tbuckley/cabot-search huggingface dataset:
Characterization of ANKRA, a Novel Ankyrin Repeat Protein that Interacts with the Cytoplasmic Domain of Megalin
Authors: KATHERINE RADER, ROBERT A. ORLANDO, XIAOJING LOU, MARILYN GIST FARQUHAR
Journal: Journal of the American Society of Nephrology (2000)

Ankyrin-repeat family A protein (ANKRA) is a novel protein that interacts directly and specifically with the cytoplasmic tail of megalin in the yeast two-hybrid system and glutathione-S-transferase pull-down assays. ANKRA has three ankyrin repeats and shows 61% overall homology to regulatory factor X, ankyrin repeat-containing protein. Mapping studies show that the three ankyrin repeats and C-terminus of ANKRA are required for binding to a unique juxtamembrane, 19-amino acid sequence on the megalin tail. Point mutational analysis reveals that a proline-rich motif (PXXPXXP) within this region is the site of ANKRA binding. ANKRA interacts with megalin but not with low-density lipoprotein receptor related protein, in keeping with the fact that the sequence of the megalin tail is unique. By cell fractionation, ANKRA is found both in the cytosol and associated with membranes enriched in megalin in L2 cells and proximal tubule cells. By immunofluorescence, ANKRA is concentrated near megalin along the plasma membrane of L2 cells and in the kidney cortex is expressed in glomerular and proximal tubule epithelia which also express megalin. These observations suggest that ANKRA may play a unique role in megalin's function as a clearance receptor in the kidney and L2 cells. In addition, ANKRA may have other partners because northern blot analysis reveals that ANKRA is more broadly expressed than megalin, and by immunofluorescence ANKRA is also expressed in connecting tubule cells and principal cells of collecting ducts.
The effect of intravenous prostaglandin F2 alpha and E2 on the motility of the sigmoid colon.
Authors: R H Hunt, J B Dilawari, J J Misiewicz
Journal: Gut (1975)

The effect of a 20-min intravenous infusion of prostaglandin E2 (0-08 mug kg-1 min-1) or of prostaglandin F2 alpha (0-8 mug kg-1 min-1) on the segmental pressures in the sigmoid colon was studied in 12 patients. Prostaglandin F2 alpha had no measurable effect, but prostaglandin E2 significantly inhibited sigmoid motility.
MORPHOLOGIC EVIDENCE FOR COLLAGEN CHANGES IN CHICH EMBRYOS TREATED WITH ß-AMINOPROPIONITRILE
Authors: Arnold van den Hooff, Charles I. Levene, Jerome Gross
Journal: The Journal of Experimental Medicine (1959)

Electron microscope analysis of thin sections of intact skin from 17 day chick embryos injected with beta-aminopropionitrile 3 days earlier, revealed markedly increased dispersion in fibril diameter both above and below the narrow distribution of normal fibril size. Extraction with cold 1 M neutral saline caused a dissolution of the fibrils to fine filaments of varying diameters. Histologic examination of the connective tissue of lathyritic skin prior to extraction revealed little difference from the normal. After extraction the collagen either disappeared almost entirely or was observed as a homogeneous smear. These results of morphologic analysis are consistent with previous chemical studies, supporting the thesis that lathyrogenic agents induce disruption of intermolecular cross-linking within normally insoluble collagen fibrils, allowing them to dissolve in cold neutral salt solutions.
Low folate levels may protect against colorectal cancer
Authors: B Van Guelpen
Journal: Gut (2006)

<b>Background and aims:</b> Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C&gt;T and 1298A&gt;C polymorphisms to the risk of developing CRC. <b>Subjects:</b> Subjects were 226 cases and 437 matched referents from the population based Northern Sweden Health and Disease Cohort. <b>Results:</b> We observed a bell-shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% confidence interval (CI) 1.13–3.56). In subjects with follow up times greater than the median of 4.2 years however, plasma folate concentrations were strongly positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52–9.87; p trend = 0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19–0.85; p trend = 0.062), and for 1298 CC versus AA, 1.62 (95% CI 0.94–2.81; p trend = 0.028). Interaction analysis suggested that the result for 1298A&gt;C may have been largely due to linkage disequilibrium with 677C&gt;T. The reduced CRC risk in 677 TT homozygotes was independent of plasma folate status. <b>Conclusions:</b> Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods.
A comparison of oral and intravenous alfacalcidol in the treatment of uremic hyperparathyroidism.
Authors: W T Lee, K Padayachi, J F Collins, T Cundy
Journal: Journal of the American Society of Nephrology (1994)

