tbuckley/cabot-search huggingface dataset:
Comparison of adenocarcinoma (ACA) and squamous cell carcinoma (SCC) of the uterine cervix: A population-based epidemiologic study of 60,000 women in Brazil.
Authors: Angelica Noguelra Rodrigues, Luiz Claudio Santos Thuler, Anke Bergmann, Suzana Sales de Aguiar, Carlos Gil Moreira Ferreira
Journal: Journal of Clinical Oncology (2013)

1587 Background: Most cancers of the uterine cervix are SCC, but the relative and absolute incidence of ACA has risen in recent years, particularly in younger patients, and ACA now accounts for about 20% of invasive cervical cancers in screened populations worldwide. However, the developing world, with sub-optimally screened women, accounts for more than 80% of incident cervical cancers. Our objective was to compare epidemiological, clinical characteristics, and treatment outcome of ACA with those of SCC of the cervix, with respect to ethnic group, age and stage at diagnosis, and pattern of response to first treatment in a sub-optimally screened population. Methods: Data of cervical cancer patients with SCC and ACA (adenosquamous + adenocarcinoma) treated from 2000 through 2009 were obtained from the Brazilian Hospital Cancer Register databases. Summary odds ratios and chi-square tests were estimated. Results: A total of 60,883 patients were analyzed: 54,425 (89.4%) cases of SCC, and 6,458 (10.6%) of ACA. Compared to ACA, the SCC cohort were younger (49.37 x 51.83 years, p&lt;0.001), more frequently black (58.1% x 49.2%, p&lt;0.001), presented higher degree of illiteracy (22.7 x 16.1%, p&lt;0.001), and alcohol (13 x 9.8%, p&lt;0.001) and tobacco dependence (41.5 x 31%, p&lt;0.001). Tumor stage at the time of diagnosis was also significantly different (p&lt;0.01). Considering prognostic factors, in both subtypes, more than 60% of the patients were stage II or inferior and ACA was associated with a significantly increased risk of inadequate response after the first course of treatment (crude OR=1.14 CI95%=1.07-1.21; adjusted OR=0.94 CI95%=0.87-1.01) and of death (crude OR=1.26 CI95%=1.15-1.38; adjusted OR=1.1 CI95%=1.00-1.23). Conclusions: Differences between ACA and SCC were found in age at diagnosis, extent of disease and ethnic distribution. In spite of these differences, the inadequate response to treatment seems to be mainly the result of more advanced stage, rather than cell type. Screening strategies with higher sensitivity are necessary, and irrespectively of histological subtype, quality of treatment must be improved in developing countries.
Prospective correlation between clinical and pathologic criteria identification of Lynch syndrome (LS) in endometrial carcinoma (EC) patients and relapse.
Authors: Ignacio Romero, Zaida Garcia-Casado, Pedro Martinez, Carmen Illueca, Cristina Zorrero, Montse Grau, Jose Manuel Bosch, Antonio Fernandez-Serra, Jose Antonio Lopez-Guerrero, Andres Poveda
Journal: Journal of Clinical Oncology (2013)

1543 Background: Prospective comparison of different methods for recognition of LS associated EC is lacking. Microsatellite instability (MSI) has been observed to be inconsistent as a prognostic factor in EC. The aim of this study was to analyze the impact of MSI and Mismatch Repair (MMR)-deficiency on LS identification and prognosis in a prospective series of EC treated in one single institution. Methods: Consecutive and prospective EC patients were included. Clinical data, family history of cancer and criteria for LS were evaluated. MSI and MMR protein expression were performed. When loss of MMR proteins and/or high MSI (MSI-H) was observed, complete sequencing and large genomic rearrangement analysis of germline MLH1, MSH2, MSH6 or PMS2 was done once MLH1 methylation was excluded. Results: Seventy-seven women diagnosed with EC were enrolled from 2009 to 2012 with a median age of 62 (31-87), 84% histological type I, 16% type II and FIGO stages I 83%, II 2.8%, III-IVA 7% and IVB 7%. Among which, 6.6% fulfilled revised Bethesda criteria (rBC), 5.3% criteria defined by the Society Gynecologic Oncology (&gt;20%-to-25% risk of LS) (SGO) and 5.3% Amsterdam II criteria (AII). Seventy-four underwent surgery with curative-intent. Tumor tissue was unavailable in 5 cases for molecular analysis. MSI-H was observed in16 cases (22%) and 18 (24%) had loss of expression of MLH1 (14), MSH2 (2), MSH6 (1) or PMS2 (1). Nine MLH1 hypermethylation, 10 K-RAS and no BRAF mutations were identified. Four (5.5%) pathogenic MMR germline mutations were recognized: 2 MSH2, one MSH6 and one PMS2. One patient (25%) with MSH6 mutation did not fulfil rBC, SGO nor AII criteria and was identified both by MSI-H and loss of MSH6 expression. Median follow-up was 23.4 (0.2-76.3) months. No correlation between MSI-H, MMR gene mutation and relapse was observed in stage I-IVA EC. Conclusions: Based on these results, rBC, AII and SGO criteria for identification of LS in EC do not identify 25% of germline MMR gene mutations. No correlation with relapse and MSI-H could be identified.
Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels
Authors: Brandon M. Brown, Heesung Shim, Palle Christophersen, Heike Wulff
Journal: The Annual Review of Pharmacology and Toxicology (2019)

