

En Suisse, le travail des ingénieurs civils constitue de plus en plus en l’analyse d’ouvrages existants. Ce travail d’analyse est très différent de celui lié à la construction de structure neuve. En effet, il s’agit de vérifier qu’un ouvrage remplit toujours bien sa fonction en utilisant des méthodes d’analyse souvent plus complexes. L’examen doit nécessairement être plus avancé et détaillé qu’une structure neuve car les coûts d’intervention sont très onéreux. En outre, la planification de l’intervention doit être finement étudiée afin de limiter les nuisances sur les usagers de l’ouvrage. Le renforcement d’une structure existante s’avère souvent peu efficace avec les méthodes traditionnelles qui engendrent des coûts disproportionnés. Au cours des dernières années, de nouveaux matériaux ont été développés et des méthodes innovantes ont été appliquées lors d’intervention avec grand succès. Le composé cimentaire fibré à ultra-haute performante (CFUP) fait partie de ces nouvelles technologies, car les exceptionnelles propriétés mécaniques et la durabilité de ce matériau conviennent parfaitement au renforcement d’un ouvrage. Ce projet de Master à l’EPFL étudie le pont du Torrent d’Allèves situé sur la route d’importance nationale du Grand-Saint-Bernard en Valais. Construit en 1962 lors de l’aménagement des voies d’accès au tunnel, cet ouvrage multi-poutres mesure 114 mètres de long. Il dispose de nombreuses travées irrégulières et de deux joints Gerber en mauvais état. En 1986, d’importants travaux ont été menés pour éviter l’effondrement de la travée entre ces joints. Encadré par le Prof. Brühwiler et le Dr Bertola, le projet consiste premièrement en l’examen de la structure existante. Puis, un projet d’intervention visant le renforcement et l’amélioration de la durabilité de l’ouvrage est élaboré. La dalle de roulement sera notamment renforcée au moyen d’une couche de CFUP, matériau extrêmement performant et novateur. Avant de développer ces deux sujets techniques, l’influence historique et culturelle de la route du Grand-Saint-Bernard est étudiée.

Impianto Idroelettrico Del Tremorgio. Scenari Di Esercizio Futuro Studio Preliminare E Progetto Di Massima

E. A. Z. Rossetti 

Optimization of the environmental impact of beams

N. I. D. Riez 

In the European Union, building construction accounts for 40% of materials consumption, 40% of overall energy consumption, and 40% of waste production [1]. It is therefore essential to reduce the environmental impact of these structures. Various levers are available to achieve this, including better use of materials and selection of the most appropriate material for a given application. This study focuses on isostatic beams, a simple application for identifying trends in shapes and materials to reduce their impact. By using a genetic algorithm to optimize the environmental impact of each beam typology (rectangular reinforced concrete, I-beams, or optimized, prestressed, steel and timber beams), and comparing them with one another, it was possible to select the most appropriate for a given scenario (use in a building, a bridge, most favorable and most unfavorable life-cycle analysis scenarios). The study emphasized the fact that beams with a small width perform better environmentally and that the optimized reinforced concrete beams have great potential in reducing the environmental impact, especially for short spans.

Development of a numerical model to assess the influence of fluid-structure interactions on the dynamic behavior of geomembrane systems in pressure waterways

S. Randin 

The need to maintain and expand hydraulic structures is a major challenge for the coming energy transition, especially in Western countries. One technique already widespread allowing to meet these issues consists in the use of geomembranes to overcome problems of permeability or deterioration of traditional linings. A recent development is the use of these geomembranes in pressure tunnels and penstocks in hydroelectric schemes in the form of geomembrane systems to increase their productivity and durability. However, although a few application cases have already been identified, little is known about the behavior of these geomembrane systems when faced with the high pressure and velocity flow that takes place in these pressure waterways and therefore very few technical recommendations are available for the installation of these systems. An in-depth study of the dynamic behavior of geomembrane systems when subjected to pressurized flow is therefore necessary to better understand how these systems interact with the flow, and in particular under what conditions membrane vibrations, potentially dangerous to the integrity of the structure, are likely to occur. The aim of this work is to contribute to this broad study of the dynamic behavior of geomembranes in pressurized flows by building a numerical model to simulate this problem, and to present the various issues and difficulties involved in its construction. The report details particularly how to take into account the hyperelastic behavior of the geomembrane material, how to define a mesh and load configuration that enable the membrane to withstand the high sollicitations imposed, and how to model the influence of the flow on the geomembrane and vice versa using the system coupling. Some preliminary results from the tests carried out show the consequences of the choices made, and give an idea of the capabilities and limits of the model. Indeed, the model still has its limitations, since, as explained in detail in this report, its development has proved far more difficult than anticipated, and numerous problems have arisen which have had to be resolved.

