tbuckley/cabot-search huggingface dataset:
Abstract LB-331: Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations
Authors: Somasekar Seshagiri, Eric Stawiski, Leonard Goldstein, Steffen Durinck, Zora Modrusan, Florian Gnad, Thong T. Nguyen, Bijay Jaiswal, Assunta De Rienzo, William Richards, Raphael Bueno
Journal: Cancer Research (2016)

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer arising from the mesothelial cells of the pleura. About 80% of mesothelioma cases are linked to asbestos exposure, while the remainder may be related to prior chest radiation, genetic predisposition or spontaneous occurrence. We analyzed transcriptomes (n = 211), whole exomes (n = 99), and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Four distinct molecular subtypes, sarcomatoid (S), epithelioid (E), biphasic-E, and biphasic-S were identified using RNA-seq data. Using exome analysis we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1, and DDX51 to be significantly mutated MPM genes. We identified recurrent mutations in several genes including splice complex factor SF3B1 (∼2% [4/216]) and TRAF7 (∼2% [5/216]). SF3B1 mutant samples showed a distinct splicing profile compared to wild-type tumors. Mutations in TRAF7 occurred primarily in the WD40 domain and except in one case were mutually exclusive with NF2 mutations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. We analyzed the tumors for infiltrating immune cells and found that M2 macrophage to T-cell ratio was predictive of reduced overall survival. Further we found sarcomatoid subtype had a significantly higher level of PD-L1 expression suggesting that this group might be prioritized for checkpoint inhibitor therapy. Integrated analysis of alterations identified changes in Hippo, mTOR, Histone methylation, RNA helicase and p53 signaling pathways in MPMs. Overall our study significantly expands on the previous genomic studies and provides a comprehensive genomics profile of mesothelioma and identifies several previously unknown alterations and biological pathways that are potential targets for drug discovery and treatment. Incorporating genomic analysis for detection of actionable alterations as part of MPM patient care will help in developing rational individualized therapy. Citation Format: Somasekar Seshagiri, Eric Stawiski, Leonard Goldstein, Steffen Durinck, Zora Modrusan, Florian Gnad, Thong T. Nguyen, Bijay Jaiswal, Assunta De Rienzo, William Richards, Raphael Bueno. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. [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 LB-331.
P0526 : Accuracy of point shear wave elastography technique (elastpq) in the non-invasive assessment of liver fibrosis in various liver diseases
Authors: M. Garcovich, M. Pompili, E. Di Stasio, M.E. Ainora, L. Riccardi, B.E. Annicchiarico, M. Siciliano, A. Grieco, G. Rapaccini, A. Gasbarrini, M.A. Zocco
Journal: Journal of Hepatology (2015)
Abstract 4244: Optical imaging of ovarian cancer metastasis in mouse models of obesity
Authors: W. Matthew Leevy, Yueying Liu, Matthew Metzinger, Kyle Lewellen, M. Sharon Stack.
Journal: Cancer Research (2016)

Abstract Epithelial ovarian cancer (EOC) is a deadly gynecologic malignancy, owing to its propensity for intraperitoneal (IP) metastasis. Indeed, almost 75% of women with EOC are diagnosed during the later stages of the disease in which metastasis is already underway. Pathogenesis of EOC is marked by diffuse and widely disseminated metastatic sites within the IP compartment, often with peritoneal ascites. Mouse models of EOC have been developed to facilitate the pre-clinical research of this deadly disease, however the quantification of metastatic tumor burden in these animals has remained challenging due to the broad distribution of lesions in the IP space. Here we describe a combined In Vivo/Post-Mortem method to monitor and measure EOC metastasis in mouse models of obesity. RFP-labeled ovarian cancer cells were injected IP in obese and control cohorts of mice, followed by weekly in vivo imaging until time of sacrifice. Subsequent post-mortem imaging was conducted after surgical exposure of the peritoneal cavity to reveal organs that were then imaged in situ. Ex vivo imaging was performed last on dissected organs from each animal. Imaging signal was enhanced via multispectral imaging methods to remove tissue auto-fluorescence. Semi-quantitative methods to measure tumor burden are demonstrated in their application to the study of metastasis in both obese and control animals. Ultimately these results demonstrated that obesity dramatically increased ovarian cancer metastatic success, and likely contributes to the reduced EOC survival rates noted in clinical reports of obese patients. Citation Format: W. Matthew Leevy, Yueying Liu, Matthew Metzinger, Kyle Lewellen, M. Sharon Stack. Optical imaging of ovarian cancer metastasis in mouse models of obesity. [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 4244.
Mumps Outbreak at a University and Recommendation for a Third Dose of Measles-Mumps-Rubella Vaccine — Illinois, 2015–2016
Authors: Justin P. Albertson, Whitney J. Clegg, Heather D. Reid, Benjamin S. Arbise, Julie Pryde, Awais Vaid, Rachella Thompson-Brown, Fredrick Echols
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Mumps is an acute viral disease characterized by fever and swelling of the parotid or other salivary glands. On May 1, 2015, the Illinois Department of Public Health (IDPH) confirmed a mumps outbreak at the University of Illinois at Urbana-Champaign. IDPH and the Champaign-Urbana Public Health District (C-UPHD) conducted an investigation and identified 317 cases of mumps during April 2015-May 2016. Because of sustained transmission in a population with high 2-dose coverage with measles-mumps-rubella (MMR) vaccine, a third MMR dose was recommended by IDPH, C-UPHD, and the university's McKinley Health Center. No formal recommendation for or against the use of a third MMR dose has been issued by the Advisory Committee on Immunization Practices (ACIP) (1). However, CDC has provided guidelines for use of a third dose as a control measure during mumps outbreaks in settings in which persons are in close contact with one another, where transmission is sustained despite high 2-dose MMR coverage, and when traditional control measures fail to slow transmission (2).
Combination candesartan–HCTZ did not reduce major CV events in patients at intermediate CV risk
Authors: Charles B. Eaton MD
Journal: Annals of Internal Medicine (2016)

