tbuckley/cabot-search huggingface dataset:
Activating Mutations in <i>PIK3CB</i> Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β
Authors: Yoshito Nakanishi, Kimberly Walter, Jill M. Spoerke, Carol O'Brien, Ling Y. Huw, Garret M. Hampton, Mark R. Lackner
Journal: Cancer Research (2016)

Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110β D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors.
The Interaction of Myc with Miz1 Defines Medulloblastoma Subgroup Identity
Authors: BaoHan T. Vo, Elmar Wolf, Daisuke Kawauchi, Anneli Gebhardt, Jerold E. Rehg, David Finkelstein, Susanne Walz, Brian L. Murphy, Yong Ha Youn, Young-Goo Han, Martin Eilers, Martine F. Roussel
Journal: Cancer Cell (2016)
Ushering Hypertension Into a New Era of Precision Medicine
Authors: Theodore A. Kotchen, Allen W. Cowley, Mingyu Liang
Journal: JAMA (2016)

Approximately 80 million US adults have hypertension, and hypertension remains a leading risk factor for stroke and cardiovascular disease.1 In 2009-2010, 48% of treated hypertensive patients in the United States were taking more than 1 drug, and blood pressure remained uncontrolled among 40% of those receiving drug treatment.1 Current guidelines for prevention and treatment of hypertension are based on observational studies in populations and clinical trials in large groups of patients. Precision medicine and epigenetics are 2 emerging and complementary strategies that have the potential to alter clinical approaches to understanding and treating hypertension. Both approaches have the goal of more effective hypertension control by providing personalized targets for preventive and therapeutic interventions.
Blood Transfusion in Major Abdominal Surgery for Malignant Tumors
Authors: Brett L. Ecker, Kristina D. Simmons, Salman Zaheer, Sarah-Lucy C. Poe, Edmund K. Bartlett, Jeffrey A. Drebin, Douglas L. Fraker, Rachel R. Kelz, Robert E. Roses, Giorgos C. Karakousis
Journal: JAMA Surgery (2016)

Blood transfusion can be a lifesaving treatment for the surgical patient, yet transfusion-related immunomodulation may underlie the association of allogeneic transfusion with increased perioperative morbidity and possibly poorer long-term oncologic outcomes.To evaluate trends in transfusion rates for major abdominal oncologic resections to assess changes in recent clinical practice (given the accumulating evidence of the deleterious effects of blood transfusion).Retrospective review of a population-based registry of all hospitals participating in the American College of Surgeons National Surgical Quality Improvement Project (2005-2013 Participant Use Data Files), which was queried for patients who underwent major resection of a pancreatic, hepatic, or gastric malignant tumor. Data analysis was performed from July to August 2015.The primary outcome was the transfusion of any quantity of packed red blood cells. Transfusion rates were calculated for the perioperative period, which was defined as the time from the start of surgery to 72 hours after surgery. Secondary outcomes included wound infection, myocardial infarction, and renal insufficiency, and the rates of these complications were calculated as well. Trend analysis was performed for each year of data to evaluate for changes over the study period.A total of 19 680 patients (median age, 65.0 years [interquartile range, 57.0-73.0 years]) were identified, of whom 5900 (30.0%) received a blood transfusion (of 13 657 patients who underwent a pancreatic resection, 4074 required transfusion [29.8%]; of 1605 patients who underwent a gastric resection, 378 required transfusion [23.6%]; and of 4418 patients who underwent a hepatic resection, 1448 required transfusion [32.8%]). There was a significant trend toward decreasing rates of transfusion during the study period (z = -7.89, P < .001), which corresponded to an absolute 6.1% decrease in the rate of transfusion of packed red blood cells from 2005 to 2013 (ie, from 32.8% to 26.7%). There was no significant change in the rates of postoperative wound infection or renal insufficiency during this time period, but there was an increased rate of perioperative myocardial infarction during the study period (0.33% absolute increase; z = 3.15, P = .002).Over 9 years of contemporary practice, a trend of less perioperative blood transfusions for oncologic abdominal surgery was observed. Further studies are needed to assess whether these trends reflect changes in operative techniques, hospital cohorts, or transfusion thresholds.
Age as a prognostic factor in recurrent breast cancer.
Authors: G Falkson, R S Gelman, F J Pretorius
Journal: Journal of Clinical Oncology (1986)

