tbuckley/cabot-search huggingface dataset:
Abstract C49: Knockdown of FOXN2 enhances adhesion and reduces migration in pancreatic cancer cells
Authors: Blanca Santibanez, Sabrina Oliveira, Kelsie Duggan, Kate Lu, Kristen Johnson
Journal: Cancer Research (2019)

Abstract FOXN2, a member of the forkhead domain binding protein family, was identified as a master regulator whose expression and activity are increased in the progression from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDA). Forkhead transcription factor proteins have been identified as essential components of both oncogenic and tumor suppressive pathways. Deregulation of FOX proteins has a direct role in cancer initiation, maintenance, progression, and drug resistance. In particular, other studies have linked FOXN2 expression to better outcomes in T-cell leukemia and glioblastoma multiforme. Additionally, recent studies indicate that FOXN2 impairs lung cancer cell proliferation in vivo and in vitro. Finally, recent studies in breast cancer cells indicate potential conflicting roles for the FOXN2 transcription factor in maintenance of cancer stem cell phenotypes and in migration and invasion. In the present study, we sought to understand the role of FOXN2 specifically in human pancreatic malignancy. Data from the TCGA database indicates that high levels of FOXN2 are associated with poor overall survival. While knockdown of FOXN2 does not significantly affect proliferation or colony formation of pancreatic cancer cells, we report that knockdown of FOXN2 in PANC-1 and BxPC-3 cells significantly enhances cellular adhesion. Additionally, FOXN2 knockdown reduces cellular invasion through collagen in transwell migration assays. Preliminary data suggest that FOXN2 may mediate some of its effects on adhesion and migration through regulation of Akt2 expression. Overall, our studies suggest that high FOXN2 expression and activity contribute to pancreatic malignancy. A better understanding of the regulation and function of the FOXN2 transcription factor should help us to uncover its potential as a therapeutic target, as well as a predictive marker for cancer. Citation Format: Blanca Santibanez, Sabrina Oliveira, Kelsie Duggan, Kate Lu, Kristen Johnson. Knockdown of FOXN2 enhances adhesion and reduces migration in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C49.
Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials
Authors: Jonathon R Campbell, Anete Trajman, Victoria J Cook, James C Johnston, Menonli Adjobimey, Rovina Ruslami, Lisa Eisenbeis, Federica Fregonese, Chantal Valiquette, Andrea Benedetti, Dick Menzies
Journal: The Lancet Infectious Diseases (2019)
Carbon monoxide: An emerging therapy for acute kidney injury
Authors: Xiaoxiao Yang, Mark de Caestecker, Leo E. Otterbein, Binghe Wang
Journal: Medicinal Research Reviews (2019)

Abstract Treating acute kidney injury (AKI) represents an important unmet medical need both in terms of the seriousness of this medical problem and the number of patients. There is also a large untapped market opportunity in treating AKI. Over the years, there has been much effort in search of therapeutics with minimal success. However, over the same time period, new understanding of the underlying pathobiology and molecular mechanisms of kidney injury have undoubtedly helped the search for new therapeutics. Along this line, carbon monoxide (CO) has emerged as a promising therapeutic agent because of its demonstrated cytoprotective, and immunomodulatory effects. CO has also been shown to sensitize cancer, but not normal cells, to chemotherapy. This is particularly important in treating cisplatin‐induced AKI, a common clinical problem that develops in patients receiving cisplatin therapies for a number of different solid organ malignancies. This review will examine and make the case that CO be developed into a therapeutic agent against AKI.
Effect of major liver resection on colon cancer metastasis in the lung and liver.
Authors: Robert M. Hoffman, Masashi Momiyama, Atsushi Suetsugu, Hiroyuki Kishimoto, Takashi Chishima, Michael Bouvet, Itaru Endo
Journal: Journal of Clinical Oncology (2012)

e14014 Background: Liver resection is a common procedure in liver-metastatic colon cancer. However, recurrence is common and distant liver metastasis may be appear after liver resection. Methods: Experimental liver metastases were established by spleen injection of the Colon 26 murine colon cancer cell line expressing green fluorescent protein (GFP) into transgenic nude mice expressing red fluorescent protein (RFP). Experimental liver metastases was established by splenic injection of Colon-26-GFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection into the spleen or tail vein, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma. Results: Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth. Major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma into the metastases compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. TGF-β was also preferentially stimulated by major resection. Conclusions: Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate metastatic growth. Stromal growth may be stimulated by TGF-β. The results of this study indicate that caution should be taken when planning a major liver resection for metastatic colorectal cancer. Conservative resections that spare liver parenchyma should be considered whenever possible.
Peptidylarginine Deiminase Autoimmunity and the Development of Anti–Citrullinated Protein Antibody in Rheumatoid Arthritis: The Hapten–Carrier Model
Authors: Isabelle Auger, Nathalie Balandraud, Emmanuel Massy, Marie F. Hemon, Elisa Peen, Fanny Arnoux, Charlotte Mariot, Marielle Martin, Pierre Lafforgue, Jean‐Marc Busnel, Jean Roudier
Journal: Arthritis & Rheumatology (2019)

