tbuckley/cabot-search huggingface dataset:
Functional profiling in stage IV colorectal cancer: A phase II trial of individualized therapy
Authors: J. B. Blitzer, I. Shbeeb, A. Neoman, K. Azaren, M. Paulsen, S. Evans, R. Nagourney
Journal: Journal of Clinical Oncology (2009)

e15124 Background: The introduction of new classes of agents has improved survival in colorectal cancer (CRC) yet the accurate selection of candidates for these often costly &amp; toxic drugs remains a challenge. Genomic platforms have identified several prognostic &amp; predictive factors e.g. ERCC1, TS, kRas mutations but the comparatively small number of known cellular analytes has limited their broad application. Methods: To address the complexity and redundancy of cell-death signaling pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R. Curr Treat Options in Oncol. 2006) to select therapies for chemo-naïve pts with metastatic CRC. This functional platform uses morphologic and metabolic endpoints to gauge cellular response to drugs &amp; signal transduction inhibitors in human tumor microspheroids isolated from surgical biopsies. Modified Z-scores &amp; synergy analyses (median-effect) were used to identify the ex vivo best regimen (EVBR) for each pt. from FDA-approved CRC drugs. All pts signed informed consent. Results: 12/13 (92%) pts are evaluable. Of the 12 there was 1/12 (8%) CR; 7/12 (58%) PR; 3/12 (25%) SD &amp; 1/12 (8%) PD for an ORR = 8/12 (66%) &amp; CBR = 11/12 (92%). 1 st line EVBR were FOLFOX 3/12 (25%); FOLFIRI 2/12 (16%); FOLFOX/Erbitux 2/12(16%); FOLFOX/Avastin 1/12 (8%); FOLFOX/Avastin/Erbitux 1/12(8%); Irinotecan/Avastin/Erbitux 2/12(16%); IROX/Avastin 1/12(8%). Three of 12 inoperable pts (25%) converted to surgical candidates. There was 1 treatment-related death. Accrual continues with current TTP ranges from 1.2–17.3 months and OS from 2.5 to 30 months. Conclusions: EVA/PCD ORR in Stage IV CRC of 66%, many durable, compares favorably with reports in this population. By examining drug-induced cell death events in native-state microspheroids, this platform has the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, now known to be crucial for clinical response prediction. EVA/PCD analysis warrants further evaluation in CRC. Supported by the Memorial Medical Center Foundation of Long Beach. [Table: see text]
Selecting Double Cord Blood Units for Adults with Hematological Malignancies: Impact of ABO, HLA and Cell Dose on Outcomes after Double Cord Blood Transplants a CBC-Cellular Therapy &amp; Immunobiology Working Party, EBMT and Eurocord Study
Authors: Vanderson Rocha, Federica Giannotti, Annalisa Ruggeri, Patrice Chevallier, Didier Blaise, Patrice Ceballos, Mauricette Michallet, Eric Deconinck, Jan Cornelissen, Regis Peffault de la Tour, Eefke Petersen, Dimitrios Karakasis, Fernanda Volt, Annalisa Paviglianiti, Eliane Gluckman
Journal: Blood (2015)
RANK‐Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis
Authors: William O'Brien, Brian M. Fissel, Yukiko Maeda, Jing Yan, Xianpeng Ge, Ellen M. Gravallese, Antonios O. Aliprantis, Julia F. Charles
Journal: Arthritis & Rheumatology (2016)

