tbuckley/cabot-search huggingface dataset:
Critical Role for Mitochondrial Oxidative Phosphorylation in the Activation of Tumor Suppressors Bax and Bak
Authors: Arata Tomiyama, Shinobu Serizawa, Ken Tachibana, Kaori Sakurada, Hirotsugu Samejima, Yoshiyuki Kuchino, Chifumi Kitanaka
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: Activation of Bax and Bak, which act to permeabilize the mitochondrial membrane, is an essential step in the cell death response and therefore in the suppression of tumorigenesis. However, the mechanisms that regulate activation are poorly understood. Methods: Bax and Bak activation (conformational change and dimerization) was monitored in Rat-1 fibroblasts and human cancer cells subjected to endoplasmic reticulum (ER) stress, DNA damage, or tumor necrosis factor-α (TNF-α) treatment. Pharmacologic inhibitors of reactive oxygen species production, electron transport in the respiratory chain, oxidative phosphorylation, and appropriate controls were used to identify potential modes by which Bax and Bak activation and the cell death response are controlled. The oligomerization state of Bax and Bak was determined by cross-linking and subsequent immunoblot analysis; Bax conformational change was analyzed by immunoprecipitation and immunoblotting with an antibody specific for the active conformation. Cell death was evaluated by dye exclusion. Results: In both fibroblasts and human cancer cells subjected to cell death stimuli, inhibition of oxidative phosphorylation by use of antimycin A or oligomycin prevented ER stress–, DNA damage–, and TNF-α–induced Bax and Bak activation and cell death (UV-induced Rat-1 cell death at 15 hours: control, mean = 33.6%, 95% confidence interval [CI] = 18.8% to 48.4%; antimycin A, mean = 10.0%, 95% CI = 0% to 21.7%; oligomycin, mean = 13.1%, 95% CI = 5.7% to 20.5%; tunicamycin-induced MCF-7 cell death at 9 hours: control, mean = 29.2%, 95% CI = 21.6% to 36.8%; antimycin A, mean = 15.3%, 95% CI = 0.8% to 29.8%; oligomycin, mean = 11.5%, 95% CI = 3.9% to 19.1%; TNF-α–induced MCF-7 cell death at 6 hours: control, mean = 24.0%, 95% CI = 12.6% to 35.4%; antimycin A, mean = 8.9%, 95% CI = 3.9% to 13.9%; oligomycin, mean = 13.3%, 95% CI = 10.4% to 16.2%). Increasing and decreasing glycolytic adenosine triphosphate production, by adding glucose and 2-deoxy- D -glucose to the cell growth medium, respectively, neither reversed nor recapitulated, respectively, the effect of compromised oxidative phosphorylation on Bax and Bak activation. Conclusion: Oxidative phosphorylation is required for the activation of Bax and Bak and cell death triggered by disparate death stimuli. The reliance of tumor cells on glycolysis in preference to oxidative phosphorylation even under normoxic conditions (Warburg effect) may therefore be a potential means by which these cells evade programmed cell death.
The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors
Authors: J PETERSON
Journal: Cardiovascular Research (2006)

At least 56 matrix metalloproteinase (MMP) inhibitors have been pursued as clinical candidates since the late 1970's when the first drug discovery program targeting this enzyme family began. Some of these clinical candidates were pursued for multiple indications. However, the two primary indications that have been targeted are cancer (24 drugs) and anti-arthritis (27 drugs). Cardiovascular disease was listed as an indication for 10 drugs. Forty-six MMP inhibitors have been discontinued, 7 remain in clinical development, and only 1 (Periostat® for periodontal disease) has been approved. Recently, negative phase II results were reported for the MMP inhibitor PG-116800, which was being evaluated as a treatment for post-ischemic myocardial remodeling to prevent heart failure. One major factor leading to the failure of PG-116800 and many of the other MMP inhibitors is the inadequate assessment of the therapeutic index, the ratio of dose required for efficacy vs. that for toxicology. This review describes the dose-limiting side effect that has hampered MMP inhibitor development (the musculoskeletal syndrome), cardiovascular clinical MMP inhibitor studies, a model of the therapeutic index using marimastat, and progress towards more selective MMP inhibitors not limited by the musculoskeletal syndrome.
Possible Impairment of Transcardiac Utilization of Adiponectin in Patients With Type 2 Diabetes
Authors: Masato Furuhashi, Nobuyuki Ura, Norihito Moniwa, Yasuyuki Shinshi, Hidemichi Kouzu, Masahiro Nishihara, Nobuaki Kokubu, Toru Takahashi, Ken-ichi Sakamoto, Manabu Hayashi, Naotoshi Satoh, Takahiro Nishitani, Yasukuni Shikano, Kazuaki Shimamoto
Journal: Diabetes Care (2004)

