tbuckley/cabot-search huggingface dataset:
Outer membrane vesicles blebbing contributes to <i>B. vulgatus</i> mpk-mediated immune response silencing
Authors: Jan Kevin Maerz, Alex Steimle, Anna Lange, Annika Bender, Birgit Fehrenbacher, Julia-Stefanie Frick
Journal: Gut Microbes (2017)

The Gram negative intestinal symbiont Bacteroides vulgatus mpk is able to prevent from induction of colonic inflammation in Rag1-/- mice and promotes immune balance in Il2-/- mice. These inflammation-silencing effects are associated with B. vulgatus mpk-mediated induction of semi-mature dendritic cells, especially in the colonic lamina propria (cLP). However the beneficial interaction of bacteria with host immune cells is limited due to the existence of a large mucus layer covering the intestinal epithelium. How can intestinal bacteria overcome this physical barrier and contact the host immune system? One mechanism is the production of outer membrane vesicles (OMVs) via ubiquitous blebbing of the outer membrane. These proteoliposomes have the ability to traverse the mucus layer. Hence, OMVs play an important role in immunomodulation and the maintenance of a balanced gut microbiota. Here we demonstrate that the stimulation of bone marrow derived dendritic cells (BMDCs) with isolated OMVs originated from B. vulgatus mpk leads to the induction of a tolerant semi-mature phenotype. Thereby, microbe- associated molecular patterns (MAMPs) delivered by OMVs are crucial for the interaction and the resulting maturation of immune cells. Additional to the binding to host TLR4, a yet unknown ligand to TLR2 is indispensable for the conversion of immature BMDCs into a semi-mature state. Thus, crossing the epithelial mucus layer and directly contact host cells, OMV mediate cross-tolerance via the transport of various Toll-like receptor antigens. These features make OMVs to a key attribute of B. vulgatus mpk for a vigorous acellular prevention and treatment of systemic diseases.
Brexit poses financial risk to NHS finances, trust leaders warn
Authors: Gareth Iacobucci
Journal: BMJ (2017)

More than half of NHS trusts believe that Brexit poses a financial risk to their organisation, a poll has found.1

Most NHS trust finance directors (68%) surveyed for the Healthcare Financial Management Association’s (HFMA) NHS financial temperature check identified agency costs as being a risk to their financial plans and a main area where they plan to make savings.

But 54% warned that the UK’s impending …
Genomic Landscape of Pediatric Mixed Phenotype Acute Leukemia
Authors: Thomas B. Alexander, Zhaohui Gu, John K Choi, Mignon L. Loh, John Horan, Barbara Buldini, Giuseppe Basso, Sarah Elitzur, C. Michel Zwaan, Valerie de Haas, Allen Eng Juh Yeoh, Dirk Reinhardt, Daisuke Tomizawa, Tim Lammens, Barbara De Moerloose, Li Zhou, Hiroki Hori, Anthony V. Moorman, Andrew S. Moore, Ondrej Hrusak, Soheil Meshinchi, Etan Orgel, Meenakshi Devidas, Stephen P. Hunger, Jamie M Guidry Auvil, Malcolm A. Smith, Tanja M. Davidsen, Leandro C. Hermida, Patee Gesuwan, Marco A. Marra, Yussanne Ma, Andrew J. Mungall, Richard Moore, Daniela S. Gerhard, Xueyuan Cao, Lei Shi, Stanley Pounds, Hiroto Inaba, Charles Mullighan
Journal: Blood (2016)
Two Outbreaks of Trichinellosis Linked to Consumption of Walrus Meat — Alaska, 2016–2017
Authors: Yuri P. Springer, Shannon Casillas, Kathryn Helfrich, Deanna Mocan, Marscleite Smith, Gabriela Arriaga, Lyndsey Mixson, Louisa Castrodale, Joseph McLaughlin
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

