tbuckley/cabot-search huggingface dataset:
The role of inflammatory biomarkers in developing targeted cardiovascular therapies: lessons from the cardiovascular inflammation reduction trials
Authors: Gabriella Passacquale, Paolo Di Giosia, Albert Ferro
Journal: Cardiovascular Research (2015)

Anti-inflammatory add-on therapy to conventional cardiovascular prophylaxis has been proposed as a novel therapeutic approach to potentially reduce residual cardiovascular risk. This hypothesis has been challenged by a series of unsuccessful Phase III studies testing the impact on clinical outcomes of novel agents with immunomodulatory actions. Specifically, the apparent ability of phospholipase A2 (PLA2) inhibitors and of antioxidants to ameliorate inflammation and to reduce coronary disease in Phase II trials did not translate into improved secondary cardiovascular prevention in larger population-based studies. Other anti-inflammatory agents are still under scrutiny. However, studies to date have lacked information on the inflammatory profile of the participants, both at baseline and at follow-up, thereby limiting the possibility of identifying subgroups of patients in whom 'residual inflammation' can be detected despite optimal conventional therapy, and who could therefore benefit from a cardiovascular prevention strategy specifically targeting inflammation. This has also rendered it difficult to interpret the results as a conclusive demonstration of inefficacy of the tested anti-inflammatory strategies in the treatment of atherosclerosis. We here discuss the importance of better patient characterization to minimize heterogeneity of the study population, so that effectiveness of different anti-inflammatory strategies can be evaluated in targeted subgroups of patients. We also illustrate how specific inflammatory biomarkers could assist in this process, with particular emphasis on the roles of high-sensitivity C-reactive protein and circulating monocyte phenotype.
Angiotensin-Converting Enzyme Inhibition Induces Apoptosis in Erythroid Precursors and Affects Insulin-Like Growth Factor-1 in Posttransplantation Erythrocytosis
Authors: Daniel Glicklich, Larry Burris, Agnes Urban, Vivian Tellis, Stuart Greenstein, Richard Schechner, Prasad Devarajan, Helena Croizat
Journal: Journal of the American Society of Nephrology (2001)

Abstract. A number of studies suggest that erythropoietin (Ep), angiotensin II, and insulin-like growth factor (IGF-1) are involved in the pathogenesis of posttransplantation erythrocytosis (PTE). Angiotensin-converting enzyme inhibitors (ACEI) are the treatment of choice in PTE, but their mechanism of action is unclear. It was shown previously that ACEI added directly to cultures of erythroid precursors from patients with PTE inhibit colony growth. In this report, the effect of ACEI on CD34+ erythroid precursor apoptosis was studied, as were hematocrit (Hct), Ep, IGF-1, and IGF-binding protein 3 (IGF-BP3) levels. Ten patients with PTE, 10 transplant control patients, and 7 normal control subjects were studied. Peripheral blood CD34+ cells were isolated, and apoptosis was assessed by annexin assay and DNA laddering before and during ACEI therapy. At the same time, Hct, Ep, IGF-1, and IGF-BP3 levels were measured. Baseline CD34+ cell number, CD34+ apoptosis, Ep, IGF-1, and IGF-BP3 levels were the same between PTE and transplant control subjects. ACEI therapy was associated with a striking increase in CD34+ cell apoptosis and a decrease in Hct in both groups. In contrast to control subjects, patients with PTE on ACEI showed a significant decrease in IGF-1 levels and a greater percentage decrease in Hct. In normal control subjects, ACEI therapy was associated with a fall in Hct but no change in CD34+ cell apoptosis. In PTE, ACEI-related increase in erythroid progenitor apoptosis may partially explain the ACEI-associated decrease in Hct. However, it is not clear that erythroid precursor apoptosis is related to changes in IGF-1 or IGF-BP3.
Auto-immune Thyroid Disease
Journal: BMJ (1960)

