tbuckley/cabot-search huggingface dataset:
IL-26 contributes to host defense against intracellular bacteria
Authors: Angeline Tilly Dang, Rosane M.B. Teles, David I. Weiss, Kislay Parvatiyar, Euzenir N. Sarno, Maria T. Ochoa, Genhong Cheng, Michel Gilliet, Barry R. Bloom, Robert L. Modlin
Journal: Journal of Clinical Investigation (2019)

IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients. IL-26 directly bound to M. leprae in axenic culture and reduced bacteria viability. Furthermore, IL-26, when added to human monocyte–derived macrophages infected with M. leprae, entered the infected cell, colocalized with the bacterium, and reduced bacteria viability. In addition, IL-26 induced autophagy via the cytoplasmic DNA receptor stimulator of IFN genes (STING), as well as fusion of phagosomes containing bacilli with lysosomal compartments. Altogether, our data suggest that the Th17 cytokine IL-26 contributes to host defense against intracellular bacteria.
Breast Cancer Risk and Insulin Resistance: Post Genome-Wide Gene–Environment Interaction Study Using a Random Survival Forest
Authors: Su Yon Jung, Jeanette C. Papp, Eric M. Sobel, Herbert Yu, Zuo-Feng Zhang
Journal: Cancer Research (2019)

Obesity-insulin connections have been considered potential risk factors for postmenopausal breast cancer, and the association between insulin resistance (IR) genotypes and phenotypes can be modified by obesity-lifestyle factors, affecting breast cancer risk. In this study, we explored the role of IR in those pathways at the genome-wide level. We identified IR-genetic factors and selected lifestyles to generate risk profiles for postmenopausal breast cancer. Using large-scale cohort data from postmenopausal women in the Women's Health Initiative Database for Genotypes and Phenotypes Study, our previous genome-wide association gene-behavior interaction study identified 58 loci for associations with IR phenotypes (homeostatic model assessment-IR, hyperglycemia, and hyperinsulinemia). We evaluated those single-nucleotide polymorphisms (SNP) and additional 31 lifestyles in relation to breast cancer risk by conducting a two-stage multimodal random survival forest analysis. We identified the most predictive genetic and lifestyle variables in overall and subgroup analyses [stratified by body mass index (BMI), exercise, and dietary fat intake]. Two SNPs (LINC00460 rs17254590 and MKLN1 rs117911989), exogenous factors related to lifetime cumulative exposure to estrogen, BMI, and dietary alcohol consumption were the most common influential factors across the analyses. Individual SNPs did not have significant associations with breast cancer, but SNPs and lifestyles combined synergistically increased the risk of breast cancer in a gene-behavior, dose-dependent manner. These findings may contribute to more accurate predictions of breast cancer and suggest potential intervention strategies for women with specific genetic and lifestyle factors to reduce their breast cancer risk. SIGNIFICANCE: These findings identify insulin resistance SNPs in combination with lifestyle as synergistic factors for breast cancer risk, suggesting lifestyle changes can prevent breast cancer in women who carry the risk genotypes.
Refractory cystic duct stump leak treated with fibrin glue
Authors: Abhilash Perisetti, Saikiran Raghavapuram, Benjamin Tharian
Journal: Endoscopy (2019)

A 39-year-old morbidly obese woman with a previous medical history of obstructive sleep apnea presented to an external hospital with right upper quadrant abdominal pain and was diagnosed with choledocholithiasis. She underwent laparoscopic cholecystectomy which was complicated by bile leakage. Endoscopic retrograde cholangiopancreatography (ERCP) showed leakage from the cystic duct stump, which was treated with biliary sphincterotomy and placement of a plastic stent.
Risk prediction model for serious infections in psoriasis
Authors: Z.Z.N. Yiu, C. Sorbe, M. Lunt, S.J. Rustenbach, L. KÜhl, M. Augustin, K.J. Mason, D.M. Ashcroft, C.E.M. Griffiths, R.B. Warren
Journal: British Journal of Dermatology (2019)

