tbuckley/cabot-search huggingface dataset:
Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice
Authors: Zhaoyong Hu, Huiling Wang, In Hee Lee, Jie Du, William E. Mitch
Journal: Journal of Clinical Investigation (2009)

Muscle wasting is associated with a number of pathophysiologic conditions, including metabolic acidosis, diabetes, sepsis, and high angiotensin II levels. Under these conditions, activation of muscle protein degradation requires endogenous glucocorticoids. As the mechanism(s) underlying this dependence on glucocorticoids have not been identified, we analyzed the effects of glucocorticoids on muscle wasting in a mouse model of acute diabetes. Adrenalectomized, acutely diabetic mice given a physiologic dose of glucocorticoids exhibited decreased IRS-1–associated PI3K activity in muscle and progressive muscle atrophy. These responses were related to increased association of PI3K with the glucocorticoid receptor (GR). In mice with muscle-specific GR deletion (referred to as MGRKO mice), acute diabetes minimally suppressed IRS-1–associated PI3K activity in muscle and did not cause muscle atrophy. However, when a physiologic dose of glucocorticoids was given to mice with muscle-specific IR deletion, muscle protein degradation was accelerated. Fluorescence resonance energy transfer and an in vitro competition assay revealed that activated GRs competed for PI3K, reducing its association with IRS-1. Reexpression of WT GRs or those with a mutation in the nuclear localization signal in the muscle of MGRKO mice indicated that competition for PI3K was a prominent mechanism underlying reduced IRS-1–associated PI3K activity. This nongenomic influence of the GR contributes to activation of muscle protein degradation. We therefore conclude that stimulation of muscle proteolysis requires 2 events, increased glucocorticoid levels and impaired insulin signaling.
Phase III, Multicenter, Randomized Trial of Maintenance Chemotherapy Versus Observation in Patients With Metastatic Breast Cancer After Achieving Disease Control With Six Cycles of Gemcitabine Plus Paclitaxel As First-Line Chemotherapy: KCSG-BR07-02
Authors: Yeon Hee Park, Kyung Hae Jung, Seock-Ah Im, Joo Hyuk Sohn, Jungsil Ro, Jin-Hee Ahn, Sung-Bae Kim, Byung-Ho Nam, Do Youn Oh, Sae-Won Han, Soohyeon Lee, In Hae Park, Keun Seok Lee, Jee Hyun Kim, Seok Yun Kang, Moon Hee Lee, Hee Sook Park, Jin Seok Ahn, Young-Hyuck Im
Journal: Journal of Clinical Oncology (2013)

The primary purpose of our study was to evaluate whether maintenance chemotherapy with paclitaxel/gemcitabine (PG) was superior to observation in improving progression-free survival (PFS) in patients with metastatic breast cancer (MBC) who achieved disease control with an initial six cycles of PG as their first-line treatment.The study was a prospective, randomized, multicenter, phase III trial. Patients MBC with who achieved disease control after six cycles of PG chemotherapy were randomly assigned to maintenance chemotherapy or observation until progression.Of 324 patients from 10 centers enrolled, 231 patients with MBC exhibited disease control (complete response + partial response + stable disease) with first-line PG and were randomly assigned to maintenance chemotherapy (n = 116) or observation (n = 115). The median age was 48 years (range, 28 to 76 years), median follow-up was 33 months, and median number of chemotherapy cycles in the maintenance group after random assignment was six. The median PFS time after random assignment was longer in the maintenance group than in the observation group (7.5 v 3.8 months, respectively; P = .026). The median overall survival (OS) time was longer in the maintenance group than in the observation group (32.3 v 23.5 months, respectively; P = .047). The rate of grade 3 or higher neutropenia after random assignment was higher in the maintenance group than in the observation group (61% v 0.9%, respectively; P < .001).In patients with MBC who achieved disease control with an initial six cycles of PG chemotherapy, maintenance PG chemotherapy resulted in better PFS and OS compared with observation.
Motor Neurons with Axial Muscle Projections Specified by Wnt4/5 Signaling
Authors: Dritan Agalliu, Shinji Takada, Ilir Agalliu, Andrew P. McMahon, Thomas M. Jessell
Journal: Neuron (2009)

