tbuckley/cabot-search huggingface dataset:
Mechanisms of regulation of P-glycoprotein expression by cytokines and bacterial peptides in colon cancer cells
Authors: Daniel Gaya, Hanna Johnsson, Marian Aldhous, Marian Thomson, Jack Satsangi, Duncan Jodrell, Sylvie Guichard
Journal: Cancer Research (2007)

2909  Extensive ulcerative colitis (UC) is an established risk factor in the development of colorectal cancer. Germline variation of the ABCB1 gene (MDR1) influences UC susceptibility, extent, and severity. P-glycoprotein, the product of ABCB1, is an ATP-dependent transporter excluding certain drugs and xenobiotics from cells, and is highly expressed in the gut. Recent data have shown that the disease-associated ABCB1 genetic polymorphisms may modify P-gp expression/function in vitro and in vivo. A large number of drugs influence P-gp expression, notably rifampicin which upregulates MDR1 transcription as a result of interaction with the PXR-RXR complex, which in turn binds to the DR4 motif of the MDR1 promoter region.  This study evaluated whether inflammatory cytokines (TNFα and IFNγ) and pathogen associated microbial peptides (PAMPs) such as muramyl dipeptide (MDP) modulate the mRNA expression of MDR1 in LS180 colon cancer cells, and the mechanism underlying any effect. LS180 cells were exposed to 20 μM rifampicin in the presence or absence of cytokines or PAMPs for 24h. MDR1 gene expression was determined by qRT-PCR 24h after the end of drug exposure. Rifampicin induced MDR1 expression from 0.3 ± 0.07 in controls to 0.6 ± 0.08 in LS180 while cytokines or PAMPs had no effect. Co-exposure of rifampicin with 1, 10 and 100 ng/ml TNFα further induced MDR1 expression up to 1.02 ± 0.2 (p  Reporter assays using the 10Kb MDR1 promoter supported these data - Rifampicin + TNFα 10 ng/ml = 2.2±0.3 compared to rifampicin alone 1.8±0.4, 6h after the start of drug exposure. A contrasting pattern was seen with both IFNγ and MDP, which decreased rifampicin-induced promoter activity at 24h: 1± 0.2 and 0.8± 0.1, respectively compared to 1.3± 0.4 for rifampicin alone.  TNFα had no influence on rifampicin-induced DR4 activity suggesting that the TNFα effect is independent of PXR-RXR interaction while both IFNγ and MDP decreased rifampicin-driven DR4 transcriptional activity (from 1.2 ± 0.2 to 0.6 ± 0.1 and 0.5 ± 0.1, respectively). Experiments are ongoing to ascertain whether over-expression of PXR would abolish this effect. TNFα is an inducer of NF-κB and, using a reporter system with NF-κB response elements, induced ~2-fold increase in NF-κB transcriptional activity compared to untreated control, increase which was abolished by 10 μM BAY11-7082 (NF-κB inhibitor). Rifampicin decreased TNFα-induced NF-κB transcriptional activity from 1.8 ± 0.2 to 1.5 ± 0.3.  MDR1 mRNA expression therefore seems to be differentially modulated by TNFα, IFNγ and MDP, an observation of importance in disease pathogenesis. In addition, these data provide further support for the use of NF-κB inhibition in the treatment of IBD and potentially reduce the risk of colon cancer development in these patients.
Demographics, Safety and Quality, and Prognostic Information in Both the Seventh and Eighth Editions of the TNM Classification in 18,973 Surgical Cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010
Authors: Jiro Okami, Yasushi Shintani, Meinoshin Okumura, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-ichi Watanabe, Hiroshi Date, Kohei Yokoi, Hisao Asamura, Takeshi Nagayasu, Etsuo Miyaoka, Ichiro Yoshino
Journal: Journal of Thoracic Oncology (2018)