Optimisation et Déploiement d’une méthode de calculation au sein d’un groupe actif dans le second oeuvre

T. Poulain 

Estimer le prix d’un chantier ? Cette étape est probablement l’une des plus complexes dans la réalisation d’un chantier. En effet, elle nécessite de prévoir au mieux les événements aléatoires qui interviendront pendant son déroulement. Cette étape, mélange entre théorie et pratique, ne doit pas perdre de vue la réalité du chantier. Mais alors, dans quelles mesures est-il possible d’optimiser la méthode de calculation ? L’idée initiale du projet était de mettre en place un modèle mathématique permettant d’estimer le prix des différentes étapes du chantier en fonction de paramètres. Cependant, ces données n’existent pas… Il est alors étudié les prix rendus aux cours des années précédentes, stockées dans le logiciel BauBit. Une base de données est mise en place afin de pouvoir l’étudier sur Python. Il est analysé les différentes caractéristiques des chantiers ainsi que les prix rendus. L’étude se focalise sur les prix du bicouche (étanchéité appliquée en deux couches). Les prix sont très dispersés et la fourniture représente la majorité du prix de vente (55 % en moyenne). La date de rendu de l’offre est le paramètre qui a le plus d’effet sur le prix. Afin d’estimer le prix en fonction des paramètres d’un chantier, il est mis en place une régression linéaire multiple, avec comme variables, les paramètres du chantier. Cependant, du fait du manque du données significatives, ce travail ne peut apporter les résultats escomptés. De plus, cette méthodologie n’est pas en adéquation avec l’utilisation du logiciel BauBit. L’amélioration de l’utilisation de ce logiciel pour la calculation est le second aspect de ce travail. Ce logiciel peut contenir la liste de tous les prix de fourniture. Il permet également de calculer le prix des différentes tâches à réaliser sur chantier en fonction du temps de travail qui y est renseigné ainsi que la quantité de fourniture. Son utilisation permet ainsi de calculer les prix de manière précise, en tenant compte de différents paramètres.

Fractures Thermal Energy Storage (FTES)

J. V. D. Naftalski 

This project aims at designing a laboratory-scale experiment to investigate the thermal performance of Fractures Thermal Energy Storage (FTES) systems. While previous field tests have focused on creating horizontal planar fractures at shallow depths, none have explored the circulation of hot fluid through fractures to assess the thermal efficiency of such systems. Similarly, no comprehensive investigation of the heat transfer mechanisms within FTES systems has been conducted at laboratory scale. This work proposes a combined modeling and experimental framework to design a laboratory-scale FTES experiment. The first part of the study introduces analytical and numerical tools to investigate the heat transfer mechanisms occurring at the well and at the fracture. A numerical model is then developed to simulate the entire FTES experiment. In the second part, an initial experimental setup, along with an identification of key operational challenges, are presented. The results obtained from the numerical model and the initial experimental tests highlight the need for improvements in the current experimental setup. Finally, recommendations are provided to address the identified challenges and ensure the successful operation of the FTES experiment.

