tbuckley/cabot-search huggingface dataset:
Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia.
Authors: H M Kwon, G Sangiorgi, E L Ritman, C McKenna, D R Holmes, R S Schwartz, A Lerman
Journal: Journal of Clinical Investigation (1998)

Coronary arteries contain a network of vasa vasorum in the adventitia. The three-dimensional anatomy of the vasa vasorum in early coronary atherosclerosis is unknown. This study was designed to visualize and quantitate the three-dimensional spatial pattern of vasa vasorum in normal and experimental hypercholesterolemic porcine coronary arteries, using a novel computed tomography technique. Animals were killed after being fed either a high cholesterol diet (n = 4) or a control diet (n = 4) for 12 wk. The proximal left anterior descending coronary artery was removed from the heart, scanned, and reconstructed, and quantitation of vasa vasorum density was performed. Two different types of vasa vasorum were defined: first-order vasa vasorum ran longitudinally parallel to the vessel and second-order originated from first-order vasa circumferentially around the vessel wall. Compared with controls in hypercholesterolemic coronary arteries, there was a significant increase in the area of the vessel wall (3.86+/-0.22 vs. 8.07+/-0.45 mm2, respectively, P < 0.01) and in the density of vasa vasorum (1. 84+/-0.05/mm2 vs. 4.73+/-0.24/mm2; respectively, P = 0.0001). This occurred especially by an increase of second-order vasa vasorum and disorientation of normal vasa vasorum spatial pattern. This study suggests that adventitial neovascularization of vasa vasorum occurs in experimental hypercholesterolemic coronary arteries and may be a part of the early atherosclerotic remodeling process.
DETECTION OF IDIOTYPIC CROSS-REACTIONS AMONG STREPTOCOCCAL ANTISERA FROM RELATED RABBITS
Authors: Thomas J. Kindt, Rochelle K. Seide, Viktor A. Bokisch, Richard M. Krause
Journal: The Journal of Experimental Medicine (1973)

Idiotypic cross-reactions among antibodies to Group C streptococcal carbohydrate were studied using idiotypic antisera prepared in allotypically matched rabbits. Antibodies with idiotypic cross-specificity to one proband antibody were detected in 58% of the antisera from related rabbits, while approximately 1% of nonrelated rabbits produced antibody with this specificity. The cross-specificity was related to the group a (V(H)) allotype of 133 rabbits tested with only one exception. Studies utilizing antisera against a second proband antibody failed to detect antibodies with idiotypic cross-reactivity among the same group of related rabbits. This result emphasizes the variation in expression of idiotypic determinants of antibodies. It was further shown that the presence of anti-IgG's in the streptococcal antisera interfere with the detection of idiotypic cross-reactions. These anti-IgG's masked the presence of antibodies with idiotypic cross-specificity when inhibition of precipitation tests were used for their detection.
Intergenerational social class stability and mobility are associated with large absolute differences in adult participation in sport and exercise
Authors: Frank Popham
Journal: British Journal of Sports Medicine (2009)

To test whether there is an association of social class (im)mobility in childhood and adulthood with absolute rates of adult participation in sport and exercise.Secondary analysis of the 2003 Scottish Health Survey.2770 Scottish men and women aged 35-54.The highest age- and sex-adjusted rate of sport and exercise was seen among those who were in the highest social class in both childhood and adulthood (62.8%), while those in the lowest social class at both stages had the lowest rate at 25.8%, 37% points lower. This gap was wider than if the assessment of participation had been based solely on childhood or adult social class. The upwardly mobile had a higher rate than their class of origin in childhood but a lower rate than their class of destination in adulthood. The downwardly mobile had a lower rate than their class of origin but a higher rate than their class of destination.There are major absolute differences in participation in sport and exercise associated with social class (im)mobility that will be important to understand in order to improve population health and to reduce health inequalities.
The effects of the 3-hydroxy, 3-methylglutaryl coenzyme a reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease
Authors: Jan W. A. Smit, Karel J. Van Erpecum, Willem Renooij, Mark F. J. Stolk, Patrick Edgar, Heleen Doornewaard, Gerard P. Vanberge-Henegouwen
Journal: Hepatology (1995)

