tbuckley/cabot-search huggingface dataset:
Can smoking lead to delay in diagnosis of prostate cancer?
Authors: Amit Mohan Algotar, Roxanna Behnejad, M Suzanne Stratton, Steven Stratton
Journal: Journal of Clinical Oncology (2015)

e16011 Background: Measurement of serum prostate specific antigen (PSA) is an important marker for diagnosis of prostate cancer (PCa). Hence any variable affecting its levels could potentially have tremendous impact on it diagnosis. Current data are inconclusive regarding the association between smoking and PSA. Hence, we conducted a study to investigate this relationship using data from men enrolled in a phase 3 chemoprevention trial. Methods: Data were obtained from 699 men participating in a randomized Phase 3 clinical trial of selenized yeast supplementation on incidence of PCa. During the course of this trial, 73 men were diagnosed with PCa. Results: As compared to non-smokers, smokers demonstrated a statistically significant inverse association with PSA (7.67 & 6.38 ng/ml, p = 0.007). The effect size increased among non-aspirin users (11.9 & 10.26 ng/ml, p = 0.003) and among men diagnosed with PCa during the course of the study (11.83 & 7.13 ng/ml, p = 0.068). The effect size is strongest among men diagnosed with PCa and those who report not taking aspirin (13.7 & 7.2 ng/ml, p = 0.05). Using the standard PSA level of 4ng/ml as a cutoff for ordering a prostate biopsy, 10.4% of smokers in this study may not have been clinically indicated for a prostate biopsy; and thus possibly misclassified as negative for PCa. 40% of smokers demonstrated high grade disease (Gleason score ≥ 7) as compared to 25% of non-smokers. Conclusions: In this study, smoking was inversely associated with PSA. This association is stronger among men not taking aspirin, men diagnosed with PCa, and men with PCa not taking aspirin. The negative association of smoking with PSA could potentially be due to effects on testosterone or through other molecular mechanisms, such as oxidative stress, and may not reflect the effect of smoking on the underlying carcinogenic process. Hence, physicians need to be cautious when interpreting PSA results for smokers to minimize the risk of delayed PCa diagnosis.
In vitro and in vivo evaluation of an electrospun-aligned microfibrous implant for Annulus fibrosus repair
Authors: Maude Gluais, Johann Clouet, Marion Fusellier, Cyrille Decante, Constantin Moraru, Maeva Dutilleul, Joëlle Veziers, Julie Lesoeur, Dominique Dumas, Jérôme Abadie, Antoine Hamel, Eric Bord, Sing Yian Chew, Jérôme Guicheux, Catherine Le Visage
Journal: Biomaterials (2019)
Studies on Digitalis
Authors: RICHARD L. KAHLER, RONALD H. THOMPSON, ELSWORTH R. BUSKIRK, ROBERT L. FRYE, EUGENE BRAUNWALD
Journal: Circulation (1963)

