tbuckley/cabot-search huggingface dataset:
Abstract 147: Exome sequencing identifies frequent histone methyltransferase mutations in metastatic SCC
Authors: Amanda Ewart Toland, Dawn Allain, Jessica Gillespie, Priyaharsini Nagarajan, Sara Peters, Hatice Gulcin Ozer, Thomas Olencki, Ayse Selen Yilmaz, Theodoros Teknos
Journal: Cancer Research (2016)

Abstract Although only a small proportion of cutaneous squamous cell carinomas (cSCC) metastasize, approximately 3900-8800 individuals in the United States die of metastatic cSCC each year. Little is known about the molecular events that lead approximately 2-6% of cSCCs to metastasize. Treatment efforts are hampered by a lack of ability to predict which lesions are more likely to recur or metastasize as these known correlates do not have high specificity for prediction. Furthermore, there is no FDA approved therapy that is specifically indicated for metastatic cSCC. Deep-sequencing efforts have identified targetable mutations and pathways for several cancers. Exome and targeted sequencing of primary cSCCs led to the discovery that inactivating mutations in NOTCH pathway genes occur in over 75% of tumors; however NOTCH mutations are not indicative of metastasis. Published studies identified frequent mutations in KMT2C and KMT2D in cSCCs with aggressive features. To identify mutations that are unique to or enriched in metastatic samples which may help to identify novel therapeutics for treating aggressive cSCCs, we performed exome sequencing of 37 samples consisting of matched normal DNAs, primary tumors and metastatic cSCCs. Many of the mutations found in the metastatic samples were also observed in the matched primary tumors. We found an enrichment of mutations in chromatin remodeling genes. Epigenetic regulatory genes mutated in the metastatic samples included KMT2D (64%), KMT2C (44%), SETD2 (45%), KAT6A (36%), EP300 (18%), and KDM6A/UTX (9%). We performed additional targeted deep-sequencing to evaluate whether candidate genes were frequently mutated in non-aggressive cSCCs. Initial analyses of targeted-sequencing of 10 non-aggressive primary cSCCs and 7 additional metastatic cSCCs as well as data from published exome studies on non-aggressive cSCCs suggest that chromatin remodeling genes are mutated at a much higher rate in metastatic cSCCs. These data provide potential pathways for therapeutic intervention for this deadly cancer. Citation Format: Amanda Ewart Toland, Dawn Allain, Jessica Gillespie, Priyaharsini Nagarajan, Sara Peters, Hatice Gulcin Ozer, Thomas Olencki, Ayse Selen Yilmaz, Theodoros Teknos. Exome sequencing identifies frequent histone methyltransferase mutations in metastatic SCC. [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 147.
Abstract 4110: Color-coded imaging of the tumor microenvironment of malignant lymphoma in a syngeneic mouse model
Authors: Takuro Matsumoto, Atsushi Suetsugu, Kosuke Hasegawa, Miki Nakamura, Hitomi Aoki, Takahiro Kunisada, Hisashi Tsurumi, Masahito Shimizu, Robert M. Hoffman
Journal: Cancer Research (2016)