During 1975-2012, CDC surveillance identified 1,680 trichinellosis cases in the United States with implicated food items; among these cases, 1,219 were attributed to consumption of raw or pork products, and 461 were attributed to nonpork products. Although trichinellosis in the United States has historically been associated with consumption of pork, multiple nonporcine species of wild game also are competent hosts for Trichinella spp. and have been collectively implicated in the majority of trichinellosis cases since the late 1990s (1-4) (Figure 1). During July 2016-May 2017, the Alaska Division of Public Health (ADPH) investigated two outbreaks of trichinellosis in the Norton Sound region associated with consumption of raw or undercooked walrus (Odobenus rosmarus) meat; five cases were identified in each of the two outbreaks. These were the first multiple-case outbreaks of walrus-associated trichinellosis in Alaska since 1992 (Figure 2). Health care providers should inquire about consumption of commercially prepared and personally harvested meats when evaluating suspected trichinellosis cases, especially in areas where consumption of wild game is commonplace.
Kinetics-mediate fabrication of multi-model bioimaging lanthanide nanoplates with controllable surface roughness for blood brain barrier transportation
Authors: Peiyuan Wang, Chengli Wang, Lingfei Lu, Xiaomin Li, Wenxing Wang, Mengyao Zhao, Lidan Hu, Ahmed Mohamed El-Toni, Qin Li, Fan Zhang
Journal: Biomaterials (2017)
The P300 ‘face’ speller is resistant to cognitive decline in ALS
Authors: Andrew M. Geronimo, Zachary Simmons
Journal: Brain-Computer Interfaces (2017)

Three different P300 paradigms, the classic matrix-based speller, one employing faces as stimuli, and one with serial stimulus presentation, were used to assess the effects of cognition and visual function on brain–computer interface (BCI) use in 22 patients with amyotrophic lateral sclerosis (ALS) and 13 control participants. The patients in the study, on average, demonstrated lower accuracy than the matched control participants. Patients had a slightly greater incidence of oculomotor limitations, but this did not translate to a measurable difference in task-specific gaze control or performance on any of the tasks. Lower cognitive screen scores were the only clinical characteristic to consistently reduce evoked responses and P300 accuracies across individuals. The late portion of the evoked potential, 500–800 ms after the stimulus, was most strongly associated with cognitive score. The early evoked potential around 170 ms, generated by the face speller, was not as strongly associated with cognition. The results indicate that patients with neurodegenerative disease may fare better using an oddball-based BCI task employing face stimuli due in part to the early evoked response that is less hindered by cognitive impairment.
Necrotising fasciitis as atypical presentation of infection with emerging Neisseria meningitidis serogroup W (MenW) clonal complex 11, the Netherlands, March 2017
Authors: Anne Russcher, Ewout Fanoy, Ger D J van Olden, Antonie D Graafland, Arie van der Ende, Mirjam J Knol
Journal: Eurosurveillance (2017)

In March 2017, a patient with necrotising fasciitis caused by Neisseria meningitidis serogroup W (MenW) clonal complex 11 was diagnosed in the Netherlands. Unusual and severe presentations of MenW infections are common in the current European epidemic. In the Netherlands, the incidence of MenW infections increased 10-fold, from an average of 0.03 per 100,000 population in 2002–2014 to 0.29 in 2016. Awareness of atypical presentations enables timely adequate treatment and public health action.
Perineal Rectosigmoidectomy (Altmeir's Operation) for Rectal Prolapse – A Single Surgeon Experience
Authors: N Kulkarni, A Joseph, P Haray
Journal: Endoscopy (2006)

Aims: To analyse the results of perineal rectosigmoidectomy for rectal prolapse done in a DGH from January1998 to December 2005 under the care of a single consultant surgeon.
Phase 1b/II study of cancer stemness inhibitor napabucasin in combination with FOLFIRI +/− bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts)
Authors: J. Bendell, J. Hubbard, B.H. O’Neil, D. Jonker, A. Starodub, J. Peyton, H. Pitot, T. Halfdanarson, B. Nadeau, J. Zubkus, B. Adesunloye, J. Edenfield, Y.Z. Li, W. Li, A. Grothey, L. Borodyansky, C.J. Li
Journal: Annals of Oncology (2017)
Anti-cancer effect among patients with familial Mediterranean fever: Outcome of 258,803 person-years analysis.
Authors: Ronen Mordechay Brenner
Journal: Journal of Clinical Oncology (2017)