Three patients with acquired valvular heart disease and cardiac enlargement who were able to perform normal everyday activity without difficulty in the absence of digitalis therapy were exercised while receiving a placebo and again while receiving digoxin. Digoxin administration did not produce a significant change in body weight or in the subjective condition of the individuals. Varying degrees of exercise were performed on a treadmill in a Metabolic Chamber and oxygen consumption was measured cotinuously before, during, and after the period of exercise, utilizing a continuous gas flow paramagnetic oxygen analyzer. The oxygen debt that developed during digoxin administration was compared to that observed during placebo administration. In all patients the oxygen debt was smaller during the period of digoxin administration, although the external work performed was identical. In the first patient, following a 7-minute walk, the oxygen debt was 53 per cent more and following a 10-minute walk it averaged 40 per cent more while not receiving digoxin than when receiving this drug. In the second subject the oxygen debt following a 7-minute walk was 34 per cent more and following 10-minute walk it averaged 74 per cent more when he was not receiving digoxin than when receiving this drug. In the third subject the oxygen debts were 46 per cent and 41 per cent greater following 10- and 15- minute walks respectively, when she was not receiving digoxin. The accumulation of a smaller oxygen debt following exercise while these subjects were receiving digoxin indicates that the functional status of their circulatory system was improved by the drug. It would appear that digitalis administration is beneficial to at least some patients who have cardiac disease and enlarged hearts and some decrease in cardiac reserve without signs or symptoms of heart failure.
Clinical BET Inhibitor RG6146 Demonstrates Potent and on-Target Activity in Pre-Clinical Models of Hematological Malignancy and Combines with Anti-CD20 and BCL-2 Inhibition to Provide Superior Efficacy
Authors: Astrid Rueflibrasse, Thomas Friess, Stephanie Lechner, Lisa Wellinger, Jurriaan Brouwer, William E. Pierceall
Journal: Blood (2017)
Течение пептических гастродуоденальных язв на фоне коморбидного сахарного диабета
Authors: O.V. Syniachenko, M.V. Ermolaeva, N.V. Gmoshinskiy
Journal: GASTROENTEROLOGY (2019)

Актуальность. Коморбидный сахарный диабет (СД) 2 типа ухудшает течение пептических язв желудка (ЯЖ) и двенадцатиперстной кишки (ЯК), а также эффективность лечебных мероприятий, при этом является независимым фактором риска развития гастродуоденальных кровотечений. Серопозитивность больных СД по носительству хеликобактерной инфекции составляет 50–60 %, которая регистрируется на 90 % чаще, чем в общей популяции. Цель: проанализировать характер течения гастродуоденальных язв на фоне коморбидного СД, выделить прогностические критерии. Материалы и методы. Под наблюдением находилось 1392 пациента с ЯЖ и ЯК. СД диагностирован у 215 больных (17 %), которые включены в основную группу, а остальные (83 %) составили группу сравнения. Соотношение ЯК : ЯЖ : ЯЖ + ЯК в группе с СД составило 6 : 2 : 1, а среди остальных обследованных — 10 : 4 : 1, соотношение мужчин и женщин в первой группе было 2 : 1, а во второй — 3 : 1, средний возраст больных — соответственно 52 года, длительность манифестации пептических язв — 6 лет. Индекс тяжести болезни составил 6 о.е., показатель глюкозы в крови — 10 ммоль/л, гликозилированного гемоглобина (HbA1c) — 8 %, инсулина — 25 мкМЕ/мл, коэффициента инсулинорезистентности (HOMA) — 12 о.е. Легкая, средней тяжести и тяжелая степень СД соотносились как 1 : 2 : 1. Результаты. СД относится к факторам риска тяжелого течения ЯЖ и ЯК, определяет локализацию ульцерации, размеры изъязвлений, развитие рефлюкс-эзофагита и дуоденогастрального рефлюкса, изменений физико-химических адсорбционно-реологических свойств желудочного сока и тяжесть гистологических повреждений слизистой оболочки желудка, которые зависят от характера инсулинорезистентности. Коморбидный СД является фактором риска тяжелого течения гастродуоденальных кровотечений, влияет на кардиоваскулярные показатели гемодинамики (уровни среднего артериального давления, периферического сосудистого сопротивления, объема циркулирующей крови) и определяет 60-часовую выживаемость больных, а к прогнознегативным критериям относятся уровни гликемии, HbA1c и НОМА. Выводы. Коморбидный СД значительно ухудшает течение пептических гастродуоденальных язв и является фактором риска их рецидивов.
PROPEL: A randomized, phase III trial evaluating the efficacy and safety of olaparib combined with abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Noel W. Clarke, Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Dingwei Ye, Joaquin Mateo, Carsten Dietrich Goessl, Jinyu Kang, Sherry Liu, Fred Saad
Journal: Journal of Clinical Oncology (2019)

