tbuckley/cabot-search huggingface dataset:
SAT0041 Metformin downregulates TH17 differentiation and attenuates murine autoimmune arthritis
Authors: K.Y. Kang, Y.-K. Kim, H. Yi, J. Kim, H.-R. Jung, I.J. Kim, J.H. Ju
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Metformin, a pharmacological AMPK activator, is one of the most widely used drugs for diabetes. In recent years, metformin takes a growing interests for its anti-inflammatory property. <h3>Objectives</h3> This study was undertaken to evaluate anti-inflammatory effect of metformin in collagen antibody-induced arthritis (CAIA) in mice. The effect of metformin on the differentiation of Th17 was also investigated <i>in vivo</i> and <i>vitro</i>. <h3>Methods</h3> CAIA mice in which inflammatory arthritis was developing were treated with metformin. Metformin was treated 100mg/kg i.p. in low dose group and 150mg/kg i.p in high dose group. The effect of treatment on clinical disease activity and histological joint destruction were studied. The propotion of Th17 in axillary draining lymph node (DLN) from CAIA mice and metformin-treated mice was analysed by FACS. Naïve T cells from CAIA mice and metformin-treated mice were differentiated to Th17 on ex vivo stimulation. The effect of metformin on Th17 differentaion in vitro was also investigated in naive T cells from DBA/1 mice. <h3>Results</h3> Metformin attenuated arthritis scores and bone destruction in CAIA mice. Metformin also decreased serum levels of inflammatory cytokines such as IL-17, TNF-a and IL-6. The number of Th17 in axillary DLN was significantly reduced in metformin treated group compared with the control group. Naive T cells of metformin treated group, as compared with those of controls, less differentiated into Th17 on ex vivo stimulation. The stimulation of CD4(+) T cells with metformin in vitro decreased Th17 differentiation in a dose-dependent manner. The transcriptional factors of Th17, such as STAT3 and RORγt, were down-regulated by metformin through AMPK-mTOR pathway. <h3>Conclusions</h3> These findings indicated that anti-inflammatory effect of metformin was due to inhibit differentiation of Th17 via AMPK-mTOR pathway. It suggests that metformin may have a possible therapeutic value for the treatment of rheumatoid arthritis. <h3>Disclosure of Interest</h3> None Declared
PROGNOSTIC SIGNIFICANCE OF MYOCARDIAL FIBROSIS DETECTED BY MAGNETIC RESONANCE IMAGING IN ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY
Authors: Takashige Tobita, Kenji Fukushima, Naoki Serizawa, Tsuyoshi Suzuki, Tsuyoshi Shiga, Nobuhisa Hagiwara
Journal: Journal of the American College of Cardiology (2015)
Abstract 2125: Somatic hypermutations in hairy cell leukemia suggest a canonical process, except in patients with the poor-prognosis VH4-34 variant
Authors: Eugeny Arons, Tara Suntun, Robert J. Kreitman
Journal: Cancer Research (2010)

