tbuckley/cabot-search huggingface dataset:
Identification of a contractile function for renal medullary interstitial cells.
Authors: A K Hughes, W H Barry, D E Kohan
Journal: Journal of Clinical Investigation (1995)

Renomedullary interstitial cells (RMIC) are unique to the renal medulla. By virtue of their anatomic location and arrangement, RMIC may hinder axial dissipation of the concentration gradient, thereby aiding urinary concentration. A more active role in urinary concentration has been postulated on the basis of speculations about RMIC contractile potential, however, RMIC contraction has not been investigated. To determine if these cells are contractile, cultured rat RMIC were exposed to endothelin-1 (ET-1), a potent vasoconstrictor which binds to RMIC, and examined using video microscopy. ET-1 (as low as 10 pM) caused a slowly developing and dose-dependent reduction in RMIC surface area. ET-1 markedly increased the number and intensity of F-actin microfilament staining. ET-1-induced RMIC contraction was not altered by nifedipine, was partially reduced by nickel, and was completely inhibited by H7, indicating that ET-1 action is mediated by protein kinase C and is partially dependent upon receptor-operated calcium channels. The ET-1 effect does not involve nitric oxide since NG-monomethyl-L-arginine did not alter ET-1-induced RMIC contraction; in addition, ET-1 had only a minor effect on cGMP levels and no effect on nitrite production. PGE2 acts in an autocrine manner to dampen ET action since indomethacin potentiates, while PGE2 inhibits, ET-1-induced RMIC contraction. The contractile response is not unique to ET-1 since vasopressin also reduces RMIC surface area and increases F-actin microfiliment staining. These studies demonstrate that RMIC in culture are contractile. The possibility is raised that contraction of RMIC plays a role in modifying urinary concentration as well as regulation of other renal medullary functions.
In Vivo Induction of Endothelial Apoptosis Leads to Vessel Thrombosis and Endothelial Denudation
Authors: E. Durand, A. Scoazec, A. Lafont, J. Boddaert, A. Al Hajzen, F. Addad, M. Mirshahi, M. Desnos, A. Tedgui, Z. Mallat
Journal: Circulation (2004)

Background— The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. Methods and Results— Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43±0.30 versus 0.93±0.44, respectively; P =0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments ( P &lt;0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P =0.04). These results were confirmed in balloon-injured atheromatous arteries. Conclusions— In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.
Quality of life (QOL) companion to CALGB 9840: A phase III study of paclitaxel (P) via weekly 1 hour (hr) versus standard 3 hour infusion every 3 weeks with trastuzumab in the treatment of patients with/without HER-2/neu-overexpressing metastatic breast cancer
Authors: M. J. Naughton, L. Gu, X. F. Wang, A. D. Seidman, E. Winer, A. B. Kornblith
Journal: Journal of Clinical Oncology (2006)

674 Background: This study determined if adding trastuzumab (Herceptin, T) to P modified the QOL of HER-2 non-overexpressors and examined QOL differences between patients treated with weekly versus standard P. Methods: Of the 585 patients treated in CALGB 9840, 394 provided QOL data. Eligibility criteria and main trial results were reported, indicating greater efficacy in weekly versus standard P, but no greater efficacy with T in HER-2 negatives (Seidman AD et al., Proc ASCO 2004, Vol. 22, No 14S, abstract 512). HER-2 non-overexpressors were randomized to 1 of 4 groups: 1) P 175 mg/m 2 over 3 hrs every 3 wks; 2) P 80 mg/m 2 over 1 hr weekly; 3) P 175 mg/m 2 over 3 hrs every 3 wks + T 4 mg/kg load, then 2 mg/kg weekly; and 4) P l 80 mg/m 2 over 1 hr weekly + T 4 mg/kg load, then 2 mg/kg weekly, all IV. All HER-2 overexpressors received T and were randomized to group 3 or 4. Patients completed QOL interviews prior to randomization, and at 3, 6, and 9 months. Main outcome measures were the EORTC-C30 with the Breast Module (QLQ-BR23). Data were analyzed using general linear models for repeated measures, with the following covariates: treatment arm, assessment point, patient age, race, education, marital status, performance status, prior chemotherapy, and prior radiation therapy. Results: HER-2 negative patients receiving weekly P with/without T as compared to standard P with/without T reported better global QOL (p=.022) and fewer cancer symptoms (p=.036). No QOL differences were observed among the HER-2 overexpressors. The use of T in the HER-2 negatives, regardless of P schedule, resulted in better role (p=.002) and emotional functioning (p=.039), and fewer arm (p=.045) and breast (p=.033) symptoms than HER-2 negative patients not receiving T. No differences in physical, social, and cognitive functioning were observed across any of these treatment groups. Conclusions: Both weekly P and T improved the QOL of HER-2 negative patients. There were no QOL differences by P schedule among the HER-2 overexpressors. The higher QOL in HER-2 negatives receiving T was unexpected, inconsistent with clinical data, and needs further exploration in the dataset. [Table: see text]
Codon-Substitution Models to Detect Adaptive Evolution that Account for Heterogeneous Selective Pressures Among Site Classes
Authors: Ziheng Yang, Willie J. Swanson
Journal: Molecular Biology and Evolution (2002)

