tbuckley/cabot-search huggingface dataset:
EFFECT OF INSULIN ON CARBOHYDRATE METABOLISM AND ON POTASSIUM IN THE FOREARM OF MAN*
Authors: Reubin Andres, Marcel A. Baltzan, Gordon Cader, Kenneth L. Zierler
Journal: Journal of Clinical Investigation (1962)

We have described a technique for quantifying skeletal muscle metabolism in man in. situ by measing blood flow through the forearm and appropriate arteriovenous differences in concentration of selected metabolites ( 1 ). The technique lends itself to analysis of local effects of hormones and other possibly potent agents. The agent can be injected into the brachial artery at constant rate with the solution of Evans blue dye used to measure blood flow. The quantity of the agent injected can be sufficiently large to exert a measurable effect in the forearm but sufficiently small so that, upon approximately 100-fold dilution when forearm venous effluent mixes with blood in the heart and great vessels, there is no measurable systemic effect. There are, therefore, no detectable systemic counter-regulatory processes set in motion by the agent to complicate the primary response of the forearm to the agent itself. It is the purpose of this report to describe the effects on forearm muscle metabolism of insulin administered in this fashion. We sought information concerning the following two problems.
Dermal Patch with Integrated Flexible Heater for on Demand Drug Delivery
Authors: Sara Bagherifard, Ali Tamayol, Pooria Mostafalu, Mohsen Akbari, Mattia Comotto, Nasim Annabi, Masoumeh Ghaderi, Sameer Sonkusale, Mehmet R. Dokmeci, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2015)

Topical administration of drugs and growth factors in a controlled fashion can improve the healing process during skin disorders and chronic wounds. To achieve this goal, a dermal patch is engineered that utilizes thermoresponsive drug microcarriers encapsulated within a hydrogel layer attached to a flexible heater with integrated electronic heater control circuitry. The engineered patch conformally covers the wound area and enables controlled drug delivery by electronically adjusting the temperature of the hydrogel layer. The drugs are encapsulated inside microparticles in order to control their release rates. These monodisperse thermoresponsive microparticles containing active molecules are fabricated using a microfluidic device. The system is used to release two different active molecules with molecular weights similar to drugs and growth factors and their release profiles are characterized. This platform is a key step towards engineering smart and closed loop systems for topical applications.
Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts
Authors: Takeshi Yamamoto, Masafumi Yano, XiaoJuan Xu, Hitoshi Uchinoumi, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Shigeki Kobayashi, Noriaki Ikemoto, Masunori Matsuzaki
Journal: Circulation (2008)

Background— We previously demonstrated that defective interdomain interaction between N-terminal (0 to 600) and central regions (2000 to 2500) of ryanodine receptor 2 (RyR2) induces Ca 2+ leak in failing hearts and that K201 (JTV519) inhibits the Ca 2+ leak by correcting the defective interdomain interaction. In the present report, we identified the K201-binding domain and characterized the role of this novel domain in the regulation of the RyR2 channel. Methods and Results— An assay using a quartz-crystal microbalance technique (a very sensitive mass-measuring technique) revealed that K201 specifically bound to recombinant RyR2 fragments 1741 to 2270 and 1981 to 2520 but not to other RyR2 fragments from the 1 to 2750 region (1 to 610, 494 to 1000, 741 to 1260, 985 to 1503, 1245 to 1768, 2234 to 2750). By further analysis of the fragment 1741–2270 , K201 was found to specifically bind to its subfragment 2114–2149 . With the use of the peptide matching this subfragment (DP 2114–2149 ) as a carrier, the RyR2 was fluorescently labeled with methylcoumarin acetate (MCA) in a site-directed manner. After tryptic digestion, the major MCA-labeled fragment of RyR2 (155 kDa) was detected by an antibody raised against the central region (Ab 2132 ). Moreover, of several recombinant RyR2 fragments, only fragment 2234–2750 was specifically MCA labeled; this suggests that the K201-binding domain 2114–2149 binds with domain 2234–2750 . Addition of DP 2114–2149 to the MCA-labeled sarcoplasmic reticulum interfered with the interaction between domain 2114–2149 and domain 2234–2750 , causing domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In failing cardiomyocytes, the frequency of spontaneous Ca 2+ spark was markedly increased compared with normal cardiomyocytes, whereas incorporation of DP 2114–2149 markedly decreased the frequency of spontaneous Ca 2+ spark. Conclusions— We first identified the K201-binding site as domain 2114–2149 of RyR2. Interruption of the interdomain interaction between the domain 2114–2149 and central domain 2234–2750 seems to mediate stabilization of RyR2 in failing hearts, which may lead to a novel therapeutic strategy against heart failure and perhaps lethal arrhythmia.
The history of dermatology in the Sheffield region
Authors: RONALD CHURCH
Journal: British Journal of Dermatology (1974)