Abstract Hairy cell leukemia (HCL) cells express an immunoglobulin (Ig) heavy chain variable (VH) gene with different degrees of somatic mutation. We recently reported that of 82 patients with HCL, 14 expressed VH4-34 and that these patients had a poorer outcome compared to the other 68 patients. Moreover, poor prognosis in the VH4-34 patients was independent of the known poor-prognosis variant of HCL, called HCLv. To confirm these findings, and to more extensively characterize the somatic mutations occurring in the non-VH4-34 patients, we studied mutations from these and an additional 32 patients. A total of 118 rearranged VH sequences from 114 HCL patients were analyzed. Four patients had 2 rearrangements each, none of them VH4-34. Seventeen (15%) of the 114 patients had VH4-34 rearrangements, comprising 10 (38%) of 26 HCLv and 7 (8%) of 88 classic HCL patients (p=0.0005). Sixteen (94%) of 17 VH4-34 rearrangements were unmutated (&amp;gt;98% homologous to germline), compared to 15 (15%) of the other 101 (p=2 × 10-10). Median homology to germline was 99.6% in VH4-34 vs 95.4% in the other rearrangements (p&amp;lt;0.0001). Previous clinical findings that VH4-34+ HCL is associated with high white blood cell count at diagnosis, inferior response and progression-free survival after initial cladribine therapy, and poor overall survival from diagnosis independent of HCLv status, were confirmed. Characterization of the locations of somatic VH mutations in lymphocytic leukemias is rare. One published study reported that in 172 chronic lymphocytic leukemia (CLL) rearrangements, mutations were concentrated in the complementarity determining (CDR) regions, with higher replacement/silent (R/S) mutation ratios for CDRs (4.60) vs framework (FR) regions (1.72) (Blood, 103:3490-3495, 2004). We found that in our 118 HCL rearrangements containing 1385 mutations, R/S was 2.40 overall, 4.29 for CDRs, and 1.83 for FRs, nearly identical to the reported CLL data. Other features reported in CLL, including mutations preferentially in RGYW hot spots and consisting predominantly of transitions rather than transversions, were also observed in HCL. These data suggest that like CLL, VH mutations in HCL result from canonical somatic hypermutation and select for stable antigen receptors, similar to the mutation process taking place in the normal germinal center. However, the origin of VH4-34+ HCL appears different and requires further study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2125.
Effects of diagnosis, laterality, and gender on brain morphology in schizophrenia
Authors: M Flaum, V W Swayze, D S O'Leary, W T Yuh, J C Ehrhardt, S V Arndt, N C Andreasen
Journal: American Journal of Psychiatry (1995)

Structural neuroimaging and neuropathological studies have demonstrated a variety of aspects of brain morphology that appear to distinguish schizophrenic patients from comparison subjects (diagnostic effects), a predominance of left-sided pathology (laterality effects), and a greater likelihood of brain abnormality among males (gender effects). However, findings have been inconsistent across studies, perhaps reflecting limited power due to small study group sizes. The goal of this study was to examine diagnostic, laterality, and gender effects of brain morphology as assessed by magnetic resonance imaging in a large, carefully evaluated group of schizophrenic and comparison subjects.One hundred two patients with schizophrenia (DSM-III-R) (70 men and 32 women) and 87 normal comparison subjects, chosen to be equivalent to the patients in terms of familial socioeconomic background, underwent magnetic resonance imaging with a 1.5-tesla scanner. All regions of interest were outlined manually by an experienced technician on all slices in which they were visualized. Region of interest volumes were compared across groups, and age, sex, and stature were controlled.Schizophrenic patients were found to have larger lateral and third ventricles and smaller thalamic, hippocampal, and superior temporal volumes than comparison subjects. No significant differences were demonstrated for intracranial, cerebral, cerebellar, temporal lobe, caudate nuclei, or temporal horn volumes. There were no significant Laterality by Diagnosis effects and no significant Gender by Diagnosis effects for any of the regions of interest.Many, but not all, of the hypotheses informed by earlier studies regarding diagnostic effects were confirmed, while hypotheses regarding gender and laterality interactions with diagnosis were not supported.
Clone Wars — The Emergence of Neoplastic Blood-Cell Clones with Aging
Authors: Janis L. Abkowitz
Journal: New England Journal of Medicine (2014)

Blood cells originate from hematopoietic stem cells (HSCs). HSCs are infrequent (<2 per 108 bone marrow cells, or about 11,000 to 22,000 per person) and rarely divide.1,2 Because mutations occur with DNA replication during cell division, HSC quiescence maximizes genomic stability and thus safety.Mutations, however, can and do occur. Most are innocuous and do not substantially alter protein quantities or structure. Some make subtle changes that contribute to cellular diversity and allow HSCs or their offspring to react efficiently to differing environmental stresses. However, if a mutation speeds HSC self-renewal divisions or slows apoptosis, this results in more . . .
Thiouracil and Allied Drugs in Hyperthyroidism
Authors: Elmer C. Bartels
Journal: New England Journal of Medicine (1948)

