tbuckley/cabot-search huggingface dataset:
Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma
Authors: Hanyin Cheng, Mizue Terai, Ken Kageyama, Shinji Ozaki, Peter A. McCue, Takami Sato, Andrew E. Aplin
Journal: Cancer Research (2015)

Abstract Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, respectively, overcome resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. Uveal melanoma xenografts growing in the liver in vivo and a subset of liver metastases of uveal melanoma patients express activated forms of ERBB2 (the coreceptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic uveal melanoma. Cancer Res; 75(13); 2737–48. ©2015 AACR.
Antifibrillarin autoantibodies present in systemic sclerosis and other connective tissue diseases interact with similar epitopes.
Authors: K N Kasturi, A Hatakeyama, H Spiera, C A Bona
Journal: The Journal of Experimental Medicine (1995)

Autoantibodies specific against fibrillarin, a 34-kD nucleolar protein associated with U3-snRNP, are present in patients with systemic sclerosis (SSc). To understand the mechanisms involved in the induction of these autoantibodies, we prepared a series of human fibrillarin recombinant proteins covering the entire molecule and analyzed their interaction with the autoantibodies present in various connective tissue diseases. Our results showed that antifibrillarin autoantibodies are present not only in SSc, as previously reported, but also in a variety of other connective tissue diseases. Patients with SSc (58%), mixed connective tissue diseases (60%), CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dismotility, sclerodactyly, and telangiectasia syndrome) (58%), systemic lupus erythematosus (39%), rheumatoid arthritis (60%), and Sjogern's syndrome (84%) showed presence of antifibrillarin autoantibodies. Results obtained from competitive inhibition radioimmunoassay and Western blot analyses with purified recombinant fusion proteins revealed that these autoantibodies react primarily with epitope(s) present in the NH2- (AA 1-80) and COOH-terminal (AA 276-321) domains of fibrillarin. Autoantibodies reacting with internal regions of fibrillarin are less frequent. Analysis of the hydrophilicity profiles of reactive peptides showed presence of three potential antigenic sites in the NH2- and two in the COOH-terminal regions. While a hexapeptide sequence NH2 terminus of fibrillarin is shared with an Epstein-Barr virus-encoded nuclear antigen, the COOH-terminal region shares sequence homology with P40, the capsid protein encoded by herpes virus type 1. Interestingly, these two regions of fibrillarin also contain the most immunodominant sequences, as predicted by surface probability and the Jameson and Wolf antigenic index. These observations suggest that molecular mimicry might play an important role in the induction of antifibrillarin autoantibodies.
Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis
Authors: B Vander Cruyssen
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Anti-cyclic citrullinated peptide (anti-CCP) antibodies are considered highly specific markers of rheumatoid arthritis. Despite the high specificity of the test, anti-CCP antibodies have also been observed in psoriatic arthritis. <b>Objective:</b> To determine the frequency of anti-CCP antibodies in psoriatic arthritis and to describe the clinical characteristics of such patients. <b>Methods:</b> Serum samples from 192 patients with psoriatic arthritis were analysed for anti-CCP antibodies. A previously defined cut off point was applied at a specificity level of ⩾98.5% (42 U/ml). Antibodies against pepA and pepB (two synthetic citrullinated peptides) were determined on samples containing anti-CCP antibodies by line immune assay. The swollen joint count and the numbers of affected joints (present or past) were recorded. Clinical features were noted and if available radiographs of hands and feet were scored for erosions. Rheumatoid factor was determined in all samples. <b>Results:</b> Anti-CCP antibodies were found in 15 patients (7.8%); 13 of 15 anti-CCP2 positive samples were also positive for anti-pepA or pepB antibodies. The prevalence of anti-CCP antibodies was higher than expected in view of the highly specific cut off applied in the test. Detailed analysis of the clinical and radiological features makes it improbable that the high prevalence of anti-CCP antibodies resulted solely from concomitant psoriasis and rheumatoid arthritis or from misclassification. <b>Conclusions:</b> Anti-CCP antibodies may be present in patients with psoriatic arthritis. Although some of the present cohort could have had psoriasis with concomitant rheumatoid arthritis, a proportion at least had the typical characteristics of psoriatic arthritis as the primary diagnosis.
Changes in glomerular hemodynamic response to angiotensin II after subacute renal denervation in rats.
Authors: B J Tucker, C A Mundy, A R Maciejewski, M P Printz, M G Ziegler, J C Pelayo, R C Blantz
Journal: Journal of Clinical Investigation (1986)