This study was carried out by a group of investigators from dermatology departments in Manchester and Hamburg. It used information from the German Psoriasis Registry and also the British Association of Dermatologists Biologic Interventions Register, or BADBIR, which collects information on the use and outcomes of new biologic drugs used for psoriasis. The team developed and then assessed a model for predicting which patients with psoriasis were most likely to develop severe infection within one year of starting systemically administered treatment (i.e. treatment that works on the whole body, rather than being applied just to the skin). The treatments assessed ranged from older methods where the drug is taken by mouth, such as methotrexate or ciclosporin, to the newer injected biologic therapies, such as etanercept or ustekinumab. Potential risk factors to be investigated, such as age, gender, disease severity and initial therapy, amongst others, were agreed by the assessment group. These serious infections were those where patients had prolonged admissions to hospital, were treated with intravenous antibiotics or where they died, within one year of starting these therapies. 1.7 % of both BADBIR and German patients developed a severe infection. Risk factors for a higher likelihood of serious infections included female gender, other underlying illnesses such as chronic lung disease, higher alcohol intake, and treatment with the biologic, infliximab. Interestingly age did not, by itself, pose a higher risk of infection. This work will prove very useful in helping dermatologists to decide which patients to treat, and with what drug, and to advise patients of lifestyle choices such as drinking alcohol.
Racial Differences in Drug Response
Authors: Hong-Hao Zhou, Richard P. Koshakji, David J. Silberstein, Grant R. Wilkinson, Alastair J.J. Wood
Journal: New England Journal of Medicine (1989)

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (±SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197±31 vs. 536±58 nmol per liter; P<0.05) and the upright position (131±27 vs. 343±39 nmol per liter; P<0.05) and after exercise testing (96±12 vs. 185±23 nmol per liter; P<0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73±5 vs. 748±7 nmol per liter; P<0.01) and in the upright position (89±5 vs. 401±6 nmol per liter; P<0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740±737 vs. 2125±214 ml per minute; P<0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained. (N Engl J Med 1989; 320:565–70.)
Mary Warnock: philosopher and author of the landmark report on the ethical framework for human fertilisation and embryology
Authors: Penny Warren
Journal: BMJ (2019)

Photo credit: Gerald Duckworth and Company

On a June day in 1984, Mary Warnock said she experienced “a mounting panic.” Princess Margaret was late to a lunch they were both attending in Oxford, delaying it further with requests for gin and cigarettes. Warnock had to race to London afterwards to present her report to Norman Fowler, minister for health.

The Report of the Committee of Inquiry into Human Fertilisation and Embryology (1984) (the “Warnock report”) set out the regulatory framework and ethical consensus that still govern human fertilisation today. It was the work of a committee chaired by Warnock, which had spent two years painstakingly sifting evidence from doctors, scientists, anti-abortion groups, faith leaders, and many more.

The inquiry was prompted by new in vitro fertilisation (IVF) techniques, which led to the birth of the first “test tube” baby, Louise Brown, in 1978. Some were uneasy about the ethics of IVF, and by 1980 MPs were lobbying for an inquiry.

Civil servants were quick to choose Warnock as chair. She had already successfully chaired another public inquiry. They wanted an outsider, …
Supporting allergen‐specific immunotherapy by inhibition of Janus kinases
Authors: Jan Gutermuth, Carsten B. Schmidt‐Weber, Simon Blank
Journal: Allergy (2019)

JG and CS-W have an issued patent “tofacitinib as vaccination immune modulator.” CS-W reports grants and personal fees from Bencard, grants from Leti Pharma, grants and personal fees from Allergopharma, and grants and personal fees from PLS Design, outside the submitted work. SB reports nonfinancial support from ALK-Abelló, grants, personal fees and nonfinancial support from Bencard Allergie GmbH, personal fees from Teomed AG, grants and personal fees from Thermo Fisher Scientific, and grants from Allergy Therapeutics, outside the submitted work.
Google Trends and pollen concentrations in allergy and airway diseases in France
Authors: Jean Bousquet, Gabrielle L. Onorato, Gilles Oliver, Xavier Basagana, Isabella Annesi‐Maesano, Sylvie Arnavielhe, Jean‐Pierre Besancenot, Isabelle Bosse, Philippe J. Bousquet, Denis André Charpin, D. Caillaud, Pascal Demoly, Philippe Devillier, Eve Mathieu‐Dupas, Jean‐François M. Fontaine, Jocelyne Just, Josep M. Anto, João Fonseca, Uwe Berger, Michel Thibaudon
Journal: Allergy (2019)

