tbuckley/cabot-search huggingface dataset:
Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis
Authors: Banishree Saha, David Tornai, Karen Kodys, Adeyinka Adejumo, Patrick Lowe, Craig McClain, Mack Mitchell, Arthur McCullough, Srinivasan Dasarathy, Aimee Kroll‐Desrosiers, Bruce Barton, Svetlana Radaeva, Gyongyi Szabo
Journal: Hepatology (2019)

Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End‐Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90‐day mortality, infection, and organ failure development, respectively. Conclusion : Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.
Association of Timing of Onset of Maternal Mental Disorders With Completion of Primary Education in Offspring
Authors: Katja Glejsted Ingstrup, Thomas Munk Laursen, Veerle Bergink, Anne Ranning, Trine Munk-Olsen
Journal: JAMA Psychiatry (2019)

Poor school performance and risk of not completing primary education have been observed in children born of mothers with severe psychiatric disorders (eg, schizophrenia) at the time of conception 1 and of mothers with mental disorders with specific onset during pregnancy and postpartum. 2,3 It is, however, unknown whether the specific timing of onset of maternal mental disorders is associated with completion of primary education in offspring.Methods | We conducted a population-based cohort study from January 1, 1996, to December 31, 2014, using data from the Danish Civil Registration System, the Danish Central Psychiatric Research Register, and the Primary Education Register.A total of 684 248 children born and living in Denmark from January 1, 1986, to December 31, 1996, were included, with complete information from birth to graduation of primary education from the Danish Civil Registration System.Data analysis was performed from July 1, 2018, to October 6, 2018.All analysis were performed according to Danish laws on the General Data Protection Regulation.In Denmark, register-based studies do not require informed consent.Data were deidentified.The study was approved by the Danish Data Protection Agency.Information on exposure of maternal mental disorders was classified using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00 to F99, obtained through the Danish Psychiatric Central Research Register. 4Timing of onset was defined as the first date of first psychiatric admission.Completion of primary education was categorized if there were records of grades or test results and no completion if there were no records of a final examination in the register. 1 We added an additional 2 years of follow-up to allow children to graduate later than expected for their age but before 18 years of age.We used a Wald 2-sided test with a 5% significance level.The main outcome of interest was completion of primary education (yes or no), analyzed using logistic regression in SAS statistical software, version 9.
BPI19-008: Racial Disparities in Breast Cancer Treatment Based on NCCN Quality Guidelines
Authors: Surbhi Agarwal, Ruta Rao, David Ansell
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: NCCN quality measures for breast cancer include (1) radiation therapy administered within 1 year of diagnosis for women under age 70 receiving breast-conserving surgery; (2) chemotherapy considered in 4 months of diagnosis for women under 70 with T1c or stage II/III ER/PR- tumors; (3) endocrine therapy administered within 1 year of diagnosis for women with AJCC T1 or stage II/III ER/PR+ breast cancer. These evidence-based measures promote accountability for providers and allow transparency in quality of care. Black women are less likely than white women to receive these therapies that are associated with a survival benefit. Improving adherence to guidelines can decrease the gap in mortality rates for minority women with breast cancer. Methods: We performed a retrospective chart review on patients with breast cancer between April 2010 and October 2015 at Rush University. Information collected included time of diagnosis, clinical stage, ER/PR status, surgical procedures, radiation, chemotherapy, endocrine therapy, and demographics. Chi-squared analysis was done to compare percent of black versus white women who met each quality guideline. Results: In total, 2,436 women were analyzed, of whom 30.3% were black, 66% were white, and 3.7% were other. Of this cohort, 779 women met inclusion criteria for quality guideline 1, and there was no significant difference between black and white women who did not receive radiation therapy ( P =.21; 24.7% vs 20.4%). For quality guideline 2 (n=382), there was also no significant difference between black and white women who did not get chemotherapy within 4 months of diagnosis ( P =.32; 36.6% vs 31.4%). However, for quality guideline 3 (n=1,222), there was a statistically significant difference between black and white women who did not get hormone therapy within a year of diagnosis ( P =.0008; 36.9% vs 26.1%). Conclusions: Endocrine therapy reduces risk of recurrence and mortality in women with ER/PR positive breast cancer; however, there is a disparity between black versus white women who meet this NCCN quality measure. Further studies are needed to understand the reason for this gap in quality of care so that specific interventions can be implemented to eliminate this disparity.