We examined the changes in glomerular hemodynamics produced by angiotensin II (AII) in both normal Munich-Wistar rats and rats which were unilaterally renal denervated (measured kidney) 4-6 d prior to the measurement periods. Measurements of glomerular dynamics were performed in a control period after plasma volume expansion and during infusion of 11 ng X 100 g body wt-1 X min-1 of AII. The glomerular hydrostatic pressure gradient increased from 38 +/- 1 to 49 +/- 1 mmHg in denervated rats compared with a lesser response in controls (from 39 +/- 1 to 45 +/- 1 mmHg, P less than 0.05). Single nephron plasma flow decreased from 213 +/- 17 to 87 +/- 4 nl X min-1 X g kidney wt (KW)-1 in denervated kidneys versus a more modest decrease in control kidneys (from 161 +/- 9 to 102 +/- 5 nl X min X gKW-1). These changes were due to a greater increase in both afferent and efferent arteriolar resistance after AII infusion in denervated compared with control kidneys. Glomerular AII receptor maximum binding was 1,196 +/- 267 fmol/mg protein in denervated kidneys compared with 612 +/- 89 fmol/mg protein (P less than 0.01) in controls with no change in receptor affinity. We conclude the subacute unilateral renal denervation results in renal vasodilation, denervation magnifies the vasoconstrictive effect of AII infusion on glomerular hemodynamics, and the observed increased response to AII after denervation is associated with increases in glomerular AII receptors.
Sirolimus Reduces Polycystic Liver Volume in ADPKD Patients
Authors: Qi Qian, Hui Du, Bernard F. King, Sumedha Kumar, Patrick G. Dean, Fernando G. Cosio, Vicente E. Torres
Journal: Journal of the American Society of Nephrology (2008)

The immunosuppressive agent sirolimus exerts an antiproliferative effect by inhibiting mammalian target of rapamycin (mTOR). Because excessive proliferation of the biliary epithelium is a prominent feature of the polycystic liver that accompanies autosomal dominant polycystic kidney disease (ADPKD), we hypothesized that sirolimus may benefit patients with this disorder. We retrospectively measured the volumes of polycystic livers and kidneys in ADPKD patients who had received kidney transplants and had participated in a prospective randomized trial that compared a sirolimus-containing immunosuppression regimen to a tacrolimus-containing regimen. Sixteen subjects (seven with sirolimus, nine with tacrolimus) had received abdominal imaging studies within 11 mo before and at least 7 mo after transplantation, making them suitable for our analysis. Treatment with the sirolimus regimen for an average of 19.4 mo was associated with an 11.9 +/- 0.03% reduction in polycystic liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14.1 +/- 0.09% increase. A trend toward a greater reduction in native kidney volume was also noted in the sirolimus group compared with the nonsirolimus group. Regarding mechanism, the epithelium that lines hepatic cysts exhibited markedly higher levels of phospho-AKT, phospho-ERK, phospho-mTOR, and the downstream effector phospho-S6rp compared with control biliary epithelium. In summary, treatment with sirolimus was associated with decreased polycystic liver volume, perhaps by preventing aberrant activation of mTOR in epithelial cells lining the cysts.
Improved suppression of recurrent atrial fibrillation with dual-site right atrial pacing and antiarrhythmic drug therapy
Authors: Sanjeev Saksena, Atul Prakash, Paul Ziegler, John D Hummel, Paul Friedman, Vance J Plumb, D.George Wyse, Eric Johnson, Stephanie Fitts, Rahul Mehra
Journal: Journal of the American College of Cardiology (2002)
A Novel Ryanodine Receptor Mutation Linked to Sudden Death Increases Sensitivity to Cytosolic Calcium
Authors: Albano C. Meli, Marwan M. Refaat, Miroslav Dura, Steven Reiken, Anetta Wronska, Julianne Wojciak, Joan Carroll, Melvin M. Scheinman, Andrew R. Marks
Journal: Circulation Research (2011)

