tbuckley/cabot-search huggingface dataset:
Antibodies Set Boundaries Limiting Microbial Metabolite Penetration and the Resultant Mammalian Host Response
Authors: Yasuhiro Uchimura, Tobias Fuhrer, Hai Li, Melissa A. Lawson, Michael Zimmermann, Bahtiyar Yilmaz, Joel Zindel, Francesca Ronchi, Marcel Sorribas, Siegfried Hapfelmeier, Stephanie C. Ganal-Vonarburg, Mercedes Gomez de Agüero, Kathy D. McCoy, Uwe Sauer, Andrew J. Macpherson
Journal: Immunity (2018)

Although the mammalian microbiota is well contained within the intestine, it profoundly shapes development and metabolism of almost every host organ. We questioned the range and depth of microbial metabolite penetration into the host, and how this is modulated by intestinal immunity. Chemically identical microbial and host metabolites were distinguished by stable isotope tracing from 13C-labeled live non-replicating Escherichia coli, differentiating 12C host isotopes with high-resolution mass spectrometry. Hundreds of endogenous microbial compounds penetrated 23 host tissues and fluids after intestinal exposure: subsequent 12C host metabolome signatures included lipidemia, reduced glycolysis, and inflammation. Penetrant bacterial metabolites from the small intestine were rapidly cleared into the urine, whereas induced antibodies curtailed microbial metabolite exposure by accelerating intestinal bacterial transit into the colon where metabolite transport mechanisms are limiting. Pervasive penetration of microbial molecules can cause extensive host tissue responses: these are limited by immune and non-immune intestinal mucosal adaptations to the microbiota.
A Pan-cancer Landscape of Interactions between Solid Tumors and Infiltrating Immune Cell Populations
Authors: David Tamborero, Carlota Rubio-Perez, Ferran Muiños, Radhakrishnan Sabarinathan, Josep M. Piulats, Aura Muntasell, Rodrigo Dienstmann, Nuria Lopez-Bigas, Abel Gonzalez-Perez
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Throughout their development, tumors are challenged by the immune system, and they acquire features to evade its surveillance. A systematic view of these traits, which shed light on how tumors respond to immunotherapies, is still lacking. Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define immunophenotypes. Finally, we identified genomic and transcriptomic traits associated to these immunophenotypes across cancer types. Results: In highly cytotoxic immunophenotypes, we found tumors with low clonal heterogeneity enriched for alterations of genes involved in epigenetic regulation, ubiquitin-mediated proteolysis, antigen presentation, and cell–cell communication, which may drive resistance in combination with the ectopic expression of negative immune checkpoints. Tumors with immunophenotypes of intermediate cytotoxicity are characterized by an upregulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immunosuppressive cells. Tumors with poorly cytotoxic immunophenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, β-catenin, and TGFβ pathways, which may cause immune depletion. Conclusions: We provide a comprehensive landscape of the characteristics of solid tumors that may influence (or be influenced by) the characteristics of their immune infiltrate. These results may help interpret the response of solid tumors to immunotherapies and guide the development of novel drug combination strategies. Clin Cancer Res; 24(15); 3717–28. ©2018 AACR.
Prognostic utility of neuraxis imaging in leptomeningeal metastasis (LM): A retrospective case series.
Authors: Marc C. Chamberlain
Journal: Journal of Clinical Oncology (2013)

