tbuckley/cabot-search huggingface dataset:
Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease
Authors: Sebastiano Sciarretta, Massimo Volpe, Junichi Sadoshima
Journal: Circulation Research (2014)

The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacological and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction, and reduce cardiac derangements caused by metabolic disorders. The optimal therapeutic strategy to target mTORC1 and increase cardioprotection is under intense investigation. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states.
Challenges and Advances in the Treatment of AKI
Authors: Gur P. Kaushal, Sudhir V. Shah
Journal: Journal of the American Society of Nephrology (2014)

Treating or preventing AKI requires treating or preventing a rise in serum creatinine as well as the immediate and remote clinical consequences associated with AKI. Because a substantial number of patients with AKI progress to ESRD, identifying patients likely to progress and halting progression are important goals for treating AKI. Many therapies for AKI are being developed, including RenalGuard Therapy, which aims to maintain high urine output; α-melanocyte-stimulating hormone, with anti-inflammatory and antiapoptotic activities; alkaline phosphatase, which detoxifies proinflammatory substances; novel, small interfering RNA, directed at p53 activation; THR-184, a peptide agonist of bone morphogenetic proteins; removal of catalytic iron, important in free-radical formation; and cell-based therapies, including mesenchymal stem cells in vivo and renal cell therapy in situ. In this review, we explore what treatment of AKI really means, discuss the emerging therapies, and examine the windows of opportunity for treating AKI. Finally, we provide suggestions for accelerating the pathways toward preventing and treating AKI, such as establishing an AKI network, implementing models of catalytic philanthropy, and directing a small percentage of the Medicare ESRD budget for developing therapies to prevent and treat AKI and halt progression of CKD.
Stage-Adapted Treatment of HIV-Associated Hodgkin Lymphoma: Results of a Prospective Multicenter Study
Authors: Marcus Hentrich, Marcel Berger, Christoph Wyen, Jan Siehl, Jürgen K. Rockstroh, Markus Müller, Gerd Fätkenheuer, Elisabeth Seidel, Maike Nickelsen, Timo Wolf, Ansgar Rieke, Dirk Schürmann, Ralf Schmidmaier, Manfred Planker, Jürgen Alt, Franz Mosthaf, Andreas Engert, Keikawus Arasteh, Christian Hoffmann
Journal: Journal of Clinical Oncology (2012)

Purpose Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL. Patients and Methods Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD. Results Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%). Conclusion In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.
Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: New perspectives for immune therapy
Authors: Carolina Boni, Amalia Penna, Graham S. Ogg, Antonio Bertoletti, Massimo Pilli, Cristina Cavallo, Albertina Cavalli, Simona Urbani, Richard Boehme, Ruggero Panebianco, Franco Fiaccadori, Carlo Ferrari
Journal: Hepatology (2001)

The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an important objective of immune therapies for chronic hepatitis B. However, amplification of CTL responses in vivo may be ineffective if HBV–specific CD8 cells are either absent or nonresponsive to exogenous stimulation. In this study, we asked whether antiviral treatments able to inhibit viral replication and to reduce viral and antigen load can successfully reconstitute CTL responses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV–specific CTL response before and during lamivudine therapy was studied longitudinally in 6 HLA–A2-positive patients with HBeAg+ chronic hepatitis B. Both HBV–specific cytotoxic T cell activity measured by chromium release assay on peptide stimulation in vitro and CD8+ T cell frequency measured ex vivo by HLA–A2/peptide tetramer staining were significantly augmented by lamivudine therapy. This enhancement followed the reconstitution of CD4 reactivity and the decline of viral load induced by therapy. Our study shows that lamivudine treatment in chronic hepatitis B can restore CTL reactivity, making CTL susceptible to exogenous stimulation. This effect may enhance the probability that T cell–based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection. (Hepatology 2001;33:963–971.)
Long-Term Clinical Protection from Falciparum Malaria Is Strongly Associated with IgG3 Antibodies to Merozoite Surface Protein 3
Authors: Christian Roussilhon, Claude Oeuvray, Christine Müller-Graf, Adama Tall, Christophe Rogier, Jean-François Trape, Michael Theisen, Aissatou Balde, Jean-Louis Pérignon, Pierre Druilhe
Journal: PLoS Medicine (2007)