Carboplatin (CBDCA), S-1 and concurrent thoracic radiotherapy (TRT) for elderly patients with locally advanced non-small cell lung cancer (NSCLC): A phase II study.
Authors: Seiji Niho, Shigeki Umemura, Yukio Hosomi, Hiroaki Okamoto, Keiji Nihei, Hiroshi Tanaka, Toyoaki Hida, Koichi Goto, Tetsuo Akimoto, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2018)

8530 Background: S-1 is an oral anticancer agent containing a mixture of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, which has been shown to have a radiosensitizing effect in preclinical models. Recent phase II studies have shown that chemoradiotherapy using cisplatin and S-1 yields promising PFS durations of 15 to 20 months in non-elderly (less than 75 years old) patients with locally advanced NSCLC. We conducted a phase II study of CBDCA, S-1 and TRT for elderly patients with locally advanced NSCLC. Methods: The eligibility criteria included patients with unresectable stage III NSCLC, a chemotherapy-naïve status, PS 0 to 1, and age ≥ 71 years. Patients received CBDCA (AUC 3) on day 1 and S-1 (40mg/m2 twice daily) on days 1 to 14, q4w, up to 4 cycles, plus concurrent TRT at a total dose of 60Gy. The primary endpoint was 1-year PFS rate. The sample size was set at 28 patients, with a one-sided alpha of 0.05, beta of 0.2, and expected and threshold values for primary endpoints of 50% and 30%. Results: Between Feb 2014 and Dec 2016, 28 patients were enrolled in this study. All 28 patients were eligible and assessable. Baseline characteristics as follows: median age (range) 77 (71-83) years; women, n = 3 (11%); ECOG PS of 0, n = 15 (54%); stage IIIB, n = 8 (29%); tumor histopathological type: adeno, n = 12 (43%), squamous, n = 13 (46%), and NSCLC-NOS, n = 3 (11%). All 4 cycles of CBDCA plus S-1 could be completed in 15 patients (54%). TRT at 60 Gy was completed in 26 patients (93%). Response rate was 71%. Grade 3-4 toxicities included neutropenia (7%), thrombocytopenia (21%), hypoalbuminemia (7%), hyponatremia (11%), anorexia (7%), fatigue (7%), and colitis (7%). Grade 3 radiation pneumonitis was observed in 5 patients (18%). No treatment-related death was observed. The 1-year PFS rate was 56% (90% CI, 40.0 to 71.7%), and the median PFS was 13.9 months (95%CI, 4.8 to 23.0 months) with a median follow-up period of 18.2 months in censored cases. Conclusions: Combination chemotherapy of CBDCA plus S-1 and concurrent TRT had promising efficacy in elderly patients with locally advanced NSCLC; however, radiation pneumonitis was frequently observed. Clinical trial information: UMIN000005794.
