tbuckley/cabot-search huggingface dataset:
Vasoactive intestinal peptide stabilizes intestinal immune homeostasis through maintaining interleukin-10 expression in regulatory B cells
Authors: Xiong Sun, Chuanyong Guo, Fang Zhao, Jianhuan Zhu, Yilu Xu, Zhi-Qiang Liu, Gui Yang, Yuan-Yi Zhang, Xia Gu, Liang Xiao, Zhanju Liu, Ping-Chang Yang
Journal: Theranostics (2019)

Rationale: Immune dysfunction is thought to play an important role in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD).However, the underlying mechanism requires further investigation.Vasoactive intestinal peptide (VIP) has immune regulatory functions, but its role in immune regulatory activities in the intestinal mucosa is not fully understood.This study aims to elucidate the role of VIP in the regulation of regulatory B cell (Breg) function in the intestine.Methods: Peripheral blood samples were collected from UC patients and healthy control (HC) subjects.Bregs were isolated from these samples and their immune regulatory function was analyzed.A murine colitis model was established to test the role of VIP in inhibiting inflammation in the intestine.Results: Serum IL-10 and VIP levels were lower in IgE + (≥0.35 IU/mL) UC patients than that in HC subjects.The immune suppressive function of Bregs isolated from IgE + UC patients was impaired.IL-10 mRNA decayed spontaneously in Bregs, which was reversed by VIP added to the culture.Tristetraprolin (TTP) bound IL-10 mRNA to speed its decay, which was blocked by VIP in the culture.Administration of VIP efficiently inhibited experimental colitis.Conclusions: Insufficient VIP levels in the microenvironment speeds IL-10 mRNA decay to cause Breg dysfunction.Administration of VIP can inhibit experimental colitis, suggesting the translational potential of VIP in the treatment of IgE + UC.
Targeted antibody and cytokine cancer immunotherapies through collagen affinity
Authors: Jun Ishihara, Ako Ishihara, Koichi Sasaki, Steve Seung-Young Lee, John-Michael Williford, Mariko Yasui, Hiroyuki Abe, Lambert Potin, Peyman Hosseinchi, Kazuto Fukunaga, Michal M. Raczy, Laura T. Gray, Aslan Mansurov, Kiyomitsu Katsumata, Masashi Fukayama, Stephen J. Kron, Melody A. Swartz, Jeffrey A. Hubbell
Journal: Science Translational Medicine (2019)

An engineered cancer immunotherapy using a collagen-binding domain enhances efficacy and reduces adverse events.
Abstract 19762: High LDL Cholesterol Levels and Risk of Peripheral Vascular Diseases - A Mendelian Randomization Study Including 106,548 Individuals From the General Population
Authors: Frida Emanuelsson, Børge G Nordestgaard, Anne Tybjaerg-Hansen, Marianne Benn
Journal: Circulation (2017)

Introduction: It is known that high LDL cholesterol, as seen in diabetic dyslipidemia, is causally involved in the pathogenesis of atherosclerosis and is causally related to an increased risk of ca...
SAT-091-The collagen hormone Endotrophin, a biomarker of type VI collagen formation-is associated with severe decompensation and predicts transplant-free survival in patients with transjugular intrahepatic portosystemic shunt
Authors: Mette Juul Nielsen, Federica Genovese, Jennifer Lehmann, Robert Schierwagen, Christian Jansen, Michael Praktiknjo, Diana Leeming, Morten Karsdal, Jonel Trebicka
Journal: Journal of Hepatology (2019)
Drive to curb prescribing of over-the-counter drugs saves less money than planned
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A major policy push by NHS England to save £100m a year by curbing GPs’ prescribing of over-the-counter drugs delivered only modest savings last year, the government has disclosed.

Figures presented in parliament1 by health minister Seema Kennedy show that NHS England cut spending by £25.9m on over-the-counter products in the year to January 2019.

