tbuckley/cabot-search huggingface dataset:
Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte–mediated immune suppression
Authors: Ryota Takahashi, Marina Macchini, Masaki Sunagawa, Zhengyu Jiang, Takayuki Tanaka, Giovanni Valenti, Bernhard W Renz, Ruth A White, Yoku Hayakawa, C Benedikt Westphalen, Yagnesh Tailor, Alina C Iuga, Tamas A Gonda, Jeanine Genkinger, Kenneth P Olive, Timothy C Wang
Journal: Gut (2020)

Objective Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression. Design We crossed LSL- Kras +/G12D ; Pdx1 -Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples. Results KC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras +/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8 + T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1 + B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival. Conclusion We show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.
Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma
Authors: Shahid A. Khan, Tracey Genus, Helen Morement, Andrew Murphy, Brian Rous, Daniela Tataru
Journal: Journal of Hepatology (2019)

We read with great interest the manuscript by Bertuccio and colleagues, which highlights an important but often neglected issue in liver cancer – rising rates of cholangiocarcinoma (CC), predominantly intrahepatic CC (ICC). However, there were some issues we feel need clarification.
Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis
Authors: Andrea Di Matteo, Kulveer Mankia, Laurence Duquenne, Edoardo Cipolletta, Richard J Wakefield, Leticia Garcia-Montoya, Jacqueline Leong Nam, Paul Emery
Journal: Annals of the Rheumatic Diseases (2020)

Objectives To investigate, in anti-cyclic citrullinated peptide antibody positive (CCP+) at-risk individuals without clinical synovitis, the prevalence and distribution of ultrasound (US) bone erosions (BE), their correlation with subclinical synovitis and their association with the development of inflammatory arthritis (IA). Methods Baseline US scans of 419 CCP+ at-risk individuals were analysed. BE were evaluated in the classical sites for rheumatoid arthritis damage: the second and fifth metacarpophalangeal (MCP2 and MCP5) joints, and the fifth metatarsophalangeal (MTP5) joints. US synovitis was defined as synovial hypertrophy (SH) ≥2 or SH ≥1+power Doppler signal ≥1. Subjects with ≥1 follow-up visit were included in the progression analysis (n=400). Results BE were found in ≥1 joint in 41/419 subjects (9.8%), and in 55/2514 joints (2.2%). The prevalence of BE was significantly higher in the MTP5 joints than in the MCP joints (p&lt;0.01). A significant correlation between BE and US synovitis in the MTP5 joints was detected (Cramer’s V=0.37, p&lt;0.01). The OR for the development of IA (ever) was highest for the following: BE in &gt;1 joint 10.6 (95% CI 1.9 to 60.4, p&lt;0.01) and BE and synovitis in ≥1 MTP5 joint 5.1 (95% CI 1.4 to 18.9, p=0.02). In high titre CCP+ at-risk individuals, with positive rheumatoid factor and BE in ≥1 joint, the OR increased to 16.9 (95% CI 2.1–132.8, p&lt;0.01). Conclusions In CCP+ at-risk individuals, BE in the feet appear to precede the onset of clinical synovitis. BE in &gt;1 joint, and BE in combination with US synovitis in the MTP5 joints, are the most predictive for the development of clinical arthritis.
Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Garrett Barry, Hector Hugo Li-Chang, Hagen F. Kennecke
Journal: Journal of Clinical Oncology (2015)