3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce biliary cholesterol saturation index (CSI) in duodenal bile in hypercholesterolemic patients and might be useful for gallstone dissolution. However, preliminary data suggest that these drugs are not effective in this respect. We therefore studied 33 patients with radiolucent gallstones in an opacifying gallbladder who were scheduled for elective cholecystectomy. Patients were treated with 40 mg pravastatin day-1 or placebo during the 3 weeks before surgery. Six patients could not be evaluated. Baseline characteristics (age, sex, body mass index, serum cholesterol, and the solitary/multiple gallstone ratio) were similar in both groups. Serum cholesterol fell by 39% in the pravastatin group (P < .001) and remained unchanged in the placebo group. Biliary cholesterol (9.5 +/- 1.3 vs. 14.3 +/- 1.5 mmol/L, P = .026), and phospholipid concentrations (24.8 +/- 3.9 vs. 36.7 +/- 3.9 mmol/L, P = .043) were lower in the pravastatin group. Although bile salt concentrations were lower in the pravastatin group (114 +/- 21 vs. 152 +/- 15 mmol/L), this difference was not significant. CSI was not different between both groups (142 +/- 27% [pravastatin] vs. 113 +/- 6% [placebo], P = NS). Cholesterol crystals were present in fresh bile in 7 of 13 patients in the pravastatin group and in 11 of 14 controls (P = NS). Nucleation time was comparable between the 2 groups (13 +/- 3 vs. 9 +/- 3 days, P = NS). Bile salt species and molecular species of phospholipids determined with high-performance liquid chromatography did not differ either between both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice
Authors: Alessandra Biffi, Alessia Capotondo, Stefania Fasano, Ubaldo del Carro, Sergio Marchesini, Hisaya Azuma, Maria Chiara Malaguti, Stefano Amadio, Riccardo Brambilla, Markus Grompe, Claudio Bordignon, Angelo Quattrini, Luigi Naldini
Journal: Journal of Clinical Investigation (2006)

Metachromatic leukodystrophy (MLD) is a demyelinating lysosomal storage disorder for which new treatments are urgently needed. We previously showed that transplantation of gene-corrected hematopoietic stem progenitor cells (HSPCs) in presymptomatic myeloablated MLD mice prevented disease manifestations. Here we show that HSC gene therapy can reverse neurological deficits and neuropathological damage in affected mice, thus correcting an overt neurological disease. The efficacy of gene therapy was dependent on and proportional to arylsulfatase A (ARSA) overexpression in the microglia progeny of transplanted HSPCs. We demonstrate a widespread enzyme distribution from these cells through the CNS and a robust cross-correction of neurons and glia in vivo. Conversely, a peripheral source of enzyme, established by transplanting ARSA-overexpressing hepatocytes from transgenic donors, failed to effectively deliver the enzyme to the CNS. These results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable. Overall, our data provide a strong rationale for implementing HSPC gene therapy in MLD patients.
Type 1 Receptor Tyrosine Kinase Profiles Identify Patients With Enhanced Benefit From Anthracyclines in the BR9601 Adjuvant Breast Cancer Chemotherapy Trial
Authors: John M.S. Bartlett, Alison Munro, David A. Cameron, Jeremy Thomas, Robin Prescott, Chris J. Twelves
Journal: Journal of Clinical Oncology (2008)

Patients with early breast cancer who receive anthracycline-containing chemotherapy experience improved relapse-free (RFS) and overall survival (OS) compared with those who receive non-anthracycline-containing chemotherapy. Such benefit, however, may be restricted to women whose tumors have specific molecular characteristics. We tested the hypothesis that HER2, epidermal growth factor receptor (EGFr)/HER1, HER3, Ki67, and topoisomerase IIalpha expression are predictive of outcome after anthracycline-based chemotherapy.Tissue microarrays from 322 of 374 women in the BR9601 trial, which compared cyclophosphamide, methotrexate, and fluorouracil (CMF) with epirubicin followed by CMF (epi-CMF), were analyzed for HER1, 2, 3, 4; Ki67; and topoisomerase IIalpha protein expression and for HER2/topoisomerase IIalpha gene amplification. Their relationships to RFS and OS were investigated, and multiple regression analysis was used to identify interactions.A significant interaction was seen between tumors with normal HER1, HER2 fluorescent in situ hybridization (FISH), or HER3 levels and the enhanced benefit from epi-CMF versus CMF for RFS (hazard ratio [HR], 0.36; HR for overexpressed HER1 or HER2 FISH or HER3, 0.92; P = .035) and for OS (HR, 0.30; HR for overexpressed HER1 or HER2 FISH or HER3), 0.98; P = .023). Neither Ki67 nor TIIalpha expressions or gene alterations showed clear predictive value for benefit from the addition of the anthracycline.Patients with HER2 amplified and those with HER1, HER2 FISH, or HER3-positive tumors did not benefit from the addition of epirubicin to CMF. Conversely, patients with HER2 nonamplified and HER1 through HER3-negative tumors showed significantly increased RFS and OS rates when treated with epi-CMF compared with CMF.
Antibody-independent complement activation by myelin via the classical complement pathway.
Authors: J C Cyong, S S Witkin, B Rieger, E Barbarese, R A Good, N K Day
Journal: The Journal of Experimental Medicine (1982)