Google Trends (GTs) is a web-based surveillance tool that explores the searching trends of specific queries via Google. This tool proposes to reflect the real-life epidemiology of allergic rhinitis and asthma. However, the validation of GTs against pollen concentrations is missing at the country level.In the present study, we used GTs (a) to compare the terms related to allergy in France, (b) to assess seasonal variations across the country for 5 years and (c) to compare GTs and pollen concentrations for 2016.Google Trends queries were initially searched to investigate the terms reflecting pollen and allergic diseases. 13- and 5-year GTs were used in France. Then, 5-year GTs were assessed in all metropolitan French regions to assess the seasonality of GTs. Finally, GTs were compared with pollen concentrations (Réseau National de Surveillance en Aerobiology) for 2016 in seven regions (GTs) and corresponding cities (pollen concentrations).The combination of searches for "allergy" as a disease, "pollen" as a disease cause and "ragweed" as a plant was needed to fully assess the pollen season in France. "Asthma" did not show any seasonality. Using the 5-year GTs, an annual and clear seasonality of queries was found in all regions depending on the predicted pollen exposure for spring and a summer peak but not for winter peaks. The agreement between GT queries and pollen concentrations is usually poor except for spring trees and grasses. Moreover, cypress pollens are insufficiently reported by GTs.Google Trends cannot predict the pollen season in France.
Addition of cyclophosphamide on insufficient response to pomalidomide and dexamethasone: results of the phase II PERSPECTIVE Multiple Myeloma trial
Authors: Katja C. Weisel, Christof Scheid, Manola Zago, Britta Besemer, Elias K. Mai, Mathias Haenel, Jan Duerig, Markus Munder, Hans-Walter Lindemann, Anja Seckinger, Christina Kunz, Axel Benner, Dirk Hose, Anna Jauch, Hans Salwender, Hartmut Goldschmidt
Journal: Blood Cancer Journal (2019)
Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination
Authors: Shelby Lennon, Ayman Oweida, Dallin Milner, Andy V. Phan, Shilpa Bhatia, Benjamin Van Court, Laurel Darragh, Adam C. Mueller, David Raben, Jorge L. Martínez-Torrecuadrada, Todd M. Pitts, Hilary Somerset, Kimberly R. Jordan, Kirk C. Hansen, Jason Williams, Wells A. Messersmith, Richard D. Schulick, Philip Owens, Karyn A. Goodman, Sana D. Karam
Journal: Clinical Cancer Research (2019)

A driving factor in pancreatic ductal adenocarcinoma (PDAC) treatment resistance is the tumor microenvironment, which is highly immunosuppressive. One potent immunologic adjuvant is radiotherapy. Radiation, however, has also been shown to induce immunosuppressive factors, which can contribute to tumor progression and formation of fibrotic tumor stroma. To capitalize on the immunogenic effects of radiation and obtain a durable tumor response, radiation must be rationally combined with targeted therapies to mitigate the influx of immunosuppressive cells and fibrosis. One such target is ephrinB2, which is overexpressed in PDAC and correlates negatively with prognosis.Experimental Design: On the basis of previous studies of ephrinB2 ligand-EphB4 receptor signaling, we hypothesized that inhibition of ephrinB2-EphB4 combined with radiation can regulate the microenvironment response postradiation, leading to increased tumor control in PDAC. This hypothesis was explored using both cell lines and in vivo human and mouse tumor models.Our data show this treatment regimen significantly reduces regulatory T-cell, macrophage, and neutrophil infiltration and stromal fibrosis, enhances effector T-cell activation, and decreases tumor growth. Furthermore, our data show that depletion of regulatory T cells in combination with radiation reduces tumor growth and fibrosis.These are the first findings to suggest that in PDAC, ephrinB2-EphB4 interaction has a profibrotic, protumorigenic role, presenting a novel and promising therapeutic target.
Newly identified T cell subsets in mechanistic studies of food immunotherapy
Authors: Vanitha Sampath, Kari C. Nadeau
Journal: Journal of Clinical Investigation (2019)