Journal Article The history of dermatology in the Sheffield region Get access RONALD CHURCH RONALD CHURCH The Hallamshire Hospital, Sheffield 10 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue 3, 1 September 1974, Pages 347–352, https://doi.org/10.1111/j.1365-2133.1974.tb12906.x Published: 01 September 1974 Article history Accepted: 31 December 1973 Published: 01 September 1974
Transgenic E2F1 Expression in the Mouse Brain Induces a Human-Like Bimodal Pattern of Tumors
Authors: Melissa V. Olson, David G. Johnson, Hong Jiang, Jing Xu, Marta M. Alonso, Kenneth D. Aldape, Gregory N. Fuller, B. Nebiyou Bekele, W.K. Alfred Yung, Candelaria Gomez-Manzano, Juan Fueyo
Journal: Cancer Research (2007)

The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb(+/-) mice suggests that loss of pRb induces brain tumors by activating E2F1. We therefore investigated the role of E2F1 in the development and maintenance of brain cancer using a transgenic mouse model engineered to express E2F1 specifically within glial cells (GFAP-tgE2F1). GFAP-tgE2F1 mice developed a highly penetrant phenotype characterized by neurologic defects, and examination of the brains revealed the presence of brain tumors in 20% of these animals. Importantly, the distribution of tumors according to mouse age suggests the existence of a bimodal pattern of tumor development, forcing a comparison with the human disease. Mice, at an early age, with deregulated E2F1 show the formation of embryonal brain tumors such as medulloblastoma, choroid plexus carcinoma, and primary neuroectodermal tumor. Conversely, at an older age, mice escaping embryonal tumor formation present with malignant gliomas, which are typically identified in the human adult population. Thus, this study offers the first evidence for a global role of E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogene in the brain.
Hepatitis C virus replication is inhibited by 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738) through enhancing interferon-β
Authors: Yoichi Hiasa, Hiroyuki Kuzuhara, Yoshio Tokumoto, Ichiro Konishi, Nobuyuki Yamashita, Bunzo Matsuura, Kojiro Michitaka, Raymond T. Chung, Morikazu Onji
Journal: Hepatology (2008)

A derivative of soyasapogenol, 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-α (IFN-α) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-β (IFN-β) and of IFN-stimulated genes (2′-5′ oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-β knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-α. Conclusion: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-β suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-α. ME3738 might be a useful anti-HCV drug either with or without IFN-α. (HEPATOLOGY 2008.)
Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma
Authors: Stephen P. Peters, Susan J. Kunselman, Nikolina Icitovic, Wendy C. Moore, Rodolfo Pascual, Bill T. Ameredes, Homer A. Boushey, William J. Calhoun, Mario Castro, Reuben M. Cherniack, Timothy Craig, Loren Denlinger, Linda L. Engle, Emily A. DiMango, John V. Fahy, Elliot Israel, Nizar Jarjour, Shamsah D. Kazani, Monica Kraft, Stephen C. Lazarus, Robert F. Lemanske, Njira Lugogo, Richard J. Martin, Deborah A. Meyers, Joe Ramsdell, Christine A. Sorkness, E. Rand Sutherland, Stanley J. Szefler, Stephen I. Wasserman, Michael J. Walter, Michael E. Wechsler, Vernon M. Chinchilli, Eugene R. Bleecker
Journal: New England Journal of Medicine (2010)

Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed.
RENAL HOMOTRANSPLANTATION IN RATS
Authors: Joseph D. Feldman, Sun Lee
Journal: The Journal of Experimental Medicine (1967)

Within 3-6 hr after the reestablishment of the circulation, a characteristic pathology developed in renal homotransplants. Blood monocytes and lymphocytes adhered to large thin-walled vessels of the septa carrying interlobular arteries, traversed their walls, and aggregated in the connective tissue spaces around them. Within 3 days, the number and size of the extravascular cells markedly increased, filling the septa completely and spreading from them centrifugally to occupy the intertubular spaces throughout the cortex. The composition of these aggregates at first was a mixture of lymphocytes and monocytes, and later consisted of large blast cells, macrophages, a few plasma cells, and polymorphonuclear leukocytes. Mitotic activity was seen 2 days after surgery among the large blast cells and increased to a maximal level a day later. Coevally with these changes, the thin-walled septal vessels, intertubular veins and capillaries, and finally, arteries and arterioles, in that order, were damaged. Focal injury of tubules was slight 24 hr after homografting; widespread cortical necrosis had developed 5-7 days later. At no time up to 7 days were concentrations of immunoglobulins detected by fluorescence microscopy in the transplanted kidneys. The morphologic manifestations and temporal sequences of renal homograft destruction suggested that several mechanisms acted synergistically to eliminate the transplant. The initial injury appeared to be the result of an interaction between host lymphoid cells and target endothelium, a phenomenon akin to allogeneic inhibition; followed by spreading ischemia; additional contact injury to tubules; and nonspecific inflammation associated with necrobiotic tissue.
Molecular analysis of argininosuccinate synthetase deficiency in human fibroblasts.
Authors: T S Su, H G Bock, A L Beaudet, W E O'Brien
Journal: Journal of Clinical Investigation (1982)

We have analyzed cultured skin fibroblasts derived from patients with argininosuccinate synthetase deficiency for alterations in gene structure, mRNA content, and protein structure. Genomic DNA was digested with the endonucleases EcoRI or HindIII, and the fragments were analyzed by Southern blotting and hybridization with a cDNA probe for argininosuccinate synthetase. The blot pattern is complex because there are at least 10 copies of argininosuccinate synthetase-like genes scattered over multiple human chromosomes. All nine patients studied showed patterns of DNA fragments that were indistinguishable from the normal control cell lines, and despite the possibility that the complexity could mask some changes, major deletions of the active gene(s) were not present. Blot hybridization of RNA indicated the presence of hybridizable mRNA of approximately normal size in seven of seven individuals examined with a suggestion of some heterogeneity. Analysis of enzyme antigen by protein transfer from NaDodSO4 containing polyacrylamide gels revealed considerable heterogeneity. This analysis revealed no cross-reacting material (CRM) in nine cell lines, CRM of normal molecular weight in one cell line, and CRM of reduced molecular weight in one cell line. These findings suggest that the genes for argininosuccinate synthetase in most citrullinemia patients are transcribed and produce stable mRNA. These mRNA either are not translated, or the translation product (enzyme) is rapidly degraded or is immunologically nonreactive. Defective gene expression in this disorder appears to involve abnormal mRNA, which may be altered by point mutations, frame shift mutations, deletions, insertions or particularly by abnormal RNA processing.
Dependence of the maximal lactate steady state on the motor pattern of exercise
Authors: R Beneke, R M Leithäuser, M Hütler
Journal: British Journal of Sports Medicine (2001)

