tbuckley/cabot-search huggingface dataset:
Evaluating non-hormonal therapy in a phase II trial of SM-88 for rising PSA prostate cancer.
Authors: Benjamin Adam Gartrell, Giuseppe Del Priore, Avi S. Retter, Wen-Tien Chen, Gerald H. Sokol, Alexander G Vandell, Mack Roach
Journal: Journal of Clinical Oncology (2019)

83 Background: Absolute PSA change is an imperfect surrogate of clinical benefit; CTCs and PSA doubling time (DT) may also be used as a surrogate of progression (PD). Hormone therapy (HT) often leads to a rapid decline in PSA, however non-HT may be effective without causing a decline in absolute PSA or testosterone (T). SM-88, a non-HT novel combination Warburg effect therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) does not affect T. We report outcomes leading to subsequent therapies of an ongoing PSA recurrent, non-metastatic PC trial. Methods: Prospective Phase II of rising PSA (per PCWG3), detectable CTCs, and no baseline lesions. Results: Since September 2016, 31 subjects enrolled with 17 on study for &gt; 12 weeks. Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean T increased 61 mg/dl from baseline 319 mg/dl (p=0.19). 82% (14/17) subjects experienced an improvement in PSA DT and 67% (10/15) experienced a decline in CTCs of &gt;30%. Overall median PSA DT time on enrollment was 5.3 (1.4 – 37.6) and improved to 6.5 (Wilcoxon p=0.02) (see table). 3/4 subjects with PD failed to maintain a CTC drop &gt;60% vs 2/17 without PD (p=.03); median time to nadir CTC was 3 cycles (1-7). Subjects avoiding subsequent therapy averaged a 50% CTC decline (15-100%). CTC and PSA DT effects were not correlated to T level. AEs possibly related to drug/unrelated were: No grade (G) 4 or 5; 0/1 G3; 1/7 G2; 13/19 G1. As reported elsewhere, typical HT-related side effects were not observed. Including all patients with &gt;1 month of data, from initial diagnosis of PSA rise (median 9 months; 3-18), 96% (22/23) have remained metastases-free and 78% (18/23) remained free of additional HT (p&lt;.05). Clinical trial information: NCT02796898. Conclusions: SM-88 may be a useful either before or as an additive to current PC treatments where normal T may be preferred. SM-88 might not worsen QOL parameters related to T level. An effect on PSA DT and CTCs were demonstrated even in an aggressive doubling time subgroup. Prospective trials are planned to confirm its utility.[Table: see text]
Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials
Authors: Daniel E. Falk, Stephanie S. O’Malley, Katie Witkiewitz, Raymond F. Anton, Raye Z. Litten, Megan Slater, Henry R. Kranzler, Karl F. Mann, Deborah S. Hasin, Bankole Johnson, Didier Meulien, Megan Ryan, Joanne Fertig
Journal: JAMA Psychiatry (2019)

The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use.To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes.Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence.Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h).Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]).WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days.ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.
Abstract P314: Physical Activity and Sedentary Behavior Phenotypes in a Majority-Minority Community-Based Sample: Houston TRAIN Study
Authors: Kelley Pettee Gabriel, Casey P Durand, Gregory Knell, Deborah Salvo, Erin Dooley, Ashleigh M Johnson, Harold W Kohl
Journal: Circulation (2019)