The effect of age as a prognostic factor in recurrent breast cancer was studied in 1,168 patients treated on Eastern Cooperative Oncology Group (ECOG) protocols. Survival was significantly shorter in patients less than 35 years of age (P = .03). This was true even when other good prognostic factors were present. Eighteen prognostic factors were analyzed, and the effect on survival in each of six age groups was studied. Patients with better performance status, less than three sites of metastases, and without visceral or nodal metastases had a better survival time. A Cox proportional hazards model of survival showed that younger age groups, irrespective of menopausal status, had shorter survival times. The predicted median survival times after the first recurrence were 491 days for patients less than 35 years of age, 590 days for patients 36 to 45 years of age, and 700 days for those greater than 45 years of age.
Expanding the diversity of DNA base modifications with N 6-methyldeoxyadenosine
Authors: Kate D. Meyer, Samie R. Jaffrey
Journal: Genome biology (2016)

Vertebrate DNA is subjected to epigenetic base modifications that have been thought to be limited to methylated and other modified forms of cytidine. A recent study shows that methylation of adenine to form N 6-methyladenine is a rare but readily detectable modification that can be mapped to distinct genomic sites in vertebrates.
Prostate brachytherapy implant quality on biochemical control.
Authors: Don Muller, Paul Monsour
Journal: Journal of Clinical Oncology (2015)

128 Background: prostate brachytherapy at our institution was analyzed for implant quality on biochemical control. Methods: We treated 368 patients with clinically localized prostate cancer. All patients underwent 1 month CT based dosimetric analysis. Follow up data was available on 289 patients with a minimum follow up of 5 years. Gleason score was 6 in 80% (n=233), and 7 in 20% (n=56). Clinical stage was T1c in 90% of cases (n=260), T2a was 8% (n=23), T2b was &lt;1% (n=3), T2c was &lt; 1% (n=2). The initial prostate-specific antigen was &lt; 10 ng/ml in 95% (n=274), 10.1-20 ng/ml in 5% (15).Patients with low risk disease ( clinical stage T1c, Gleason score 6 with a PSA &lt; 10 ng/ml) n=228. Patients with intermediate risk disease Gleason 7 adenocarcinoma or with a PSA&gt; 10 ng/ml &lt; 20 ng/ml )n= 61. All patients were treated with I (125). All patients underwent a 1-month CT-based dosimetric analysis. The implant dose was defined as the dose delivered to 90% of the prostate volume on post implant dosimetry (D(90)). Results: At minimum follow up of 5 years overall freedom from biochemical failure was 91.4%. For Gleason grade 6 freedom from biochemical failure was 95%. For Gleason grade 7 freedom from biochemical failure was 77%. Based on PSA freedom from biochemical failure for PSA &lt;10 ng/ml at diagnosis was 92 % and for PSA &gt;10 ng/ml and &lt;20 ng/ml was 80%. In patients with low risk disease ( clinical stage T1c, Gleason 6 adenocarcinoma with a PSA &lt; 10ng/ml) the freedom from biochemical failure was 94%. In patients with intermediate risk disease (Gleason 7 adenocarcinoma or with a PSA &gt;10 ng/ml &lt;20 ng/ml ) freedom from biochemical failure was 84%. Patients with optimal dose implants n=264 freedom from biochemical failure was 95%. Patients with suboptimal dose implants n=25 freedom from biochemical failure was 52% Conclusions: With a minimum follow up of 5 years our data support the use of implant alone in low risk prostate cancer patients with a freedom from biochemical failure of 94%. Our data also shows the importance of implant quality in achieving optimal out comes.
The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15
Authors: Rebecca B. Delconte, Wei Shi, Priyanka Sathe, Takashi Ushiki, Cyril Seillet, Martina Minnich, Tatiana B. Kolesnik, Lucille C. Rankin, Lisa A. Mielke, Jian-Guo Zhang, Meinrad Busslinger, Mark J. Smyth, Dana S. Hutchinson, Stephen L. Nutt, Sandra E. Nicholson, Warren S. Alexander, Lynn M. Corcoran, Eric Vivier, Gabrielle T. Belz, Sebastian Carotta, Nicholas D. Huntington
Journal: Immunity (2016)
Administration of Dexamethasone during Initial Exposure to Factor VIII Induces Durable and Antigen-Specific Tolerance to Factor VIII in Hemophilia Α Mice with a Humanized Major Histocompatibility Complex II Transgene
Authors: Paul C. Moorehead, Maria T. Georgescu, Alice S. van Velzen, Kate Sponagle, Barbara Vidal, Birgit M. Reipert, Katharina Nora Steinitz, Christine Hough, David Lillicrap
Journal: Blood (2014)
Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD
Authors: C Echevarria, J Steer, K Heslop-Marshall, SC Stenton, PM Hickey, R Hughes, M Wijesinghe, RN Harrison, N Steen, AJ Simpson, GJ Gibson, SC Bourke
Journal: Thorax (2016)