Développement d’une méthodologie d’application des RSI et RSA au thème des chantiers routiers

B. Mury 

Crack kinematics prediction in concrete structures and assessment of their criticality

L. Menoud 

The observation of cracks in normally functioning reinforced concrete (RC) structures is expected as the tensile strength of concrete is relatively low. However, one or more of those cracks can start to propagate with increasing crack openings, localizing strains and potentially indicating structural safety shortcomings. In the present project, RC members with low amounts of transverse reinforcements subjected to shear forces have been studied with the help of digital image correlation (DIC). In such structures, a critical shear crack (CSC) typically develops rapidly and can cause brittle failures. Assessing the criticality of such a crack could be a useful tool for engineers to prevent unpredictable failures that can be deadly. The present study is in continuation of Hugo Nick’s Master thesis (2023) [17] where the first avenue of a method to predict crack kinematics evolution from a given initial state was proposed. Obtaining relia-ble predictions of the failure crack kinematics in RC members with shear reinforcements proved to be challenging. Indeed, several hypotheses valid for RC elements without shear reinforcement must be questioned even for elements with low shear reinforcement ratios, notably the rigid-body hypothesis. The presence of stirrups and secondary cracks connected to the CSC strongly influence its kinematics and create a complicated deformation scheme with local flexion. Only approximative predictions have been achieved in the present study and the crack kinematics prediction question remains open. Knowing the crack kinematics allows to compute the shear transfer actions (STA). Identifying the load level at which the sum of the STA start decaying as the actual shear force continues to augment could indicate an unstable crack propagation and the structure’s imminent failure. A decrease of the total STA was indeed observed around 90% of the ultimate load for the specimens with a shear reinforcement ratio 𝜌𝑤>0.1%, but not on the other specimens. Individually studying the STA revealed a high sensitiv-ity of the residual tensile strength of concrete to the minimal crack width considered, and by extension the DIC error. It was also the case to a lesser extent for aggregate interlock. This parameter should be carefully selected. Even though the individual STA show variability across load levels and specimens, the statistical analysis of the sum of the STA for all SM10 specimens demonstrates that it follows the applied load relatively closely. An attempt at understanding the CSC propagation as a function of the load level was also conducted and lead to the discovery of a load-propagation experimental relationship depending on the position of the failure crack tip at an initial load level and approximately proportional to the square of the shear rein-forcement ratio. This relation offers an estimation that captures the general load-propagation trend despite the variability on the actual crack propagation. It was applicable on all tested specimens but could be limited to their specific experimental conditions. An attempt to predict the ultimate load has also been conducted using this load-propagation empirical relationship. A common way of determining whether a RC structure is close to failure or not is to compare the acting loads with the strength obtained from nonlinear finite element analysis (NLFEA) . However, its applica-tion on RC elements with localised cracking, such as low transverse reinforcement ratio beams subject-ed to shear can lead to unrealistically high results. Mesh sensitivity and localisation issues were identi-fied in the tested models. It is therefore important to study the limitations of NLFEA in such cases that differ from the habitual scope in order to avoid misinterpretation of the results.

Étude intégrale d’un processus scan-to- BIM pour la mise à jour d’une maquette numérique

M. Mdidech 

Le présent mémoire expose le travail réalisé pour la conception d’un processus de mise à jour de la géométrie d’une maquette numérique d’un bâtiment par l’intermédiaire de la méthode du scan-to- BIM. Réalisée au sein de l’entreprise HRS Real Estate SA (HRS) dans un contexte de recherche et développement, cette étude a abordé des notions pluridisciplinaires, alliant des aspects technologiques, organisationnels et informatiques. En conclusion, ce mémoire a abouti à l’établissement d’une méthodologie pour la mise à jour de la géométrie d’une maquette numérique dans le cadre de projets réels de construction au sein de l’entreprise HRS. En combinant habilement les concepts du BIM, de l’IFC, des technologies openBIM et du scannage 3D, cette méthodologie s’avère être une approche prometteuse de digitalisation de la construction.