IntroductionThe Japanese Joint Committee of Lung Cancer Registry performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations between the seventh and the eighth editions of the TNM classification were investigated. The principal results were compared with those of previous Japanese Joint Committee of Lung Cancer Registry studies.MethodsThe clinicopathologic profiles, staging, and prognosis of patients who had an operation for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed.ResultsThe cohort consisted of 18,973 patients from 297 hospitals (11,771 males, mean age 68.3 years). Tumor smaller than 2.0 cm was seen in 39.0% of patients, and limited resection was performed in 22.7%. The 30- and 90-day mortality rates were 0.43 and 1.26%, respectively. The overall and disease-free survival rates at 5 years were 74.7 and 67.8%, respectively. The respective 5-year survival rates by pathological stage in the seventh edition in the present study (2010) and in the previous study (2004) were 88.9% and 86.8% for stage IA, 76.7% and 73.9% for stage IB, 64.1% and 61.6% for stage IIA, 56.1% and 49.8% for stage IIB, 47.9% and 40.9% for stage IIIA, 30.2% and 27.8% for stage IIIB, and 36.1% and 27.9% for stage IV. The 5-year survival rates by clinical stage in the eighth edition in the present study were 97.0% for stage 0, 91.6% for stage IA1, 81.4% for stage IA2, 74.8% for stage IA3, 71.5% for stage IB, 60.2% for stage IIA, 58.1% for stage IIB, 50.6% for stage IIIA, 40.5% for stage IIIB, 37.5% for stage IIIC, and 36.0% for IVA/B. With restaging, the overall survival rates of clinical stage IA and IB in the seventh edition were stratified into stages 0 to IA3 and stages IA1 to IIA in the eighth edition, respectively.ConclusionsThis study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the eighth edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.
Extensively Drug-Resistant Typhoid — Are Conjugate Vaccines Arriving Just in Time?
Authors: Jason R. Andrews, Farah N. Qamar, Richelle C. Charles, Edward T. Ryan
Journal: New England Journal of Medicine (2018)

Extensively Drug-Resistant Typhoid More than 1000 cases of XDR Salmonella Typhi have been confirmed in Pakistan. Until recently, vaccines against typhoid have had limited efficacy and durability of immunogenicity, but an effective conjugate vaccine is now available to be used in typhoid-control efforts.
Minding Our Metaphors
Authors: Kristen Ann Ehrenberger, Alexandra Mieczkowski
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia
Authors: David R. Spiciarich, Stephen T. Oh, Amy Foley, Seamus B. Hughes, Michael J. Mauro, Omar Abdel-Wahab, Richard D. Press, Rosa Viner, Sarah L. Thompson, Qiushi Chen, Parastoo Azadi, Carolyn R. Bertozzi, Julia E. Maxson
Journal: Cancer Research (2018)

: Mutations in the colony-stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as acute myeloid leukemia. Here, we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation. SIGNIFICANCE: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia.
Rheumatoid arthritis–associated DNA methylation sites in peripheral blood mononuclear cells
Authors: Hong Zhu, Long-Fei Wu, Xing-Bo Mo, Xin Lu, Hui Tang, Xiao-Wei Zhu, Wei Xia, Yu-Fan Guo, Ming-Jun Wang, Ke-Qin Zeng, Jian Wu, Ying-Hua Qiu, Xiang Lin, Yong-Hong Zhang, Yao-Zhong Liu, Neng-Jun Yi, Fei-Yan Deng, Shu-Feng Lei
Journal: Annals of the Rheumatic Diseases (2018)