<h3>Background</h3> Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools. <h3>Methods</h3> The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identified by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve. <h3>Results</h3> In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV<sub>1</sub> 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality. <h3>Conclusions</h3> DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0–1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3–6) for escalation planning or appropriate early palliation. <h3>Trial registration number</h3> UKCRN ID 14214.
Pyridinoline excretion is related to bone loss abd cartilage damage in early active rheumatoid arthritis: abstract
Authors: P. Geusens, A.C. Verhoeven, M. Boers, W.H. van der Laan, H.M. Markusse, S. van der Linden, J.M. TeKoppele
Journal: Annals of the Rheumatic Diseases (2000)
Referral to Medical Oncologists: Are There Barriers at the Gate?
Authors: Alfred I. Neugut, Victor R. Grann
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.7.1716 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11919225 Referral to Medical Oncologists: Are There Barriers at the Gate? Alfred I. NeugutxAlfred I. NeugutSearch for articles by this author , Victor R. GrannxVictor R. GrannSearch for articles by this author Show More Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY https://doi.org/10.1200/JCO.2002.20.7.1716 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Abstract 15618: Prognostic Utility of Myocardial Autophagy and Ultrastructural Findings in Early Dilated Cardiomyopathy: Comparison With Cardiac Magnetic Resonance
Authors: Tsunenori Saito, Kuniya Asai, Shigeru Sato, Yasuo Amano, Hitoshi Takano, Kyoichi Mizuno, Wataru Shimizu
Journal: Circulation (2013)
CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer
Authors: Mark L. McCleland, Kathryn Mesh, Edward Lorenzana, Vivek S. Chopra, Ehud Segal, Colin Watanabe, Benjamin Haley, Oleg Mayba, Murat Yaylaoglu, Florian Gnad, Ron Firestein
Journal: Journal of Clinical Investigation (2016)

Colon tumors arise in a stepwise fashion from either discrete genetic perturbations or epigenetic dysregulation. To uncover the key epigenetic regulators that drive colon cancer growth, we used a CRISPR loss-of-function screen and identified a number of essential genes, including the bromodomain and extraterminal (BET) protein BRD4. We found that BRD4 is critical for colon cancer proliferation, and its knockdown led to differentiation effects in vivo. JQ1, a BET inhibitor, preferentially reduced growth in a subset of epigenetically dysregulated colon cancers characterized by the CpG island methylator phenotype (CIMP). Integrated transcriptomic and genomic analyses defined a distinct superenhancer in CIMP+ colon cancers that regulates cMYC transcription. We found that the long noncoding RNA colon cancer-associated transcript 1 (CCAT1) is transcribed from this superenhancer and is exquisitely sensitive to BET inhibition. Concordantly, cMYC transcription and cell growth were tightly correlated with the presence of CCAT1 RNA in a variety of tumor types. Taken together, we propose that CCAT1 is a clinically tractable biomarker for identifying patients who are likely to benefit from BET inhibitors.
Abstract P134: Lifetime Cigarette Smoking is Associated with Increased Indices of Abdominal Obesity Independent of Body Mass Index: The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA)
Authors: Akira Fujiyoshi, Katsuyuki Miura, Sayaka Kadowaki, Aya Kadota, Takayoshi Ohkubo, Naoko Miyagawa, Takashi Hisamatsu, Saitoh Yoshino, Sayuki Torii, Itsuko Miyazawa, Kenichi Mitsunami, Hiroshi Maegawa, Kiyoshi Murata, Hirotsugu Ueshima
Journal: Circulation (2014)

Background: Literature has suggested that smoking is causally associated with insulin resistance and type 2 diabetes. The smoking-diabetes association is often believed to be mediated by abdominal obesity. However, literature is scarce concerning whether smoking is related to visceral adipose tissue (VAT) beyond body mass and other lifestyle factors that influence abdominal fatness. We examined whether lifetime cigarette smoking is independently associated with VAT among Japanese men. Method: We cross-sectionally investigated community-based samples of Japanese men recruited from Shiga, Japan from 2006 to 2008, aged 40 to 64 years and free of cardiovascular disease. Areas of VAT and subcutaneous adipose tissues (SAT) were calculated upon a computer tomography image taken at the level of participant’s L 4-5 . Adipose tissue was defined as -190 to -30 Hounsfield Unit. Amount of cigarette smoking was assessed using structured self-administered questionnaire, and quantified as Brinkman Index (BI, the number of cigarettes smoked per day multiplied by the number of years of smoking). Using linear regression, we calculated adjusted means of abdominal obesity indices (VAT, SAT, VAT-SAT ratio [VSR], and waist-hip ratio [WHR]) according to tertiles. Adjusting covariates included age, education, body mass index (BMI), physical activity at workplace, and drinking. Results: 533 men were studied (mean age 56.1 years; 40.1% for current-, 43.5% for former-smoker). Average BMI, VAT, SAT, and VSR were 23.8 kg/m 2 , 117 (cm 2 ),122 (cm 2 ), and 1.01. Although significant associations between smoking and VAT and SAT were absent, VSR increased significantly with increasing BI ( p =0.02) independent of BMI and other covariates (Table). Conclusion: In Japanese men, cigarette smoking is adversely associated with a rise in the faction of visceral to subcutaneous adipose tissue independent of BMI and other lifestyle factors. Visceral fat may, in part, mediate the smoking-diabetes association.
Glutathione peroxidase-1 as a therapeutic target in influenza A virus-induced lung disease
Authors: Selcuk Yatmaz, Huei Jiunn Seow, Rosa Gualano, Zi Xin Wong, Peter Crack, Steven Bozinovski, Gary Anderson, Ross Vlahos
Journal: European Respiratory Journal (2011)