utoimmune thyroid disease is the commonest category of autoimmune disease in humans. Prevalences of up to 10% are quoted, with a higher prevalence in women than men. The two leading types are Hashimoto's type autoimmune thyroiditis (AIT), including the atrophic form, which presents as primary myxedema, and autoimmune thyroiditis, which is also known as Graves' disease (or Basedow's disease in a number of European countries). Rarer forms of autoimmune thyroiditis are silent thyroiditis, the iatrogenic thyroiditides, and postpartum thyroiditis. De Quervain's sub acute thyroiditis and Riedel's goiter are additional types of thyroiditis which are of non-autoimmune etiology, and will therefore be excluded from this discussion. Methods A literature search of PubMed was conducted from 1980 to 2006, using the following terms: Hashimotos's thyroiditis, autoimmune thyroiditis, Graves' disease, etiology, pathogenesis, anti-TPO auto antibodies, anti-Tg auto antibodies, TSH receptor auto antibodies, outcome prediction, endocrine ophthalmopathy. Autoimmune thyroiditides Classification The commonest form of autoimmune thyroiditis (AIT) is hypertrophic thyroiditis of the Hashimoto type. As part of the process of lymphocytic destruction, this can develop into a secondary atrophic form. Silent thyroiditis is a clinically milder variant. In clinical practice this is often subsumed under the heading of AIT, and in any case, a definite categorization is only possible during the course of the illness. In postpartum thyroiditis, and in the iatrogenic thyroiditides, autoimmune elements can often be demonstrated, which is why this form is counted among the autoimmune thyroiditides. Genetic and environmental factors Studies have shown an association between HLA class 2 molecules DR3, DR4 and DR5 and the incidence of Hashimoto's thyroiditis. However, the data are as yet inconclusive. The cytotoxic T cell surface molecule clearly has a role in AIT. Predisposing environmental
A20 suppresses hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression
Authors: Haiyang Chen, Liang Hu, Zaili Luo, Jian Zhang, Cunzhen Zhang, Bijun Qiu, Liwei Dong, Yexiong Tan, Jin Ding, Shanhua Tang, Feng Shen, Zhong Li, Hongyang Wang
Journal: Molecular Cancer (2015)

Aberrant expression of A20 has been reported in several human malignancies including hepatocellular carcinoma (HCC). However, its clinical relevance and potential role in HCC remain unknown. Quantitative PCR, Western blots and immunohistochemistry analyses were used to quantify A20 expression in HCC samples and cell lines. The correlation of A20 expression with clinicopathologic features was analyzed in a cohort containing 143 patients with primary HCC. Kaplan-Meier curves were used to evaluate the association between A20 expression and patient survival. Functional studies were performed to determine the effects of A20 on proliferation and metastasis of HCC cells in vitro and in vivo. Expression of A20 was increased in HCC tissues and cell lines. Increased expression of A20 was negatively correlated with the tumor size, TNM stage, tumor thrombus formation, capsular invasion and serum AFP levels. Patients with higher A20 expression had a prolonged disease-free survival and overall survival than those with lower A20 expression. Forced expression of A20 significantly inhibited the proliferative and invasive properties of HCC cells both in vitro and in vivo, whereas knockdown of A20 expression showed the opposite effects. Further studies revealed that expression of A20 was inversely correlated with Twist1 levels and NF-κB activity in HCC tissues and cell lines. A20-induced suppression of proliferation and migration of HCC cells were mainly mediated through inhibition of Twist1 expression that was regulated at least partly by A20-induced attenuation of NF-κB activity. Our results demonstrate that A20 plays a negative role in the development and progression of HCC probably through inhibiting Twist1 expression. A20 may serve as a novel prognostic biomarker and potential therapeutic target for HCC patients.
Effects of Lowering Glycemic Index of Dietary Carbohydrate on Plasma Uric Acid Levels: The OmniCarb Randomized Clinical Trial
Authors: Stephen P. Juraschek, Mara McAdams‐Demarco, Allan C. Gelber, Frank M. Sacks, Lawrence J. Appel, Karen J. White, Edgar R. Miller
Journal: Arthritis & Rheumatology (2015)

