tbuckley/cabot-search huggingface dataset:
Global burden of cancers attributable to infections in 2012: a synthetic analysis
Authors: Martyn Plummer, Catherine de Martel, Jerome Vignat, Jacques Ferlay, Freddie Bray, Silvia Franceschi
Journal: The Lancet Global Health (2016)

BackgroundInfections with certain viruses, bacteria, and parasites are strong risk factors for specific cancers. As new cancer statistics and epidemiological findings have accumulated in the past 5 years, we aimed to assess the causal involvement of the main carcinogenic agents in different cancer types for the year 2012.MethodsWe considered ten infectious agents classified as carcinogenic to human beings by the International Agency for Research on Cancer. We calculated the number of new cancer cases in 2012 attributable to infections by country, by combining cancer incidence estimates (from GLOBOCAN 2012) with estimates of attributable fraction (AF) for the infectious agents. AF estimates were calculated from the prevalence of infection in cancer cases and the relative risk for the infection (for some sites). Estimates of infection prevalence, relative risk, and corresponding 95% CIs for AF were obtained from systematic reviews and pooled analyses.FindingsOf 14 million new cancer cases in 2012, 2·2 million (15·4%) were attributable to carcinogenic infections. The most important infectious agents worldwide were Helicobacter pylori (770 000 cases), human papillomavirus (640 000), hepatitis B virus (420 000), hepatitis C virus (170 000), and Epstein-Barr virus (120 000). Kaposi's sarcoma was the second largest contributor to the cancer burden in sub-Saharan Africa. The AFs for infection varied by country and development status—from less than 5% in the USA, Canada, Australia, New Zealand, and some countries in western and northern Europe to more than 50% in some countries in sub-Saharan Africa.InterpretationA large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available.FundingFondation de France.
Are movement parameters recognizably coded in the activity of single neurons
Authors: Eberhard E. Fetz
Journal: Behavioral and Brain Sciences (1992)

To investigate neural mechanisms of movement, physiologists have analyzed the activity of task-related neurons in behaving animals. The relative onset latencies of neural activity have been scrutinized for evidence of a functional hierarchy of sequentially recruited centers, but experiments reveal that activity changes occur largely in parallel. Neurons whose activity covaries with movement parameters have been sought for evidence of explicit coding of parameters such as active force, limb displacement, and behavioral set. Neurons with recognizable relations to the task are typically selected from a larger population, ignoring those cells with complex relations to the task and unmodulated cells. Selective interpretations are also used to support the notion that different motor regions perform different motor functions; again, current evidence suggests that units with similar properties are distributed over widely different regions.These coding issues are reexamined for premotoneuronal (PreM) cells, whose correlational links with motoneurons are revealed by spike-triggered averages. PreM cells are recruited over long times relative to their target muscles; they show diverse response patterns relative to the muscle force they produce; functionally disparate PreM cells such as afferent fibers and descending corticomotoneuronal and rubromotoneuronal cells can exhibit similar patterns. Neural mechanisms have been further elucidated by neural network simulations of sensorimotor behavior; the pre-output hidden units typically show diverse response patterns in relation to their target units. Thus, studies in which both the activity and the connectivity of the same units are known reveal that units with both simple and complex relations to the task contribute significantly to the output. This suggests that the search for explicit coding may be diverting us from understanding distributed neural mechanisms that operate without literal representations.
Abstract 600: Melanoma and ovarian cancer cells tested for drug sensitivity using anchorage-independent growth
Authors: Asaf Rotem, Benjamin Izar, Levi A. Garraway
Journal: Cancer Research (2016)

