tbuckley/cabot-search huggingface dataset:
Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism
Authors: Thibaut Duparc, Hubert Plovier, Vannina G Marrachelli, Matthias Van Hul, Ahmed Essaghir, Marcus Ståhlman, Sébastien Matamoros, Lucie Geurts, Mercedes M Pardo-Tendero, Céline Druart, Nathalie M Delzenne, Jean-Baptiste Demoulin, Schalk W van der Merwe, Jos van Pelt, Fredrik Bäckhed, Daniel Monleon, Amandine Everard, Patrice D Cani
Journal: Gut (2016)

To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.
Recent thymic emigrants are tolerized in the absence of inflammation
Authors: Travis J. Friesen, Qingyong Ji, Pamela J. Fink
Journal: The Journal of Experimental Medicine (2016)

T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen. After encounter with TRAs in the absence of inflammation, RTEs exhibited defects in proliferation, diminished cytokine production, elevated expression of anergy-associated genes, and diminished diabetogenicity. These properties were mirrored in vitro by enhanced RTE susceptibility to regulatory T cell-mediated suppression. In the presence of inflammation, RTEs and mature T cells were, in contrast, equally capable of inducing diabetes, proliferating, and producing cytokines. Thus, recirculating RTEs encounter TRAs during a transitional developmental stage that facilitates tolerance induction, but inflammation converts antigen-exposed, tolerance-prone RTEs into competent effector cells.
Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population
Authors: Pär Hallberg, Niclas Eriksson, Luisa Ibañez, Emmanuelle Bondon-Guitton, Reinhold Kreutz, Alfonso Carvajal, M Isabel Lucena, Esther Sancho Ponce, Mariam Molokhia, Javier Martin, Tomas Axelsson, Qun-Ying Yue, Patrik K E Magnusson, Mia Wadelius
Journal: The Lancet Diabetes & Endocrinology (2016)
Esophagitis Dissecans Superficialis Endoscopically Induced in a Patient With Pemphigus Vulgaris and Gastrointestinal Complaints
Authors: Taylor Braunberger, Jason E. Hawkes, Jennie T. Clarke, Kathleen K. Boynton, Kristin M. Leiferman
Journal: JAMA Dermatology (2016)

1,2 The commonly reported cutaneous adverse reactions are acneiform eruption, pruritus, xerosis, paronychia, hyperpigmentation, and alopecia. 2However, EGFR can occasionally induce atypical skin reactions, and NME is thought to be extremely rare. 3Usually, NME is the hallmark of glucagonoma syndrome, but it is rarely reported in patients with liver disease, malabsorptive disease, pancreatic neoplasm, and certain drug use in the absence of glucagonoma. 3,4he cause of the NME-like eruption in the present patient was difficult to determine but might have been related to the administration of gefitinib: the lesions dramatically cleared after discontinuation of gefitinib therapy and reappeared with readministration.The epidermal alterations observed could have been the result of the production of inflammatory cytokines acting on keratinocytes.During gefitinib therapy, inflammatory cell chemoattractants such as CXC motif chemokine ligands and CC motif chemokine ligands are released in the epidermis of the involved area, which is similar to the induction of glucagonoma syndrome, in which inflammatory mediators are released in the epidermis by elevated glucagon. 5,6t may contribute to the development of epidermal necrolysis and painful erythematous eruption. 5,6Our patient had to discontinue gefitinib treatment owing to serious NME-like eruption in spite of the antitumor effect of gefitinib, and treatment discontinuation could change his prognosis.
P0811 : Sofosbuvir-based direct-acting antivirals treatment for elderly chronic hepatitis C patients: A cost-effectiveness analysis
Authors: A. Ciaccio, P.A. Cortesi, G. Bellelli, Matteo Rota, Monica Rota, S. Okolicsanyi, L.G. Mantovani, G. Annoni, M. Strazzabosco
Journal: Journal of Hepatology (2015)
Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy
Authors: Lauren E. Johns, Kelly K. Ferguson, Thomas F. McElrath, Bhramar Mukherjee, John D. Meeker
Journal: Environmental Health Perspectives (2016)

Background:Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women.Objectives:We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection.Methods:Data were obtained from pregnant women (n = 439) participating in a nested case–control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy.Results:Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation.Conclusions:These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women.Citation:Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808–1815; http://dx.doi.org/10.1289/EHP170
Susceptibility loci associated with prostate cancer progression and mortality.
Authors: D. J. Gallagher, V. Joseph, A. Cronin, A. J. Vickers, V. E. Reuter, H. I. Scher, J. Eastham, H. Lilja, T. Kirchhoff, K. Offit
Journal: Journal of Clinical Oncology (2010)

