tbuckley/cabot-search huggingface dataset:
Metabolite profiling reveals the interaction of chitin-glucan with the gut microbiota
Authors: Julie Rodriguez, Audrey M. Neyrinck, Zhengxiao Zhang, Benjamin Seethaler, Julie-Anne Nazare, Cándido Robles Sánchez, Martin Roumain, Giulio G. Muccioli, Laure B. Bindels, Patrice D. Cani, Véronique Maquet, Martine Laville, Stephan C. Bischoff, Jens Walter, Nathalie M. Delzenne
Journal: Gut Microbes (2020)

Dietary fibers are considered beneficial nutrients for health. Current data suggest that their interaction with the gut microbiota largely contributes to their physiological effects. In this context, chitin-glucan (CG) improves metabolic disorders associated with obesity in mice, but its effect on gut microbiota has never been evaluated in humans. This study explores the effect of a 3-week intervention with CG supplementation in healthy individuals on gut microbiota composition and bacterial metabolites. CG was given to healthy volunteers (n = 15) for three weeks as a supplement (4.5 g/day). Food diary, visual analog and Bristol stool form scales and a "quality of life" survey were analyzed. Among gut microbiota-derived metabolites, bile acids (BA), long- and short-chain fatty acids (LCFA, SCFA) profiling were assessed in stool samples. The gut microbiota (primary outcome) was analyzed by Illumina sequencing. A 3-week supplementation with CG is well tolerated in healthy humans. CG induces specific changes in the gut microbiota composition, with Eubacterium, Dorea and Roseburia genera showing the strongest regulation. In addition, CG increased bacterial metabolites in feces including butyric, iso-valeric, caproic and vaccenic acids. No major changes were observed for the fecal BA profile following CG intervention. In summary, our work reveals new potential bacterial genera and gut microbiota-derived metabolites characterizing the interaction between an insoluble dietary fiber -CG- and the gut microbiota.
Gelling hypotonic polymer solution for extended topical drug delivery to the eye
Authors: Yoo Chun Kim, Matthew D. Shin, Sean F. Hackett, Henry T. Hsueh, Raquel Lima e Silva, Abhijit Date, Hyounkoo Han, Byung-Jin Kim, Amy Xiao, Youngwook Kim, Laolu Ogunnaike, Nicole M. Anders, Avelina Hemingway, Ping He, Albert S. Jun, Peter J. McDonnell, Charles Eberhart, Ian Pitha, Donald J. Zack, Peter A. Campochiaro, Justin Hanes, Laura M. Ensign
Journal: Nature Biomedical Engineering (2020)
Cost-Effectiveness of Initial Versus Delayed Lanreotide for Treatment of Metastatic Enteropancreatic Neuroendocrine Tumors
Authors: James I. Barnes, John K. Lin, Divya Gupta, Douglas K. Owens, Jeremy D. Goldhaber-Fiebert, Pamela L. Kunz
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: The Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) trial showed prolonged progression-free survival in patients initially treated with lanreotide versus placebo. We evaluated the cost-effectiveness of upfront lanreotide versus active surveillance with lanreotide administered after progression in patients with metastatic enteropancreatic neuroendocrine tumors (NETs), both of which are treatment options recommended in NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors. Methods: We developed a Markov model calibrated to the CLARINET trial and its extension. We based the active surveillance strategy on the CLARINET placebo arm. We calculated incremental cost-effectiveness ratios (ICERs) in dollars per quality-adjusted life-year (QALY). We modeled lanreotide’s cost at $7,638 per 120 mg (average sales price plus 6%), used published utilities (stable disease, 0.77; progressed disease, 0.61), adopted a healthcare sector perspective and lifetime time horizon, and discounted costs and benefits at 3% annually. We examined sensitivity to survival extrapolation and modeled octreotide long-acting release (LAR) ($6,183 per 30 mg). We conducted one-way, multiway, and probabilistic sensitivity analyses. Results: Upfront lanreotide led to 5.21 QALYs and a cost of $804,600. Active surveillance followed by lanreotide after progression led to 4.84 QALYs and a cost of $590,200, giving an ICER of $578,500/QALY gained. Reducing lanreotide’s price by 95% (to $370) or 85% (to $1,128) per 120 mg would allow upfront lanreotide to reach ICERs of $100,000/QALY or $150,000/QALY. Across a range of survival curve extrapolation scenarios, pricing lanreotide at $370 to $4,000 or $1,130 to $5,600 per 120 mg would reach ICERs of $100,000/QALY or $150,000/QALY, respectively. Our findings were robust to extensive sensitivity analyses. The ICER modeling octreotide LAR is $482,700/QALY gained. Conclusions: At its current price, lanreotide is not cost-effective as initial therapy for patients with metastatic enteropancreatic NETs and should be reserved for postprogression treatment. To be cost-effective as initial therapy, the price of lanreotide would need to be lowered by 48% to 95% or 27% to 86% to reach ICERs of $100,000/QALY or $150,00/QALY, respectively.
Impact of Quality Improvement (QI) Program on 5-Year Risk of Diabetes-Related Complications: A Simulation Study
Authors: Hui Shao, Vivian Fonseca, Roy Furman, Luigi Meneghini, Lizheng Shi
Journal: Diabetes Care (2020)

