tbuckley/cabot-search huggingface dataset:
Association of Urinary Injury Biomarkers with Mortality and Cardiovascular Events
Authors: Mark J. Sarnak, Ronit Katz, Anne Newman, Tamara Harris, Carmen A. Peralta, Prasad Devarajan, Michael R. Bennett, Linda Fried, Joachim H. Ix, Suzanne Satterfield, Eleanor M. Simonsick, Chirag R. Parikh, Michael G. Shlipak
Journal: Journal of the American Society of Nephrology (2014)

Kidney damage is a common sequela of several chronic pathologic conditions. Whether biomarkers of kidney damage are prognostic for more severe outcomes is unknown. We measured three urinary biomarkers (kidney injury molecule-1 [KIM-1], IL-18, and albumin) in 3010 individuals enrolled in the Health, Aging and Body Composition (Health ABC) study and used Cox proportional hazards models to investigate the associations of urinary KIM-1/creatinine (cr), IL-18/cr, and albumin/cr (ACR) with all-cause mortality and cardiovascular disease (CVD). Multivariable models adjusted for demographics, traditional CVD risk factors, and eGFR. Mean age of participants was 74 years, 49% of participants were men, and 41% of participants were black. During the median 12.4 years of follow-up, 1450 deaths and 797 CVD outcomes occurred. Compared with the lowest quartile, successive quartiles had the following adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) for mortality: KIM-1/cr: (1.21; 1.03 to 1.41), (1.13; 0.96 to 1.34), and (1.28; 1.08 to 1.52); IL-18/cr: (1.02; 0.88 to 1.19), (1.16; 0.99 to 1.35), and (1.06; 0.90 to 1.25); ACR: (1.08; 0.91 to 1.27), (1.24; 1.06 to 1.46), and (1.63; 1.39 to 1.91). In similar analyses, only ACR quartiles associated with CVD: (1.19; 0.95 to 1.48), (1.35; 1.08 to 1.67), and (1.54; 1.24 to 1.91). Urinary KIM-1 had a modest association with all-cause mortality but did not associate with CVD, and urinary IL-18 did not associate with either outcome. In contrast, albuminuria strongly associated with all-cause mortality and CVD. Future studies should evaluate reasons for these differences in the prognostic importance of individual kidney injury markers.
Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca <sup>2+</sup> Leak Independent of Luminal Ca <sup>2+</sup> and Trigger Ventricular Arrhythmias in Mice
Authors: Nagesh Chopra, Prince J. Kannankeril, Tao Yang, Thinn Hlaing, Izabela Holinstat, Kristen Ettensohn, Karl Pfeifer, Brandy Akin, Larry R. Jones, Clara Franzini-Armstrong, Björn C. Knollmann
Journal: Circulation Research (2007)

Cardiac calsequestrin-null mice (Casq2-/-) display catecholaminergic ventricular tachycardia akin to humans with CASQ2 mutations. However, the specific contribution of Casq2 deficiency to the arrhythmia phenotype is difficult to assess because Casq2-/- mice also show significant reductions in the sarcoplasmic reticulum (SR) proteins junctin and triadin-1 and increased SR volume. Furthermore, it remains unknown whether Casq2 regulates SR Ca2+ release directly or indirectly by buffering SR luminal Ca2+. To address both questions, we examined heterozygous (Casq2+/-) mice, which have a 25% reduction in Casq2 but no significant decrease in other SR proteins. Casq2+/- mice (n=35) challenged with isoproterenol displayed 3-fold higher rates of ventricular ectopy than Casq2+/+ mice (n=31; P<0.05). Programmed stimulation induced significantly more ventricular tachycardia in Casq2+/- mice than in Casq2+/+ mice. Field-stimulated Ca2+ transients, cell shortening, L-type Ca2+ current, and SR volume were not significantly different in Casq2+/- and Casq2+/+ myocytes. However, in the presence of isoproterenol, SR Ca2+ leak was significantly increased in Casq2+/- myocytes (Casq2+/- 0.18+/-0.02 F(ratio) versus Casq2+/+ 0.11+/-0.01 F(ratio), n=57, 60; P<0.01), resulting in a significantly higher rate of spontaneous SR Ca2+ releases and triggered beats. SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction. As a result, the relationship between SR Ca2+ leak and SR luminal Ca2+ was significantly different between Casq2+/- and Casq2+/+ myocytes (P<0.01). Thus, even modest reductions in Casq2 increase SR Ca2+ leak and cause ventricular tachycardia susceptibility under stress. The underlying mechanism is likely the direct regulation of SR Ca2+ release channels by Casq2 rather than altered luminal Ca2+.
Treating breast cancer before surgery
Authors: R. Epstein
Journal: BMJ (1996)

The benefits of systemic treatment of breast cancer have been recognised in Britain for over a century1; but for most of this period international medical practice has been more influenced by enthusiasm for aggressive local treatments, including radical breast surgery.2 The rise of evidence based research revived interest in medical anticancer treatment, culminating in recent confirmation of longer survival after adjuvant systemic treatments.3 In contrast, randomised trials of local breast cancer treatments failed to establish any substantive overall survival benefit.4 Happily, this failure spawned the first revolution of 20th century breast cancer treatment: the advent of conservative surgery.

