tbuckley/cabot-search huggingface dataset:
Investigation on the MyD88 mediated TLR3 signaling via cell surface in breast cancer
Authors: A. Singh, A. Basu, R. Devkar
Journal: Annals of Oncology (2019)

Background: Toll-like receptor -3 is a nucleic acid-sensing innate immune receptor that detects RNA released from narcotic cells in the tumor microenvironment. TLR3 is expressed on the endosomal compartments but the surface expression of TLR3 has also been reported in various cancers, including breast cancer from our group (Bandopadhya et al., 2015). TLR3 exclusively uses TRIF dependent pathway to mediate its effect on cellular apoptosis and hence used in different clinical trials. But, the outcomes of clinical trials using TLR3 agonists are not always favorable. In the present work, we have addressed the involvement of canonical MyD88 mediated pathway through cell surface to explain the anti-apoptotic effect. Methods: Human breast cancer cells MDA-MB-231, MCF-7 and T47D were challenged with TLR3 ligand Poly (I:C) and MyD88 inhibitor (ST2825). Cell proliferation, BrdU incorporation assay, ELISA, Confocal Microscopy, Western blotting, Co-Immunoprecipitation, and immunohistochemistry were carried out to investigate the signaling cascade. Results: Poly (I:C) treatment enhances the cell proliferation, DNA content and cell viability while MyD88 inhibitor reversed the effect of Poly (I:C). The expression level of secretary IL-6 as well as nuclear localization of NF-kB (p65) was significantly increased with Poly (I:C) addition but the level was decreased with the addition of MyD88 inhibitor. The expression level of P-IRAK1, P-TAK1, IRAK1, TAK1, TAB1, TRAF-6, and Cyclin D1 had significantly increased with Poly (I:C) addition but the level was decreased with the addition of MyD88 inhibitor. The formation of TRAF-6, TAK1 and TAB1 complex also showed the same pattern. Conclusions: The mechanistic process includes surface ligand bound TLR3 induces MyD88 dimerization, which promotes the early phase nuclear localization of p65, to up-regulate IL-6 production and finally promote Cyclin-D1 production. Elevated Cyclin-D1 can justify cellular proliferation than apoptosis which is independent of established TRIF meditated TLR3 signaling promoting apoptosis. Thus, this is the first time reporting the surface TLR3 might use MyD88 mediated canonical pathway. Thus our work can help to TLR3 ligand mediated immunotherapy that got set back earlier clinical trial. Legal entity responsible for the study: Anupam Basu, PhD Molecular Biology and Human Genetics Laboratory Professor Department of Zoology the University of Burdwan Purbo Bardhaman - 713104. Funding: Science and Engineering Research Board, Department of Science & Technology, Government of India. Disclosure: All authors have declared no conflicts of interest.
ROLE OF THE NOVEL INTRODUCED PAN-INTESTINAL CAPSULE ENDOSCOPY SYSTEM IN CELIAC DISEASE
Authors: F Foerster, K Mönkemüller, PR Galle, H Neumann
Journal: Endoscopy (2019)

Capsule endoscopy has proven its efficacy in diagnosing villous atrophy and lymphoma in patients with celiac disease. Most recently, a novel capsule endoscopy system was introduced, allowing for visualization of the small and large bowel. Its role in patients with celiac disease has not been evaluated yet.
ARE WE DOING UNNECESSARY DUODENAL BIOPSIES FOR COELIAC DISEASE IN PATIENTS REFERRED WITH IRON DEFICIENCY ANAEMIA (IDA)?
Authors: A Nassar, M Hunsley, D Singh
Journal: Endoscopy (2019)