646 Background: Epidermal Growth Factor Receptor Inhibitors (EGFRi) are effective agents in the treatment of mCRC but up to one third of KRAS wt tumors do not respond. The primary objective was to identify a gene expression signature associated with primary resistance to panitumumab (Pmab) monotherapy and identify genomic markers associated with resistance. Methods: Patients with previously treated codon 12/13 KRAS wt mCRC were administered Pmab 6mg/kg IV q2weeks in a prospective phase II study. The primary endpoint was tumor response by RECIST and patients with progressive disease 8 weeks after initial Pmab were classified as resistant. Gene expression analysis was performed using a Nanostring-based assay with candidate genes implied in EGFRi resistance expression patterns. Differentially expressed genes were identified by Significance Analysis of Microarrays. Further interrogation of the HER2 signaling pathway was performed by immunohistochemistry and in situ hybridization. Illumina-based targeted resequencing was conducted on 20 cancer-implicated genes. Results: Of 34 patients treated with Pmab, 11 (32%) had progressive disease at 8 weeks and were classified Pmab resistant. A 5-gene expression signature was significantly associated with Pmab resistance (p = 0.001), including ERBB2, MLPH, IRX3, c11orf9, and KLK6. HER2 protein was overexpressed in 4/11 resistant and 0/21 responding cases (p = 0.035). Two (2) resistant tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 RAS mutation occurred in one treatment-resistant patient and was mutually exclusive with ERBB2 mutation, amplification, or HER2 overexpression. Four BRAF mutations were detected, two occurring in resistant patients. Conclusions: In this prospective study, a 5-gene signature including ERBB2 was associated with primary resistance to single agent Pmab. A subgroup of patients had evidence of aberrant HER2/ERBB2 signaling by protein over-expression and gene amplification. Results suggest a significant portion of KRAS wt tumors unresponsive to EGFRi may be identified by gene signature analysis. Clinical trial information: NCT00853931.
Abstract 14071: Association of Aortic Stiffness With Subclinical Left Ventricular Remodeling in African Americans
Authors: Inbar Raber, Floyd F Washington, Solomon K Musani, James G Terry, Adebamike A Oshunbade, William G Hundley, Gary F Mitchell, Ervin R Fox, Connie W Tsao
Journal: Circulation (2019)

Introduction: The relations between aortic stiffness and regional left ventricular (LV) structure and function are not well-established in African Americans. Hypothesis: Greater aortic stiffness is...
Predicting respiratory failure in amyotrophic lateral sclerosis: still a long way to go
Authors: Jason Ackrivo, Lauren Elman, Steven M. Kawut
Journal: European Respiratory Journal (2019)

<b>Prediction modelling is critical for improving ALS respiratory care. Assessing external validity of a model should account for discrimination, calibration, and cohort characteristics. Further work on outcomes is necessary before practice implementation.</b>http://bit.ly/2XbfeUq
Porphyria cutanea tarda and hepatitis C and B viruses infection: A retrospective study
Authors: S NAVAS
Journal: Hepatology (1995)

Based on the knowledge that patients with porphyria cutanea tarda (PCT) usually have chronic liver disease, several authors studied a possible relationship to hepatotropic virus infections. However, the prevalence of hepatitis B virus (HBV)-DNA by polymerase chain reaction (PCR) in serum of these patients, as well as the presence of hepatitis C virus (HCV)-RNA in paired liver, peripheral blood mononuclear cells (PBMCs), and serum samples in these patients has not been reported. We have studied 34 patients with sporadic PCT. Antibodies against HBV were detected in 91% of the patients, but in only 41% of the patients against HBV (P < .01). Viral genomes of HCV and HBV were detected in 65% and 40% of our patients, respectively (P < .05). Genomic and antigenomic HCV strands were found in liver biopsy specimens (100% and 54%), mononuclear cells (100% and 54%), and serum (45% and 0%) from 11 patients. Twelve patients were retrospectively studied, and no correlation was observed between the appearance or disappearance of viral genomes and the simultaneous presence of both genomes with the course of porphyria. In our patients with PCT, detection of viral genomes did not correlate with phlebotomy or length of time since PCT was diagnosed. Our findings demonstrate that HCV infection may be underestimated when detection is performed only in serum of PCT patients, and that HBV infection might also be increased in PCT.
Exploring which gene alterations are found in acral melanoma in Asian people
Authors: Y.‐S. Sheen, K.‐T. Tan, K.‐P. Tse, Y.‐H. Liao, M.‐H. Lin, J.‐S. Chen, J.‐Y. Liau, Y.‐J. Tseng, C.‐H. Lee, C.‐H. Hong, J.‐B. Liao, H.‐T. Chang, C.‐Y. Chu
Journal: British Journal of Dermatology (2020)

