Miracle-dz/UniFAR-FTUs huggingface dataset:
CTGF and SMADs, Maintenance of Scleroderma Phenotype Is Independent of SMAD Signaling*

In normal adult fibroblasts, transforming growth factor-β (TGFβ) induces the expression of connective tissue growth factor (CTGF). CTGF independently promotes fibroblast proliferation and matrix deposition, and in acute models of fibrosis promotes cell proliferation and collagen deposition acting synergistically with TGFβ. In contrast to normal fibroblasts, fibroblasts cultured from fibrotic tissues express high basal levels of CTGF, even in the absence of added TGFβ. Induction of transcription by TGFβ requires the action of SMAD proteins. In this report we have investigated the role of SMADs in the TGFβ-induction of CTGF in normal fibroblasts and in the elevated levels of CTGF expression found in dermal fibroblasts cultured from lesional areas of patients with scleroderma, a progressive fibrotic disorder that can affect all organs of the body. We have identified a functional SMAD binding site in theCTGF promoter. TGFβ-induction of CTGFis dependent on SMAD3 and SMAD4 but not SMAD2 and is p300-independent. However, mutation of the SMAD binding site does not reduce the high level of CTGF promoter activity observed in dermal fibroblasts cultured from lesional areas of scleroderma patients. Conversely, the previously termed TGFβRE in the CTGFpromoter is required for basal CTGF promoter activity in normal fibroblasts and for the elevated level of CTGFpromoter activity in scleroderma fibroblasts. Thus, the maintenance of the fibrotic phenotype in scleroderma fibroblasts, as visualized by excess CTGF expression, appears to be independent of SMAD-dependent TGFβ signaling. Furthermore, given CTGF's activities, the high level of CTGF expression observed in scleroderma lesions may contribute to the excessive scarring observed in this disorder.
Impact of socioeconomic status on the course of rheumatoid arthritis and on related use of health care services.

OBJECTIVE To quantify the impact of socioeconomic status (SES) among patients with rheumatoid arthritis on 1) health outcomes and related health care utilization in relation to disease duration and 2) changes in health outcomes and related health care utilization over a 2-year period. METHODS A questionnaire survey was conducted among 878 patients with rheumatoid arthritis (RA), varying in disease duration from 0 to more than 15 years. To determine the impact of SES on the health outcomes and health care use, patients were compared within and between 3 disease duration groups. Additionally, longitudinal changes in health outcomes and health care use were assessed with a followup questionnaire sent out 2 years later. RESULTS Patients with low SES have worse disease activity, physical health, mental health, and quality of life than patients with high SES. These differences, however, decreased over time. Regarding health care use, we found that patients with low SES made considerably less use of allied health care than patients with high SES. CONCLUSION Efforts should be undertaken in health care to alleviate the health disadvantages of RA patients in lower socioeconomic groups. In particular, the access to allied health care could be improved.
CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell Lung Cancer

Introduction: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. Methods: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non–small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. Results: p16 inactivation was the major mechanism of RB pathway perturbation in non–small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. Conclusion: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.
Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors

Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT1) and type 2 (AT2). In rodents, two AT1 subtypes were identified (AT1a and AT1b). To determine receptor‐specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT1 subtypes. All combinations lacking AT1a were distinguished by reduced heart rate. AT1a deletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT1b and/or AT2 had no effect. However, the additional lack of AT1b in AT1a‐deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the reninangiotensin system and to search for angiotensin II effects independent of AT1 and AT2. —Gembardt, F. , Heringer‐Walther, S. , van Esch, J. H. M. , Sterner‐Kock, A. , van Veghel, R. , Le, T. H. , Garrelds, I. M. , Coffman, T. M. , Danser, A. H. J., Schultheiss, H. ‐P., and Walther, T. Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors. FASEB J. 22, 3068–3077 (2008)
Significance of surgical resection for the treatment of multiple brain metastases.