The i.v. bolus administration of 1 alpha hydroxylated vitamin D derivatives is effective in the treatment of uremic hyperparathyroidism. However, few of the published studies of this mode of treatment have been adequately controlled, and recent reports have suggested that p.o. bolus administration may be just as effective. In this study, 16 hemodialysis patients with mild to moderate hyperparathyroidism were assigned, after a 4-wk run-in period, to receive a 6-wk course of either thrice-weekly i.v. or p.o. alfacalcidol (initial dose, 4 micrograms). Then, after a further control period, they received a second 6-wk course, with either p.o. or i.v. alfacalcidol (whichever was not given in the first treatment period). Plasma parathyroid hormone (PTH) was measured weekly by the use of an intact hormone assay. Both routes of therapy resulted in a significant suppression of plasma PTH (P = 0.005) and an elevation in plasma ionized calcium (P = 0.01). The magnitude of the responses was similar for the two treatment phases, as was the relationship between the increment in calcium and the decrement in PTH. The most complete suppression of PTH was seen in those with the greatest increment in plasma calcium. The incidence of hypercalcemia and the mean dose reductions necessary were also similar in the two treatment phases. Oral bolus therapy and i.v. bolus therapy with alfacalcidol are equally effective in suppressing hyperparathyroidism. The postulated advantages of i.v. over p.o. therapy with 1 alpha hydroxylated vitamin D derivatives remain to be confirmed by controlled studies.
Studies on the relationship between plasma free fatty acids and growth hormone secretion in man
Authors: Hans-Jürgen Quabbe, Hans-Jürgen Bratzke, Ulrike Siegers, Kadip Elban
Journal: Journal of Clinical Investigation (1972)

The influence of plasma free fatty acid (FFA) concentration on the secretion of human growth hormone (HGH) was investigated. (a) FFA depression was produced by means of a nicotinic acid (NA) infusion for either 1 or 5 hr in the presence of glucose-induced hyperglycemia. Controls received only saline. (b) FFA depression was also produced by a 90 min NA infusion and then rapid FFA elevation by a lipid-plus-heparin (lipid) infusion. This procedure was compared with a similar NA infusion not followed by lipid. (c) FFA elevation was produced either by a lipid or by a norepinephrine (NE) infusion and then HGH secretion was stimulated by insulin-induced hypoglycemia. Each subject in this group received both the lipid and the NE infusion on seperate days as well as two control tests (insulin alone and NE alone). Depression of FFA resulted in an increase of HGH with a lag period of approximately 2 hr. Maximal HGH rise after 1 hr NA infusion was 7.7+/-1.9 ng/ml and with 5 hr NA infusion 14.3+/-3.6 ng/ml (both significantly higher than during saline infusion, P < 0.025 and < 0.005 respectively) and occurred despite continuous hyperglycemia. Lipid infusion just before the expected HGH increase prevented the HGH response to FFA depression. HGH rise during insulin hypoglycemia (32.2+/-6.5 ng/ml) was significantly inhibited by prior FFA elevation whether achieved by lipid infusion (maximum HGH rise 11.4+/-1.6 ng/ml) or by NE infusion (maximum HGH rise 19.0+/-6.2 ng/ml). The results are suggestive of a negative feedback loop between plasma FFA and HGH secretion, of importance for subacute rather than acute changes in the plasma FFA concentration. FFA lack itself seems to be the signal for HGH release despite the lag period between FFA decrease and HGH increase. Glucose and FFA can at least not fully replace each other in their respective influence on HGH release.
Genetic variants in<i>IL15</i>associate with progression of joint destruction in rheumatoid arthritis: a multicohort study
Authors: R Knevel, A Krabben, E Brouwer, M D Posthumus, A G Wilson, E Lindqvist, T Saxne, D de Rooy, N Daha, M P M van der Linden, G Stoeken, L van Toorn, B Koeleman, R Tsonaka, A Zhernakoza, J J Houwing-Duistermaat, R Toes, T W J Huizinga, A van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in <i>IL15</i> with the rate of joint destruction in RA. <h3>Method</h3> 1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. <h3>Results</h3> Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09-fold rate of joint destruction compared to other patients (p=4.0×10<sup>−6</sup>, p=3.8×10<sup>−4</sup>, p=5.0×10<sup>−3</sup>, p=5.0×10<sup>−3</sup> and p=9.4×10<sup>−3</sup>). <h3>Discussion</h3> Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p&lt;0.001; rs7665842, p&lt;0.001; rs4371699, p=0.01; rs6821171, p=0.01). These SNPs were also significant after correction for multiple testing. <h3>Conclusion</h3> Genetic variants in IL-15 are associated with progression of joint destruction in RA.
Marathon performance in relation to maximal aerobic power and training indices in female distance runners.
Authors: R D Hagan, S J Upton, J J Duncan, L R Gettman
Journal: British Journal of Sports Medicine (1987)

