tbuckley/cabot-search huggingface dataset:
Abstract P324: Body Mass Index, Walking Pace, and Risk of Coronary Heart Disease: a Mendelian Randomization and Mediation Analysis
Authors: Tao Zhou, Dianjianyi Sun, Xiang Li, Mengyu Fan, Yoriko Heianza, JoAnn Manson, Lu Qi
Journal: Circulation (2019)

Introduction: Being obese has been related to changes in physical fitness, such as pace-speed declination, which was recently associated with increased coronary heart disease (CHD) risk. The causal link between obesity, walking pace declination, and CHD remains to be established. Hypothesis: High BMI is causally related to slower walking pace, and the relationship between high BMI and CHD that is mediated by altered walking pace. Methods: Data form UK biobank including 408,836 white British participants (enrolled from 2006 to 2010) was used in this study. The usual walking pace was self-reported as slow, steady/average, and brisk, among 352,663 participants with 3,634 CHD cases (enrolled from 2006 to 2010 and followed up to 2016). The causal relation between BMI and walking pace was assessed by Mendelian randomization analysis using 97 BMI related single-nucleotide polymorphisms. A further mediation analysis was performed to assess the association between BMI, walking pace, and incident CHD. Results and Conclusions: In Mendelian randomization analysis performed among 408,836 individuals in the UK Biobank (baseline mean [SD] age, 56.8 [8.0] years; 54.1% (221,196 of 408,836) women), we found a significant causal relationship between genetically instrumented higher BMI and slower walking pace (odds ratio: 1.58, 95% CI: 1.45-1.71, per 1 SD increase in BMI), independent of age, sex, socioeconomic status, alcohol intake, and smoking. In mediation analysis, we found that slow and average walking pace was estimated to mediate 29% and 19% of the association between BMI and incident CHD, respectively, compared with brisk walking pace (p&lt;.001). In conclusion, our results indicate that higher BMI may be causally related to a slower walking pace, which mediates a significant proportion of the association between high BMI and CHD risk.
Preclinical Evaluation of MEDI2228, a BCMA-Targeting Pyrrolobenzodiazepine-Linked Antibody Drug Conjugate for the Treatment of Multiple Myeloma
Authors: Krista Kinneer, John Meekin, Reena Varkey, Xiaodong Xiao, Haihong Zhong, Shannon Breen, Elaine Hurt, Suneetha Thomas, Matt Flynn, Paul Hynes, Binyam Bezabeh, Cui (Tracy) Chen, Leslie Wetzel, Ruoyan Chen, Yu-Tzu Tai, Kenneth C Anderson, Ronald Herbst, David Tice
Journal: Blood (2017)
Inhibition of NF-κB–Dependent Signaling Enhances Sensitivity and Overcomes Resistance to BET Inhibition in Uveal Melanoma
Authors: Grazia Ambrosini, Catherine Do, Benjamin Tycko, Ronald B. Realubit, Charles Karan, Elgilda Musi, Richard D. Carvajal, Vivian Chua, Andrew E. Aplin, Gary K. Schwartz
Journal: Cancer Research (2019)

Abstract Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here, we evaluated the mechanisms of BETi resistance in uveal melanoma, a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107 and RNA sequencing of BETi-resistant cells. NF-κB inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment. Furthermore, genes involved in NF-κB signaling were upregulated in BETi-resistant cells, and the transcription factor CEBPD contributed to the mechanism of resistance. These findings suggest that inhibitors of NF-κB signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma. Significance: These findings provide evidence that inhibitors of NF-κB signaling synergize with BET inhibition in in vitro and in vivo models, suggesting a clinical utility of these targeted therapies in patients with uveal melanoma.
Abstract 16844: Relative Endothelial Toxicity of Tobacco Smoke and E-Cigarette Aerosol: A Functional and Mechanistic Assessment
Authors: Leila Mohammadi, Ronak Derakhshandeh, Daniel D Han, Adam Whitlatch, Abel Huang, Suzaynn F Schick, Matthew L Springer
Journal: Circulation (2018)