The nonsynonymous to synonymous substitution rate ratio (omega = d(N)/d(S)) provides a sensitive measure of selective pressure at the protein level, with omega values <1, =1, and >1 indicating purifying selection, neutral evolution, and diversifying selection, respectively. Maximum likelihood models of codon substitution developed recently account for variable selective pressures among amino acid sites by employing a statistical distribution for the omega ratio among sites. Those models, called random-sites models, are suitable when we do not know a priori which sites are under what kind of selective pressure. Sometimes prior information (such as the tertiary structure of the protein) might be available to partition sites in the protein into different classes, which are expected to be under different selective pressures. It is then sensible to use such information in the model. In this paper, we implement maximum likelihood models for prepartitioned data sets, which account for the heterogeneity among site partitions by using different omega parameters for the partitions. The models, referred to as fixed-sites models, are also useful for combined analysis of multiple genes from the same set of species. We apply the models to data sets of the major histocompatibility complex (MHC) class I alleles from human populations and of the abalone sperm lysin genes. Structural information is used to partition sites in MHC into two classes: those in the antigen recognition site (ARS) and those outside. Positive selection is detected in the ARS by the fixed-sites models. Similarly, sites in lysin are classified into the buried and solvent-exposed classes according to the tertiary structure, and positive selection was detected at the solvent-exposed sites. The random-sites models identified a number of sites under positive selection in each data set, confirming and elaborating the results of the fixed-sites models. The analysis demonstrates the utility of the fixed-sites models, as well as the power of previous random-sites models, which do not use the prior information to partition sites.
SEROLOGICAL EQUIVALENCE OF ENDEMIC ZINGA VIRUS AND RIFT VALLEY FEVER VIRUS IN CENTRAL AFRICAN REPUBLIC
Authors: AlainJ. Georges, S. Abdul Wahid, D.Y.M. Meunier, Marie Claude Georges, JeanF. Saluzzo, ClarenceJ. Peters, JosephB. McCormick, JeanP. Gonzalez
Journal: The Lancet (1983)
Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling
Authors: Yuichiro Maekawa, Toshihisa Anzai, Tsutomu Yoshikawa, Yasushi Asakura, Toshiyuki Takahashi, Shiro Ishikawa, Hideo Mitamura, Satoshi Ogawa
Journal: Journal of the American College of Cardiology (2002)
Immediate hypersensitivity in colon of children with chronic Trichuris trichiura dysentery
Authors: E.S. Cooper, D.A.P. Bundy, C.A.M. Whyte-Alleng, S. Venugopal, J. Spencer, P. Whitney, O. Cromwell, B. Haynes, T.T. MacDonald
Journal: The Lancet (1991)
Decision Framework for Chemotherapeutic Interventions for Metastatic Non-Small-Cell Lung Cancer
Authors: J.-M. Berthelot, B. P. Will, W. K. Evans, D. Coyle, C. C. Earle, L. Bordeleau
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Best supportive care has long been considered to be the standard therapy for metastatic non-small-cell lung cancer (NSCLC). There is now evidence from randomized trials that a number of chemotherapy regimens can palliate cancer-related symptoms and modestly improve survival. We show how cost-effectiveness 1analyses can be used to make choices between different (ambulatory) chemotherapy regimens. Methods: Clinical algorithms describing the diagnosis, staging, and treatment of metastatic NSCLC were incorporated into Statistics Canada's Population Health Model. Using consistent methodology, we assessed the cost-effectiveness of several chemotherapeutic interventions: a combination of vindesine (VDS) plus cisplatin, etoposide (VP-16) plus cisplatin, vinblastine (VLB) plus cisplatin, vinorelbine (Navelbine; NVB) plus cisplatin, paclitaxel (Taxol) plus cisplatin, and gemcitabine (GEM) and NVB alone. We calculated the total chemotherapy costs in 1995 Canadian dollars, the cost per case, the average life-years saved, and the cost per life-year saved. Using the Population Health Model, we then constructed an advanced decision framework that rank-ordered the various treatment regimens so as to optimize benefit below various cost-effectiveness thresholds. Results: One regimen (VLB plus cisplatin) appears to result in better survival and lower health care expenditures than best supportive care. By use of cost-effectiveness thresholds of $25 000 and $50 000 per life-year gained, NVB plus cisplatin is the preferred regimen. When quality of life is considered, however, GEM is preferred to NVB plus cisplatin at a threshold value of $50 000. At thresholds of $75 000 and $100 000, paclitaxel plus cisplatin at a dose of 135 mg/m2 is the preferred regimen. At thresholds of $50 000 and above, best supportive care is the least preferred regimen. Conclusions: This decision framework allows the comparison of different treatment regimens based on various cost-effectiveness thresholds. Our analysis also supports the use of chemotherapy regimens and the abandonment of best supportive care as the standard of care for patients with advanced NSCLC. [J Natl Cancer Inst 2000;92:1321–9].
Docetaxel Followed by Castration Improves Outcomes in LNCaP Prostate Cancer–Bearing Severe Combined Immunodeficient Mice
Authors: Yao Tang, Mohammad A. Khan, Olga Goloubeva, Dong I. Lee, Danijela Jelovac, Angela M. Brodie, Arif Hussain
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer. Experimental Design: Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase–mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors. Results: Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment. Conclusion: A treatment sequence of docetaxel followed by hormone ablation may be more effective in treating prostate cancer than concurrent docetaxel/hormone therapy or hormone ablation followed by docetaxel.
Exemestane Following Tamoxifen in Postmenopausal Women With Primary Breast Cancer
Authors: Henning T. Mouridsen
Journal: Journal of Clinical Oncology (2004)