Abstract This study aims to test patient-derived melanoma and ovarian cancer cells for their sensitivity to clinically available drugs and drug combinations. The experiments were performed by using the growth in low attachment (GILA) assay, which is equivalent to the classic soft-agar assay and allows screening of 3D ex vivo cultures, which resemble the tumor and its microenvironment. To assay tumor cells from malignant lesions we isolated ovarian cancer cells from peritoneal fluid (ascites) derived from patients and melanoma cells from metastatic melanoma patients. The fresh samples were enriched for tumor cells and later cultured in an ex vivo manner on either high- or low-attachment surfaces. These cells were subjected to drug treatments and cellular viability was measured at the end of these experiments. Our experiments demonstrate that the GILA assay is a highly sensitive method for pharmacological tests, as compared to the traditional 2D method (growth on high-attachment surfaces). By using GILA assay we found that melanoma cells are sensitive to drugs that inhibit driver oncogenes, such as BRAF or MEK. In addition, we found interesting targets in metastatic melanoma lesions that carry an unknown mutational background. Drug sensitivity assays for ovarian cancer cells using the GILA approach showed that cancer cells from various patients with the same cancer type display differential sensitivity to drugs. Additionally, ovarian cancer cells were found to have a different drug-sensitivity threshold when grown in spheres. Our studies present an approach that utilizes the unique ability of transformed cells to grow in anchorage-independent conditions and enables ex vivo drug sensitivity testing. This phenotypic approach is complementary to a genetic approach that uses DNA sequencing to identify putative oncogenes that confer sensitivity to drugs designed to specifically inhibit the identified oncoprotein. Citation Format: Asaf Rotem, Benjamin Izar, Levi A. Garraway. Melanoma and ovarian cancer cells tested for drug sensitivity using anchorage-independent growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 600.
Assessing the Validity of the NIH Response Criteria for Chronic Graft-Versus-Host Disease (cGVHD): Consensus Measures Correlate with Clinical Outcomes,
Authors: Lana Grkovic, Sandra A. Mitchell, Kristin Baird, Seth M. Steinberg, Edward W. Cowen, Kirsten M. Williams, Manuel B. Datiles, Dean Aria, Carol Bassim, Galen Joe, Leora Comis, Drazen Pulanic, Judy Baruffaldi, Dan Zhang, Claude Sportes, Rachel B. Salit, Dan H. Fowler, Frances T. Hakim, Ronald E. Gress, Steven Z. Pavletic
Journal: Blood (2011)
Abstract SY38-03: Quantifying tumor heterogeneity in the microenvironment
Authors: Florian Markowetz
Journal: Cancer Research (2016)

Abstract Cancer has long been understood as a somatic evolutionary process, but many details of tumor progression remain elusive. Here, I will talk about computational methods to infer evolutionary pathways leading to tumour heterogeneity. Using a study in ovarian cancer I will describe how summary statistics of phylogenetic quantification of genetic heterogeneity can predict patient survival. Then, I will present probabilistic frameworks to reconstruct intra-tumor evolution from data obtained by bulk bisulfite sequencing of mixed tumor samples or single cell genomes. Our approaches jointly estimates the number and composition of clones in the sample as well as the most likely tree connecting them. I will finish with an outlook how to put cancer genomes in a tissue context by using image analysis and deconvolution of gene expression data. Citation Format: Florian Markowetz. Quantifying tumor heterogeneity in the microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY38-03.
Abstract 230: The role of integrated stress response (ISR) transcription factor ATF4 in metabolic adaptation of tumors to c-Myc activation
Authors: Feven Tameire, Maria A. Monroy, Constantinos Koumenis
Journal: Cancer Research (2016)

Abstract The ability of cancer cells to adapt to non-cell autonomous (extrinsic) and cell autonomous (intrinsic) stresses is critical for maintaining cell viability and growth. The Integrated Stress Response (ISR) pathway is essential in cancer cell adaptation to extrinsic stresses such as hypoxia and nutrient deprivation both in vitro and in vivo. The ISR kinases, PERK and GCN2, phosphorylate eIF2α, transiently inhibiting protein translation during times of stress. Phosphorylation of eIF2α promotes the preferential translation of the transcription factor ATF4, which activates a gene expression program that enhances uptake and synthesis of amino acids, antioxidant defense and chaperone expression to promote recovery from nutrient deprivation and ER stress. Here, we demonstrate the importance of ISR signaling in MYC oncogene induced intrinsic stress both in vitro and in vivo. We previously reported that activation of PERK, during c-Myc induction is vital for activating cytoprotective autophagy and suppressing c-Myc induced apoptosis. Here, we demonstrate GCN2 is also robustly activated during c-Myc induction. GCN2 activation after c-Myc induction regulates ATF4 transcription and translation. ATF4 was necessary for survival and suppression of oxidative stress during c-Myc activation. We have identified ATF4 targets that regulate amino acid uptake and involved in amelioration of oxidative stress. Furthermore, siRNA mediated knockdown or genetic knockout of GCN2 was synthetic lethal with c-Myc activation. Interestingly, PERK is still able to phosphorylate eIF2α in the absence of GCN2. However, eIF2α phosphorylation was completely inhibited in the absence of both kinases suggesting that these kinases compensate for each other and both are required for optimal phosphorylation of eIF2α after c-Myc activation. Consistent with our in vitro data, we observe higher levels of p-eIF2α and ATF4 in lymphoma cells compared to WT B cells in vivo in a mouse model of Myc driven lymphoma. These findings highlight a novel mechanism of stress response pathway activation to support c-Myc driven tumorigenesis involving an amino acid sensor kinase GCN2. Citation Format: Feven Tameire, Maria A. Monroy, Constantinos Koumenis. The role of integrated stress response (ISR) transcription factor ATF4 in metabolic adaptation of tumors to c-Myc activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 230.
Abstract 3745: Tumor fibroblast targeting via uPAR retargeted measles virus: <i>In vitro</i> and <i>in vivo</i> effects
Authors: Yuqi Jing, Julia Zaias, Jaime Merchan
Journal: Cancer Research (2016)