2037 Background: Correlate imaging of the central nervous system that includes both brain and spine MRI and radio-isotope cerebrospinal fluid [CSF] flow studies with survival in a retrospective case series of patients with LM. Methods: 240 adult patients with LM (125 non-brain solid tumor patients with positive CSF cytology; 40 non-brain solid tumor patients with negative CSF cytology and MRI consistent with LM; 50 lymphoma and 25 leukemia patients with positive CSF flow cytometry), all considered appropriate for LM-directed treatment, underwent prior to treatment brain and entire spine MRI and radio-isotope CSF flow studies. Results: Median overall survival was significantly shortened in patients with large volume MRI defined disease (defined as measurable tumor &gt; 5 x 10 mm in orthogonal diameters) and in patients with non-corrected CSF flow obstruction irrespective of primary tumor histology. Additionally, cause of death differed wherein patients with large volume of disease or uncorrected obstructed CSF flow more often died of progressive LM disease whereas patients with normal or small volume disease and patients with normal or re-established CSF flow more often died of progressive systemic disease. Conclusions: Neuraxis imaging utilizing brain and spine MRI as well as radio-isotope CSF flow studies appears to have prognostic significance and may be predictive of median overall survival in this large cohort of patients with LM all of whom were considered for treatment with LM.
Exclusive image-guided IMRT versus radical prostatectomy followed by postoperative IMRT for localized prostate cancer: A matched-pair analysis based on risk groups.
Authors: Caroline Azelie, Mélanie Gauthier, Céline Mirjolet-Didelot, Luc Cormier, Etienne Martin, Karine Peignaux-Casasnovas, Gilles Truc, Philippe Maingon, Gilles Crehange
Journal: Journal of Clinical Oncology (2012)

135 Background: To investigate whether patients treated for a localized prostate cancer require prior radical prostatectomy followed by postoperative radiotherapy or exclusive radiotherapy, in the modern era of image-guided IMRT. Methods: One hundred and seventy-eight patients with localized prostate cancer were referred for daily on-line exclusive image-guided IMRT (IG-IMRT), while 69 patients were referred for postoperative IMRT without image guidance after radical prostatectomy (RP+IMRT). The patients were matched in a 1:1 ratio according to their baseline risk group before any treatment. Late toxicity was scored using the CTV v3.0 scale. Biochemical failure was defined as a postoperative PSA ≥ 0.1 ng/mL followed by 1 consecutive rise in PSA for the postoperative group of patients and by the Phoenix definition (nadir+2 ng/mL) for the group of patients treated with exclusive radiotherapy. Results: A total of 98 patients were matched (49:49). Thirty patients had a low-risk (30.6%), 62 patients an intermediate risk (63.3%) and 6 patients a high risk (6.1%). In the RP+IMRT group, the median PSA value before radiotherapy in the RP+IMRT group was 0.28 ng/mL [undetectable-6.99]. The median radiation dose in the IG-IMRT group was 77.4Gy [73.0-79.8 Gy] whereas it was 66.0 Gy [31.4-70.3 Gy] in the RP+IMRT group. The duration of the hormones was similar in both groups (p= 0.438). From the start of any treatment, the median follow-up was 56.6 months (95% CI = [49.6-61.2], range [18.2-115.1]. No patients had late gastrointestinal grade ≥ 2 toxicity in the IG-IMRT group vs. 4% in the RP+IMRT group. Forty-two percent of the patients in both groups had late grade ≥ 2 genitourinary toxicity. The 5-year freedom from biochemical failure rates in the IG-IMRT group and in the RP+IMRT groups were 93.1% [80.0-97.8] and 76.5% [58.3-87.5], respectively (p= 0.031). Conclusions: Patients with localized prostate cancer treated with IG-IMRT had a better oncological outcome than patients treated with RP+IMRT. Further improvements in postoperative IMRT using image guidance and dose escalation need to be evaluated to determine whether it could eventually be superior to IG-IMRT.
A comprehensive population‐based characterization of heart failure with mid‐range ejection fraction
Authors: Angela S. Koh, Wan Ting Tay, Tiew Hwa Katherine Teng, Ola Vedin, Lina Benson, Ulf Dahlstrom, Gianluigi Savarese, Carolyn S.P. Lam, Lars H. Lund
Journal: European Journal of Heart Failure (2017)
Abstract 76: Effects of Long-term Angiotensin-II Infusion on Cardiac and Renal Fibrosis are Blunted in TNFR1-deficient Mice
Authors: Magdalena Mayr, Clemens Duerrschmid, Dorellyn B Lee, Guillermo Medrano, George E Taffet, Mark L Entman, Sandra B Haudek
Journal: Circulation Research (2015)