To identify novel DNA methylation sites significant for rheumatoid arthritis (RA) and comprehensively understand their underlying pathological mechanism.We performed (1) genome-wide DNA methylation and mRNA expression profiling in peripheral blood mononuclear cells from RA patients and health controls; (2) correlation analysis and causal inference tests for DNA methylation and mRNA expression data; (3) differential methylation genes regulatory network construction; (4) validation tests of 10 differential methylation positions (DMPs) of interest and corresponding gene expressions; (5) correlation between PARP9 methylation and its mRNA expression level in Jurkat cells and T cells from patients with RA; (6) testing the pathological functions of PARP9 in Jurkat cells.A total of 1046 DNA methylation positions were associated with RA. The identified DMPs have regulatory effects on mRNA expressions. Causal inference tests identified six DNA methylation-mRNA-RA regulatory chains (eg, cg00959259-PARP9-RA). The identified DMPs and genes formed an interferon-inducible gene interaction network (eg, MX1, IFI44L, DTX3L and PARP9). Key DMPs and corresponding genes were validated their differences in additional samples. Methylation of PARP9 was correlated with mRNA level in Jurkat cells and T lymphocytes isolated from patients with RA. The PARP9 gene exerted significant effects on Jurkat cells (eg, cell cycle, cell proliferation, cell activation and expression of inflammatory factor IL-2).This multistage study identified an interferon-inducible gene interaction network associated with RA and highlighted the importance of PARP9 gene in RA pathogenesis. The results enhanced our understanding of the important role of DNA methylation in pathology of RA.
Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome
Authors: Tenzin Gayden, Fernando E. Sepulveda, Dong-Anh Khuong-Quang, Jonathan Pratt, Elvis T. Valera, Alexandrine Garrigue, Susan Kelso, Frank Sicheri, Leonie G. Mikael, Nancy Hamel, Andrea Bajic, Rola Dali, Shriya Deshmukh, Dzana Dervovic, Daniel Schramek, Frédéric Guerin, Mikko Taipale, Hamid Nikbakht, Jacek Majewski, Despina Moshous, Janie Charlebois, Sharon Abish, Christine Bole-Feysot, Patrick Nitschke, Brigitte Bader-Meunier, David Mitchell, Catherine Thieblemont, Maxime Battistella, Simon Gravel, Van-Hung Nguyen, Rachel Conyers, Jean-Sebastien Diana, Chris McCormack, H. Miles Prince, Marianne Besnard, Stephane Blanche, Paul G. Ekert, Sylvie Fraitag, William D. Foulkes, Alain Fischer, Bénédicte Neven, David Michonneau, Geneviève de Saint Basile, Nada Jabado
Journal: Nature Genetics (2018)
Differential and persistent risk of excess mortality from Hurricane Maria in Puerto Rico: a time-series analysis
Authors: Carlos Santos-Burgoa, John Sandberg, Erick Suárez, Ann Goldman-Hawes, Scott Zeger, Alejandra Garcia-Meza, Cynthia M Pérez, Noel Estrada-Merly, Uriyoan Colón-Ramos, Cruz María Nazario, Elizabeth Andrade, Amira Roess, Lynn Goldman
Journal: The Lancet Planetary Health (2018)