Abstract EL4-RFP lymphoma cells were injected in the spleen of C57/BL6 GFP transgenic mice. EL4-RFP metastasis was observed in the lymph nodes of the supra mediastinum and abdomen and in the liver 28 days later. The EL4-RFP tumors in the spleen (primary injection site), liver, supra mediastinum lymph nodes, abdominal lymph nodes, bone marrow, and lung were visualized with the Olympus FV1000 scanning laser confocal microscope. EL4-RFP tumors in the liver, lymph nodes, and bone marrow in C57/BL6 GFP mice were rich in GFP stromal cells such as macrophages, fibroblasts, dendritic cells, and normal lymphocytes derived from the host animal. Phagocytosis of EL4-RFP lymphoma cells by macrophages, as well as dendritic cells and fibroblasts, were observed in culture. Small tumors were observed in the spleen (primary injection site), but the stroma cells in the spleen tumors were abundant. We could observe that in the lung, no mass formation of lymphoma cells occurred, but lymphoma cells circulated in lung peripheral blood vessels. Citation Format: Takuro Matsumoto, Atsushi Suetsugu, Kosuke Hasegawa, Miki Nakamura, Hitomi Aoki, Takahiro Kunisada, Hisashi Tsurumi, Masahito Shimizu, Robert M. Hoffman. Color-coded imaging of the tumor microenvironment of malignant lymphoma in a syngeneic mouse model. [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 4110.
Corrigendum: A microRNA switch regulates the rise in hypothalamic GnRH production before puberty
Authors: Andrea Messina, Fanny Langlet, Konstantina Chachlaki, Juan Roa, Sowmyalakshmi Rasika, Nathalie Jouy, Sarah Gallet, Francisco Gaytan, Jyoti Parkash, Manuel Tena-Sempere, Paolo Giacobini, Vincent Prevot
Journal: Nature Neuroscience (2016)
Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
Authors: Maria Secrier, Xiaodun Li, Nadeera de Silva, Matthew D Eldridge, Gianmarco Contino, Jan Bornschein, Shona MacRae, Nicola Grehan, Maria O'Donovan, Ahmad Miremadi, Tsun-Po Yang, Lawrence Bower, Hamza Chettouh, Jason Crawte, Núria Galeano-Dalmau, Anna Grabowska, John Saunders, Tim Underwood, Nicola Waddell, Andrew P Barbour, Barbara Nutzinger, Achilleas Achilleos, Paul A W Edwards, Andy G Lynch, Simon Tavaré, Rebecca C Fitzgerald
Journal: Nature Genetics (2016)
Everolimus in patients with advanced, progressive pancreatic neuroendocrine tumors: Overall survival results from the phase III RADIANT-3 study after adjusting for crossover bias.
Authors: Marianne E. Pavel, Catherine Lombard-Bohas, Eric Van Cutsem, Du Hung Lam, Tiffany Kunz, Ulrike Brandt, Jaume Capdevila, Elisabeth De Vries, Paola Tomassetti, Timothy J. Hobday, Rodney F. Pommier, James C. Yao
Journal: Journal of Clinical Oncology (2015)

4091 Background: In the RADIANT-3 study, everolimus (EVE) improved progression-free survival (PFS) by 6.4 mo versus placebo (PBO; HR, 0.35; 95% CI, 0.27-0.45; P < 0.001) in patients (pts) with advanced, progressive pancreatic neuroendocrine tumors (pNET). Here we present final overall survival (OS) results of the RADIANT-3 study with updated safety and also report OS adjusted for confounding due to crossover. Methods: A total of 410 pts with advanced, progressive, low-/intermediate-grade pNET were randomized to EVE 10 mg/d (n = 207) or PBO (n = 203), both with best supportive care. Upon disease progression in double-blind phase, crossover from PBO to open-label EVE was allowed at investigator’s discretion. At the end of core phase, ongoing pts from both arms were unblinded and switched to open-label EVE. OS was analyzed by one-sided stratified log-rank test. Rank-preserving structural failure time (RPSFT) analysis was performed to estimate treatment effect corrected for crossover bias. Results: A total of 225 pts received open-label EVE; including 85% (172 of the 203) pts randomized to PBO arm. Median OS (95% CI) was 44.0 (35.6-51.8) mo for pts initially randomized to EVE and 37.7 (29.1-45.8) mo for those randomized to PBO (HR, 0.94; 95% CI, 0.73-1.20; P= 0.30). RPSFT analysis showed a relative survival benefit of 3.27 (95% CI, 0.10-13.93) with survival rates of 82.6% vs 74.9% and 67.7% vs 55.6% at 12 and 24 mo, respectively for EVE vs RPSFT corrected PBO arm. The most frequently reported drug-related adverse events included stomatitis (45%), rash (37%), and diarrhea (26%) in open-label EVE arm. Conclusions: The randomized, placebo-controlled, phase III RADIANT-3 study reports unprecedented median OS of 44 mo with EVE in advanced, progressive pNET. Although statistically not significant, a survival benefit of 6.3 mo with EVE was observed, consistent with PFS benefit reported previously. A stronger OS advantage with EVE after a correction for crossover effect confirms that crossover of majority of PBO pts (85%) likely confounded the survival results. The safety profile of EVE remained consistent with earlier experience. Clinical trial information: NCT00510068.
Radiotherapy Overcomes Adverse Prognostic Role Of COX-2 Expression On Reed-Sternberg Cells In Early Hodgkin Lymphoma
Authors: Antonio Gutierrez, Mestre Francesc, Jose Rodriguez, Jordi Martinez-serra, Rafael Ramos, Ines Herraez, Antonia M Bautista-Gili, Leyre Bento, Lucia Garcia, Jordi Gines, Teresa Ros, Albert Perez, Paloma Lopez-Perezagua, Jaime Daumal, Juan Besalduch
Journal: Blood (2013)
Cell-Extrinsic MHC Class I Molecule Engagement Augments Human NK Cell Education Programmed by Cell-Intrinsic MHC Class I
Authors: Jeanette E. Boudreau, Xiao-Rong Liu, Zeguo Zhao, Aaron Zhang, Leonard D. Shultz, Dale L. Greiner, Bo Dupont, Katharine C. Hsu
Journal: Immunity (2016)
Le point de l'OMS sur la grippe A (H5N1) de Hong Kong
Authors: D Lavanchy
Journal: Eurosurveillance (1998)

