tbuckley/cabot-search huggingface dataset:
CD14<sup>+ </sup>CD15<sup>− </sup>HLA-DR<sup>−</sup> myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure
Authors: Christine Bernsmeier, Evangelos Triantafyllou, Robert Brenig, Fanny J Lebosse, Arjuna Singanayagam, Vishal C Patel, Oltin T Pop, Wafa Khamri, Rooshi Nathwani, Robert Tidswell, Christopher J Weston, David H Adams, Mark R Thursz, Julia A Wendon, Charalambos Gustav Antoniades
Journal: Gut (2017)

Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo.Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
Testing of <i>BRCA 1/2</i> gene mutations in FFPE samples of patients with high-grade serous ovarian cancer and limits of its bioinformatic interpretation.
Authors: Katarina Janikova, Zora Lasabova, Marian Grendar, Anna Farkasova, Karla Scheerova, Pavol Slavik, Barbora Vanova, Katarina Zelinova, Marianna Jagelkova, Lukas Plank
Journal: Journal of Clinical Oncology (2017)

e17060 Background: BRCA1/2 mutations represent first genetically defined predictive markers for targeted therapy of patients with recurrent high-grade serous carcinoma (HGSC), therefore patients with HGSC should be tested for a germline and somatic BRCA mutation (g BRCAm and s BRCAm, resp.). In our study we analyzed possibilities and limits for determination of both origin and pathogenicity of mutations detected by HGSC biopsies analyses. Methods: We present data obtained by massive parallel sequencing on Miseq (Illumina). Library for sequencing was prepared by Somatic BRCA Tumor MASTR Plus kit (Multiplicom) from DNA isolated from HGSC FFPE tissue of 42 patients allowing simultaneous identification of g BRCAm and s BRCAm. For the pathogenicity evaluations we followed American College of Medical Genetics and Genomics (ACMG) criteria and used various bioinformatic tools. Results: All sequencing data were interpreted by SOPHIA DDM (Sophia Genetics) commercial tool. BRCA1/2 mutation was absent in 43% and present in 50% of patients, while 7% of cases had to be retested due to low coverage. Data of 28/42 patients were analyzed also by Ingenuity (Qiagen), the comparison of both the tools identified discrepant pathogenic determinationin 29% of them. The discrepancies in origin and pathogenicity of already detected mutations were found also by analyzing the data in other non-commercial databases (dbSNP, COSMIC, ClinVar, BIC, etc.). Conclusions: At least in a certain proportion of the cases, the data obtained by HGSC biopsy specimen mutational analyses and interpreted by accessible bioinformatic tools may lead to an equivocal assessment of both origin and pathogenicity of detected BRCA1/2 mutations. Other studies are necessary to eliminate the observed discrepancies.
Prognostic factors in breast cancer patients evaluated by PET/CT prior to neoadjuvant chemotherapy.
Authors: Mark K Farrugia, Geraldine M. Jacobson, Mohamad Adham Salkeni
Journal: Journal of Clinical Oncology (2017)