Background: Brief systemic infusion of Angiotensin-II (Ang-II) to wild-type (WT) mice initiates the development of cardiac interstitial fibrosis. Genetic deletion of tumor necrosis factor receptor 1 (TNFR1) obviates this development and concurrently inhibits Ang-II-induced cardiac remodeling and dysfunction. We now investigated long-term effects of Ang-II on the heart, kidney, and cardiorenal function. Methods: WT and TNFR1-KO mice were infused with 1.5 ug/kg/min Ang-II for 1 and 6 weeks (no uninephrectomy or high-salt diet). Heart, kidney, and serum were isolated and evaluated by histology, cytometry, qPCR, and ELISA techniques. Cardiac function was determined by 2D-echocardiography, systolic blood pressure by tail-cuff plethysmography. Results: Brief infusion of Ang-II to WT mice did not evoke a fibrotic response in the kidney. However, after 6 weeks, WT kidneys developed minimal, but significant interstitial collagen deposition which was supported by upregulation of collagen-I, collagen-III, and alpha-smooth muscle actin gene activation. This fibrotic development was associated with the appearance of myeloid fibroblast precursors, pro-inflammatory M1 and pro-fibrotic M2 cells, and myofibroblasts. Transcriptional expression of pro-inflammatory and pro-fibrotic genes was also increased. These changes were not seen in Ang-II-infused TNFR1-KO kidneys. In WT hearts, despite the disappearance of myeloid cells, cardiac fibrosis persisted throughout the 6-week infusion. WT hearts developed clear evidence of accelerated cardiac hypertrophy and remodeling associated with impaired systolic function. Again, these changes were not seen in Ang-II-infused TNFR1-KO hearts. By contrast, both WT and TNFR1-KO mice responded identically with similar elevations of systolic blood pressure, and serum blood urea nitrogen and creatinine levels. Conclusions: Ang-II-infusion induced an immediate fibrotic response in the heart while fibrosis in the kidney developed slowly. The cardiac fibrosis was accompanied by progressive adverse remodeling and worsening of function over time. TNFR1-KO mice were protected from the Ang-II-induced cardiac and renal fibrosis, despite similar increases in blood pressure and renal dysfunction.
A novel ability of endocytoscopy to diagnose histological grade of differentiation in T1 colorectal carcinomas
Authors: Tomoya Sako, Shin-ei Kudo, Hideyuki Miyachi, Kunihiko Wakamura, Kenta Igarashi, Masashi Misawa, Yuichi Mori, Toyoki Kudo, Takemasa Hayashi, Atsushi Katagiri, Fumio Ishida, Takeshi Azuma, Haruhiro Inoue, Shigeharu Hamatani
Journal: Endoscopy (2017)

Endocytoscopic images closely resemble histopathology. We assessed whether endocytoscopy could be used to determine T1 colorectal cancer histological grade.Endocytoscopic images of 161 lesions were divided into three types: tubular gland lumens, unclear gland lumens, and fused gland formations on endocytoscopy (FGFE). We retrospectively compared endocytoscopic findings with histological grade in the resected specimen superficial layer, and examined the incidence of risk factors for lymph node metastasis.Of the 118 eligible lesions, the sensitivity, specificity, accuracy, negative predictive value, and positive likelihood ratio of tubular or unclear gland lumens to identify well-differentiated adenocarcinomas were 91.0 %, 93.1 %, 91.5 %, 77.1 %, and 13.20, respectively. To identify moderately differentiated adenocarcinomas for FGFE, these values were 93.1 %, 91.0 %, 91.5 %, 97.6 %, and 10.36, respectively. In the 35 lesions with FGFE, the rates of massive invasion, lymphovascular infiltration, and tumor budding were 97.1 %, 60.0 %, and 37.1 %, respectively.Endocytoscopy could be used to diagnose T1 colorectal cancer histological grade, and FGFE was a marker for recommending surgery.
<i>Notes from the Field:</i> Outbreak of Campylobacter jejuni Associated with Consuming Undercooked Chicken Liver Mousse — Clark County, Washington, 2016
Authors: Derel Glashower, Jennifer Snyder, Diane Welch, Shannon McCarthy
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