THE introduction by Astwood of new and potent antithyroid substances has permitted a great advance in the treatment of hyperthyroidism and has given a new tool with which to further knowledge of the pathological physiology of diseases of the thyroid gland. This report deals with the clinical application of these drugs, which are capable of reducing to normal the elevated basal metabolic rate of hyperthyroidism resulting from either primary hyperthyroidism or adenomatous goiter. With the fall in the basal metabolic rate there is gradual amelioration of all hyperthyroid signs and symptoms except those of the eye, if these signs are . . .
ASSESSMENT OF PERI-STRUT LOW INTENSITY AREAS IDENTIFIED BY OPTICAL COHERENCE TOMOGRAPHY AFTER STENT IMPLANTATION: AN EX VIVO HISTOLOGICAL VALIDATION STUDY
Authors: Kenji Kawai, Kenichi Fujii, Hiroyuki Hao, Masahiko Shibuya, Takahiro Imanaka, Ten Saita, Rika Kawakami, Hiroto Tamaru, Akinori Sumiyoshi, Tetsuo Horimatsu, Seiichi Hirota, Tohru Masuyama, Masaharu Ishihara
Journal: Journal of the American College of Cardiology (2016)
Safety of surgery in patients (pts) with locally recurrent (LR) or metastatic breast cancer (mBC) treated with docetaxel (D) plus bevacizumab (BV) or placebo (PL) in the AVADO phase III study.
Authors: J Cortés, X Pivot, A Schneeweiss, N Wilcken, P Ellis, BK Linderholm, N Ribelles, M Clemens, F Haslbauer, DW Miles
Journal: Cancer Research (2009)

Abstract Abstract #1030 Background: The monoclonal antibody BV (Avastin®) specifically inhibits the biological activity of VEGF to disrupt tumour angiogenesis. The addition of BV to first-line taxane chemotherapy (CTx) increased clinical benefit in two randomised phase III studies of pts with LR or mBC, E2100 and AVADO. It is hypothesised that VEGF is essential for wound-healing, so it is recommended that BV therapy is interrupted prior to surgery and not restarted until the wound is fully healed. Incidence of wound-healing complications and bleeding events was investigated in pts undergoing surgery during the AVADO study.&amp;#x2028; Methods: Pts with HER2-negative, inoperable LR or mBC, no CTx 6 months prior to randomisation (12 months if taxane-based), ECOG PS 0–1, adequate LVEF were randomised to BV (7.5 or 15mg/kg q3w) + D (100mg/m2 q3w for ≤9 cycles) or PL + D until disease progression or unacceptable toxicity. Safety of BV was evaluated in pts undergoing surgery. Major surgery was defined as any surgery requiring opening of a body cavity or more than local anaesthesia.&amp;#x2028; Results: 42 surgical procedures were performed on the ITT population of 736 pts; ranging from minimally invasive procedures to major operations. The number of surgical events was similar in each study arm (PL: 17, BV 7.5mg/kg: 17, BV 15mg/kg: 8). Bleeding and wound-healing events reported in these pts after the date of surgery are presented below.&amp;#x2028; &amp;#x2028; Conclusions: This is the first analysis of the safety of surgery in pts with LR or mBC receiving BV. Treatment with BV + D did not affect the number of pts undergoing surgery. No effect of BV therapy was seen on the frequency of grade 3–5 bleeding and wound-healing adverse events in these pts. BV therapy was interrupted for longer periods pre- and post-major surgery, which may explain why bleeding and wound-healing adverse events are not increased in pts undergoing these procedures. Larger studies are required to obtain a more accurate picture of the safety of surgery in advanced breast cancer pts treated with BV. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1030.
Screening of the Portuguese BRCA2 Founder Mutation in Breast Cancer Patients Unselected for Family History.
Authors: A. Opinião, A. Opinião, S. Fragoso, P. Lourenco, P. Sousa, S. Braga, S. Braga, A. Luís, A. Luís, P. Machado, P. Rodrigues, H. Vicente, J. Oliveira, J. Bruges-Armas, F. Vaz, F. Vaz, F. Vaz
Journal: Cancer Research (2009)