According to British Society of Gastroenterologists (BSG) guidance, all patients referred with iron deficiency anaemia (IDA) should first be screened for Coeliac Disease (CD) with serology, Tissue Transglutaminase (TTG). If Coeliac serology is negative, duodenal biopsies do not need to be collected at gastroscopy unless there are specific clinical features to suggest CD. The aim of this study was to evaluate the investigation of Coeliac Disease amongst patients referred with IDA to the Two Week Wait suspected Gastrointestinal (GI) cancer pathway.
Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis
Authors: Thirusha Lane, Marianna Fontana, Ana Martinez-Naharro, Candida Cristina Quarta, Carol J. Whelan, Aviva Petrie, Dorota M. Rowczenio, Janet A. Gilbertson, David F. Hutt, Tamer Rezk, Svetla G. Strehina, Joan Caringal-Galima, Richa Manwani, Faye A. Sharpley, Ashutosh D. Wechalekar, Helen J. Lachmann, Shameem Mahmood, Sajitha Sachchithanantham, Edmund P.S. Drage, Harvey D. Jenner, Rosie McDonald, Ottavia Bertolli, Alan Calleja, Philip N. Hawkins, Julian D. Gillmore
Journal: Circulation (2019)

Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease.We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients.There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9-27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P<0.001) and had worse measures of cardiac disease ( P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P<0.001) in comparison with the other subgroups.ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.
Assessment of Accuracy of Waterfall Plot Representations of Response Rates in Cancer Treatment Published in Medical Journals
Authors: Myung Sun Kim, Vinay Prasad
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Response rates are a well-recognized outcome of clinical trials and provide an objective measure of drug activity. <h3>Objectives</h3> To quantify the difference between objective response rate and visual representation of response in waterfall plots in recent articles in major medical journals and to assess the change in frequency over time with which waterfall plots are used. <h3>Design, Setting, and Participants</h3> In a cross-sectional study, original articles of 6 top journals between July 2016 and June 2018 were manually reviewed to identify articles including a waterfall plot to describe a treatment effect of cancer therapy. Response rates visually represented in waterfall plots were compared with response rates reported as study outcomes. The number of original articles with a waterfall plot as a percentage of total original articles was evaluated, sampling articles from January, February, and March for the years 2004, 2008, 2012, 2016, and 2018. <h3>Main Outcomes and Measures</h3> Difference between response rates depicted in waterfall plots and response rates reported as study outcomes. <h3>Results</h3> One hundred twenty-six articles were selected for analysis. Of the 97 articles reporting investigator-assessed response rates, waterfall plots showed response rates a median (interquartile range) of 6.1% (1.8%-12.0%) higher than rates derived from investigator assessment. Forty-two articles reported response rates based on central assessment as an outcome, and waterfall plots showed response rates a median (interquartile range) of 12.0% (7.7%-18.5%) higher compared with centrally assessed response rates. The estimated percentage of original articles using waterfall plots increased from 0% in 2004 to 7% in 2018. <h3>Conclusions and Relevance</h3> This study suggests that waterfall plots are becoming more common in oncology literature. Waterfall plots provide a visual overestimate of response rate of cancer therapies and should be evaluated with caution.
Oral lichen planus: A disease or a spectrum of tissue reactions? Types, causes, diagnostic algorhythms, prognosis, management strategies
Authors: Marco Carrozzo, Stephen Porter, Valeria Mercadante, Stefano Fedele
Journal: Periodontology 2000 (2019)