Background: Smoking cigarettes decreases expression of eNOS in the endothelium, resulting in lower nitric oxide (NO) secretion and decreased flow-mediated dilation in the conducting arteries. In contrast, the effects of e-cigarettes (e-cigs) on endothelial function are just beginning to be studied and the mechanisms of action are unclear. Aim: To test the hypothesis that circulating factors from e-cigarette users decrease endothelial eNOS protein levels and NO secretion in primary endothelial cell cultures, relative to nonsmokers and cigarette smokers. Methods: 36 healthy individuals were recruited and grouped as nonsmokers (n=12), cigarette smokers (n=7), and e-cig users (n=17). Human umbilical vein endothelial cells (HUVECs) were cultured at 20,000 cells per well in 24-well culture plate. Serum samples from individual subjects and endothelial growth media were added at a 1:1 ratio to confluent cells and incubated for 12 hours (basal condition), followed by fresh medium containing VEGF at 50 ng/ml for 30 min (stimulated condition). The amount of NO liberated from cells was measured in culture supernatants by the chemilumin- escence method using a NO analyzer. Endothelial NO synthase (eNOS) protein levels in HUVECs was measured in cell lysates by ELISA. NO and eNOS results were normalized to cell number. Results: The cells treated with serum from e-cig users vs. nonsmokers produced less NO upon stimulation (P&lt;.03) and contained less eNOS protein (P&lt;.03). eNOS protein level was lower in the e-cig user serum group than in the cigarette smoker serum group (P&lt;.05), although stimulated NO production was decreased less by e-cig user serum than by smoker serum. Lower eNOS levels in the cigarette group vs. non-smoker group was not significant, but stimulated NO was significantly lower in the cigarette group vs. nonsmoker (P&lt;.006; see figure). Conclusion: Exposure of cultured endothelial cells to circulating factors from e-cig users, relative to non-users, leads to lower eNOS protein levels and decreased NO production.
Survival and toxicity outcomes in patients age 40 or older with relapsed metastatic germ cell tumors (mGCT) treated with high-dose chemotherapy (HDCT) and autologous peripheral-blood stem cell transplant (PBSCT).
Authors: Nabil Adra, Costantine Albany, Rafat Abonour, Mohammad Issam Abu Zaid, Dannillo Pereira, Sandra K. Althouse, Cheryl K Sullivan, Nasser H. Hanna, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2019)

522 Background: HDCT plus PBSCT is effective salvage therapy for relapsed mGCT but has potential toxicity which can be more pronounced in older patients. We report survival and toxicity outcomes in pts with relapsed mGCT age ≥ 40 at time of HDCT. Methods: 440 consecutive pts with relapsed mGCT were treated with HDCT and PBSCT with tandem cycles at Indiana University (IU) between 2004-2017 per our previous reported regimen (N Engl J Med 2007; 357: 340-8). Kaplan-Meier methods were used for progression free survival (PFS) analysis. Results: 110 pts were age ≥ 40 while 330 pts were age &lt; 40. Among pts age ≥ 40, median AFP was 6.6 (range, 1-2,709) and median hCG was 5.3 (range, 1-42, 453). Of the 110 pts age ≥ 40, 75 had complete remission without relapse during a median follow-up of 23 months. There were 3 treatment-related deaths. Conclusions: HDCT plus PBSCT is safe and effective salvage therapy in pts age ≥ 40 with relapsed mGCT. [Table: see text]
Coronary Angiography after Cardiac Arrest without ST-Segment Elevation
Authors: Jorrit S. Lemkes, Gladys N. Janssens, Nina W. van der Hoeven, Lucia S.D. Jewbali, Eric A. Dubois, Martijn Meuwissen, Tom A. Rijpstra, Hans A. Bosker, Michiel J. Blans, Gabe B. Bleeker, Rémon Baak, Georgios J. Vlachojannis, Bob J.W. Eikemans, Pim van der Harst, Iwan C.C. van der Horst, Michiel Voskuil, Joris J. van der Heijden, Albertus Beishuizen, Martin Stoel, Cyril Camaro, Hans van der Hoeven, José P. Henriques, Alexander P.J. Vlaar, Maarten A. Vink, Bas van den Bogaard, Ton A.C.M. Heestermans, Wouter de Ruijter, Thijs S.R. Delnoij, Harry J.G.M. Crijns, Gillian A.J. Jessurun, Pranobe V. Oemrawsingh, Marcel T.M. Gosselink, Koos Plomp, Michael Magro, Paul W.G. Elbers, Peter M. van de Ven, Heleen M. Oudemans-van Straaten, Niels van Royen
Journal: New England Journal of Medicine (2019)

Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography and percutaneous coronary intervention (PCI) in the treatment of patients who have been successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains uncertain.
Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T‐cell therapy for chronic lymphocytic leukemia
Authors: Steven M. Bair, David L. Porter
Journal: American Journal of Hematology (2019)

Abstract Studies of chimeric antigen receptor (CAR) T‐cell therapy in chronic lymphocytic leukemia (CLL) have demonstrated the potential to produce deep remissions—and possibly cures—in some patients with heavily pretreated, high‐risk, relapsed, and refractory disease. Unfortunately, most clinical trials of CAR T cells in CLL report complete responses only in the minority of patients, although recent studies have begun to elucidate the factors most predictive of response. These studies have suggested strategies for optimizing CAR T‐cell fitness as well as the pre‐existing host immune response, approaches that will likely lead to improvements in the efficacy of CAR T cells in CLL. Treating patients earlier in the course of their disease or using combination therapies with CAR T cells may further enhance efficacy. In this review, we summarize the existing literature on CAR T cell therapy in CLL, discuss mechanisms of response and resistance, and describe challenges facing the field.
Phase 1, first-in-human study of ARQ 087, an oral pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, in patients (pts) with advanced solid tumors.
Authors: Kyriakos P. Papadopoulos, Anthony W. Tolcher, Amita Patnaik, Drew Warren Rasco, Glenda Chambers, Murali Beeram, Ronald Savage, Terence Hall, Brian E. Schwartz, Julia Kazakin, Patricia LoRusso
Journal: Journal of Clinical Oncology (2015)

2545 Background: ARQ 087 is a novel, orally bioavailable, ATP-competitive inhibitor of multiple kinases, including FGFR1-3. It has potent in vitro and in vivo inhibitory effects on a variety of human tumor cell lines and xenograft models dependent on FGFR signaling. Methods: This first-in-human 2-step study was initiated in pts with advanced solid tumors. Step 1: dose escalation/food-effect to characterize PK, safety, maximum tolerated and recommended Phase 2 Dose (RP2D; unselected for FGFR aberration). Step 2: expansion cohort to to assess safety and clinical activity of ARQ 087 in selected tumor types, including FGFR gene amplification, translocation and mutation. Assessments included tumor molecular status, response by RECIST v.1.1 every 8 weeks (wks), plasma concentrations of FGF19, 21, 23, fasting glucose and phosphate. Results: 61pts were treated (dose range 25-425mg QOD or QD) in Step 1; the majority were female (61%), mean age 64 yrs (34 -78). The RP2D was defined as 300 mg QD continuous dosing. Dose-limiting toxicities included increased liver enzymes (reversible Grade (G) 3 AST increase). Common drug-related adverse events (AEs; mostly G ≤ 2) were fatigue (53%), elevated LFTs (45%), nausea (45%), vomiting (20%) and diarrhea (20%). Only 2 pts (3%) experienced G1 drug-related hyperphosphatemia. Drug t1/2 was 2-11 days, PK was unaffected by food. FGF 19/21/23 concentrations post-treatment were increased 1.5-6 fold. Ten pts in Step 1 had confirmed stable disease (SD) ≥ 16 wks (adrenocortical [2], endometrial, ovarian, NSCLC, choroidal melanoma, carcinoid, sarcoma [3]). A squamous NSCLC pt with Src amplification had SD (24% tumor reduction) for 32 wks. One adrenocortical carcinoma pt with FGFR1 amplification remains on study > 22 months. Two ongoing pts with intrahepatic cholangiocarcinoma with FGFR2 fusions demonstrated a partial response and SD > 24 wks with 26% decrease in target lesions, respectively. Conclusions: ARQ 087 has manageable, mostly G ≤ 2 AEs. It has demonstrated preliminary antitumor activity in pts with FGFR-pathway aberrations. Further evaluation of ARQ 087 in pre-defined tumor types is ongoing. Clinical trial information: NCT01752920.
<i>Notes from the Field:</i> HIV Diagnoses Among Persons Who Inject Drugs — Northeastern Massachusetts, 2015–2018
Authors: Kevin Cranston, Charles Alpren, Betsey John, Erica Dawson, Kathleen Roosevelt, Amanda Burrage, Janice Bryant, William M. Switzer, Courtney Breen, Philip J. Peters, Tracy Stiles, Ashley Murray, H. Dawn Fukuda, William Adih, Linda Goldman, Nivedha Panneer, Barry Callis, Ellsworth M. Campbell, Liisa Randall, Anne Marie France, R. Monina Klevens, Sheryl Lyss, Shauna Onofrey, Christine Agnew-Brune, Michael Goulart, Hongwei Jia, Matthew Tumpney, Paul McClung, Sharoda Dasgupta, Danae Bixler, Kischa Hampton, Jenifer Leaf Jaeger, Kate Buchacz, Alfred DeMaria
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Opioid overdose deaths have increased rapidly in northeastern Massachusetts since 2013, with postmortem fentanyl detection increasing statewide. Molecular data indicate multiple introductions of human immunodeficiency virus (HIV) among persons who inject drugs as well as recent and rapid transmission in the context of some longstanding HIV infections.
Clinical utility study of confirms mdx for prostate cancer in a community urology practice.
Authors: Paul Yonover, Sandra Steyaert, Justin J. Cohen, Celeste Ruiz, Karolina Grafczynska, Elizabeth Garcia, Jessica DeHart, Michael Brawer, Jack Groskopf, Wim Van Criekinge
Journal: Journal of Clinical Oncology (2019)