Source Citation Lonn EM, Bosch J, López-Jaramillo P, et al; HOPE-3 Investigators. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374:2009-20. 27041480
Categorization of Cancer Survivors: Why We Need It
Authors: Antonella Surbone, Paolo Tralongo
Journal: Journal of Clinical Oncology (2016)

The number of people diagnosed with cancer who live longer than 5 years from diagnosis or end of acute treatment, along with the number of patients who live with cancer in a chronic state, is increasing in industrialized countries. Consequently, survivorship care is now an established branch of oncology and is a growing health care and research priority. Yet, several gaps in the contemporary study of survivorship were identifi ed through an American Society of ClinicalOncology(ASCO)electronicsurveyof679memberswho acted as principal or coprincipal investigators of survivorshiprelated studies and of 838 professionals engaged in survivorship research at National Cancer Institute–designated cancer centers. 1 Identified gaps included the predominance of breast cancer studies, limited research on older survivors, persistent research dearth of long-term (. 5 years) survivors, lack of intervention studies on young survivors, and areas of deficiency in research objectives, such as biologic or genetic components and care delivery. 1 An additional gap in survivorship care and research remains unaddressed—identifi cation of categories of cancer survivors on the basis of clinical and epidemiologic data to provide better tailored care to people who are now lumped together under the umbrella of cancer survivors. In this article, we analyze the reasons for the categorization of cancer survivors and the benefits that may be derived from clinical and organizational categorizations intended to increase physical and psychosocial well-being of patients in a global sociocultural perspective.
Time at the Bedside (Computing)
Authors: Zuzanna Czernik, C. T. Lin
Journal: JAMA (2016)

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Abstract 27: Understanding mechanisms of nutrient homeostasis: Amino acid availability and regulation of V-ATPase activity
Authors: Laura A. Stransky, Michael Forgac
Journal: Cancer Research (2016)

