tbuckley/cabot-search huggingface dataset:
A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2′-Deoxycytidine
Authors: Benjamin R. Leadem, Ioannis Kagiampakis, Catherine Wilson, Tommy K. Cheung, David Arnott, Patrick Trojer, Marie Classon, Hariharan Easwaran, Stephen B. Baylin
Journal: Cancer Research (2017)

Abstract The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA-demethylating agent 5-aza-2′-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing H3K4me3 peaks. Furthermore, cells treated with the drug combination exhibited increased promoter and gene body H3K4me3 occupancy at DAC-responsive genes compared with DAC alone. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. KDM5i synergized with DAC to reduce the viability of luminal breast cancer cells in in vitro assays. Our study provides the first look into the molecular effects of a novel KDM5i compound and suggests that combinatorial inhibition along with DAC represents a new area to explore in translational epigenetics. Significance: This study offers a first look into the molecular effects of a novel KDM5 inhibitory compound, suggesting how its use in combination with DNA methylation inhibitors presents new opportunities to explore in translational cancer epigenetics. Cancer Res; 78(5); 1127–39. ©2017 AACR.
Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression
Authors: Eva De Smedt, Ken Maes, Stefaan Verhulst, Hui Lui, Alboukadel Kassambara, Anke Maes, Nicolas Robert, Carlo Heirman, Andrew Cakana, Dirk Hose, Karine Breckpot, Leo A. van Grunsven, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jérôme Moreaux, Elke De Bruyne
Journal: Cancer Research (2017)

Abstract RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression. Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155–68. ©2017 AACR.
Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial
Authors: Kyaw L. Aung, Sandra E. Fischer, Robert E. Denroche, Gun-Ho Jang, Anna Dodd, Sean Creighton, Bernadette Southwood, Sheng-Ben Liang, Dianne Chadwick, Amy Zhang, Grainne M. O'Kane, Hamzeh Albaba, Shari Moura, Robert C. Grant, Jessica K. Miller, Faridah Mbabaali, Danielle Pasternack, Ilinca M. Lungu, John M.S. Bartlett, Sangeet Ghai, Mathieu Lemire, Spring Holter, Ashton A. Connor, Richard A. Moffitt, Jen Jen Yeh, Lee Timms, Paul M. Krzyzanowski, Neesha Dhani, David Hedley, Faiyaz Notta, Julie M. Wilson, Malcolm J. Moore, Steven Gallinger, Jennifer J. Knox
Journal: Clinical Cancer Research (2017)

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344-54. ©2017 AACR.
Comparative genomics of the major parasitic worms
Authors: Avril Coghlan, Rahul Tyagi, James A. Cotton, Nancy Holroyd, Bruce A. Rosa, Isheng Jason Tsai, Dominik R. Laetsch, Robin N. Beech, Tim A. Day, Kymberlie Hallsworth-Pepin, Huei-Mien Ke, Tzu-Hao Kuo, Tracy J. Lee, John Martin, Rick M. Maizels, Prudence Mutowo, Philip Ozersky, John Parkinson, Adam J. Reid, Neil D. Rawlings, Diogo M. Ribeiro, Lakshmipuram Seshadri Swapna, Eleanor Stanley, David W. Taylor, Nicolas J. Wheeler, Mostafa Zamanian, Xu Zhang, Fiona Allan, Judith E. Allen, Kazuhito Asano, Simon A. Babayan, Germanus Bah, Helen Beasley, Hayley M. Bennett, Stewart A. Bisset, Estela Castillo, Joseph Cook, Philip J. Cooper, Teresa Cruz-Bustos, Carmen Cuellar, Eileen Devaney, Stephen R. Doyle, Mark L. Eberhard, Aidan Emery, Keeseon S. Eom, John S. Gilleard, Daria Gordon, Yvonne Harcus, Bhavana Harsha, John M. Hawdon, Dolores E. Hill, Jane Hodgkinson, Petr Horák, Kevin L. Howe, Thomas Huckvale, Martin Kalbe, Gaganjot Kaur, Taisei Kikuchi, Georgios Koutsovoulos, Sujai Kumar, Andrew R. Leach, Jane Lomax, Benjamin Makepeace, Jacqueline B. Matthews, Antonio Muro, Noel Michael O'Boyle, Peter D. Olson, Antonio Osuna, Felix Partono, Kenneth Pfarr, Gabriel Rinaldi, Pilar Foronda, David Rollinson, Mercedes Gomez Samblas, Hiroshi Sato, Manuela Schnyder, Tomas Scholz, Myriam Shafie, Vincent N. Tanya, Rafael Toledo, Alan Tracey, Joseph F. Urban, Lian-Chen Wang, Dante Zarlenga, Mark L. Blaxter, Makedonka Mitreva, Matthew Berriman
Journal: Nature Genetics (2018)