Abstract MP05: N Terminal Pro B Type Natriuretic Peptide as a Stroke Risk Factor in the European Population: Results From the Biomarcare Consortium
Authors: Augusto Filippo Di Castelnuovo, Giovanni Veronesi, Simona Costanzo, Marialaura Bonaccio, Tanja Zeller, Renate Schnabel, Torben Joergensen, Veikko Salomaa, John Yarnell, Marco Ferrario, Simona Giampaoli, Christa Meisinger, Frank Kee, Wolfgang Koenig, Ulf Landmesser, Giovanni de Gaetano, Kari Kuulasmaa, Stefan Blankenberg, Licia Iacoviello
Journal: Circulation (2018)

Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a risk factor for atrial fibrillation and a marker of cardiac function used in detection of heart failure. Few studies evaluated the role of NT-proBNP as risk factor for stroke. Hypothesis: Given the link between cardiac dysfunction and stroke, NT-proBNP is a candidate marker of stroke risk. Our aim was to evaluate the association of NT-proBNP with stroke outcomes and to determine the predictive value beyond a panel of established risk factors for stroke. Methods: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project we analysed data of 43,815 participants (48.3% men; mean age 52 yr) free of cardiovascular disease from 6 prospective population-based cohorts across Europe with a maximum follow-up of 22 years. All NT-proBNP measurements were performed on frozen samples in the central BiomarCaRE laboratory. The endpoints considered were validated fatal and non-fatal stroke. Results: We observed 565 stroke events (78 fatal) in men and 290 (54) in women. Growing quartiles of NT-proBNP were associated with increasing risk of stroke (Table; multivariable cox regression analysis adjusted for the base model: age, centre, smoking, BMI, diabetes, hypertension medication, systolic and diastolic blood pressure, total and HDL cholesterol), both in men (p for trend &lt;0.0001) and in women (P&lt;0.0001). Examining C-statistics for prediction of stroke we could observe only very small changes after the addition of NT-proBNP to the base model (delta AUC=0.0053 and 0.0048 in men and women, respectively). Conclusions: In European individuals free of cardiovascular disease, levels of NT-proBNP in the top quartile (&gt;87.7 pg/mL) are associated with a doubled risk of stroke. However, the addition of NT-proBNP to variables of established risk score poorly improves prediction of stroke disease.
EPR19-74: Risk of Cabozantinib-Associated Gastrointestinal and Hepatic Toxicities in Patients With Metastatic Solid Tumors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Anita Sultan, Sriman Swarup, Francis Mogollon-Duffo, Ye Aung, Yin M. Myat, Myo H. Zaw, Rachana Yendala, Nicholas D’Cunha, Kyaw Z. Thein
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Cabozantinib is an oral inhibitor of multiple tyrosine kinases and is used in treatment of multiple solid tumors, targeting several pathways such as vascular endothelial growth factor signaling pathway and proto-oncogenes MET, KIT, RET. These pathways are implicated in several tumor development and progression. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities among patients with metastatic solid tumors treated with cabozantinib. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception to September 2018 were queried. Phase 3 RCTs that mention GI and elevation of liver enzymes as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: We included 4 phase 3 RCTs with a total of 2,703 patients with various solid tumors. The study arm used cabozantinib while the control arm utilized everolimus or placebo or prednisone. The relative risks of all-grade side effects were as follows: diarrhea, 2.495 (95% CI: 2.149–2.897, P &lt;.0001); nausea, 1.849 (95% CI: 1.649–2.072; P &lt;.0001); vomiting, 2.335 (95% CI: 1.724–3.163; P &lt;.0001); stomatitis, 4.541 (95% CI: 0.908–22.696; P =.065); dysgeusia, 4.428 (95% CI: 2.67–7.343; P &lt;.0001); elevated AST, 2.002 (95% CI: 1.331–3.011; P =.001); and elevated ALT, 1.988 (95% CI: 0.936–4.222; P =.074). The RR of high-grade side effects were as follows: diarrhea, 5.913 (95% CI: 3.655–9.566; P &lt;.0001); nausea, 3.098 (95% CI: 1.266–7.581; P =.013); vomiting, 1.298 (95% CI: 0.395–4.265; P =.668); stomatitis, 3.837 (95% CI: 0.749–19.665; P =.107); dysgeusia, 1.522 (95% CI: 0.159–14.574; P =.716); elevated AST, 1.733 (95% CI: 1.101–2.728; P =.018); and elevated ALT, 2.489 (95% CI: 1.164–5.326; P =.019). Conclusion: The risk of developing all grades of diarrhea, nausea, elevated AST, and any-grade vomiting, dysgeusia as well as high-grade elevated ALT, was high in cabozantinib group. Timely recognition and providing good supportive care will enhance patients’ quality of life.