Abstract Cellular homeostasis requires accurate sensing of nutrient levels and subsequent regulation of biosynthetic and catabolic cellular processes. In cancer cells, metabolism is frequently disregulated to meet the increased demand for cellular building blocks to enable growth and proliferation. Thorough understanding of how homeostatic processes are regulated is necessary to determine how these processes could be manipulated to stop tumor growth. This study aims to understand amino acid homeostasis, with particular focus on the regulation of lysosomal activity, which allows protein breakdown and release of free amino acids. We have identified a novel mechanism of amino acid homeostasis whereby amino acid starvation leads to increased activity of the Vacuolar-ATPase (V-ATPase), as indicated by measurement of V-ATPase-dependent FITC-dextran fluorescence quenching in isolated lysosomes. The V-ATPase is the proton pump responsible for acidifying intracellular compartments, which is necessary for lysosomal function and protein degradation. This increased activity is due to an increase in the amount of fully assembled holoenzymes, as detected by cell fractionation and Western blotting to assess peripheral subunit association with membranes. Assembly of V-ATPase holoenzymes is a tightly controlled process. We describe the function of these changes with respect to lysosomal protein turnover and mTORC1 activation, in which the V-ATPase plays a critical role. We have also sought to characterize the signaling events that transmit the amino acid starvation signal and controls V-ATPase activity in response to changes in amino acid availability in normal and cancer cells that rely on lysosomal function. These changes do not depend on PI3K or mTORC1 activity, both of which have been linked to changes in V-ATPase activity and assembly in other response to other stimuli, such as glucose and growth factor stimulation and are highly activated across cancers. Together, these results shed light on a poorly understood aspect of cellular biology and novel mechanisms of amino acid homeostasis. Citation Format: Laura A. Stransky, Michael Forgac. Understanding mechanisms of nutrient homeostasis: Amino acid availability and regulation of V-ATPase activity. [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 27.
Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle
Authors: David W. Frederick, Emanuele Loro, Ling Liu, Antonio Davila, Karthikeyani Chellappa, Ian M. Silverman, William J. Quinn, Sager J. Gosai, Elisia D. Tichy, James G. Davis, Foteini Mourkioti, Brian D. Gregory, Ryan W. Dellinger, Philip Redpath, Marie E. Migaud, Eiko Nakamaru-Ogiso, Joshua D. Rabinowitz, Tejvir S. Khurana, Joseph A. Baur
Journal: Cell Metabolism (2016)
Gene signature model for breast cancer risk prediction for women with sclerosing adenosis.
Authors: Derek C Radisky, Amy C. Degnim, Aziza Nassar, Melody Stallings-Mann, S. Keith Anderson, Ann L. Oberg, Stacey J Winham, Robert A. Vierkant, Ryan D. Frank, Chen Wang, Marlene H. Frost, Daniel W. Visscher
Journal: Journal of Clinical Oncology (2015)

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.
Abstract CT155: The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial
Authors: Yanlei Ma, Qing Wei, Yongzhi Yang, Huanlong Qin
Journal: Cancer Research (2016)

Abstract This study was designed to mainly evaluate the anti-infective effects of perioperative probiotic treatment in patients receiving confined colorectal cancer (CRC) respective surgery. From November 2011 to September 2012, a total of 60 patients diagnosed with CRC were randomly assigned to receive probiotic (n = 30) or placebo (n = 30) treatment. The operative and post-operative clinical results including intestinal cleanliness, days to first - flatus, defecation, fluid diet, solid diet, duration of pyrexia, average heart rate, length of intraperitoneal drainage, length of antibiotic therapy, blood index changes, rate of infectious and non-infectious complications, postoperative hospital stay, and mortality were investigated. The patient demographics were not significantly different (p &amp;gt; 0.05) between the probiotic treated and the placebo groups. The days to first flatus (3.63 versus 3.27, p = 0.0274) and the days to first defecation (4.53 versus 3.87, p = 0.0268) were significantly improved in the probiotic treated patients. The incidence of diarrhea was significantly lower (p = 0.0352) in probiotics group (26.67%, 8/30) compared to the placebo group (53.33%, 16/30). There were no statistical differences (p &amp;gt; 0.05) in other infectious and non-infectious complication rates including wound infection, pneumonia, urinary tract infection, anastomotic leakage, and abdominal distension. In conclusion, for those patients undergoing confined CRC resection, perioperative probiotic administration significantly influenced the recovery of bowel function, and such improvement may be of important clinical significance in reducing the short-term infectious complications such as bacteremia. Trial Registrations: ChiCTR-TRC-13003332 (http://www.chictr.org/en/) Citation Format: Yanlei Ma, Qing Wei, Yongzhi Yang, Huanlong Qin. The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial. [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 CT155.
India is urged to resist US pressure to rein in its affordable medicines policies
Authors: Sophie Cousins
Journal: BMJ (2016)

India must not bow to pressure from the US government and drug companies to curb the development of quality affordable generic medicines, global leaders attending the International Aids Conference in Durban, South Africa, have warned.

India has provided more than 80% of the world’s generic anti-HIV drugs used around the world, but activists, experts, and leaders were concerned that Narendra Modi’s government would bow to outside pressure and change its policies on affordable medicines, with potentially serious consequences for people with HIV.