The purpose of this study was to examine the relationships of marathon performance time (MPT) to maximal aerobic power (VO2 max), physical characteristics, and training indices recorded for 12 weeks prior to a race in 35 female distance runners. The marathon experience of the subjects ranged from two to fifteen races. Physical and aerobic power characteristics (mean +/- S.D.) were: age, 35.7 +/- 8.5 yr; height, 166.4 +/- 5.7 cm; weight, 55.1 +/- 5.7 kg; body fat, 15.7 +/- 5.0%; VO2 max, 56.5 +/- 6.2 ml . kg-1 . min-1. Marathon time for this race averaged 227.0 +/- 31.6 min. Records from individual training diaries indicated the runners averaged 71.0 +/- 10.0 workout days, 10.0 +/- 10.0 two X day-1 workouts, 81.0 +/- 8.0 total workouts, 12.3 +/- 1.8 mean km . workout-1, 5402.8 +/- 1302.6 total training min, 187.0 +/- 18.0 m . min-1 training pace, 112.2 +/- 32.1 max km . wk-1, 83.1 +/- 23.4 mean km . wk-1, 998.8 +/- 282.6 km . 12 wk-1 and 13.8 +/- 2.4 mean km . day-1. MPT was positively correlated to body mass index (r = 0.52), and body fat (r = 0.52) but negatively related to VO2 max (r = -0.65). MPT was also negatively related to previous marathons completed (r = -0.47), workout days (r = -0.47), two X day-1 workouts (r = -0.52), total workouts (r = -0.56), mean km . workout-1 (r = -0.58), total training min (r = -0.56), m . min-1, training pace (r = -0.66), max km . wk-1 (r = -0.70), mean km . wk-1 (r = -0.74), km . 12 wk-1 (r = -0.74), and mean km . day-1 (r = -0.77). MPT for our population of runners may be predicted (r = 0.82, R2 = 0.68) by the following equation: MPT, (min) = 449.88 - 7.61 (-/x km.day-1 run) - 0.63 (m.min-1, training pace); SEE = +/- 18.4 min.
The Elevated 10-Year Risk of Cervical Precancer and Cancer in Women With Human Papillomavirus (HPV) Type 16 or 18 and the Possible Utility of Type-Specific HPV Testing in Clinical Practice
Authors: Michelle J. Khan, Philip E. Castle, Attila T. Lorincz, Sholom Wacholder, Mark Sherman, David R. Scott, Brenda B. Rush, Andrew G. Glass, Mark Schiffman
Journal: JNCI Journal of the National Cancer Institute (2005)

