tbuckley/cabot-search huggingface dataset:
Predicting risk of developing invasive breast cancer in the African American female population
Authors: A. J. Wheeler, A. Y. Zhang, B. Drohan, C. Lawrence, C. Roche, D. B. Kopans, R. H. Moore, B. L. Smith, J. Sharko, H. S. Kevin
Journal: Journal of Clinical Oncology (2009)

11080 Background: African Americans (AA) have a lower incidence of breast cancer with a poorer prognosis than Caucasians. It is unclear whether AA women have fewer known risk factors for breast cancer or that risk factors have a lesser effect in AA. We evaluated the accuracy of the race-based modification Gail Model in predicting the risk of developing invasive breast cancer in the AA population. Methods: With IRB approval, we performed a retrospective analysis of data obtained from women (n=15,973) ages 40–79 presenting to our Breast Center(5/2003 to 7/2005) for a screening mammogram. The five-year probability of breast cancer for AA (n=702) versus Caucasians (n=15,721) was calculated for each individual using 3 methods: 1) the race specific Gail model, 2) the Gail model ignoring race (AA using the Caucasian model), and 3) age and race matched SEER projection using DevCan (v6.1.1) software. Results: There was no significant difference between the 5-year probability of breast cancer for Caucasians as calculated by the Gail model vs. the SEER prediction (p=NS), suggesting our population was representative of the larger study population from which SEER data was derived. As compared to SEER prediction, the modified Gail model underestimated the breast cancer risk for all age groups of AA (p&lt;0.0001). When the Gail Model without the race-based modification was applied to the AA population, the projected risk was not significantly different from the SEER prediction (p=0.1049). Conclusions: This study suggests that the race-based modification of the Gail Model underestimate the risk of breast cancer in AA women. When the model is applied to AA women without incorporating the modification for race, the Gail model accurately reflects SEER 5-year projections of risk of invasive cancer in AA women. Differences in risk factor distribution among race, rather than a differential effect of those factors on risk, may have a substantial role in explaining the lower incidence in AA women as compared to Caucasian women over 40. [Table: see text] No significant financial relationships to disclose.
Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease
Authors: Aran Singanayagam, Nicholas Glanville, Leah Cuthbertson, Nathan W. Bartlett, Lydia J. Finney, Elena Turek, Eteri Bakhsoliani, Maria Adelaide Calderazzo, Maria-Belen Trujillo-Torralbo, Joseph Footitt, Phillip L. James, Peter Fenwick, Samuel V. Kemp, Thomas B. Clarke, Jadwiga A. Wedzicha, Michael R. Edwards, Miriam Moffatt, William O. Cookson, Patrick Mallia, Sebastian L. Johnston
Journal: Science Translational Medicine (2019)

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp -/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.
Gene Mutation Profile and Risk Stratification in AML1-ETO-Positive Acute Myeloid Leukemia Based on Next-Generation Sequencing
Authors: Guopan Yu, Changxin Yin, Fuqun Wu, Ling Jiang, Zhongxin Zheng, Dan Xu, Jiaheng Zhou, Xuejie Jiang, Qifa Liu, Fanyi Meng
Journal: Blood (2018)
Feldshers and “Feldsherism”
Authors: Victor W. Sidel
Journal: New England Journal of Medicine (1968)