She wrote: “We are informed by NHS England that, …
Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis
Authors: Simone Benitz, Tobias Straub, Ujjwal Mukund Mahajan, Jurik Mutter, Stefan Czemmel, Tatjana Unruh, Britta Wingerath, Sabrina Deubler, Lisa Fahr, Tao Cheng, Sven Nahnsen, Philipp Bruns, Bo Kong, Susanne Raulefs, Güralp O Ceyhan, Julia Mayerle, Katja Steiger, Irene Esposito, Jörg Kleeff, Christoph W Michalski, Ivonne Regel
Journal: Gut (2019)

Background and aims Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. Design With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. Results The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. Conclusions Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.
THU-188-Retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus infection and prior DAA failure: An analysis from the German hepatitis C registry (DHC-R)
Authors: Johannes Vermehren, Albrecht Stoehr, Julian Schulze zur Wiesch, Hartwig Klinker, Markus Cornberg, Jung Maria-Christina, Karl-Georg Simon, Yvonne Serfert, Michael P. Manns, Heiner Wedemeyer, Christoph Sarrazin, Deutsches Hepatitis C-Register
Journal: Journal of Hepatology (2019)
FRI-013-A combined blood and MR imaging risk score for monitoring liver inflammation in paediatric AIH
Authors: Kamil Janowski, Andrea Dennis, Maciej Pronicki, Wieslawa Grajkowska, Matgorzata Woźniak, Piotr Pawliszak, Elżbieta Jurkiewicz, Matt Kelly, Stefan Neubauer, Rajarshi Banerjee, Piotr Socha
Journal: Journal of Hepatology (2019)
THU-265-In severe alcoholic hepatitis, serum transferrin indicates impaired HNF4a signaling and predicts mortality independently of disease severity
Authors: Karim Hamesch, Stephen Atkinson, Igor Spivak, Nurdan Gueldiken, Igor Theurl, Heinz ZOLLER, Josepmaria Argemi, Ramon Bataller, Christian Trautwein, Mark Thursz, Pavel Strnad
Journal: Journal of Hepatology (2019)
Use of Crowd Innovation to Develop an Artificial Intelligence–Based Solution for Radiation Therapy Targeting
Authors: Raymond H. Mak, Michael G. Endres, Jin H. Paik, Rinat A. Sergeev, Hugo Aerts, Christopher L. Williams, Karim R. Lakhani, Eva C. Guinan
Journal: JAMA Oncology (2019)

Radiation therapy (RT) is a critical cancer treatment, but the existing radiation oncologist work force does not meet growing global demand. One key physician task in RT planning involves tumor segmentation for targeting, which requires substantial training and is subject to significant interobserver variation.To determine whether crowd innovation could be used to rapidly produce artificial intelligence (AI) solutions that replicate the accuracy of an expert radiation oncologist in segmenting lung tumors for RT targeting.We conducted a 10-week, prize-based, online, 3-phase challenge (prizes totaled $55 000). A well-curated data set, including computed tomographic (CT) scans and lung tumor segmentations generated by an expert for clinical care, was used for the contest (CT scans from 461 patients; median 157 images per scan; 77 942 images in total; 8144 images with tumor present). Contestants were provided a training set of 229 CT scans with accompanying expert contours to develop their algorithms and given feedback on their performance throughout the contest, including from the expert clinician.The AI algorithms generated by contestants were automatically scored on an independent data set that was withheld from contestants, and performance ranked using quantitative metrics that evaluated overlap of each algorithm's automated segmentations with the expert's segmentations. Performance was further benchmarked against human expert interobserver and intraobserver variation.A total of 564 contestants from 62 countries registered for this challenge, and 34 (6%) submitted algorithms. The automated segmentations produced by the top 5 AI algorithms, when combined using an ensemble model, had an accuracy (Dice coefficient = 0.79) that was within the benchmark of mean interobserver variation measured between 6 human experts. For phase 1, the top 7 algorithms had average custom segmentation scores (S scores) on the holdout data set ranging from 0.15 to 0.38, and suboptimal performance using relative measures of error. The average S scores for phase 2 increased to 0.53 to 0.57, with a similar improvement in other performance metrics. In phase 3, performance of the top algorithm increased by an additional 9%. Combining the top 5 algorithms from phase 2 and phase 3 using an ensemble model, yielded an additional 9% to 12% improvement in performance with a final S score reaching 0.68.A combined crowd innovation and AI approach rapidly produced automated algorithms that replicated the skills of a highly trained physician for a critical task in radiation therapy. These AI algorithms could improve cancer care globally by transferring the skills of expert clinicians to under-resourced health care settings.
Smoking does not protect patients with axial spondyloarthritis from attacks of uveitis
Authors: Sizheng Steven Zhao, Gary J Macfarlane, Gareth T Jones, Karl Gaffney, David M Hughes, Robert J Moots, Nicola J Goodson
Journal: Annals of the Rheumatic Diseases (2019)