Background Surrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite) to molecules that are considered as valuable vaccine candidates. Methods and Findings We analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults). The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3), was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week). Finally, the target epitopes of these antibodies were found to be fully conserved. Conclusions Since anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be possible to elicit by vaccination early in life. Since these antibodies have been found to achieve parasite killing under in vitro and in vivo conditions, and since they can be readily elicited by immunisation in naïve volunteers, our immunoepidemiological findings support the further development of MSP3-based vaccine formulations.
Clinical Lectures on Dislocations, Delivered at the Charing Cross Hospital. Summer Session, 1844
Authors: H. Hancock
Journal: BMJ (1844)

J.Havding the ece4ing lectures described.to you tIne noiou trqturW hi ente.rinto the iormation fthtjoi hi hoidout to you their charac- t9, m,is d4inion, vi will now pass on to t ItIa4 those accidentsoccurring to joints, wjere,bom,hqihuln.`surfaces of the bones being of4, i i propcw sinbatin4 thV constitut tlepO tif, 9, net4.sloton.o)3 p~e iep, +"vffis,l4 i 3ugta ¶ed accoZrd- i,~*$degp e ojp wen * t)~vo1<ge donxe to the s# q sdto of tebones.lent,e the ed complete, incomplete, simple, com- pounJ;'nd -mplicaited.A itoknplete dhdidcation is where the articulating process of one bone is entirely tbrown out of itsimturl tuation^, so as no longer to be in conact with' the irtceIaesrfact with which itit aturallW'conneted.Ththbhsd of ti*e himerusais tht6wnb&6 the axifla it sw 41 .ogrnrIn contact with the glanoid canity of she se*ai, hitis " completely dislocated."An incom- $ete dislocation iswhen the articdar surfaces, although to a certain extent displaced, remain partially in con-
A rare cause of weight loss
Authors: Paul K Flanagan, Sarah E Coupland, Arvind Arumainathan, Chris S J Probert
Journal: Gut (2013)

<b>Objectives:</b> The study investigated the effectiveness in increasing seat belt use of Ford’s belt reminder system, a supplementary system that provides intermittent flashing lights and chimes for five minutes if drivers are not belted. <b>Methods:</b> Seat belt use of drivers in relatively new cars with and without the reminder system was unobtrusively observed as vehicles were brought to dealerships for service. <b>Results:</b> Overall use rates were estimated at 71% for drivers in vehicles without the reminder system and 76% for drivers in vehicles with belt reminders (p&lt;0.01). <b>Conclusions:</b> Seat belt use is relatively low in the United States. The present study showed that vehicle based reminder systems can be at least modestly effective in increasing belt use, which may encourage further development of such systems.
Immune regulation by intralymphatic immunotherapy with modular allergen translocation <scp>MAT</scp> vaccine
Authors: A. Zaleska, T. Eiwegger, Ö. Soyer, W. van de Veen, C. Rhyner, M. B. Soyka, C. Bekpen, D. Demiröz, A. Treis, S. Söllner, O. Palomares, W. W. Kwok, H. Rose, G. Senti, T. M. Kündig, N. Ozoren, M. Jutel, C. A. Akdis, R. Crameri, M. Akdis
Journal: Allergy (2014)

