tbuckley/cabot-search huggingface dataset:
Modulation of Cell-Mediated Alloimmunity by BCG. I. Antagonism and Potentiation of Immunosuppression Caused by Cytarabine&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: R I Murahata, M S Mitchell
Journal: JNCI Journal of the National Cancer Institute (1982)

The ability of iv administered BCG to antagonize immunosuppression caused by injection of the antimetabolite cytarabine (beta-cytosine arabinoside; ara-C) was investigated in C57BL/6 mice. Treatment with BCG 10 days before alloimmunization with killed L1210 tumor cells decreased spleen T-cell-mediated cytolysis against allogeneic P815Y tumor cells, as measured by a short-term 51Cr release assay, and potentiated immunosuppression due to ara-C. In contrast, spleen cell-mediated immunity (CMI) that was assayed by a 48-hour microcytotoxicity assay (MCA) was augmented by systemic BCG administered before alloimmunization. Pretreatment with BCG resulted in a complete and long-lasting protection against the immunosuppressive effects of ara-C on this CMI as measured by the MCA. Treatment with BCG after cytoreductive therapy resulted in a significant, although transient, reversal of immunosuppression. Depending on the type of response and thus the type of effector cell measured, BCG acts as a moderate immunosuppressive agent or a strong immunopotentiator of CMI.
<i>CDKN2B</i> Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma
Authors: Andrew S. McNeal, Kevin Liu, Vihang Nakhate, Christopher A. Natale, Elizabeth K. Duperret, Brian C. Capell, Tzvete Dentchev, Shelley L. Berger, Meenhard Herlyn, John T. Seykora, Todd W. Ridky
Journal: Cancer Discovery (2015)

Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here, we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E)-activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Furthermore, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma.Although BRAF(V600E) mutations cause melanocytes to initially proliferate into benign moles, mechanisms responsible for their eventual growth arrest are unknown. Using melanocytes from human moles, we show that BRAF activation leads to a CDKN2B induction that is critical for restraining BRAF oncogenic effects, and when lost, contributes to melanoma.
The American General Practitioner in Hospital
Authors: A. J. M. Cavenagh
Journal: BMJ (1971)

In the U.S.A. and Canada full access of general practitioners to hospital beds and facilities is regarded as an essential privilege of their work. All hospital constitutions require a review of the credentials of staff applicants and continuing evaluation of their performance. Staff appointment carries administrative as well as clinical responsibilities and hospital work occupies a considerable proportion of the general practitioner's day. The disciplinary machinery for safeguarding standards is strict by comparison with British hospital practice.This system produces an obvious excellence of clinical standards, postgraduate education, and communication between specialist and general practitioner and is attractive to the more able young British graduate. A pilot experiment of hospital staffing on North American lines in one of our new district general hospitals would be a worthwhile proposition.
Stretch-induced modifications of myocardial performance: from ventricular function to cellular and molecular mechanisms
Authors: B. Crozatier
Journal: Cardiovascular Research (1996)

The purpose of this review is to give an integrative view of the effect of stretch on the myocardium from ventricular function changes to cellular and molecular mechanisms. The general approach will be to discuss the cellular and molecular events which can explain the findings obtained in the whole ventricle. Following the historical development, the classical analysis of the Starling mechanism and the basis of the length-dependent process are rapidly reviewed. We then analyze in greater detail the recent findings on the mechanisms of length-dependent activation changes in contractile protein affinity for calcium, changes in intracellular calcium release, action potential changes and stretch-activated ion channels and discuss the opposite effects of stretch on ventricular contraction (mainly deactivation shortening and viscoelastic properties of the myocardium). Besides the short-term contractile response to stretch, the longer-term effects of myocardial stretch which lead to ventricular hypertrophy will be also rapidly reviewed.
On the nature of Mycobacterium tuberculosis-latent bacilli
Authors: P-J. Cardona, J. Ruiz-Manzano
Journal: European Respiratory Journal (2004)

Mycobacterium tuberculosis -latent bacilli are microorganisms that adaptto stressful conditions generated by the infected host against them. By slowing metabolism or becoming dormant, they may counterbalance these conditions and appear as silent to the immune system. Moreover, the dynamic turnover of the infected cells provokes a constant reactivation of the latent bacilli when the environmental conditions are favourable, or an activation after being dormant in necrotic and fibrotic lesions for a long period of time. Since there is no in vivo nor in vitro evidence for quick resuscitation of dormant bacilli, the current authors strongly favour the possibility that latent tuberculosis infection can be maintained for no longer than ∼10 yrs, which is, nowadays, a time period very close to that considered for “primary” tuberculosis. This concept may also be helpful for newer epidemiological considerations regarding the real impact of reinfection in tuberculosis.
Induction of Lymphocyte Apoptosis by Tumor Cell Secretion of FasL-bearing Microvesicles
Authors: Giovanna Andreola, Licia Rivoltini, Chiara Castelli, Veronica Huber, Paola Perego, Paola Deho, Paola Squarcina, Paola Accornero, Francesco Lozupone, Luana Lugini, Annarita Stringaro, Agnese Molinari, Giuseppe Arancia, Massimo Gentile, Giorgio Parmiani, Stefano Fais
Journal: The Journal of Experimental Medicine (2002)