Finite element investigation of the Slotted-Hidden-Gap (SHG) connection for square HSS bracing members under cyclic loading

J. Luu 

The Slotted-Hidden-Gap (SHG) connection is an improved version of the conventional welded tube-togusset connection between hollow braces and framing elements used in Concentrically Braced Frames (CBFs), offering an enhanced performance without the need for additional reinforcement. Previous studies have demonstrated the efficiency of this feature in circular and square Hollow Structural Section (HSS) braces under monotonic tensile loading conditions, leading to the development of a design methodology based on the CSA S16-19 to construct the connection. However, limited research has been dedicated to investigating the compressive behavior of the brace and its connections. In order to obtain a more comprehensive understanding of the seismic behavior of the SHG connection, a numerical parametric study is conducted to examine the inelastic response of the connection under reversed cyclic loading conditions. Various parameters are considered, including the square HSS tube’s size, the weld’s length and size, the brace’s slenderness, and the degree of confinement of the gusset plate that plays a crucial role in the development of a plastic hinge. Designed based on the previously developed methodology, the simulated braces demonstrated their ability to withstand compression cycles without fracturing at the connection, making it capacity design protected. The findings indicate that all confinement degrees of the gusset plate in the numerically tested models, from a constrained gusset plate to a linear clearance, led to a fracture away from the connection at mid-length of the brace. Notably, the use of a constrained gusset plate that redirected the moment towards the HSS tube’s end resulted in an average additional 2.85% of plastic strains at the brace’s slots compared to an elliptical or linear offset in the gusset plate. This effect was observed in stockier braces, yet no fracturing occurred.

La logistique urbaine à Lausanne : diagnostic sur les cases de livraison au centre-ville

A. Klotz 

Ce projet de Master se focalise sur le parc de cases de livraison au centre-ville lausannois afin d’établir un bilan de la situation actuelle concernant l’adéquation de l’offre et de la demande. Il avance des recommandations d’actions pour le service Mobilité et Aménagement des espaces Publics (MAP) de la Ville de Lausanne, dans le but de résoudre les problèmes identifiés lors de ce diagnostic. Une enquête est donc réalisée au centre-ville de Lausanne, sur un périmètre composé de trois zones de typologie différente. Pour chacune des zones, les cases de livraison sont répertoriées. Les établissements autour de ses cases sont recensés, et des entrevues dirigées à destination de ces établissements sont réalisées à l’aide de questionnaires. Les données découlant de cette enquête sont ensuite analysées. Les résultats obtenus nous apprennent que l’offre en case de livraison disponible n’est pas adaptée à la demande actuelle, il y a donc une inadéquation entre l’offre et la demande. De plus, les résultats relèvent aussi les nuisances directement ou indirectement générées par cet état de fait : la prédation de l’espace public due aux livraisons hors case, la congestion de la circulation que ces comportements entrainent, la pollution atmosphérique et sonore y afférente, accentuée par un mode de livraison essentiellement carboné. Enfin, des recommandations sont suggérées, inspirées par les nombreuses solutions existantes ou en phase de test, détaillées dans la revue de littérature. Les recommandations sont indépendantes mais cumulables, et ont des degrés de mise en oeuvre différents. Elles évoluent d’une simple campagne de communication sur la bonne utilisation des cases de livraison, à la mise en place d’une Zone à Faibles Émissions (ZFE).

Passerelle CFF Delémont. Rapport technique

J. Grezet 

La ville de Delémont a décidé de lancer un concours pour construire une nouvelle passerelle piétonne car les possibilités de franchissement des voies ferrées entre le Nord et le Sud de la ville sont peu confortables. Les possibilités pour les cyclistes sont insuffisantes et mal sécurisées. Pour les piétons, il existe des variantes mais la passerelle existante n’a qu’un seul accès par escaliers et doit être bientôt assainie. Le but de cette construction étant, entre autres, l’optimisation du coût et de l’utilisation des matériaux afin d’élaborer un projet économiquement intéressant.