4503 Background: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools. Genetic markers may facilitate more accurate outcome prediction. Methods: We investigated associations between 29 single nucleotide polymorphisms (SNPs) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Genotyping was performed on prospectively-collected blood samples from 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007 at a single center. An independent replication was additionally performed on a subset of this cohort using a high resolution panel of 13 SNPs. Results: On univariate analysis, 3 SNPs were associated (p<0.05) with biochemical recurrence; 4 SNPs were associated with castrate metastasis; and 1 SNP was associated with prostate cancer specific mortality. Applying a Bonferroni correction (p<0.0017), one association with biochemical recurrence (p=0.0009) was significant and the association with prostate-specific survival nearly achieved significance (p=0.0017). Five SNPs showed associations on multivariable analysis, although none of these were significant after correcting for multiple testing. A secondary subset analysis using a high resolution SNP panel identified a strong association with prostate cancer-specific mortality in KLK3 (p<0.0005 by both univariate and multivariable analysis). Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical endpoints. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region associated strongly with prostate cancer-specific survival, and rs10486567 in 7JAZF1 gene associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. No significant financial relationships to disclose.
Factors Associated with Second Line Paclitaxel Efficacy in Non-Asian Patients (Pts) with Advanced Oesophagogastric (Og) Cancer
Authors: N. Tarazona, E. Smyth, C. Peckitt, I. Chau, D. Watkins, S. Rao, N. Starling, D. Cunningham
Journal: Annals of Oncology (2014)
Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort
Authors: V. Bonadona, N. Voirin, O. Sinilnikova, H. Mignotte, A. Bremond, P. Mathevet, P. Romestaing, D. Raudrant, G. Lenoir, C. Lasset
Journal: Journal of Clinical Oncology (2006)

591 Background: The debate concerning poorer survival for patients with breast cancer (BC) carrying a BRCA1 germline mutation is unresolved, and requires additional data from population-based studies. Methods: We followed 232 women with invasive BC under age 46, ascertained prospectively through a French population-based BC registry, and tested for BRCA1/2 mutations (median follow-up: 82 months). We compared tumour characteristics and survival rates between 21 BRCA1/2 deleterious mutation carriers and 211 non-carriers. Results: As compared to sporadic tumours, BRCA1/2 tumours showed higher grade (p = 0.02), fewer ductal carcinoma in situ (p = 0.02), more frequent medullary histology (p = 0.02), more frequent negative oestrogen and progesterone receptors (p = 0.001 each). At five years, BC-specific survival, metastasis-free survival, ipsilateral recurrence-free survival and contralateral BC-free survival rates for BRCA1/2 mutation carriers were 95.0%, 94.7%, 100% and 90.0% respectively, compared with 89.6%, 78.2%, 88.8% and 94.4% respectively, for non-carriers (not significant). Rates for women carrying only a BRCA1 mutation were 93.3%, 93.3%, 100%, 86.7%, respectively. 76% of BRCA1/2 carriers received chemotherapy. Conclusions: Despite unfavourable tumour features, we found no evidence for poorer short-term survival in BRCA1 mutation carriers compared to non-carriers in this prospective population-based cohort. The high rate of BRCA1 carriers who received chemotherapy for their BC should question the positive impact of this treatment, as suggested by preclinical studies showing increased chemosensitivity of BRCA1-associated tumours. No significant financial relationships to disclose.
Clinical activity and safety from a phase II study (FIR) of MPDL3280A (anti-PDL1) in PD-L1–selected patients with non-small cell lung cancer (NSCLC).
Authors: David R. Spigel, Jamie E. Chaft, Scott N. Gettinger, Bo H. Chao, Luc Yves Dirix, Peter Schmid, Laura Quan Man Chow, Colombe Chappey, Marcin Kowanetz, Alan Sandler, Roel Peter Funke, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2015)