Overlapping neural systems underlying “incentive hope” and apprehension
Authors: Mattie Tops
Journal: Behavioral and Brain Sciences (2019)

Abstract Positioning “incentive hope” in a general model of behavioral control systems removes artificial boundaries between mechanisms of incentive motivation in foraging behavior and other functions of the striatum and connected systems. Specifically, incentive hope may involve mechanisms of anticipation of both reward and threat, explaining why anxious individuals show stronger potentiation of incentive motivation under conditions of reward uncertainty.
Repurposing Ponatinib as a Potent Agent against <i>KIT</i> Mutant Melanomas
Authors: Yong Han, Ziyue Gu, Jing Wu, Xiaojuan Huang, Rong Zhou, Chaoji Shi, Wenjie Tao, Lizhen Wang, Yanan Wang, Guoyu Zhou, Jiang Li, Zhiyuan Zhang, Shuyang Sun
Journal: Theranostics (2019)

Rationale: Mutations in KIT, a major cancer driver gene, are now considered as important drug targets for the treatment of melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for KIT-mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with KIT mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of KIT-mutation-bearing melanomas are urgently needed. Methods: A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring KIT mutations (KITV560D, KITK642E and KITD816V) were established, characterized, and then used to test the in vitro and, subsequently, in vivo inhibitory effects of a panel of known KIT inhibitors. Results: Ponatinib was more potent than imatinib against cells bearing KIT mutations. In vivo drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of KIT-mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the KITD816V mutant protein than does imatinib. Conclusions: Our study of KIT-mutation-and KITWT-bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-mutation-bearing melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have KIT mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.
Contribution of specific diseases and injuries to changes in health adjusted life expectancy in 187 countries from 1990 to 2013: retrospective observational study
Authors: He Chen, Gong Chen, Xiaoying Zheng, Yan Guo
Journal: BMJ (2019)

Abstract Objective To quantify and compare the contribution of 306 diseases and injuries to the changes in health adjusted life expectancy at birth (HALE 0 ) between 1990 and 2013. Design Retrospective demographic analysis based on aggregated data and using life table technique, Sullivan method, and decomposition method for differences in health expectancy. Setting The globe, 21 regions, and 187 countries, covered in the Global Burden of Disease Study (GBD) 2013. Main outcome measures Cause specific contribution to changes in HALE 0 between 1990 and 2013 in terms of mortality effect, disability effect, and total effect. Results Between 1990 and 2013, global HALE 0 increased by 5.31 years for males and 5.73 years for females. The cross national Gini coefficient of HALE 0 for both sexes combined decreased by 15.22% from 0.0736 to 0.0624. HALE 0 declined in 11 countries during the period, predominantly owing to HIV/AIDS except in Belize, Belarus, and Paraguay. Controlling communicable, maternal, neonatal, and nutritional diseases accounted for 56.47% (3.10 years) of changes in HALE 0 for both sexes combined, followed by non-communicable diseases (30.05%; 1.65 years) and injuries (13.67%; 0.75 years). Globally, HIV/AIDS caused the biggest reduction in HALE 0 (–0.28 years) and mainly afflicted residents in southern (–7.86 years), western (–1.53 years), and eastern (–1.38 years) sub-Saharan Africa. Diabetes had the second biggest negative total effect on changes in HALE 0 (–0.12 years), which was quite widespread across regions. Despite their positive total effect in high income regions, such non-communicable diseases as ischaemic heart disease, cerebrovascular disease, and hypertensive heart disease had a negative total effect in many low and middle income regions. Mortality reduction was the predominant driver (93.62%; 5.14 years) for improvement in HALE 0 , accompanied by an increase of 0.80 years in life expectancy lived with disability at birth. Only 44 (27%) of 163 causes at level 3 in the GBD cause hierarchy influenced changes in HALE 0 , mainly or only through disability. Conclusions Between 1990 and 2013, the globe made achievements in not only promoting population health as a whole but reducing health inequality between countries. This study pinpoints the priority diseases and injuries for altering the declining health trend in 11 countries, for curbing the epidemic of non-communicable diseases in low and middle income countries, and for promoting compression of morbidity worldwide. The detailed country specific decomposition results of effects of diseases and injuries on change in population health will further facilitate the development of national health policies.