Etude géotechnique de la section Plaines du Loup Blécherette du métro m3 de Lausanne

J. Gouin 

Développement d’une méthode de calcul par élément orienté coût pour l’estimation économique de projets incluant un processus BIM dans le contexte de l’entreprise

A. Glaus 

La dimension des coûts dans le BIM est un sujet novateur mais complexe dans la construction. C’est l’un des domaines les moins digitalisés parmi les divers domaines de l’industrie. Dans ce cadre-ci, ce projet de master s’attaque à lier une maquette numérique avec les prix d’une soumission CAN à l’aide d’une méthode de calcul développée durant tout le semestre de printemps. Cette démarche vise à identifier précisément les différents éléments de la maquette numérique et de leur attribuer individuellement un prix. Ensuite, cette méthode attribue un prix fixé par le personnel d’encadrement comme objectif ainsi que le prix réel du chantier. Finalement, ces différentes valeurs peuvent être comparées afin de donner une meilleure compréhension de l’avancement d’un chantier et être lues au travers d’une feuille de gestion de chantier.

Passage supérieur sur l’autoroute A1 à Bavois. Vérification de la structure existante et dimensionnement d’un nouvel ouvrage en CFUP armé

A. Gatta 

Seismic Assessment of a Masonry Church and Retrofitting Propositions. Case study of the Kapela Sveti Nikola in Petrinja

M. Frick 

The seismic assessment of historical unreinforced masonry buildings is a challenging task, because of their vulnerability to earthquakes and the uncertainties about the material properties. This work studies the case of the Kapela Sveti Nikola, a chapel in Petrinja (Croatia) which was damaged by an earthquake in 2020. The present report includes the seismic assessment of the church thanks to numerical simulation and hand calculations, and propositions for the retrofitting of the structure. The numerical simulation consists of static pushover analysis on a finite element model of the church performed on the software Abaqus. The approach for the modelling is the homogenised material model with 2D shell elements. Local failure mechanisms are also analysed through hand calculations. This seismic evaluation of the church, along with the observed damage on the church’s structure, is the basis for the propositions of strengthening measures. Some retrofitting ideas are advanced and their adequacy in the case of this church is discussed, but no structural analysis of the retrofitted building is carried out.

Conception et dimensionnement durable : Étude comparative et conception multi-matériaux

F. Dumont 

Les émissions de CO2 émises par le secteur de la construction représentent 11% des émissions globales de l’humanité (2019). En raison de l’urgence climatique, il est nécessaire de les réduire. Dans ce contexte et selon les conclusions données par la pré-étude, les dalles en béton armé contribuent en majeur partie à alourdir le bilan CO2 d’un ouvrage. Ainsi, cette étude consiste en une étude comparative de différentes alternatives aux dalles en béton armé. Ces alternatives prennent en compte les critères de résistance, de déformation et de vibration, mais également les exigences acoustiques et de régulation de température. Cette approche holistique permet d’anticiper des aspects ultérieurs du processus de conception, et ainsi d’obtenir une prévision globale des émissions de CO2 et des coûts. Cette étude portant sur un bâtiment à géométrie complexe, ses dimensions et résultats lui sont propres. Les critères de dimensionnement et les exigences sont tirés des normes de construction suisses, des Eurocodes et des documents techniques usuels. Le dimensionnement des différentes variantes a été réalisé en appliquant les formules de dimensionnement des normes ou à la suite d’une modélisation sur le logiciel SCIA Engineer. Un métré a ensuite été réalisé et il a été possible d’en calculer les émissions de CO2 (facteurs d’émissions tirés du document de la KBOB) et d’en estimer les coûts. Il existe des systèmes de plancher intrinsèquement plus économes qu’une dalle en béton armé si l’on ne considère que l’aspect structurel, mais ces derniers sont vite limités par les contraintes acoustiques, les exigences vibratoires et les systèmes de régulation de température. Ces derniers critères imposent une surcharge importante et ainsi la nécessité d’avoir une structure porteuse plus robuste. Ces implications sont si importantes qu’il n’est plus possible de trouver une variante de plancher significativement meilleure que la solution en béton armé tant la réduction des émissions est éclipsée par la forte hausse des coûts. Cependant, au global, le passage à un système léger engendre des gains écologiques (-11%) et financiers (-3%) notamment grâce à la réduction des efforts dans les porteurs verticaux et dans les fondations, et à la réduction des efforts sismiques. Pour le bâtiment en entier, il est possible de réduire les émissions de 29.3% au prix d’une hausse des coûts de 40.2%. Ces résultats sont très dépendants des facteurs d’émissions de la KBOB. Ceux-ci étant réévalués régulièrement et manquant de transparence sur les hypothèses faites, les résultats obtenus pourraient être amenés à changer lors des prochaines années.

