tbuckley/cabot-search huggingface dataset:
Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010
Authors: Valery L Feigin, Mohammad H Forouzanfar, Rita Krishnamurthi, George A Mensah, Myles Connor, Derrick A Bennett, Andrew E Moran, Ralph L Sacco, Laurie Anderson, Thomas Truelsen, Martin O'Donnell, Narayanaswamy Venketasubramanian, Suzanne Barker-Collo, Carlene M M Lawes, Wenzhi Wang, Yukito Shinohara, Emma Witt, Majid Ezzati, Mohsen Naghavi, Christopher Murray
Journal: The Lancet (2013)
Mechanisms of Mitogen-Activated Protein Kinase Activation in Experimental Diabetes
Authors: MIDORI AWAZU, KENJI ISHIKURA, MARIKO HIDA, MAKIKO HOSHIYA
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Various growth factors and vasoactive substances are implicated in the pathogenesis of renal growth seen in early diabetes mellitus (DM). Mitogen-activated protein kinase (MAPK) is an important mediator of these extracellular stimuli. Protein kinase C (PKC), an enzyme known to be stimulated in DM, also activates MAPK. Thus, MAPK activity was examined in glomeruli from streptozotocin-induced DM rats. MAPK activity, measured as myelin basic protein kinase, was elevated by approximately 50% in DM versus controls (CON). Increased protein contents of p42 mapk and p44 mapk , as well as increased tyrosine phosphorylation and mobility shift of p42 mapk , were also observed in DM. Tyrosine dephosphorylation of pp42 mapk , on the other hand, assessed by incubating glomerular membrane with or without sodium orthovanadate (vanadate), was significantly diminished in DM. Protein expression of MAPK phosphatase-1 (MKP-1), a dual specificity phosphatase that inactivates MAPK, was approximately 60% of CON. Reduction in MKP-1 was reproduced in cultured mesangial cells grown under high glucose (30 mM; HG). The suppression of MKP-1 was PKC-dependent since incubation of HG cells with phorbol 12-myristate 13-acetate for 24 h abolished it. Furthermore, calcium ionophore A23187 reversed the suppression, suggesting that blunted Ca 2+ signalling, characteristic of HG cells secondary to PKC stimulation, may be the cause. These results demonstrate that glomerular MAPK is activated in DM by multiple mechanisms i.e. , increases in protein contents, increased phosphorylation, and decreased dephosphorylation of the enzyme due to suppression of MKP-1. These alterations may have an implication in the pathogenesis of diabetic nephropathy.
Short-term diabetes alters K+ currents in rat ventricular myocytes.
Authors: Y Shimoni, L Firek, D Severson, W Giles
Journal: Circulation Research (1994)

The electrophysiological properties of single ventricular myocytes from control rats and from rats made diabetic by streptozotocin (STZ) injection (100 mg/kg body weight) have been investigated using whole-cell voltage-clamp measurements. Our major goal was to define the effects of diabetes on rate-dependent changes in action potential duration and the underlying outward K+ currents. As early as 4 to 6 days after STZ treatment, significant elevation of plasma glucose levels occurs, and the action potential duration increases. In both control and diabetic rats, when the stimulation rate is increased, the action potential is prolonged, but this lengthening is considerably more pronounced in myocytes from diabetic rats. In ventricular myocytes from diabetic rats, the Ca(2+)-independent transient outward K+ current (I(t)) is reduced in amplitude, and its reactivation kinetics are slowed. These changes result in a smaller I(t) at physiological heart rates. The steady-state outward K+ current (IK) also exhibits rate-dependent attenuation, and this phenomenon is more pronounced in cells from diabetic rats. These STZ-induced changes in I(t) and IK also develop when a lower dose (55 mg/kg) of STZ is used and measurements are made after 7 weeks of treatment. These electrophysiological effects are not related to the hypothyroid conditions that accompany the diabetic state, since they cannot be reversed by replacement of the hormone L-triiodothyronine to physiological levels. Direct effects of STZ could be ruled out, since preceding the STZ injection with a bolus injection of 3-O-methylglucose, which prevents development of hyperglycemia, prevents the electrophysiological changes.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of Heat Shock Protein 27–Mediated Resistance to DNA Damaging Agents by a Novel PKCδ-V5 Heptapeptide
Authors: Eun-Ho Kim, Hae-June Lee, Dae-Hoon Lee, Sangwoo Bae, Jae-Won Soh, Dooil Jeoung, Joon Kim, Chul-Koo Cho, Yoon-Jin Lee, Yun-Sil Lee
Journal: Cancer Research (2007)