Melanoma is a life‐threatening type of skin cancer. It affected about 351,800 people worldwide in 2015. Acral melanoma occurs on non‐hairy acral skin (palms, soles, and nail beds) and is not thought to be linked to ultraviolet radiation (e.g. from the sun), unlike other melanoma types (non‐acral melanoma). This study, conducted by researchers based in Taiwan, aimed to find out which mutations (abnormalities) in certain genes underly acral melanoma and non‐acral melanoma in Asians. This is known as ‘genomic profiling’, and allows scientists to find out about the genetic information related to a person or cell type and the way genes interact with each other. This profiling can be done using a type of genetic testing called next‐generation sequencing. The authors performed comprehensive genomic profiling of 409 cancer‐associated genes in 66 melanomas, comprised of 45 acral melanomas and 21 non‐acral melanomas. The authors found that the non‐acral melanomas showed a significantly higher frequency of a type of mutation called BRAF mutations than the acral melanomas. Meanwhile, the frequencies of other alterations (NRAS/KRAS mutations, cell cycle aberrations, anti‐apoptosis pathway alterations, and receptor tyrosine kinase gene gains) were significantly higher in the acral melanomas. Ulceration, in which the skin on the surface of the melanoma breaks down, was found at significantly higher rates in the acral melanomas and non‐acral melanomas with cell cycle aberrations and receptor tyrosine kinase gene gains. Notably, cell cycle aberrations and anti‐apoptosis pathway alterations were associated with a lower rate of survival in all 66 melanoma patients, and especially in the 45 acral melanoma patients. This study strengthens our understanding of the patterns and repercussions of gene mutations in acral and non‐acral melanoma in Asians. The study revealed that, in addition to treatments called immunotherapies, acral melanoma patients might benefit from treatments that target NRAS/KRAS mutations, cell cycle aberrations, receptor tyrosine kinase gains, and anti‐apoptosis pathways, a possibility which warrants study in the future. This is a summary of the study: Genetic alterations in primary melanoma in Taiwan.
Increased Alternative Complement Pathway Function and Improved Survival during Critical Illness
Authors: William Bain, Huihua Li, Rick van der Geest, Sara R. Moore, Tolani F. Olonisakin, Brian Ahn, Erin Papke, Kaveh Moghbeli, Rebecca DeSensi, Sarah Rapport, Melissa Saul, Mei Hulver, Zeyu Xiong, Rama K. Mallampalli, Prabir Ray, Alison Morris, Lina Ma, Yohei Doi, Yingze Zhang, Georgios D. Kitsios, Hrishikesh S. Kulkarni, Bryan J. McVerry, Viviana P. Ferreira, Mehdi Nouraie, Janet S. Lee
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement activity, during critical illness.
Use of DNA polymerase η protein expression to predict treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy.
Authors: K. Teng, R. Xu
Journal: Journal of Clinical Oncology (2010)

e14632 Background: DNA polymerase η (pol η) is capable of bypassing DNA adducts caused by cisplatin or oxaliplatin and is associated with cellular tolerance to platinums. Previous studies showed that defective pol η resulted in enhanced cisplatin or oxaliplatin sensitivity in some cell lines. The purpose of the present study was to investigate the role of pol η protein expression in metastatic gastric adenocarcinoma. Methods: Four gastric adenocarcinoma cell lines were chosed to explore the relationship between pol η protein expression level and oxaliplatin sensitivity by western blotting and MTT assay. Eighty metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX regimen as first-line chemotherapy were collected, corresponding pretreatment formalin-fixed paraffin-embedded tumor tissues were used to detect pol η protein expression by Immunohistochemistry. Relationship between pol η protein expression and clinical features and outcome of these patients was analysis. Results: A positive linear relationship between pol η protein expression level and 48h IC50 values of oxaliplatin in four gastric cancer cell lines was observed. Positivity of pol η protein expression were strongly associated with poor treatment response, and also shorter survival at both univariate (8 versus 14 months; p < 0.001) and multivariate (hazard ratio, 3.932; 95% confidence interval, 2.278-6.785; p < 0.001) in eighty metastatic gastric adenocarcinoma. Conclusions: Above data indicates pol η is a treatment-response predictive marker of treatment response and survival of metastatic gastric adenocarcinoma patients treated with first-line FOLFOX or XELOX chemotherapy and it is worthy of further randomed controlled clinical trials to confirm. No significant financial relationships to disclose.
Pharmacologic and Nonpharmacologic Treatments for Urinary Incontinence in Women
Authors: Ethan M. Balk, Valerie N. Rofeberg, Gaelen P. Adam, Hannah J. Kimmel, Thomas A. Trikalinos, Peter C. Jeppson
Journal: Annals of Internal Medicine (2019)