Abstract Tumor stromal cell components, in particular cancer associated fibroblasts, play an important role in cancer progression. Few studies have focused on stromal fibroblast targeting by oncolytic viruses. The urokinase receptor (uPAR) is a clinically and biologically validated target, which is overexpressed in tumor and stromal cells compared to non-cancer tissues. MV-h-uPA and MV-m-uPA are fully retargeted oncolytic measles viruses directed against human and murine uPAR, respectively, which have shown in vitro and in vivo safety and antitumor effects. Species specific retargeted viral vectors allow to dissect the specific effects of the viruses on murine vs. human tissues in xenograft models. Our aim is to characterize the in vitro and in vivo effects of stromal targeting by oncolytic measles virus via uPAR, with a focus on tumor fibroblasts. In vitro, MV-h-uPA and MV-m-uPA preferentially infected and induced cytotoxicity in human cancer associated fibroblasts (CAF 19, CAF 23) as well as murine fibroblasts (3T3), compared to non-tumorigenic fibroblasts. Murine-murine and human-human fibroblast to cancer cell viral transfer via heterofusion was observed after fibroblast infection by species specific MV-uPA, in breast, colon and renal cancer models, while no viral transfer was observed between cells of different species. In vivo, systemic administration of the murine uPA retargeted virus (MV-m-uPA) significantly decreased tumor progression and prolonged survival in a human breast cancer xenograft model (MDA-MD231), where the host stroma expresses murine uPAR (target of MV-m-uPA). Tumor studies revealed induction of apoptosis (TUNEL assay), while no significant effects on cancer cell proliferation was observed. Dual staining for measles virus nucleocapsid proteins and fibroblasts markers demonstrated viral infection of fibroblasts in treated tumors. Gene expression studies using murine as well as human specific arrays were performed to characterize the effects of stromal targeting by the murine retargeted virus on murine stroma as well as the indirect effects on human cancer cells in vivo. In conclusion, for the first time our results show feasibility and antitumor effects of stromal fibroblast targeting by oncolytic measles virus via uPAR and demonstrate that stromal fibroblasts are viable targets for oncolytic virotherapy. Studies characterizing other stromal cell components and evaluation of the molecular changes in the tumor stroma as result of viral infection are underway. Citation Format: Yuqi Jing, Julia Zaias, Jaime Merchan. Tumor fibroblast targeting via uPAR retargeted measles virus: In vitro and in vivo effects. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3745.
Abstract 2856: Inhibition of glycolysis sensitizes cancer cells to metformin-induced anoikis
Authors: Yong Yi, Zhi-Xiong Jim Xiao
Journal: Cancer Research (2016)

Abstract Metformin is a widely used medicine to treat type 2 diabetes. Clinical studies have shown that metformin can reduce cancer incidence, yet the molecular mechanism of which is not totally understood. The p53-related p63 plays a critical role in regulation of cell proliferation, apoptosis, differentiation and development. We and others have shown that the major isform of p63 proteins, ΔNp63α, is important in regulation of squamous carcinoma cell proliferation, survival and cancer metastasis (Bergholz et al.,Oncogene 33:212-224, 2014;Li et al.,CDDis,2013, e943; doi:10.10384). In this study, we show that metformin can induce instability of ΔNp63α protein, leading to subsequent anoikis. In addition, glucose restriction or inhibition of glycolysis significantly sensitizes cells to metformin. Furthermore, we show that integrin β1 is involved in this process. Taken together, this study reveals a novel molecular mechanism by which metformin inhibits squamous carcinoma formation in vitro and in vivo. Citation Format: Yong Yi, Zhi-Xiong Jim Xiao. Inhibition of glycolysis sensitizes cancer cells to metformin-induced anoikis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2856.
Renal Dysfunction Does Not Affect Clinical Response in Multiple Myeloma (MM) Patients Treated with Bortezomib-Based Regimens.
Authors: Sikander Ailawadhi, Terry L. Mashtare, Marie V. Coignet, Dawn M. Depaolo, Kena C. Miller, Gregory Wilding, Asher Alban Chanan-Khan
Journal: Blood (2007)
674 Examination of autoantibody profiles in a novel congenic mouse strain with biliary tract disease, the NOD.IDD3/10/17/18/9 mouse
Authors: D SASS, S KOARADA, Y WU, N FERTIG, M NALESNIK, J TODD, P LYONS, J FENYKMELODY, L WICKER, L PETERSON
Journal: Hepatology (2003)
Lymhoma of the Oral Cavity. A Rare Entity with Favorable Prognosis. Ten-Year Experience of a Single Hematology Unit.
Authors: Marina P. Siakantaris, Tatiana Tzenou, Theodoros P. Vassilakopoulos, Marie-Christine Kyrtsonis, Maria K. Angelopoulou, Maria N. Dimopoulou, Styliani I. Kokoris, Evangelia N. Dimitriadou, Penelope Korkolopoulou, Efstratios Patsouris, Panayiotis Tsaftaridis, Eleni Variamis, George Laskaris, Gerassimos A. Pangalis
Journal: Blood (2004)
Abstract CT118: Efficient basket trial designs
Authors: Kristen M. Cunanan, Alexia Iasonos, Ronglai Shen, David Hyman, Colin Begg, Mithat Gonen
Journal: Cancer Research (2016)