e12113 Background: Neoadjuvant chemotherapy (NAC) is an important modality in breast cancer treatment. We sought to identify pre-treatment prognostic factors in patients who had positron emission tomography paired with diagnostic quality contrast-enhanced CT (PET/CT) prior to neoadjuvant chemotherapy with respect to pathologic complete response (pCR) , survival and relapse-free survival (RFS). Methods: We retrospectively analyzed 118 breast cancer patients who had pre-treatment PET/CT imaging and received NAC from 2008-2014. We collected data on molecular markers, PET/CT, pCR, survival, and disease status. Results: The median follow up was 44 months(range 7.3-101.5),median age was 51 years; 47% were stage II, 53% stage III. 52% of patients had hormone receptor (HR) positive/HER2 negative disease, 31% of tumors were HER2 positive, and 17% of tumors were triple-negative. 92.5% with HER2 positive tumors received NAC containing at least one HER2 targeted agent. Pre-treatment standard uptake value (SUV) max of the primary breast tumor showed no statistically significant relationship to survival, RFS, or pCR. PET avid (&gt;2 SUV) extra-axillary nodes such as internal mammary and supraclavicular was associated with a non-statistically significant trend towards reduced RFS (p=0.06, HR=0.13-1.06). pCR overall was 37.5% for HER2 positive tumors, 15% in triple-negative tumors, and 8% in HR positive/HER2 negative tumors. Log-rank analysis with post-hoc pairwise comparisons showed a significant difference between the RFS of triple-negative tumors and HER2 positive tumors (p=0.001), while comparison between HR positive/HER2 negative and HER2 positive was not statistically significant (p=0.11). Multivariate cox regression analysis, which included grade and stage of tumors, showed HER2 positivity to be associated with a favorable outcome (p=0.04, HR=0.22 (0.05-0.94)). Conclusions: Within this cohort, pre-treatment SUV max of the primary tumor showed no prognostic value with regard pCR or RFS. PET avid extra-axillary metastasis trended towards reduced RFS. Patients with HER2 positive tumors had the highest pCR and RFS comparable to classically favorable subgroups such as HR positive/HER 2 negative.
A Correction to the Research Article Titled: "Personalized Epigenomic Signatures That Are Stable Over Time and Covary with Body Mass Index" by A. P. Feinberg, R. A. Irizarry, D. Fradin, M. J. Aryee, P. Murakami, T. Aspelund, G. Eiriksdottir, T. B. Harris, L. Launer, V. Gudnason, M. D. Fallin
Journal: Science Translational Medicine (2011)
Optimal Surveillance Strategies After Surgery for Renal Cell Carcinoma
Authors: Mark D. Tyson, Sam S. Chang
Journal: Journal of the National Comprehensive Cancer Network (2017)

One in 5 patients who undergo surgical resection for clinically localized renal cell carcinoma (RCC) develop local and/or distant recurrences which, when detected early, may be amenable to salvage local and systemic therapies. When considering that approximately half of these recurrences will occur during the first 2 years, a clear rationale exists for optimizing surveillance strategies after surgery. Although there is a notable dearth of high-quality data on this subject, clinical principles can guide clinicians as they attempt to balance the burden of surveillance strategies with potential clinical benefit. The objective of this review is to summarize the evidence regarding optimal surveillance protocols after surgery for RCC. We provide an overview of the rationale supporting surveillance after surgery, a summary of the American Urological Association and NCCN guidelines, reasons against routine long-term surveillance, surveillance costs, and ancillary issues, such as the utility of bone scan, PET/CT scan, and surveillance after thermoablation.
Abstract 243: End Stage heart Failure Cardiac Stem Cells has Strong Regenerative Ability compared to Congenital Heart Cardiac Stem cells
Authors: Rachana Mishra, Sudhish Sharma, David Simpson, Savitha Desmukh, Sunjay Kaushal
Journal: Circulation Research (2013)