On July 13, 2016, Clark County (Washington) Public Health (CCPH) received a report of diarrheal illness in four of seven members of a single party who dined at a local restaurant on July 6, 2016. The report was received through an online/telephone system for reporting food service-associated illness complaints. Members of the five households in the party reported that their only shared exposure was the restaurant meal. CCPH ordered closure of the restaurant kitchen on July 13, 2016, and began an investigation to identify the source of diarrheal illness and implement additional control measures.
Reply
Authors: Alessandro Soria, Giuseppe Lapadula, Massimiliano Fabbiani, Andrea Gori
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Fabbiani advises, is on the speakers' bureau, and received grants from Bristol‐Myers Squibb and Gilead. He is on the speakers' bureau and received grants from MSD, ViiV, and Janssen‐Cilag. Dr. Gori advises and received grants from Bristol‐Myers Squibb and Gilead. She received grants from ViiV and MSD. Reply: We are grateful to Dr. Chtioui for his interest in our work and for giving us the chance to clarify some details that could not be explained in the article, due to the inherent brevity of short communications.1 In our cohort, all patients, including those diagnosed with hepatocellular carcinoma (HCC) during or soon after treatment with direct‐acting antivirals (DAA), had a negative liver ultrasonography performed within 6 months before treatment initiation, as standard surveillance for HCC among patients with cirrhosis and because, according to Italian prescribing policies, DAAs cannot be prescribed to patients with active HCC (unless they are on the list for liver transplantation). All HCCs were then diagnosed during the following routine ultrasonographic screening. Although we are unable to determine with certainty whether HCC was already present when DAA treatment was initiated, in 3 cases the diagnosis occurred when the patients were still on DAA treatment and, in the other cases, the short interval between DAA end‐of‐treatment and HCC diagnosis allowed us to presume that unknown active HCC was already present during the course of DAA. In the same cohort of 155 patients with cirrhosis we described 5 patients with past diagnosis of HCC who responded to DAAs, thus providing indirect evidence that active HCC and not HCC per se could hinder virologic response, as concomitantly and independently found by Prenner et al.2 One possible explanation of this phenomenon is the reduced uptake of DAA into HCC cells: Chtioui correctly argues that only paritaprevir and simeprevir are substrates of OATP1B1; thus, its possible down‐regulation on HCC cells could be involved in treatment failure in just 1 or 2 among the 5 patients. We agree that this hypothesis, although plausible, could not be the exclusive mechanism to justify our observation, though altered expression of other membrane transporters (down‐regulation of P‐glycoprotein, overexpression of breast cancer resistance protein) could also contribute to reduced DAA uptake in liver cells. Further increasing the complexity of this issue, other factors adding to the already postulated explanations are possible different levels of hepatitis C virus replication in HCC, as suggested by Chtioui, and a sort of hepatitis C virus segregation into HCC cells, with different viral evolution, favored by possible different penetration of drugs and immune cells due to capillarization of liver sinusoids.3 In vitro studies should be performed to test these complex and intertwined hypotheses.
Preservation of Cell Structure, Metabolism, and Biotransformation Activity of Liver‐On‐Chip Organ Models by Hypothermic Storage
Authors: Marko Gröger, Julia Dinger, Michael Kiehntopf, Frank T. Peters, Ursula Rauen, Alexander S. Mosig
Journal: Advanced Healthcare Materials (2017)

The liver is a central organ in the metabolization of nutrition, endogenous and exogenous substances, and xenobiotic drugs. The emerging organ-on-chip technology has paved the way to model essential liver functions as well as certain aspects of liver disease in vitro in liver-on-chip models. However, a broader use of this technology in biomedical research is limited by a lack of protocols that enable the short-term preservation of preassembled liver-on-chip models for stocking or delivery to researchers outside the bioengineering community. For the first time, this study tested the ability of hypothermic storage of liver-on-chip models to preserve cell viability, tissue morphology, metabolism and biotransformation activity. In a systematic study with different preservation solutions, liver-on-chip function can be preserved for up to 2 d using a derivative of the tissue preservation solution TiProtec, containing high chloride ion concentrations and the iron chelators LK614 and deferoxamine, supplemented with polyethylene glycol (PEG). Hypothermic storage in this solution represents a promising method to preserve liver-on-chip function for at least 2 d and allows an easier access to liver-on-chip technology and its versatile and flexible use in biomedical research.
Abstract 214: Cbl Inhibition Improves Cardiac Function and Survival in Response to Myocardial Ischemia
Authors: Khadija Rafiq, Mikhail Kolpakov, Rachid Seqqat, Jianfen Guo, Xinji Guo, Archana Sanjay, Steven R Houser, Abdelkarim Sabri
Journal: Circulation Research (2012)