OBJECTIVE We successfully implemented the American Diabetes Association’s (ADA) Diabetes INSIDE (INspiring System Improvement with Data-Driven Excellence) quality improvement (QI) program at a university hospital and safety-net health system (Tulane and Parkland), focused on system-wide improvement in poorly controlled type 2 diabetes (HbA1c &amp;gt;8.0% [64 mmol/mol]). In this study, we estimated the 5-year risk reduction in complications and mortality associated with the QI program. RESEARCH DESIGN AND METHODS The QI implementation period was 1 year, followed by the postintervention period of 6 months to evaluate the impact of QI on clinical measures. We measured the differences between the baseline and postintervention clinical outcomes in 2,429 individuals with HbA1c &amp;gt;8% (64 mmol/mol) at baseline and used the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes model to project the 5-year risk reduction of diabetes-related complications under the assumption that intervention benefits persist over time. An alternative assumption that intervention benefits diminish by 30% every year was also tested. RESULTS The QI program was associated with reductions in HbA1c (−0.84%) and LDL cholesterol (LDL-C) (−5.94 mg/dL) among individuals with HbA1c level &amp;gt;8.0% (64 mmol/mol), with greater reduction in HbA1c (−1.67%) and LDL-C (−6.81 mg/dL) among those with HbA1c level &amp;gt;9.5% at baseline (all P &amp;lt; 0.05). The implementation of the Diabetes INSIDE QI program was associated with 5-year risk reductions in major adverse cardiovascular events (MACE) (relative risk [RR] 0.78 [95% CI 0.75–0.81]) and all-cause mortality (RR 0.83 [95% CI 0.82–0.85]) among individuals with baseline HbA1c level &amp;gt;8.0% (64 mmol/mol), and MACE (RR 0.60 [95% CI 0.56–0.65]) and all-cause mortality (RR 0.61 [95% CI 0.59–0.64]) among individuals with baseline HbA1c level &amp;gt;9.5% (80 mmol/mol). Sensitivity analysis also identified a substantially lower risk of diabetes-related complications and mortality associated with the QI program. CONCLUSIONS Our modeling results suggest that the ADA’s Diabetes INSIDE QI program would benefit the patients and population by substantially reducing the 5-year risk of complications and mortality in individuals with diabetes.
A cross-sectional study of 502 patients found a diffuse hyperechoic kidney medulla pattern in patients with severe gout
Authors: Thomas Bardin, Quang D. Nguyen, Khoy M. Tran, Nghia H. Le, Minh D. Do, Pascal Richette, Emmanuel Letavernier, Jean-Michel Correas, Mathieu Resche-Rigon
Journal: Kidney International (2020)