Human papillomavirus (HPV) types 16 and 18 cause 60%-70% of cervical cancer worldwide, and other HPV types cause virtually all remaining cases. Pooled HPV testing for 13 oncogenic types, including HPV16 and 18, is currently used in clinical practice for triage of equivocal cytology and, in conjunction with Pap tests, is an option for general screening among women 30 years of age and older. It is not clear to what extent individual identification of HPV16 or HPV18 as an adjunct to pooled oncogenic HPV testing might effectively identify women at particularly high risk of cervical cancer or its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3).From April 1, 1989, to November 2, 1990, a total of 20 810 women in the Kaiser Permanente health plan in Portland, OR, enrolled in a cohort study of HPV and cervical neoplasia. Women were tested for 13 oncogenic HPV types by Hybrid Capture 2 (HC2), and those women with a positive HC2 test were tested for HPV16 and 18. Enrollment Pap smear interpretation and HPV test results were linked to histologically confirmed CIN3 and cervical cancer (> or = CIN3) occurring during 10 years of cytologic follow-up. We calculated cumulative incidence rates with 95% confidence intervals for each interval up to 122 months using Kaplan-Meier methods.The 10-year cumulative incidence rates of > or = CIN3 were 17.2% (95% confidence interval [CI] = 11.5% to 22.9%) among HPV16+ women and 13.6% (95% CI = 3.6% to 23.7%) among HPV18+ (HPV16-) women, but only 3.0% (95% CI = 1.9% to 4.2%) among HC2+ women negative for HPV16 or HPV18. The 10-year cumulative incidence among HC2- women was 0.8% (95% CI = 0.6% to 1.1%). A subanalysis among women 30 years of age and older with normal cytology at enrollment strengthened the observed risk differences.HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may identify women at the greatest risk of > or = CIN3 and may permit less aggressive management of other women with oncogenic HPV infections.
Survival, Integration, and Differentiation of Cardiomyocyte Grafts
Authors: Hans Reinecke, Ming Zhang, Trudy Bartosek, Charles E. Murry
Journal: Circulation (1999)

Background —Cardiomyocyte grafting augments myocyte numbers in the heart. We investigated (1) how developmental stage influences graft survival; (2) whether acutely necrotic or healing cardiac lesions support grafts; and (3) the differentiation and integration of cardiomyocyte grafts in injured hearts. Methods and Results —Cardiomyocytes from fetal, neonatal, or adult inbred rats were grafted into normal myocardium, acutely cryoinjured myocardium, or granulation tissue (6 days after injury). Adult cardiomyocytes did not survive under any conditions. In contrast, fetal and neonatal cardiomyocytes formed viable grafts under all conditions. Time-course studies with neonatal cardiomyocytes showed that the grafts recapitulated many aspects of normal development. The adherens junction protein N-cadherin was distributed circumferentially at day 1 but began to organize into intercalated disk–like structures by day 6. The gap junction protein connexin43 followed a similar but delayed pattern relative to N-cadherin. From 2 to 8 weeks, there was progressive hypertrophy and the formation of mature intercalated disks. In some hearts, graft cells formed adherens and gap junctions with host cardiomyocytes, suggesting electromechanical coupling. More commonly, however, grafts were separated from the host myocardium by scar tissue. Gap and adherens junctions formed between neonatal and adult cardiomyocytes in coculture, as evidenced by dye transfer and localization of cadherin and connexin43 at intercellular junctions. Conclusions —Grafted fetal and neonatal cardiomyocytes form new, mature myocardium with the capacity to couple with injured host myocardium. Optimal repair, however, may require reducing the isolation of the graft by the intervening scar tissue.
The Effect of Digitalis on Ventricular Ejection in Normal Human Subjects
Authors: ARNOLD M. WEISSLER, WILLIAM G. GAMEL, HARVEY E. GRODE, SIDNEY COHEN, CLYDE D. SCHOENFELD
Journal: Circulation (1964)

The administration of deslanoside to normal subjects was associated with an abbreviation in the duration of all phases of mechanical systole in the absence of a change in cardiac output. The decrease in the ejection time index following deslanoside is an expression of the [see figure in the PDF file] diminution in the duration of ventricular ejection relative to heart rate and reflects the enhanced mean rate of left ventricular ejection following the drug. These observations lend additional evidence for the positive inotropic effect of digitalis in the normal heart. Serial determinations of the left ventricular ejection time index following deslanoside afforded observations on the temporal course of the effect of the drug. The decrease in the left ventricular ejection time index proved to be dose dependent, lending evidence for a direct relationship between the positive inotropic effect and the decreased duration of left ventricular ejection.
Cost-Effectiveness of Hypertension Therapy According to 2014 Guidelines
Authors: Andrew E. Moran, Michelle C. Odden, Anusorn Thanataveerat, Keane Y. Tzong, Petra W. Rasmussen, David Guzman, Lawrence Williams, Kirsten Bibbins-Domingo, Pamela G. Coxson, Lee Goldman
Journal: New England Journal of Medicine (2015)