Axial muscles are innervated by motor neurons of the median motor column (MMC). In contrast to the segmentally restricted motor columns that innervate limb, body wall, and neuronal targets, MMC neurons are generated along the entire length of the spinal cord. We show that the specification of MMC fate involves a dorsoventral signaling program mediated by three Wnt proteins (Wnt4, Wnt5a, and Wnt5b) expressed in and around the floor plate. These Wnts appear to establish a ventralhigh to dorsallow signaling gradient and promote MMC identity and connectivity by maintaining expression of the LIM homeodomain proteins Lhx3/4 in spinal motor neurons. Elevation of Wnt4/5 activity generates additional MMC neurons at the expense of other motor neuron columnar subtypes, whereas depletion of Wnt4/5 activity inhibits the production of MMC neurons. Thus, two dorsoventral signaling pathways, mediated by Shh and Wnt4/5, are required to establish an early binary divergence in motor neuron columnar identity.
Quantitative Echocardiographic Analysis of the Aortic Arch Predicts Outcome of Balloon Angioplasty of Native Coarctation of the Aorta
Authors: Stephen F. Kaine, E. O'Brian Smith, Antonio R. Mott, Charles E. Mullins, Tal Geva
Journal: Circulation (1996)

Background The use of balloon angioplasty for treatment of native aortic coarctation is controversial. Cineangiographic data suggest that aortic arch hypoplasia and isthmic narrowing are associated with angioplasty failure. This study of echocardiographic measurements of preangioplasty aortic arch morphology was performed to identify potential anatomic predictors of outcome noninvasively. Methods and Results The preangioplasty echocardiograms of 105 patients 3 days to 17 years old with native coarctation of the aorta were analyzed off-line. Angioplasty was considered successful if the residual coarctation gradient was &lt;20 mm Hg and no intervention for recoarctation occurred. Univariate analysis identified young age at angioplasty, presence of a patent ductus arteriosus, and the diameters of the aortic isthmus, distal transverse arch, and aortic valve as predictors of early and late outcomes. Multivariate analysis showed that the preangioplasty aortic isthmus z value was the best independent predictor of outcome, eliminating the effect on outcome of age and associated cardiac defects. An isthmus z value ≤−2.16 predicted early failure with 91% sensitivity and 85% specificity. Kaplan-Meier analysis demonstrated that 90% of patients with an isthmus z value &gt;−1.0 remained free of recoarctation at late follow-up, whereas 89% of patients with a preangioplasty isthmus z value ≤−2.0 developed recoarctation within 36 months. Conclusions Echocardiographic measurements of the aortic arch predict both early and late outcomes of balloon angioplasty for native aortic coarctation, and the preangioplasty aortic isthmus z value was the best independent predictor. Quantitative aortic arch analysis may improve selection of angioplasty candidates who are likely to benefit from the procedure.
T Cells and Minimal Change Disease
Authors: Robyn Cunard, Carolyn J. Kelly
Journal: Journal of the American Society of Nephrology (2002)

It is one of the ironies of medical practice that as physicians we can competently and confidently treat diseases of whose pathogenesis we remain woefully ignorant. Such is the case with minimal change disease, the most common diagnosis associated with the nephrotic syndrome in children (MCNS). The
Tamoxifen-Induced Reduction in Mammographic Density and Breast Cancer Risk Reduction: A Nested Case-Control Study
Authors: J. Cuzick, J. Warwick, E. Pinney, S. W. Duffy, S. Cawthorn, A. Howell, J. F. Forbes, R. M. L. Warren
Journal: JNCI Journal of the National Cancer Institute (2011)

Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug. We conducted a nested case–control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12–18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided. In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction. The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.
Screening for Subclinical Stenosis in Native Vessel Arteriovenous Fistulae
Authors: MARCELLO TONELLI, KAILASH JINDAL, DAVID HIRSCH, SANDRA TAYLOR, CHRISTOPHER KANE, SUSAN HENBREY
Journal: Journal of the American Society of Nephrology (2001)

Guidelines recommend the use of ultrasound dilution techniques (UDT), including measurement of access recirculation (AR) and access blood flow (Q(a)), to screen for subclinical vascular access dysfunction. Although these techniques are efficacious in polytetrafluoroethylene grafts, data in native vessel arteriovenous fistulae (AVF) are lacking. A prospective observational study was conducted to evaluate the utility of UDT screening in AVF. Q(a) and AR were measured bimonthly. Positive studies required fistulograms and were defined by Q(a) < 500 ml/min, DeltaQ(a) > 20% from baseline or AR > 5%. Accesses with stenosis underwent percutaneous angioplasty. After 1 yr, there were 1355 mo of follow-up in 177 patients. There were 44 positive studies in 40 patients. Q(a) was <500 ml/min in 36 (82%), DeltaQ(a) was >20% in 5 (11%), and AR was >5% in 6 (14%). Of patients with Q(a) < 500 ml/min, 29 (81%) had stenosis. Only two patients (40%) with DeltaQ(a) > 20% but Q(a) > 500 ml/min had stenosis. No patient with AR > 5% had stenosis unless Q(a) was also <500 ml/min. Immediate patency rate was 93% post-PTA. Mean Q(a) increased from 303 +/- 154 ml/min to 602 +/- 220 ml/min (P < 0.0001), and mean urea reduction ratio increased from 70.4 +/- 8.4% to 74.6 +/- 6.5% (P = 0.003) post-PTA. The results demonstrate that UDT could detect subclinical stenoses in AVF, and most lesions were amenable to angioplasty. AVF that underwent PTA delivered higher Q(a) and urea reduction ratio, and immediate patency rates were acceptable. Access failure after negative UDT was unusual. Measuring AR increases the time required to perform UDT but does not improve utility. Serial measurements of Q(a) alone may be the best strategy for screening AVF.
Macrosialin, a macrophage-restricted membrane sialoprotein differentially glycosylated in response to inflammatory stimuli.
Authors: S S Rabinowitz, S Gordon
Journal: The Journal of Experimental Medicine (1991)