Hence the only intervention proved to alter the natural course of breast cancer is effective adjuvant systemic treatment. Despite this, adjuvant prescribing habits have been one of Britain's most volatile therapeutic variables in recent years.5 A new NHS report6 has invoked this variability to help explain startling survival differences (12–23% at five years) reported between specialist and non-specialist breast cancer units.7 The down side of this upbeat view of adjuvant treatment is the …
Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma
Authors: Jiro Kikuchi, Daisuke Koyama, Taeko Wada, Tohru Izumi, Peter O. Hofgaard, Bjarne Bogen, Yusuke Furukawa
Journal: Journal of Clinical Investigation (2015)

Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3-lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion-dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug-induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index.
Screening for Colorectal Cancer: A Guidance Statement From the American College of Physicians
Authors: Amir Qaseem
Journal: Annals of Internal Medicine (2012)

Colorectal cancer is the second leading cause of cancer-related deaths for men and women in the United States. The American College of Physicians (ACP) developed this guidance statement for clinicians by assessing the current guidelines developed by other organizations on screening for colorectal cancer. When multiple guidelines are available on a topic or when existing guidelines conflict, ACP believes that it is more valuable to provide clinicians with a rigorous review of the available guidelines rather than develop a new guideline on the same topic.The authors searched the National Guideline Clearinghouse to identify guidelines developed in the United States. Four guidelines met the inclusion criteria: a joint guideline developed by the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology and individual guidelines developed by the Institute for Clinical Systems Improvement, the U.S. Preventive Services Task Force, and the American College of Radiology. GUIDANCE STATEMENT 1: ACP recommends that clinicians perform individualized assessment of risk for colorectal cancer in all adults. GUIDANCE STATEMENT 2: ACP recommends that clinicians screen for colorectal cancer in average-risk adults starting at the age of 50 years and in high-risk adults starting at the age of 40 years or 10 years younger than the age at which the youngest affected relative was diagnosed with colorectal cancer. GUIDANCE STATEMENT 3: ACP recommends using a stool-based test, flexible sigmoidoscopy, or optical colonoscopy as a screening test in patients who are at average risk. ACP recommends using optical colonoscopy as a screening test in patients who are at high risk. Clinicians should select the test based on the benefits and harms of the screening test, availability of the screening test, and patient preferences. GUIDANCE STATEMENT 4: ACP recommends that clinicians stop screening for colorectal cancer in adults over the age of 75 years or in adults with a life expectancy of less than 10 years.
Matrix Metalloproteinases as Novel Disease Markers in Takayasu Arteritis
Authors: Akifumi Matsuyama, Naohiko Sakai, Masato Ishigami, Hisatoyo Hiraoka, Susumu Kashine, Ayumu Hirata, Tadashi Nakamura, Shizuya Yamashita, Yuji Matsuzawa
Journal: Circulation (2003)

Takayasu arteritis (TA) is a chronic vasculitis that primarily affects large elastic arteries. Monitoring of disease activity is crucial because the disease tends to progress despite treatment with glucocorticoid and/or immunosuppressive agents. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have generally been used as disease activity markers, but these are nonspecific inflammatory markers and lack the sensitivity and specificity to accurately monitor the disease status. Given the histological findings characterized by destruction of elastic fibers, we hypothesized that matrix metalloproteinases (MMPs) could be useful as markers of disease activity in TA.A consecutive series of 25 patients with TA were enrolled in this study. According to the National Institutes of Health criteria of disease activity, 11 were in an active phase and the remaining 14 were in remission. Circulating levels of MMP-2, MMP-3, and MMP-9 were determined by ELISA in all patients with TA and controls. MMP-2 levels were higher in patients with TA than in controls, but no correlation was found between serum MMP-2 and disease activity score. In contrast, MMP-3 and MMP-9 levels in patients with active disease were higher than in patients in remission and controls, and a positive correlation was demonstrated between circulating levels of MMP-3 or MMP-9 and disease activity score. The high levels of MMP-3 and MMP-9 improved when patients underwent remission.The present results indicate that MMP-2 can be helpful in diagnosing TA and that MMP-3 and MMP-9 can be used as activity markers for TA.
Angiotensin II Activates H+-ATPase in Type A Intercalated Cells
Authors: Vladimír Pech, Wencui Zheng, Truyen D Pham, Jill W Verlander, Susan M Wall
Journal: Journal of the American Society of Nephrology (2008)