large and well-designed randomized trial of sequential adjuvant endocrine therapy for estrogen receptor–positive primary breast cancer in postmenopausal women (Intergroup Exemestane Study [IES]). Following 2 to 3 years of tamoxifen therapy, patients were randomly assigned to receive the steroidal aromatase inhibitor, exemestane, or to continue on tamoxifen for the remainder of 5 years’ total treatment. Compared with standard tamoxifen for 5 years, switching to exemestane midcourse significantly improved disease-free survival (DFS) at a median follow-up of 30.6 months, which was characterized by a 32% reduction in risk of recurrence, new contralateral breast cancer, or death, which corresponded to an absolute DFS benefit of 4.7% at 3 years after random assignment. These IES results are consistent with improvements seen in previously reported large randomized adjuvant trials that evaluated the nonsteroidal aromatase inhibitors anastrozole and letrozole. In the Arimidex, Tamoxifen Alone, or in Combination (ATAC) trial, 5 years of anastrozole resulted in an absolute improvement in estimated 4-year DFS of 2.4% compared with 5 years of tamoxifen, at 47 months’ median follow-up. 2 The MA.17 trial followed 5 years of tamoxifen with randomization to 5 years of letrozole or placebo, and at 2.4 years’ median follow-up, there was a 6% absolute improvement in estimated 4-year DFS in the letrozole arm compared with the placebo arm. 3 The optimal use of these aromatase inhibitors as adjuvant therapy, either instead of, or sequenced with, tamoxifen, remains to be determined, and ongoing trials such as the Breast International Group study BIG 1-98, which is addressing these issues with letrozole, should provide more definitive direction. I am concerned with the safety profile reported for exemestane in the IES trial. It was particularly disappointing that exemestane was associated with substantial bone loss and related consequences, given preclinical study results suggesting a bone-protecting effect. 4 Exemestane treatment resulted in higher incidences of osteoporosis (7.4% v 5.7%, respectively; P .05) and fractures (3.1% v 2.3%, respectively; P .08) than tamoxifen. 1 Some bone
Coronary Artery Calcification in Obese Youth: What Are the Phenotypic and Metabolic Determinants?
Authors: Fida Bacha, Daniel Edmundowicz, Kim Sutton-Tyrell, SoJung Lee, Hala Tfayli, Silva A. Arslanian
Journal: Diabetes Care (2014)