94 Background: There is an unmet need for methods to better identify patients most likely to benefit from repeat prostate biopsy after an initial negative biopsy. ConfirmMDx is a molecular test clinically validated for detection of prostate cancer (PCa) in tissue from PCa-negative biopsies. In this clinical utility study, we evaluated the impact of ConfirmMDx on the management of patients being considered for repeat prostate biopsy in a community urology practice. Methods: The study population consisted of 605 men with a prior PCa-negative prostate biopsy, who were counseled on the need to undergo repeat biopsy at a large community urology practice due to persistent elevated risk of PCa. All tissue cores from each PCa-negative patient were tested with the ConfirmMDx methylation-specific PCR test, and positive or negative ConfirmMDx results based on the presence or absence of GSTP1, APC or RASSF1 methylation in the biopsy tissue. ConfirmMDx results were provided to the physician for use in repeat biopsy decision-making. Medical record review was conducted at a minimum of nine months after ConfirmMDx results were reported. Results: Of the 605 subjects enrolled, 308 (51%) had a negative ConfirmMDx test result and 297 (49%) were positive. For the entire study population, average age was 64 (median 64, interquartile range 59 to 69), average serum PSA level 6.8 ng/mL (5.7, 4.3 to 8.1). The median follow-up for both Confirm positives and negatives was 10 months post-testing. Repeat biopsy rates for ConfirmMDx positive and negative men were 32.3% (96/297) and 5.8% (15/308), respectively (P &lt; 0.001). For patients who received a biopsy during the follow-up period, the time between ConfirmMDx and repeat biopsy was shorter for ConfirmMDx positive men versus ConfirmMDx negatives (median 4 vs. 8 months, P = 0.007). Conclusions: In this utility study, ConfirmMDx had a significant impact on repeat prostate biopsy decision-making in a U.S. community urology setting. Repeat biopsy rates in ConfirmMDx positive men were six-fold higher than in ConfirmMDx negatives. These results reflect the clinical utility of ConfirmMDx for biopsy decision-making in real world clinical practice.
Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice
Authors: Ian Huck, Sumedha Gunewardena, Regina Espanol‐Suner, Holger Willenbring, Udayan Apte
Journal: Hepatology (2018)