Background: Inadequate physical activity and prolonged sedentary behavior is related to premature mortality and suboptimal cardiovascular health. Yet, the health impacts of these behaviors are typically considered in isolation using a single method assessment approach. Use of accelerometer and reported data from a diverse sample provides the novel opportunity to identify and characterize distinct phenotypes to improve exposure ascertainment. Methods: Data are from 366 participants (61.4% female; 70.3% non-white; aged 50.7 years) enrolled in the Houston Travel Related Activity in Neighborhoods (TRAIN) Study; a natural experiment designed to determine the effect of a light rail train expansion on transit use and physical activity. Latent class analysis using baseline accelerometer (ActiGraph wGT3X-BT) and reported (self-administered, 7-day Modifiable Activity Questionnaire) data were used to derive the phenotypes and multinomial regression models were used to determine correlates of membership. Results: Four phenotypes emerged with the majority classified as Phenotype 4 or insufficient activity and high sedentary ( Table 1 ). When compared to Phenotype 2 (reference group), women were less likely than men to be classified as Phenotype 1 or 3. Every 1 kg/m 2 increase in body mass index increases the odds of membership in Phenotype 3 or 4 when compared to Phenotype 2. Black participants were more likely, and participants identifying as mixed race were less likely, than white participants to be classified as Phenotype 3 compared to Phenotype 2 (all p &lt;0.05). Age was not a significant correlate of phenotype membership. Conclusions: A phenotype characterized by insufficient physical activity and high sedentary behavior represented the majority of study participants. This supports continued development of physical activity interventions targeting minority groups. Study findings also support use of methodological approaches to combine accelerometer and reported data to reduce potential exposure misclassification.
Chromatin remodeling mediated by ARID1A is indispensable for normal hematopoiesis in mice
Authors: Lin Han, Vikas Madan, Anand Mayakonda, Pushkar Dakle, Teoh Weoi Woon, Pavithra Shyamsunder, Hazimah Binte Mohd Nordin, Zeya Cao, Janani Sundaresan, Ienglam Lei, Zhong Wang, H. Phillip Koeffler
Journal: Leukemia (2019)

Precise regulation of chromatin architecture is vital to physiological processes including hematopoiesis. ARID1A is a core component of the mammalian SWI/SNF complex, which is one of the ATP-dependent chromatin remodeling complexes. To uncover the role of ARID1A in hematopoietic development, we utilized hematopoietic cell-specific deletion of Arid1a in mice. We demonstrate that ARID1A is essential for maintaining the frequency and function of hematopoietic stem cells and its loss impairs the differentiation of both myeloid and lymphoid lineages. ARID1A deficiency led to a global reduction in open chromatin and ensuing transcriptional changes affected key genes involved in hematopoietic development. We also observed that silencing of ARID1A affected ATRA-induced differentiation of NB4 cells, suggesting its role in granulocytic differentiation of human leukemic cells. Overall, our study provides a comprehensive elucidation of the function of ARID1A in hematopoiesis and highlights the central role of ARID1A-containing SWI/SNF complex in maintaining chromatin dynamics in hematopoietic cells.
Clinical impact of Bacillus Calmette-Guérin (BCG) Therapy on prognosis in patients with carcinoma in situ (CIS) of the upper urinary tract: A retrospective comparison with nephroureterectomy.
Authors: Takahiro Yoneyama, Osamu Soma, Yuuichiro Suzuki, Tohru Yoneyama, Kazuyuki Mori, Hayato Yamamoto, Atsushi Imai, Shingo Hatakeyama, Yasuhiro Hashimoto, Chikara Ohyama
Journal: Journal of Clinical Oncology (2019)