Abstract Oral lichen planus and lichenoid lesions comprise a group of disorders of the oral mucosa that likely represent a common reaction pattern to 1 or more unknown antigens. The coexistence of hyperkeratotic striation/reticulation, varying degrees of mucosal inflammation from mild erythema to severe widespread ulceration, and a band‐like infiltrate of mononuclear inflammatory cells including activated T lymphocytes, macrophages, and dendritic cells, are considered suggestive of oral lichen planus and lichenoid lesions. Several classification systems of oral lichen planus and lichenoid lesions have been attempted, although none seem to be comprehensive. In this paper, we present a classification of oral lichen planus and lichenoid lesions that includes oral lichen planus, oral lichenoid contact lesions, oral lichenoid drug reactions, oral lichenoid lesions of graft vs. host disease, discoid lupus erythematosus, and systemic lupus erythematosus, lichen planus‐like variant of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, chronic ulcerative stomatitis, lichen planus pemphigoides, solitary fixed drug eruptions, and lichen sclerosus. We present the clinical and diagnostic aspects of oral lichen planus and lichenoid lesions, and discuss related treatment options.
FRI0202 Low-dose oral cyclophosphamide in the treatment of “active” systemic sclerosis: an open prospective 2-year study
Authors: G Cuomo, S D’Angelo, C Naclerio, M Menegozzo, G Valentini
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Previous studies have reported cyclophosphamide (CYC) to be active in the treatment of fibrosing alveolitis in its early, inflammatory stages. Akesson <i>et al</i>.<sup>1</sup> demonstrated, in CYC treated SSc patients with alveolitis, an effect on inflammation parameters and skin thickening. <h3>Objectives</h3> To test, by a prospective 2-years trial, the efficacy and safety of low-dose oral CYC in the treatment of ?active? SSc whatever the disease manifestation underlying activity. <h3>Methods</h3> SSc patients consecutively admitted were divided into 2 groups: group I with active disease (i.e. patients who had a new disease manifestation and/or a deterioration of a previously present one in the six months preceding the enrollment or who presented laboratory alterations indicating immune-inflammatory activity such as hypergammaglobulinemia and/or hypocomplementemia) and group II with inactive disease (i.e. patients with neither feature). Group I patients were treated with oral CYC (50 mg/daily) in addition to the previously administered symptomatic treatment; group II patients were only treated with symptomatic therapy. The following parameters (total skin score; ulcer healing; FVC; DLCO; EF; gammaglobulin levels; complement levels) and the severity scales recently proposed by Medsger <i>et al</i>.<sup>2</sup> were carried out at 12 and 24 months. <h3>Results</h3> Out of the 45 recruited patients (42 F, 3M; aged 30 to 72 years, median age 49; 34 with lcSSc, 11 with dcSSc; disease duration ranging from 1 to 34, median 16 years) 22 were included in group I and 23 in group II. The study was discontinued for lack of efficacy in 5 out of the 19 group I patients and 8 out of the 19 group II patients who had at least the 12-months assessment (p &gt; 0.05). No significant difference was detected between the 2 groups in any clinical, laboratory and instrumental parameters assessed, including Medsger?s severity scales. C3 and C4 significantly increased in the group I patients after 12 and 24 months; ESR decreased in group I patients only after 12 months. <h3>Conclusion</h3> Our results suggest that CYC might be able to contrast the evolution of disease in a significant percentage of SSc active patients. The role as a disease-modifying drug of SSc as a whole must be further investigated. <h3>References</h3> Akesson, <i>et al</i>. Arthritis Rheum. 1994;37:729–35 Medsger TA, <i>et al</i>. J Rheumatol. 1999;26:2159–67
THE USE OF AN ADDITIONAL WORKING CHANNEL (AWC) IN ENDOSCOPIC MUCOSAL RESECTION (EMR+) COMPARED TO CONVENTIONAL EMR
Authors: RF Knoop, E Wedi, V Ellenrieder, A Neesse, S Kunsch
Journal: Endoscopy (2019)

Endoscopic mucosal resection (EMR) can be enhanced by a new external additional working channel (AWC, Ovesco Endoscopy, Tuebingen, Germany) to “EMR+”. The AWC is mounted on a standard endoscope similar to the setup known from the full-thickness resection device (FTRD). So far, we do not have much data evaluating EMR+. We compared EMR+ to the gold standard of classical EMR.
PREDICTORS OF FAILURE OF PNEUMATIC DILATION IN ACHALASIA
Authors: M Ayari, S Ayedi, E Bel Hadj Mabrouk, Y Zaimi, L Mouelhi, R Debbeche
Journal: Endoscopy (2019)

Although endoscopic peroral endoscopic myotomy (POEM) is an innovative and promising technique, its place remains to be defined and the first line treatment is still based on pneumatic dilation (PD) in several countries. The purpose of this study is to assess the results of endoscopic dilation and to determine the predictive factors for failure of this treatment.
Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress
Authors: Lucy A. Young, Lenka Oplustil O'Connor, Christelle de Renty, Margaret H. Veldman-Jones, Thierry Dorval, Zena Wilson, David R. Jones, Deborah Lawson, Rajesh Odedra, Apolinar Maya-Mendoza, Corinne Reimer, Jiri Bartek, Alan Lau, Mark J. O'Connor
Journal: Cancer Research (2019)

DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and CDKN2A/B deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G1 cells leading to G1 arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis. In vivo xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need. SIGNIFICANCE: ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.
Social, biological, and programmatic factors linking adolescent pregnancy and early childhood undernutrition: a path analysis of India's 2016 National Family and Health Survey
Authors: Phuong Hong Nguyen, Samuel Scott, Sumanta Neupane, Lan Mai Tran, Purnima Menon
Journal: The Lancet Child & Adolescent Health (2019)

Adolescent pregnancy and child undernutrition are major social and public health concerns. We aimed to examine associations between adolescent pregnancy and child undernutrition in India, where one in five adolescents live, and one in three of the world's stunted children.Data were from India's fourth National Family Health Survey, 2015-16. Primiparous women aged 15-49 years who gave birth between 2010 and 2016 were classified on the basis of age at first birth: 10-19 years (adolescence), 20-24 years (young adulthood), and 25 years or older (adulthood). Primary outcomes were anthropometric measures of offspring undernutrition. Multivariable regression and structural equation models were used to understand the extent to which these measures were linked to adolescent pregnancy and the potential social, biological, and programmatic pathways.Of the 60 096 women in the sample, 14 107 (25%) first gave birth during adolescence. Children born to adolescent mothers had lower Z scores for length or height-for-age (mean difference -0·53 SD), weight-for-age (-0·40 SD), and weight-for-length or height (-0·16 SD) than children born to adult mothers. Compared with adult mothers, adolescent mothers were shorter (-1·21 cm, 95% CI -1·78 to -0·65), more likely to be underweight (18 percentage points, 15-21) and anaemic (8 percentage points, 6-11), less likely to access health services (-4 to -15 percentage points), and had poorer complementary feeding practices (-3 to -9 percentage points). Adolescent mothers also had less education (-3·30 years, 95% CI -3·68 to -2·91), less bargaining power (-7 to -15 percentage points), and lived in poorer households (-0·66 SD, 96% CI -0·82 to -0·50) with poorer sanitation (-28 percentage points, -32 to -24). In the path analysis, these intermediate factors predicted child anthropometry, with the strongest links being mother's education (18%), socioeconomic status (13%), and weight (15%).Children born to adolescent mothers are at risk of being undernourished. Adolescent pregnancy is related to child undernutrition through poor maternal nutritional status, lower education, less health service access, poor complementary feeding practices, and poor living conditions. Policies and programmes to delay pregnancy and promote women's rights could help break the intergenerational cycle of undernutrition through many routes.Bill & Melinda Gates Foundation through Partnerships and Opportunities to Strengthen and Harmonize Actions for Nutrition in India, led by the International Food Policy Research Institute.
SMSA SCORE FOR COLORECTAL ENDOSCOPIC SUBMUCOSAL DISSECTION (CR-ESD): IS IT USEFUL FOR PLANNING RESOURCES OR PREDICTING PROCEDURAL OUTCOMES? A MULTICENTER SPANISH PROSPECTIVE STUDY
Authors: JC Marín-Gabriel, A Herreros de Tejada Echanojauregui, F Múgica-Aguinaga, F Ramos-Zabala, E Albéniz-Arbizu, PJ Rosón-Rodríguez, J de la Peña-García, Á Terán-Lantarón, J Rodríguez-Sánchez, D García-Romero, A Amorós-Tenorio, A Sánchez-Yagüe, H Uchima, AJ del Pozo-García, C Dolz-Abadía, MG Fernández-Esparrach, J Santiago-García, Ó Nogales-Rincón, A Álvarez-Delgado, H Cortes-Pérez, R Durán-Bermejo
Journal: Endoscopy (2019)