The Status of the FeldsherThe feldsher holds the place in society of one who has graduated from a Technicum — a secondary vocational school — rather than an institute or university. He is in the position of the technician as compared to the physicist, or the draftsman as compared to the architect. Rut in the rural areas where the physician is not available, the feldsher's role and prestige is consequently greater.Pay scales are tailored to preserve the distinction between the "higher" and the "middle" medical graduate, but the disparity appears to be nowhere near as great as it . . .
RoB 2: a revised tool for assessing risk of bias in randomised trials
Authors: Jonathan A C Sterne, Jelena Savović, Matthew J Page, Roy G Elbers, Natalie S Blencowe, Isabelle Boutron, Christopher J Cates, Hung-Yuan Cheng, Mark S Corbett, Sandra M Eldridge, Jonathan R Emberson, Miguel A Hernán, Sally Hopewell, Asbjørn Hróbjartsson, Daniela R Junqueira, Peter Jüni, Jamie J Kirkham, Toby Lasserson, Tianjing Li, Alexandra McAleenan, Barnaby C Reeves, Sasha Shepperd, Ian Shrier, Lesley A Stewart, Kate Tilling, Ian R White, Penny F Whiting, Julian P T Higgins
Journal: BMJ (2019)

Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
A novel approach for generation of fully human monoclonal antibodies in humanized RAG-hu mice
Authors: Alexander Lifke, Valeria Lifke, Birgit Bossenmaier, Hans-Willi Krell, Tobias Schnitzer, Bernd Mueller-Beckmann
Journal: Cancer Research (2007)

4090  BACKGROUND: The currently well-established methods for developing fully human mAbs are human hybridoma technology, transgenic mice and phage display. Common limitations of these approaches are either low affinity and cross-reactivity or restricted Ab diversity. The new humanized Rag2-/-gamma c-/- mouse model (RAG-hu) created by intrahepatic injection of CD34 hematopoietic stem cells sustains long-term multi-lineage human hematopoiesis and is capable of mounting immune responses. We reasoned that this model could be suited for generation of antigen specific human B cells and might have considerable promise for development of human therapeutic mAbs against e.g. cancer, autoimmune or infectious diseases. RESULTS: Here we demonstrate that RAG-hu mice produce after immunization abundant antibody-producing human B cells specific for a disease-associated human antigen and that B cells isolated form these mice can be used to generate hybridomas for the production of human mAbs. To assess the capacity of these mice to generate antigen-specific human B cells, they were challenged with either antigenic protein with adjuvant or with plasmid DNA encoding the target antigen. The specific humoral response was assessed by ELISA and FACS. Human B cells were isolated from spleens of immunized RAG-hu mice and used for hybridoma generation. Our results show that both protein and genetic immunizations are capable of generating antigen-specific human B cells in RAG-hu mice and that specific titer rises depending on boost injection and lasts for at least 20 weeks. Moreover, we were able to generate hybridoma lines from extracted human CD19 B cells secreting fully human mAbs with high binding specificity. CONCLUSION: The humanized RAG-hu mouse model has been proven suitable for generation and future immortalization of human B cells specific for a disease-associated human antigen. The considerable advantage of this approach is the possibility to generate a more diverse panel of mAbs with a greater range of characteristics, because the use of entire human B cells repertoire as well as other cellular components of the human immune system and other biomolecules required for antibody development. Therefore, the humanized RAG-hu mouse model holds great promise for immunotherapy development.
Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome
Authors: Joshua M. Adams, Kari A. Huppert, Eumenia C. Castro, Mario F. Lopez, Nima Niknejad, Sanjay Subramanian, Neda Zarrin‐Khameh, Milton J. Finegold, Stacey S. Huppert, Hamed Jafar‐Nejad
Journal: Hepatology (2019)