Rationale: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during β-adrenergic stimulation. Objective: This study sought to determine the effects of a novel RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca 2+ ). Methods and Results: Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2. RyR2 channels were measured to examine the regulation of the channels by cytosolic versus luminal sarcoplasmic reticulum Ca 2+ . A 50-year-old white man with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. cAMP-dependent protein kinase–phosphorylated RyR2-G230C channels exhibited a significantly higher open probability at diastolic Ca 2+ concentrations, associated with a depletion of calstabin2. The luminal Ca 2+ sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like. Conclusions: The RyR2-G230C mutant exhibits similar biophysical defects compared with previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca 2+ dependence for activation under conditions that simulate exercise, consistent with a “leaky” channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca 2+ activation. Thus, diastolic sarcoplasmic reticulum Ca 2+ leak caused by reduced calstabin2 binding and a leftward shift in the Ca 2+ dependence for activation by diastolic levels of cytosolic Ca 2+ is a common mechanism underlying CPVT.
Relapse of acute leukemia after marrow transplantation: natural history and results of subsequent therapy.
Authors: J Mortimer, M A Blinder, S Schulman, F R Appelbaum, C D Buckner, R A Clift, J E Sanders, R Storb, E D Thomas
Journal: Journal of Clinical Oncology (1989)

Of 455 acute nonlymphocytic leukemia (ANL) patients who underwent marrow transplantation, 95 (21%) relapsed a median of 6.5 months posttransplantation and 62 received further treatment. Twenty achieved remission. Success of therapy was related to the length of time from marrow transplant to relapse and to the use of cytarabine (Ara-C) and daunomycin. Aggressive chemotherapy for patients relapsing within 100 days of marrow transplant was associated with a high incidence of early death (six of 14 patients) and a low probability of remission (one of 14). Of 23 patients who relapsed in excess of 1 year from marrow transplant, 15 achieved a complete remission. The median disease-free survival is 6 months (range, 0.4 to 53+ months). Acute lymphocytic leukemia (ALL) recurred in 130 of 366 patients (36%), and 94 received further therapy. Fifty-two achieved a remission. Remissions were more common in late relapse patients (greater than 1 year from transplantation): 65% v 7% for those relapsing within 100 days from transplant (P less than .05). Testicular relapse occurred in 11 patients and was the sole site of relapse in seven. Three are alive and free of disease 58 to 109+ months after relapse. The median survival for the treated patients is 10.5 months (range, 5 to 109+ months). We propose that reinduction be attempted in all patients relapsing greater than 1 year from marrow transplantation. Ara-C and daunomycin should be employed in the treatment of ANL. The decision for treatment of patients relapsing earlier than 1 year should be made on an individual basis.
Inspiratory pressure support reduces slowing of inspiratory muscle relaxation rate during exhaustive treadmill walking in severe COPD.
Authors: M I Polkey, D Kyroussis, G H Mills, C H Hamnegard, S E Keilty, M Green, J Moxham
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