Abstract Heat shock protein 27 (HSP27), which is highly expressed in human lung and breast cancer tissues, induced resistance to cell death against various stimuli. Treatment of NCI-H1299 cells, which express a high level of HSP27, with small interference RNA specifically targeting HSP27 resulted in inhibition of their resistance to radiation or cisplatin, suggesting that HSP27 contributed to cellular resistance in these lung cancer cells. Furthermore, because HSP27 interacts directly with the COOH terminus of the protein kinase Cδ (PKCδ)-V5 region with ensuing inhibition of PKCδ activity and PKCδ-mediated cell death, we wished to determine amino acid residues in the V5 region that mediate its interaction with HSP27. Investigation with various deletion mutants of the region revealed that amino acid residues 668 to 674 of the V5 region mediate its interaction with HSP27. When NCI-H1299 cells were treated with biotin or with FITC-tagged heptapeptide of the residues 668 to 674 (E-F-Q-F-L-D-I), the cells exhibited dramatically increased cisplatin or radiation-induced cell death with the heptapeptide having efficient interaction with HSP27, which in turn restored the PKCδ activity that had been inhibited by HSP27. In vivo nude mice grafting data also suggested that NCI-H1299 cells were sensitized by this heptapeptide. The above data strongly show that the heptapeptide of the PKCδ-V5 region sensitized human cancer cells through its interaction with HSP27, thereby sequestering HSP27. The heptapeptide may provide a novel strategy for selective neutralization of HSP27. [Cancer Res 2007;67(13):6333–9]
Ghrelin Improves Endothelial Function in Patients With Metabolic Syndrome
Authors: Manfredi Tesauro, Francesca Schinzari, Micaela Iantorno, Stefano Rizza, Domenico Melina, Davide Lauro, Carmine Cardillo
Journal: Circulation (2005)

Metabolic syndrome importantly accelerates the atherosclerotic process, the earliest event of which is endothelial dysfunction. Ghrelin, a gastric peptide with cardiovascular actions, has been shown to inhibit proatherogenic changes in experimental models. This study therefore investigated whether ghrelin administration might beneficially affect endothelial function in metabolic syndrome.Endothelium-dependent and -independent vasodilator responses to intra-arterial infusion of increasing doses of acetylcholine and sodium nitroprusside (SNP), respectively, were assessed by strain-gauge plethysmography before and after local administration of human ghrelin (200 microg/min). During saline, the vasodilator response to acetylcholine was significantly blunted (P=0.008) in patients with metabolic syndrome (n=12, 5 female) compared with controls (n=12, 7 female), whereas the vasodilator response to SNP was not different between groups (P=0.68). In patients with metabolic syndrome, basal plasma ghrelin was significantly lower than in controls (P=0.02). In these patients, ghrelin infusion markedly increased intravascular concentrations of the peptide (P<0.001) and resulted in a potentiation of the vasodilator response to acetylcholine (P=0.001 versus saline) but not to SNP (P=0.22). This effect was likely related to enhanced nitric oxide bioavailability because, in a group of patients with metabolic syndrome (n=6, 2 female), ghrelin had no effect on the vasodilator response to acetylcholine (P=0.78 versus saline) after nitric oxide inhibition by NG-monomethyl-L-arginine.These findings indicate that ghrelin reverses endothelial dysfunction in patients with metabolic syndrome by increasing nitric oxide bioactivity, thereby suggesting that decreased circulating levels of the peptide, such as those found in these patients, might play a role in the pathobiology of atherosclerosis.
Exposure to biomass smoke and chronic airway disease in Mexican women. A case-control study.
Authors: R Pérez-Padilla, J Regalado, S Vedal, P Paré, R Chapela, R Sansores, M Selman
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