417 Background: Clinical benefit of bacillus Calmette-Guérin (BCG) therapy for the management of upper urinary tract carcinoma in situ (CIS) remain unclear. We investigated safety and long-term oncological outcome of BCG therapy for upper urinary tract CIS compared with nephroureterectomy. Methods: We treated consecutive 490 patients with upper urinary tract carcinoma Aomori, Japan. We retrospectively reviewed the post-treatment course of 60 patients with CIS of the upper urinary tract who had undergone either a radical nephroureterectomy (RNU group) or BCG therapy (BCG group). Clinical effectiveness, safety, and oncological outcomes were compared between the groups. Multivariate Cox regression analysis via inverse propensity treatment weighted (IPTW) methods was performed to identify the impact of BCG therapy on prognosis. Results: The number of patients in RNU and BCG groups were 22 and 38, respectively. Median follow-up was 59 months in this cohort. There was no significant difference in background of patients including age, sex, performance status between the groups. The reason of selection for BCG therapy were bilateral CIS of upper urinary tract (50%), solitary kidney (26%), and others (24%). The cytology became negative in 30 (79%) patients after 6-week course of BCG. BGC related adverse events were observed 92% of patients. Most common events were cystitis (76%) followed by fever (50%). Two patients experienced grade 3 sepsis after BCG therapy. 13 patients (43%) experienced tumor recurrence after BCG therapy. There were no significant differences in recurrence-free survival, cancer-specific survival, and overall survival between the RNU and BCG groups. Multivariate analysis revealed BCG therapy did not worse the prognosis of those patients. Conclusions: Although mild adverse events were frequented in BCG therapy for CIS of the upper urinary tract, it might be a useful alterative in patients with CIS of the upper urinary tract who are ineligible for radical nephroureterectomy. Further prospective studies are needed to confirm the benefits of BCG therapy for CIS of the upper urinary tract.
Abstract P318: The Association of Physical Activity With Serum Metabolomics: Findings From the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Jun Xu, Kelley P Gabriel, Eric Boerwinkle, Bing Yu
Journal: Circulation (2019)

Background: Habitual physical activity can attenuate the risk of developing a variety of non-communicable diseases, however, the underlying mechanisms that explain these benefits remain unclear. Metabolomics profiling, a tool to provide metabolic phenotypes characterization, holds promise to describe the perturbed energy metabolism associated with physical activity. Identifying a pattern of physical activity related metabolites may provide novel insights into disease etiology. Methods: Metabolomic profiling was performed in 2,472 African Americans (AAs) and 1,551 European Americans (EAs) from the Atherosclerosis Risk in Communities (ARIC) Study. Two hundred forty five serum metabolites were identified and quantified by liquid and gas chromatography-mass spectrometry. Adjusted linear and ordinal logistic regression models were performed to examine the metabolite associations with reported, leisure-time moderate-to-vigorous intensity physical activity (MVPA), expressed continuously (METhrwk -1 ) and categorically based on the American Heart Association (AHA) Recommendations for Ideal Physical Activity (ideal, intermediate, or poor). Covariates included: age, gender, race, body mass index, smoking status, and study center. A metabolite risk score (MRS) was constructed using metabolites related to both MVPA and AHA recommendations to evaluate whether it better characterizes the metabolism associated with physical activity. Results: The mean MVPA was 5.8 METhrwk -1 and 11.1 METhrwk -1 for AAs and EAs respectively, 22.5% and 43.5% met the ideal category of AHA-recommended guideline. We identified eight metabolites that were significantly associated with MVPA (p &lt; 2.04x10 -4 , Bonferroni correction), including indole propionate, docosahexaenoate (DHA; 22:6n3), 1-docosahexaenoylglycerophosphocholine (22:6n3), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), N-acetylcarnosine, glycerate, threonate, and stachydrine. All eight metabolites showed individual significance in EAs, but only half (the latter four metabolites) had individual significance in AAs (p &lt; 0.006). Except DHA and it derivative, the other six MVPA-related metabolites were also associated with AHA recommendations (p &lt; 2.04x10 -4 ). One METhrwk -1 increase was associated with 2.18 SD increase of MRS (95% CI: 1.56-2.80), and stratification by race revealed a stronger effect in EAs compared to AAs. Conclusion: A set of metabolites are associated with physical activity in AAs and EAs, including known biomarkers for cardiometabolic diseases, and the MRS was associated with lower heart failure risk. Our findings provide novel insight into the mechanisms underlying the health effects of physical activity.
Circular RNA cTFRC acts as the sponge of MicroRNA-107 to promote bladder carcinoma progression
Authors: Hongwei Su, Tao Tao, Zhao Yang, Xing Kang, Xu Zhang, Danyue Kang, Song Wu, Chong Li
Journal: Molecular Cancer (2019)