Hepatocyte nuclear factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4α in liver regeneration (LR) is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during LR. Western blotting analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels, accompanied with decreased target gene expression, within 1 hour after two-thirds partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO [knockout]) in mice resulted in 100% mortality post-PH, despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated that HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by c-Myc and cyclin D1 overexpression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes delayed, but did not prevent, initiation of regeneration after PH. Finally, adeno-associated virus serotype 8 (AAV8)-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression, and improved survival of HNF4α-KO mice post-PH. Conclusion: In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of LR. These results indicate the role of HNF4α in LR and have implications for therapy of liver failure.
EFFECT OF HIGH-INTENSITY INTERVAL TRAINING ON TOTAL AND ABDOMINAL FAT MASS IN OUTPATIENT CARDIAC REHABILITATION PATIENTS WITH MYOCARDIAL INFARCTION
Authors: Yaoshan Dun, Joshua R. Smith, Jose R. Medina-Inojosa, Mary C. MacGillivary, Randal J. Thomas, Suixin Liu, Ying Cai, Thomas P. Olson
Journal: Journal of the American College of Cardiology (2019)
Assessing financial toxicity in insured patients with multiple myeloma.
Authors: Scott F. Huntington, Brendan M. Weiss, Dan T. Vogl, Adam D. Cohen, Alfred L. Garfall, Jalpa A. Doshi, Edward A. Stadtmauer
Journal: Journal of Clinical Oncology (2015)

6600 Background: Financial toxicity is increasingly recognized for its potential to adversely impact the quality of life and health outcomes of patients undergoing treatment for cancer. Patients with multiple myeloma (MM) may be particularly vulnerable due to high utilization of novel therapeutics and extended treatment duration. Methods: Patients with at least 3 months of ongoing treatment for MM were invited to participate in a survey during follow up visits at our institution. The survey was derived from published instruments and included the recently developed 11-item COST measure (financial toxicity score 0 – 44). Electronic health records informed insurance and treatment data. Results: Of 111 patients approached for the study, 100 individuals completed the survey. The median reported annual household income was between $60,000-79,999 and all participants were insured (43% private, 49% Medicare, 8% Medicaid/dual). Median time from diagnosis was 31 months, 75% had exposure to both lenalidomide and bortezomib, and 58% had undergone autologous transplantation. The majority (59%) labelled treatment costs as higher than expected and 70% endorsed at least minor financial burden. Thirty-six patients reported applying for financial assistance, including 18% of individuals with income over $100,000. Use of savings to pay for MM treatment was common (46%), 21% borrowed money to pay for medications, and 17% reported delays in their MM treatment due to cost. COST scores were normally distributed (median 20.5, range 0-43) and correlated with patient reported incomes, use of savings, borrowing of money, and treatment delays (p < 0.001). After controlling for potential confounders on linear regression, time since diagnosis was directly related (p < 0.03), while age and income were inversely related with COST scores (p < 0.03; p < 0.001). Conclusions: Financial burden and request for financial assistance were common in our insured population with MM. Younger age, lower household income, and time since diagnosis were associated with higher financial toxicity as measured by the COST score. Additional attention to rising treatment costs and cost-sharing is needed to address the growing evidence of financial toxicity impacting patients with cancer.
The vasculature in sepsis: delivering poison or remedy to the brain?
Authors: Benjamin H. Singer
Journal: Journal of Clinical Investigation (2019)

Survivors of sepsis and other forms of critical illness frequently experience significant and disabling cognitive and affective disorders. Inflammation, ischemia, and glial cell dysfunction contribute to this persistent brain injury. In this issue of the JCI, Hippensteel et al. show that endothelial injury in animal models of sepsis or endotoxemia leads to shedding of heparan fragments from the endothelial glycocalyx. These fragments directly sequester brain-derived neurotrophic factor and impair hippocampal long-term potentiation, an electrophysiologic correlate of memory. The authors further explore the specific characteristics of heparan fragments that bind neurotrophins and the presence of these fragments in the circulation of patients who survive sepsis. This study highlights an important mechanism by which vascular injury can impair brain function.