Les virus grippaux se repartissent entre les types A, B et C, plus des sous-types du type A. Les types A et B circulent dans les populations humaines et subissent de constantes mutations, si bien qu'un vaccin modifie doit etre prepare chaque annee. Il arrive qu'apparaisse un nouveau virus grippal contre lequel personne n'est immunise puisque personne n'y a ete precedemment expose.
Patient/treatment characteristics and prognostic factors in small-cell bladder cancer (SCBC).
Authors: Vadim S Koshkin, Hamid Emamekhoo, Paul Elson, Jesse McKenney, Cristina Magi-Galluzzi, Kim Schach, Andrew J. Stephenson, Brian I. Rini, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2016)

e16037 Background: SCBC is rare; data on treatment and outcomes is limited. There is a need to define patient (pt) and treatment related prognostic factors that can be used for clinical decision and trial design. Methods: A retrospective review of pts with biopsy-confirmed SCBC at Cleveland Clinic (1993-2015) was done. Univariate / multivariate analyses (UVA / MVA) were used to identify predictors of time to progression (TTP), progression-free survival (PFS), overall survival (OS) from diagnosis (p < 0.1). Results: 67 pts with biopsy-confirmed SCBC had available data. Median age at diagnosis was 71 (39-90), 84% men, 11/64 had hydronephrosis; 45 had cystectomy. Small cell was dominant histology for 33 pts (rest had unclear or other dominant histology with small cell features). 20/67 pts had primary chemotherapy (CTX) with curative intent; 10/20 then had cystectomy, 6/20 definitive radiation (RT), 4/20 no further therapy. The other 47 pts had upfront cystectomy (33), palliative therapy for advanced stage (6) or no other therapy (8). 19/67 eventually had systemic CTX for advanced/recurrent disease. Of 45 pts with cystectomy, 18 had pN+, 1 had metastasis at that time; 31/40 had -ve margins (5 had no margins reported); 13/45 pts had adjuvant CTX after cystectomy. A total of 19 pts had RT, 6 of them definitive RT after (4) or concurrent with (2) primary CTX. 33/67 pts recurred/progressed; 44/67 died. Median OS from diagnosis was 22.8 months (m) (95%CI 12.3-42.4); estimated PFS 13.1 m (95%CI 10.9-16.4); TTP 16.4 m (95% CI 11.7-92.2). In MVA +ve margins and higher pT stage correlated with shorter OS (Table, N = 45). Small cell dominant histology impacted PFS negatively. Median PFS from start of primary CTX was longer with definitive RT (N = 6) vs. subsequent cystectomy (N = 10) (p = 0.007) without OS difference. Conclusions: Higher pT stage, +ve margins, and small cell dominant histology correlated with worse outcomes. OS from Cystectomy OS from Diagnosis Factor HR (95%CI) p Factor HR (95%CI) p Margins (+ve vs -ve) 2.98 (1.28- 6.94) .01 Margins (+ve vs -ve) 2.28 (1.01 -5.13) .05 pT stage (3/4 vs 1/2) 2.20 (0.90 -5.36) .08 Prognostic Groups N of poor factors N (%) Median OS (m) p Favorable 0 12 (32%) 42.4 .004 Intermediate 1 17 (46%) 23.5 Unfavorable 2 8 (22%) 7.1
The evolution of general intelligence
Authors: Judith M. Burkart, Michèle N. Schubiger, Carel P. van Schaik
Journal: Behavioral and Brain Sciences (2016)