Objective The effects of carbohydrates on plasma uric acid levels are a subject of controversy. We determined the individual and combined effects of carbohydrate quality (the glycemic index) and quantity (the proportion of total daily energy [percentage of carbohydrates]) on uric acid levels. Methods We conducted a randomized, crossover trial of 4 different diets in overweight or obese adults without cardiovascular disease (n = 163). Participants consumed each of 4 diets over a 5‐week period, each of which was separated by a 2‐week washout period. Body weight was kept constant. The 4 diets were high glycemic index (≥65) with high percentage of carbohydrates (58% kcal), low glycemic index (≤45) with low percentage of carbohydrates (40% kcal), low glycemic index with high percentage of carbohydrates, and high glycemic index with low percentage of carbohydrates. Plasma uric acid levels were measured at baseline and after completion of each 5‐week period for comparison between the 4 diets. Results Of the 163 study participants, 52% were women and 50% were non‐Hispanic African American subjects; their mean age was 52.6 years, and their mean ± SD uric acid level was 4.7 ± 1.2 mg/dl. Reducing the glycemic index lowered uric acid levels when the percentage of carbohydrates was low (−0.24 mg/dl; P &lt; 0.001) or high (−0.17 mg/dl; P &lt; 0.001). Reducing the percentage of carbohydrates marginally increased the uric acid level only when the glycemic index was high ( P = 0.05). The combined effect of lowering the glycemic index and increasing the percentage of carbohydrates was −0.27 mg/dl ( P &lt; 0.001). This effect was observed even after adjustment for concurrent changes in kidney function, insulin sensitivity, and products of glycolysis. Conclusion Reducing the glycemic index lowers uric acid levels. Future studies should examine whether reducing the glycemic index can prevent gout onset or flares.
High Doses of Vitamin D to Reduce Exacerbations in Chronic Obstructive Pulmonary Disease
Authors: An Lehouck, Chantal Mathieu, Claudia Carremans, Femke Baeke, Jan Verhaegen, Johan Van Eldere, Brigitte Decallonne, Roger Bouillon, Marc Decramer, Wim Janssens
Journal: Annals of Internal Medicine (2012)

Low serum vitamin D levels have been associated with inflammation and infection and occur in many patients with severe chronic obstructive pulmonary disease (COPD). This randomized trial assigned 1...
Cost-effectiveness of incorporating bedaquiline into a treatment regimen for MDR/XDR-TB in Germany
Authors: Lara J. Wolfson, Judith Gibbert, Daniel Wirth, Roland Diel
Journal: European Respiratory Journal (2015)

The emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has re-established TB as a major worldwide health concern [1–3]. Compared with conventional TB drug regimens, treatments for MDR-TB and XDR-TB are more toxic, expensive and associated with poorer outcomes [3, 4]. In Germany, 102 (2.4%) of the 4318 TB cases reported for 2013 were MDR-TB, including 10 patients with XDR-TB [5], increasing from 54 (1.8%) cases in 2011 [5, 6]. An important factor behind the increase in Germany is migration, with more cases occurring in patients from the former Soviet Union than in native Germans [5]. Adding bedaquiline to the background regimen is likely to be cost-effective for treatment of MDR/XDR-TB in Germany <http://ow.ly/SwMdv>
Contrasting evolutionary rates in the duplicate chaperonin genes of Mycobacterium tuberculosis and M. leprae.
Authors: A L Hughes
Journal: Molecular Biology and Evolution (1993)

