tbuckley/cabot-search huggingface dataset:
Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC).
Authors: Scott Joseph Antonia, Julie R. Brahmer, Scott N. Gettinger, Laura Quan Man Chow, Rosalyn A. Juergens, Frances A. Shepherd, Scott Andrew Laurie, David E. Gerber, Jonathan Wade Goldman, Yun Shen, Christopher Harbison, Suresh Alaparthy, Allen C. Chen, Hossein Borghaei, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2014)

8113 Background: First-line PT-DC has demonstrated 1-yr overall survival (OS) rates of up to 54% in NSCLC; however, there remains a need for therapies with improved long-term survival. We report an updated analysis of a phase I multi-cohort study evaluating nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, plus PT-DC in chemotherapy-naive patients (pts) with advanced NSCLC, with longer follow up and additional pts. Methods: Pts (N=56) with advanced NSCLC were assigned based on histology to 4 cohorts to receive nivolumab 10 mg/kg IV Q3W plus concurrent IV gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2 (squamous [sq]) or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (non-sq), or nivolumab 5 or 10 mg/kg IV Q3W plus IV paclitaxel 200 mg/m2+ carboplatin AUC6 (sq + non-sq), in a phase I dose de-escalation trial to assess dose-limiting toxicity (DLT). PT-DC was given for 4 cycles, followed by nivolumab until progression or unacceptable toxicity. Objective response rate (ORR) was assessed by RECIST 1.1. Results: No DLTs were seen during the first 6 wks of treatment. Grade 3-4 treatment-related adverse events were reported in 45% of pts (25-73% across arms), including pneumonitis (4 pts, 7%; managed by protocol algorithm), and fatigue and acute renal failure (3 pts [5%] each). Across arms, ORR (≥10 months follow up) was 33–50% and progressive disease (PD) as best overall response (BOR) was infrequent (Table). One-year OS rates were 59–87% (Table). Conclusions: Nivolumab combined with standard PT-DC regimens used for first-line treatment of NSCLC demonstrated antitumor activity, with encouraging 1-yr OS and an acceptable tolerability profile. Clinical trial information: NCT01454102. Nivo 10 + gem/cis Sq Nivo 10 + pem/cis Non-sq Nivo 10 + pac/carb Sq + Non-sq Nivo 5 + pac/carb Sq + Non-sq N 12 15 15 14 ORR, a n (%) 4 (33) 7 (47) 7 (47) 7 (50) Median duration of response (Kaplan-Meier),a wk (range) 20.9 (12.1–41.7+) 32.0 (13.1–42.1+) 25.6 (11.4+–39.0+) Not reached (11.4–37.3+) PD as BOR, n (%) 0 0 3 (20) 1 (7) PFS rate wk 24, % 36 71 38 57 1-yr OS, % 59 87 59 Insufficient follow-up a Confirmed responses only. + Ongoing.
Abstract 4506: Identification of druggable transcriptional outliers in urothelial carcinoma
Authors: Bishoy S. M. Faltas, Rohan Bareja, Ethan Shelkey, Rebecca Mayer, Andrea Sboner, Mark A. Rubin, Olivier Elemento
Journal: Cancer Research (2016)