The three small-conductance calcium-activated potassium (K Ca 2) channels and the related intermediate-conductance K Ca 3.1 channel are voltage-independent K + channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. K Ca 2 and K Ca 3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of K Ca channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule K Ca 2 and K Ca 3.1 modulators. Finally, we describe the progress that has been made in advancing K Ca 3.1 blockers and K Ca 2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.
Antibiotic pretreatment alleviates liver transplant damage in mice and humans
Authors: Kojiro Nakamura, Shoichi Kageyama, Takahiro Ito, Hirofumi Hirao, Kentaro Kadono, Antony Aziz, Kenneth J. Dery, Matthew J. Everly, Kojiro Taura, Shinji Uemoto, Douglas G. Farmer, Fady M. Kaldas, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski
Journal: Journal of Clinical Investigation (2019)

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.
Image Gallery: Multiple yellowish papules and verrucous plaques on the vulva
Authors: Y.‐T. Qian, S. Vano‐Galvan, J.‐W. Liu, W. Liu, D.‐L. Ma
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none to declare. Dear Editor, An otherwise healthy 57‐year‐old woman presented with asymptomatic, multiple light yellowish papules and verrucous plaques of 3 months’ duration on (a, b) both labia majora, the clitoris, mons pubis and right groin. No associated lichen sclerosus or lichen planus was found. Liver function and fasting serum lipid profiles were normal. Serological syphilis tests and aceto‐whitening test were negative. Skin biopsy revealed (c) verrucous epidermal hyperplasia and aggregates of foamy histiocytes in the papillary dermis (haematoxylin and eosin, original magnification × 200). (d) Immunohistochemically, foamy cells were positive for CD68 (original magnification × 200), and negative for P16 and human papilloma virus. The patient was diagnosed with verruciform xanthoma (VX), a benign tumour that commonly involves the oral and anogenital region. Vulval VX with or without associated lichen sclerosus or other vulval condition has been reported previously.1 Vulval VX can be easily misdiagnosed as condyloma acuminatum, but the histology findings are different. Plastic surgery was recommended, but the patient refused. ...
Reccurent and prolonged panctopenia with rituximab therapy
Authors: A. Jajeh
Journal: Journal of Clinical Oncology (2009)