TPS340 Background: A Phase II trial showed olaparib (tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; hazard ratio 0.65, 95% CI 0.44–0.97, P=0.034) in patients (pts) with mCRPC in the second-line metastatic setting who received prior docetaxel (Clarke et al. Lancet Oncol 2018). Treatment benefits were achieved irrespective of homologous recombination repair (HRR) mutation status, suggesting potential synergy between the two treatments that could impact a broader patient population. PROpel (EudraCT: 2018-002011-10) is the follow-on study to this, and the first Phase III trial to assess a PARP inhibitor in combination with abiraterone as first-line treatment in a genetically unselected mCRPC pt population. Methods: PROpel is a double-blind, placebo-controlled, international, multicenter study of pts randomized (1:1), as for the Phase II trial, to abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) plus either olaparib (tablets, 300 mg bid) or placebo. Pts must not have received prior chemotherapy, new hormonal agents or other systemic treatment at mCRPC stage (except docetaxel at metastatic hormone-sensitive prostate cancer stage [mHSPC]). Randomization is stratified according to site of metastases (bone only vs visceral vs other) and docetaxel treatment at mHSPC stage (yes, no). The primary endpoint is investigator-assessed rPFS (RECIST v1.1 [soft tissue] and Prostate Working Cancer Group 3 [PCWG-3 criteria; bone]). Secondary objectives include time to first subsequent therapy or death, time to pain progression, overall survival, and health-related quality of life. Safety and tolerability will also be described. Exploratory endpoints include HRR subgroup analyses to confirm that efficacy is independent of HRR status. Screening across ~200 sites in 20 countries is being conducted to identify a target sample of ~720 pts. Enrollment is expected to begin in October 2018. (Study 8, NCT01972217). Clinical trial information: NCT03732820.
RNAseq in addition to next generation sequencing in advanced genitourinary cancers reveals transcriptomic silencing of DNA mutations: Implications for resistance to targeted therapeutics.
Authors: Jacob J. Adashek, Shumei Kato, Rahul Parulkar, Christopher Szeto, Sandeep K. Reddy, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2019)

583 Background: Next generation sequencing (NGS) for advanced tumors is becoming more routine. However, not all patients respond to precision matched treatments. We hypothesized that one potential reason for treatment failure with targeted therapy could be discrepancies between DNA alterations and RNA expression. Methods: Tumor samples from patients with metastatic kidney, bladder, and prostate cancer were analyzed by whole exome or whole genome NGS and RNA sequencing (CLIA-certified laboratory; NantOmics LLC, Santa Cruz, CA). Only known pathogenic driver alterations were analyzed in the current study. Results: Of 45 patients, 10 had kidney cancer, 18 had bladder cancer; and 17 had prostate cancer. Median age was 66 years (range, 28 - 86). The most commonly altered genes were TP53 (35.6% [16/45]), PIK3CA (15.6% [7/45]), FGFR3 (11.1% [5/45]), ALK (8.9% [4/45]), and ATM (8.9% [4/45]). In total, 86 pathogenic DNA alterations were identified; 17 of these (19.8%) were not observed at the RNA level. Among 45 patients, 31.1% (14/45) had ≥1 DNA alteration that was not expressed at the RNA level. Discordance between DNA and RNA was seen in 40% of patients with kidney cancer (4/10), 28% of patients with bladder cancer (5/18), and 29% with prostate cancer (5/17). Examples of genes that had pathogenic DNA alterations not seen at the RNA level included ALK (four discordant cases), KDR (three discordant cases) and GNAS (one discordant case). On the other hand, alterations involving certain genes showed 100% concordance between DNA and RNA: TP53 [N = 16], PIK3CA [N = 7], and FGFR3 [N = 5]). Conclusions: A significant number of patients with genitourinary tumors had DNA alterations that are silenced at the RNA level (19.8%). Transcriptomic silencing merits additional investigation as a mechanism that could mediate resistance to therapeutics targeted at cognate alterations.
A phase III trial of docetaxel versus docetaxel and radium-223 (Ra-223) in patients with metastatic castration-resistant prostate cancer (mCRPC): DORA.
Authors: Michael J. Morris, Ronald De Wit, Nicholas J. Vogelzang, Scott T. Tagawa, Celestia S. Higano
Journal: Journal of Clinical Oncology (2020)