<h3>Abstract</h3> Recent research suggests that biological age, based on DNA methylation or neuroimaging measures, may predict health traits in adulthood more accurately than chronological age. However, whether these findings apply to earlier stages in life is unknown. We therefore aimed to characterise the performance of and interdependence between measures of biological age during adolescence, leveraging longitudinal data from a subsample of young adolescents from the population-based ALSPAC cohort (n=386). We derived four methylation age measures in late adolescence (17-19 years) and a measure of brain age derived from structural neuroimaging data (18-24 years). We then examined associations between these measures of biological age, and their relationship with five measures of physical, cognitive and mental health (8-18 years). Brain age was largely independent of different measures of methylation age, even after accounting for age, cell type composition, array and study (beta range: -0.60 to 0.17, all p&gt;0.05). Smoking and BMI predicted three measures of advanced methylation age (beta range: -0.39 to 0.52, all p&lt;0.05), but not brain age. Depressive symptoms and cognitive ability were unrelated to all measures of biological age. Our findings emphasize the variability of and independence between these methylation- and brain-based measures of age in adolescents. They also highlight the importance of tracking the mosaic of ageing in younger populations.
Change in alcohol consumption and risk of death from all causes and from ischaemic heart disease.
Authors: N B Lazarus, G A Kaplan, R D Cohen, D J Leu
Journal: BMJ (1991)

To examine the association between alcohol consumption and mortality from all causes and from ischaemic heart disease with a focus on differentiating between long term abstainers and more recent non-drinkers.Cohort study of changes in alcohol consumption from 1965 to 1974 and mortality from all causes and ischaemic heart disease during 1974-84.Population based study of adult residents of Alameda County, California.2225 women and 1845 men aged 35 and over in 1965.Alcohol consumption in 1964 and 1974 and mortality from all causes and from ischaemic heart disease during 1974-84.There was a significantly higher risk of death from all causes and from ischaemic heart disease in women who gave up drinking between 1965 and 1974 than in women who continued to drink (relative risk 1.72, 95% confidence interval 1.11 to 2.66, and 2.75, 1.44 to 5.23, for all causes and ischaemic heart disease respectively). A significant increase in risk was not seen in men who gave up drinking (1.32, 0.87 to 2.01, and 0.95, 0.41 to 2.20, respectively). Among men, long term abstainers compared with drinkers were at increased risk of death from all causes and from ischaemic heart disease, though the associations were not significant (1.40, 0.98 to 2.00, and 1.40, 0.76 to 2.58, for all causes and ischaemic heart disease respectively).Some of the increased risk of death from all causes and from ischaemic heart disease associated with not drinking in women seems to be accounted for by higher risks among those who gave up drinking. Men who are long term abstainers may also be at an increased risk of death. The heterogeneity of the non-drinking group should be considered when comparisons are made with drinkers.
Multimodal nutritional rehabilitation improves clinical outcomes of malnourished patients with chronic respiratory failure: a randomised controlled trial
Authors: C. M. Pison, N. J. Cano, C. Cherion, F. Caron, I. Court-Fortune, M.-T. Antonini, J. Gonzalez-Bermejo, L. Meziane, L. C. Molano, J.-P. Janssens, F. Costes, B. Wuyam, T. Similowski, B. Melloni, M. Hayot, J. Augustin, C. Tardif, H. Lejeune, H. Roth, C. Pichard
Journal: Thorax (2011)

In chronic respiratory failure (CRF), body composition strongly predicts survival.A prospective randomised controlled trial was undertaken in malnourished patients with CRF to evaluate the effects of 3 months of home rehabilitation on body functioning and composition. 122 patients with CRF on long-term oxygen therapy and/or non-invasive ventilation (mean (SD) age 66 (10) years, 91 men) were included from eight respiratory units; 62 were assigned to home health education (controls) and 60 to multimodal nutritional rehabilitation combining health education, oral nutritional supplements, exercise and oral testosterone for 90 days. The primary endpoint was exercise tolerance assessed by the 6-min walking test (6MWT). Secondary endpoints were body composition, quality of life after 3 months and 15-month survival.Mean (SD) baseline arterial oxygen tension was 7.7 (1.2) kPa, forced expiratory volume in 1 s 31 (13)% predicted, body mass index (BMI) 21.5 (3.9) kg/m2 and fat-free mass index (FFMI) 15.5 (2.4) kg/m2. The intervention had no significant effect on 6MWT. Improvements (treatment effect) were seen in BMI (+0.56 kg/m2, 95% CI 0.18 to 0.95, p=0.004), FFMI (+0.60 kg/m2, 95% CI 0.15 to 1.05, p=0.01), haemoglobin (+9.1 g/l, 95% CI 2.5 to 15.7, p=0.008), peak workload (+7.2 W, 95% CI 3.7 to 10.6, p<0.001), quadriceps isometric force (+28.3 N, 95% CI 7.2 to 49.3, p=0.009), endurance time (+5.9 min, 95% CI 3.1 to 8.8, p<0.001) and, in women, Chronic Respiratory Questionnaire (+16.5 units, 95% CI 5.3 to 27.7, p=0.006). In a multivariate Cox analysis, only rehabilitation in a per-protocol analysis predicted survival (HR 0.27, 95% CI 0.07 to 0.95, p=0.042).Multimodal nutritional rehabilitation aimed at improving body composition increased exercise tolerance, quality of life in women and survival in compliant patients, supporting its incorporation in the treatment of malnourished patients with CRF. Clinical Trial number NCT00230984.
The significant relationship between ANA prevalence and male never-smokers with mixed ventilation disorders
Authors: Hiroshi Nakano, Yoko Shibata, Sumito Inoue, Akira Igarashi, Keiko Yamauchi, Shuichi Abe, Masamichi Sato, Yasuko Aida, Hiroyuki Kishi, Keiko Nunomiya, Takamasa Kayama, Isao Kubota
Journal: European Respiratory Journal (2013)

Background. 

Abnormal autoimmunity is associated with the pathogenesis of chronic obstructive pulmonary disease. The relationship between serum antinuclear antibody (ANA) value and pulmonary function has not been investigated in a general population.

Methods. 

Blood sampling and spirometry were performed in 3257 subjects from Takahata study that was based on an annual community health check in Japan. We compared characteristics of ANA-positive and ANA-negative subjects and investigated the relationship between ANA value and spirometric measures.

Results. 

The prevalence of ANA positivity was significantly different among the spirometric classifications only in male never-smokers. The prevalence of ANA positivity in pure restrictive and pure obstructive subjects was not significantly different from that of normal subjects, in contrast, it was significantly greater in subjects with mixed pulmonary disorder than in other groups of male never-smokers. In male subjects, there were significant inverse relationships between ANA values and % predicted values for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximal midexpiratory flow (MMF), as well as FEV1/FVC.

Conclusion. 

Autoimmune mechanism may involve in the development of airflow obstruction in never-smokers.
Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia
Authors: Eric D Berglund, Tiemin Liu, Xingxing Kong, Jong-Woo Sohn, Linh Vong, Zhuo Deng, Charlotte E Lee, Syann Lee, Kevin W Williams, David P Olson, Philipp E Scherer, Bradford B Lowell, Joel K Elmquist
Journal: Nature Neuroscience (2014)
Validation Study of a Quantitative Multigene Reverse Transcriptase–Polymerase Chain Reaction Assay for Assessment of Recurrence Risk in Patients With Stage II Colon Cancer
Authors: Richard G. Gray, Philip Quirke, Kelly Handley, Margarita Lopatin, Laura Magill, Frederick L. Baehner, Claire Beaumont, Kim M. Clark-Langone, Carl N. Yoshizawa, Mark Lee, Drew Watson, Steven Shak, David J. Kerr
Journal: Journal of Clinical Oncology (2011)

We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer.We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy.Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95).The continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit.
Relative Effect Potency Estimates of Dioxin-like Activity for Dioxins, Furans, and Dioxin-like PCBs in Adults Based on Two Thyroid Outcomes
Authors: Tomáš Trnovec, Todd A. Jusko, Eva Šovˇcíková, Kinga Lancz, Jana Chovancová, Henrieta Patayová, L’ubica Palkoviˇcová, Beata Drobná, Pavel Langer, Martin Van den Berg, Ladislav Dedik, Soˇna Wimmerová
Journal: Environmental Health Perspectives (2013)

Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these "intake" TEFs are commonly-but incorrectly-used by regulatory authorities to calculate "systemic" toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect.We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest.We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia.REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (β)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators.Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin-like compounds.