Introduction and Hypothesis: Proteasome degradation of ubiquitin-targeted proteins plays an important role in the development of cardiomyopathy and heart failure. The mechanisms that control proteasome function and protein ubiquitination and turnover remain poorly defined. The proto-oncogene Casitas b-lineage lymphoma (Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets tyrosine kinases, resulting in their ubiquitination and down-regulation. Although Cbl is a crucial signaling molecule in many cells, the role of Cbl in the heart is unknown. Methods and Results: We show increased Cbl expression in human failing hearts and in response to pathological stress stimuli in mice. Cbl deficient mice demonstrated a more robust functional recovery after ischemia reperfusion injury, as well as significantly reduced myocyte apoptosis and epidermal growth factor receptor and focal adhesion (FA) protein ubiquitination and downregulation. Cbl Knockdown in-vitro protected cardiomyocytes against H2O2-induced apoptosis. Cbl deficient mice also show greater functional recovery after myocardial ischemia. This cardioprotective effect of Cbl deletion can be attributed, at least in part, to enhanced neoangiogenesis in the infarcted region via upregulation of vascular endothelial growth factor-a. Conclusions: Cbl activation regulates myocyte apoptosis and angiogenesis and contributes to adverse cardiac remodeling post-MI. These findings point to Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling post-MI.
Acute kidney injury in cardiogenic shock: definitions, incidence, haemodynamic alterations, and mortality
Authors: Tuukka Tarvasmäki, Mikko Haapio, Alexandre Mebazaa, Alessandro Sionis, José Silva‐Cardoso, Heli Tolppanen, Matias Greve Lindholm, Kari Pulkki, John Parissis, Veli‐Pekka Harjola, Johan Lassus
Journal: European Journal of Heart Failure (2017)
Whistleblowing: a word of warning from an unreasonable man
Authors: Hendrik J Beerstecher
Journal: BMJ (2017)

Oliver points to the moral, ethical, and professional guidance for blowing the whistle on systematic problems in the NHS.1 This is all well and good if you want to be investigated by the NHS and the General Medical Council (GMC). But if you want to keep your job and registration and to avoid years of …
Natural Killer Cell Activities Against iPSCs-Derived HLA-Knockout Platelets and Megakaryocytes Reveal Perfect Rejection Profiles for Allotransfusion
Authors: Daisuke Suzuki, Naoshi Sugimoto, Norihide Yoshikawa, Hiroshi Endo, Sou Nakamura, Akitsu Hotta, Koji Eto
Journal: Blood (2016)
Prognostic Role of Immunoglobulin G Fragment C Receptor Polymorphisms in Solid Tumors
Authors: Alessandro Adriano Viansone, Daniela Boggiani, Antonino Musolino
Journal: JAMA Oncology (2017)

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CORRECTION
Authors: J S H Gaston, T Kvien, J Rovensky, A Eijsbouts, T Th, A Jansen, M Mr, A-K Tausche, H Schro
Journal: Annals of the Rheumatic Diseases (2004)

Is IV infliximab better than IV methylprednisolone for the treatment of patients with RA when methotrexate fails?
Notice of Retraction and Replacement. Wansink B, Just DR, Payne CR. Can Branding Improve School Lunches? <i>Arch Pediatr Adolesc Med</i>. 2012;166(10):967-968. doi: 10.1001/archpediatrics.2012.999
Authors: Brian Wansink, David R. Just, Collin R. Payne
Journal: JAMA Pediatrics (2017)