OBJECTIVE Obesity in adolescence has been associated with increased risk for coronary heart disease in adulthood. This study evaluated subclinical atherosclerosis in obese youth and the underlying risk factors. RESEARCH DESIGN AND METHODS Ninety obese adolescents (37 normal glucose tolerant, 27 prediabetes, and 26 type 2 diabetes) underwent evaluation of coronary artery calcifications (CACs) by electron beam computed tomography, aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT), lipids, leptin, inflammatory markers, and body composition (DEXA). A total of 68 underwent evaluation of insulin sensitivity (IS) (hyperinsulinemic-euglycemic clamp) and abdominal adiposity (computed tomography). RESULTS A total of 50% had CACs (CAC+: Agatston CAC score ≥1). CAC+ youth had higher BMI, fat mass, and abdominal fat, with no difference in sex, race, IS per fat-free mass (ISFFM), glucose tolerance, PWV, or IMT compared with the CAC− group. PWV was inversely related to IS. In multiple regression analyses with age, race, sex, HbA1c, BMI (or waist circumference), ISFFM, diastolic blood pressure, non–HDL cholesterol, and leptin as independent variables, BMI (or waist) (R2 = 0.41; P = 0.001) was the significant determinant of CAC; leptin (R2 = 0.37; P = 0.034) for PWV; and HbA1c, race, and age (R2 = 0.34; P = 0.02) for IMT. CONCLUSIONS Early in the course of obesity, there is evidence of CAC independent of glycemia. The different biomarkers of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia, age, and race for IMT, and leptin and IS for arterial stiffness. These findings highlight the increased cardiovascular disease risk in obese youth and the need for early interventions to reverse obesity and atherosclerosis.
Angiotensin II Stimulates Tyrosine Phosphorylation of Phospholipase C-γ–Associated Proteins
Authors: Udo Schmitz, Mari Ishida, Bradford C. Berk
Journal: Circulation Research (1997)

Abstract Stimulation of phospholipase C-γ (PLC-γ) is a critical event in angiotensin II (Ang II) signal transduction. We have previously shown that in rat aortic smooth muscle (RASM) cells Ang II stimulates tyrosine phosphorylation of PLC-γ via activation of c-Src. Because we failed to demonstrate a direct association between c-Src and PLC-γ, we hypothesized that a linker protein mediates the interaction between these molecules. To identify PLC-γ–associated proteins, RASM cells were labeled with [ 32 P]orthophosphate and stimulated with 100 nmol/L Ang II for 5 minutes. PLC-γ was immunoprecipitated, and associated proteins were characterized by autoradiography and Western blotting with anti-phosphotyrosine antibodies. Ang II stimulated the phosphorylation of 47-, 60-, 84-, and 97-kD PLC-γ–associated proteins. Because Ang II increased tyrosine phosphorylation of only the 97-kD protein, we characterized p97 further. An important role for Src in tyrosine phosphorylation of p97 was suggested by findings that p97 phosphorylation was inhibited by the selective Src-family kinase inhibitor CP-118,556, diminished in mouse aortic smooth muscle (MASM) cells from c-Src knockout mice compared with wild-type MASM cells, and increased in v-Src–transformed NIH-3T3 cells compared with wild-type NIH-3T3 cells. These studies are the first to define a PLC-γ–associated protein that may be required for Ang II–mediated signal transduction.
Effect of Chronic Myocardial Ischemia on the Activity of Carnitine Palmitylcoenzyme A Transferase of Isolated Canine Heart Mitochondria
Authors: JEANIE MCMILLIN WOOD, LOUIS A. SORDAHL, ROBERT M. LEWIS, ARNOLD SCHWARTZ
Journal: Circulation Research (1973)

The effect of chronic ischemia on the activity of carnitine palmitylcoenzyme A transferase (PCoAT) was examined. Control mitochondria were isolated from the left ventricle of normal hearts and from the uninvolved areas of ischemic hearts. Mitochondria from ischemic tissue were isolated from the left ventricle of chronically ischemic hearts. Formation of the enzyme product, palmityl- 14 C-carnitine, was markedly depressed in control mitochondria isolated from ischemic hearts; however, the pH optimums of the enzymes from control and ischemic mitochondria were in the same range. After 1 day of chronic ischemia, the kinetics of the enzyme from ischemic mitochondria (compared with that of the enzyme from control mitochondria) showed marked changes in Vmax. Periods of ischemia longer than 1 day significantly decreased the K m of carnitine PCoAT for carnitine from 2.59 ± 0.476 mM to 0.713 ± 0.148 mM, and Vmax was still depressed (15 to 3 nmoles/min mg -1 ). The K m for palmitylCoA was not significantly affected. Arrhenius plots for the enzyme from ischemic (32 hours) mitochondria revealed a single phasic response to temperature change. Two nonintersecting slopes were characteristic of the normal 1-day ischemic and the normal sonicated activity. As a result of ischemia, changes in the lipid components in the membrane containing carnitine PCoAT were postulated: alterations in the hydrophobic environment of the enzyme produce interference in the binding of palmitylCoA to the second substrate site and may result in a decrease in the K m of the enzyme for carnitine. The single phasic response of the enzyme to temperature change may be additional evidence for membrane lipid alterations. A defect in the transport of long-chain fatty acids may be an early change associated with myocardial ischemia.