Cellular based therapy is an important component of cardiac regenerative medicine. We have already identified and characterized a small population of undifferentiated cells present throughout the human heart that have the characteristics of cardiac stem cells. To date, no study has examined the potential application of human cardiac derived stem cells (hCDCs) generated from End Stage Heart Failure (ESFH) pediatric patient’s heart. In this study, we characterized samples from ESFH (recipients of heart transplant) and CDH (donors of the heart transplantation) to quantify the expression of various cardiac progenitor markers by immunofluorescence, flow cytometry and RT-PCR. The numbers of cardiac progenitor cells were highest in the right atria as compared to other chambers of the end-stage heart. FACS and IF analysis demonstrated significantly higher c-kit (9.36±1.384 vs 3.056±0.39, n=5) and ISL1 (33.61±4.0 vs 3.708±0.93) expressions in hCDCs derived from ESFH compare to CDH myocardium. Also, there was a tendency for increased FLK1 and Sca-1 expression in ESFH patients respectively. To determine, the functional potential, hCDCs were transplanted into a rodent myocardial infarct (MI) model. ESFH-derived hCDCs produced a stronger recovery of ventricular function than CDH-derived hCDCs (ESFH, n=5, EF=57+3% vs. CDH, n=5, 41.5±3%, P&lt;0.05). We also observed significantly higher secretion of VEGF (ESFH, n=5: 1.928±0.3623 vs CDH, n=5: 0.93±0.08, P&lt;0.05) and SDF-1α (ESFH, n=5: 3.1±0.6934 vs CDH, n=5: 0.99±0.1471, P&lt;0.05) by the ESFH-derived hCDCs as compared to CDH-derived hCDCs. This correlated with increased angiogenesis in the MI model at 28days. This study demonstrates that ESFH-derived hCDCs are highly functional and secrete angiogenic cytokines, more than CDH-derived hCDCs. To understand the mechanism of this activity will be critical for future clinical study.
Massive Intra-abdominal Mass
Authors: Zaynab A. R. Jawad, Arul Selvam
Journal: JAMA Surgery (2017)

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Abstract P199: Placental Growth Factor Regulates Cardiac Adaptation and Hypertrophy Through a Paracrine Mechanism
Authors: Federica Accornero, Jop Van Berlo, Matthew D Benard, Peter Carmeliet, Jeffery D Molkentin
Journal: Circulation Research (2011)

Objective. Paracrine growth factor-mediated crosstalk between cardiac myocytes and non-myocytes in the heart is critical for programming adaptive cardiac hypertrophy in which myocyte size, capillary density, and the extracellular matrix function coordinately. Here we examined the role that placental growth factor (PGF) plays in the heart as a paracrine regulator of myocyte to non-myocyte communication and its influence on cardiac adaptation to stress stimulation using overexpressing and PGF knockout mice. Methods and results. We identified PGF as a secreted factor that is predominantly produced in the heart during pressure overload. We studied mice with conditional post-natal PGF overexpression (PGF DTG). While these mice did not have a baseline phenotype, except increased fibrosis with aging, they responded to pressure overload stimulation induced by transverse aortic constriction (TAC) by an increase in hypertrophy (VW/BW (mg/g): 6.6 ± 0.2 for PGF DTG versus 5.6 ± 0.2 for controls; n ≥ 6 per group; p&lt;0.01), capillary density (vessels/myocyte: 1.6 ± 0.05 for PGF DTG versus 1.4 ± 0.03 for controls; n ≥ 7 per group; p&lt;0.01) and fibrosis. Despite a mild increase in fibrosis, cardiac function remained intact even after 12 weeks of pressure overload. On the other hand, PGF knockout mice (Pgf-/-) succumbed to heart failure within a week of pressure overload (fractional shortening (%): 20.2 ± 2.3 for Pgf-/- versus 30.4 ± 1.1 for controls; n ≥ 7 per group; p&lt;0.01). These hearts displayed dilation and capillary rarefaction (vessels/myocyte: 1 ± 0.05 for Pgf-/- versus 1.2 ± 0.04 for controls; n ≥ 7 per group; p&lt;0.01). Mechanistically we show that PGF has no direct effect on the cardiomyocytes but works through its direct actions on endothelial cells and fibroblasts by inducing capillary growth and fibroblasts proliferation. Conclusion. PGF is a secreted factor that supports hypertrophy and cardiac function during pressure overload by affecting endothelial cells and fibroblasts.
18F-FDOPA PET Imaging in Prolactinoma
Authors: Merwan Ginet, Thomas Cuny, Emmanuelle Schmitt, Pierre-Yves Marie, Antoine Verger
Journal: Clinical Nuclear Medicine (2017)