The C3a/C3aR axis mediates anti-inflammatory activity and protects against uropathogenic E coli–induced kidney injury in mice
Authors: Kun-Yi Wu, Ting Zhang, Guo-Xiu Zhao, Ning Ma, Shu-Juan Zhao, Na Wang, Jia-Xing Wang, Zong-Fang Li, Wuding Zhou, Ke Li
Journal: Kidney International (2019)
Association Between Treatment Facility Volume, Therapy Types, and Overall Survival in Patients With Stage IIIA Non–Small Cell Lung Cancer
Authors: Anuhya Kommalapati, Sri Harsha Tella, Adams Kusi Appiah, Lynette Smith, Apar Kishor Ganti
Journal: Journal of the National Comprehensive Cancer Network (2019)

There is significant heterogeneity in the treatment of stage IIIA non-small cell lung cancer (NSCLC). This study evaluated the therapeutic and survival disparities in patients with stage IIIA NSCLC based on the facility volume using the National Cancer Database.Patients with stage IIIA NSCLC diagnosed from 2004 through 2015 were included. Facilities were classified by tertiles based on mean patients treated per year, with low-volume facilities treating ≤8 patients, intermediate-volume treating 9 to 14 patients, and high-volume treating ≥15 patients. Cox multivariate analysis was used to determine the volume-outcome relationship.Analysis included 83,673 patients treated at 1,319 facilities. Compared with patients treated at low-volume facilities, those treated at high-volume centers were more likely to be treated with surgical (25% vs 18%) and trimodality (12% vs 9%) therapies. In multivariate analysis, facility volume was independently associated with all-cause mortality (P<.0001). Median overall survival by facility volume was 15, 16, and 19 months for low-, intermediate-, and high-volume facilities, respectively (P<.001). Compared with patients treated at high-volume facilities, those treated at intermediate- and low-volume facilities had a significantly higher risk of death (hazard ratio, 1.09 [95% CI, 1.07-1.11] and 1.11 [95% CI, 1.09-1.13], respectively).Patients treated for stage IIIA NSCLC at high-volume facilities were more likely to receive surgical and trimodality therapies and had a significant improvement in survival.
Outcomes of Donation After Circulatory Death Heart Transplantation in Australia
Authors: Hong Chee Chew, Arjun Iyer, Mark Connellan, Sarah Scheuer, Jeanette Villanueva, Ling Gao, Mark Hicks, Michelle Harkness, Claudio Soto, Andrew Dinale, Priya Nair, Alasdair Watson, Emily Granger, Paul Jansz, Kavitha Muthiah, Andrew Jabbour, Eugene Kotlyar, Anne Keogh, Chris Hayward, Robert Graham, Phillip Spratt, Peter Macdonald, Kumud Dhital
Journal: Journal of the American College of Cardiology (2019)
Relapse-Initiating Clones Preexisting at Diagnosis in B- Cell Acute Lymphoblastic Leukemia Help Predict Molecular Pathways of Relapse
Authors: Laura Garcia Prat, Stephanie M. Dobson, Michelle Chan-Seng-Yue, Robert Vanner, Alex Murison, Jeffery Wintersinger, Esme Waanders, Olga I. Gan, Jessica McLeod, Debbie Payne-Turner, Michael Edmonson, Zhaohui Gu, Xiaotu Ma, Yiping Fan, Pankaj Gupta, Michael Rusch, Ying Shao, John Easton, Jinghui Zhang, Mark D. Minden, Quaid Morris, Mathieu Lupien, Charles G. Mullighan, John E. Dick
Journal: Blood (2018)
Hypoxia alleviation-triggered enhanced photodynamic therapy in combination with IDO inhibitor for preferable cancer therapy
Authors: Lei Xing, Jia-Hui Gong, Yi Wang, Yong Zhu, Zhang-Jian Huang, Jun Zhao, Fei Li, Jian-Hua Wang, Hao Wen, Hu-Lin Jiang
Journal: Biomaterials (2019)