1566 Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease that causes recurrent serosal inflammation. The association between FMF and malignancy has not been previously described. We estimated cancer risk in a large single-institution cohort of FMF patients. Methods: The study cohort consisted of 8,534 FMF patients registered in the Israel National FMF Center at Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and stratified by age and gender. Standardized incidence ratios (SIR) for cancers were calculated. Results: Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. Overall cancer risk among patients with FMF was significantly lower than that expected in the following gender and population groups, based on cancer incidence rates in those groups in the Israeli population: males of Jewish ethnicity SIR 0.66, CI 95% [0.55-0.77], p&lt; 0.001; females of Jewish ethnicity SIR 0.75 CI 95% [0.64-0.86], p&lt; 0.001; males of Arabic ethnicity SIR 0.34, CI 95% [0.07-0.99], p= 0.024. Conclusions: FMF patients have a significantly lower incidence of cancer than the general population. This pattern was demonstrated in two different ethnic populations, Jewish and Arabic. We speculate that the lower cancer incidence could be attributed to the direct physiological effect of FMF or to the anti-FMF treatment.
Outcomes of Allogeneic Stem Cell Transplantation in Pediatric Patients with Myelodysplastic Syndrome and Bone Marrow Failure Due to GATA2 Haploinsufficiency: A Case Control Study
Authors: Inga Hofmann, Serine Avagyan, Alyssa Stetson, Dongjing Guo, Hasan Al-Sayegh, Wendy B. London, Leslie Lehmann
Journal: Blood (2016)
Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab
Authors: Robert W. Hoffman, Joan T. Merrill, Marta M. E. Alarcón‐Riquelme, Michelle Petri, Ernst R. Dow, Eric Nantz, Laura K. Nisenbaum, Krista M. Schroeder, Wendy J. Komocsar, Narayanan B. Perumal, Matthew D. Linnik, David C. Airey, Yushi Liu, Guilherme V. Rocha, Richard E. Higgs
Journal: Arthritis & Rheumatology (2016)

To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab.Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString.At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti-double-stranded DNA (anti-dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti-dsDNA antibody, C3, and immunoglobulin levels.SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE-1 and ILLUMINATE-2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
Tumor location in patients with colorectal cancer treated with bevacizumab
Authors: Teresa Delgado Ureña Ma, Beatriz González-Astorga, Marta Legeren Alvarez, Maria Moreno Raya Patricia, Irene González Cebrián, Fernando Gálvez Montosa, José Rodríguez González Carlos, Marisol Yelamos Vargas, Miguel Jurado García Jose
Journal: Annals of Oncology (2017)
Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity
Authors: Andrés Alloatti, Derek C. Rookhuizen, Leonel Joannas, Jean-Marie Carpier, Salvador Iborra, Joao G. Magalhaes, Nader Yatim, Patrycja Kozik, David Sancho, Matthew L. Albert, Sebastian Amigorena
Journal: The Journal of Experimental Medicine (2017)

CD8+ T cells mediate antigen-specific immune responses that can induce rejection of solid tumors. In this process, dendritic cells (DCs) are thought to take up tumor antigens, which are processed into peptides and loaded onto MHC-I molecules, a process called "cross-presentation." Neither the actual contribution of cross-presentation to antitumor immune responses nor the intracellular pathways involved in vivo are clearly established because of the lack of experimental tools to manipulate this process. To develop such tools, we generated mice bearing a conditional DC-specific mutation in the sec22b gene, a critical regulator of endoplasmic reticulum-phagosome traffic required for cross-presentation. DCs from these mice show impaired cross-presentation ex vivo and defective cross-priming of CD8+ T cell responses in vivo. These mice are also defective for antitumor immune responses and are resistant to treatment with anti-PD-1. We conclude that Sec22b-dependent cross-presentation in DCs is required to initiate CD8+ T cell responses to dead cells and to induce effective antitumor immune responses during anti-PD-1 treatment in mice.
Experience at Informed Consent Forms (ICF) Procedures in an Endoscopic Unit in Greece
Authors: V Koussoulas, S Vassiliou, G Tassias, A Spyridaki, V Karagianni, EJ Giamarellos-Bourboulis, C Barbatzas
Journal: Endoscopy (2006)

Background: Clarified data in informed consent forms (ICF) procedures to endoscopic units in Greece is lacking. Aim of this study was to record the experience to the convention of ICF in a study Greek population with peptic ulcer disease.
Stereotactic body radiotherapy: A promising approach for colorectal lung oligometastases
Authors: Kevin Molina-Mata, Arturo Navarro-Martin, Mercedes Martínez-Villacampa, Milana Bergamino Sirven, Gemma Soler, Maria Cambray, Ricardo Ramos, Cristina Santos, del Mar Arnaiz Maria, Javier Pérez Martín Francisco, Ramon Salazar
Journal: Annals of Oncology (2017)
Abstract 240: Temporally-Stiffening Hydrogel Enhances Cardiomyocyte Maturation via Activation of Mechanosensitive Pathways
Authors: Jennifer L Young, Kyle Kretchmer, Adam J Engler
Journal: Circulation Research (2013)