Acute anterior uveitis (AAU) is the the most common extra-axial manifestation in axial spondyloarthritis (axSpA) and can lead to visual impairment if untreated. Cross-sectional axSpA studies have consistently reported lower odds of AAU in current smokers than ex or never smokers,1 2 which is in contrast to higher AAU risk among smokers in the general population.3 One explanation for this apparent paradox is behaviour change; those with AAU may be more likely to quit smoking. However, this does not explain the higher odds of AAU in never smokers. Another possibility is that smoking is protective for AAU as it is for ulcerative colitis, which shares patho-aetiology with axSpA and AAU.4 If smoking is protective of AAU, it should also reduce the frequency of flares. We examined the impact of smoking status on the number of AAU episodes among patients with AAU.

The British Society for Rheumatology Biologics Register for Ankylosing Spondylitis …
Carbon monoxide improves haemodynamics during extracorporeal resuscitation in pigs
Authors: Jakob Wollborn, Christoph Steiger, Eva Ruetten, Christoph Benk, Fabian A Kari, Christian Wunder, Lorenz Meinel, Hartmut Buerkle, Martin A Schick, Ulrich Goebel
Journal: Cardiovascular Research (2019)

Heart disease of different aetiology remains the leading cause of cardiac arrest (CA). Despite efforts to improve the quality of cardiopulmonary resuscitation (CPR), subsequent myocardial and systemic damage after CA still present a major long-term burden. Low-dose carbon monoxide (CO) is known to exert protective effects in cardiovascular pathophysiology but clinical applications are challenged by unfavourable delivery modes. We tested the hypothesis that extracorporeal resuscitation (E-CPR) in combination with controlled fast onset CO delivery results in improved cardiac physiology and haemodynamics. Damage-associated molecular pattern (DAMP) signalling may be part of the molecular mechanism.In an established porcine model, E-CPR was performed. While E-CPR leads to similar results as compared to a conventional CPR strategy, CO delivery in combination with E-CPR demonstrated significant cardioprotection. Cardiac performance analysis using echocardiography and thermodilution techniques showed a CO-dependent improved cardiac function compared to severe myocardial dysfunction in CPR and E-CPR (left ventricular ejection fraction: Sham 49 ± 5; CPR 26 ± 2; E-CPR 25 ± 2; CO-E-CPR 31 ± 4; P < 0.05). While sublingual microcirculation was significantly compromised in CPR and E-CPR, CO delivery demonstrated a significant improvement in microvascular function (microvascular flow index: Sham 2.9 ± 0.1; CPR 2.2 ± 0.1; E-CPR 1.8 ± 0.1; CO-E-CPR 2.7 ± 0.1; P < 0.01). Histological and serological myocardial damage markers were significantly reduced (hsTroponin-T Sham 0.01 ± 0.001; CPR 1.9 ± 0.2; E-CPR 3.5 ± 1.2; CO-E-CPR 0.5 ± 0.2 ng/mL; P < 0.05). DAMP signalling was decreased ipse facto leading to influence of cardioprotective heat shock and cyclooxygenase response.CO treatment restores myocardial function and improves systemic macro- and microhaemodynamics in E-CPR through a reduction in DAMPs.
Clinical Accountability and Measuring Surgical Readmissions
Authors: Karan R. Chhabra, Rachel M. Werner, Justin B. Dimick
Journal: JAMA Network Open (2019)

Laura A. Graham, PhD, MPH; Hillary J. Mull, PhD, MPP; Todd H. Wagner, PhD; Melanie S. Morris, MD; Amy K. Rosen, PhD; Joshua S. Richman, MD, PhD; Jeffery Whittle, MD, MPH; Edith Burns, MD; Laurel A. Copeland, PhD; Kamal M. F. Itani, MD; Mary T. Hawn, MD, MPH
Predictive value of the pattern of β-catenin expression for pathological response to neoadjuvant chemotherapy in breast cancer patients.
Authors: Shereef Elsamany, Omaima Elemam, Abdullah Saeed Alzahrani, Mohammed M. Abbas, Soha Elmorsy
Journal: Journal of Clinical Oncology (2015)