Synthetic Generation of Activity-related data

Q. P. Bochud 

The field of synthetic data is more and more present in our everyday life. The transportation domain is particularly interested in improving the methods for the generation of synthetic data in order to address the privacy and availability issue of real data. Since we want to generate data for Activity Based Models, the key challenge of this project is to expand the existing simulation generation method, Markov Chain Monte Carlo (MCMC), to generate data about the activities of individuals. This allows us to anonymize people’s trips and to analyze how people’s behavior is related to their trips (e.g. home-work-supermarket-home for people living alone or home-study-sport-home for students). The generated data can be useful for other studies or for planning in the professional transportation field. Once data is generated, we have to validate the representativity of the synthetic sample compared to the real one. The first step in using MCMC is to prepare the inputs by creating conditional probabilities. The construction of these vectors varies depending on the type of data that we want to generate (e.g. continuous, discrete). In the current version of the existing framework, only discrete attributes are defined. We plan to expand on the generation of continuous attributes and sequential data. The data used are from the Swiss Mobility and Transport Micro Census Data (MTMC). The Federal Office for Spatial Development (ARE) and the Federal Statistical Office (FSO) conducted a national survey to gather the data. This data sample gathers information on people’s mobility behaviors. Respondents list their socioeconomic features, their daily mobility routines (such as time or distance to work), and detailed records of their travels throughout a reference period (1 day).

Conception d’une passerelle de mobilité douce

G. Baumgartner 

Response history analysis of steel buildings with highly inelastic panel zones

D. Balmer 

Outil SIG d’évaluation d’un indice de performance du territoire pour le transport de marchandises urbain

N. Balimann 

Le transport de marchandises urbain et la problématique du dernier kilomètre gagnent en importance au sein de la logistique urbaine et dans les réflexions liées au transport en général. Afin d’accompagner cette évolution, il devient nécessaire aux divers acteurs d’être en mesure d’évaluer et cartographier la performance d’un réseau routier au regard du transport de marchandises. Ainsi, un outil a été développé pour pouvoir calculer la performance sur un réseau donné en entrée et selon divers paramètres. Il permet de caractériser le réseau avec deux notes, l’une associée à la circulation de véhicules de livraison et l’autre qui décrit l’accessibilité des zones à livrer. Pour l’évaluation, onze indicateurs ont été sélectionnés et répartis dans deux groupes : Circulation et Accessibilité. Les indicateurs sont issus de la littérature et d’entretiens avec des professionnels du transport de marchandises. La possibilité d’obtenir des données géospatiales et de les traiter a également été prise en compte. Trois outils ont été programmés en langage Python et sont utilisables dans le logiciel de SIG ArcGIS Pro. Ils font partie intégrante d’un processus : extraction de la couche de réseau pour la zone d’étude, calcul des indicateurs et publication de la couche sur ArcGIS Online. En complément, une application web a été créée pour consulter et partager les résultats en ligne. Les indices pour tout le réseau sont obtenus par une combinaison entre l’offre et la demande. L’offre est issue des notes que le réseau a obtenu avec l’outil de calcul et la demande est représentée par l’importance du trafic ou par le nombre de générateur de livraison, dépendamment du groupe d’indicateurs L’étude de cas réalisée sur les réseaux de la Ville de Genève, de Carouge-Lancy et de Meyrin a permis de montrer que les trois contraintes les plus fortes sont la présence de place de stationnement, le nombre de voie de circulation et la congestion. Également, les axes structurants du réseau de transport sont généralement mieux notés par les indicateurs du groupe Circulation que ceux du groupe Accessibilité. De plus, les réseaux obtiennent généralement un indice de Circulation plus élevé que celui d’Accessibilité, dans le cas de l’analyse avec les poids lourds et les véhicules utilitaires légers. Cependant, cette tendance s’inverse pour l’analyse avec les vélos cargos. Globalement, l’outil de calcul montre que les vélos cargos sont largement plus performants sur les réseaux étudiés. Ceci contraste avec la réalité, car ce mode de livraison est encore très peu utilisé. Cela signifie donc que d’autres contraintes plus importantes existent et qu’un effort de la part des acteurs est nécessaire pour combler les contraintes identifiées dans ce projet. Les résultats de l’outil de calcul développé dans ce projet correspondent aux hypothèses et les considérations des entreprises récoltées lors des entretiens. Néanmoins, l’outil peut être amélioré en confrontant les résultats à l’avis des experts et en modifiant les paramètres, notamment les valeurs des seuils de notation. Il faut également porter une attention particulière à la justesse des données spatiales exploitées lors des analyses. En utilisant des données générales, l’outil gagne en flexibilité, mais perd en précision. La question de l’accessibilité des données se pose aussi.