As cells migrate and differentiate throughout development, they secrete and assemble extracellular matrix, giving rise to time-dependent, tissue-specific stiffness, i.e. myocardium stiffens ~10-fold during maturation. When mimicked in vitro with a thiolated hyaluronic acid/poly(ethylene glycol) diacrylate hydrogel, myocardial matrix stiffening enhanced cardiac specific gene expression and myofibril organization in isolated embryonic cardiomyocytes vs. static hydrogels. Mechanical cues alone, even when time-dependent, were insufficient to induce cardiogenesis in mouse embryonic stem cell (mESCs), but a combination of precisely timed developmentally-relevant chemical cues (e.g. BMP4, Activin A, DKK-1) and dynamic matrix mechanical cues at the cardiac mesoderm induction stage enhanced maturation of mESC-derived cardiomyocytes vs. static hydrogels. On dynamic hydrogels, measurement of sarcomere length shows mESC-derived cardiomyocytes exhibited greater than 30% more mature myofibrils compared to cells plated on static, stiffer matrices. While active mechanotransduction aided maturation, the specific proteins responsible for responding to time-dependent stiffness remain unknown. In order to assess matrix-mediated mechanotransduction, we examined the expression and phosphorylation state of 890 protein kinases, as well as organization of mechanosensitive proteins, e.g. focal adhesion kinase and vinculin, of embryonic cardiomyocytes plated on matrices with either dynamic or static cardiac tissue-specific stiffness. Microarray analysis of protein kinases showed differential expression as a function of mechanics, confirmed by ratiometric western blotting. Several cardiogenic pathways exhibited time-dependent up-regulation on dynamic vs. static matrices, including PI3K/Akt and p38 MAPK, while GSK3β, a known inhibitor of cardiomyocyte maturation was down regulated. These data indicate that mechanically driven maturation is at least partially achieved via active mechanosensing at focal adhesions. Identifying mechanosensitive pathways that are active in cardiomyogenesis can lead to a better understanding of how stem cell differentiation and development are mediated by extracellular matrix properties.
Comprehensive genomic profiling (CGP) versus conventional molecular diagnostic testing of patients with advanced non-small cell lung cancer (NSCLC): Overall survival (OS) and cost in a U.S. health plan population.
Authors: James Signorovitch, Zhou Zhou, Jason Ryan, Anita Chawla
Journal: Journal of Clinical Oncology (2017)

6599 Background: Molecular diagnostic testing options in NSCLC include conventional testing (specific alterations in single genes or multi-gene panels), and CGP (all classes of genomic alterations—base pair substitutions, copy number, insertions/deletions, and rearrangements in multi-gene panels). Guidelines recommend broad molecular profiling to enable genomic matching with available compendia-based and investigational treatment options. This study estimated the incremental benefits and costs of CGP versus conventional testing of patients with advanced NSCLC. Methods: The impacts of increased use of CGP (via FoundationOne) versus conventional molecular testing on OS and on a commercial US health plan budget were estimated using a decision-analytic model. The number of patients needed to test with CGP to add 1 life year was also estimated. Model inputs were based on published literature (incidence rates, OS associated with drugs indicated for advanced NSCLC), real-world data (testing rates, and biopsy, conventional testing, and medical service costs from administrative claims data analyses), list price of FoundationOne, and assumptions for clinical trial participation. Results: Among 2 million covered lives, an estimated 532 had advanced NSCLC and 266 received molecular diagnostic testing. An increase in CGP use from 2% to 10% (+21 patients receiving CGP) was associated with +2 years in population OS and a budget impact of $0.018 per member per month (PMPM). The budget impact was primarily attributable to changes in drug use, longer treatment, and longer survival (collectively $0.013 PMPM) with the remainder due to CGP cost ($0.005 PMPM). Approximately 11 patients need to be tested with CGP versus conventional molecular diagnostic testing to add 1 life year. Conclusions: An increase in molecular diagnostic testing with CGP versus conventional testing to inform treatment decisions in patients with advanced NSCLC was associated with a gain in OS and a modest health plan budget impact, with most of the added costs attributable to increased use of effective treatments and prolonged survival.
Influence of epigenetic inactivation of the RUNX3 gene at 1p36 to survival in human pancreatic cancer
Authors: Shuji Nomoto, Toshiaki Mori, Takashi Kinoshita, Koichi Katoh, Satoshi Otani, Shin Takeda, Naohito Kanazumi, Hiroyuki Sugimoto, Akimasa Nakao
Journal: Cancer Research (2007)