Background —Blood lactate concentration (BLC) can be used to monitor relative exercise intensity. The highest BLC representing an equilibrium between lactate production and elimination is termed maximal lactate steady state (MLSS). MLSS is used to discriminate qualitatively between continuous exercise, which is limited by stored energy, from other types of exercise terminated because of disturbance of cellular homoeostasis. Aim —To investigate the hypothesis that MLSS intraindividually depends on the mode of exercise. Methods —Six junior male rowers (16.5 (1.4) years, 181.7 (3.1) cm, 69.8 (3.3) kg) performed incremental and constant load tests on rowing and cycle ergometers. Measurements included BLC, sampled from the hyperaemic ear flap, heart rate, and oxygen uptake. MLSS was defined as the highest BLC that increased by no more than 1.0 mmol/l during the final 20 minutes of constant workload. Results —In all subjects, MLSS was lower (p≤0.05) during rowing (2.7 (0.6) mmol/l) than during cycling (4.5 (1.0) mmol/l). No differences between rowing and cycling were found with respect to MLSS heart rate (169.2 (9.3) v 172.3 (6.7) beats/min), MLSS workload (178.7 (29.8) v 205.0 (20.7) W), MLSS intensity expressed as a percentage (63.3 (6.6)% v 68.6 (3.8)%) of peak workload (280.8 (15.9) v 299.2 (28.4) W) or percentage (76.4 (3.4)% v 75.1 (3.0)%) of peak oxygen uptake (60.4 (3.4) v 57.2 (8.6) ml/kg/min). Conclusions —In rowing and cycling, the MLSS but not MLSS workload and MLSS intensity intraindividually depends on the motor pattern of exercise. MLSS seems to decrease with increasing mass of the primarily engaged muscle. This indicates that task specific levels of MLSS occur at distinct levels of power output per unit of primarily engaged muscle mass.
Behavioral and Pharmacotherapy Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Women: U.S. Preventive Services Task Force Recommendation Statement
Authors: Albert L. Siu
Journal: Annals of Internal Medicine (2015)

Update of the 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on counseling and interventions to prevent tobacco use and tobacco-related disease in adults, including pregnant women.The USPSTF reviewed the evidence on interventions for tobacco smoking cessation that are relevant to primary care (behavioral interventions, pharmacotherapy, and complementary or alternative therapy) in adults, including pregnant women.This recommendation applies to adults aged 18 years or older, including pregnant women.The USPSTF recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and U.S. Food and Drug Administration-approved pharmacotherapy for cessation to adults who use tobacco. (A recommendation). The USPSTF recommends that clinicians ask all pregnant women about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant women who use tobacco. (A recommendation). The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of pharmacotherapy interventions for tobacco cessation in pregnant women. (I statement). The USPSTF concludes that the current evidence is insufficient to recommend electronic nicotine delivery systems for tobacco cessation in adults, including pregnant women. The USPSTF recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety (previously stated). (I statement).
Mitochondrial STAT3 Activation and Cardioprotection by Ischemic Postconditioning in Pigs With Regional Myocardial Ischemia/Reperfusion
Authors: Gerd Heusch, Judith Musiolik, Nilguen Gedik, Andreas Skyschally
Journal: Circulation Research (2011)

Rationale: Timely restoration of coronary blood flow is the only way to salvage myocardium from infarction, but reperfusion per se brings on additional injury. Such reperfusion injury and the resulting size of myocardial infarction is attenuated by ischemic postconditioning, ie, the repeated brief interruption of coronary blood flow during early reperfusion. The signal transduction of ischemic postconditioning is under intense investigation, but no signaling step has yet been identified as causal for such protection in larger mammals in situ. Objective: We have now in an in situ pig model of regional myocardial ischemia/reperfusion addressed the role of mitochondrial signal transducer and activator of transcription 3 (STAT3). Methods and Results: We demonstrated reduction of infarct size by ischemic postconditioning (26±3% of area at risk versus 38±2% in controls with immediate full reperfusion) along with more markedly increased tyrosine 705 phosphorylation of STAT3 in myocardial biopsies (at 10 minutes reperfusion: 9.2±3.0-fold from baseline versus 6.6±2.9-fold in controls with immediate full reperfusion). Increased tyrosine 705 phosphorylation of STAT3 and better preservation of complex 1 respiration and calcium retention capacity were also present in isolated mitochondria from postconditioned myocardium in vitro. Prior janus kinase/STAT inhibition with AG490 in vivo abrogated the infarct size reduction and the better preservation of mitochondrial function, and the STAT3 inhibitor Stattic in vitro also abrogated better preservation of mitochondrial function. Conclusions: Our data support a causal role for mitochondrial STAT3 activation to mediate cardioprotection through better mitochondrial function.
Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells
Authors: Yoshiyuki Takahashi, Nanae Harashima, Sachiko Kajigaya, Hisayuki Yokoyama, Elena Cherkasova, J. Philip McCoy, Ken-ichi Hanada, Othon Mena, Roger Kurlander, Tawab Abdul, Ramaprasad Srinivasan, Andreas Lundqvist, Elizabeth Malinzak, Nancy Geller, Michael I. Lerman, Richard W. Childs
Journal: Journal of Clinical Investigation (2008)