Objective Proinflammatory molecules promote osteoclast‐mediated bone erosion by up‐regulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as tumor necrosis factor (TNF) plus interleukin‐6 (IL‐6), induce RANKL‐independent osteoclastogenesis. The purpose of this study was to better understand TNF/IL‐6–induced osteoclast formation and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis. Methods Myeloid precursors from wild‐type (WT) mice or mice with either germline or conditional deletion of Rank , Nfatc1 , Dap12 , or Fcrg were treated with either RANKL or TNF plus IL‐6. Osteoprotegerin, anti–IL‐6 receptor (anti–IL‐6R), and hydroxyurea were used to block RANKL, the IL‐6R, and cell proliferation, respectively. Clinical scoring, histologic assessment, micro–computed tomography, and quantitative polymerase chain reaction (qPCR) were used to evaluate K/BxN serum–transfer arthritis in WT and RANK‐deleted mice. Loss of Rank was verified by qPCR and by osteoclast cultures. Results TNF/IL‐6 generated osteoclasts in vitro that resorbed mineralized tissue through a pathway dependent on IL‐6R, NFATc1, DNAX‐activation protein 12, and cell proliferation, but independent of RANKL or RANK. Bone erosion and osteoclast formation were reduced, but not absent, in arthritic mice with inducible deficiency of RANK. TNF/IL‐6, but not RANKL, induced osteoclast formation in bone marrow and synovial cultures from animals deficient in Rank . Multiple IL‐6 family members (IL‐6, leukemia inhibitory factor, oncostatin M) were up‐regulated in the synovium of arthritic mice. Conclusion The persistence of bone erosion and synovial osteoclasts in Rank ‐deficient mice, and the ability of TNF/IL‐6 to induce osteoclastogenesis, suggest that more than one cytokine pathway exists to generate these bone‐resorbing cells in inflamed joints.
Factors Associated With Outcome After Cord Blood Transplantation in Children With Acute Leukemia
Authors: Franco Locatelli, Vanderson Rocha, Claude Chastang, William Arcese, Gerard Michel, Manoel Abecasis, Chiara Messina, Juan Ortega, Isabel Badell-Serra, Emanuel Plouvier, Gerard Souillet, Jean Pierre Jouet, Ricardo Pasquini, Euripedes Ferreira, Federico Garnier, Eliane Gluckman
Journal: Blood (1999)
Addition of <i>Mycobacterium indicus pranii</i> vaccine as an immunotherapeutic to standard chemotherapy in borderline leprosy: a double-blind study to assess clinical improvement (preliminary report)
Authors: R. Kamal, V. Pathak, A. Kumari, M. Natrajan, K. Katoch, H.K. Kar
Journal: British Journal of Dermatology (2016)

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Biodegradable Mg-Cu alloy implants with antibacterial activity for the treatment of osteomyelitis: In vitro and in vivo evaluations
Authors: Yang Li, Lina Liu, Peng Wan, Zanjing Zhai, Zhenyang Mao, Zhengxiao Ouyang, Degang Yu, Qi Sun, Lili Tan, Ling Ren, Zhenan Zhu, Yongqiang Hao, Xinhua Qu, Ke Yang, Kerong Dai
Journal: Biomaterials (2016)
Use of gene expression signatures to predict in vivo sensitivity of human metastatic colorectal cancer to chemotherapy and to identify novel drug combinations.
Authors: J. B. VanDeusen, T. Osada, M. Morse, B. M. Clary, H. K. Lyerly, J. R. Nevins, T. M. Clay, P. G. Febbo, S. D. Hsu
Journal: Journal of Clinical Oncology (2010)

e14064 Background: Current chemotherapy regimens for colorectal cancer exhibit only 50% response rates; we hypothesize that responses to chemotherapy agents can be predicted by gene expression profiles. We thus evaluated the use of gene expression profiling to predict responses to cytotoxic agents among patients with metastatic colorectal cancer and extended these techniques to create prediction models for novel drug combinations. Methods: Affymetrix microarray data from cell lines representing extremes of in vitro drug sensitivity were used to generate gene expression signatures predicting sensitivity to oxaliplatin and irinotecan. Fifteen separate human tumor explants were injected into NOD/SCID mice and responses to oxaliplatin treatment were used to validate predicted sensitivity in vivo. Finally, gene expression signatures assessing intracellular pathway activation from 37 metastatic colorectal tumor samples were combined with chemotherapy sensitivity prediction models to identify novel drug combinations that may exhibit synergy. Results: Genomic-derived in vitro signatures of oxaliplatin sensitivity were shown to accurately predict sensitivity of tumor explants in vivo (accuracy = 14/15 [93.3%], sensitivity = 100% [8/8] and specificity = 85.6% [6/7]). Further, combining genomic data on intracellular pathway activation with predicted chemotherapy sensitivity from patient tumors identified three distinct sample clusters. Cluster 1 did not appear to have any distinct patterns of growth pathway deregulation. Cluster 2 was characterized by increased deregulation of the Myc and PI3 Kinase pathways and sensitivity to irinotecan. Cluster 3 was characterized by increased deregulation of the Beta-catenin and Src pathways and sensitivity to oxaliplatin. Conclusions: Geneexpression analysis is a powerful tool that may predict patient responses to current therapy and holds promise for strengthening the design of future clinical trials studying novel drug combinations. No significant financial relationships to disclose.
Exposure to human immunodeficiency virus/hepatitis C virus in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types
Authors: Shadi Salloum, Jacinta A. Holmes, Rohit Jindal, Shyam S. Bale, Cynthia Brisac, Nadia Alatrakchi, Anna Lidofsky, Annie J. Kruger, Dahlene N. Fusco, Jay Luther, Esperance A. Schaefer, Wenyu Lin, Martin L. Yarmush, Raymond T. Chung
Journal: Hepatology (2016)

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection accelerates progressive liver fibrosis; however, the mechanisms remain poorly understood. HCV and HIV independently induce profibrogenic markers transforming growth factor beta-1 (TGFβ1) (mediated by reactive oxygen species [ROS]) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) in hepatocytes and hepatic stellate cells in monoculture; however, they do not account for cellular crosstalk that naturally occurs. We created an in vitro coculture model and investigated the contributions of HIV and HCV to hepatic fibrogenesis. Green fluorescent protein reporter cell lines driven by functional ROS (antioxidant response elements), NFκB, and mothers against decapentaplegic homolog 3 (SMAD3) promoters were created in Huh7.5.1 and LX2 cells, using a transwell to generate cocultures. Reporter cell lines were exposed to HIV, HCV, or HIV/HCV. Activation of the 3 pathways was measured and compared according to infection status. Extracellular matrix products (collagen type 1 alpha 1 (CoL1A1) and tissue inhibitor of metalloproteinase 1 (TIMP1)) were also measured. Both HCV and HIV independently activated TGFβ1 signaling through ROS (antioxidant response elements), NFκB, and SMAD3 in both cell lines in coculture. Activation of these profibrotic pathways was additive following HIV/HCV coexposure. This was confirmed when examining CoL1A1 and TIMP1, where messenger RNA and protein levels were significantly higher in LX2 cells in coculture following HIV/HCV coexposure compared with either virus alone. In addition, expression of these profibrotic genes was significantly higher in the coculture model compared to either cell type in monoculture, suggesting an interaction and feedback mechanism between Huh7.5.1 and LX2 cells.HIV accentuates an HCV-driven profibrogenic program in hepatocyte and hepatic stellate cell lines through ROS, NFκB, and TGFβ1 up-regulation; coculture of hepatocyte and hepatic stellate cell lines significantly increased expression of CoL1A1 and TIMP1; and our novel coculture reporter cell model represents an efficient and more authentic system for studying transcriptional fibrosis responses and may provide important insights into hepatic fibrosis. (Hepatology 2016;64:1951-1968).
Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4 + T Cell Immunity
Authors: Deshapriya S. Karunarathne, Joshua M. Horne-Debets, Johnny X. Huang, Rebecca Faleiro, Chiuan Yee Leow, Fiona Amante, Thomas S. Watkins, John J. Miles, Patrick J. Dwyer, Katryn J. Stacey, Michael Yarski, Chek Meng Poh, Jason S. Lee, Matthew A. Cooper, Laurent Rénia, Derek Richard, James S. McCarthy, Arlene H. Sharpe, Michelle N. Wykes
Journal: Immunity (2016)
Intragenic EGFR and EGFR2 mutations in hepatobiliary tumors and potential role in predicting response to agents that target EGFR
Authors: T. S. Bekaii-Saab, T. Sawada, N. Williams, W. Frankel, C. Plass, M. Villalona-Calero, C. Eng
Journal: Journal of Clinical Oncology (2005)

4037 Background: Data from 2 recent studies strongly suggested that gain-of-function somatic mutations in non-small cell lung carcinomas (NSCLC) affecting the catalytic domain (specifically the ATP binding site, exons 18–21) of the gene encoding the epidermal growth factor receptor (EGFR) was strongly associated with a response to Gefitinib, an EGFR-tyrosine kinase inhibitor. More recently, 10% NSCLC were also shown to have EGFR2 (HER2/NEU) mutations. In this study, we sought to determine if similar gain-of-function EGFR and EGFR2 mutations were present in hepatoma (HCC) and biliary cancers (BC) to determine the potential for EGF -targeted therapy. Materials and Methods: Genomic DNA from 40 HCC and BC samples and 40 adenocarcinomas of the lung (AC) were extracted and subjected to PCR-based semi-automated double stranded nucleotide sequencing targeting exons 18–21 (exon-intron junctions and flanking intronic regions) of EGFR and EGFR2. Results: All 40 HCC and BC tested were negative for gain-of-function somatic mutations affecting the catalytic domain of the EGFR gene. Power calculations suggest that our negative results predict that no more than 3% of HCC/BC would eventually be found to carry such mutations. As a control, we sequenced EGFR exons 18–21 in 44 AC and found 2 (5%) with somatic delE746-A750 mutations, previously reported to be associated with gefitinib responsiveness. In contrast, 2 (11%) of the 18 HCC had somatic H878Y mutations in exon 21 of EGFR2 while none of the BCs were found to have somatic mutations. The corresponding germline DNA from these two tumors did not have this mutation. The H878Y missense mutation occurring in the activation domain of EGFR2 alters a basic hydrophilic residue to an acidic hydrophilic residue and so is predicted to affect function. Conclusions: From this study, we conclude that gain-of-function somatic mutations affecting the catalytic domain of EGFR as described in non-small cell lung carcinomas have a predicted low yield in both HCC and BC. In contrast and based on our novel data showing ∼11% EGFR2 mutation frequency in HCC, we hypothesize that somatic EGFR2 mutations may be germane in predicting response to agents that targets erbB2 in HCC. No significant financial relationships to disclose.
Clinical guidelines and indications for bronchoalveolar lavage (BAL): Report of the European Society of Pneumology Task Group on BAL
Journal: European Respiratory Journal (1990)

This group report was developed jointly by: U . Costabel (Essen), C . Danel (Paris), L.M. Fabbri (Padova), P.L . Haslam (London), C. Hutter (Vienna) secretary, D. Israel-Biet (Paris), H. Klech (Vienna) chairman, W. Pohl (Vienna) secretary, L.W . Poulter (London), E. Pozzi (Torino), S .I . Rennard (Omaha), V. De Rose (Torino), G.A. Rossi (Genova), M. Rust (Frankfurt), G. Semenzato (Padova), B. Wallaert (Lille) . Edited by H. Klech' and C. Hutter
Clinicians underwhelmed by “watered down” childhood obesity strategy
Authors: Adrian O’Dowd
Journal: BMJ (2016)

The government’s long awaited childhood obesity plan for England has been roundly criticised as weak, disappointing, watered down, and underwhelming by doctors’ leaders, dentists, local government, national charities, and campaign groups.

The Department of Health described its strategy,1 published on 18 August, as a “far reaching” plan to curb childhood obesity by urging industry to cut the amount of sugar in food and drinks and investing millions of pounds in school sport.

Nearly a third of children aged 2 to 15 are considered to be overweight or obese, making them more likely to have health problems later in life.

The document said that the NHS in England spent around £5.1 billion (€5.9bn; $6.7bn) on overweight and obesity related ill health in 2014-15.

Under the obesity plan, the food and drinks industry will be encouraged to work towards a 20% reduction in the sugar used in products popular with children—including a 5% reduction in year one—achieved through cutting sugar levels, making portions smaller, or encouraging the uptake of lower sugar alternatives.

Progress made by the industry will be reviewed by Public Health England who will publish updates every six months.

There will also be a new soft …
Occupational and Environmental Medicine
Authors: D H Wegman, L J Fine
Journal: JAMA (1996)

Occupational diseases, acknowledged from the time of Hippocrates, were first systematically described by Bernadino Ramazzini in De Morbis Artificum . 1 In 1985, the World Health Organization expanded our understanding, introducing the concept of work-related diseases. This term brought new focus to the interaction of work and disease, a critically underappreciated area that the World Health Organization noted offered a wide range of opportunities for disease prevention and health promotion in most adults. Important developments concerning 2 increasingly common problems (asthma and low back pain) have brought new awareness of the impact of work on health.  In the United States, as elsewhere, a substantial increase in asthma morbidity and mortality has been noted with increased prevalence largely limited to those younger than 45 years, increased physician visits primarily among those older than 15 years, and increased mortality for those younger than 35 years. 2 Attention to the role of work in
Effect of azacitidine (AZA) on overall survival in higher-risk myelodysplastic syndromes (MDS) without complete remission
Authors: A. F. List, P. Fenaux, G. J. Mufti, E. Hellström-Lindberg, S. Gore, J. M. Bennett, L. R. Silverman, J. Backstrom, A. R. Allen, C. L. Beach
Journal: Journal of Clinical Oncology (2008)

7006 Background: A large international phase III trial (AZA-001) showed that AZA is the first MDS treatment to significantly extend overall survival (OS) compared with conventional care regimens (CCR) (Fenaux, Blood 2007;110:817). While the IWG 2000 emphasizes the importance of complete remission (CR) to extend survival (Cheson, Blood 2006;108:419), clinical validation in MDS is lacking. This analysis evaluated effects of AZA vs conventional care regimens (CCR) on 1-year survival according to IWG 2000 defined response categories in the AZA-001 study. Methods: MDS patients (pts) with FAB RAEB, RAEB-T, or CMML, and IPSS Int-2 or High risk, were included. Pts were randomized to AZA (75 mg/m2/d SC x 7d q 28d; n=179) + best supportive care (BSC: transfusions, antibiotics, and G-CSF for neutropenic infection) or to CCR (n=179). CCR + BSC included: low-dose ara-C (20 mg/m2/d x 14d q 28d), or standard chemotherapy (7+3 regimen), or BSC only. Erythropoietin was not allowed. One-year survival rates were determined for all treated pts in each arm, and for AZA subsets according to IWG-defined CR or partial remission (PR), stable disease (SD), or hematologic improvement (HI) as best response, or disease progression (DP). Results: AZA maintained a significant survival benefit vs CCR with exclusion of CR pts from the analysis (hazard ratio for OS = 0.65, 95%CI: 0.48, 0.88). The 1-year survival rates were significantly higher in AZA-treated pts than in CCR- treated pts: 68.2% vs 55.6%, respectively (p=0.015). When analyzed by IWG 2000 best response, all response categories including SD showed an OS benefit with AZA treatment: CR (96.7%), PR (85.5%), HI (96.0%), or SD (73.3%), while only 28.6% of AZA pts with DP were alive at 1 year. Conclusions: AZA is a disease-modifying agent that improves 1-year OS regardless of IWG 2000 best response. The data from this trial are the first to show that achievement of CR is not an obligate state for extended survival in higher-risk MDS. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion Amgen, Celgene, Pharmion Pharmion Amgen, Celgene, Cephalon, Johnson & Johnson, Pharmion, Roche Pharmion
Novel Munc13-4 Mutations in Patients with Hemophagocytic Lymphohistiocytosis.
Authors: Alessandra Santoro, Sonia Cannella, Antonino Trizzino, Cesare Danesino, Daniela Pende, Carmen De Fusco, Concetta Micalizzi, Patrizia Bertolini, Lorenzo Moretta, Luigi D. Notarangelo, Gillian M. Griffiths, Maurizio Aricò
Journal: Blood (2005)
Non-alcoholic fatty liver disease and progression of coronary artery calcium score: a retrospective cohort study
Authors: Dong Hyun Sinn, Danbee Kang, Yoosoo Chang, Seungho Ryu, Seonhye Gu, Hyunkyoung Kim, Donghyeong Seong, Soo Jin Cho, Byoung-Kee Yi, Hyung-Doo Park, Seung Woon Paik, Young Bin Song, Mariana Lazo, Joao A C Lima, Eliseo Guallar, Juhee Cho, Geum-Youn Gwak
Journal: Gut (2016)

Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, was associated with subclinical atherosclerosis in many cross-sectional studies, but the prospective association between NAFLD and the progression of atherosclerosis has not been evaluated. This study was conducted to evaluate the association between NAFLD and the progression of coronary atherosclerosis.This retrospective cohort study included 4731 adult men and women with no history of cardiovascular disease (CVD), liver disease or cancer at baseline who participated in a repeated regular health screening examination between 2004 and 2013. Fatty liver was diagnosed by ultrasound based on standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls. Progression of coronary artery calcium (CAC) scores was measured using multidetector CT scanners.The average duration of follow-up was 3.9 years. During follow-up, the annual rate of CAC progression in participants with and without NAFLD were 22% (95% CI 20% to 23%) and 17% (16% to 18%), respectively (p<0.001). The multivariable ratio of progression rates comparing participants with NAFLD with those without NAFLD was 1.04 (1.02 to 1.05; p<0.001). The association between NAFLD and CAC progression was similar in most subgroups analysed, including in participants with CAC 0 and in those with CAC >0 at baseline.In this large cohort study of adult men and women with no history of CVD, NAFLD was significantly associated with the development of CAC independent of cardiovascular and metabolic risk factors. NAFLD may play a pathophysiological role in atherosclerosis development and may be useful to identify subjects with a higher risk of subclinical disease progression.
The biomarkers of immune dysregulation and inflammation response in Parkinson disease
Authors: Li Chen, Mingshu Mo, Guangning Li, Luan Cen, Lei Wei, Yousheng Xiao, Xiang Chen, Shaomin Li, Xinling Yang, Shaogang Qu, Pingyi Xu
Journal: Translational Neurodegeneration (2016)

Parkinson's disease (PD) is referring to the multi-systemic α-synucleinopathy with Lewy bodies deposited in midbrain. In ageing, the environmental and genetic factors work together and overactive major histocompatibility complex pathway to regulate immune reactions in central nerve system which resulting in neural degeneration, especially in dopaminergic neurons. As a series of biomarkers, the human leukocyte antigen genes with its related proteomics play cortical roles on the antigen presentation of major histocompatibility complex molecules to stimulate the differentiation of T lymphocytes and i-proteasome activities under their immune response to the PD-related environmental alteration and genetic variation. Furthermore, dopaminergic drugs change the biological characteristic of T lymphatic cells, affect the α-synuclein presentation pathway, and inhibit T lymphatic cells to release cytotoxicity in PD development. Taking together, the serum inflammatory factors and blood T cells are involved in the immune dysregulation of PD and inspected as the potential clinic biomarkers for PD prediction.