A case-control study was performed in women older than 40 yr of age to evaluate the risk of cooking with traditional wood stoves for chronic bronchitis and chronic airway obstruction (CAO). The subjects were recruited from patients attending a referral chest hospital in Mexico City. We selected 127 patients with chronic bronchitis or CAO, of which 63 had chronic bronchitis alone, 23 had CAO alone (FEV1 less than 75% of predicted), and 41 had both chronic bronchitis and CAO (cases). Four control groups were selected: 83 patients with pulmonary tuberculosis, 100 patients with interstitial lung diseases, 97 patients with ear, nose and throat ailments, and 95 healthy visitors to the hospital (controls). Exposure to wood smoke, assessed as any or none, and as hour-years (years of exposure multiplied by average hours of exposure per day) was significantly higher in cases than in controls. Crude odds ratios for wood smoke exposure were 3.9 (95% CI, 2.0 to 7.6) for chronic bronchitis only, 9.7 (95% CI, 3.7 to 27) for CAO plus chronic bronchitis, and 1.8 (95% CI, 0.7 to 4.7) for CAO only. Differences in exposure to wood smoke persisted after adjusting by stratification and logistic regression for age, income, education, smoking, place of residence, and place of birth. Risk of chronic bronchitis alone and chronic bronchitis with CAO increased linearly with hour-years of cooking with a wood stove; odds ratios for exposure to more than 200 hour-years compared with nonexposed were 15.0 (95% CI, 5.6 to 40) for chronic bronchitis only and 75 (95% CI, 18 to 306) for chronic bronchitis with CAO. The findings support a causal role of domestic wood smoke exposure in chronic bronchitis and chronic airflow obstruction.
Successful Chemotherapeutic Modality of Doxorubicin Plus Dacarbazine for the Treatment of Desmoid Tumors in Association With Familial Adenomatous Polyposis
Authors: Makoto Gega, Hidenori Yanagi, Reigetsu Yoshikawa, Masafumi Noda, Hiroki Ikeuchi, Kiyoshi Tsukamoto, Tsutomu Oshima, Yoshinori Fujiwara, Nobuhisa Gondo, Kazuo Tamura, Joji Utsunomiya, Tomoko Hashimoto-Tamaoki, Takehira Yamamura
Journal: Journal of Clinical Oncology (2005)

Desmoid tumors are locally aggressive and can be fatal in familial adenomatous polyposis (FAP) patients if they are not suitable for surgery or radiation therapy. Here, we prospectively investigated the efficacy of a chemotherapeutic regimen involving doxorubicin (DOX) and dacarbazine (DTIC) for inoperable FAP-associated desmoid tumors.From an initial group of 120 FAP patients, seven of the 11 individuals with symptomatic unresectable desmoid tumors that were unresponsive to conventional hormone therapy were enrolled onto this study. The general chemotherapy regimen comprised four or five cycles of DOX (20 mg/m2 daily) plus DTIC (150 mg/m2 daily) throughout 4 days of drip intravenous infusion (day 1 through 4) every 28 days, followed by the cyclooxygenase-2 inhibitor meloxicam (10 mg/m2). The primary end point was relapse-free survival. The secondary end points included toxicity, clinical improvement, and tumor regression according to computed tomography.Significant tumor regression was observed clinically and radiologically in all seven patients. Three patients showed a complete response. The average progression-free survival period was 74.0 months (range, 32.5 to 107.5 months). Three patients showed grade 3 adverse events with no treatment-related mortality. All seven patients survived and remained without tumor progression. An adenomatous polyposis coli germline-mutation analysis revealed no mutations in the specified regions.A chemotherapeutic regimen of DOX plus DTIC followed by meloxicam is an effective and safe treatment for FAP-associated desmoid tumors. This modality should be considered for use as first-line chemotherapy in symptomatic desmoid tumors that are unresponsive to conventional medical therapy, due to the absence of useful presymptomatic markers.
βIV-Spectrin regulates TREK-1 membrane targeting in the heart
Authors: Thomas J. Hund, Jedidiah S. Snyder, Xiangqiong Wu, Patric Glynn, Olha M. Koval, Birce Onal, Nicholas D. Leymaster, Sathya D. Unudurthi, Jerry Curran, Celia Camardo, Patrick J. Wright, Philip F. Binkley, Mark E. Anderson, Peter J. Mohler
Journal: Cardiovascular Research (2014)

Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K+ channels have been well characterized in the heart, much less is known about regulation and/or targeting of two-pore K+ channel (K2P) family members, despite their potential importance in modulation of heart function. Here, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in the heart, and is required for TREK-1 membrane targeting. Mice expressing βIV-spectrin lacking TREK-1 binding (qv4J) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal βIV-spectrin levels in human heart failure. These data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.
What is the actual role of diagnosis and how to assess it: Reply
Authors: Shruti H. Mehta, Bryan Lau, Nezam H. Afdhal, David L. Thomas
Journal: Journal of Hepatology (2009)

To the Editor: Drs. Colli and Fraquelli underscore several important implications of our analysis of non-invasive liver fibrosis test validity [1Colli A. Fraquelli M. What is the actual role of diagnosis and how to assess it?.J Hepatol. 2009; 50: 828-829Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 2Mehta S.H. Lau B. Afdahl N.H. Thomas D.L. Exceeding the limits of liver histology markers.J Hepatol. 2009; 50: 36-41Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. The central finding is that limitations in the validity of an imperfect gold standard obviate precise characterization of the validity of surrogates. When applied to the liver biopsy, our calculations demonstrate that a perfect marker of liver fibrosis could not be distinguished from what many consider to be a clinically unacceptable one, unless the biopsy sensitivity and specificity are above 90%. The degree to which error in the biopsy might affect the apparent validity of a surrogate should always be considered in non-invasive marker research. Drs. Colli and Fraquelli make an excellent observation about the use of test results in medical management. Clinicians interpret a single test result in light of the outcome of other tests, their intrinsic validities, the pre-test probability of the condition, and many other considerations. Our study does not address the integration of these multiple factors but rather the simple interpretation of a substitute for a single test. A logical extension of our study would be to assess the performance of multiple diagnostic tests (e.g., serum marker panel and elastography). In addition, liver biopsy provides information on other factors like steatosis that cannot be ascertained from some non-invasive surrogates, and our computations do not account for these added diagnostic benefits. Likewise, Drs. Colli and Fraquelli correctly point out that our data showing the limitations in the traditional way that surrogate markers are evaluated does not answer the pressing clinical question of what to do when there is a difference. Fortunately, non-invasive markers are increasingly being assessed in clinical trials of hepatitis C treatment. Results of these studies, and others employing alternative 'gold standards' like the natural history of disease, will be necessary to improve our use of pre-treatment testing to manage patients with chronic hepatitis C.
Defective DNA Strand Break Repair after DNA Damage in Prostate Cancer Cells
Authors: Rong Fan, Tirukalikundram S. Kumaravel, Farid Jalali, Paula Marrano, Jeremy A. Squire, Robert G. Bristow
Journal: Cancer Research (2004)