Objective The presence of autoantibodies to citrullinated proteins ( ACPA s) often precedes the development of rheumatoid arthritis ( RA ). Citrullines are arginine residues that have been modified by peptidylarginine deiminases ( PAD s). PAD 4 is the target of autoantibodies in RA . ACPA s could arise because PAD 4 is recognized by T cells, which facilitate the production of autoantibodies to proteins bound by PAD 4. We previously found evidence for this hapten–carrier model in mice. This study was undertaken to investigate whether there is evidence for this model in humans. Methods We analyzed antibody response to PAD 4 and T cell proliferation in response to PAD 4 in 41 RA patients and 36 controls. We tested binding of 65 PAD 4 peptides to 5 HLA – DR alleles ( DRB 1*04:01, *04:02, *04:04, *01:01, and *07:01) and selected 11 PAD 4 peptides for proliferation studies using samples from 22 RA patients and 27 controls. Peripheral blood lymphocytes from an additional 10 RA patients and 7 healthy controls were analyzed by flow cytometry for CD 3, CD 4, CD 154, and tumor necrosis factor expression after PAD 4 stimulation. Results Only patients with RA had both antibodies and T cell responses to PAD 4. T cell response to peptide 8, a PAD 4 peptide, was associated with RA ( P = 0.02), anti‐PAD4 antibodies ( P = 0.057), and the shared epitope ( P = 0.05). Conclusion ACPA immunity is associated with antibodies to PAD 4 and T cell responses to PAD 4 and PAD 4 peptides. These findings are consistent with a hapten–carrier model in which PAD 4 is the carrier and citrullinated proteins are the haptens.
Abstract PR08: Intratumoral T-cell distribution in murine and patient pancreatic cancer correlates with tissue heterogeneity and survival
Authors: Julienne L. Carstens, Pedro Correa de Sampaio, Soutik Barua, Huamin Wang, Jared K. Burks, Arvind Rao, Valerie S. LeBleu, Raghu Kalluri
Journal: Cancer Research (2019)

Abstract The complex microenvironment characteristic of pancreatic ductal adenocarcinoma (PDAC) has been implicated as a critical mediator of tumor progression and therapeutic response. Spatial relationships of individual cellular and acellular components within tumors may offer novel insights into the dynamic and complex functions of PDAC. Using eight-color multiplex immunohistochemistry and novel spatial analysis algorithms, we report a heterogeneous and increased population of infiltrating T lymphocytes in the tumors compared to uninvolved pancreatic tissues of treatment-naïve PDAC patients. Spatial distribution of cytotoxic T cells in proximity to cancer cells independently correlates with increased overall patient survival. Collagen-I and aSMA-positive fibroblasts do not correlate with a paucity of T-cell accumulation around cancer cells, suggesting that PDAC desmoplasia may not be a simple physical barrier. However, T-cell infiltration was reduced in proximity to specific cancer cell subpopulations, supporting cancer-cell intrinsic mechanisms for immune avoidance. Further expansion of this technology using early and late primary tumors and metastatic tissue of genetically engineered mouse models (KrasLSL-G12D; p53R172H; PDX1-Cre; EYFPLSL) demonstrates similar T-cell heterogeneity and spatial associations. These data support the validity of multiplex and spatial analysis platforms for exploring the structure-function relationships in the PDAC microenvironment and suggest differential spatial relationships between cancer subtypes and the surrounding microenvironment may be a determining factor in PDAC progression. This abstract is also being presented as Poster A04. Citation Format: Julienne L. Carstens, Pedro Correa de Sampaio, Soutik Barua, Huamin Wang, Jared K. Burks, Arvind Rao, Valerie S. LeBleu, Raghu Kalluri. Intratumoral T-cell distribution in murine and patient pancreatic cancer correlates with tissue heterogeneity and survival [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR08.
Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study
Authors: Magdy El-Salhy, Jan Gunnar Hatlebakk, Odd Helge Gilja, Anja Bråthen Kristoffersen, Trygve Hausken
Journal: Gut (2019)