On the basis of the 2014 guidelines for hypertension therapy in the United States, many eligible adults remain untreated. We projected the cost-effectiveness of treating hypertension in U.S. adults according to the 2014 guidelines.We used the Cardiovascular Disease Policy Model to simulate drug-treatment and monitoring costs, costs averted for the treatment of cardiovascular disease, and quality-adjusted life-years (QALYs) gained by treating previously untreated adults between the ages of 35 and 74 years from 2014 through 2024. We assessed cost-effectiveness according to age, hypertension level, and the presence or absence of chronic kidney disease or diabetes.The full implementation of the new hypertension guidelines would result in approximately 56,000 fewer cardiovascular events and 13,000 fewer deaths from cardiovascular causes annually, which would result in overall cost savings. The projections showed that the treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs for men between the ages of 35 and 74 years and for women between the ages of 45 and 74 years. The treatment of men or women with existing cardiovascular disease or men with stage 2 hypertension but without cardiovascular disease would remain cost-saving even if strategies to increase medication adherence doubled treatment costs. The treatment of stage 1 hypertension was cost-effective (defined as <$50,000 per QALY) for all men and for women between the ages of 45 and 74 years, whereas treating women between the ages of 35 and 44 years with stage 1 hypertension but without cardiovascular disease had intermediate or low cost-effectiveness.The implementation of the 2014 hypertension guidelines for U.S. adults between the ages of 35 and 74 years could potentially prevent about 56,000 cardiovascular events and 13,000 deaths annually, while saving costs. Controlling hypertension in all patients with cardiovascular disease or stage 2 hypertension could be effective and cost-saving. (Funded by the National Heart, Lung, and Blood Institute and others.).
Sinusoidal portal hypertension in hepatic amyloidosis.
Authors: E Bion, R Brenard, E A Pariente, D Lebrec, C Degott, F Maitre, J P Benhamou
Journal: Gut (1991)

Hepatic venous catheterisation and transvenous liver biopsy were performed in five patients with hepatic amyloidosis. In three patients, hepatic venous pressures were normal and histological examination of the liver biopsy specimen showed discrete and sparse perisinusoidal amyloid deposits. In the other two, however, the gradient between wedged and free hepatic venous pressures was increased (12 and 16 mmHg; normal 1-4 mmHg) and amyloid deposits were abundant and diffuse in the Disse9s space. This study shows that portal hypertension in patients with hepatic amyloidosis is of the sinusoidal type and is related to the reduction of vascular space of hepatic sinusoids by massive perisinusoidal amyloid deposits. Furthermore, portal hypertension is associated with a poor prognosis in patients with hepatic amyloidosis.
Generation of Oligodendrocyte Precursor Cells from Mouse Dorsal Spinal Cord Independent of Nkx6 Regulation and Shh Signaling
Authors: Jun Cai, Yingchuan Qi, Xuemei Hu, Min Tan, Zijing Liu, Jianshe Zhang, Qun Li, Maike Sander, Mengsheng Qiu
Journal: Neuron (2005)
Autocrine Motility Factor Promotes HER2 Cleavage and Signaling in Breast Cancer Cells
Authors: Dhong Hyo Kho, Pratima Nangia-Makker, Vitaly Balan, Victor Hogan, Larry Tait, Yi Wang, Avraham Raz
Journal: Cancer Research (2012)

Abstract Trastuzumab (Herceptin) is an effective targeted therapy in HER2-overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here, we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2. Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth. Furthermore, we found that HER2 expression and AMF secretion were inversely related in breast carcinoma cells. On the basis of this evidence that AMF may contribute to HER2-mediated breast cancer progression, our findings suggest that AMF–HER2 interaction might be a novel target for therapeutic management of patients with breast cancer, whose disease is resistant to trastuzumab. Cancer Res; 73(4); 1411–9. ©2012 AACR.