Murine or rabbit whole brain homogenates were shown to activate human complement via the classical pathway by an antibody-independent reaction. This activity required Ca++ ions. Anticomplementary activity in fractionated murine brain was found to reside in the myelin fraction and in purified myelin. It was absent, however, both from highly purified myelin basic protein (MBP) and from the MBP-free residue. Because purified MBP is a monomer and this protein exists in brain tissue largely as a dimer, the ability of the cross-linked form of MBP to activate complement was investigated. MBP, dimerized with difluorodinitrobenzene, was highly anticomplementary. The murine brain, inactive when taken from the newborn mouse, was shown to first acquire the capacity to activate complement at 7 d after birth. This finding is consistent with the report that the synthesis of myelin protein has been shown to be initiated in murine brain 8 d after birth. Complement activation by MBP could play an important role in the pathological changes observed in neurological disorders.
Treatment of Chlamydia pneumoniae infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial
Authors: Franz-Josef Neumann, Adnan Kastrati, Thomas Miethke, Gisela Pogatsa-Murray, Julinda Mehilli, Christian Valina, Nader Jogethaei, Clarissa P da Costa, Hermann Wagner, Albert Schömig
Journal: The Lancet (2001)
The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice
Authors: Aimin Xu, Yu Wang, Hussila Keshaw, Lance Yi Xu, Karen S.L. Lam, Garth J.S. Cooper
Journal: Journal of Clinical Investigation (2003)

Adiponectin has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes. Replenishment of recombinant adiponectin in mice can decrease hyperglycemia, reverse insulin resistance, and cause sustained weight loss without affecting food intake. Here we report its potential roles in alcoholic and nonalcoholic fatty liver diseases in mice. Circulating concentrations of adiponectin decreased significantly following chronic consumption of high-fat ethanol-containing food. Delivery of recombinant adiponectin into these mice dramatically alleviated hepatomegaly and steatosis (fatty liver) and also significantly attenuated inflammation and the elevated levels of serum alanine aminotransferase. These therapeutic effects resulted partly from the ability of adiponectin to increase carnitine palmitoyltransferase I activity and enhance hepatic fatty acid oxidation, while it decreased the activities of two key enzymes involved in fatty acid synthesis, including acetyl-CoA carboxylase and fatty acid synthase. Furthermore, adiponectin treatment could suppress the hepatic production of TNF-α and plasma concentrations of this proinflammatory cytokine. Adiponectin was also effective in ameliorating hepatomegaly, steatosis, and alanine aminotransferase abnormality associated with nonalcoholic obese, ob/ob mice. These results demonstrate a novel mechanism of adiponectin action and suggest a potential clinical application of adiponectin and its agonists in the treatment of liver diseases.
Galectin-3 inhibition using novel inhibitor GR-MD-02 improves survival and immune function while reducing tumor vasculature
Authors: Stefanie Linch, Melissa J Kasiewicz, Michael McNamara, Ian Hilgart, Mohammad Farhad, William Redmond
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunosuppression and reduced cytolytic function of tumor-infiltrating lymphocytes are major obstacles to creating effective therapies for patients. It is known that Galectin-3 (Gal3), a lectin family member, is expressed and secreted by numerous cancers and immune cell subsets.
Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies
Authors: Robert Z. Orlowski, Thomas E. Stinchcombe, Beverly S. Mitchell, Thomas C. Shea, Albert S. Baldwin, Stephanie Stahl, Julian Adams, Dixie-Lee Esseltine, Peter J. Elliott, Christine S. Pien, Roberto Guerciolini, Jessica K. Anderson, Natalie D. Depcik-Smith, Rita Bhagat, Mary Jo Lehman, Steven C. Novick, Owen A. O’Connor, Steven L. Soignet
Journal: Journal of Clinical Oncology (2002)

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.
Manipulating the environment of cancer cells in bone: a novel therapeutic approach
Authors: T. John Martin
Journal: Journal of Clinical Investigation (2002)

The fact that human cancers have preferential sites of distant spread indicates that metastasis is a highly specific and regulated process rather than a random event. Breast cancer is one of several cancers, including prostate, thyroid, and kidney, that display a very high frequency of metastasis to bone (1). The predilection for breast cancer to spread to bone was recognized more than a hundred years ago by Paget (2), who proposed that bone provides a favorable and specific “soil,” or microenvironment, for the growth of specific “seed,” or breast cancer cells.