Abstract Background Allergen‐specific immunotherapy ( SIT ) faces problems related to side effects and limited efficacy. Direct administration of allergen extracts into lymph nodes induces increased specific IgG production and T‐cell responses using significantly lower allergen doses. Methods In this study, mechanisms of immune regulation by MAT vaccines in vitro and in allergen‐ SIT of cat‐allergic rhinitis patients, who received 3 inguinal intra‐lymph node injections of MAT ‐Fel d 1 vaccine, were investigated in PBMC and cell cultures for specific T‐cell proliferation, Fel d 1‐tetramer‐specific responses, and multiple immune regulatory molecules. Results MAT ‐Fel d 1 vaccine was efficiently internalized by antigen‐presenting cells. This was followed by precaspase 1 cleavage to caspase 1 and secretion of IL ‐1β, indicating inflammasome activation. Mat‐Fel d 1 induced specific T‐cell proliferation and an IL ‐10‐ and IFN ‐γ‐dominated T‐cell responses with decreased Th2 cytokines at 100 times lower doses than Fel d 1. Induction of immune tolerance by MAT ‐Fel d 1‐ ILIT involved multiple mechanisms of immune suppression. Early Fel d 1‐specific T‐cell activation was followed by full T‐cell unresponsiveness to allergen after 1 year in the MAT ‐Fel d 1 group, characterized by increased allergen‐specific T regulatory cells, decreased circulating Fel d 1 tetramer‐positive cells, increased IL ‐10 and FOXP 3 expression, and change in the HR 2/ HR 1 ratio toward HR 2. Conclusions This study demonstrates the induction of allergen tolerance after 3 intra‐lymph node injections of MAT ‐Fel d 1 vaccine, mediated by increased cellular internalization of the allergen, activation of inflammasome, and generation of allergen‐specific peripheral T‐cell tolerance.
Aplasia cutis congenita with dystrophic epidermolysis bullosa: clinical and mutational study
Authors: C. Chiaverini, A. Charlesworth, A. Fernandez, S. Barbarot, D. Bessis, C. Bodemer, A.-C. Bursztejn, A.-M. Cobo, M. Del Rio, M. D'Incan, C. Labrèze, C. Langlet, J. Mazereeuw, J. Miquel, P. Vabres, G. Meneguzzi, J.-P. Lacour
Journal: British Journal of Dermatology (2013)

Aplasia cutis congenita (ACC) has been associated with all clinical forms of inherited epidermolysis bullosa (EB), including dominant and recessive dystrophic EB (DDEB and RDEB). To date, only a few patients with DEB specifically combined with ACC have been described and genotyped and almost all cases represent dominant forms of the condition.The aim of this study was to describe new mutations of COL7A1 in patients with DEB and ACC and investigate possible genotype-phenotype correlations.Twenty-two patients with DEB and ACC were included among the 123 patients with DEB whose COL7A1 mutations have been identified in the Reference Centre in Nice.Seven patients presented a severe generalized RDEB phenotype (RDEB-sev-gen), while the other 15 suffered from milder phenotypes. We identified 28 mutations in COL7A1, of which nine are novel. Patients with severe phenotypes have mostly mutations leading to premature termination codon (PTC) and/or splice-site or missense mutations. Patients with the milder phenotypes have mostly glycine or arginine substitutions associated or not with other types of mutations. All amino acid substitutions fell within the carboxyl portion of the triple helix domain (THD) of collagen VII, close to the THD interruptions.Our findings suggest that ACC is a frequent manifestation in patients with DEB irrespective of the severity of the disease, and is due to leg rubbing in utero. In children with a moderate form of DEB with no or moderate skin fragility, a glycine substitution near the THD interruption domain of the collagen VII leading to thermolabile protein could explain this phenomenon.
Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting.
Authors: C S Greenberg, C C Miraglia, F R Rickles, M A Shuman
Journal: Journal of Clinical Investigation (1985)