Allergen-specific immunotherapy has shown promise for the treatment of food allergy and is currently being evaluated in clinical trials. Although immunotherapy can induce desensitization, the mechanisms underlying this process are not completely understood. Recent advances in high-throughput technologies along with concomitant advances in data analytics have enabled monitoring of cells at the single-cell level and increased the research focus on upstream cellular factors involved in the efficacy of immunotherapy, particularly the role of T cells. As our appreciation of different T cell subsets and their plasticity increases, the initial simplistic view that restoring Th1/Th2 balance by decreasing Th2 or increasing Th1 responses can ameliorate food allergy is being enhanced by a more complex model involving other T cell subsets, particularly Tregs. In this Review, we focus on the current understanding of T cell functions in food allergy, tolerance, and immunotherapy.
Identification of transcription factor binding sites using ATAC-seq
Authors: Zhijian Li, Marcel H. Schulz, Thomas Look, Matthias Begemann, Martin Zenke, Ivan G. Costa
Journal: Genome biology (2019)

Transposase-Accessible Chromatin followed by sequencing (ATAC-seq) is a simple protocol for detection of open chromatin. Computational footprinting, the search for regions with depletion of cleavage events due to transcription factor binding, is poorly understood for ATAC-seq. We propose the first footprinting method considering ATAC-seq protocol artifacts. HINT-ATAC uses a position dependency model to learn the cleavage preferences of the transposase. We observe strand-specific cleavage patterns around transcription factor binding sites, which are determined by local nucleosome architecture. By incorporating all these biases, HINT-ATAC is able to significantly outperform competing methods in the prediction of transcription factor binding sites with footprints.
Smad3 mediates TGF-beta induced apoptosis through the control of survivin expression
Authors: Dong-Weon Song, Jianguo Wu, Sudhakar Ammanamanchi, Junhua Yang, Jennie Hauser, Fengzhi Li, Michael Brattain
Journal: Cancer Research (2005)

4501  Transforming growth factor-β (TGF-β) pathway initiates signaling by assembling receptor complexes that activate Smad transcription factors. TGF-β plays a key role in cell proliferation, differentiation and apoptosis. The mechanism of TGF-β induced apoptosis has not been elucidated. We have approached the blockade of Smad3 by using stable ectopic anti-sense Smad3 (AS-Smad3) expression in a breast cancer cell line to understand how the loss of Smad3 affects on the inhibitory TGF-β mediated cell death. In AS-Smad3 MCF-7E cells, we found that the expression of Smad3 mRNA and protein was reduced up to ∼40-45% and were less sensitive to autocrine TGF-β responses than empty vector control using the p3TP-Lux reporter construct. We demonstrated that AS-Smad3 cells showed enhanced anchorage independent growth and cell proliferation. Furthermore, AS-Smad3 cells exhibited delayed apoptosis. We examined whether increased cell survival is involved in the regulation of inhibitor of apoptotic protein (IAP), survivin. We demonstrated that the expression of survivin in AS-Smad3 cells was increased and was reduced by inhibitory TGF-β treatment and rescued by reintroducing wild type Smad3 plasmid in AS-Smad3 cells. In addition, we exhibited that TGF-β signaling regulates the 5’ flanking region (-124 to -113) of human survivin gene in a Smad3 dependent manner. These results indicate that the role of Smad3 in antiproliferative TGF-β pathway converges into the down-regulation of survivin expression resulting in acceleration of tumorigenesis and inhibitory TGF-β induced apoptosis.
Abstract P231: Cumulative Body Mass Index and Incident Prediabetes Over 30 Years of Follow Up: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Pamela J Schreiner, Sejong Bae, Norrina Allen, Kiang Liu, Jared P Reis, Colin O Wu, Katherine H Ingram, Donald M Lloyd-Jones, Cora E Lewis, Jamal S Rana
Journal: Circulation (2017)