e12013 Background: Previous studies that addressed the relation of β-catenin expression by immunohistochemistry (IHC) with the outcome of breast cancer (BC) patients have shown mixed results. This study aims to explore the association of β-catenin expression pattern with pathological response to neoadjuvant chemotherapy in BC patients. Methods: In this retrospective study, data of 50 BC patients who received neoadjuvant chemotherapy was recorded. Using IHC, β-catenin expression was classified as either membranous or cytoplasmic according to the pattern of staining. Staining of 15 normal breast tissue specimens was also performed. Distributions of different clinico-pathological parameters and tumour phenotype according to β-catenin expression were assessed using Chi-square test. Logistic regression analysis was used to assess the relation of the pattern of β-catenin expression with pathological complete response (pCR). Results: Cytoplasmic β-catenin expression was detected in 34% of BC tumours but not in any of normal breast tissue specimens. Among BC patients, 52% were hormonal receptors (HR)-positive, 24% were HER2-positive, 78% had clinical T3/T4 tumours and 74% received both anthracycline and taxane-based chemotherapy. A higher percentage of patients with cytoplasmic expression were younger than 40 years at diagnosis (cytoplasmic, 41.2% vs. Membranous 12.1%, p = 0.03). By doing t-test, cytoplasnic β-catenin expression was linked with higher body mass index compared to membranous expression (mean± SD, 32.95 ± 4.467 vs. 29.55 ±6.013, respectively, p = 0.046). No significant associations were found between β-catenin expression and other factors including HR and HER2 status, tumour grade, multicentricity and lymphovascular invasion. The pCR rate was almost doubled in patients with membranous expression but without statistical significance (membranous, 33.3% vs. Cytoplasmic, 17.6%, OR = 2.3, 95% CI = 0.55-9.87, p = 0.24). Conclusions: This study suggests that cytoplasmic β-catenin expression may be linked with lower probability of achieving pCR after neoadjuvant chemotherapy. This data needs to be validated in a larger cohort of patients.
Patients With Acute on Chronic Liver Failure Grade 3 Have Greater 14‐Day Waitlist Mortality Than Status‐1a Patients
Authors: Vinay Sundaram, Parth Shah, Robert J. Wong, Constantine J. Karvellas, Brett E. Fortune, Nadim Mahmud, Alexander Kuo, Rajiv Jalan
Journal: Hepatology (2019)

Patients listed for liver transplantation (LT) as status 1a currently receive the highest priority on the waiting list. The presence of acute on chronic liver failure (ACLF) with three or more organs failing (ACLF‐3) portends low survival without transplantation, which may not be reflected by the Model for End‐Stage Liver Disease‐Sodium (MELD‐Na) score. We compared short‐term waitlist mortality for patients listed status 1a and those with ACLF‐3 at listing. Data were analyzed from the United Network for Organ Sharing database, years 2002‐2014, for 3,377 patients listed status 1a and 5,099 patients with ACLF‐3. Candidates with ACLF were identified based on the European Association for the Study of the Liver Chronic Liver Failure Consortium criteria. MELD‐Na score was treated as a categorical variable of scores &lt;36, 36‐40, and &gt;40. We used competing risks regression to assess waitlist mortality risk. Evaluation of outcomes through 21 days after listing demonstrated a rising trend in mortality among ACLF‐3 patients at 7 days (18.0%), 14 days (27.7%), and 21 days (32.7%) ( P &lt; 0.001) compared to a stable trend in mortality among individuals listed as status 1a at 7 days (17.9%), 14 days (19.3%), and 21 days (19.8%) ( P = 0.709). Multivariable modeling with adjustment for MELD‐Na category revealed that patients with ACLF‐3 had significantly greater mortality (subhazard ratio, 1.45; 95% confidence interval, 1.31‐1.61) within 14 days of listing compared to status‐1a candidates. Analysis of the interaction between MELD‐Na category and ACLF‐3 showed that patients with ACLF‐3 had greater risk of 14‐day mortality than status‐1a‐listed patients, across all three MELD‐Na categories. Conclusion : Patients with ACLF‐3 at the time of listing have greater 14‐day mortality than those listed as status 1a, independent of MELD‐Na score; these findings illustrate the importance of early transplant evaluation and consideration of transplant priority for patients with ACLF‐3.
Peripheral blood biomarkers as prognostic factors for immunotherapy in advanced non-small cell lung cancer (aNSCLC) patients
Authors: A. Prelaj, S.E. Rebuzzi, P. Pizzutilo, M. Bilancia, M. Montrone, F. Pesola, V. Longo, G. Del Bene, V. Lapadula, F. Cassano, P. Petrillo, D. Bafunno, N. Varesano, V. Lamorgese, A. Mastranrdea, D. Ricci, A. Catino, D. Galetta
Journal: Annals of Oncology (2019)