Rat monoclonal antibody FA/11 has been used to identify macrosialin, a sialoglycoprotein confined to murine mononuclear phagocytes and related cells. Originally identified as a macrophage-associated glycoprotein predominantly localized in intracellular membranes (Smith, M.J., and G.L.E. Koch. 1987. J. Cell Sci. 87:113), the antigen is widely expressed on tissue macrophages, including those in lymphoid areas, and is expressed at low levels on isolated dendritic cells. Immuno-adsorption experiments reported here show that macrosialin is identical to the major 87-115-kD sialoglycoprotein previously identified by lectin blotting in exudate but not resident peritoneal macrophages (Rabinowitz, S., and S. Gordon. 1989. J. Cell Sci. 93:623). Resident peritoneal macrophages express low levels of macrosialin antigen in a glycoform that does not bind 125I wheat germ agglutinin or 125I peanut agglutinin; inflammatory stimuli upregulate expression of this antigen (up to 17-fold), in an alternative glycoform that is detected by these lectins. Pulse-chase experiments reveal a 44-kD core peptide that initially bears high-mannose chains (giving Mr 66 kD) and is subsequently processed to a mature protein of Mr 87-104 kD. Each glycoform contains N-linked glycan, as well as O-linked sugar structures that show alternative processing. Poly-N-acetyllactosamine structures are detected in the exudate cell glycoform only. This new marker for mononuclear phagocytes illustrates two strategies by which macrophages remodel their membranes in response to inflammatory stimuli. Its predominantly intracellular location and restricted cell distribution suggest a possible role in membrane fusion or antigen processing.
Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial
Authors: Ganesh Raghu, Rachel Million-Rousseau, Adele Morganti, Loïc Perchenet, Juergen Behr, N. Goh, A. Glanville, M. Musk, P. Hopkins, D. C. Lien, C. Chan, J. D. Rolf, P. Wilcox, P. G. Cox, H. Manganas, V. Cottin, D. Valeyre, B. Walleart, S. Andreas, C. Neurohr, A. Guenther, N. Schönfeld, A. Koch, M. Kramer, R. Breuer, I. Ben-Dov, G. Fink, Y. Schwarz, C. Albera, M. Confalonieri, C. Saltini, S. Harari, M. Flezar, M. Greenblatt, G. J. Ras, F. Morell, J. L. Alvarez-Sala, A. Xaubet, A. Sueiro, M. J. Linares, M. Sköld, O. Kayacan, N. Mogulkoc, Andrew Chan, J. Chapman, J. Parambil, N. Ettinger, J. Golden, K. C. Meyer, J. J. Swigris, G. L. Yung, D. Antin-Ozerkis, P. K. Mohabir, L. J. Wesselius, J. De Andrade, F. Cordova, Z. Safdar, M. Wencel
Journal: European Respiratory Journal (2013)

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group.
Prevention of Chemotherapy-Induced Neuropathy: Leukemia Inhibitory Factor
Authors: Martin J. van den Bent
Journal: Clinical Cancer Research (2005)

Peripheral neurotoxicity is a dose-limiting and disabling side effect of several important chemotherapeutic agents. In particular, vincristine, cisplatin, oxaliplatin, paclitaxel, and docetaxel are frequently used antineoplastic agents, which are known causes of a peripheral neuropathy. The recently
Clinical Validation of a Customized Multiple Signature Microarray for Breast Cancer
Authors: Benita K.T. Tan, Lay Keng Tan, Kun Yu, Puay Hoon Tan, Ming Lee, Lang Hiong Sii, Chow Yin Wong, Gay Hui Ho, Allen W.Y. Yeo, Pierce K.H. Chow, Heng Nung Koong, Wei Sean Yong, Dennis T.H. Lim, London L.P.J. Ooi, Khee Chee Soo, Patrick Tan
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Current histopathologic systems for classifying breast tumors require evaluation of multiple variables and are often associated with significant interobserver variability. Recent studies suggest that gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we investigated the use of a customized microarray as a potential tool for clinical practice. Experimental Design: We fabricated custom 188-gene microarrays containing expression signatures for three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2), and “basaloid”], the Nottingham prognostic index (NPI-ES), and low histologic grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort of 165 patients with primary breast cancer. Results: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry reported on diagnosis (P &amp;lt; 0.001). This remained unchanged at 89% (P &amp;lt; 0.001) when the immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio ≥2.2; P &amp;lt; 0.001), which further improved to 89% when the ratio cutoff was raised to ≥5. A proportion of low-level FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2 signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry. Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002) and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019). Conclusion: The consistency of the MSA platform in an independent patient population suggests that custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH in clinical practice.
The VISA-A questionnaire: a valid and reliable index of the clinical severity of Achilles tendinopathy
Authors: J M Robinson, J L Cook, C Purdam, P J Visentini, J Ross, N Maffulli, J E Taunton, K M Khan
Journal: British Journal of Sports Medicine (2001)