Abstract Background: Urothelial carcinoma (UC) is a major public health problem affecting new 75,000 patients and resulting in 15,000 deaths annually. Despite a variety of genetic and epigenetic alterations described in UC, few therapeutically exploitable drivers have been identified and validated. We hypothesized that transcriptional outliers from primary tumor biopsies could reveal such therapeutically exploitable weaknesses. Identification of these druggable outliers would be critical for individualized therapy of patients with UC. Methods: In order to identify transcriptional outliers we calculated Z-scores for a set of 72 druggable cancer-related genes from RNA sequencing data from our Institute of Precision Medicine (IPM) cohort of advanced platinum-resistant UC. We performed similar outlier analyses on The Cancer Genome Atlas (TCGA) cohort of UC and the Cancer Cell Line Encyclopedia (CCLE) database of urothelial cell lines. Common outliers between IPM and CCLE datasets or between TCGA and CCLE datasets were nominated for further in-vitro testing. Sensitivity scores of cell lines for 130 drugs were extracted from the publicly available cell line browser database and the variance these sensitivity scores across (640) cell lines was calculated. The drugs targeting the outlier genes (real sensitivity z-score) were compared to the mean z-scores of randomly chosen drugs associated with those genes (control sensitive z-score). To investigate the mechanisms underlying comparison of outliers methylation patterns of the promoter regions of outlier genes were examined. Results: 6 druggable outlier genes were common between IPM and CCLE cohorts, and 15 outlier genes between CCLE and TCGA cohorts. Common outliers included FGFR3, KIT, BCL2, ABL1, and SMO. The presence of outlier genes in cell lines correlated with higher sensitivity to drugs predicted to target these genes in comparison to randomly selected drugs (p&amp;lt;0.05). In vitro cell viability assays confirmed sensitivity of RT112 and RT4 cell lines to Dovitinib, an FGFR3 inhibitor as predicted by our algorithm. Outlier genes were frequently involved in gene fusions, amplification or DNA hypomethylation (p&amp;lt;0.02). Conclusions: Identification of druggable transcriptional outliers can elucidate novel oncogenic dependencies and aid in selecting precision therapies for UC patients. Citation Format: Bishoy S. M. Faltas, Rohan Bareja, Ethan Shelkey, Rebecca Mayer, Andrea Sboner, Mark A. Rubin, Olivier Elemento. Identification of druggable transcriptional outliers in urothelial carcinoma. [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 4506.
Effects of drugs on preventing recurrent myocardial infarction in patients with healed myocardial infarction
Authors: Kinji Ishikawa, Ken Kanamasa, Junkichi Hama, Iwao Ogawa, Toshihiko Takenaka, Takeo Naito, Noriaki Kamata, Shoji Nakai, Tadahiko Yamamoto, Miki Oyaizu, Akio Kimura, Kentaro Yamamoto, Ryo Katori
Journal: Circulation (1995)
Abstract 1666: Biomarkers for early detection of radiation nephropathy
Authors: Feifei Song, Jidhin Jacob, Arnab Chakravarti, Naduparambil K. Jacob
Journal: Cancer Research (2016)

Abstract Purpose/Background: Chronic kidney disease is among the common late effects detected in patients receiving chemotherapy and/or radiotherapy. Currently, there are no biomarkers that allow detection of normal tissue toxicity in late responding organs such as kidney. Developing predictive biomarkers could help identify individuals that are at high risk for close follow-up and prophylactic treatments. Our studies show that miRNAs detectable in cell-free body fluids can be developed as biomarkers of acute radiation syndromes. In the present study, we sought to investigate the potential of serum and urine miRNAs as indicators of radiation induced kidney damage in rodent models. Methods and Results: An amplification-free hybridization based nCounter assay was optimized for evaluating the changes of miRNAs in body fluids. Comparison of cell-free miRNAs in urine as well as serum, collected from control versus irradiated mice, enabled us to identify candidate biomarkers that are potential indicators of radiation response. Over 40 miRNAs were detectable in urine samples collected from mice and over 80 miRNAs were detectable in serum. Molecules such as miR-1224, miR-804, miR-714 and miR-709 showed significant increase in their urine level after radiation, which peaked 6-8 hours after exposure to acute doses. On the other hand, markers such as miR-378 that are also abundant in urine did not show significant change after radiation, hence serving as an internal control. Comparison of urinary response in mice exposed to 2, 4, 6 and 8 Gy TBI revealed good dose response. Furthermore, the same markers exhibited a dose and time dependent changes following exposure to fractionated myeloablative regimen (6 × 2 Gy, bid) that is commonly used in leukaemia patients, prior to stem cell transplantation. Specifically, two of these biomarkers, miR-714 and miR-1224 exhibited a dose dependent increase in their serum level after fractionated or acute single dose exposure. In-situ hybridization displayed an overall increase in signals of miR-1224 and miR-714 at outer medulla after radiation. Increased signals detected in tubular epithelial cells indicate the possible tubular origin of the urinary miRNAs that are responsive to radiation. Conclusion: We have developed a panel of miRNAs for non-/minimally invasive detection of radiation response in kidney. Several of the urinary miRNA biomarkers exhibited a dose and time dependent changes, suggesting their potential as biomarkers for non-invasive evaluation of radiation response in organs such as kidney for which early detection of damage is a major challenge. Citation Format: Feifei Song, Jidhin Jacob, Arnab Chakravarti, Naduparambil K. Jacob. Biomarkers for early detection of radiation nephropathy. [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 1666.
Abstract 4950: Collagen, type I, alpha 1 (COL1A1): a potential urinary biomarker that can distinguish between benign prostate hyperplasia and localized prostate cancer
Authors: Andrej Jedinak, Camille Vuichoud, Andrew El-Hayek, Kevin R. Loughlin, Marsha A. Moses
Journal: Cancer Research (2016)