Abstract Background: Basket trials are used to study targeted treatments across a range of tumor sites. In these designs all patients have the same target altered and receive the same regimen but they are placed in baskets defined by the site of primary tumor. This design is particularly appealing since the prevalence of the target mutation is typically low in any given tumor site, and the drug sponsor is naturally interested in as broad an indication for use as possible. Given the multiple baskets, this design requires the investigation of whether the activity of the regimen applies uniformly to all baskets, i.e., homogeneity of treatment effect, and if not, which baskets show sufficient response. Many basket trial designs to date have resembled parallel phase II studies, using Simon's two-stage design separately for each basket. The inclusion of multiple baskets increases the overall false positive rate in the trial, an aspect that is commonly not taken into account in current designs. More importantly, the use of independent, parallel phase II trials fails to take advantage of the opportunity to combine baskets in the event that the interim results suggest common responsiveness across baskets, either common evidence of efficacy or common evidence of lack of efficacy. Methods: We develop a novel, adaptive study design that makes use of an interim assessment of the heterogeneity of treatment effect across baskets to determine the most appropriate statistical analysis, while controlling the overall false positive rate in the trial. Our proposed design allows for aggregation of baskets in stage 2 when evidence points to a common effect of the drug, while retaining the option to maintain selected individual baskets in stage 2, if the interim evidence supports this strategy. Similar to conventional designs, our proposed design allows for early termination of baskets for lack of responsiveness. Using simulations we demonstrate the potential reduction in the number of patients required compared with the traditional strategy based on parallel Simon two-stage designs, while maintaining similar levels of Type I and II errors. Citation Format: Kristen M. Cunanan, Alexia Iasonos, Ronglai Shen, David Hyman, Colin Begg, Mithat Gonen. Efficient basket trial designs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT118.
Androgen deprivation therapy and the incidence of autoimmune diseases.
Authors: Adi Joseph Klil-Drori, Koray Tascilar, Hui Yin, Armen G. Aprikian, Laurent Azoulay
Journal: Journal of Clinical Oncology (2015)

e16010 Background: The importance of androgen deprivation therapy (ADT) for the treatment of advanced prostate cancer has been recognized for more than seven decades. However, given that androgens regulate the immune system, little is known on the effect of ADT use on the incidence of autoimmune diseases. Methods: A population-based cohort of 36,052 patients diagnosed with prostate cancer between 1988 and 2014 was identified from the United Kingdom Clinical Practice Research Datalink. Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% CI of inflammatory bowel disease (IBD), psoriasis, and rheumatoid arthritis (RA) associated with the use of ADT. Results: During a mean follow-up of 4.5 years (SD: 3.6), there were 79, 263, and 130 incident cases of IBD, psoriasis, and RA, respectively. Compared to non-use, current use of ADT was associated with a 44% decreased risk of IBD (HR: 0.56, 95% CI: 0.32-0.98). Current use of ADT was not associated with the incidence of psoriasis (HR: 1.02, 95% CI: 0.75-1.38) and RA (HR: 0.93, 95% CI: 0.61-1.43). Past use of ADT was not associated with the incidence of any of these conditions. Conclusions: Current use of ADT in men with prostate cancer may decrease the risk of IBD. The clinical significance of androgens and androgen deprivation in autoimmunity in general, and gut inflammation specifically, warrants further investigation.
Csnk2β Knockout during Hematopoiesis Results in Lethality at Mid/Late Gestation Mostly Due to Impaired Fetal Erythropoiesis
Authors: Laura Quotti Tubi, Sara Canovas Nunes, Alessandro Casellato, Elisa Mandato, Fortunato Zaffino, Alessandra Brancalion, Odile Filhol-Cochet, Brigitte Boldyreff, Sabrina Manni, Gianpietro Semenzato, Francesco Piazza
Journal: Blood (2014)