OBJECTIVE—Adiponectin, an adipocyte-derived protein, has been suggested to enhance insulin sensitivity and prevent atherosclerosis. Circulating adiponecin levels are reduced in states of insulin resistance such as type 2 diabetes. We examined transcardiac utilization of adiponectin in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 17 male type 2 diabetic patients and 17 male nondiabetic patients were investigated. Venous blood samples were taken to measure glucose and lipid variables. Blood samples for the measurement of adiponectin were collected simultaneously from the aortic root and coronary sinus. Angiographic semiquantitative stenosis score of coronary artery was also evaluated. RESULTS—The adiponectin levels in both the aortic root and coronary sinus in the diabetic patients were significantly lower than those in the nondiabetic patients. The adiponectin level was significantly lower in the coronary sinus than in the aortic root in the nondiabetic patients, but there was no significant difference between adiponectin levels in the aortic root and coronary sinus in the diabetic patients. The total stenosis score, as an index of severity of coronary artery stenosis, was significantly higher in the diabetic patients than in the nondiabetic patients. The stenosis score was correlated with the degree of transcardiac utilization of adiponectin from the aortic root to coronary sinus in the nondiabetic patients but not in the diabetic patients. CONCLUSIONS—Diabetic patients not only have a decreased adiponectin level in the basal state compared with nondiabetic patients but also have impaired utilization of adiponectin in the coronary artery and/or the heart, which may promote the development of atherosclerosis.
Improvement of severe pulmonary hypertension in a patient with SLE.
Authors: M Karmochkine, B Wechsler, P Godeau, F Brenot, J L Jagot, G Simonneau
Journal: Annals of the Rheumatic Diseases (1996)

rarely described.9Hypothyroidism, as was present in our second patient, has also been described in association with watermelon stomach.'o Our patients represent cases in which gastrointestinal bleeding secondary to the watermelon stomach was an early manifestation of their scleroderma.Similarly, Rosekrans, et al described one patient in whom anaemia secondary to bleeding from the watermelon stomach predated the diagnosis of scleroderma.4Most cases of watermelon stomach, however, have been reported to occur in those who already have well established scleroderma.3Bleeding from the watermelon stomach and activity of scleroderma did not necessarily parallel each other.In the first case recurrent bleeding from the watermelon stomach occurred when other manifestations of scleroderma were quiescent.In the second case the manifestations of the watermelon stomach and the activity of the scleroderma progressed concurrently.Progression of scleroderma and concomitant bleeding from the watermelon stomach have been reported,5 but it is not known whether this is always the case.Further cases will need to be examined to determine the relation between the activity of the watermelon stomach and progression of the scleroderma.Doctors should be aware that watermelon stomach may be an early manifestation of scleroderma, and bleeding from the water- melon stomach may occur any time during the course of disease.
The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience
Authors: J. Rodríguez, E. Conde, A. Gutiérrez, R. Arranz, Á. León, J. Marín, M. Bendandi, C. Albo, M.D. Caballero
Journal: Annals of Oncology (2007)
Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease
Authors: Matthew L Hemming, Michaela Patterson, Casper Reske-Nielsen, Ling Lin, Ole Isacson, Dennis J Selkoe
Journal: PLoS Medicine (2007)