e19550 Background: Rituximab, a monoclonal antibodies designed against a CD20 glycoprotein expressing lymphocytes. This drug has been implemented in the treatment of B cell lymphoproliferative disorders as well as non-neoplastic disease such as autoimmune thrombocytopenia, immune hemolytic anemia and other disorders related to overexpression of antibodies against the host. Rituximab doccumented side effects such as allergic infusion reaction, tumor lysis syndrome and lymphodepletion are frequently seen. However, transient neutropenia is less common. This abstract reports recurrent and long standing pancytopenia that had adverse deadly sequellae. Methods: This abstract report five cases of recurrent and prolonged pancytopenia not related to concomittant cytotoxic effect of chemotherapy. It is a retrospective analysis of treating three hundred patients in the last six years. Results: Five patient sustained recurrent prolonged pancytopenia post rituximab therapy. Two females (age 33 and 55) and three males (age 40, 50 and sixty). Mean age is 46 years. All developed sever neutropenia as well as pancytopenia. One patient, a female( age 33) had rheumatoid arthritis and the rest had non hodgekin's lymphoma. This female patient died due to sever long standing neutropenia/pancytopenia with pneumonia. All patients had bone marrow biopsy for evaluation. Decreased cellularity below 40% seen. None of the patients with non hodgkin's lymphoma had bone marrow involvement. The four patients are still in remmission. Conclusions: In conclusion the etiology of sustained neutropenia and pancytopenia is not understood. Whether, bone marrow aplasia, dysplasia or other immune mechanism exist need more study. No significant financial relationships to disclose.
Modeling the combined efficacy of rilotumumab (R; AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) for the treatment of locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer.
Authors: Sameer Doshi, Steven Kathman, Rui Tang, Per Olsson Gisleskog, Elwyn Loh, Sarita Dubey, Yizhou Jiang, Kelly S. Oliner, Ross C. Donehower, Timothy Iveson, Min Zhu
Journal: Journal of Clinical Oncology (2012)

2594 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF) that inhibits signaling though the MET receptor. In a double-blind, placebo-controlled, phase 2 trial of 121 patients with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved progression-free survival (PFS) and overall survival compared to ECX alone. The combined effects of R and ECX on tumor reduction and PFS were modeled using the phase 2 data. Methods: A population pharmacokinetic (PK) model was used to estimate R PK parameters and individual R concentrations (C) over time. A tumor dynamic model was developed to characterize the combined effects of R with ECX on tumor growth and cell death and to evaluate the impact of baseline patient characteristics and lab values on model parameters. A discrete time-survival model was developed with PFS and C data to evaluate the effect of R, ECX, and the interaction between R and ECX on PFS within a given time interval. Results: R exhibited linear PKs with an estimated mean clearance of 0.216 L/d/70 kg. The tumor dynamic model suggested that R and ECX worked jointly to reduce tumor size from baseline via inhibition of the tumor growth rate constant (K growth ) and stimulation of the death rate of tumor cells (K death ). Assuming the maximal inhibition of K growth is 100%, the estimated mean C that provided 50% maximal K growth inhibition (EC 50 ) was 6.71 µg/mL. The mean (SD) estimated effect of 7.5 and 15 mg/kg R on K growth was 90.1% (3.8%) and 95.5% (1.9%) inhibition, respectively. None of the tested baseline factors appeared to significantly affect tumor reduction by R + ECX. In the discrete time-survival model, the R and ECX combination significantly improved PFS, and the model suggests that the magnitude of the effect of one treatment was dependent on the other. Conclusions: R and ECX appeared to work in combination to decrease tumor size and to improve PFS.
Вплив симвастатину та антагоніста рецепторів інтерлейкіну-1 на експресію АРІЛ-гідрокарбонових рецепторів (AhR) в умовах експериментального гострого ілеїту
Authors: O.S. Zherebiatiev, O.M. Kamyshnyi
Journal: GASTROENTEROLOGY (2020)