BACKGROUND We investigated the role of surgery in the treatment of multiple brain metastases when performed with radiation therapy. PATIENTS AND METHODS One hundred and thirty-eight patients who underwent resection for brain metastases and received 30 Gy or more of adjuvant radiation therapy were entered into this study. Seventy-seven of the 138 patients (56%) had single brain metastases (Single Group), while the remaining 61 patients (44%) had multiple foci (Multiple Group). The 138 patients were divided into four subgroups; patients in Single Group treated with total or subtotal resection (Group A), those in Multiple Group who underwent total or subtotal resection and had remaining tumors smaller than 2 cm (Group B), those in Single Group treated with partial resection (Group C), and the other patients in Multiple Group (Group D). RESULTS The median survival was 8.7 and 9.2 months for the Single Group and the Multiple Group, respectively (not statistically different). The median survival was 9.6, 12.4, 3.7, and 4.5 months for Groups A, B, C, and D, respectively. Survival duration differed significantly between Groups A/B and Groups C/D (p < 0.05). CONCLUSIONS Surgical reduction of tumor volume which is approximately larger than 2 cm improves the efficacy of adjuvant radiation therapy and contributes to survival even in the patients with multiple brain metastases.
ER-positive breast cancer patients with more than three positive nodes or grade 3 tumors are at high risk of late recurrence after 5-year adjuvant endocrine therapy

Purpose Currently, although several clinical trials available give strong suggestions that extension of endocrine therapy has benefits, the risk level at which patients may benefit from extended endocrine therapy remains uncertain. This study aimed to identify the proportion of patients at a substantial risk of late recurrence after 5-year adjuvant endocrine therapy. Patients and methods We reviewed 1,056 female patients with primary breast cancer who underwent curative resection between January 2006 and December 2011. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model to identify prognostic factors. Results A total of 327 eligible patients were eventually enrolled in this study. Among them, 42 (12.8%) patients suffered from distant metastasis and 34 (10.4%) patients experienced locoregional recurrence after 5-year adjuvant endocrine therapy. In multivariate analysis, patients with more than three positive nodes (hazard ratio [HR] =2.176, 95% CI=1.071–4.421; P=0.032) and histologic grade 3 disease (HR=2.098, 95% CI=1.300–3.385; P=0.002) were significantly associated with high risk of late recurrence. However, only histologic grade 3 (HR=2.212, 95% CI=1.166–4.194; P=0.015) was significantly associated with high risk of distant metastasis. Conclusion Late relapse after completion of 5-year adjuvant endocrine therapy was still common, and grade 3 and more than three positive nodes were the risk factors of late recurrence, while grade 3 was the only risk factor of late distant metastasis. These patients might benefit from extended endocrine therapy.
Serum 25-hydroxyvitamin D, parathyroid hormone, and mortality in older men.

CONTEXT Low 25-hydroxyvitamin D [25(OH)D] and high PTH may contribute to increased mortality risk in older adults. OBJECTIVE The aim of the study was to test the association between 25(OH)D, PTH, and mortality in older men. DESIGN AND SETTING The prospective Osteoporotic Fractures in Men (MrOS) study was conducted at six U.S. clinical centers. PARTICIPANTS We studied community-dwelling men at least 65 yr old (n = 1490). MAIN OUTCOME MEASURE Multivariate-adjusted proportional hazards models estimated the hazard ratio (HR) for mortality; cause of death was classified as cancer, cardiovascular, and other by central review of death certificates. RESULTS During 7.3 yr of follow-up, 330 (22.2%) participants died: 97 from cancer, 110 from cardiovascular disease, and 106 from other causes. The adjusted HR per sd decrease in 25(OH)D for all-cause mortality was 1.01 (95% CI, 0.89, 1.14); no association between 25(OH)D and cardiovascular or other-cause mortality was seen. Unexpectedly, lower 25(OH)D levels were modestly associated with a decreased risk of cancer mortality (adjusted HR per sd decrease, 0.80; 95% CI, 0.64, 0.99). Analyzing 25(OH)D as a categorical variable did not alter these results. Higher PTH levels (log-transformed) were associated with an increased risk of all-cause mortality (adjusted HR per sd increase, 1.15; 95% CI, 1.03, 1.29) and cardiovascular mortality (adjusted HR per sd increase in PTH, 1.21; 95% CI, 1.00, 1.45). CONCLUSIONS In contrast to previous studies, lower 25(OH)D levels were not associated with an increased risk of all-cause or cause-specific mortality in older men. Higher PTH levels were associated with a modest increase in mortality risk.
Air Pollution and Hospital Admissions for Asthma in a Subtropical City: Taipei, Taiwan