We have previously shown that ultrasonography can detect hyperechogenic crystal deposits in the kidney medulla of patients with gout. In this cross-sectional study we investigated the frequency and clinical correlates of hyperechogenic kidney medulla in 502 consecutive primary consultants for gout (ACR/EULAR criteria) at the Vien Gut medical center in Ho Chi Minh City, Vietnam. None of these patients received urate-lowering drugs. Kidney medulla echogenicity on B-mode ultrasonography was compared to that of the kidney cortex. Overall, 36% patients showed a hyperechoic pattern of Malpighi pyramids. On univariate analysis, the pattern was significantly associated with age, estimated gout duration, steroid-dependency, clinical tophi, urate arthropathy, double contour thickness at the scanned joints, coronary heart disease, arterial hypertension, hyperuricemia, proteinuria, leukocyturia, and decreased estimated glomerular filtration rate. On multivariable analysis, the hyperechoic pattern was associated with estimated disease duration, clinical tophi, urate arthropathy, double contour thickness and decreased estimated glomerular filtration rate. No hyperechoic pattern was observed in 515 consecutive consultants without gout. Thus, hyperechoic kidney medulla was frequently demonstrated in Vietnamese patients with tophaceous gout and associated with features of tubulointerstitial nephritis. This finding revives the hypothesis of microcrystalline nephropathy of gout, predominantly seen in untreated gouty patients, which could be an important target for urate-lowering therapy.
Cross-sectional and Prospective Associations of Rest-Activity Rhythms With Metabolic Markers and Type 2 Diabetes in Older Men
Authors: Qian Xiao, Jingyi Qian, Daniel S. Evans, Susan Redline, Nancy E. Lane, Sonia Ancoli-Israel, Frank A.J.L. Scheer, Katie Stone
Journal: Diabetes Care (2020)

OBJECTIVE Disruption of rest-activity rhythms is cross-sectionally associated with metabolic disorders, including type 2 diabetes, yet it remains unclear whether it predicts impaired glucose metabolism and homeostasis. The aim of this study is to examine the cross-sectional and prospective associations between rest-activity rhythm characteristics and glycemic measures in a cohort of older men. RESEARCH DESIGN AND METHODS Baseline rest-activity rhythms were derived from actigraphy with use of extended cosine model analysis. With subjects fasting, glucose, insulin, and HOMA of insulin resistance (HOMA-IR) were measured from blood at baseline and after ∼3.5 years. Type 2 diabetes was defined based on self-report, medication use, and fasting glucose. RESULTS In the cross-sectional analysis (n = 2,450), lower 24-h amplitude-to-mesor ratio (i.e., mean activity-adjusted rhythm amplitude) and reduced overall rhythmicity were associated with higher fasting insulin and HOMA-IR (all Ptrend &amp;lt; 0.0001), indicating increased insulin resistance. The odds of baseline type 2 diabetes were significantly higher among those in the lowest quartile of amplitude (Q1) (odds ratio [OR]Q1 vs. Q4 1.63 [95% CI 1.14, 2.30]) and late acrophase group (ORlate vs. normal 1.46 [95% CI 1.04, 2.04]). In the prospective analysis (n = 861), multiple rest-activity characteristics predicted a two- to threefold increase in type 2 diabetes risk, including a lower amplitude (ORQ1 vs. Q4 3.81 [95% CI 1.45, 10.00]) and amplitude-to-mesor ratio (OR 2.79 [95% CI 1.10, 7.07]), reduced overall rhythmicity (OR 3.49 [95% CI 1.34, 9.10]), and a late acrophase (OR 2.44 [1.09, 5.47]). CONCLUSIONS Rest-activity rhythm characteristics are associated with impaired glycemic metabolism and homeostasis and higher risk of incident type 2 diabetes.
Abstract 5768: Peripartum blood transfusions are associated with increased risk of cancer: A national retrospective cohort study
Authors: Young Kwang Chae, Michael S. Oh, Misuk Lee, Sukjoo Cho, Jonghanne Park, Geum Joon Cho
Journal: Cancer Research (2020)