When patients with COPD walk to a state of intolerable dyspnea, there is excessive inspiratory muscle loading, as evidenced by slowing of the maximum relaxation rate of the inspiratory muscles, measured from esophageal pressure during a sniff (Sn Pes MRR). In this setting, inspiratory pressure support (IPS) delivered via an orofacial mask increases walking distance and reduces dyspnea, but the mechanism by which this benefit is achieved remains unclear. In this study we compared Sn Pes MRR after equidistant treadmill walking in six men with severe COPD (mean FEV1: 0.6 L, 22% predicted). After the free walk there was a mean slowing of Sn Pes MRR of 41% (p < 0.03). After the IPS-assisted walks, the slowing of Sn Pes MRR was 20% of baseline; this was significantly less than after the free walk (p < 0.05). Four subjects performed shorter walks; after free walks of one third and two thirds of maximum distance, the mean slowing of Sn Pes MRR was 23% and 28%, respectively. We conclude that when patients with COPD walk to exhaustion, IPS reduces slowing of inspiratory muscle MRR, and that this represents a considerable unloading of the inspiratory muscles. The magnitude of the reduction is approximately the same as reducing the distance walked by two thirds.
Effects of ML-236B (Compactin) on Sterol Synthesis and Low Density Lipoprotein Receptor Activities in Fibroblasts of Patients with Homozygous Familial Hypercholesterolemia
Authors: Toshihiro Haba, Hiroshi Mabuchi, Akira Yoshimura, Akira Watanabe, Takanobu Wakasugi, Ryozo Tatami, Kosei Ueda, Ryosei Ueda, Tomio Kametani, Junji Koizumi, Susumu Miyamoto, Ryoyu Takeda, Haruo Takeshita
Journal: Journal of Clinical Investigation (1981)

We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of 125I-LDL were 0.5±0.3 ng/mg protein (mean±SEM), 14±8 and 8±6 ng/mg protein per 6 h (four normal cells; 44±3, 386±32, and 1,335±214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of 125I-LDL were 6±2, 29±8, and 90±32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed ∼46% of the normal activities of receptor.
Activation of the Androgen Receptor by Intratumoral Bioconversion of Androstanediol to Dihydrotestosterone in Prostate Cancer
Authors: James L. Mohler, Mark A. Titus, Suxia Bai, Brian J. Kennerley, Fred B. Lih, Kenneth B. Tomer, Elizabeth M. Wilson
Journal: Cancer Research (2011)

Abstract The androgen receptor (AR) mediates the growth of benign and malignant prostate in response to dihydrotestosterone (DHT). In patients undergoing androgen deprivation therapy for prostate cancer, AR drives prostate cancer growth despite low circulating levels of testicular androgen and normal levels of adrenal androgen. In this report, we demonstrate the extent of AR transactivation in the presence of 5α-androstane-3α,17β-diol (androstanediol) in prostate-derived cell lines parallels the bioconversion of androstanediol to DHT. AR transactivation in the presence of androstanediol in prostate cancer cell lines correlated mainly with mRNA and protein levels of 17β-hydroxysteroid dehydrogenase 6 (17β-HSD6), one of several enzymes required for the interconversion of androstanediol to DHT and the inactive metabolite androsterone. Levels of retinol dehydrogenase 5, and dehydrogenase/reductase short-chain dehydrogenase/reductase family member 9, which also convert androstanediol to DHT, were lower than 17β-HSD6 in prostate-derived cell lines and higher in the castration-recurrent human prostate cancer xenograft. Measurements of tissue androstanediol using mass spectrometry demonstrated androstanediol metabolism to DHT and androsterone. Administration of androstanediol dipropionate to castration-recurrent CWR22R tumor-bearing athymic castrated male mice produced a 28-fold increase in intratumoral DHT levels. AR transactivation in prostate cancer cells in the presence of androstanediol resulted from the cell-specific conversion of androstanediol to DHT, and androstanediol increased LAPC-4 cell growth. The ability to convert androstanediol to DHT provides a mechanism for optimal utilization of androgen precursors and catabolites for DHT synthesis. Cancer Res; 71(4); 1486–96. ©2011 AACR.
Venomotor Tone in Hemorrhage and Shock
Authors: ROBERT S. ALEXANDER
Journal: Circulation Research (1955)