To assess the ability of SMSA to predict clinical outcomes of CR-ESD: length of the procedure and percentages of piecemeal resections, aborted procedures and complications.
Inflammatory breast cancer cells are characterized by abrogated TGFβ1-dependent cell motility and SMAD3 activity
Authors: C. Rypens, C. Van Berckelaer, C. Billiet, J. Hauspy, F. Bertucci, G. Devi, P. Vermeulen, L.Y. Dirix, S.J. Van Laere
Journal: Annals of Oncology (2019)

Background: Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer with elevated metastatic potential, characterized by the frequent presence of tumor emboli in dermal and parenchymal lymph vessels. This study examines the role of TGFβ signaling in the molecular biology of IBC. Methods: TGFβ1 induced cell motility (i.e. xCELLigence, wound healing assays) and gene expression (RNA sequencing) were investigated in a panel of three IBC and three subtype-matched nIBC cell lines. In addition, a series of tissue samples from 75 and 135patients with and without IBC was investigated for nuclear expression of total SMAD2, SMAD3 and SMAD4 using immunohistochemistry. SMAD protein expression data were related to gene expression data from patients with available Affymetrix HGU133plus2 profiles. Results: TGFβ1-induced cell motility was strongly abrogated in all IBC cells (P = 0.003), independent of their molecular subtype. Genes differentially expressed between IBC and nIBC cells post 4 hours of TGFβ1 revealed attenuated expression of SMAD3 transcriptional regulators with concomitant overexpression of MYC target genes in IBC. IBC patient samplesdemonstrated a near absence of nuclear SMAD3 expression in the primary tumors from (P < 0.001) and a further reduction of SMAD3 staining intensity was observed in tumor emboli (P = 0.019). Integration of gene and protein expressiondata revealed that a substantial fraction of the IBC signature genes correlated with SMAD3 and these genes (i.e. 21/24; P < 0.001) are indicative of attenuated SMAD3 signaling in IBC. Conclusions: We demonstrate that IBC cells are characterized by attenuated SMAD3 protein expression and transcriptional activity, leading to obliteration of the cell motility inducing capacity of TGFβ1. Recent studies revealed that SMAD3 is essential for TGFβ1 induced cell motility through induction of epithelial to mesenchymal transition (EMT). This study suggests that in the absence of SMAD3 expression, a partial EMT is induced leading to collectively invading cancer cells that are gifted with a high metastatic potential, thereby providing an intriguing explanatory model of the biology of tumor emboli in IBC. Legal entity responsible for the study: University of Antwerp. Funding: Kom Op Tegen kanker - Emmanuel Van der Schueren. Disclosure: All authors have declared no conflicts of interest.
The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13
Authors: Yan Hu, Meilian Zhang, Ningyu Tian, Dengke Li, Fan Wu, Peishan Hu, Zhixing Wang, Liping Wang, Wei Hao, Jingting Kang, Bin Yin, Zhi Zheng, Tao Jiang, Jiangang Yuan, Boqin Qiang, Wei Han, Xiaozhong Peng
Journal: Journal of Clinical Investigation (2019)

Gliomas account for approximately 80% of primary malignant tumors in the central nervous system. Despite aggressive therapy, the prognosis of patients remains extremely poor. Glioma stem cells (GSCs) which considered as the potential target of therapy for their crucial role in therapeutic resistance and tumor recurrence, are believed to be key factors for the disappointing outcome. Here, we took advantage of GSCs as the cell model to perform high-throughput drug screening and the old antibiotic, clofoctol, was identified as the most effective compound, showing reduction of colony-formation and induction of apoptosis of GSCs. Moreover, growth of tumors was inhibited obviously in vivo after clofoctol treatment especially in primary patient-derived xenografts (PDXs) and transgenic xenografts. The anticancer mechanisms demonstrated by analyzing related downstream genes and discovering the targeted binding protein revealed that clofoctol exhibited the inhibition of GSCs by upregulation of Kruppel-like factor 13 (KLF13), a tumor suppressor gene, through clofoctol's targeted binding protein, Upstream of N-ras (UNR). Collectively, these data demonstrated that induction of KLF13 expression suppressed growth of gliomas and provided a potential therapy for gliomas targeting GSCs. Importantly, our results also identified the RNA-binding protein UNR as a drug target.