Faecal microbiota transplantation (FMT) from healthy donors to patients with irritable bowel syndrome (IBS) has been attempted in two previous double-blind, placebo-controlled studies. While one of those studies found improvement of the IBS symptoms, the other found no effect. The present study was conducted to clarify these contradictory findings.This randomised, double-blind, placebo-controlled study randomised 165 patients with IBS to placebo (own faeces), 30 g FMT or 60 g FMT at a ratio of 1:1:1. The material for FMT was obtained from one healthy, well-characterised donor, frozen and administered via gastroscope. The primary outcome was a reduction in the IBS symptoms at 3 months after FMT (response). A response was defined as a decrease of 50 or more points in the total IBS symptom score. The secondary outcome was a reduction in the dysbiosis index (DI) and a change in the intestinal bacterial profile, analysed by 16S rRNA gene sequencing, at 1 month following FMT.Responses occurred in 23.6%, 76.9% (p<0.0001) and 89.1% (p<00.0001) of the patients who received placebo, 30 g FMT and 60 g FMT, respectively. These were accompanied by significant improvements in fatigue and the quality of life in patients who received FMT. The intestinal bacterial profiles changed also significantly in the groups received FMT. The FMT adverse events were mild self-limiting gastrointestinal symptoms.FMT is an effective treatment for patients with IBS. Utilising a well-defined donor with a normal DI and favourable specific microbial signature is essential for successful FMT. The response to FMT increases with the dose. Trial registration www.clinicaltrials.gov (NCT03822299) and www.cristin.no (ID657402).
Identifying and Prioritizing Chemicals with Uncertain Burden of Exposure: Opportunities for Biomonitoring and Health-Related Research
Authors: Edo D. Pellizzari, Tracey J. Woodruff, Rebecca R. Boyles, Kurunthachalam Kannan, Paloma I. Beamer, Jessie P. Buckley, Aolin Wang, Yeyi Zhu, Deborah H. Bennett
Journal: Environmental Health Perspectives (2019)

Background: The National Institutes of Health’s Environmental influences on Child Health Outcomes (ECHO) initiative aims to understand the impact of environmental factors on childhood disease. More than 40,000 chemicals are currently in commercial use in the United States. The challenge is to prioritize chemicals for biomonitoring that may present health risk concerns. Objectives: Our aim was to prioritize chemicals that may elicit child health effects of interest to ECHO but that have not been biomonitored nationwide and to identify gaps needing additional research. Methods: We searched databases and the literature for chemicals in environmental media and in consumer products that were potentially toxic. We selected chemicals that were not measured in the National Health and Nutrition Examination Survey. From over 700 chemicals, we chose 155 chemicals and created eight chemical panels. For each chemical, we compiled biomonitoring and toxicity data, U.S. Environmental Protection Agency exposure predictions, and annual production usage. We also applied predictive modeling to estimate toxicity. Using these data, we recommended chemicals either for biomonitoring, to be deferred pending additional data, or as low priority for biomonitoring. Results: For the 155 chemicals, 97 were measured in food or water, 67 in air or house dust, and 52 in biospecimens. We found in&nbsp;vivo endocrine, developmental, reproductive, and neurotoxic effects for 61, 74, 47, and 32 chemicals, respectively. Eighty-six had data from high-throughput in vitro assays. Positive results for endocrine, developmental, neurotoxicity, and obesity were observed for 32, 11, 35, and 60 chemicals, respectively. Predictive modeling results suggested 90% are toxicants. Biomarkers were reported for 76 chemicals. Thirty-six were recommended for biomonitoring, 108 deferred pending additional research, and 11 as low priority for biomonitoring. Discussion: The 108 deferred chemicals included those lacking biomonitoring methods or toxicity data, representing an opportunity for future research. Our evaluation was, in general, limited by the large number of unmeasured or untested chemicals. https://doi.org/10.1289/EHP5133
Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial
Authors: Masatoshi Kudo, Kazuomi Ueshima, Masafumi Ikeda, Takuji Torimura, Nobukazu Tanabe, Hiroshi Aikata, Namiki Izumi, Takahiro Yamasaki, Shunsuke Nojiri, Keisuke Hino, Hidetaka Tsumura, Teiji Kuzuya, Norio Isoda, Kohichiroh Yasui, Hajime Aino, Akio Ido, Naoto Kawabe, Kazuhiko Nakao, Yoshiyuki Wada, Osamu Yokosuka, Kenichi Yoshimura, Takuji Okusaka, Junji Furuse, Norihiro Kokudo, Kiwamu Okita, Philip James Johnson, Yasuaki Arai
Journal: Gut (2019)

This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE.Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing.Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities.TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials.NCT01217034.
Call for New Therapies in Heart Failure
Authors: Mathew S. Maurer
Journal: JACC CardioOncology (2019)

It’s the treatment, stupid. — Analogous to James Carville’s statement on presidential re-election campaigns 

Cardiologists and oncologists often differ in their treatment approach. This is illustrated in the management of light chain cardiac amyloidosis (also known as AL cardiac amyloidosis)
Greetings from the editor 2020
Authors: Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2019)

A new decade of the 21st century is starting. We have experienced multiple shake-ups in the course of the last decade, the ‘teens-decade’—political ones and social ones, such as the climate crisis which affects us globally and might even influence the epidemiology of rheumatic diseases in the not too distant future. Hopefully the new decade will find solutions for some of the burning problems of the planet and its societies.