TPS5594 Background: Ra-223, a bone-targeted alpha therapy, prolongs survival in patients (pts) with symptomatic mCRPC to bone. Docetaxel targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. We hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. We previously determined the dose and schedule of co-administering Ra-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have improved declines in prostate specific antigen (PSA) and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone. We are now conducting a phase III study to determine the clinical benefit of the regimen. Methods: Randomization (1:1) of 738 men with mCRPC to docetaxel or docetaxel + Ra-223 is planned with a projected hazard ratio for treatment effect (15 vs 20 months median survival) of 0.75. Pts with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0-1 and normal organ function. Key exclusion criteria are: use of anticancer therapy ≤4 weeks (wks) before randomization and use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 wks). Subjects receive docetaxel 75 mg/m 2 IV q3w for 10 doses or docetaxel 60 mg/m 2 IV q3w for 10 doses + Ra-223 55 kBq/kg IV q6w for 6 doses. The primary endpoint is overall survival. Secondary and exploratory endpoints include: radiographic progression-free survival, symptomatic skeletal event-free survival, safety, markers of bone metabolism, alterations in circulating tumor cells and DNA, detection of androgen-receptor splice variant 7, changes in automated bone scan index (aBSI), and assessment of patient-reported outcome instruments (FACT-P, Brief Pain Inventory, Brief Fatigue Inventory). The study is open at 25 sites in the US and Netherlands, sponsored by Memorial Sloan Kettering Cancer Center, and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT03574571 .
RAS and TP53, Not NOTCH1, Can Predict Survival in Adults with Acute T-Cell Lymphoblastic Leukemia Treated with Hypercvad
Authors: Ali Sakhdari, Sanam Loghavi, Rashmi Kanagal-Shamanna, C. Cameron Yin, Zhuang Zuo, Mark Routbort, Keyur P. Patel, Raja Luthra, L. Jeffrey Medeiros, Chi Young Ok
Journal: Blood (2018)
Regulation of miRNA Biogenesis and Histone Modification by K63-Polyubiquitinated DDX17 Controls Cancer Stem-like Features
Authors: Shih-Han Kao, Wei-Chung Cheng, Yi-Ting Wang, Han-Tsang Wu, Han-Yu Yeh, Yu-Ju Chen, Ming-Hsui Tsai, Kou-Juey Wu
Journal: Cancer Research (2019)

Markers of cancer stemness predispose patients to tumor aggressiveness, drug and immunotherapy resistance, relapse, and metastasis. DDX17 is a cofactor of the Drosha-DGCR8 complex in miRNA biogenesis and transcriptional coactivator and has been associated with cancer stem-like properties. However, the precise mechanism by which DDX17 controls cancer stem-like features remains elusive. Here, we show that the E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 under hypoxia to control stem-like properties and tumor-initiating capabilities. Polyubiquitinated DDX17 disassociated from the Drosha-DGCR8 complex, leading to decreased biogenesis of anti-stemness miRNAs. Increased association of polyubiquitinated DDX17 with p300-YAP resulted in histone 3 lysine 56 (H3K56) acetylation proximal to stemness-related genes and their subsequent transcriptional activation. High expression of HectH9 and six stemness-related genes (BMI1, SOX2, OCT4, NANOG, NOTCH1, and NOTCH2) predicted poor survival in patients with head and neck squamous cell carcinoma and lung adenocarcinoma. Our findings demonstrate that concerted regulation of miRNA biogenesis and histone modifications through posttranslational modification of DDX17 underlies many cancer stem-like features. Inhibition of DDX17 ubiquitination may serve as a new therapeutic venue for cancer treatment. SIGNIFICANCE: Hypoxia-induced polyubiquitination of DDX17 controls its dissociation from the pri-miRNA-Drosha-DCGR8 complex to reduce anti-stemness miRNA biogenesis and association with YAP and p300 to enhance transcription of stemness-related genes.
Level of Evidence and Ethical Considerations for Locoregional Treatments in Metastatic Cervical Cancer
Authors: Antoine Schernberg, Christine Haie-Meder, Cyrus Chargari
Journal: JAMA Oncology (2019)