Abstract Background: The effect of blood transfusions on the risk of developing primary cancer remains unclear, especially when administered in the peripartum period. Methods: We conducted a retrospective cohort study of 270,529 pregnant women who delivered between January 1, 2007 and December 31, 2009, with data obtained from three national databases in South Korea. From this cohort, we identified 4,569 patients who received peripartum blood transfusions. We calculated hazard ratios (HRs) for new diagnoses of cancer, and adjusted them for relevant clinical factors using a Cox proportional hazards model. Results: During follow-up, patients who received peripartum transfusions had an increased risk of developing cancer, with an adjusted HR of 1.16 (95% confidence interval [CI], 1.01-1.34). This risk was significant only among patients who received 3 or more units of blood, with an adjusted HR of 1.40 (95% CI, 1.10-1.79). Increased risk after transfusions were seen with brain, lung, ovarian, and gallbladder cancers. The difference in cancer risk between the transfusion and no-transfusion groups remained significant during both the first (1.34% vs 1.10%, p &amp;lt; 0.01) and second year (0.78% vs 0.58%, p &amp;lt; 0.01) after delivery. Conclusion: Receipt of 3 or more blood transfusions in the peripartum period was associated with a significantly increased risk of developing cancer. Citation Format: Young Kwang Chae, Michael S. Oh, Misuk Lee, Sukjoo Cho, Jonghanne Park, Geum Joon Cho. Peripartum blood transfusions are associated with increased risk of cancer: A national retrospective cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5768.
Comprehensive Genomic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
Authors: Alberto Puccini, Kelsey Poorman, Mohamed E. Salem, Davide Soldato, Andreas Seeber, Richard M. Goldberg, Anthony F. Shields, Joanne Xiu, Francesca Battaglin, Martin D. Berger, Ryuma Tokunaga, Madiha Naseem, Afsaneh Barzi, Syma Iqbal, Wu Zhang, Shivani Soni, Jimmy J. Hwang, Philip A. Philip, Stefania Sciallero, W. Michael Korn, John L. Marshall, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2020)

Abstract Purpose: GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors. Experimental Design: GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and in situ hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 724 GEP-NENs were examined: GI (N = 469), PNEN (N = 255), HG (N = 135), and LG (N = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%), and MEN1 (10%). HG tumors showed TP53 (51%), KRAS (30%), APC (27%), and ARID1A (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% (P = 0.04), PD-L1 overexpression 1% vs. 6% (P = 0.03), TMB-high 1% vs. 7% (P = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in BRAF (5.4% vs. 0%, P &amp;lt; 0.0001), KRAS (29.4% vs. 2.6%, P &amp;lt; 0.0001), and PI3KCA (7% vs. 0.3%, P &amp;lt; 0.0001). When compared with GI, PNEN carried higher frequency of MEN1 (25.9% vs. 0.0%, P &amp;lt; 0.0001), FOXO3 (8.6% vs. 0.8%, P = 0.005), ATRX (20.6% vs. 2.0%, P = 0.007), and TSC2 (6.3% vs. 0.0%, P = 0.007), but lower frequency of mutations in APC (1.0% vs. 13.8%, P &amp;lt; 0.0001). Conclusions: Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.
Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome
Authors: Alan P. Jacobsen, Inbar Raber, Cian P. McCarthy, Roger S. Blumenthal, Deepak L. Bhatt, Ronan W. Cusack, Patrick W.J.C. Serruys, William Wijns, John W. McEvoy
Journal: Circulation (2020)

Four decades have passed since the first trial suggesting the efficacy of aspirin in the secondary prevention of myocardial infarction. Further trials, collectively summarized by the Antithrombotic Trialists' Collaboration, solidified the historical role of aspirin in secondary prevention. Although the benefit of aspirin in the immediate phase after a myocardial infarction remains incontrovertible, a number of emerging lines of evidence, discussed in this narrative review, raise some uncertainty as to the primacy of aspirin for the lifelong management of all patients with chronic coronary syndrome (CCS). For example, data challenging the previously unquestioned role of aspirin in CCS have come from recent trials where aspirin was discontinued in specific clinical scenarios, including early discontinuation of the aspirin component of dual antiplatelet therapy after percutaneous coronary intervention and the withholding of aspirin among patients with both CCS and atrial fibrillation who require anticoagulation. Recent primary prevention trials have also failed to consistently demonstrate net benefit for aspirin in patients treated to optimal contemporary cardiovascular risk factor targets, indicating that the efficacy of aspirin for secondary prevention of CCS may similarly have changed with the addition of more modern secondary prevention therapies. The totality of recent evidence supports further study of the universal need for lifelong aspirin in secondary prevention for all adults with CCS, particularly in stable older patients who are at highest risk for aspirin-induced bleeding.
Abstract 6057: Discovery of a novel function for USP7 inhibitors: Reprogramming the tumor microenvironment
Authors: Xavier Jacq, Anamarija Jurisic, Julien Daubriac, Ian T. Lobb, Mark Wappett, Aaron Cranston, Peggy Sung, Gerald Gavory, Colin O'Dowd, Tim Harisson
Journal: Cancer Research (2020)