Background and Aims Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y‐box 9) in late embryonic and neonatal livers of Jag1 ‐deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. Approach and Results Conditional removal of one copy of Sox9 in Jag1+/− livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1+/− livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+/− livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5‐month‐old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1+/− mice without ectopic hepatocyte‐to‐cholangiocyte transdifferentiation or long‐term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. Conclusions Our results establish Sox9 as a dosage‐sensitive modifier of Jag1+/− liver phenotypes with a permissive role in biliary development. Our data further suggest that liver‐specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.
P167 Association of changes of body composition in scleroderma patients with disease activity, physical activity and serum levels of inflammatory cytokines
Authors: S Oreska, M Spiritovic, P Cesak, M Cesak, H Storkanova, H Smucrova, B Hermankova, O Ruzickova, H Mann, K Pavelka, L Senolt, J Vencovsky, R Becvar, M Tomcik
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> Fibrosis of the skin and visceral organs, especially digestive tract, and musculoskeletal involvement in systemic sclerosis (SSc) can have a negative impact on body composition and physical activity. <h3>Objectives</h3> The aim was to assess body composition and physical activity of SSc patients and healthy controls (HC) and the association with selected inflammatory cytokines in SSc. <h3>Methods</h3> 59 patients with SSc (50 females; mean age 52.5; disease duration 6.7 years; lcSSc:34/dcSSc:25) and 59 age-/sex-matched HC (50 females, mean age 52.5) without rheumatic or tumour diseases were included. SSc patients fulfilled ACR/EULAR 2013 criteria. We assessed body composition (densitometry: iDXA Lunar, bioelectric impedance: BIA-2000-M), physical activity (Human Activity Profile, HAP questionnaire), disease activity (ESSG activity index) and serum levels of 27 cytokines (commercial multiplex ELISA kit, Bio-Rad Laboratories). Data are presented as mean ±SD. <h3>Results</h3> Compared to HC, patients with SSc had significantly lower body mass index (BMI), body fat% (BF%) and visceral fat weight (VF), and also significantly decreased lean body mass (LBM), and bone mineral density (BMD). Compared to HC, patients with SSc had increased extracellular mass/body cell mass (ECM/BCM) ratio, reflecting deteriorated nutritional status and worse muscle predispositions for physical activity. Increased ECM/BCM in SSc positively correlated with disease activity (ESSG), skin score (mRSS) and inflammation (CRP, ESR), and was associated with worse quality of life (HAQ, SHAQ), fatigue (FSS), and decreased physical activity (HAP). ESSG negatively correlated with BF%. HAP positively correlated with BMD. Increased serum levels of several inflammatory cytokines were associated with alterations of body composition. <h3>Conclusions</h3> Compared to healthy age-/sex-matched individuals we found significant negative changes in body composition of our SSc patients, which are associated with the disease activity and physical activity, and could reflect their nutritional status, and gastrointestinal and musculoskeletal involvement. Serum levels of certain inflammatory cytokines were associated with alterations of body composition in SSc patients. <h3>References</h3> none <h3>Acknowledgements</h3> Supported byAZV NV18–01-00161A, MHCR 023728 and GAUK 312218. <h3>Disclosure of Interest</h3> None declared.
AKT‐dependent hyperproliferation of keratinocytes in familial hidradenitis suppurativa with a <i>NCSTN</i> mutation: a potential role of defective miR‐100‐5p
Authors: Y. He, C. Li, H. Xu, Z. Duan, Y. Liu, R. Zeng, M. Li, B. Wang
Journal: British Journal of Dermatology (2019)
Trends in Cardiometabolic Mortality in the United States, 1999-2017
Authors: Nilay S. Shah, Donald M. Lloyd-Jones, Martin O’Flaherty, Simon Capewell, Kiarri Kershaw, Mercedes Carnethon, Sadiya S. Khan
Journal: JAMA (2019)

This study evaluates the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research to compare trends in heart disease, stroke, diabetes, and hypertension mortality rates by race and sex from 1999 to 2017.
Timing of Elevations of Autoantibody Isotypes Prior to Diagnosis of Rheumatoid Arthritis
Authors: Lindsay B. Kelmenson, Brandie D. Wagner, Bryan K. McNair, Ashley Frazer‐Abel, M. Kristen Demoruelle, Dylan T. Bergstedt, Marie L. Feser, Laura K. Moss, Mark C. Parish, Elizabeth A. Mewshaw, Ted R. Mikuls, Jess D. Edison, V. Michael Holers, Kevin D. Deane
Journal: Arthritis & Rheumatology (2019)