Pituitary macroadenoma constitutes a frequently misdiagnosed benign tumor. We report herein a case where such macroadenoma, a prolactinoma, was incidentally discovered in a 63-year-old man who had been referred to F-FDG PET and F-FDOPA PET imaging for a pharmacoresistant epilepsy. An increased uptake was documented for both radiotracers within the sellar region, although with a much higher contrast for F-FDOPA than for F-FDG. This case presents an increased uptake documented within a prolactinoma owing to the high contrast and image quality provided by F-FDOPA PET.
Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits
Authors: Anke R Hammerschlag, Sven Stringer, Christiaan A de Leeuw, Suzanne Sniekers, Erdogan Taskesen, Kyoko Watanabe, Tessa F Blanken, Kim Dekker, Bart H W te Lindert, Rick Wassing, Ingileif Jonsdottir, Gudmar Thorleifsson, Hreinn Stefansson, Thorarinn Gislason, Klaus Berger, Barbara Schormair, Juergen Wellmann, Juliane Winkelmann, Kari Stefansson, Konrad Oexle, Eus J W Van Someren, Danielle Posthuma
Journal: Nature Genetics (2017)
PREVENTING CONCUSSIONS IN YOUTH ICE HOCKEY: THE EFFECT OF LOCAL BODY CHECKING POLICY CHANGE
Authors: Amanda M. Black, Brent E. Hagel, Kathryn J. Schneider, Willem H. Meeuwisse, Luz Palacios-Derflingher, Shelina Babul, Martin Mrazik, Carolyn A. Emery
Journal: British Journal of Sports Medicine (2017)

Background In 2013, Hockey Canada announced a national policy change delaying the introduction of body checking in ice hockey until Bantam (ages 13–14). Following this change, several local organizations in Canada changed policy to also disallow body checking in Bantam non-elite levels (lower 60–70% by division of play). Objective To determine if the risk of concussion and severe concussion differs for non-elite Bantam ice hockey players in leagues where body checking is permitted compared with leagues where local policy change removed body checking. Design Cohort study. Setting Ice hockey rinks (2014/15, 2015/16 seasons). Participants Youth ice hockey players in non-elite Bantam body checking leagues (52 teams, 653 players) in Calgary and Edmonton (2014/15) and non-body checking leagues (33 teams, 396 players) in Kelowna and Vancouver (2014/15) and Calgary (2015/16), Canada. Assessment of Risk Factors Exposure to a Bantam league where body checking was not allowed. Main Outcome Measurements Suspected concussions were identified by a team designate and referred to a sport medicine physician. Severe concussions were defined by greater than 10 days of time-loss from ice hockey. Results There were 47 game-related concussions (Incidence Proportion per 100 players [IP] =7.2; 95% CI; 5.33-9.46) and 27 severe concussions (IP=4.1; 95% CI; 2.74-5.96) in body checking leagues. In non-body checking leagues there were 12 concussions (IP=3.03; 95% CI; 1.58-5.23) and 8 severe concussions (IP=2.02; 95% CI; 0.87-3.94). There was no evidence of a difference between the non-body checking leagues in Kelowna and Vancouver (2014/15) and Calgary (2015/16). Preliminary univariate analysis indicates a protective effect of policy disallowing body checking [risk ratio (RR)=0.42 (95% CI; 0.2-0.88) for concussion and RR=0.49 (95% CI; 0.23-1.04) for severe concussion. Conclusions This preliminary analysis suggests a 58% lower risk of game-related concussion in non-elite Bantam leagues where local policy disallows body checking.
Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management
Authors: Carla Scaroni, Marialuisa Zilio, Michelangelo Foti, Marco Boscaro
Journal: Endocrine Reviews (2017)

An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.
A Paper-Based Device for Performing Loop-Mediated Isothermal Amplification with Real-Time Simultaneous Detection of Multiple DNA Targets
Authors: Youngung Seok, Hyou-Arm Joung, Ju-Young Byun, Hyo-Sung Jeon, Su Jeong Shin, Sanghyo Kim, Young-Beom Shin, Hyung Soo Han, Min-Gon Kim
Journal: Theranostics (2017)