A phylogenetic analysis of chaperonin (heat shock protein 60) sequences from prokaryotes and eukaryotes indicated that a single gene duplication event in the common ancestor of Mycobacterium tuberculosis, M. leprae, and Streptomyces albus gave rise to the duplicate chaperonin genes found in these species (designated HSP65 and GroEL in the mycobacterial species). Comparison of rates of synonymous and nonsynonymous nucleotide substitution in different gene regions suggested that the 5' end of the HSP65 gene was homogenized by an ancient recombination event between M. tuberculosis and M. leprae. In S. albus, the two duplicated chaperonin genes have evolved at essentially the same rate. In both M. tuberculosis and M. leprae, however, the GroEL gene has evolved considerably more rapidly at nonsynonymous nucleotide sites than has the HSP65 gene. Because this difference is not seen at synonymous sites, it must be due to a difference in selective constraint on the proteins encoded by the two genes, rather than to a difference in mutation rate. The difference between GroEL and HSP65 is striking in regions containing epitopes recognized by T cells of the vertebrate host; in certain cross-reactive epitopes conserved across all organisms, nonsynonymous sites in GroEL have evolved twice as fast as those in HSP65. It is suggested that these differences are correlated with differences in the way in which the duplicate chaperonins of M. tuberculosis and M. leprae interact with the host immune system.
Retraction: Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis
Authors: Pingyu Zhang, Yanwen Yang, Patrick Zweidler-McKay, Dennis P M Hughes
Journal: Clinical Cancer Research (2013)

The authors wish to retract the article titled Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis, which was published in the May 15, 2008, issue of Clinical Cancer Research (1). Many years after this article was published, we obtained new information showing that two of the cell lines used in this publication, OS 187 and COL, are not osteosarcoma cell lines. Both lines were first reported by us (2). Each of these cell lines has now been tested by DNA fingerprint analysis. OS 187testedidenticallytothecommonNCI60coloncancerlineHCT15,evenina vial from passage 2 in our laboratory that had been frozen in 2002. Injection of OS187intothececumofNOD/SCID/IL-2Rg / miceyieldedacolonicprimary with metastasis to the liver (data not shown). Therefore, all of our published results with OS 187 likely reflect the biology of colon cancer. Given the subsequent report by another group that Notch pathway signaling promotes invasionandmetastasisofcoloncancer(3),thedatawereportedforOS187are not surprising. The pattern observed for tumor growth after injection of COL cells into the tibia of NOD/SCID/IL-2Rg / mice (no bone primary, rapid growth of liver tumors, with additional masses arising in skin and retro-orbital spaces) suggested that this cell line likely represented neuroblastoma. We have recently reported the subsequent testing confirming that COL is a neuroblastoma (4). In this article, OS 187 and COL were included in Figs. 1 and 2. OS 187 was amongthecelllinesshowninFig.3andistheonlycelllineshowninFigs.4and 5. When these two cell lines are removed from the data presented, two findings reported should be interpreted with caution. First, the only real osteosarcoma cell lines in which Notch was directly manipulated genetically were SAOS2 (with low levels of Notch) and LM7 (a subline of SAOS2 with high levels of Notch).AlthoughtransductionofSAOS2withconstitutivelyactiveintracellular Notch1 (ICN1) or the Notch target gene Hes1 increased in vitro invasiveness, LM7 was not able to grow after transduction with these constructs, as indicated in the original publication. Thus, we have not proved that osteosarcoma invasiveness can be increased by further upregulating Notch activity in Notch-positive osteosarcoma. Second, because only OS 187 was used in vivo in this report, we can no longer say that our publication proves Notch’s role in metastasis in vivo for osteosarcoma. However, the subsequent confirmation of this function of Notch by other groups (5) renders it likely that this conclusion remains valid for osteosarcoma. Nonetheless, because the data provided from bonafideosteosarcomacelllinesarenolongeradequatetosupporttheassertions and conclusions of the article, the authors respectfully request its retraction.
Response to Comment on American Diabetes Association. Approaches to Glycemic Treatment. Sec. 7. In <i>Standards of Medical Care in Diabetes—2015</i>. Diabetes Care 2015;38(Suppl. 1):S41–S48
Authors: William H. Herman
Journal: Diabetes Care (2015)