This network meta-analysis of 84 randomized trials compared the effectiveness of 14 categories of nonpharmacologic and pharmacologic treatments for urinary incontinence in women.
T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis*1
Authors: D JONES
Journal: Hepatology (1995)

Primary biliary cirrhosis (PBC) is an autoimmune condition that results in destruction of the intrahepatic biliary epithelial cells and is characterized by autoantibodies to pyruvate dehydrogenase complex (PDC). The portal tract T-cell infiltrate and up-regulation of HLA class I, HLA class II, and cell adhesion molecules such as intercellular adhesion molecule-1 on the biliary epithelial cells suggest that T cells play a significant role in mediating this damage. The authors have characterized the peripheral blood T-cell proliferative responses of 24 PBC patients and 48 controls (20 normal, 28 non-PBC chronic liver disease) to the dominant autoantigen PDC, and its constituent components E1, E2 and protein X (which co-purify), and E3. A significant proportion of both PBC patients and controls showed T-cell responses to whole PDC (12 of 24 vs. 24 of 48 SI > 2.5 P = NS) and E1 (15 of 24 vs. 25 of 48 P = NS). Responses to PDC and El are thus seen in normal individuals and are not limited to PBC patients. T-cell responses to E2/X were seen in most PBC patients (14 of 24), but in only a small number of controls (6 of 48, P < .0001), responses to E2/X being significantly more frequent in pre-cirrhotic PBC patients (stages I to III, 12 of 15) than cirrhotic (stage IV, 2 of 9 P < .05). Peripheral blood T-cell responses to E2/X are thus strongly associated with early PBC. Responses to E3 were low in both PBC patients and controls. No differences were seen in responses to the control antigen tetanus toxoid between PBC patients and controls. These in vitro observations are compatible with the view that peripheral mechanisms may play a significant role in maintaining self-tolerance to PDC in the normal state, and that the expression of specific Tcell responses to PDC-E2/X in vivo in PBC patients may be a consequence of impairment of these mechanisms of peripheral tolerance.
Three-dimensional echocardiographic assessment of annular dimension, shape, and dynamics in the normal and regurgitant mitral valve
Authors: S. Kaplan, F.H. Sheehan, G. Bashoin, B. Munt, M. Sivarajan, M.L. Zeppa, E.L. Bolson, R.W. Martin
Journal: Journal of the American College of Cardiology (1998)
Collagen Peptides in Urine: a New Promising Biomarker for the Detection of Colorectal Liver Metastases
Authors: Zarina Lalmahomed, Mirelle Bröker, Henk Roest, Nick Van Huizen, Lennerd Dekker, Wim Calame, Cornelis Verhoef, Jan Ijzermans, Theo Luider
Journal: Annals of Oncology (2013)
Human alveolar macrophages produce a fibroblast-like collagenase and collagenase inhibitor.
Authors: H G Welgus, E J Campbell, Z Bar-Shavit, R M Senior, S L Teitelbaum
Journal: Journal of Clinical Investigation (1985)

Human macrophages have been implicated in connective tissue remodeling; however, little is known about their direct effects upon collagen degradation. We now report that human alveolar macrophages in culture produced both a collagenase and a collagenase inhibitor. The collagenase was secreted in latent form and could be activated by exposure to trypsin. Collagenase production could be increased three- to fourfold by incubating the cells with lipopolysaccharide, but synthesis was largely unaffected by exposure to phorbol myristate acetate. By several criteria, macrophage collagenase was the same as the collagenase secreted by human skin fibroblasts: (a) they were antigenically indistinguishable in double immunodiffusion; (b) both degraded type III collagen preferentially to type I, had little activity against type II collagen, and none against types IV and V, and (c) their affinity for susceptible collagens was equivalent, Michaelis constant = 1-2 microM. Collagenase inhibitory activity was also present in the macrophage-conditioned medium, and was accounted for by an antigen that showed immunologic and functional identity with the collagenase inhibitor secreted by human skin fibroblasts. The amount of inhibitor released by unstimulated cells, approximately 100 ng/10(6) cells per 24 h, was substantially augmented by both phorbol and lipopolysaccharide, although considerable variability in response to these agents was observed between macrophage populations derived from different subjects. As negligible quantities of collagenase or collagenase inhibitor were detectable intracellularly, it appeared that both proteins were secreted rapidly after synthesis. Thus, human macrophages have the capacity to modulate collagen degradation directly by production of collagenase and collagenase inhibitor.
Underwater endoscopic submucosal dissection of a non-granular laterally spreading tumor of the hepatic flexure
Authors: Paolo Cecinato, Fabio Bassi, Giuliana Sereni, Mariachiara Campanale, Veronica Iori, Romano Sassatelli
Journal: Endoscopy (2020)