Thrombin cleavage of blood coagulation Factor XIII (a2b2) and fibrinogen was studied during in vitro clotting to determine the physiologic sequence of these events. First, the time course of fibrin formation and cleavage of Factor XIII was measured in platelet-rich plasma. Cleavage of fibrinogen was measured by using a radioimmunoassay for fibrinopeptide A. Conversion of trace amounts of radioiodinated a-chains of 125I-Factor XIII to thrombin-modified a-chains was measured in unreduced 10% sodium dodecyl sulfate-polyacrylamide gels. During spontaneous clotting, a similar percentage of 125I-Factor XIII and fibrinogen was cleaved at each time point. Visible gelation of polymerized fibrin monomer occurred when 24 +/- 8% of fibrinogen was cleaved and 21 +/- 6% of Factor XIII was converted to Factor XIII'. Thrombin cleavage of Factor XIII and fibrinogen was also studied in platelet-poor plasma to which thrombin was added. In order to measure Factor XIIIa activity, fibrin polymerization was completely inhibited by the addition of Gly-Pro-Arg-Pro. Factor XIIIa formation was measured by the incorporation of [3H]putrescine into casein. The concentration of added thrombin required to cleave 50% of fibrinogen and Factor XIII was 0.65 U/ml and 0.35 U/ml, respectively. The rate of cleavage of fibrinogen by thrombin was 43-fold greater than cleavage of Factor XIII. Lower Gly-Pro-Arg-Pro concentrations were used to determine the effects of incompletely inhibiting fibrin polymerization on cleavage of Factor XIII and fibrinogen. Thrombin cleavage of Factor XIII but not fibrinogen was dependent on the extent of fibrin polymerization. The more marked the degree of inhibition of fibrin polymerization, the slower the rate of Factor XIIIa formation. Thus, in platelet-rich plasma, thrombin cleavage of Factor XIII and fibrinogen are closely related events during spontaneous clotting. Furthermore, cleavage of Factor XIII during clotting is enhanced by fibrin polymerization in platelet-poor plasma.
Extracellular Signal-Regulated Kinase Positively Regulates the Oncogenic Activity of MCT-1 in Diffuse Large B-Cell Lymphoma
Authors: Bojie Dai, X. Frank Zhao, Patrick Hagner, Paul Shapiro, Krystyna Mazan-Mamczarz, Shuchun Zhao, Yasodha Natkunam, Ronald B. Gartenhaus
Journal: Cancer Research (2009)

Abstract The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal-regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor–induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis. [Cancer Res 2009;69(19):7835–43]
FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature
Authors: Amélie Sabine, Esther Bovay, Cansaran Saygili Demir, Wataru Kimura, Muriel Jaquet, Yan Agalarov, Nadine Zangger, Joshua P. Scallan, Werner Graber, Elgin Gulpinar, Brenda R. Kwak, Taija Mäkinen, Inés Martinez-Corral, Sagrario Ortega, Mauro Delorenzi, Friedemann Kiefer, Michael J. Davis, Valentin Djonov, Naoyuki Miura, Tatiana V. Petrova
Journal: Journal of Clinical Investigation (2015)

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.
Dependence of Immediate Hypersensitivity in the Adolescent Period on Factors Encountered in Infancy
Authors: Ilpo Suoniemi, Fred Björkstén, Tari Haahtela
Journal: Allergy (1981)

708 unselected adolescents 15–17 years old were studied. They were physically examined, interviewed and skin prick tested with 12 common allergens. Questionnaires were distributed to the adolescents and their parents to investigate past and present symptoms and environmental influences. Emphasis was on the first year of life. Exposition to allergens (pollens and cat epithelium) during the first 6 months of life, eczema during the First year of life, and atopic heredity were found to be major risk factors in die development of positive skin tests and respiratory allergy apparent in the teenage period. Infections and wheezing during the first year of life were also risk factors, but less important.
Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial
Authors: Yu Jo Chua, Yolanda Barbachano, David Cunningham, Jacqui R Oates, Gina Brown, Andrew Wotherspoon, Diana Tait, Alison Massey, Niall C Tebbutt, Ian Chau
Journal: The Lancet Oncology (2010)