We would like to thank Pinsker et al. (1) for their thoughtful letter addressing the American Diabetes Association’s article about glycemic treatment in the Standards of Medical Care in Diabetes—2015 (2). The Professional …
Melphalan, Antimelanoma Immunity, and Inflammation—Response
Authors: Abhishek D. Garg, Aleksandra M. Dudek-Peric, Patrizia Agostinis
Journal: Cancer Research (2015)

Our recent publication described the CD8+ T-cell–dependent immunogenic effects of melphalan (Mel), with implications for clinical melphalan-based isolated limb-perfusion/infusion (ILP/ILI; ref. [1][1]). We would like to thank Martner and colleagues for corroborating our preclinical findings,
Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis
Authors: Kevin T. Nead, Stephen J. Sharp, Deborah J. Thompson, Jodie N. Painter, David B. Savage, Robert K. Semple, Adam Barker, John R. B. Perry, John Attia, Alison M. Dunning, Douglas F. Easton, Elizabeth Holliday, Luca A. Lotta, Tracy O’Mara, Mark McEvoy, Paul D. P. Pharoah, Rodney J. Scott, Amanda B. Spurdle, Claudia Langenberg, Nicholas J. Wareham, Robert A. Scott
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.
Cumulative Muscle Protein Synthesis and Protein Intake Requirements
Authors: Erin Simmons, James D. Fluckey, Steven E. Riechman
Journal: Annual Review of Nutrition (2016)

Muscle protein synthesis (MPS) fluctuates widely over the course of a day and is influenced by many factors. The time course of MPS responses to exercise and the influence of training and nutrition can only be pieced together from several different investigations and methods, many of which create unnatural experimental conditions. Measurements of cumulative MPS, the sum synthesis over an extended period, using deuterium oxide have been shown to accurately reflect muscle responses and may allow investigations of the response to exercise, total protein intake requirements, and interaction with protein timing in free-living experimental conditions; these factors have yet to be carefully integrated. Such studies could include clinical and athletic populations to integrate nutritional and exercise recommendations and help guide their revisions to optimize the skeletal muscle function that is so important to overall health.
Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies
Authors: Koshika Yadava, Céline Pattaroni, Anke K. Sichelstiel, Aurélien Trompette, Eva S. Gollwitzer, Olawale Salami, Christophe von Garnier, Laurent P. Nicod, Benjamin J. Marsland
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Changes in the pulmonary microbiota are associated with progressive respiratory diseases including chronic obstructive pulmonary disease (COPD). Whether there is a causal relationship between these changes and disease progression remains unknown.To investigate the link between an altered microbiota and disease, we used a murine model of chronic lung inflammation that is characterized by key pathological features found in COPD and compared responses in specific pathogen-free (SPF) mice and mice depleted of microbiota by antibiotic treatment or devoid of a microbiota (axenic).Mice were challenged with LPS/elastase intranasally over 4 weeks, resulting in a chronically inflamed and damaged lung. The ensuing cellular infiltration, histological damage, and decline in lung function were quantified.Similar to human disease, the composition of the pulmonary microbiota was altered in diseased animals. We found that the microbiota richness and diversity were decreased in LPS/elastase-treated mice, with an increased representation of the genera Pseudomonas and Lactobacillus and a reduction in Prevotella. Moreover, the microbiota was implicated in disease development as mice depleted, or devoid, of microbiota exhibited an improvement in lung function, reduced inflammation, and lymphoid neogenesis. The absence of microbial cues markedly decreased the production of IL-17A, whereas intranasal transfer of fluid enriched with the pulmonary microbiota isolated from diseased mice enhanced IL-17A production in the lungs of antibiotic-treated or axenic recipients. Finally, in mice harboring a microbiota, neutralizing IL-17A dampened inflammation and restored lung function.Collectively, our data indicate that host-microbial cross-talk promotes inflammation and could underlie the chronicity of inflammatory lung diseases.