This study was undertaken to determine whether there is an association between exposure to air pollutants levels and number of hospital admissions for asthma in Taipei, Taiwan. Hospital admissions for asthma and ambient air pollution data for Taipei were obtained for the period from 1996 through 2003. The relative risk of hospital admission for asthma was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single-air-pollutant model, on warm days (≥25°C) statistically significant positive associations were found for SO2, NO2, and CO levels with an increase in asthmatic admissions. On cool days (<25°C), all air pollutants were significantly associated with elevated asthma admissions except SO2. For the two-air-pollutant model, CO significantly increases hospital admissions for asthma in combination with each of the other four pollutants on warm days. On cool days, NO2 and O3 significantly elevated asthma rates in all the two-air-pollutant models. This study provides evidence that higher levels of ambient air pollutant concentrations increase the risk of hospital admissions for asthma.
Increasing hematocrit reduces early posttransplant cardiovascular risk in diabetic transplant recipients1

Background. Cardiovascular disease remains epidemic in transplant recipients, despite aggressive treatment of cardiovascular risk factors. Thus, novel risk factors could play a role in the genesis of cardiovascular events in this population. Methods. We evaluated the impact of early posttransplant anemia on cardiovascular events. We examined rolling average hematocrit values at 30-day intervals and determined the effect of increasing hematocrit on the risk for cardiovascular (CV) events in a single-center population of 404 type 1 diabetic end-stage renal disease patients who underwent either cadaveric kidney transplantation alone or simultaneous pancreas-kidney transplantation. Results. Greater than 60% of the individuals in the study cohort had hematocrit less than or equal to 30% at least once during the first 30 days posttransplant. Forty-two individuals (10.4% of the study population) had at least one 30-day rolling hematocrit less than or equal to 30% and a CV event (myocardial infarction, CV death, angina, congestive heart failure) during the first 26 weeks of the posttransplant course. Increasing hematocrit (>30%) led to a reduction in the risk ratio (RR) for a CV event compared with hematocrit less than or equal to 30% (RR, 0.237; P =0.015). The association between anemia and CV events remained statistically significant in a multivariate analysis (RR, 0.65; P =0.022) that also included age and a history of pretransplant ischemic heart disease. Conclusions. These data suggest that anemia is an important risk factor for early posttransplant CV events in a high-risk population. Prospective studies of anemia management therapy in this setting are warranted to determine whether this will reduce early posttransplant CV risk.
Tacrolimus‐induced cholestatic syndrome following pediatric liver transplantation and steroid‐resistant graft rejection

Abstract: Several factors may contribute to post‐transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus‐based immunosuppression following liver transplantation and all of them suffered from previous steroid‐resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid‐resistant graft rejection, even if given in therapeutic doses.
Risk guided use of the direct thrombin inhibitor bivalirudin: insights from recent trials and analyses.

During percutaneous coronary intervention, dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist are combined with one of three major strategies for antithrombotic therapy: heparins, bivalirudin, or heparin with an intravenous IIb/IIIa platelet receptor antagonist. Economic constraints in the United States are increasingly driving the choice between these therapies.
The Value and Valuation of Maritime Cultural Heritage

Abstract Maritime cultural heritage is made up of finite and nonrenewable cultural resources including coastal or submerged prehistoric and indigenous archaeological sites and landscapes, historic waterfront structures, the remnants of seagoing vessels, and the maritime traditions and lifeways of the past and present. To date, evaluative tools used to assess the social and economic “value” of this heritage are extremely limited, the lack of which often results in the loss of maritime cultural resources and unrealized socioeconomic opportunities. Market and nonmarket valuations, derived from ecological economics and ecosystem assessments, are viable techniques that may be integrated into existing U.S. environmental and historic preservation regulatory procedures to support resource significance determinations. In doing so, decision-making regarding maritime cultural heritage can include assessments of the short- and long-term trade-offs of human actions, and can examine the socioeconomic costs and benefits of heritage conservation projects.
Risk Assessment in Shellfish-Borne Outbreaks of Hepatitis A