Employing the injection technic for venous distensibility determinations in intestinal loops of anesthetized dogs, an index to venomotor tone has been developed by measuring the volumes of blood required to produce specified changes in venous pressure. Application of this index in hemorrhage and shock experiments demonstrates a marked venomotor compensation to hemorrhage, and oscillations in venomotor tone correlating with the vasomotor waves in arterial blood pressure encountered in hemorrhagic hypotension. In the hypotension of shock, a serious deficiency in venomotor compensation develops, which should result in pooling of blood in the venous system and contribute significantly to the circulatory failure.
Application of <sup>68</sup>Ga-PRGD2 PET/CT for α<sub>v</sub>β<sub>3</sub>-integrin Imaging of Myocardial Infarction and Stroke
Authors: Yi Sun, Yong Zeng, Yicheng Zhu, Feng Feng, Weihai Xu, Chenxi Wu, Bing Xing, Weihong Zhang, Peiling Wu, Liying Cui, Renzhi Wang, Fang Li, Xiaoyuan Chen, Zhaohui Zhu
Journal: Theranostics (2014)

Purpose: Ischemic vascular diseases, including myocardial infarction (MI) and stroke, have been found to be associated with elevated expression of αvβ3-integrin, which provides a promising target for semi-quantitative monitoring of the disease.For the first time, we employed 68 Ga-S-2-(isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-PEG3-E[c(RGDyK)]2 ( 68 Ga-PRGD2) to evaluate the αvβ3-integrin-related repair in post-MI and post-stroke patients via positron emission tomography/computed tomography (PET/CT).Methods: With Institutional Review Board approval, 23 MI patients (3 days-2 years post-MI) and 16 stroke patients (3 days-13 years post-stroke) were recruited.After giving informed consent, each patient underwent a cardiac or brain PET/CT scan 30 min after the intravenous injection of 68 Ga-PRGD2 in a dose of approximately 1.85 MBq (0.05 mCi) per kilogram body weight.Two stroke patients underwent repeat scans three months after the event.Results: Patchy 68 Ga-PRGD2 uptake occurred in or around the ischemic regions in 20/23 MI patients and punctate multifocal uptake occurred in 8/16 stroke patients.The peak standardized uptake values (pSUVs) in MI were 1.94 ± 0.48 (mean ± SD; range, 0.62-2.69),significantly higher than those in stroke (mean ± SD, 0.46 ± 0.29; range, 0.15-0.93;P < 0.001).Higher 68 Ga-PRGD2 uptake was observed in the patients 1-3 weeks after the initial onset of the MI/stroke event.The uptake levels were significantly correlated with the diameter of the diseases (r = 0.748, P = 0.001 for MI and r = 0.835, P = 0.003 for stroke).Smaller or older lesions displayed no uptake.Conclusions: 68 Ga-PRGD2 uptake was observed around the ischemic region in both MI and stroke patients, which was correlated with the disease phase and severity.The different image patterns and uptake levels in MI and stroke patients warrant further investigations.
Clinical trials in acute severe asthma: are type II errors important?
Authors: M J Ward
Journal: Thorax (1986)

Many studies in acute severe asthma have had low power. Fifteen randomised double blind studies investigating the treatment of acute severe asthma published during 1974-84 were analysed for power and 95% confidence limits. Twelve studies failed to detect a significant difference in bronchodilatation produced by two treatments and reported the treatments to produce equal effect. Each study had, however, less than a 60% probability of detecting a true 25% difference in bronchodilatation.
Clinical Trial of the Effect of Vitamin B12 in Elderly Subjects with Low Serum B12 Levels
Authors: D. Hughes, P. C. Elwood, N. K. Shinton, R. J. Wrighton
Journal: BMJ (1970)

A clinical trial of the effect of vitamin B<sub>12</sub> therapy was conducted in 39 elderly subjects who had been found, in a community screening survey, to have low levels of serum B<sub>12</sub> without a macrocytic anaemia or neuropathy. The study produced no evidence which suggests that in such subjects B<sub>12</sub> is superior to placebo in effecting an improvement in psychiatric state or general well-being. There was a clear tendency for all the subjects to show an improvement during the trial, but this probably represents the therapeutic effect of involvement in a research exercise of this kind.