Circular RNA (circRNA) represents a broad and diverse endogenous RNAs that can regulate gene expression in cancer. However, the regulation and function of bladder cancer (BC) circRNAs remain largely unknown. Here we generated circRNA microarray data from three BC tissues and paired non-cancerous matched tissues, and detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. We subsequently performed functional analyses in cell lines and an animal model to support clinical findings. Mechanistically, we demonstrated that cTFRC could directly bind to miR-107 and relieve suppression for target TFRC expression. We detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. Knock down of cTFRC inhibited invasion and proliferation of BC cell lines in vitro and tumor growth in vivo. Furthermore, the expression of cTFRC correlated with TFRC and negatively correlated with miR-107 both in BC cell lines and BC clinical samples. In addition, up-regulation of cTFRC promoted TFRC expression and contributed to an epithelial to mesenchymal transition phenotype in BC cells. Finally, we found that cTFRC acts as a competing endogenous RNA (ceRNA) for miR-107 to regulate TFRC expression. cTFRC may exert regulatory functions in BC and may be a potential marker of BC diagnosis or progression.
Blood and urine markers of metabolic dysfunction in colorectal cancer: a pilot study.
Authors: Katarzyna Joanna Jerzak, Marissa Laureano, Peter Kavsak, Sukhbinder K. Dhesy-Thind, Kevin M. Zbuk
Journal: Journal of Clinical Oncology (2015)

e14611 Background: Intra-tumor hypoxia portends a poor prognosis and may result in resistance to chemotherapy and radiotherapy, but systemic markers of hypoxia have not been investigated. In this study, by-products of anaerobic metabolism were measured in the blood and urine of patients with metastatic colorectal cancer (mCRC) and compared to patients with local disease. Methods: In this prospective pilot study, 40 patients (20 with metastatic and 20 with local colorectal adenocarcinoma) were recruited at the Juravinski Hospital and Cancer Centre in Hamilton/ON. Exclusion criteria included insulin-dependent diabetes, chemotherapy or radiation therapy within 2 weeks, infection requiring antibiotics, hospitalization within 2 weeks and creatinine clearance < 30 mL/min. Plasma lactate, ketones, venous blood gas, 24-hour urine citrate and indirect markers of small molecules, both charged (anion gap) and un-charged (osmolar gap) were investigated. Results of patients with metastatic CRC were compared to i) results of the local CRC cohort, and ii) the upper or lower levels of the reference interval using t-tests. Results: The average pCO2 [50.2 (95%CI 45.6-54.7)] borders the upper limit of normal among patients with metastatic CRC. Further, the average pCO2 [50.2 (95%CI 45.6-54.7) vs. 39.7 (95%CI 29.7-49.8)mmHg, p = 0.03] and calculated serum osmolality [292.9 (95%CI 290.5-295.4) vs. 285.9 (95%CI 280.5-291.2)mmol/kg, p = 0.01] were higher among patients with metastatic CRC as compared to those with local disease. Blood ketones were negative in all patients and there was no significant difference in lactate, pH, bicarbonate levels, calculated anion and osmolar gaps and the 24-hour urine citrate between the two groups. Conclusions: In our pilot study, pCO2 and calculated serum osmolality were statistically higher in mCRC patients as compared to those with local disease. While higher calculated serum osmolality levels likely stem from minor deviations in sodium, blood urea nitrogen and glucose concentrations, higher pCO2 levels may stem from a perturbed metabolism in patients with metastatic CRC. Whether pCO2 levels correlate with intra-tumor hypoxia or clinical prognosis requires further study.
Abstract P186: Comparison of Hypertension Prevalence, Treatment, and Control Among African Immigrants and African Americans in the US
Authors: Danielle S Mensah, Yvonne Commodore-Mensah, Kathryn Foti, Ruth-Alma Turkson-Ocran, Nishit Patel, Cheryl Dennison Himmelfarb, Elizabeth Selvin
Journal: Circulation (2019)