Leena Menghaney, from the Medecins Sans …
Abstract 4621: Rapamycin inhibits the phosphorylation of mSin1 by targeting a new mTOR complex
Authors: Shile Huang, Yan Luo, Lei Liu
Journal: Cancer Research (2016)

Abstract Current knowledge indicates that mTOR functions as two complexes, mTORC1 and mTORC2, in mammalian cells. mTORC1 comprises mTOR, mLST8 and raptor, and is sensitive to acute rapamycin treatment, whereas mTORC2 consists of mTOR, mLST8, rictor, mSin1 and Protor, and is sensitive to chronic rapamycin treatment in some cases. It is well known that mTORC1 phosphorylates 4E-BP1 and S6K1, while mTORC2 phosphorylates Akt and SGK1. Recently, we and others have observed that rapamycin inhibits the phosphorylation of mSin1. However, little is known about the molecular mechanism by which rapamycin inhibits mSin1 phosphorylation. Here we show that rapamycin inhibits mSin1 phosphorylation in mTOR kinase dependent manner. This is strongly supported by the findings that expression of rapamycin-resistant mTOR (mTOR-T), but not rapamycin-resistant and kinase dead mTOR (mTOR-TE) prevented rapamycin from inhibiting mSin1 phosphorylation; Knockdown of mTOR inhibited mSin1 phosphorylation. However, surprisingly, disruption of either mTORC1 or mTORC2 (by silencing raptor and rictor, respectively) failed to inhibit the phosphorylation of mSin1 as rapamycin did. Similarly, downregulation of S6K1 or Akt did not inhibit mSin1 phosphorylation as rapamycin did either. Of interest, knockdown of mLST8, a component shared by mTORC1/2, inhibited mSin1 phosphorylation. Furthermore, rapamycin treatment reduced the physical interaction of mSin1 with mLST8 and mTOR, but not with rictor. The results suggest that rapamycin inhibits mSin1 phosphorylation, which is not by inhibiting mTORC1 or mTORC2, but via inhibiting a new mTOR complex, which contains at least mTOR and mLST8. (Supported by the FWCC, LSU Health Sciences Center) Citation Format: Shile Huang, Yan Luo, Lei Liu. Rapamycin inhibits the phosphorylation of mSin1 by targeting a new mTOR complex. [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 4621.
Abstract 420: Translational strategy for targeting MCL1 amplified tumors with CDK9 inhibitor
Authors: Ziping Yang, Ricky Bellin, Paul Hessler, Xin Lu, Tamar Uziel, Lloyd T. Lam
Journal: Cancer Research (2016)

Abstract BCL-2, BCL-XL, and MCL-1 are members of the prosurvival family of proteins that regulate the mitochondrial apoptotic pathway. These proteins are often amplified or overexpressed in multiple tumor types. Previously, we showed that non-small cell lung cancer (NSCLC) cell lines with low BCL-XL expression (high MCL-1 / BCL-XL ratio) are MCL-1-dependent. TCGA data shows MCL1 amplification is one of the frequent genetic events in NSCLC adenocarcinoma (20%) and breast cancer (15%), while BCL2 is frequently amplified in activated B-cell like diffuse large B cell lymphoma (11%) and BCL2L1 in colorectal cancer (15%). We hypothesize that cancer cell lines with MCL1 amplification and/or high MCL-1 / BCL-XL ratio depend on MCL-1 for survival and are sensitive to inhibition of CDK9, a component of the transcriptional elongation complex that regulates MCL-1 expression. In this study, we demonstrate that NSCLC, triple negative breast cancer (TNBC) and ovarian cell lines with amplified MCL1 or low BCL-XL expression (high MCL-1 / BCL-XL expression ratio) are MCL-1-dependent, and are sensitive to dinaciclib, a CDK9 inhibitor. Cell lines with high BCL-XL expression could be re-sensitized to dinaciclib when co-treated with BCL2/BCL-XL inhibitor navitoclax (ABT-263) or BCL-XL-selective inhibitor A-1155463, suggesting BCL-XL as a resistance factor. Indeed, exogenous expression of BCL-XL rescues sensitive cell lines from dinaciclib. As reported in TCGA, ovarian, NSCLC and TNBC patients with MCL1 amplification also have high MCL-1 expression, and we hypothesized that these patients to be sensitive to CDK9 inhibitors. We developed a fluorescence in situ hybridization (FISH) assay to detect MCL1 amplification which can potentially select patients that may benefit from dinaciclib treatment. We show that fifteen percent of NSCLC patients have high MCL1 amplification, similar to published data. In addition, we have identified other predictive biomarkers associated with sensitivity in TNBC cell lines from gene expression analysis. In conclusion, we have developed a translational strategy for identifying MCL-1-dependent cancers that may be sensitive to CDK9 inhibitors in the clinic. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication Citation Format: Ziping Yang, Ricky Bellin, Paul Hessler, Xin Lu, Tamar Uziel, Lloyd T. Lam. Translational strategy for targeting MCL1 amplified tumors with CDK9 inhibitor. [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 420.