8028 Background: MPDL3280A (anti-PDL1) has shown activity across a number of tumor types. In FIR, we assessed the efficacy of MPDL3280A in NSCLC pts based on PD-L1 expression. Methods: FIR is a single arm study of MPDL3280A in stage IIIB/IV NSCLC. Cohort 1 included chemo-naive pts, cohort 2 included ≥ 2L pts without brain metastases and cohort 3 included ≥ 2L pts with treated asymptomatic brain metastases. Pts received 1200 mg MPDL3280A IV q3w (last pt entered Jun 27, 2014). Here, we report investigator-assessed ORR per RECIST v1.1 (data cutoff Oct 23, 2014). PD-L1 expression was centrally assayed by an SP142 IHC antibody in archival or fresh tumor biopsies (required for cohorts 2 and 3) and scored as IC 0, 1, 2 or 3 and TC 0, 1, 2 or 3. Pts with PD-L1 TC 2/3 and/or IC 2/3 tumors were enrolled. Results: Of 1,009 pts screened, 205 pts were selected based on tumor PD-L1 status. Of the 138 pts that were enrolled, 137 pts were safety-evaluable. The median age was 66 y (range, 42-85 y) and 58% of pts were male. The AE profile was similar across cohorts. Treatment-related AEs occurred in 67% of pts, most often fatigue (26%), nausea (15%) and decreased appetite (14%). Related Grade 3-4 AEs occurred in 15% of pts, with one related death due to constrictive pericarditis. 114 pts were efficacy-evaluable with ≥ 3-mo follow up in cohort 1 and ≥ 6-mo follow up in cohorts 2 and 3. The highest ORR was seen in pts with PD-L1 TC3 or IC3 tumors (Table). The median DOR has not been reached in cohorts 1 and 2 (Table). Conclusions: MPDL3280A showed clinical efficacy in both chemo-naive and previously treated NSCLC. High PD-L1 expression (TC3 or IC3) was associated with a higher ORR. The safety profile of MPDL3280A in pts with NSCLC was consistent with previous reports. (NCT01846416) Clinical trial information: NCT01846416.Efficacy results. Pt population Cohort 1a Cohort 2b Cohort 3b ORR (95% CI), % n n n All 31 29 (13-45) 71 17 (8-26) 12 17 (0-38) TC3 or IC3 7 29 (0-62) 26 27 (10-44) 8 25 (0-55) DOR range, wk All 9 7-30+c 12 11+-69+c 2 - TC3 or IC3 2 12-18+c 7 30+-69+c 2 - 24-wk PFS (95% CI), % All 31 39 (22-56) 71 35 (23-46) 12 - TC3 or IC3 7 43 (6-80) 26 49 (30-69) 8 - aUnconfirmed ORR. bConfirmed ORR. 2 pts had unknown IC/TC status. c Median not reached.
Labelling food with the exercise needed to expend its calories may lack integrity when activity is summed over the course of a whole day
Authors: Simon J Howard
Journal: BMJ (2016)

In relation to overweight and obesity, Cramer suggests “innovative schemes to change behaviour at the population level.”1 I agree, but “activity equivalent” labelling may have a perverse effect on behaviour because of a failure to consider basal metabolic energy used.

If all foodstuffs were labelled with an “activity equivalent,” the …
Probe-based confocal laser endomicroscopy (pCLE) images of submucosal growth of a duodenal mucous neck cell adenoma
Authors: Tomomitsu Tahara, Noriyuki Horiguchi, Mitsuo Nagasaka, Yoshihito Nakagawa, Tetsuya Tsukamoto, Tomoyuki Shibata, Naoki Ohmiya
Journal: Endoscopy (2016)

Probe-based confocal laser endomicroscopy (pCLE) is an imaging technique that provides in vivo and real-time endomicroscopic analysis [1] [2]. We show images of a duodenal mucous neck cell adenoma growing in the submucosa that was visualized by pCLE.
Abstract 5327: Simultaneous inhibition of ATR and PARP greatly sensitizes colon cancer cell lines to irinotecan
Authors: David Davidson, Atlal Abu-Sanad, Yunzhe Wang, Fatemeh Hasheminasab, Justin Panasci, Raquel Aloyz, Lawrence Panasci
Journal: Cancer Research (2015)