Introduction: Higher body mass index (BMI) is associated with incident prediabetes, but whether the association is related to higher BMI or duration is unclear. Methods: We examined cumulative BMI (cBMI) in 4227 black and white men and women, ages 18-30 years at baseline, who were free of prediabetes and diabetes at baseline and did not transition directly from normoglycemia to diabetes. cBMI was a time-varying measure defined as the BMI at a given study visit multiplied by the time until the next available BMI measurement, summed across exams. Prediabetes was defined as fasting glucose of 100-125 mg/dL, 2-hour oral glucose tolerance of 140-199 mg/dL, or HbA1c of 5.7-6.4%. Proportional hazards regression was used to estimate hazard ratios for incident prediabetes across tertiles of cBMI over a maximum of 30 years, without and with adjustment for lifestyle and demographic variables. Results: Over an average of 20.4 years of follow up (range 7 to 30 years), there were 2406 incident prediabetes events (56.9% of the sample). Incident events were observed in each cBMI tertile across the full range of follow-up time. In crude models (Table), the hazard ratios for the second and third tertiles of cBMI were statistically significantly and positively associated with incident prediabetes relative to the first tertile. Multivariable adjustment attenuated the associations such that only the third cBMI tertile remained statistically significant, with an 83% higher rate of prediabetes compared to those in the first tertile. These associations did not differ by race, sex or age. Conclusions: Cumulative BMI, a measure capturing both BMI level and duration, was strongly associated with prediabetes only when a relatively high threshold was reached. These results suggest that a high cumulative burden over a wide range of BMI values and persistence from young adulthood is associated with prediabetes by middle age, allowing primary prevention before middle age and progression to frank diabetes.
Predispositional genome sequencing in healthy adults: design, participant characteristics, and early outcomes of the PeopleSeq Consortium
Authors: Emilie S. Zoltick, Michael D. Linderman, Molly A. McGinniss, Erica Ramos, Madeleine P. Ball, George M. Church, Debra G. B. Leonard, Stacey Pereira, Amy L. McGuire, C. Thomas Caskey, Saskia C. Sanderson, Eric E. Schadt, Daiva E. Nielsen, Scott D. Crawford, Robert C. Green
Journal: Genome Medicine (2019)

Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of predispositional genome sequencing projects, which is examining the medical, behavioral, and economic outcomes of returning genomic sequencing information to healthy individuals. Apparently healthy adults who participated in four of the sequencing projects in the Consortium were included. Web-based surveys were administered before and after genomic results disclosure, or in some cases only after results disclosure. Surveys inquired about sociodemographic characteristics, motivations and concerns, behavioral and medical responses to sequencing results, and perceived utility. Among 1395 eligible individuals, 658 enrolled in the Consortium when contacted and 543 have completed a survey after receiving their genomic results thus far (mean age 53.0 years, 61.4% male, 91.7% white, 95.5% college graduates). Most participants (98.1%) were motivated to undergo sequencing because of curiosity about their genetic make-up. The most commonly reported concerns prior to pursuing sequencing included how well the results would predict future risk (59.2%) and the complexity of genetic variant interpretation (56.8%), while 47.8% of participants were concerned about the privacy of their genetic information. Half of participants reported discussing their genomic results with a healthcare provider during a median of 8.0 months after receiving the results; 13.5% reported making an additional appointment with a healthcare provider specifically because of their results. Few participants (< 10%) reported making changes to their diet, exercise habits, or insurance coverage because of their results. Many participants (39.5%) reported learning something new to improve their health that they did not know before. Reporting regret or harm from the decision to undergo sequencing was rare (< 3.0%). Healthy individuals who underwent predispositional sequencing expressed some concern around privacy prior to pursuing sequencing, but were enthusiastic about their experience and not distressed by their results. While reporting value in their health-related results, few participants reported making medical or lifestyle changes.