1784   Alteration in transforming growth factor-s signaling pathway is one of the main causes of pancreatic cancer. The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including pancreatic cancer. Therefore, we examined epigenetic alterations of RUNX3 in pancreatic cancer. Thirty-two patients with pancreatic cancer were investigated in this study. We examined the methylation status of RUNX3 promoter region at the gene of 1p36. Then, these results were compared with clinicopathological data. Promoter hypermethylation was detected in 21 (65.6%) of 32 pancreatic cancer tissues by methylation specific PCR (MSP). By comparison with clinicopathological data, survival in patients with hypermethylation was significantly worth than un-methylated cases (p = 0.014). Hypermethylation appears to be a common mechanism for inactivation of RUNX3 in pancreatic cancer. Therefore, RUNX3 may be an important tumor suppressor gene at 1p36 and related to carcinogenesis in pancreatic cancer. In addition, hypermethylation of the RUNX3 gene might be a prediction marker for the patients with pancreatic cancer.
Predictive role of clinical benefit (CB) at 1st line on the outcome of subsequent lines in metastatic breast cancer (MBC) patients: analysis of a “real life” population.
Authors: Ornella Garrone, Massimo Di Maio, Anna Maria Vandone, Rodolfo Brizio, Paola Vanella, Emanuela Miraglio, Alberto Comino, Marco Carlo Merlano
Journal: Journal of Clinical Oncology (2016)

e12027 Background: Many treatments are available for MBC patients (pts), and the “right” choice is commonly based on pts characteristics, hormone receptor (HR) and HER2 status, sites of disease and prior therapy. Most pts receive multiple lines. Our aim is (i) to describe proportion of pts obtaining CB with each line, and (ii) to describe the predictive role of CB at 1st line on the outcome of subsequent lines (2nd - 4th), in a “real life” setting. Methods: We retrieved medical records of pts diagnosed with MBC from 1993 to 2015 at our Institution. The first 4 lines of treatment were considered in this analysis. For each line, CB was defined as progression-free status 6 months after treatment start. CB in a subsequent line was defined as CB obtained with 2nd, 3rd or 4th line. Analysis was conducted in the whole series and in 3 subgroups: HR+HER2-, HER2+ and triple negative (TN). Results: 394 pts were included in the analysis (256 HR+HER2-, 61 HER2+, 26 TN). Median PFS at 1st line in the whole population, HR+HER2-, HER2+ and TN was 12.0, 12.8, 9.7 and 5.7 months respectively. Overall survival in the whole population, HR+HER2-, HER2+ and TN was 34.7, 35.9, 31.1 and 16.1 months respectively. In the whole population, CB was achieved in 71%, 51%, 40% and 42% in 1st, 2nd, 3rd and 4th line respectively. In the same lines, CB was achieved in 75%, 52%, 39% and 44% in HR+HER2-; 70%, 54%, 41% and 39% in HER2+; 50%, 28 %, 7% and 0 in TN. In the whole series, CB in 2nd – 4th line was obtained in 53% of pts with CB in 1st line vs 30% of pts without CB in 1st line (OR 2.67, 95%CI 1.66-4.31, p = 0.0001). Similarly, proportion of pts obtaining CB was higher in those with CB in 1st line in HR+HER2- pts (50% vs 34%, OR 1.95, 95%CI 1.07-3.56, p = 0.03), in HER2+ pts (65% vs 24%, OR 6.04, 95%CI 1.65-22.04, p = 0.0065) while the difference was not significant in TN pts (31% vs 15%, OR 2.44, 95%CI 0.36-16.54, p = 0.36). Conclusions: In MBC pts receiving multiple treatment lines, chance of CB in 2nd or later lines is higher in those who obtain CB in 1st line. However, chance of subsequent CB is not negligible even in pts without CB at 1st line, especially in HR+HER2- and HER2+ pts. Our ability of predicting the best treatment sequence remains limited.