Abstract Enhanced DNA damage repair is one mechanism behind colon cancer drug resistance. Thus, targeting molecular components of repair pathways with specific small molecule inhibitors may improve the efficacy of chemotherapy. ABT-888 and VE-821, inhibitors of poly-ADP-ribose-polymerase (PARP) and the serine/threonine-kinase Ataxia telangiectasia related (ATR), respectively, were used to treat colon cancer cell lines in combination with the topoisomerase-I inhibitor irinotecan (SN38). Our findings show that each of these molecules at nontoxic single agent concentrations synergized with SN38 to produce a 2.2 to 3 fold reduction in the 50% inhibitory concentration (IC50) of SN38 (Table 1). When combined, nontoxic concentrations of ABT-888 and VE-821 produced a 4.5 to 27 fold reduction in the IC50 of SN38. Furthermore, the combination of all three agents was associated with maximal G2-M arrest and enhanced DNA-damage (γH2AX). The mechanism of this enhanced synergy was associated with maximal suppression of SN38 induced PARP activity in the presence of both inhibitors. Furthermore, VE-821 enhancement of SN38 induced DNA-PK phosphorylation was abrogated by ABT-888, resulting in more unrepaired DNA damage. This novel combination of DNA repair inhibitors may be useful to enhance the activity of DNA damaging chemotherapies such as irinotecan and help circumvent resistance to this drug in colon cancer. Cell LineVE-821 (μM)ABT-888 (μM)SN38 (IC50) ± SE (nM)I valueP valueLoVo13.5±1.214.5±1.90.30.020.55.8±2.00.40.030.59.4±1.00.70.0610.53.0±1.20.20.010.50.54.7±1.90.40.02HCT-1168.1±0.713.5±0.50.50.010.55.2±0.60.70.030.53.9±1.10.50.0310.50.3±0.030.10.010.50.52.1±0.40.30.01HT-2920.5±1.819.3±0.60.60.010.512.2±1.30.70.020.512.9±0.70.60.0210.53.9±0.50.30.010.50.56.1±0.20.40.01 Table 1 Colon cancer cell lines LoVo, HCT-116 and HT-29 were treated with SN38 alone or in combination with various concentrations of the ATR inhibitor VE-821 and/or the PARP inhibitor ABT-888. The IC50 values of SN38 were significantly reduced in the presence of VE-821 and/or ABT-888 for all cell lines. Drug synergy (I) values were determined, according to Berenbaum (1978), by calculating the ratio: (IC50 SN38 with inhibitors/IC50 SN38 alone) + (inhibitor concentration used/IC50 inhibitor alone); I less than 1 = synergism, I equal to 1 = additive effect and I greater than 1 = antogonism. Citation Format: David Davidson, Atlal Abu-Sanad, Yunzhe Wang, Fatemeh Hasheminasab, Justin Panasci, Raquel Aloyz, Lawrence Panasci. Simultaneous inhibition of ATR and PARP greatly sensitizes colon cancer cell lines to irinotecan. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5327. doi:10.1158/1538-7445.AM2015-5327
Prognostic Value of Residual Disease in Breast and Nodes (Rdbn), a Histopathologic System to Evaluate the Response After Neoadjuvant Chemotherapy (Nac) in Breast Cancer
Authors: V. Pons, J.A. Pérez-Fidalgo, O. Burgués, M.T. Martinez, P. Martín, B. Bermejo, J.M. Cejalvo, K. Pinilla, A. Lluch-Hernandez
Journal: Annals of Oncology (2014)
Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants
Authors: Willemijn E. Corpeleijn, Marita de Waard, Viola Christmann, Johannes B. van Goudoever, Marijke C. Jansen-van der Weide, Elisabeth M. W. Kooi, Jan F. Koper, Stefanie M. P. Kouwenhoven, Hendrik N. Lafeber, Elise Mank, Letty van Toledo, Marijn J. Vermeulen, Ineke van Vliet, Diny van Zoeren-Grobben
Journal: JAMA Pediatrics (2016)

Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother's milk when compared with formula. When own mother's milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear.To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother's milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality.The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed.Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mother's milk was not (sufficiently) available.The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life.A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mother's milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 [44.7%] [formula] vs 77 [42.1%] [donor milk]; mean difference, 2.6%; 95% CI, -12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37).In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mother's milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary.trialregister.nl Identifier: NTR3225.
Assessment of Medical Practices
Authors: Arnold S. Relman
Journal: New England Journal of Medicine (1980)

OF all the ways proposed to control the runaway costs of health care in this country, "technology assessment" is probably the least controversial. (It isn't exactly noncontroversial, but nothing is these days.) The idea that we could save money through better evaluation of medical practices is powerfully appealing because it offers the possibility of improving the quality of care while moderating its cost. If we only knew more about the efficacy and safety of the tests and procedures that we use in practice, so the reasoning goes, we could concentrate on the best, reduce usage of the marginal, and eliminate . . .