The presence of general intelligence poses a major evolutionary puzzle, which has led to increased interest in its presence in nonhuman animals. The aim of this review is to critically evaluate this question and to explore the implications for current theories about the evolution of cognition. We first review domain-general and domain-specific accounts of human cognition in order to situate attempts to identify general intelligence in nonhuman animals. Recent studies are consistent with the presence of general intelligence in mammals (rodents and primates). However, the interpretation of a psychometric g factor as general intelligence needs to be validated, in particular in primates, and we propose a range of such tests. We then evaluate the implications of general intelligence in nonhuman animals for current theories about its evolution and find support for the cultural intelligence approach, which stresses the critical importance of social inputs during the ontogenetic construction of survival-relevant skills. The presence of general intelligence in nonhumans implies that modular abilities can arise in two ways, primarily through automatic development with fixed content and secondarily through learning and automatization with more variable content. The currently best-supported model, for humans and nonhuman vertebrates alike, thus construes the mind as a mix of skills based on primary and secondary modules. The relative importance of these two components is expected to vary widely among species, and we formulate tests to quantify their strength.
BMI, long-term changes in BMI, and risk of cancer mortality in a large cohort study.
Authors: Niloofar Taghizadeh, Judith M. Vonk, H. Marike Boezen
Journal: Journal of Clinical Oncology (2012)

1502 Background: There are indications of an association between Body Mass Index (BMI) and risk of different cancer types. There is dispute whether this association differs between males and females. Methods: We studied the association of BMI at the first survey with risk of mortality from the most common types of cancer (lung, colorectal, breast and prostate cancer) in a large general population-based cohort study (Vlagtwedde-Vlaardingen, 1965-1990) with follow-up on mortality status until 2009. Additionally, we assessed this association based on tertiles of the annual change in BMI (defined as the difference between BMI at last survey and first survey divided by the time between last and first survey). We used 3 categories of BMI (&lt; 25 kg/m 2 , 25-30 kg/m 2 , and ≥ 30 kg/m 2 ) and changes in BMI (&lt; 0.02 kg/m 2 /yr, 0.02-0.2 kg/m 2 /yr, and &gt; 0.2 kg/m 2 /yr) in the analyses. The multivariate Cox regression model was adjusted for age, smoking, gender. Analyses were additionally stratified by gender and smoking. Results: Among all 8645 subjects, 1194 died due to cancer (lung cancer: 275; colorectal cancer: 134; breast cancer: 117; prostate cancer: 83). Mortality from all types of cancer was significantly increased in subjects with BMI &gt; 30 kg/m 2 (HR (95 % CI)) = 1.22 (1.00-1.48)), especially in females (1.38 (1.06-1.81)) and in never smokers (1.39 (1.02-1.90)). Prostate cancer mortality was significantly increased in males with BMI 25-30 kg/m 2 (2.04 (1.90-3.83)) and &gt; 30 kg/m 2 (2.61 (1.02-6.67)). This association between prostate cancer mortality and BMI was higher in smokers. Lung cancer mortality risk was decreased in subjects with BMI 25-30 kg/m 2 (0.71 (0.54-0.93)) and &gt; 30 kg/m 2 (0.82 (0.50-1.32)), especially in males, in smokers, and in smoking males. There were no significant associations between BMI and colorectal or breast cancer mortality nor between change in BMI and mortality from all analyzed types of cancer. Conclusions: We show that an increase in BMI is associated with an increased risk of mortality from all types of cancer in females and with an increased mortality risk from prostate cancer in males but with a decreased lung cancer mortality risk, especially in males. More research is needed into the biological mechanisms that link BMI to cancer.
BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis
Authors: Roham Parsa, Harald Lund, Anna-Maria Georgoudaki, Xing-Mei Zhang, André Ortlieb Guerreiro-Cacais, David Grommisch, Andreas Warnecke, Andrew L. Croxford, Maja Jagodic, Burkhard Becher, Mikael C.I. Karlsson, Robert A. Harris
Journal: The Journal of Experimental Medicine (2016)