Abstract Background and Objective: The identification of BRCA2 c.156_157insAlu as a founder mutation of Portuguese origin and the optimization of its screening method, allows for fast genetic diagnosis in positive families. Although prevalent in Portuguese families with hereditary breast cancer risk (45% of the families with identified mutations in our Institute are positive for BRCA2 c.156_157insAlu), its prevalence in the general population of Portuguese breast cancer patients unselected for family history is unknown. Our objective was to determine the frequency of c.156_157insAlu in general Portuguese breast cancer (BC) population.Material and methods: After Ethics approval, recruitment started in April 2008.Two centres started the study: the Cancer Institute in Lisbon that observes patients from the Centre and South of the country, and the Hospital of Terceira Island in Azores (patients recruited in Terceira Island were originated from all Azorean Islands). All these patients had the diagnosis of invasive breast cancer, and after counselling a peripheral blood sample was collected and BRCA2 c.156_157insAlu screened by a three-step PCR method (Machado PM et al; J Clin Oncol 25:2027-2034, 2007). Post-test counselling was given at the Breast Cancer Risk Evaluation Clinic, where all patients had their family history analyzed. If at high risk for hereditary cancer, women were advised to enter general screening of BRCA1/2 mutations, when negative for BRCA2 c.156_157insAlu.Results: Three hundred twenty three BC patients (226 from Azores; 97 from the Continent) were recruited for this study and have already been screened. Eighty-three patients from Azores met criteria for familial breast cancer (37%). In the Continent only 10 high-risk patients have been identified so far. Average age at diagnosis was 55.8 yrs; 13 patients had bilateral BC (4%); 18 (6%) patients (all from Azores) had a second cancer diagnosis. Two women (1% of all, and 2% of the patients from the Continent) were positive for the BRCA2 c.156_157insAlu mutation: 1- breast cancer diagnosis at age 45 and a maternal aunt with breast cancer at age 60; 2- bilateral BC (ages 35 and 37), no family history for breast and/or ovarian cancer. The 10 high-risk patients BRCA2 c.156_157insAlu negative accepted to proceed with general BRCA1/2 screening.Patient recruitment is still open.Conclusions: Although we cannot conclude that c.156_157insAlu screening is relevant in the unselected population, one of the positive patients did not meet criteria for counselling outside this study. Our data also suggest that, even for familial BC, c.156_157insAlu may not be as prevalent in the Azorean population. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3061.
Heavy Metals in the Environment: an Overview
Authors: Bruce A. Fowler
Journal: Environmental Health Perspectives (1973)

Heavy metals such as lead, cadmium, and mercury are widely distributed throughout the environment as the result of soil erosion and industrial and agricultural processes.These elements constitute a very important group of environmental toxicants since they are potent metabolic poisons to plants, animals, and man.The symposium on "Heavy Metals in the Environment" was sponsored by the National Institute of Environmental Health Sciences to bring together the many aspects of heavy metal research presently underway in the Research Triangle and to encourage commu- nication and cooperation among scientists engaged in this area of investigation.
MicroRNA profiling of triple negative breast cancer: predicting outcome and targets.
Authors: TS Paranjape, SV Nallur, K Keanie, M Martel, BG Haffty, DP Tuck, F Slack, JB Weidhaas
Journal: Cancer Research (2009)

Abstract Abstract #2040 Background: Breast tumors have been categorized on their molecular basis into ER- and/or PR positive, HER2 gene amplified and triple-negative tumors. Among these, triple-negative tumors represent the most aggressive subclass of breast tumors that are most prevalent in African American women. Currently, no effective targeted therapies or potential biomarkers have been identified to predict outcome within this group.&amp;#x2028; MicroRNAs(miRNAs) are global regulatory RNAs misregulated in almost every cancer and may function as tumor suppressor genes or proto-oncogenes. Specific miRNAs are aberrantly expressed in breast tumor versus normal tissue. Although miRNA expression profiles for the ER positive and HER2 positive subtype have been reported, the triple negative subtype remains to be studied.&amp;#x2028; Hypothesis: We hypothesize that identifying the miRNA signature of the triple negative tumors as a subclass as well as differences in this signature between triple negative patients with known outcome will lead to the identification of miRNAs predictive of outcome. For these studies we will use a large, well-annotated database of triple negative breast cancer patients with long-term follow-up. We will then test the identified miRNAs in a well-established cell-culture system to determine which miRNAs can act as potential therapeutic agents in triple negative breast tumors.&amp;#x2028; Study Design: We have performed miRNA microarray analysis to identify miRNA expression patterns in over 40 triple negative breast cancers using both fresh frozen tumors and formalin-fixed paraffin embedded (FFPE) samples. We have used the Ambion miRNA Taqman Low Density Array for analysis of these samples. The potential of specific miRNAs to predict outcome is currently being determined using statistical analysis.&amp;#x2028; Results: Our initial studies indicated that the triple negative subgroup has a significantly different miRNA signature than the HER2 positive subtype. We also additionally found unique miRNA expression patterns that may define triple negative cancers as a class. The triple negative tumors are known to have low levels of p53 and our microarray data showed that miR-34a which has been shown to be co-regulated by p53 and has similar expression levels as p53 in tissues, was significantly low in the triple negative compared to HER 2 positive breast cancer. We are currently evaluating the impact of altering mir-34 expression in these cell lines in vitro. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2040.
Harnessing Plasticity to Reset Dysfunctional Neurons
Authors: Andres M. Lozano
Journal: New England Journal of Medicine (2011)