Understanding the mechanisms of amyloid-beta protein (Abeta) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Abeta levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Abeta in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Abeta levels in AD. The objective of this study was to determine if enhancing the clearance of Abeta in the brain by ex vivo gene delivery of an Abeta-degrading protease can reduce amyloid plaque burden.We generated a secreted form of the Abeta-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Abeta in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of beta-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively).Ex vivo gene delivery of an Abeta-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Abeta-degrading proteases as a means to therapeutically lower Abeta levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.
The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro
Authors: J. J. Maguire, K. L. Jones, R. E. Kuc, M. C. H. Clarke, M. R. Bennett, A. P. Davenport
Journal: Cardiovascular Research (2013)

The chemokine receptor CCR5 and its inflammatory ligands have been linked to atherosclerosis, an accelerated form of which occurs in saphenous vein graft disease. We investigated the function of vascular smooth muscle CCR5 in human coronary artery and saphenous vein, vascular tissues susceptible to atherosclerosis, and vasospasm.CCR5 ligands were vasoconstrictors in saphenous vein and coronary artery. In vein, constrictor responses to CCL4 were completely blocked by CCR5 antagonists, including maraviroc. CCR5 antagonists prevented the development of a neointima after 14 days in cultured saphenous vein. CCR5 and its ligands were expressed in normal and diseased coronary artery and saphenous vein and localized to medial and intimal smooth muscle, endothelial, and inflammatory cells. [(125)I]-CCL4 bound to venous smooth muscle with KD = 1.15 ± 0.26 nmol/L and density of 22 ± 9 fmol mg(-1) protein.Our data support a potential role for CCR5 in vasoconstriction and neointimal formation in vitro and imply that CCR5 chemokines may contribute to vascular remodelling and augmented vascular tone in human coronary artery and vein graft disease. The repurposing of maraviroc for the treatment of cardiovascular disease warrants further investigation.
Repetitive strain disorder: towards diagnostic criteria.
Authors: H A Bird, J Hill
Journal: Annals of the Rheumatic Diseases (1992)

Thirteen women (mean age 48.2 years; range 25-60 years) all of whom had developed musculoskeletal symptoms during employment in an industrial job with repetitive tasks were referred by their trade unions for adjudication on the cause of symptoms. One had rheumatoid arthritis. A study of the other 12 women provided an opportunity to document the natural history of repetitive strain disorder. Early symptoms of weakness were diffuse but were always relieved by rest. Several months later localisation of symptoms at a tendon, nerve, or enthesis could be predicted from the analysis of the action required in the particular repetitive task. Six of the 12 women required an operation several years later, thus providing histological confirmation of the presence of a lesion. Early loss of grip strength measured by a sphygmomanometer cuff compared with an unaffected control subject and improved by rest may be the most valuable sign in excluding compensation neurosis. The estimated prevalence of repetitive strain disorder defined by these strict criteria was at least 2% in conveyor belt workers.
Clinical and histologic characteristics of malignant melanoma in families with a germline mutation in CDKN2A
Authors: Jasper I. van der Rhee, Pieta Krijnen, Nelleke A. Gruis, Femke A. de Snoo, Hans F.A. Vasen, Hein Putter, Nicole A. Kukutsch, Wilma Bergman
Journal: Journal of the American Academy of Dermatology (2011)
Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC)
Authors: M. Arnedos, A. Nerurkar, P. Osin, R. A'Hern, I.E. Smith, M. Dowsett
Journal: Annals of Oncology (2009)
Generic Medications and Blood Pressure Control in Diabetic Hypertensive Subjects
Authors: Doyle M. Cummings, Abraham J. Letter, George Howard, Virginia J. Howard, Monika M. Safford, Valerie Prince, Paul Muntner
Journal: Diabetes Care (2012)