Abstract During the transition from healthy tissue to cancer and metastasis, the tumor microenvironment (TME) initiates crucial changes that licenses the progression from primary tumors to aggressive and metastatic disease. Our understanding of the specific factors and molecular mechanisms underpinning these transitions in the TME is critical for influencing the potency and scope of existing cancer therapy strategies but is still evolving and subject to substantial and widespread investigations. Here we uncover a novel molecular mechanism actioned by fibroblasts in the TME to modulate the secretion of the vascular endothelial growth factor (VEFG) via the hypoxia-inducible transcription factor (HIF1α). Utilizing primary human cells co-culture systems in combination with highly potent and selective USP7 inhibitors, we demonstrate that the deubiquitinating enzyme USP7 modulates the stability of HIF1α in primary human fibroblasts and secreted VEGF levels in primary fibroblasts as well as cancer-associated fibroblasts. This USP7-mediated modulation of VEGF secretion in the TME does not occur in cancer cells, immune cells or endothelial cells, rather it is restricted to the fibroblastic compartment. Importantly, the modulation of VEGF secretion by USP7 in fibroblasts is not mediated via the Mdm2 axis: Mdm2 antagonists are unable to recapitulate the VEGF modulation in fibroblasts. Knock-down of USP7 in primary fibroblasts validates the phenotype obtained with potent and selective USP7 inhibitors. In line with their effects on the TME in primary cell cultures, potent, selective USP7 inhibitors demonstrated tumour growth inhibition in vivo in a syngeneic cancer xenograft model that does not respond to USP7 inhibitors in vitro. Collectively, our studies reveal a molecular mechanism whereby USP7 inhibition leads to TME reprogramming mediated by an increased destabilization of HIF1α leading to reduced levels of VEGF in the TME and improved anti-tumor activity. Our results support further investigations of combination of a USP7 inhibitor with immune checkpoint inhibitors, as well as other TME modulating agents. Citation Format: Xavier Jacq, Anamarija Jurisic, Julien Daubriac, Ian T. Lobb, Mark Wappett, Aaron Cranston, Peggy Sung, Gerald Gavory, Colin O'Dowd, Tim Harisson. Discovery of a novel function for USP7 inhibitors: Reprogramming the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6057.
Abstract 4621: Polymorphisms in JAK/STAT signaling pathway genes and risk of breast cancer
Authors: Manuela Gago-Dominguez, Maria E. Martinez, Roger Milne, Marcos Matabuena, Carmen Redondo, José Esteban Castelao, Catriona Jamieson
Journal: Cancer Research (2020)

Abstract Background. Impaired function of JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway genes leads to immunodeficiency; genetic variation in this pathway could affect breast cancer risk. Methods. We evaluated associations between genetic polymorphisms (SNPs) in 14 genes in the JAK/STAT pathway (JAK3, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, SCOS1, SCOS2, SCOS3, SCOS4, APOBEC and ADAR) and breast cancer risk using data from the OncoArray. As the JAK/STAT pathway interacts with ER and PR, we also examined these associations by breast cancer subtype. We examined a total of 203 genetic variants in 60,106 cases (38,531 ER positive, and 9,363 ER negative) and 46,300 controls. Results. SNP rs738308 in APOBEC was associated with risk of overall breast cancer (P value &amp;lt;0.001), and ER+ breast cancer (P value &amp;lt; 0.002). SNPs in ADAR1/STAT were associated with risk of ER+ breast cancer (P value &amp;lt; 0.01). The associations were more pronounced for advanced-stage disease. Other SNPs, exhibited potential, weaker associations. Conclusion. We found increased breast cancer risk associated with rs738308 in APOBEC, and SNPs in ADAR1, both involved in RNA editing processes. APOBEC has been linked with cancer development and cholesterol control. Increased ADAR expression has been found in 50% of triple negative breast cancers (TNBC), which has been associated with increased recurrence and worse survival. RNA seq analysis showed that ADAR1 is among the top 5% of upregulated genes in relapsed lobular breast cancer. Activation of the JAK2/STAT3 pathway has been associated with TNBC poor prognosis. Our next step is to analyze these genetic variants using the iCOGs dataset which includes 116,587 additional patients and controls. Citation Format: Manuela Gago-Dominguez, Maria E. Martinez, Roger Milne, Marcos Matabuena, Carmen Redondo, José Esteban Castelao, Catriona Jamieson. Polymorphisms in JAK/STAT signaling pathway genes and risk of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4621.