Prolonged infections or adjuvant usage can trigger emergency granulopoiesis (EG), leading to dysregulation in neutrophil blood counts. However, the impact of EG on T and B cell function remains largely unknown. In this study, to address this question, we used a mouse model of neutropenia and studied immune activation after adjuvant administration. The initial neutropenic state fostered an environment of increased dendritic cell activation and T cell-derived IL-17 production. Interestingly, neutropenic lysozyme 2-diphtheria toxin A mice exhibited striking EG and amplified neutrophil recruitment to the lymph nodes (LNs) that was dependent on IL-17-induced prostaglandin activity. The recruited neutrophils secreted a B cell-activating factor that highly accelerated plasma cell generation and antigen-specific antibody production. Reduction of neutrophil functions via granulocyte colony-stimulating factor neutralization significantly diminished plasma cell formation, directly linking EG with the humoral immune response. We conclude that neutrophils are capable of directly regulating T cell-dependent B cell responses in the LN.
A Life of Neurotransmitters
Authors: Solomon H. Snyder
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Development of scientific creativity is often tied closely to mentorship. In my case, two years with Julius Axelrod, the sum total of my research training, was transformative. My mentoring generations of graduate students and postdoctoral fellows has been as nurturing for me as it has been for them. Work in our lab over fifty years has covered the breadth of neurotransmitters and related substances, focusing on the discovery and characterization of novel messenger molecules. I can't conceptualize a more rewarding professional life.
Abstract 2800: Target RNA sequencing analysis of hypoxia induced expression of stem cell genes in primary cultures of prostate cancer cells
Authors: Hong Yin, Adam H. Greer, Glenn Mills
Journal: Cancer Research (2016)

Abstract Hypoxia plays important regulatory roles in expanding the tumor stem cell population. In prostate cancer, hypoxia is a feature of poor prognosis. The association of prostate cancer stem cells with hypoxia has been investigated. The altered stem cell gene expression in prostate cancer cells under the hypoxic condition has been documented. The majority of the investigations were performed with established prostate cancer cell lines. However, little is known about the expression of stem cell genes in primary cultures of prostate cancer. In this study, we examined the hypoxia-regulated expression of stem cell genes with primary cultures of human prostate cancer. Cells were isolated from three patient's prostate cancer samples. Isolated cells were cultured in prostate epithelium culture medium CnT-52. After 48 hours of exposure to 1% oxygen, RNA was extracted and quantified. The library was prepared with Illumina's TruSeq Targeted RNA Expression Stem Cell Panel. The sequencing was performed on Miseq platform with MiSeq Reagent Kits v2 (300cycles). FastQ files were generated by Miseq Reporter and analyzed further by Truseg Target RNA v1.0(Illumina), Cufflinks Assembly &amp;DE(Illumina), and Biomedical Genomics Workstation(Qiagen).The results showed that of the 100 tested stem cell genes, seven genes were significantly upregulated(FDR p-value&amp;lt;0.05). They are BMP1, BMP2, FZD7, JUND, NOTCH1, NOTCH3, and PPARD. Three genes, PSEN2, SDAD1, and SOX2, were significantly down-regulated. To validate sequencing results, we examined NOTCH1 and NOTCH3 expression with RT-PCR. Compared to cells under normoxic condition, hypoxia induced expression of NOTCH1 increased by 3.7, 3.9 and 3.1 fold, respectively among three hypoxic cultures, while the expression of NOTCH3 increased by 8.1, 5.9, and 7.5 fold, respectively. However, the investigation of hypoxia affected expression of stem cell genes in LNCaP, an established prostate cell line, showed that the significant decreased expression of BMP1, FZD7, PPARD, and NOTCH3 was seen under hypoxic condition(FDR p-value &amp;lt;0.05). RT-PCR analysis showed that expression of NOTCH3 in hypoxic LNCaP, PC3, and DU145 cells was decreased by 7.7, 6.1, and 1.2 fold, respectively. The expression profile of stem cell genes in response to hypoxia was different between primary cultures of prostate cancer cells and established prostate cancer cell lines. The activation of BMP-NOTCH signaling could be one character of stemness of prostate cancer in response to hypoxia. Citation Format: Hong Yin, Adam H. Greer, Glenn Mills. Target RNA sequencing analysis of hypoxia induced expression of stem cell genes in primary cultures of prostate cancer cells. [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 2800.