ABSTRACT In the present work, we aimed at determining the relationship between the hepatitis A virus (HAV) numbers in imported frozen coquina clams involved in two hepatitis outbreaks, as well as the risk for human health. Due to HAV unculturability, a standardized TaqMan real-time reverse transcription-PCR controlling the virus/nucleic acid extraction and enzyme efficiencies was employed to figure the exposure dose for clams responsible for hepatitis cases. HAV numbers were then employed to figure the risk of infection based on a dose-response model for echovirus 12. The estimated risk of infection after consumption of lightly cooked clams matched actual attack rates. Our data show that prospective monitoring of bivalve samples may fail to prevent the occurrence of outbreaks, since HAV was detected in 44% of samples directly associated with cases but was undetectable in samples that were randomly collected from the importers and belonged to the same batches. A correlation was nevertheless observed between the prevalence of hepatitis A cases in the harvesting areas and positive HAV isolation in clams, which points to the need to identify and prevent hazards rather than relying on random sampling of finished products to ensure safety. However, when evidence shows that a critical limit of viral contamination has been exceeded in the potential sources of contamination discharging into the shellfish-growing beds, quantitative virological analysis addressing quality assurance and quality control requirements should be performed with the bivalves. This work provides the first evidence of accurate HAV levels in shellfish involved in outbreaks that could be of use for risk assessment purposes.
Grb 10 Promotes Lipolysis and Thermogenesis by Phosphorylation-Dependent Feedback Inhibition of mTORC 1

Meilian Liu,1,2,7 Juli Bai,1,2 Sijia He,1,2 Ricardo Villarreal,3 Derong Hu,1 Chuntao Zhang,1,4 Xin Yang,3 Huiyun Liang,3 Thomas J. Slaga,1 Yonghao Yu,5 Zhiguang Zhou,2 John Blenis,5 Philipp E. Scherer,6 Lily Q. Dong,3 and Feng Liu1,2,* 1Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA 2Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China 3Department of Cellular and Structural Biology, University of Texas Health ScienceCenter at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA 4The Department of Microbiology, School of Basic Medicine, Xinjiang Medical University, 393 Xinyi Road, Urumqi, Xinjiang 830011, China 5Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA 6Touchstone Diabetes Center, Department of Internal Medicine, and Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8549, USA 7Present address: Department of Biochemistry and Molecular Biology, University of New Mexico Health Science Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA *Correspondence: liuf@uthscsa.edu http://dx.doi. org/10.1016/j.cmet. 2014.03. 018
Cytokinetics and regulation of progenitor cells

Four different assay methods of bone marrow stem cells have been examined with regard to the kinetic pattern following perturbation of the steady‐state system, e.g., by irradiation. Basically, the stem cell assays fall into two categories: those depending on grafting hemopoietic cells into suitably treated recipients, and those in which recovery of the population is allowed in the animal in which the perturbation was produced, without handling the cells. Evidence is accumulating which indicates that in the grafting techniques, a selective loss of stem cells may occur, especially stem cells in cell cycle; hence, in early stages of recovery of the population, unduly low numerical values might be noted. In view of this evidence, the concept of the colony‐forming cell may have to be replaced by the concept of the colony‐forming property of the stem cell.
Telomerase inhibition and telomere loss in BEL-7404 human hepatoma cells treated with doxorubicin.

AIM To study the effects of doxorubicin on telomerase activity and telomere length in hepatocellular carcinoma. METHODS Telomerase activity was assayed with a non-radioisotopic quantitative telomerase repeat amplification protocol-based method. The effect of doxorubicin (DOX) on the growth of BEL-7404 human hepatoma cells was determined by microculture tetrazolium assay. Mean telomere length (terminal restriction fragment) was detected by Southern blot method. The expression of telomerase subunits genes was investigated by RT-PCR. Cell apoptosis and cell cycle distribution were evaluated by flow cytometry. RESULTS Telomerase activity was inhibited in a dose and time-dependent manner in BEL-7404 human hepatoma cells treated with DOX for 24, 48 or 72 h in concentrations from 0.156 to 2.5 microM which was correlated with the inhibition of cell growth. No changes were found in the mRNA expression of three telomerase subunits (hTERT, hTR and TP1) after drug exposure for 72 h with indicated concentrations. The cells treated with DOX showed shortened mean telomere length and accumulated at the G(2)/M phase. However, there was almost no effects on cell apoptosis by DOX. CONCLUSION The telomerase inhibition and the telomere shortening by DOX may contribute to its efficiency in the treatment in hepatocellular carcinoma.