Together with cell cycle checkpoint control, DNA repair plays a pivotal role in protecting the genome from endogenous and exogenous DNA damage. Although increased genetic instability has been associated with prostate cancer progression, the relative role of DNA double-strand break repair in malignant versus normal prostate epithelial cells is not known. In this study, we determined the RNA and protein expression of a series of DNA double-strand break repair genes in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145, and PC-3) prostate cultures. Expression of genes downstream of ATM after ionizing radiation-induced DNA damage reflected the p53 status of the cell lines. In the malignant prostate cell lines, mRNA and protein levels of the Rad51, Xrcc3, Rad52, and Rad54 genes involved in homologous recombination were elevated approximately 2- to 5-fold in comparison to normal PrEC cells. The XRCC1, DNA polymerase-beta and -delta proteins were also elevated. There were no consistent differences in gene expression relating to the nonhomologous end-joining pathway. Despite increased expression of DNA repair genes, malignant prostate cancer cells had defective repair of DNA breaks, alkali-labile sites, and oxidative base damage. Furthermore, after ionizing radiation and mitomycin C treatment, chromosomal aberration assays confirmed that malignant prostate cells had defective DNA repair. This discordance between expression and function of DNA repair genes in malignant prostate cancer cells supports the hypothesis that prostate tumor progression may reflect aberrant DNA repair. Our findings support the development of novel treatment strategies designed to reinstate normal DNA repair in prostate cancer cells.
The Use of Cylexin (CY-1503) in Prevention of Reperfusion Lung Injury in Patients Undergoing Pulmonary Thromboendarterectomy
Authors: KIM M. KERR, WILLIAM R. AUGER, JAMES J. MARSH, ROBERTA M. COMITO, REBEKAH L. FEDULLO, GERARD J. SMITS, DAVID P. KAPELANSKI, PETER F. FEDULLO, RICHARD N. CHANNICK, STUART W. JAMIESON, KENNETH M. MOSER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Pulmonary thromboendartectomy (PTE) for chronic thromboembolic pulmonary hypertension may be complicated by reperfusion lung injury. This has previously been demonstrated to be neutrophil-mediated. We postulated that blocking selectin-mediated adhesion of neutrophils to the endothelium with Cylexin (CY-1503) would prevent reperfusion lung injury in this patient population. In this double-blind, randomized, placebo-controlled, parallel study, 26 patients received Cylexin the day of surgery and 25 received placebo. Significantly fewer patients in the treated group (31%) compared with the placebo group (60%) developed lung injury (p = 0.036). However, the average number of days of mechanical ventilation, days in the intensive care unit (ICU) and hospital, as well as mortality were not significantly different between the treatment groups. Those with reperfusion lung injury had significantly elevated percent neutrophils, total protein, and soluble P-selectin in bronchoalveolar lavage fluid compared with those without lung injury. We conclude that reperfusion lung injury after PTE is a high-permeability lung injury and its incidence can be reduced by the administration of Cylexin on the day of surgery.
Association of LETM1 and MRPL36 Contributes to the Regulation of Mitochondrial ATP Production and Necrotic Cell Death
Authors: Longzhen Piao, Yuwen Li, Soung Jung Kim, Hee Sun Byun, Song Mei Huang, Soon-Kyung Hwang, Keum-Jin Yang, Kyeong Ah Park, Minho Won, Janghee Hong, Gang Min Hur, Jeong Ho Seok, Minho Shong, Myung-Haing Cho, Derek P. Brazil, Brian A. Hemmings, Jongsun Park
Journal: Cancer Research (2009)

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis.
Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis
Authors: Gang Liu, Shengjun Lu, Xuanjun Wang, Stephanie T. Page, Celestia S. Higano, Stephen R. Plymate, Norman M. Greenberg, Shaoli Sun, Zihai Li, Jennifer D. Wu
Journal: Journal of Clinical Investigation (2013)

The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cell–based cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization.
A child with painful legs
Authors: Paola Rosati, Renata Boldrini, Rita Devito, Antonio Menditto, Domenico Barbuti, Franco Nibbi, Sandro Mancini, Antonino Reale, Elettra Vignati, Massimo Romanini, Maria Iannelli, Maria Rosaria Marchili, Vincenzo Fierimonte, Marco Castelli, Luigi Vitale, Alberto Villani
Journal: The Lancet (2005)