OBJECTIVE To investigate temporal improvements in blood pressure (BP) control in subjects with diabetes and policy changes regarding generic antihypertensives. RESEARCH DESIGN AND METHODS In a cross-sectional study we used logistic regression models to investigate the temporal relationship between access to generic antihypertensive medications and BP control (&amp;lt;130/80 mmHg) in 5,375 subjects (mean age, 66 ± 9 years; 61% African American) with diabetes and hypertension (HTN) enrolled in the national Results from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study between 2003 and 2007. At enrollment, BP was measured and medications in the home determined by medication label review by a trained professional. Generic antihypertensive medication status was ascertained from the U.S. Food and Drug Administration. RESULTS The percentage of subjects accessing generically available antihypertensive medications increased significantly from 66% in 2003 to 81% in 2007 (P &amp;lt; 0.0001), and the odds of achieving a BP &amp;lt;130/80 mmHg in 2007 was 66% higher (odds ratio 1.66 [95% CI 1.30–2.10]) than in 2003. Nevertheless, &amp;lt;50% of participants achieved this goal. African American race, male sex, limited income, and medication nonadherence were significant predictors of inadequate BP control. There was no significant relationship between access to generic antihypertensives and BP control when other demographic factors were included in the model (0.98 [0.96–1.00]). CONCLUSIONS Among African American and white subjects with HTN and diabetes, BP control remained inadequate relative to published guidelines, and racial disparities persisted. Although access to generic antihypertensives increased, this was not independently associated with improved BP control, suggesting that poor BP control is multifactorial.
Multimodality Screening of High-Risk Women: A Prospective Cohort Study
Authors: Susan P. Weinstein, A. Russell Localio, Emily F. Conant, Mark Rosen, Kathleen M. Thomas, Mitchell D. Schnall
Journal: Journal of Clinical Oncology (2009)

Mammography has been established as the primary imaging screening method for breast cancer; however, the sensitivity of mammography is limited, especially in women with dense breast tissue. Given the limitations of mammography, interest has developed in alternative screening techniques. This interest has led to numerous studies reporting mammographically occult breast cancers detected on magnetic resonance imaging (MRI) or ultrasound. In addition, digital mammography was shown to be more sensitive than film mammography in selected populations. Our goal was to prospectively compare cancer detection of digital mammography (DM), whole-breast ultrasound (WBUS), and contrast-enhanced MRI in a high-risk screening population previously screened negative by film screen mammogram (FSM).During a 2-year period, 609 asymptomatic high-risk women with nonactionable FSM examinations presented for a prospective multimodality screening consisting of DM, WBUS, and MRI. The FSM examinations were reinterpreted by study radiologists. Patients had benign or no suspicious findings on clinical examination. The cancer yield by modality was evaluated.Twenty cancers were diagnosed in 18 patients (nine ductal carcinomas in situ and 11 invasive breast cancers). The overall cancer yield on a per-patient basis was 3.0% (18 of 609 patients). The cancer yield by modality was 1.0% for FSM (six of 597 women), 1.2% for DM (seven of 569 women), 0.53% for WBUS (three of 567 women), and 2.1% for MRI (12 of 571 women). Of the 20 cancers detected, some were only detected on one imaging modality (FSM, n = 1; DM, n = 3; WBUS, n = 1; and MRI, n = 8).The addition of MRI to mammography in the high-risk group has the greatest potential to detect additional mammographically occult cancers. The incremental cancer yield of WBUS and DM is much less.
Radionuclide Monitoring of Cardiac Adaptations to Volume Loading in Patients With Dilated Cardiomyopathy and Mild Heart Failure
Authors: Massimo Volpe, Maria A.E. Rao, Alberto Cuocolo, Rosaria Russo, Antonio Nappi, Alessandro F. Mele, Iolanda Enea, Bruno Trimarco, Mario Condorelli
Journal: Circulation (1995)