A 68-year-old man was referred to our hospital for endoscopic treatment of a nongranular pseudodepressed laterally spreading tumor (LST) of the hepatic flexure with a histological diagnosis of adenocarcinoma discovered in another center and for which he refused surgery.
Low levels of <scp>ADAMTS</scp>‐13 with high <scp>anti‐ADAMTS</scp>‐13 antibodies during remission of immune‐mediated thrombotic thrombocytopenic purpura highly predict for disease relapse: A multi‐institutional study
Authors: Francesca Schieppati, Laura Russo, Marina Marchetti, Luca Barcella, Maurizio Cefis, Patricia Gomez‐Rosas, Gloria Caldara, Monica Carpenedo, Mariella D'Adda, Alessandro Rambaldi, Chiara Savignano, Atto Billio, Massimiliano Bruno Franco, Vincenzo Toschi, Anna Falanga
Journal: American Journal of Hematology (2020)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening immune-mediated thrombotic microangiopathy. Daily therapeutic plasma exchange (TPE) and the optimized use of rituximab have strikingly improved the outcome of this disease, however the rate of disease recurrence remains high. Specific predictors of relapse in patients in remission can be relevant for an optimal patient management. In this study, we aimed to identify predictive variables of disease relapse in a multicenter cohort of 74 out of 153 iTTP patients. They were tested at different time points during remission for the levels of ADAMTS-13 activity and autoantibody, and did not receive pre-emptive treatment for ADAMTS-13 activity deficiency during remission. The results showed that the association of ADAMTS13 activity ≤20% with a high anti-ADAMTS-13 titer at remission, and the time to response to first line treatment ≥13 days, were independent predictive factors of disease relapse. In addition, the use of rituximab in patients with exacerbation or refractoriness to TPE was significantly associated with reduced relapse rate. By Cox regression analysis, patients with ADAMTS-13 activity ≤20% plus anti-ADAMTS13 antibody titer ≥15 U/mL at remission had an increased risk of relapse (HR 1.98, CI 95% 1.087-3.614; P < .02). These findings may help to outline more personalized therapeutic strategies in order to provide faster and sustained responses to first-line iTTP treatment and prevent relapses in these patients.
Oral aztreonam, a poorly absorbed yet effective therapy for bacterial diarrhea in US travelers to Mexico
Authors: H. L. DuPont
Journal: JAMA (1992)

Objective.  —To evaluate a poorly absorbed antimicrobial with in vitro activity against all major bacterial enteropathogens in oral therapy for bacterial diarrhea.  Design.  —One hundred ninety-one US students with diarrhea acquired in Mexico received 100 mg of aztreonam or matching placebo three times a day for 5 days. Stools were cultured for bacterial enteropathogens before and after therapy.  Setting.  —We studied US students who acquired diarrhea in Mexico (travelers' diarrhea) in view of the high frequency of bacterial agents in this setting.  Main Outcome Measure.  —We examined time of clinical recovery, treatment failures, adverse experiences, and microbiologic eradication from stool of the etiologic agent in subjects randomized to receive aztreonam or placebo.  Results.  —Aztreonam reduced the average duration of diarrhea compared with the placebo: for all cases, by 40 hours ( P  Escherichia coli diarrhea, by 50 hours ( P  P , not significant [small sample size]); for all bacterial agents, by 57 hours ( P  P  P   Conclusions.  —Oral aztreonam, which is poorly absorbed, was well tolerated and was an effective therapy for bacterial diarrhea in US adults in Mexico.  ( JAMA . 1992;267:1932-1935)