Аріл-гідрокарбоновий рецептор (AhR) — фактор транскрипції, який активується великим числом факторів навколишнього середовища і може відігравати роль у патогенезі запальних захворювань кишечника у людини та в мишачих моделях. Ми вивчали можливість застосування симвастатину й антагоніста рецепторів інтерлейкіну-1 для фармакологічної корекції гострого ілеїту у щурів з акцентом на дослідженні інтенсивності експресії AhR лімфоцитами тонкої кишки. AhR-імунопозитивні лімфоцити визначали за допомогою методу непрямої імунофлюоресценції з використанням моноклональних антитіл щура. Ми встановили, що розвиток ілеїту супроводжувався зміною кількості AhR+-лімфоцитів і щільності їх на імунопозитивних клітинах. Застосування препаратів під час розвитку експериментальної патології супроводжувалося змінами експресії AhR та їх щільності на лімфоцитах.
Stathmin 1 Is Highly Expressed in Acute Promyelocytic Leukemia and Microtubule Dynamics Is a Potential Target for ATRA-Resistant APL Cells
Authors: João Agostinho Machado-Neto, Juan Luiz Coelho-Silva, Antonio R. Lucena-Araujo, Priscila S Scheucher, Raul Antônio Morais Melo, Rosane Bittencourt, Ricardo Pasquini, Katia B B Pagnano, Evandro Maranhão Fagundes, Maria de Lourdes Chauffaille, Carlos Chiattone, Eduardo Magalhães Rego, Fabiola Traina
Journal: Blood (2017)
Comparative characterization of B cells specific for HBV nucleocapsid and envelope proteins in patients with chronic hepatitis B
Authors: Nina Le Bert, Loghman Salimzadeh, Upkar Singh Gill, Charles-Antoine Dutertre, Floriana Facchetti, Anthony Tan, Magdeleine Hung, Nikolai Novikov, Pietro Lampertico, Simon Paul Fletcher, Patrick Thomas Francis Kennedy, Antonio Bertoletti
Journal: Journal of Hepatology (2019)
Weak Agonistic LPS Restores Intestinal Immune Homeostasis
Authors: Alex Steimle, Lena Michaelis, Flaviana Di Lorenzo, Thorsten Kliem, Tobias Münzner, Jan Kevin Maerz, Andrea Schäfer, Anna Lange, Raphael Parusel, Kerstin Gronbach, Kerstin Fuchs, Alba Silipo, Hasan Halit Öz, Bernd J. Pichler, Ingo B. Autenrieth, Antonio Molinaro, Julia-Stefanie Frick
Journal: Molecular Therapy (2019)

Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c+ cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases. Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c+ cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases.
Benchmarking of alignment-free sequence comparison methods
Authors: Andrzej Zielezinski, Hani Z. Girgis, Guillaume Bernard, Chris-Andre Leimeister, Kujin Tang, Thomas Dencker, Anna Katharina Lau, Sophie Röhling, Jae Jin Choi, Michael S. Waterman, Matteo Comin, Sung-Hou Kim, Susana Vinga, Jonas S. Almeida, Cheong Xin Chan, Benjamin T. James, Fengzhu Sun, Burkhard Morgenstern, Wojciech M. Karlowski
Journal: Genome biology (2019)

Alignment-free (AF) sequence comparison is attracting persistent interest driven by data-intensive applications. Hence, many AF procedures have been proposed in recent years, but a lack of a clearly defined benchmarking consensus hampers their performance assessment.Here, we present a community resource (http://afproject.org) to establish standards for comparing alignment-free approaches across different areas of sequence-based research. We characterize 74 AF methods available in 24 software tools for five research applications, namely, protein sequence classification, gene tree inference, regulatory element detection, genome-based phylogenetic inference, and reconstruction of species trees under horizontal gene transfer and recombination events.The interactive web service allows researchers to explore the performance of alignment-free tools relevant to their data types and analytical goals. It also allows method developers to assess their own algorithms and compare them with current state-of-the-art tools, accelerating the development of new, more accurate AF solutions.
Abstract 19051: Characterization of Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using Human Adult Cardiac Progenitor Cells or Patient-Matched Fibroblasts
Authors: Claudia Altomare, Enea Pianezzi, Elisabetta Cervio, Vanessa Biemmi, Alessandra Ciullo, Sara Bolis, Patrizia Benzoni, Giovanni Camici, Tiziano Moccetti, Lucio Barile, Giuseppe Vassalli
Journal: Circulation (2016)

Introduction: Induced pluripotent stem cells (iPSCs) are a unique source of cardiomyocytes (CMs) for disease modelling and regenerative medicine. Multiple cell types have been reprogrammed to iPSCs...
Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
Authors: Ming-Chuan Hsu, Ya-Li Tsai, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Skye Hung-Chun Cheng, Li-Tzong Chen, Wen-Chun Hung
Journal: Journal of Hematology & Oncology (2019)

The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo. Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer.
The value of giving autistic testimony a substantial role in the science of autism
Authors: Janette Dinishak
Journal: Behavioral and Brain Sciences (2019)

Abstract Jaswal &amp; Akhtar argue that taking seriously autistic testimony will help make the science of autism more humane, accurate, and useful. In this commentary, I pose two questions about autistic testimony's role(s) in a better science of autism and extract a general lesson about the value of autistic testimony from the authors’ arguments.