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Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in <i>KRAS</i>-Mutant Pancreatic and Colorectal Cancer
Authors: Jörn Weisner, Ina Landel, Christoph Reintjes, Niklas Uhlenbrock, Marija Trajkovic-Arsic, Niklas Dienstbier, Julia Hardick, Swetlana Ladigan, Marius Lindemann, Steven Smith, Lena Quambusch, Rebekka Scheinpflug, Laura Depta, Rajesh Gontla, Anke Unger, Heiko Müller, Matthias Baumann, Carsten Schultz-Fademrecht, Georgia Günther, Abdelouahid Maghnouj, Matthias P. Müller, Michael Pohl, Christian Teschendorf, Heiner Wolters, Richard Viebahn, Andrea Tannapfel, Waldemar Uhl, Jan G. Hengstler, Stephan A. Hahn, Jens T. Siveke, Daniel Rauh
Journal: Cancer Research (2019)

Abstract Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. Significance: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.
Abstract P358: Association of Antidepressant Medication Type With the Incidence of Cardiovascular Disease in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Zakaria Almuwaqqat, Maan Jokhadar, Faye Norby, Pamela Lutsey, Wesley T O’Neal, Amanda Seyerle, Elsayed Z Soliman, Lin Y Chen, Douglas J Bremner, Viola Vaccarino, Amit J Shah, Alvaro Alonso
Journal: Circulation (2019)

Background: Although antidepressant medications (ADM) are effective in treating depression, a well-established cardiovascular risk factor, they are associated with autonomic dysfunction, also linked to the future risk of cardiovascular disease (CVD). It is unclear if a certain type of ADM’s is associated with less CVD risk than others. We hypothesized that selective serotonin reuptake inhibitors (SSRI) are associated with reduced hazards of atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI) and ischemic stroke (IS) as compared to non-SSRI ADM’s. Methods: We studied 2027 participants from the Atherosclerosis Risk in Communities (ARIC) Study (mean age 63 ± 10 years; 29% men; 78% white) who self-reported ADM use during at least one of the five study visits (1987 through 2013). Participants were classified as SSRI users (47%) vs non-SSRI users (53%). Those who never used ADM’s were excluded due to the concern of unmeasured confounding by their underlying depression. CVD events were adjudicated based on hospital records, participant and physician interviews, and death certificates, using validated criteria. Cox regression adjusted for sociodemographic and clinical variables (sex, age, race, center, level of education, cigarette smoking, alcohol use, BMI, use of antihypertensive medications, diabetes, systolic blood pressure, diastolic blood pressure, aspirin, and calendar year of AD initiation) were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of CVD by type of ADM. Results: Participants were followed up from ADM initiation up to 2016 for a median of 13.5 years. In this sample we identified a total of 329 AF events, 366 HF events, 198 MI events and 134 IS events. In multivariable Cox regression models, SSRI use was not significantly associated with hazards of AF, HF, MI and IS, when compared to non-SSRI ADMs (HR= 1.11, 95%CI 0.88-1.40 for AF; HR= 0.93, 95%CI 0.72-1.20 for HF; HR= 0.91, 95%CI, 0.65-1.27 for MI; and HR= 1.02, 95%CI 0.67-1.56 for IS). Conclusion: In a community-based sample of individuals using ADM’s, ADM class (SSRI vs non-SSRI) was not associated with significantly different risk of incident CVD. These results do not provide evidence supporting the use of a particular ADM over another in relation to CVD risk.