In rheumatology, the first decade of this millennium brought novel therapies especially for rheumatoid arthritis (RA),1 2 changing the lives of millions of patients with RA around the world and making rheumatology one of the most successful medical specialties, attracting many young people to specialise in the field. The second decade brought several major therapeutic advances beyond tumour necrosis factor inhibitors especially for patients with psoriatic arthritis and axial spondyloarthritis3 4; the advent of biosimilars …
HOPS: automated detection and authentication of pathogen DNA in archaeological remains
Authors: Ron Hübler, Felix M. Key, Christina Warinner, Kirsten I. Bos, Johannes Krause, Alexander Herbig
Journal: Genome biology (2019)

Abstract High-throughput DNA sequencing enables large-scale metagenomic analyses of complex biological systems. Such analyses are not restricted to present-day samples and can also be applied to molecular data from archaeological remains. Investigations of ancient microbes can provide valuable information on past bacterial commensals and pathogens, but their molecular detection remains a challenge. Here, we present HOPS (Heuristic Operations for Pathogen Screening), an automated bacterial screening pipeline for ancient DNA sequences that provides detailed information on species identification and authenticity. HOPS is a versatile tool for high-throughput screening of DNA from archaeological material to identify candidates for genome-level analyses.
Association of Prehospital Plasma Transfusion With Survival in Trauma Patients With Hemorrhagic Shock When Transport Times Are Longer Than 20 Minutes
Authors: Anthony E. Pusateri, Ernest E. Moore, Hunter B. Moore, Tuan D. Le, Francis X. Guyette, Michael P. Chapman, Angela Sauaia, Arsen Ghasabyan, James Chandler, Kevin McVaney, Joshua B. Brown, Brian J. Daley, Richard S. Miller, Brian G. Harbrecht, Jeffrey A. Claridge, Herb A. Phelan, William R. Witham, A. Tyler Putnam, Jason L. Sperry
Journal: JAMA Surgery (2019)

Both military and civilian clinical practice guidelines include early plasma transfusion to achieve a plasma to red cell ratio approaching 1:1 to 1:2. However, it was not known how early plasma should be given for optimal benefit. Two recent randomized clinical trials were published, with apparently contradictory results. The Prehospital Air Medical Plasma (PAMPer) clinical trial showed a nearly 30% reduction in mortality with plasma transfusion in the prehospital environment, while the Control of Major Bleeding After Trauma (COMBAT) clinical trial showed no survival improvement.To facilitate a post hoc combined analysis of the COMBAT and PAMPer trials to examine questions that could not be answered by either clinical trial alone. We hypothesized that prehospital transport time influenced the effects of prehospital plasma on 28-day mortality.A total of 626 patients in the 2 clinical trials were included. Patients with trauma and hemorrhagic shock were randomly assigned to receive either standard care or 2 U of thawed plasma followed by standard care in the prehospital environment. Data analysis was performed between September 2018 and January 2019.Prehospital transfusion of 2 U of plasma compared with crystalloid-based resuscitation.The main outcome was 28-day mortality.In this post hoc analysis of 626 patients (467 men [74.6%] and 159 women [25.4%]; median [interquartile range] age, 42 [27-57] years) who had trauma with hemorrhagic shock, a Cox regression analysis showed a significant overall survival benefit for plasma (hazard ratio [HR], 0.65; 95% CI, 0.47-0.90; P = .01) after adjustment for injury severity, age, and clinical trial cohort (COMBAT or PAMPer). A significant association with prehospital transport time was detected (from arrival on scene to arrival at the trauma center). Increased mortality was observed in patients in the standard care group when prehospital transport was longer than 20 minutes (HR, 2.12; 95% CI, 1.05-4.30; P = .04), while increased mortality was not observed in patients in the prehospital plasma group (HR, 0.78; 95% CI, 0.40-1.51; P = .46). No serious adverse events were associated with prehospital plasma transfusion.These data suggest that prehospital plasma is associated with a survival benefit when transport times are longer than 20 minutes and that the benefit-risk ratio is favorable for use of prehospital plasma.ClinicalTrials.gov identifiers: NCT01838863 (COMBAT) and NCT01818427 (PAMPer).