Background —There is no disease specific, reliable, and valid clinical measure of Achilles tendinopathy. Objective —To develop and test a questionnaire based instrument that would serve as an index of severity of Achilles tendinopathy. Methods —Item generation, item reduction, item scaling, and pretesting were used to develop a questionnaire to assess the severity of Achilles tendinopathy. The final version consisted of eight questions that measured the domains of pain, function in daily living, and sporting activity. Results range from 0 to 100, where 100 represents the perfect score. Its validity and reliability were then tested in a population of non-surgical patients with Achilles tendinopathy (n = 45), presurgical patients with Achilles tendinopathy (n = 14), and two normal control populations (total n = 87). Results —The VISA-A questionnaire had good test-retest ( r = 0.93), intrarater (three tests, r = 0.90), and interrater ( r = 0.90) reliability as well as good stability when compared one week apart ( r = 0.81). The mean (95% confidence interval) VISA-A score in the non-surgical patients was 64 (59–69), in presurgical patients 44 (28–60), and in control subjects it exceeded 96 (94–99). Thus the VISA-A score was higher in non-surgical than presurgical patients (p = 0.02) and higher in control subjects than in both patient populations (p&lt;0.001). Conclusions —The VISA-A questionnaire is reliable and displayed construct validity when means were compared in patients with a range of severity of Achilles tendinopathy and control subjects. The continuous numerical result of the VISA-A questionnaire has the potential to provide utility in both the clinical setting and research. The test is not designed to be diagnostic. Further studies are needed to determine whether the VISA-A score predicts prognosis.
Heritability and Genome-Wide Linkage in US and Australian Twins Identify Novel Genomic Regions Controlling Chromogranin A
Authors: Daniel T. O'Connor, Gu Zhu, Fangwen Rao, Laurent Taupenot, Maple M. Fung, Madhusudan Das, Sushil K. Mahata, Manjula Mahata, Lei Wang, Kuixing Zhang, Tiffany A. Greenwood, Pei-an Betty Shih, Myles G. Cockburn, Michael G. Ziegler, Mats Stridsberg, Nicholas G. Martin, John B. Whitfield
Journal: Circulation (2008)

Background— Chromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits catecholamine release. We approached catestatin heritability using twin pairs, coupled with genome-wide linkage, in a series of twin and sibling pairs from 2 continents. Methods and Results— Hypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in twins was 44% to 60%. Six hundred fifteen nuclear families yielded 870 sib pairs for linkage, with significant logarithm of odds peaks on chromosomes 4p, 4q, and 17q. Because acidification of catecholamine secretory vesicles determines CHGA trafficking and processing to catestatin, we genotyped at positional candidate ATP6N1 , bracketed by peak linkage markers on chromosome 17q, encoding a subunit of vesicular H + -translocating ATPase. The minor allele diminished CHGA secretion and processing to catestatin. The ATP6N1 variant also influenced blood pressure in 1178 individuals with the most extreme blood pressure values in the population. In chromaffin cells, inhibition of H + -ATPase diverted CHGA from regulated to constitutive secretory pathways. Conclusions— We established heritability of catestatin in twins from 2 continents. Linkage identified 3 regions contributing to catestatin, likely novel determinants of sympathochromaffin exocytosis. At 1 such positional candidate ( ATP6N1 ), variation influenced CHGA secretion and processing to catestatin, confirming the mechanism of a novel trans -QTL for sympathochromaffin activity and blood pressure.
Complement factor 2 deficiency: a clinical and serological family study.
Authors: D D'Cruz, J Taylor, T Ahmed, R Asherson, M Khamashta, G R Hughes
Journal: Annals of the Rheumatic Diseases (1992)

Inherited complement deficiencies are associated with a variety of connective tissue diseases. A family with inherited deficiency of complement factor 2 (C2) is described in which two family members with homozygous C2 deficiency developed cutaneous vasculitis and sicca syndrome. The other family members had heterozygous C2 deficiency and each member had the HLA-A25, B18, DR2 (w15) haplotype. The mother had seropositive rheumatoid arthritis. Further studies showed the presence of cryoglobulins, antibodies against endothelial cells, and anticardiolipin antibodies.