As a densely mineralized tissue, bone represents a particularly harsh environment for successful tumor cell establishment and growth. Older ideas of pathogenesis favor the view that tumor cells themselves directly cause bone breakdown as a result of their general invasive properties. Such invasive capability is essential, of course, but there is little doubt that the most important specific property required of cancer cells to metastasize in bone is the ability to promote bone resorption, thereby providing a niche in which tumor cells can grow and expand in this otherwise hostile environment. The resorption by host osteoclasts is essential to provide space for tumor establishment and expansion within the mineralized bone matrix (3). Human breast cancer deposits in bone are surrounded by active osteoclasts (3, 4), and evidence obtained from animal models demonstrates active softening, resorption, and destruction of bony tissue (osteolysis) (4, 5) metastasis to bone (6). Furthermore, inhibition of osteoclast-mediated bone resorption is effective in reducing bone metastatic burden in clinical (7) and experimental studies (8). In this issue of the JCI, Gallwitz and colleagues (9) investigate the inhibition of osteolytic bone destruction associated with metastatic human breast cancer cells.
Abstract 4958: Fluorescent barcoding offers increased dimensionality in tracking tumor cells in vitro and in vivo
Authors: Katie E. Hebron, Tatiana Ketova, Shanna Arnold, H. Charles Manning, Julie Sterling, Florent Elefteriou, Andries Zijsltra
Journal: Cancer Research (2014)

Abstract Fluorescent or luminescent imaging of tumors in animal models is a critical element in dynamic and longitudinal monitoring of tumor burden, tumor growth, and metastatic dissemination. Currently, most imaging strategies are limited to one or two different colors per animal. To improve utility of current imaging technologies, we have developed a library of fluorescent and luminescent tracking vectors designed to expand the color dimensions possible within a single model through a multi-label approach to fluorescent barcoding. The library was built using Multisite Gateway® Cloning technology, which offers a fast and simple recombination-based cloning approach that allows for efficient expression of several genes driven by one promoter on a single vector backbone. Our lentiviral-based vectors express firefly luciferase and one of seven spectrally unique fluorescent proteins covering the entire fluorescent protein color palette from blue to far-red. We have stably labeled bone-derived MDA-MB-231 cells with the vectors by viral transduction. Using these individually colored cell lines, we have demonstrated that the seven FPs are uniquely identifiable by spectral un-mixing with the Maestro Q Imaging System and by flow cytometry. The combination of luciferase and fluorescent labeling allows us to monitor tumor growth by luciferase activity and distinguish individual cell populations by their fluorescent label. We are currently verifying that the cells retain stable expression of the vectors in mouse models; preliminary results are promising. In the future, this system will be used to develop an elegant multi-label-based fluorescent barcoding strategy that will allow us to identify individual cell populations from a heterogeneous environment in vivo. By exploiting combinations of the seven fluorescent proteins, we could potentially create over 200 uniquely identifiable cells populations. This ability will not only reduce the number of animals necessary per experiment (as control and several experimental populations can be individually analyzed in a single mouse); but will also allow us to mimic the heterogeneous environment common to all human tumors. Citation Format: Katie E. Hebron, Tatiana Ketova, Shanna Arnold, H. Charles Manning, Julie Sterling, Florent Elefteriou, Andries Zijsltra. Fluorescent barcoding offers increased dimensionality in tracking tumor cells in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4958. doi:10.1158/1538-7445.AM2014-4958
Bronchial Responsiveness and Five-year FEV<sub>1</sub> Decline
Authors: PAUL HODGINS, PAUL K. HENNEBERGER, MEI-LIN WANG, EDWARD L. PETSONK
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Increased nonspecific bronchial responsiveness (NSBR) may be a risk factor for the development of chronic airflow obstruction. We evaluated this hypothesis in a cohort of 378 underground coal miners and working nonminers. Methacholine testing was performed at the beginning and end of a 5-yr study period. Spirometry was repeated at 6-mo intervals and individual 5-yr FEV1 slopes were calculated by linear regression. Relationships between FEV1 slopes and NSBR were examined using multiple linear regression models, controlling for FEV1 level, smoking, and mining. Increasing NSBR at the initial survey was associated with a somewhat greater rate of subsequent FEV1 decline. Methacholine responders at the final survey had a considerably increased rate of decline during the previous years. Responsiveness status changed over the 5 yr in 22% of the subjects. Both the development and persistence of increased NSBR were strongly associated with higher rates of FEV1 decline. In contrast, FEV1 declines were not accelerated among workers with increased NSBR that reverted to normal. Smoking and mining were both independently associated with FEV1 declines, but did not substantially modify the effect of NSBR. Due to its variability over time, NSBR testing predicts lung function decline only in some individuals, and its value as a prognostic test for chronic airway disorders is limited. Because improvement in bronchial hyperresponsiveness was associated with a reduction in the rate of FEV1 loss, interventions directed at preventing or reducing nonspecific airway hyperresponsiveness should be investigated.