Transplanted donor lymphocytes infused during hematopoietic stem cell transplantation (HSCT) have been shown to cure patients with hematological malignancies. However, less is known about the effects of HSCT on metastatic solid tumors. Thus, a better understanding of the immune cells and their target antigens that mediate tumor regression is urgently needed to develop more effective HSCT approaches for solid tumors. Here we report regression of metastatic renal cell carcinoma (RCC) in patients following nonmyeloablative HSCT consistent with a graft-versus-tumor effect. We detected RCC-reactive donor-derived CD8+ T cells in the blood of patients following nonmyeloablative HSCT. Using cDNA expression cloning, we identified a 10-mer peptide (CT-RCC-1) as a target antigen of RCC-specific CD8+ T cells. The genes encoding this antigen were found to be derived from human endogenous retrovirus (HERV) type E and were expressed in RCC cell lines and fresh RCC tissue but not in normal kidney or other tissues. We believe this to be the first solid tumor antigen identified using allogeneic T cells from a patient undergoing HSCT. These data suggest that HERV-E is activated in RCC and that it encodes an overexpressed immunogenic antigen, therefore providing a potential target for cellular immunity.
Identification of Soluble NH2-Terminal Fragment of Glypican-3 as a Serological Marker for Early-Stage Hepatocellular Carcinoma
Authors: Yoshitaka Hippo, Kiyotaka Watanabe, Akira Watanabe, Yutaka Midorikawa, Shogo Yamamoto, Sigeo Ihara, Susumu Tokita, Hiroko Iwanari, Yukio Ito, Kiyotaka Nakano, Jun-ichi Nezu, Hiroyuki Tsunoda, Takeshi Yoshino, Iwao Ohizumi, Masayuki Tsuchiya, Shin Ohnishi, Masatoshi Makuuchi, Takao Hamakubo, Tatsuhiko Kodama, Hiroyuki Aburatani
Journal: Cancer Research (2004)

Abstract For detection of hepatocellular carcinoma (HCC) in patients with liver cirrhosis, serum α-fetoprotein has been widely used, but its sensitivity has not been satisfactory, especially in small, well-differentiated HCC, and complementary serum marker has been clinically required. Glypican-3 (GPC3), a heparan sulfate proteoglycan anchored to the plasma membrane, is a good candidate marker of HCC because it is an oncofetal protein overexpressed in HCC at both the mRNA and protein levels. In this study, we demonstrated that its NH2-terminal portion [soluble GPC3 (sGPC3)] is cleaved between Arg358 and Ser359 of GPC3 and that sGPC3 can be specifically detected in the sera of patients with HCC. Serum levels of sGPC3 were 4.84 ± 8.91 ng/ml in HCC, significantly higher than the levels seen in liver cirrhosis (1.09 ± 0.74 ng/ml; P &amp;lt; 0.01) and healthy controls (0.65 ± 0.32 ng/ml; P &amp;lt; 0.001). In well- or moderately-differentiated HCC, sGPC3 was superior to α-fetoprotein in sensitivity, and a combination measurement of both markers improved overall sensitivity from 50% to 72%. These results indicate that sGPC3 is a novel serological marker essential for the early detection of HCC.