Introduction: African immigrants make up a growing share of Blacks in the US. However, little is known about their cardiovascular health because data are combined with African Americans, despite cultural, socioeconomic, and genetic differences. Hypothesis: There will be significant differences in hypertension prevalence, treatment, and control between samples of African immigrants and African Americans. Methods: We included participants in the African Immigrant Health Study, a community-engaged study of African immigrants in Baltimore-Washington, D.C. Participants ≥ 30 years old were recruited from community groups and religious institutions from 2017-2018. They were English-speaking and born in West Africa. We compared them to a weighted sample of African Americans who were ≥ 30 years old from the 2015-2016 NHANES. We used t-test and chi-squared tests to compare hypertension prevalence, treatment, and control between the groups. Results: We compared 326 African immigrants (mean age 46; 60% women) to 928 African Americans (mean age 51; 56% women). African immigrants (60%) were more likely to have ≥ college education than African Americans (22%). African Americans (87%) were more likely to be insured than African immigrants (58%) and less likely (12%) to report a household income of ≥ $100,000 than African immigrants (21%). Age-standardized hypertension prevalence was higher in African Americans than African immigrants ( Table ). However, among those with hypertension, African Americans were more likely to be treated and controlled. Both groups had similar high rates of overweight/obesity; diabetes prevalence was higher in African Americans. Conclusions: Hypertension prevalence among African immigrants was lower than African Americans. However, hypertension treatment and control rates were lower in African immigrants and this may be due to poor healthcare access. Future studies may further elucidate reasons for differences among Black ethnic groups in hypertension prevalence, treatment, and control.
Assessment of staffing need through a workload analysis in Jhenaidah and Moulvibazar, Bangladesh: a Workload Indicator of Staffing Need (WISN) study
Authors: Taufique Joarder, Samiun Nazrin Bente Kamal Tune, Taqbir Us Samad Talha, Md Nuruzzaman, Sabina Alam, Valeria de Oliveira Cruz, Tomas Zapata
Journal: The Lancet Global Health (2019)

BackgroundImprovement of health workers' performance is vital for the improvement of health-care service delivery, and workload management is an important factor in improving performance. This study aimed to assess the current workload and staffing need for delivering optimum health-care services in the public-sector district health system in Bangladesh.MethodsBetween July 2, 2017, and Nov 30, 2017, we followed the steps of WHO's Workload Indicator of Staffing Need (WISN) methodology. We combined qualitative (document reviews, key informant interviews, in-depth interviews, observations) and quantitative methods (time-motion survey), to collect data in 24 health facilities from district hospitals up to community clinics in Jhenaidah and Moulvibazar districts, Bangladesh. The study included physicians, nurses, medical assistants, family welfare visitors, community care providers, and family welfare assistants. Workload components were defined on the basis of inputs from experts (n=5), refined further by actual service providers (n=87). We used WHO WISN software to calculate standard workload, category allowance factor, individual allowance factor, total required number of staff, WISN difference, and WISN ratio.FindingsSeven of the 20 staff categories had a very high workload (WISN ratio 0·30–0·49), and five staff categories had extremely high workload (0·10–0·29) indicating an overall high workload in the service providers studied. Medical consultants had the highest workload (WISN ratio 0·16), followed by other specialists. The staff category with the most number of positions needing to be filled was nurses at district hospitals (a mean of 136 vacant positions per facility), followed by general physicians (35). We noted that nurses were predominantly occupied with support activities (60% in the case of district nurses and 50% in sub-district facilities), instead of actual nursing care. If the vacant posts were filled, the workload for existing workers is reduced. However, simply filling the vacant posts would not be sufficient to reduce staff workload in some staff categories, such as nursing.InterpretationWISN method of estimating workload and staff requirements can aid policymakers in making the best uses of existing human resources. Thus, WISN should be incorporated as a planning tool for managers at the district level. Implementation research should be carried out on how the workload-based staffing decisions can be effectively integrated into health systems.FundingWHO Bangladesh.