To evaluate patterns of elevations of isotypes of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) pre-rheumatoid arthritis (RA) diagnosis and post-RA diagnosis.Using the Department of Defense Serum Repository we identified 214 RA cases and 210 matched controls. Up to 3 pre-RA diagnosis and 1 post-RA diagnosis serum samples per subject were tested for RF and for IgA, IgG, and IgM ACPAs. The timing and trajectories of elevations of autoantibodies were evaluated.Autoantibody levels were elevated in cases versus controls a mean of 17.9 years before RA diagnosis for IgG ACPA, 14.2 years for IgA-RF, 7.2 years for IgM-RF, 6.2 years for IgA ACPA, and 5.0 years for both IgM ACPA and IgG-RF (P < 0.01 for all comparisons). There were similar relationships for positive or negative autoantibody status, with cases first showing positivity for IgG ACPA 1.9 years pre-RA and for IgA-RF 1.7 years pre-RA, followed by the other isotypes. Only IgA ACPA positivity was significantly increased in post-RA diagnosis samples (19% 0-2 years pre-RA versus 39% >2 years post-RA diagnosis; P = 0.04). All autoantibody levels demonstrated an early initial elevation, a period of stability, then an increase immediately before RA diagnosis. A pre-RA endotype of early elevation of autoantibodies was associated with increased use of biologic therapy, and a higher prevalence of sicca symptoms and lung disease post-RA diagnosis.Differences in patterns of elevations of autoantibody isotypes have implications for understanding the pathophysiology of RA development. These include understanding what factors drive initial autoantibody elevations compared to what factors (including mucosal) drive later increases in autoantibody levels and a transition to clinically apparent RA, and how pre-RA endotypes may influence post-RA diagnosis phenotypes.
A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma
Authors: Yiyin Zhang, Jin Xu, Jie Hua, Jiang Liu, Chen Liang, Qingcai Meng, Miaoyan Wei, Bo Zhang, Xianjun Yu, Si Shi
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Programmed cell death protein 1 (PD-1) is a key immune checkpoint that regulates peripheral tolerance and protects against autoimmunity. Programmed death ligand-2 (PD-L2) is a less studied ligand to PD-1 and has yet to be fully explored, especially in pancreatic ductal adenocarcinoma (PDAC). <h3>Methods</h3> In this study, we performed immunohistochemistry to detect the PD-L2, CD3, CD8, transforming growth factor-β2 (TGF-β2) and FOXP3 levels in paraffin sections from 305 patients with resected PDAC as a training set. Expression levels of intratumoral and stromal immune markers were compared in relation to survival using Kaplan-Meier curves, random survival forest model and survival tree analysis. A multivariable Cox proportional-hazards model of associated markers was used to calculate the risk scores. <h3>Results</h3> PD-L2 was expressed in 71.5% of PDAC samples and showed strong correlations with CD3+, CD8+ T cells and FOXP3+ regulatory T cell densities. High levels of intratumoral PD-L2 and FOXP3 were related to poor survival; only stromal FOXP3 overexpression was associated with worse prognosis. Four patterns generated from survival tree analysis demonstrated that PD-L2<sup>low</sup><sub>stromal</sub>FOXP3<sup>low</sup> patients had the longest survival, while PD-L2<sup>high</sup><sub>intratumoral</sub>CD3<sup>low</sup> patients had the shortest survival (<i>P</i> &lt; &nbsp;0.001). The area under the curve was 0.631(95% confidence interval (CI): 0.447–0.826) for the immune marker-based signature and 0.549 (95% CI: 0.323–0.829; <i>P</i> &lt; &nbsp;0.001) for the clinical parameter-based signature, which was consistent with the results in the validation set including 150 patients (<i>P</i> &lt; &nbsp;0.001). A higher risk score indicated shorter survival and could serve as an independent prognostic factor. PD-L2 was also showed associated with TGF-β2 and other immune molecules based on bioinformatics analysis. <h3>Conclusions</h3> Our work highlighted PD-L2 as a promising immunotherapeutic target with prognostic value combined with complex tumor infiltrating cells in PDAC.
<i>C-kit</i>, <i>B-raf</i>, and <i>N-ras</i> mutations in melanoma subtypes.
Authors: Marc Pracht, Ariane Mogha, Alain Fautrel, Alexandra Lespagnol, Nicolas Mouchet, Francois Le Gall, Emmanuel Oger, Marie-Dominique Galibert, Thierry Lesimple
Journal: Journal of Clinical Oncology (2012)