Abstract Benign prostate hyperplasia (BPH) is the most frequent benign disease among men worldwide and its incidence increases with age. Prostate cancer (PCa) and BPH share similar symptoms and an elevated serum prostate-specific antigen (PSA) can be observed with either benign or malignant growth of the prostate. It is the demographic overlap of BPH and PCa, and the lack of discrimination between these two prostate diseases by PSA, that defines the diagnostic dilemma faced by clinicians when treating prostate disease. The goal of the current study was to identify novel non-invasive, biomarkers that can distinguish between BPH and PCa. We utilized iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) mass spectrometry techniques to sensitively and accurately identify the urinary proteome of men with BPH vs. men with PCa. We then performed functional enrichment analysis and pathways enrichment analysis of these proteins using Ingenuity Pathway Analysis (IPA) tools to determine differentially expressed pathways and functions in PCa as compared to BPH. Network analysis identified differences in a number of signaling molecules including ERK1/2, TGFβ, PI3K, p38 MAPK and NFκB, with a high degree of interactivity. Protein expression was validated by immunoblot analyses using monospecific antibodies. Here, we focused on collagen, type I, alpha 1 (COL1A1), one of a number of extracellular matrix-associated proteins detected. We found that COL1A1 was significantly (P &amp;lt; 0.001) elevated in the urine of patients diagnosed with early or localized PCa but not in the urine of men with BPH. Complementary studies were conducted on human BPH and PCa cells. Our data suggest that COL1A1 may represent a novel non-invasive biomarker that can discriminate between BPH and early PCa. (Supported by The Ellison Foundation) Citation Format: Andrej Jedinak, Camille Vuichoud, Andrew El-Hayek, Kevin R. Loughlin, Marsha A. Moses. Collagen, type I, alpha 1 (COL1A1): a potential urinary biomarker that can distinguish between benign prostate hyperplasia and localized prostate cancer. [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 4950.
Knowledge and perceptions of breast cancer risk in adolescent girls at high risk and population risk for breast cancer.
Authors: A. R. Bradbury, L. J. Patrick-Miller, L. Tuchman, C. Moore, P. Rauch, C. B. Sands, H. Schmidheiser, M. B. Daly
Journal: Journal of Clinical Oncology (2010)

e12037 Background: Evidence suggests that early events may influence or modify adult breast cancer (BC) risk. Little is known about how adolescents from hereditary BC families understand, respond to and incorporate hereditary risk. Methods: Seventeen 11-17 YO girls (13 high risk, HR; 4 population risk, PR) completed semi-structured interviews evaluating knowledge and perceptions of BC risk and health behaviors (anticipated enrollment: 35). Descriptive responses were coded and response proportions utilized to summarize findings. Results: Genetic predisposition (n = 11) and family history (n = 6) were the most frequently reported reasons women develop BC. All girls indicated that BC can be inherited from the mother's family; while 12/17 indicated risk can be inherited from the father's family. The majority of girls (12/13 HR, 2/4 PR) reported perceived self risk for adult BC to be higher than other girls their age. Participants' perceived numerical BC risk in the general population (GP), participant's mother and self varied widely (GP 1%-60%, mom 4%-90%, self 6%-75%). 41% (7/17) girls reported the youngest age of BC development for themselves was ≤ 25 YO (range, 11-25 YO). All daughters indicated that BC screening could help women, including themselves, detect BC early. Three girls 16-17YO (2HR, 1PR) indicated that they perform self-breast exam. The most frequently reported sources of information for BC included mother (16), media (12), doctors (10) and school (9). Frequently reported sources of information about BC risk included mother (9) and internet (3). Conclusions: Many HR girls, and some PR girls, perceive themselves to be at increased risk for adult BC. Some adolescent girls have misperceptions, suggesting potential areas for educational intervention. Further research evaluating knowledge and perceptions of BC risk and numeracy skills throughout adolescent development and their impact on psychosocial, health and risk behaviors, including factors that mediate and moderate these relationships, could lead to innovative interventional strategies to optimize psychosocial responses to cancer risk and promote health behaviors during adolescence that will reduce adult breast cancer risk. No significant financial relationships to disclose.
Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine
Authors: Shinhee Park, Sunny Lihua Cheng, Julia Yue Cui
Journal: Acta Pharmaceutica Sinica B (2016)

Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type and Car −/− mice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice, Car mRNA was down-regulated by TCPOBOP in liver and duodenum. Car −/− mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs ( Cyp2b10, Cyp3a11, Aldh1a1, Aldh1a7, Gsta1, Gsta4, Gstm1-m4, Gstt1, Ugt1a1, Ugt2b34, Ugt2b36 , and Mrp2–4 ) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical. Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR) is known as an important xenobiotic-sensing transcription factor in liver. The present study used wild-type and CAR -null mice and showed that many critical drug-metabolizing enzymes and transporters are also bona fide CAR-target genes in intestine.
The Role of Exercise in a Weight-Loss Program on Clinical Control in Obese Adults with Asthma. A Randomized Controlled Trial
Authors: Patricia D. Freitas, Palmira G. Ferreira, Aline G. Silva, Rafael Stelmach, Regina M. Carvalho-Pinto, Frederico L. A. Fernandes, Marcio C. Mancini, Maria N. Sato, Milton A. Martins, Celso R. F. Carvalho
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Clinical control is difficult to achieve in obese patients with asthma. Bariatric surgery has been recommended for weight loss and to improve asthma control; however, the benefits of nonsurgical interventions have been poorly investigated.To examine the effect of exercise training in a weight-loss program on asthma control, quality of life, inflammatory biomarkers, and lung function.Fifty-five obese patients with asthma were randomly assigned to either a weight-loss program plus exercise (WL + E group, n = 28) or a weight-loss program plus sham (WL + S group, n = 27), where the weight-loss program included nutrition (caloric restriction) and psychological therapies. The WL + E group incorporated aerobic and resistance muscle training, whereas the WL + S group incorporated breathing and stretching exercises.The primary outcome was clinical improvement in asthma control over 3 months. Secondary outcomes included quality of life, lung function, body composition, aerobic capacity, muscle strength, and inflammatory/antiinflammatory biomarkers. After 3 months, 51 patients were analyzed. Compared with the WL + S group, the WL + E group demonstrated improved clinical control scores (median [25th to 75th percentile], -0.7 [-1.3 to -0.3] vs. -0.3 [-0.9 to 0.4]; P = 0.01) and greater weight loss (mean ± SD, -6.8% ± 3.5 vs. -3.1% ± 2.6; P < 0.001) and aerobic capacity (median [25th to 75th percentile], 3.0 [2.4 to 4.0] vs. 0.9 [-0.3 to 1.3] ml O2 × kg-1 × min-1; P < 0.001). These improvements in the WL + E group were also accompanied by improvements in lung function, antiinflammatory biomarkers, and vitamin D levels, as well as reductions in airway and systemic inflammation.Adding exercise to a short-term weight-loss program should be considered as a useful strategy for achieving clinical control of asthma in obese patients. Clinical trial registered with www.clinicaltrials.gov (NCT 02188940).
Abstract 779: The role of exosome-mediated cell-cell communication in inducing phenotypic changes
Authors: Mingyang Lu, Michela Capello, Satyendra C. Tripathi, Herbert Levine, Eshel Ben-Jacob, Samir M. Hanash, José Onuchic
Journal: Cancer Research (2016)

Abstract A new class of intercellular communication has recently emerged that involves transfer of exosomes, especially during the interactions between tumor and the immune system. However, the advantage of exosome-mediated cell-cell communication over direct cell to cell communication mechanisms or through soluble factors is unclear. We have performed mass spectrometry based proteomic profiling of exosomes isolated from pancreatic cancer cell lines, for the exosome cell surface and for the protein cargo. The resulting profiles were compared with proteomic profiles of corresponding cell lysates. We uncovered substantial enrichment in protein pairs in exosomes across cell lines but not in cell lysates, suggestive of a mechanism of exosome-based protein sorting and packaging that favor specific protein combinations. Stochastic simulations and analytical analysis provide supportive evidence that exosomes enable recipient cells to rewire gene regulatory networks to induce robust phenotypic transitions among different gene states. Moreover, from the simulation of two-way exosome-mediated communication of two cell types, we show that cells could achieve synchronized decision making through exosomes. Our integrative approach provides new insights into unique features of exosome-mediated cell-cell communication. Citation Format: Mingyang Lu, Michela Capello, Satyendra C. Tripathi, Herbert Levine, Eshel Ben-Jacob, Samir M. Hanash, José Onuchic. The role of exosome-mediated cell-cell communication in inducing phenotypic changes. [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 779.
Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: national population based cohort study
Authors: Samuel Adamsson Eryd, Soffia Gudbjörnsdottir, Karin Manhem, Annika Rosengren, Ann-Marie Svensson, Mervete Miftaraj, Stefan Franzén, Staffan Björck
Journal: BMJ (2016)

<b>Objectives</b>&nbsp;To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease. <b>Design</b>&nbsp;Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years. <b>Setting</b>&nbsp;861 Swedish primary care units and hospital outpatient clinics. <b>Participants</b>&nbsp;187 106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease. <b>Main outcome measures</b>&nbsp;Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for different levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates. <b>Results</b>&nbsp;The group with the lowest systolic blood pressure (110-119 mm Hg) had a significantly lower risk of non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% confidence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality. <b>Conclusions</b>&nbsp;Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment.