tbuckley/cabot-search huggingface dataset:
Postoperative Adjuvant Chemotherapy or Radiation Therapy for Rectal Cancer: Results From NSABP Protocol R-011
Authors: B. Fisher, N. Wolmark, H. Rockette, C. Redmond, M. Deutsch, D. L. Wickerham, E. R. Fisher, R. Caplan, J. Jones, H. Lerner, P. Gordon, M. Feldman, A. Cruz, S. Legault-Poisson, M. Wexler, W. Lawrence, A. Robidoux
Journal: JNCI Journal of the National Cancer Institute (1988)

Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986. Their average time on study was 64.1 months. The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients). The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = .006) and in survival (P = .05). Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions. Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy. When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs. 47%; P < .001; relative odds, 2.00) and in survival (37% vs. 60%; P = .001; relative odds, 1.93), was restricted to males. When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients. When the group receiving postoperative radiation (4,600–4,700 rad in 26–27 fractions; 5, 100–5, 300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = .06). No significant benefit in overall disease-free survival (P = .4) or survival (P =.7) from the use of radiation has been demonstrated. The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant. In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer. The observed advantage was restricted to males. Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival. [J Natl Cancer Inst 1988; 80: 21–29]
Refining Predictive Models in Critically Ill Patients with Acute Renal Failure
Authors: Ravindra L. Mehta, Maria T. Pascual, Carmencita G. Gruta, Shunping Zhuang, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Mortality rates in acute renal failure remain extremely high, and risk-adjustment tools are needed for quality improvement initiatives and design (stratification) and analysis of clinical trials. A total of 605 patients with acute renal failure in the intensive care unit during 1989-1995 were evaluated, and demographic, historical, laboratory, and physiologic variables were linked with in-hospital death rates using multivariable logistic regression. Three hundred and fourteen (51.9%) patients died in-hospital. The following variables were significantly associated with in-hospital death: age (odds ratio [OR], 1.02 per yr), male gender (OR, 2.36), respiratory (OR, 2.62), liver (OR, 3.06), and hematologic failure (OR, 3.40), creatinine (OR, 0.71 per mg/dl), blood urea nitrogen (OR, 1.02 per mg/dl), log urine output (OR, 0.64 per log ml/d), and heart rate (OR, 1.01 per beat/min). The area under the receiver operating characteristic curve was 0.83, indicating good model discrimination. The model was superior in all performance metrics to six generic and four acute renal failure-specific predictive models. A disease-specific severity of illness equation was developed using routinely available and specific clinical variables. Cross-validation of the model and additional bedside experience will be needed before it can be effectively applied across centers, particularly in the context of clinical trials.
Abstract 1190: Integration of mRNA and miRNA signatures induced by BRCA1 gene
Authors: Miljana Tanic, Magdalena Zajac, Gonzalo Gomez-Lopez, Javier Benitez, Beatriz Martinez-Delgado
Journal: Cancer Research (2011)

Abstract During the past years it has been well established that microRNAs (miRNAs) modulate the activity of mRNAs. Microarray-based techniques are being useful to obtain miRNA and gene expression signatures associated to different samples. The aim of this study is to integrate data from both types of microarray experiments to obtain significant relationships between miRNA profile and gene expression signature associated to the absence or presence of BRCA1 gene in a cellular system. Whole genome transcriptional mRNA profiling and global miRNA expression profiling was performed on a BRCA1 deficient, HCC1937 breast cancer cell line, and the isogenic HCC1937 expressing BRCA1. We have related each differentially expressed miRNA and their miRanda predicted transcripts targets obtained from miRBase and TargetScan, to find consistent pairs of downregulated targets for upregulated miRNAs and viceversa, which were non randomly associated (Fisher, FDR&amp;lt;0.05). In our study we found over 8000 differentially expressed genes and 9 differentially expressed miRNAs between HCC1937 and HCC1937/BRCA1 cells (FDR p&amp;lt;0.05). Integration of these data revealed significant interactions between three differentially upregulated microRNAs and their downregulated targets. Moreover, we have evaluated the role of these experimentally consistent pairs at the biological pathways level (Ingenuity Pathway Analysis). We identified potential signaling pathways significantly repressed associated with miRNA upregulation in BRCA1-expressing HCC1937 cells, which included MAPK or NFκB pathway. Down regulation of these pathways was experimentally validated by luciferase assays. Integration analysis between miRNA-mRNA data allows us to define genes and pathways controlled by differentially expressed miRNA upon BRCA1 expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1190. doi:10.1158/1538-7445.AM2011-1190
Depressive Symptoms, Health Behaviors, and Risk of Cardiovascular Events in Patients With Coronary Heart Disease
Authors: Mary A. Whooley, Peter de Jonge, Eric Vittinghoff, Christian Otte, Rudolf Moos, Robert M. Carney, Sadia Ali, Sunaina Dowray, Beeya Na, Mitchell D. Feldman, Nelson B. Schiller, Warren S. Browner
Journal: JAMA (2008)

<h3>Context</h3>Depressive symptoms predict adverse cardiovascular outcomes in patients with coronary heart disease, but the mechanisms responsible for this association are unknown.<h3>Objective</h3>To determine why depressive symptoms are associated with an increased risk of cardiovascular events.<h3>Design and Participants</h3>The Heart and Soul Study is a prospective cohort study of 1017 outpatients with stable coronary heart disease followed up for a mean (SD) of 4.8 (1.4) years.<h3>Setting</h3>Participants were recruited between September 11, 2000, and December 20, 2002, from 12 outpatient clinics in the San Francisco Bay Area and were followed up to January 12, 2008.<h3>Main Outcome Measures</h3>Baseline depressive symptoms were assessed using the Patient Health Questionnaire (PHQ). We used proportional hazards models to evaluate the extent to which the association of depressive symptoms with subsequent cardiovascular events (heart failure, myocardial infarction, stroke, transient ischemic attack, or death) was explained by baseline disease severity and potential biological or behavioral mediators.<h3>Results</h3>A total of 341 cardiovascular events occurred during 4876 person-years of follow-up. The age-adjusted annual rate of cardiovascular events was 10.0% among the 199 participants with depressive symptoms (PHQ score ≥10) and 6.7% among the 818 participants without depressive symptoms (hazard ratio [HR], 1.50; 95% confidence interval, [CI], 1.16-1.95; P = .002). After adjustment for comorbid conditions and disease severity, depressive symptoms were associated with a 31% higher rate of cardiovascular events (HR, 1.31; 95% CI, 1.00-1.71; P = .04). Additional adjustment for potential biological mediators attenuated this association (HR, 1.24; 95% CI, 0.94-1.63; P = .12). After further adjustment for potential behavioral mediators, including physical inactivity, there was no significant association (HR, 1.05; 95% CI, 0.79-1.40; P = .75).<h3>Conclusion</h3>In this sample of outpatients with coronary heart disease, the association between depressive symptoms and adverse cardiovascular events was largely explained by behavioral factors, particularly physical inactivity.
The influence of the parathyroid glands on the hypercalcemia of experimental magnesium depletion in the rat
Authors: H. J. Gitelman, S. Kukolj, L. G. Welt
Journal: Journal of Clinical Investigation (1968)

Magnesium-deficient rats develop significant hypercalcemia, hypophosphatemia, and hyperphosphaturia. These changes suggest a state of hyperparathyroidism. This study examines the regulation of parathyroid gland activity in magnesium-deficient rats. Magnesium deficiency was induced in intact and chronically parathyroidectomized animals by feeding them a diet free of this cation. Control animals were pair fed and treated identically except for the inclusion of magnesium in their gavage solution.Magnesium-deficient rats with intact parathyroid glands developed significant hypercalcemia and hypophosphatemia. In addition, the concentration of ionic calcium in plasma was significantly elevated. In contrast, magnesium-deficient parathyroidectomized animals did not have a higher level of calcium in plasma than their nondeficient controls; they developed a decreased concentration of ionic calcium in the absence of a difference in the concentration of phosphate in plasma when compared with appropriate controls. The increased urinary excretion of phosphate was independent of the parathyriod status of the animals.It can be concluded that the hypercalcemia and hypophosphatemia of magnesium deficiency demands parathyroid gland activity and that the regulation of this activity is modified in the magnesium-deficient state to permit the maintenance of an elevated concentration of ionic calcium in plasma. Additional explanations must be found for the hyperphosphaturia.
Collaborative care of hypertensives, using a shared record.
Authors: S Ezedum, D N Kerr
Journal: BMJ (1977)

A shared hospital-GP record for control of hypertension was studied in a sample of 60 patients. Over 80% of patients brought the record to hospital duly completed. Two-thirds of GPs, and the hospital staff, assessed the record as a useful aid in the care of hypertensives. It is still employed enthusiastically, three years after its introduction.
Overexpression of tumor necrosis factor (TNF)-α and interferon (IFN)-γ by bone marrow cells from patients with myelodysplastic syndromes
Authors: M Kitagawa, I Saito, T Kuwata, S Yoshida, S Yamaguchi, M Takahashi, T Tanizawa, R Kamiyama, K Hirokawa
Journal: Leukemia (1997)
Biomarkers Predicting Outcome in Patients with Advanced Renal Cell Carcinoma: Results from Sorafenib Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial
Authors: Carol Peña, Chetan Lathia, Minghua Shan, Bernard Escudier, Ronald M. Bukowski
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Plasma proteins [vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), carbonic anhydrase IX (CAIX), tissue inhibitor of metalloproteinase 1 (TIMP-1), and Ras p21] and one tumor gene (VHL) were analyzed to identify prognostic biomarkers or indicators of response to sorafenib in a subset of patients enrolled in the Treatment Approaches in Renal Cancer Global Evaluation Trial. Experimental Design: Nine hundred three patients with advanced renal cell carcinoma (RCC) were randomized to 400 mg sorafenib twice a day or placebo. Samples collected at baseline and after 3 and 12 weeks were subjected to enzyme-linked immunosorbent assays. VHL exons were sequenced from tumor biopsies. Results: Baseline biomarker data were available for VEGF (n = 712), sVEGFR-2 (n = 713), CAIX (n = 128), TIMP-1 (n = 123), Ras p21 (n = 125), and VHL mutational status (n = 134). Higher Eastern Cooperative Oncology Group performance status (ECOG PS) score correlated with elevated baseline VEGF (P &amp;lt; 0.0001) and a higher incidence of VHL mutations (P = 0.008), whereas higher Memorial Sloan-Kettering Cancer Center (MSKCC) score correlated with elevated VEGF (P &amp;lt; 0.0001), CAIX (P = 0.027), and TIMP-1 (P = 0.0001). Univariable analyses of baseline levels in the placebo cohort identified VEGF (P = 0.0024), CAIX (P = 0.034), TIMP-1 (P = 0.001), and Ras p21 (P = 0.016) as prognostic biomarkers for survival. TIMP-1 remained prognostic for survival in a multivariable analysis model (P = 0.002) that also included ECOG PS, MSKCC score, and the other biomarkers assayed. In the placebo cohort, TIMP-1 (P &amp;lt; 0.001) and Ras p21 (P = 0.048) levels increased at 12 weeks. In the sorafenib cohort, VEGF levels increased at 3 and 12 weeks of treatment (both weeks P &amp;lt; 0.0001), whereas sVEGFR-2 (both weeks P &amp;lt; 0.0001) and TIMP-1 levels (P = 0.002, week 3; P = 0.006, week 12) decreased. Conclusions: VEGF, CAIX, TIMP-1, and Ras p21 levels were prognostic for survival in RCC patients. Of these, TIMP-1 has emerged as being independently prognostic. Clin Cancer Res; 16(19); 4853–63. ©2010 AACR.
Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial.
Authors: H Drexler, U Banhardt, T Meinertz, H Wollschläger, M Lehmann, H Just
Journal: Circulation (1989)

To discover the underlying mechanisms involved in the beneficial long-term effects of angiotensin converting enzyme (ACE) inhibitors, we investigated the systemic and peripheral effects of short- and long-term ACE inhibition in patients with chronic heart failure. After assessing the short-term effects and dose titration with cilazapril, a new long-acting ACE inhibitor, 21 patients were randomized to receive either placebo or the ACE inhibitor. Seventeen patients completed the 3-month treatment. Central hemodynamic output, femoral blood flow (measured by thermodilution), oxygen saturation, and lactate and norepinephrine levels were determined simultaneously in the femoral vein and radial artery during treatment and after a 3-month rest and during symptom-limited bicycle exercise. Short-term ACE inhibition improved rest and exercise hemodynamic output, but it did not alter peak femoral blood flow, calculated leg oxygen consumption, or systemic oxygen uptake during exercise, despite significant reduction in femoral norepinephrine extraction and arterial angiotensin levels during exercise. In contrast, long-term ACE inhibition further improved exercise cardiac output and increased leg blood flow (from 2.3 to 2.9 l/min, p less than 0.05), leg oxygen consumption (from 277 to 403 ml/min, p less than 0.05), and systemic oxygen uptake (from 1,133 to 1,453 ml/min, p less than 0.05), whereas these variables remained unchanged with placebo treatment (p less than 0.02 between groups). Moreover, a moderate but significant increase in femoral oxygen extraction occurred after long-term therapy (ACE inhibitor: from 76% to 83%, p less than 0.05; placebo: from 75% to 74%, NS; p less than 0.01 between groups). We conclude that long-term ACE inhibition is clinically beneficial in that it improves blood flow to skeletal muscle during exercise over time. The long-term effects of ACE inhibition are, in part, probably related to peripheral (vascular) mechanisms, for example, by reversing the inability of peripheral vessels to dilate and by improving oxygen utilization.
CLINICAL CHARACTERISTICS AND RISK FACTORS FOR BILE SALT MALABSORPTION
Authors: K Sager, S Subramanian
Journal: Gut (2013)

<h3>Introduction</h3> Bile acid malabsorbtion (BAM) is a known cause of chronic diarrhoea. The condition is easily diagnosed by performing a selenium homocholic acid taurine (SeHCAT) test, with 7-day retention of &lt;10% indicating BAM. BAM negatively impacts on quality of life but responds well to bile acid sequestrants. Patients with undiagnosed BAM are often labelled as diarrhoea-predominant IBS (IBS-D), especially those with idiopathic or type 2 BAM. We aimed to investigate the clinical characteristics of patients diagnosed with type 2 BAM. <h3>Method</h3> We performed a retrospective study of patients who underwent a SeHCAT scan for investigation of diarrhoea at the Royal Liverpool Hospital between 18/03/2009 and 03/01/2012. Clinical details including demographics and response to treatment were abstracted from electronic case notes. <h3>Results</h3> 161 patients who attended for SeHCAT scan for investigation for diarrhoea were reviewed. 60 patients had BAM with a 7 day Selenium retention of &lt;10%. 22 of these patients had primary (type 2) BAM, of which 12 were female and 10 were male, median age 48.5 (range 23–68). 12 of these patients were labelled as IBS-D by their clinicians prior to the SeHCAT test. 19 received treatment with bile acid sequestrants. 13 had follow up data, 6 are awaiting clinic review and 3 patients were lost to follow up. 12 (92%) of the 13 patients reviewed in clinic responded well to treatment, taken as significant reduction in bowel frequency or dramatic improvement suggested by the patient. 1 (8%) patient did not respond despite 2 different bile acid sequestrants. 35 of the remaining 38 patients had secondary BAM due to ileal Crohn9s (57%), cholecystectomy (20%), intestinal resection (8.5%), both cholecystectomy and ileal Crohn9s (5.7%), coeliac disease (5.7%), and chronic pancreatitis (2.9%). Of these patients 23 were female and 12 were male, median age 45 (range 16–80). 30 patients received treatment with bile acid sequestrants. 23 had follow up data, and 7 are awaiting clinic review. 20 (87%) of the 23 patients reviewed in clinic responded well to treatment and 3 (13%) did not respond despite 2 different bile acid sequestrants. <h3>Conclusion</h3> BAM is a cause of chronic diarrhoea that can be easily managed with bile acid sequestrants. Patients with chronic diarrhoea and in particular those who have been labelled as IBS-D should be referred for a SeHCAT scan to rule out BAM. If the test is not available locally then referral to another centre should be considered.
Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Authors: M. G. Forest
Journal: Human Reproduction Update (2004)

Congenital adrenal hyperplasias (CAH) are inherited defects of cortisol biosynthesis. More than 90% of CAH are caused by 21-hydroxylase deficiency (21-OHD), found in 1:10 000 to 1:15 000 live births. Females with 'classical' 21-OHD, being exposed to excess androgens prenatally, are born with virilized external genitalia. Potentially lethal adrenal insufficiency is characteristic of two-thirds to three-quarters of patients with the classical salt wasting (SW) form of 21-OHD. Non-SW 21-OHD may be diagnosed on genital ambiguity in affected females, and/or later on the occurrence of androgen excess in both sexes. Non-classical 21-OHD, detected in ≥1:100 of certain populations, may present as precocious pubarche in children or polycystic ovarian syndrome in young women. 21-OHD is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombination between CYP21 and the closely linked CYP21P pseudogene. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disorder. This close association between genotype and phenotype makes it possible to predict clinical outcome in affected subjects. The risk of SW and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment, but additional therapies are being developed. A first trimester prenatal diagnosis should be proposed in families in whom molecular studies have been performed previously. The state of heterozygotism can be predicted by hormonal testing and confirmed by molecular studies. Prenatal diagnosis by direct mutation detection in previously genotyped families permits prenatal treatment of affected females in order to avoid or minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before SW crises develop, reducing mortality in this disorder.
Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor, Inhibits HIF-1α Expression in an AhR-Independent Fashion
Authors: Erika Terzuoli, Maura Puppo, Annamaria Rapisarda, Badarch Uranchimeg, Liang Cao, Angelika M. Burger, Marina Ziche, Giovanni Melillo
Journal: Cancer Research (2010)

Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1beta/AhR, which is shared with HIF-1alpha, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacologic activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1alpha transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1alpha by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1alpha expression in Ah(R100) cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1alpha in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1alpha mRNA expression by approximately 50%. Notably, actinomycin-D completely abrogated the ability of AF to downregulate HIF-1alpha mRNA, indicating that active transcription was required for the inhibition of HIF-1alpha expression. Finally, AF inhibited HIF-1alpha protein accumulation and the expression of HIF-1 target genes in MCF-7 xenografts. These results show that AF inhibits HIF-1alpha in an AhR-independent fashion, and they unveil additional activities of AF that may be relevant for its further clinical development.