e19037 Background: The recent understanding of melanomas’ molecular pathways improved their classification and clinical strategies. Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alterations being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). These include Superficial Spreading Melanomas (SSM) and Nodular Melanomas (NM). Other studies showed that c-Kit mutations are present at low rate (20-40%) in Acro-Lentiginous Melanomas (ALM), Mucous Melanomas (MM) and in melanomas arising on CSD skins. C-kit mutation pattern is complex with four exons being affected leading to numerous mutations. Because c-Kit targeted therapy is a critical clinical issue, we aimed to identify the most frequent mutations to propose appropriate screening test and adapted therapy. Methods: 186 melanoma samples corresponding to an homogeneous white-caucasian population (Brittany, France) were screened. c-Kit exons 11, 13,17 and 18 were sequenced, c-Kit copy number was quantified by q-PCR and level of c-Kit determined by immunohistochemistry (CD117). Samples were also analyzed for B-Raf mutations (codon 464, 466, 469, 600) and for N-Ras mutations (codon 12, 13, 61) by pyrosequencing. Results: Detectedmutations are shown in the table. Uveal melanomas (n=13) were never mutated. These mutations were never overlaped and comparable profiles were obtained between the primary tumour, nodes or metastatic lesions from a same patient. Conclusions: C-Kit mutations are much less common than in other previously described populations especially for MM or ALM. B-Raf/N-Ras mutations appeared also less frequent than waited in non-CSD , reaching 46% in SSM. Interestingly our population presents a high incidence of N-Ras mutations, especially in SSM and NM. Screening of B-Raf/N-Ras mutations is fundamental not only for SSM but also for NM, CSD and ALM for prescribing targeted therapies such as MEK-inhibitors. [Table: see text]
NHS staff shortages are undermining targets for faster cancer diagnosis, warns charity
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The government’s failure to adequately boost NHS staffing levels is undermining its ambition12 to diagnose more cancers at an earlier stage, a leading charity has warned.

An analysis3 by Cancer Research UK released on 2 September estimates that around 115 000 patients with cancer each year in England are diagnosed too late to give them the best chance of survival, with nearly half of all cancers diagnosed at stage 3 or 4.

Of these, around 67 000 people are diagnosed at stage 4—the most advanced stage—which leaves patients with fewer treatment options and less chance of …
Promoting Pediatric Drug Research and Labeling — Outcomes of Legislation
Authors: Florence T. Bourgeois, Aaron S. Kesselheim
Journal: New England Journal of Medicine (2019)

Congress has modified regulations of the Food and Drug Administration to promote research assessing the efficacy and safety of drugs in children. The authors examine how this legislation has affected pediatric drug development and research over the past 20 years and discuss options for additional reforms to accelerate progress in this area.
AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management
Authors: Catherine R. Weiler, K. Frank Austen, Cem Akin, Marla S. Barkoff, Jonathan A. Bernstein, Patrizia Bonadonna, Joseph H. Butterfield, Melody Carter, Charity C. Fox, Anne Maitland, Thanai Pongdee, S. Shahzad Mustafa, Anupama Ravi, Mary C. Tobin, Harissios Vliagoftis, Lawrence B. Schwartz
Journal: Journal of Allergy and Clinical Immunology (2019)