Paper-based diagnostic devices have many advantages as a one of the multiple diagnostic test platforms for point-of-care (POC) testing because they have simplicity, portability, and cost-effectiveness. However, despite high sensitivity and specificity of nucleic acid testing (NAT), the development of NAT based on a paper platform has not progressed as much as the others because various specific conditions for nucleic acid amplification reactions such as pH, buffer components, and temperature, inhibitions from technical differences of paper-based device. Here, we propose a paper-based device for performing loop-mediated isothermal amplification (LAMP) with real-time simultaneous detection of multiple DNA targets. We determined the optimal chemical components to enable dry conditions for the LAMP reaction without lyophilization or other techniques. We also devised the simple paper device structure by sequentially stacking functional layers, and employed a newly discovered property of hydroxynaphthol blue fluorescence to analyze real-time LAMP signals in the paper device. This proposed platform allowed analysis of three different meningitis DNA samples in a single device with single-step operation. This LAMP-based multiple diagnostic device has potential for real-time analysis with quantitative detection of 102-105 copies of genomic DNA. Furthermore, we propose the transformation of DNA amplification devices to a simple and affordable paper system approach with great potential for realizing a paper-based NAT system for POC testing.
MRI and MRS of intracerebral C6 and 9L/lacZ rat gliomas: Assessment of glioma models and antioxidant treatment
Authors: Sabrina Doblas, Rheal A. Towner, Debra Saunders, Quentin Pye, Yasvir Tesiram, Andrew Abbott, Melinda West, Yashige Kotake, Kenneth Hensley, Robert A. Floyd
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

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Malignant gliomas, which are the most common primary brain tumors, still lead to poor prognosis, because of the difficulty of an early and accurate diagnosis. More efficient treatments need to be found. In this point of view, magnetic resonance (MR) techniques would be an interesting non-invasive tool to monitor the growth of gliomas, to give a diagnosis and to follow the efficiency of treatments. We are using MR imaging (MRI) and MR spectroscopy (MRS) to monitor the progression of brain tumors from two cell lines with different degrees of malignancy, C6 (non-aggressive) and 9L/lacZ (9L) (aggressive and infiltrative), and the treatment of these gliomas by 2 antioxidants (phenyl-tert-butyl-nitrone and γ-tocopherol) in a rat model. C6 or 9L cells (106) were injected intracranially in the cortex of male Fischer 344 rats (2 mm from midline, 2 mm anterior to the bregma, and a depth of 3 mm) fed a choline-deficient diet. Treated rats were given 0.065% phenyl-tert-butyl-nitrone in the drinking water or 35 mg/kg γ-tocopherol intraperitoneally at different time points before and after cell injection. MRI (RARE and echo-planar imaging methods) and MRS (PRESS) are performed at 7 Tesla at days 7-10 after cells injection and then every 5-7 days. The echo-planar imaging method is used to create a 3D-reconstruction of the brain, allowing us to measure the size of gliomas and to compare these results to histology. MR spectroscopy is used to monitor several brain tumor biomarkers such as N-acetyl-aspartate, creatine, choline and mobile lipids. After rat death, the brain is extracted for histology. Our preliminary studies showed us that our rat models of non-aggressive and more aggressive gliomas can be differentiated by MR methods. MRI allows the monitoring of the growth of gliomas and estimations of their doubling rates. With MRS, we are able to differentiate gliomas by monitoring metabolic profiles. These results rival those from histology evaluations, with the advantage that MRI and MRS can provide in vivo brain tumor diagnosis. Furthermore these methods can help in the evaluation of therapeutic agents, such as antioxidants and anti-inflammatory agents, which inhibit brain glioma growth and/or infiltration. Grant support for this project is provided by NIH R01 CA-82506 and NIH P20RR016478.