Examen d’un pont sur le Rhône à Raron (VS)

Y. A. Antille 

Projet d’intervention pour la remise en état et la conformité sismique du Viaduc de l’île Falcon

Abdeljalil Saad 

RF Measurements of Unconventional Miniaturised Filters and Diplexers

R. F. Bonny 

Densification des villages alpins : vers un nouveau mode de vie

D. Zanolo 

Ce travail fait suite à l’énoncé théorique intitulé La montagne en métamorphose, ou comment une vallée de montagne s’est développée au contact des étrangers. Retraçant l’évolution de la vallée du Trient à travers le prisme des regards indigènes et étrangers, différents enjeux territoriaux ont été identifiés et font alors l’objet du projet explorant l’avenir de la commune de Salvan. Son emplacement géographique attractif, qui offre à la fois une grande proximité à la plaine et un cadre de vie montagnard, vaut à Salvan de connaître un fort essor démographique, et cette tendance ne semble pas ralentir au vu des enjeux d’habitabilité métropolitaine liés au climat auxquels l’habitabilité montagnarde répond. De fait, et en prévision de cette attractivité croissante, la commune a prévu des zones de densification, représentant près de 30% de la surface actuellement constructible. Ces zones représentent alors l’opportunité de développer un mode de vie plus écologique et plus collectif. En effet, l’aménagement territorial actuel est très individualiste : bien souvent, un parking occupe le centre du village et la typologie du chalet individuel demeure la référence. Ainsi, entre redéfinition des espaces publics villageois, propositions typologiques et interventions écologiques, le projet propose une nouvelle manière de concevoir la vie en montagne.

Maison de l’Algoculture: transformation de la STEP de Rolle

S. Yun 

Le parc des stations d’épuration des eaux usées (STEP) vaudois est en train de considérablement évoluer afin de répondre à de nouvelles exigences en matière de traitement des micropolluants dans nos eaux. Ainsi, il est prévu de mettre hors service une soixantaine d’installations existantes à l’horizon 2035, ce qui soulève la question de l’avenir de ces structures une fois désaffectées. C’est dans ce contexte que le projet propose de reconvertir la STEP de Rolle en un lieu de production de microalgues destinées à l’alimentation humaine. En adoptant ce nouvel usage qui entraîne la production d’une source alternative de protéines ayant un faible impact écologique, la Maison de l’algoculture continuera de servir la société et de contribuer à la protection de l’environnement. De plus, une retranscription des flux hydriques est mise en place à travers le choix d’une enveloppe solaire thermique et la mise en œuvre d’un processus de production de microalgues nécessitant une quantité significative d’eau. Par cette transformation minutieuse d’un patrimoine industriel aujourd’hui à l’écart de notre attention, le projet permettra non seulement de valoriser les qualités spatiales et volumétriques de la structure existante, mais également de contribuer à une redéfinition de la perception des infrastructures de STEP dans notre société.