Introduction: Oxidative stress and reactive oxygen species (ROS) are implicated in influenza A virus-induced lung inflammation and damage. Current therapies primarily target viral infection and replication, with little attention directed at the host immune response. The antioxidant enzyme glutathione peroxidase-1 (GPx-1) has a protective role against various diseases involving ROS.

Aim: To study the role of GPx-1 in influenza A virus-induced lung inflammation.

Methods: Male WT (C57BL/6) and GPx-1-/-mice were infected with 1×104 PFU of HKx31 (H3N2) influenza A virus. Viral titre, BALF and lung inflammation, body weight, pro-inflammatory chemokine (MIP-1α, MIP-2, KC) and protease (MMP-9) expression were assessed 3 and 7 days post infection.

Results: WT mice infected with HKx31 had significantly more BALF total cells, macrophages, neutrophils and lymphocytes at day 3 and 7 than naive WT animals (n=5-8, P<0.05). However, GPx-1-/- mice infected with HKx31 had significantly more BALF total cells and neutrophils than infected WT mice (P<0.05). Viral titre was significantly reduced in GPx-1-/- mice at day 3 compared to WT mice (P<0.05). Infected GPx-1-/- mice lost similar amounts of weight to infected WT mice. Gene expression analysis revealed that GPx-1-/- mice had more whole lung MIP-1α, KC and MIP-2 than WT mice at day 3 and 7. Infected GPx-1-/- mice had more active MMP-9 protease in BALF and greater peribronchial inflammation and bronchial inflammatory cell exudates than infected WT mice.

Conclusions: These data indicate that GPx-1 reduces some aspects of influenza A virus-induced lung inflammation, which may improve overall outcomes of influenza infection.
Phase I trial of docetaxel, oxaliplatin and capecitabine (TEX) in patients with metastatic gastric cancer
Authors: W. Grothe, R. D. Hofheinz, L. Mantovani Loeffler, J. Böhme, D. Arnold, U. Radestock, A. Hochhaus, H. Schmoll
Journal: Journal of Clinical Oncology (2006)

14051 Background: Combination regimens of 3 active drugs have shown promising activity in treatment of metastatic gastric cancer (GC). Docetaxel (D) combined with cisplatin and 5-FU (CF) yielded superior overall survival and response rates when compared to standard CF. However, toxicity profile showed the need for development of less toxic modifications. In this phase I trial, D was combined with oxaliplatin (Ox) and capecitabine (Cape) in order to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) in patients (pts) with metastatic GC. Methods: Pts had to have metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, no prior chemotherapy. Four dose levels were planned planned for the TEX regimen: D 35–40 mg/m 2 , Ox 70 mg/m 2 d1 and d88, with Cape 800–1000 mg/m 2 bid d1–14 q d22. Toxicity was assessed 3-weekly whereas CT scans were repeated 9-weekly. Results: 14 pts were enrolled: 9m/5f, age 64 (42–76) yrs, ECOG PS 1 [0–2]. All pts. had distant metastatis, 10 no gastrectomy. On dose level 1 (D 35 mg/m 2 , Ox 70 mg/m 2 , Cape 800 mg/m 2 ) 3 pts were included initially. 1 pt. had grade 4 bleeding from primary tumor site after 2 nd administration and therefore was excluded. For safety reasons, 6 more pts. were enrolled - without further DLT. On dose level 2 (D 40 mg/m 2 , Ox 70 mg/m 2 , Cape 800 mg/m 2 ), diarrhea and mucositis grade 3 occurred as DLT in 2/2 patients. Level 1 was determined as MTD and 5 more pts were included to a total of 12 with toxicity displayed at the table. Out of 10 pts with measurable disease, 3 had a PR, 4 more had disease stabilization. Median PFS of all pts (5 censored) is 3.9+ (1–9.3+) mos. whereas median OS is not yet reached. Conclusion: TEX can safely be administered without higher graded toxicity in pts with GC. Preliminary efficacy results indicate promising activity that merits further testing in a phase II trial. [Table: see text] [Table: see text]