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms. Comparative study of 81 genomes of parasitic and non-parasitic worms identifies gene family births and expanded gene families at key nodes in the phylogeny that are relevant to parasitism and proteins historically targeted for drug development.
Choosing Successful Residents
Authors: David A. Harris, Stanley W. Ashley, Jennifer L. Irani
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus
Authors: Robert P. Giugliano, Christopher P. Cannon, Michael A. Blazing, José C. Nicolau, Ramón Corbalán, Jindřich Špinar, Jeong-Gun Park, Jennifer A. White, Erin A. Bohula, Eugene Braunwald
Journal: Circulation (2017)

Background: Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM). Methods: In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup. Results: The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each P &lt;0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, P &lt;0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both P &lt;0.001). In patients with DM, E/S reduced the 7-year Kaplan–Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91–1.04; P int =0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary end point regardless of DM ( P int =0.91), whereas patients &lt;75 years of age with DM had greater benefit than those without ( P int =0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin ( P int =0.034). Conclusions: In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.
Intracellular translocation of Inositol Hexakisphosphate Kinase 2 during IFN-β- or radiation-induced apoptosis
Authors: Bei H. Morrison, Zhuo Tang, Barbara S. Jacobs, Joseph A. Bauer, Daniel J. Lindner
Journal: Cancer Research (2004)

4129   Inositol Hexakisphosphate Kinase 2 (IHPK2) gene is a growth suppressive and apoptosis-enhancing gene identified by an antisense technical knockout approach. Previously, we have reported that overexpression of IHPK2 sensitizes ovarian carcinoma cell lines to the growth suppressive and apoptotic effects of IFN-β treatment and γ -irradiation (Morrison, B. H., etc., J. Biol. Chem. 2001). To further understand the mechanism of apoptotic effect of IHPK2, we studied intracellular distribution of IHPK2 basally and during induction of apoptosis by IFN-β (100U/ml for 16 h) or γ -irradiation (1, 2, or 4 Gy). To study the subcellular localization of IHPK2, we utilized plasmids encoding two fusion proteins, wildtype IHPK2-EGFP, and a mutant, IHPK2-NLS-EGFP containing point mutations in the nuclear localization sequence. We determined localization of these Enhanced Green Fluorescent Protein-tagged constructs. NIH-OVCAR-3 cells were transiently transfected IHPK2-EGFP, or with IHPK2-NLS-EGFP. In untreated IHPK2-EGFP cells, the fusion protein resides in cytoplasm and perinuclear region. After treatment with IFN-β (100U/ml for 16 h), IHPK2-EGFP translocated into the nucleus. In cells transfected with mutant IHPK2-NLS-EGFP, the fusion protein remained trapped in the cytoplasm. Similar translocation occurred in γ -irradiated transfected cells. To determine effects of NLS mutation upon cell growth, we performed antiproliferative assays. We treated stably transfected cells with IFN-β 10-200U/ml for 6 days. The ID 50  of untransfected and pCXN2 (vector) transfected cells were both 40U/ml. The ID 50  of IHPK2-pCXN2 cells was 8U/ml and the ID 50  of IHPK2-NLS-pCXN2 cells was 120U/ml. We conclude that IHPK2 enhanced apoptotic effects of IFN-β and dominant negative mutant IHPK2-NLS conferred IFN-β resistance. Nuclear localization of IHPK2 contributes to the induction of apoptosis by IFN-β or γ -irradiation.
Combined Mutation of <i>Apc, Kras</i>, and <i>Tgfbr2</i> Effectively Drives Metastasis of Intestinal Cancer
Authors: Eri Sakai, Mizuho Nakayama, Hiroko Oshima, Yuta Kouyama, Atsushi Niida, Satoshi Fujii, Atsushi Ochiai, Keiichi I Nakayama, Koshi Mimori, Yutaka Suzuki, Chang Pyo Hong, Chan-Young Ock, Seong-Jin Kim, Masanobu Oshima
Journal: Cancer Research (2017)

Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. ApcΔ716 mutation caused intestinal adenomas and combination with Trp53R270H mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of ApcΔ716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either ApcΔ716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a ApcΔ716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upregulated genes in ApcΔ716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.Significance: These findings illuminate how key driver mutations in colon cancer cooperate to drive the development of metastatic disease, with potential implications for the development of suitable prevention strategies. Cancer Res; 78(5); 1334-46. ©2017 AACR.
Plasma Alkylresorcinol Metabolite, a Biomarker of Whole-Grain Wheat and Rye Intake, and Risk of Type 2 Diabetes and Impaired Glucose Regulation in a Chinese Population
Authors: Taoping Sun, Ying Rong, Xiaoli Hu, Yalun Zhu, Hao Huang, Liangkai Chen, Peiyun Li, Shuzhen Li, Wei Yang, Jinquan Cheng, Xuefeng Yang, Ping Yao, Frank B. Hu, Liegang Liu
Journal: Diabetes Care (2017)

OBJECTIVE To examine the association of plasma alkylresorcinol metabolite 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, with type 2 diabetes (T2D) and impaired glucose regulation (IGR) in a Chinese population. RESEARCH DESIGN AND METHODS A total of 1,060 newly diagnosed T2D patients, 736 newly diagnosed IGR patients, and 1,443 control subjects with normal glucose tolerance were recruited in the case-control study. Plasma DHPPA concentrations were determined by high-performance liquid chromatography–tandem mass spectroscopy. Multivariate logistic regression analysis was used to evaluate the independent association of plasma DHPPA concentrations with the likelihood of T2D and IGR. RESULTS After adjustment for age, sex, BMI, and family history of diabetes, the odds ratios (95% CI) of T2D and IGR were 0.57 (0.45, 0.73) and 0.66 (0.50, 0.85), respectively, comparing the lowest with the highest quartile of plasma DHPPA concentrations. Further adjustment for current smoking status, current alcohol consumption, physical activity, history of hypertension, and educational level did not change the observed association materially. Similar results were also obtained in T2D and IGR groups combined. The inverse association of plasma DHPPA with T2D persisted in stratified analyses according to age, sex, BMI, current smoking status, current alcohol consumption, physical activity, family history of diabetes, and history of hypertension. CONCLUSIONS These findings suggested that higher plasma DHPPA concentrations were associated with lower odds of T2D and IGR. Further studies are warranted to confirm these findings in prospective cohorts.
Comparison of Serum Eosinophil-Derived Neurotoxin Levels between Wheezing and Non-wheezing Groups in Children with Respiratory Tract Infections
Authors: Ali Raza, Young-Ho Kim, Jin-Sung Park, Eun-mi Kwon, Fuyong Jiao, Chang Keun Kim
Journal: Journal of Allergy and Clinical Immunology (2018)
Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism
Authors: Virginie Deswaerte, Paul Nguyen, Alison West, Alison F. Browning, Liang Yu, Saleela M. Ruwanpura, Jesse Balic, Thaleia Livis, Charlotte Girard, Adele Preaudet, Hiroko Oshima, Ka Yee Fung, Hazel Tye, Meri Najdovska, Matthias Ernst, Masanobu Oshima, Cem Gabay, Tracy Putoczki, Brendan J. Jenkins
Journal: Cancer Research (2017)

Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1β, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res; 78(5); 1293-307. ©2017 AACR.