BackgroundHurricane Maria struck Puerto Rico on Sept 20, 2017, devastating the island. Controversy surrounded the official death toll, fuelled by estimates of excess mortality from academics and investigative journalists. We analysed all-cause excess mortality following the storm.MethodsWe did a time-series analysis in Puerto Rico from September, 2017, to February, 2018. Mortality data were from the Puerto Rico Vital Statistics System. We developed two counterfactual scenarios to establish the population at risk. In the first scenario, the island's population was assumed to track the most recent census estimates. In the second scenario, we accounted for the large-scale population displacement. Expected mortality was projected for each scenario through over-dispersed log-linear regression from July, 2010, to August, 2017, taking into account changing distributions of age, sex, and municipal socioeconomic development, as well as both long-term and seasonal trends in mortality. Excess mortality was calculated as the difference between observed and expected deaths.FindingsBetween September, 2017, and February, 2018, we estimated that 1191 excess deaths (95% CI 836–1544) occurred under the census scenario. Under the preferred displacement scenario, we estimated that 2975 excess deaths (95% CI 2658–3290) occurred during the same observation period. The ratio of observed to expected mortality was highest for individuals living in municipalities with the lowest socioeconomic development (1·43, 95% CI 1·39–1·46), and for men aged 65 years or older (1·33, 95% CI 1·30–1·37). Excess risk persisted in these groups throughout the observation period.InterpretationAnalysis of all-cause mortality with vital registration data allows for unbiased estimation of the impact of disasters associated with natural hazards and is useful for public health surveillance. It does not depend on certified cause of death, the basis for the official death toll in Puerto Rico. Although all sectors of Puerto Rican society were affected, recovery varied by municipal socioeconomic development and age groups. This finding calls for equitable disaster preparedness and response to protect vulnerable populations in disasters.FundingForensic Science Bureau, Department of Public Safety, and Milken Institute School of Public Health of The George Washington University (Washington, DC, USA).
Abstract A42: Prexasertib (LY2606368) is highly active as a monotherapy or in combination with chemotherapy in preclinical models of pediatric bone and soft tissue sarcoma
Authors: Caitlin D. Lowery, Wayne Blosser, Michele Dowless, Matthew Renschler, Jennifer Stephens, Richard Beckmann, Louis Stancato
Journal: Cancer Research (2018)

Abstract The serine/threonine kinase checkpoint kinase 1 (CHK1) is a crucial mediator of replication stress and helps maintain genome integrity by governing the S-phase and G2/M cell cycle checkpoints following DNA damage, facilitating DNA repair through homologous recombination, and licensing replication forks during S phase. The CHK1 small-molecule inhibitor prexasertib (LY2606368) is currently under clinical investigation in pediatric cancer patients with recurrent or refractory solid tumors (NCT02808650). Reduced proliferation was observed at low nanomolar concentrations in a panel of pediatric bone and soft tissue sarcoma cell lines. In addition, prexasertib caused DNA damage and cell death in vitro as measured by Western blot analysis and high content imaging. Prexasertib as a monotherapy was superior to doxorubicin or actinomycin D in several cell line-derived and patient-derived xenograft (PDX) models of pediatric soft tissue sarcoma, with two models of alveolar rhabdomyosarcoma (aRMS) demonstrating a complete response to prexasertib; however, acquired resistance to prexasertib was observed. In addition, preclinical PDX mouse models of Ewing’s sarcoma and osteosarcoma typically demonstrated intrinsic resistance to single-agent prexasertib. Importantly, combination with cytotoxic chemotherapy could not only overcome intrinsic prexasertib resistance in vivo, as would be expected given the potential for prexasertib to act as a chemopotentiator, but also prevented the emergence of acquired resistance following single-agent prexasertib treatment. In vitro experiments were performed to evaluate the effect of prexasertib plus chemotherapy on cell proliferation. Future preclinical studies include genomic analysis of pediatric bone and soft tissue sarcoma models to delineate the molecular underpinnings of sensitivity and acquired resistance to prexasertib and to identify predictive biomarkers for response. Citation Format: Caitlin D. Lowery, Wayne Blosser, Michele Dowless, Matthew Renschler, Jennifer Stephens, Richard Beckmann, Louis Stancato. Prexasertib (LY2606368) is highly active as a monotherapy or in combination with chemotherapy in preclinical models of pediatric bone and soft tissue sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A42.
Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma
Authors: Jinhuan Xu, Qiuxiang Wang, Hao Xu, Chaojiang Gu, Lijun Jiang, Jue Wang, Di Wang, Bin Xu, Xia Mao, Jin Wang, Zhiqiong Wang, Yi Xiao, Yicheng Zhang, Chunrui Li, Jianfeng Zhou
Journal: Journal of Hematology & Oncology (2018)

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome still has no standard treatment. On the basis that both POEMS syndrome and myeloma have an underlying plasma cell dyscrasia, anti-myeloma therapy can be expected to be useful for POEMS syndrome. Chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) has been used in the treatment of relapsed and refractory multiple myeloma (RRMM). No POEMS syndrome cases treated with anti-BCMA CAR-T cells have been reported. Here, we, for the first time, report a POEMS syndrome case treated with anti-BCMA CAR-T cells. A 49-year-old female with incapacitating POEMS syndrome that progressed on lenalidomide treatment was enrolled in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113). Another patient with RRMM who had undergone six prior lines treatments was also enrolled in the study. They received infusions of anti-BCMA CAR-T cells. Both patients achieved a stringent complete response. Complete remission persisted in the patient with POEMS syndrome and lasted for 7.6 months before a relapse in RRMM patient. Both patients had toxicity consistent with the grade 1 cytokine release syndrome. This is the first report of treatment by anti-BCMA CAR-T cells in POEMS syndrome. Our findings demonstrate the anti-BCMA CAR-T cell treatment may be a feasible therapeutic option for patients with POEMS syndrome and RRMM who do not respond well to traditional therapies. ChiCTR-OPC, ChiCTR-OPC-16009113 . Registered 29 August 2016.
Hands are vehicles for transmission of <i>Streptococcus pneumoniae</i> in novel controlled human infection study
Authors: Victoria Connor, Esther German, Sherin Pojar, Elena Mitsi, Caroline Hales, Elissavet Nikolaou, Angela Hyder-Wright, Hugh Adler, Seher Zaidi, Helen Hill, Simon P. Jochems, Hassan Burhan, Neil French, Timothy Tobery, Jamie Rylance, Daniela M. Ferreira
Journal: European Respiratory Journal (2018)

Streptococcus pneumoniae (pneumococcus) is a major cause of acute otitis media, sinusitis, pneumonia and meningitis worldwide [1]. More than 1.2 million infant deaths are attributed to S. pneumoniae annually [2]. Hands can be vehicles for of transmission of pneumococcus leading to nasopharyngeal colonisation, even after drying <http://ow.ly/svlu30liKqP> The authors thank the respiratory research team; trial steering committee members; Stephen Gordon, Malawi–Liverpool–Wellcome Trust Clinical Research Programme; clinicians who provided safety on-call cover; John Blakey, Steve Aston and Ben Morton, and the Liverpool School of Tropical Medicine (LSTM) respiratory group.
Review of 2-D/3-D Reconstruction Using Statistical Shape and Intensity Models and X-Ray Image Synthesis: Toward a Unified Framework
Authors: Cornelius Johannes Frederik Reyneke, Marcel Luthi, Valerie Burdin, Tania S. Douglas, Thomas Vetter, Tinashe E. M. Mutsvangwa
Journal: IEEE Reviews in Biomedical Engineering (2018)

Patient-specific three-dimensional (3-D) bone models are useful for a number of clinical applications such as surgery planning, postoperative evaluation, as well as implant and prosthesis design. Two-dimensional-to-3-D (2-D/3-D) reconstruction, also known as model-to-modality or atlas-based 2-D/3-D registration, provides a means of obtaining a 3-D model of a patient's bones from their 2-D radiographs when 3-D imaging modalities are not available. The preferred approach for estimating both shape and density information (that would be present in a patient's computed tomography data) for 2-D/3-D reconstruction makes use of digitally reconstructed radiographs and deformable models in an iterative, non-rigid, intensity-based approach. Based on a large number of state-of-the-art 2-D/3-D bone reconstruction methods, a unified mathematical formulation of the problem is proposed in a common conceptual framework, using unambiguous terminology. In addition, shortcomings, recent adaptations, and persisting challenges are discussed along with insights for future research.
Malignant melanoma in paranasal sinus without expression of S-100 protein: a case report and review in literature
Authors: Midori Takada, Midori Koike, Keiichi Nakata, Yuma Tada, Akihisa Hino, Shigeo Fuji, Hiroaki Masaie, Hitoshi Yoshida, Taiki Isei, Jun Ishikawa
Journal: Annals of Oncology (2018)