Background Cardiac adaptations to volume overload have been poorly investigated in heart failure. The aim of this study was to assess dynamic left ventricular responses to acute volume loading by continuous radionuclide monitoring in patients with asymptomatic to mildly symptomatic left ventricular dysfunction. Methods and Results Left ventricular end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), and peak filling rate (PFR) were monitored by a radionuclide detector (Vest) before and during volume expansion (sodium chloride, 0.9%, 0.25 mL · kg −1 · min −1 for 2 hours) in 10 patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (New York Heart Association class I or II, ejection fraction &lt;50%). The patients were studied off treatment and after 6 to 8 weeks of oral treatment with enalapril (5 mg/d). A control group of 11 age- and sex-matched healthy volunteers (N group) was also studied. In the N group, volume loading caused prompt and sustained increases of EDV, EF, and PFR (all P &lt;.001), whereas ESV was progressively reduced ( P &lt;.001), and heart rate and blood pressure did not change. In contrast, in DCM, EDV showed a smaller increase than in the N group (two-way ANOVA: F =5.98, P &lt;.001), ESV increased ( P &lt;.001), and EF and PFR remained unchanged. After enalapril, the cardiac adaptations to volume loading were restored to normal. In particular, EDV, EF, and PFR increased ( P &lt;.001), and ESV was reduced ( P &lt;.001). In 6 additional DCM patients studied before and after 6 to 8 weeks of placebo treatment, left ventricular responses to volume loading remained unchanged. Conclusions Left ventricular dynamic adaptations to acute volume loading are compromised in patients with idiopathic DCM and mild heart failure. These impaired responses are ameliorated by treatment with enalapril.
Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology [see comments]
Authors: JN George, SH Woolf, GE Raskob, JS Wasser, LM Aledort, PJ Ballem, VS Blanchette, JB Bussel, DB Cines, JG Kelton, AE Lichtin, R McMillan, JA Okerbloom, DH Regan, I Warrier
Journal: Blood (1996)
Gene transfection efficacy and biocompatibility of polycation/DNA complexes coated with enzyme degradable PEGylated hyaluronic acid
Authors: Wendi Zhang, Qiang Cheng, Shutao Guo, Daoshu Lin, Pingsheng Huang, Juan Liu, Tuo Wei, Liandong Deng, Zicai Liang, Xing-Jie Liang, Anjie Dong
Journal: Biomaterials (2013)
Neointima formation in a restenosis model is suppressed in midkine-deficient mice
Authors: Mitsuru Horiba, Kenji Kadomatsu, Eishin Nakamura, Hisako Muramatsu, Shinya Ikematsu, Sadatoshi Sakuma, Kenji Hayashi, Yukio Yuzawa, Seiichi Matsuo, Masafumi Kuzuya, Tadashi Kaname, Makoto Hirai, Hidehiko Saito, Takashi Muramatsu
Journal: Journal of Clinical Investigation (2000)

Neointima formation is a common feature of atherosclerosis and restenosis after balloon angioplasty. To find a new target to suppress neointima formation, we investigated the possible role of midkine (MK), a heparin-binding growth factor with neurotrophic and chemotactic activities, in neointima formation. MK expression increased during neointima formation caused by intraluminal balloon injury of the rat carotid artery. Neointima formation in a restenosis model was strongly suppressed in MK-deficient mice. Continuous administration of MK protein to MK-deficient mice restored neointima formation. Leukocyte recruitment to the vascular walls after injury was markedly decreased in MK-deficient mice. Soluble MK as well as that bound to the substratum induced migration of macrophages in vitro. These results indicate that MK plays a critical role in neointima formation at least in part owing to its ability to mediate leukocyte recruitment.
Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study
Authors: Ana Djarmati, Susanne A Schneider, Katja Lohmann, Susen Winkler, Heike Pawlack, Johann Hagenah, Norbert Brüggemann, Simone Zittel, Tania Fuchs, Aleksandar Raković, Alexander Schmidt, Hans-Christian Jabusch, Robert Wilcox, Vladimir S Kostić, Hartwig Siebner, Eckart Altenmüller, Alexander Münchau, Laurie J Ozelius, Christine Klein
Journal: The Lancet Neurology (2009)