Background: Second-line immunotherapy showed an overall survival (OS) benefit, but only a low percentage of aNSCLC patients (pts) respond to therapy. The identification of new biomarkers to select patients for immunotherapy (IO) is a crucial topic. In our study we aim to investigate the role of peripheral blood biomarkers (PBBs) that can predict response and outcome in aNSCLC pts treated with IO. Methods: We conducted a retrospective analysis on 154 aNSCLC patients receiving single-agent nivolumab or pembrolizumab as second-line (68%) and >3rd line (32%) therapy. We recorded complete blood cell count at baseline (T0), at second (T1) and third cycle (T2), assessing absolute blood count and their ratio such as neutrophil-lymphocyte ratio (NLR), derived-NLR (dNLR) and lymphocyte-monocyte ratio (LMR). Univariate and multivariate analysis were performed to evaluate the correlation between overall response rate (ORR), PFS and OS and PBBs. Results: The univariate analysis for PFS and OS showed that, at T1 and T2, ANC≥7000/µL, AMC≥900/µL, NLR≥4, dNLR>2.2 were statistically significantly associated with worse survival outcomes and increased LMR>1.8 with better survival outcomes. ALC≥1200/µL was associated with higher PFS and OS at T1; AEC<100/µL was associated with worse PFS and OS at T1 and only PFS at T2. The multivariate analysis for PFS confirmed as statistically significant independent predictive factors ANC, ALC and dNLR at both T1 and T2, and AEC at T1, AMC and LMR at T2. The multivariate analysis for OS confirmed as statistically significant independent prognostic factors ANC, ALC, AMC and LMR at both T1 and T2 while dNLR only at T1 and NLR at T2. Conclusions: In conclusion, factors such as high ANC, AMC, NLR and dNLR level can be considered as negative prognostic factors, and high AEC and LMR as positive prognostic factors in NSCLC patients treated with immunotherapy in ≥ second line setting and their change after IO could help monitoring the response and outcome. Further prospective analyses are needed. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Exploiting vulnerabilities of cancer by targeting nuclear receptors of stromal cells in tumor microenvironment
Authors: Hong Sheng Cheng, Jeannie Xue Ting Lee, Walter Wahli, Nguan Soon Tan
Journal: Molecular Cancer (2019)

The tumor microenvironment is a complex and dynamic cellular community comprising the tumor epithelium and various tumor-supporting cells such as immune cells, fibroblasts, immunosuppressive cells, adipose cells, endothelial cells, and pericytes. The interplay between the tumor microenvironment and tumor cells represents a key contributor to immune evasiveness, physiological hardiness and the local and systemic invasiveness of malignant cells. Nuclear receptors are master regulators of physiological processes and are known to play pro−/anti-oncogenic activities in tumor cells. However, the actions of nuclear receptors in tumor-supporting cells have not been widely studied. Given the excellent druggability and extensive regulatory effects of nuclear receptors, understanding their biological functionality in the tumor microenvironment is of utmost importance. Therefore, the present review aims to summarize recent evidence about the roles of nuclear receptors in tumor-supporting cells and their implications for malignant processes such as tumor proliferation, evasion of immune surveillance, angiogenesis, chemotherapeutic resistance, and metastasis. Based on findings derived mostly from cell culture studies and a few in vivo animal cancer models, the functions of VDR, PPARs, AR, ER and GR in tumor-supporting cells are relatively well-characterized. Evidence for other receptors, such as RARβ, RORγ, and FXR, is limited yet promising. Hence, the nuclear receptor signature in the tumor microenvironment may harbor prognostic value. The clinical prospects of a tumor microenvironment-oriented cancer therapy exploiting the nuclear receptors in different tumor-supporting cells are also encouraging. The major challenge, however, lies in the ability to develop a highly specific drug delivery system to facilitate precision medicine in cancer therapy.