For a long time, it was thought that the adult mammalian brain was hard-wired and that once circuits were laid down and their functions assigned, little change was possible. This notion is no longer tenable. The brain has a lifelong inherent ability to change and adapt: individual neurons and neural circuits can change their "job descriptions" and their allegiance in response to demands. The mechanisms underlying this process are complex, have varying time courses (from milliseconds to months), and are incompletely understood. They include changes in synaptic strength, the pruning and growth of neuronal connections, and even the introduction of . . .
Abstract 17630: Reduction in Lipoprotein (a) with the PCSK9 Inhibitor AMG145 in Hypercholesterolemic Patients on Background Statin: Results from the LAPLACE-TIMI 57 Trial
Authors: Payal Kohli, Nihar R Desai, Robert P Giugliano, Michelle L O'Donoghue, Ransi Somaratne, Elaine B Hoffman, Fannie Huang, Scott M Wasserman, Robert Scott, Marc S Sabatine
Journal: Circulation (2012)

Background: Epidemiological and Mendelian randomization studies suggest that lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. Currently, there are limited treatment options to lower Lp(a). AMG 145 is a fully human monoclonal antibody that binds proprotein subtilisin kexin 9 (PCSK9) and was shown to significantly lower LDL cholesterol (LDL-C) and Lp(a) in Phase 1 studies. We examined its effect on circulating levels of Lp(a) in LAPLACE-TIMI 57, a Phase 2, double-blind, dose-ranging, randomized, placebo-controlled trial of AMG145 in patients with hypercholesterolemia on background statin therapy. Methods: Lp(a) was measured (Polymedco immunoturbidometric assay, Cortlandt Manor, New York) at baseline and at week 12 (2 or 4 weeks after last dose of study drug) in 612 patients who were randomized and received drug. The percent change in Lp(a) between these two timepoints was calculated in each treatment arm and the medians of this value were compared with placebo using the Wilco...
Erdheim-Chester Disease
Authors: Emanuel Della Torre, Lorenzo Dagna, Paola Mapelli, Renata Mellone, Maria Grazia Sabbadini
Journal: Clinical Nuclear Medicine (2011)

Erdheim-Chester disease (ECD) is a rare form of systemic non-Langerhans cell histiocytosis with characteristic bone involvement. However, extraskeletal involvement occurs in approximately half of the patients. Because of its protean findings, the diagnosis of ECD is often delayed; thus, a clinical suspicion may prompt specific imaging studies to recognize suggestive signs of organ involvement. In this study, a case of a patient with ECD with representative progressive multisystemic involvement has been reported; although the final diagnosis was confirmed by histologic analysis, imaging studies with almost pathognomonic findings guided the diagnostic process and prompted different therapeutic approaches according to the localization of the disease.
Familial Aggregation of Low Birth Weight among Whites and Blacks in the United States
Authors: Xiaobin Wang, Barry Zuckerman, Gerald A. Coffman, Michael J. Corwin
Journal: New England Journal of Medicine (1995)

Studies have shown that the birth weight of infants is correlated with the birth weights of their siblings and their mothers. We investigated whether the birth weights of mothers and index children were jointly associated with the risk of low birth weight in the siblings of the index children.