The hypothesis that FasL expression by tumor cells may impair the in vivo efficacy of antitumor immune responses, through a mechanism known as ‘Fas tumor counterattack,’ has been recently questioned, becoming the object of an intense debate based on conflicting results. Here we definitely show that FasL is indeed detectable in the cytoplasm of melanoma cells and its expression is confined to multivesicular bodies that contain melanosomes. In these structures FasL colocalizes with both melanosomal (i.e., gp100) and lysosomal (i.e., CD63) antigens. Isolated melanosomes express FasL, as detected by Western blot and cytofluorimetry, and they can exert Fas-mediated apoptosis in Jurkat cells. We additionally show that melanosome-containing multivesicular bodies degranulate extracellularly and release FasL-bearing microvesicles, that coexpress both gp100 and CD63 and retain their functional activity in triggering Fas-dependent apoptosis of lymphoid cells. Hence our data provide evidence for a novel mechanism potentially operating in Fas tumor counterattack through the secretion of subcellular particles expressing functional FasL. Such vesicles may form a sort of front line hindering lymphocytes and other immunocompetent cells from entering neoplastic lesions and exert their antitumor activity.
LONG-TIME-SCALE HEART RATE DYNAMICS DETECTED BY PHASE-RECTIFIED SIGNAL AVERAGING PREDICTS MORTALITY AFTER ACUTE MYOCARDIAL INFARCTION
Authors: Masaya Kisohara, Mari Suzuki, Narushi Iizuka, Robert Carney, Phyllis Stein, Lana L. Watkins, Kenneth Freedland, James Blumenthal, Junichiro Hayano
Journal: Journal of the American College of Cardiology (2012)
Biomaterials to Enhance Stem Cell Function in the Heart
Authors: Vincent F.M. Segers, Richard T. Lee
Journal: Circulation Research (2011)

Transplantation of stem cells into the heart can improve cardiac function after myocardial infarction and in chronic heart failure, but the extent of benefit and of reproducibility of this approach are insufficient. Survival of transplanted cells into myocardium is poor, and new strategies are needed to enhance stem cell differentiation and survival in vivo. In this review, we describe how biomaterials can enhance stem cell function in the heart. Biomaterials can mimic or include naturally occurring extracellular matrix and also instruct stem cell function in different ways. Biomaterials can promote angiogenesis, enhance engraftment and differentiation of stem cells, and accelerate electromechanical integration of transplanted stem cells. Biomaterials can also be used to deliver proteins, genes, or small RNAs together with stem cells. Furthermore, recent evidence indicates that the biophysical environment of stem cells is crucial for their proliferation and differentiation, as well as their electromechanical integration. Many approaches in regenerative medicine will likely ultimately require integration of molecularly designed biomaterials and stem cell biology to develop stable tissue regeneration.
Benefit from the inclusion of self-treatment guidelines to a self-management programme for adults with asthma
Authors: J.J. Klein, J. van der Palen, S.M. Uil, G.A. Zielhuis, E.R. Seydel, C.L.A. van Herwaarden
Journal: European Respiratory Journal (2001)

This study assessed the long-term efficacy of adding self-treatment guidelines to a self-management programme for adults with asthma. In this prospective randomized controlled trial, 245 patients with stable, moderate to severe asthma were included. They were randomized into a self-treatment group (group S) and a control group (group C). Both groups received self-management education. Additionally, group S received self-treatment guidelines based on peak expiratory flow (PEF) and symptoms. Outcome parameters included: asthma symptoms, quality of life, pulmonary function, and exacerbation rate. The 2‐yr study was completed by 174 patients. Both groups showed an improvement in the quality of life of 7%. PEF variability decreased by 32% and 29%, and the number of outpatient visits by 25% and 18% in groups S and C, respectively. No significant differences in these parameters were found between the two groups. After 1 yr, patients in both groups perceived better control of asthma and had more self-confidence regarding their asthma. The latter improvements were significantly greater in group S as compared to group C. There were no other differences in outcome parameters between the groups. Individual self-treatment guidelines for exacerbations on top of a general self-management programme does not seem to be of additional benefit in terms of improvements in the clinical outcome of asthma. However, patients in the self-treatment group had better scores in subjective outcome measures such as perceived control of asthma and self-confidence than patients in the control group.
The gut-joint axis: cross reactive food antibodies in rheumatoid arthritis
Authors: M Hvatum
Journal: Gut (2006)

Patients with rheumatoid arthritis (RA) often feel there is an association between food intake and rheumatoid disease severity. To investigate a putative immunological link between gut immunity and RA, food antibodies were measured in serum and perfusion fluid from the jejunum of RA patients and healthy controls to determine the systemic and mucosal immune response.IgG, IgA, and IgM antibodies to dietary antigens were measured in serum and jejunal perfusion fluid from 14 RA patients and 20 healthy subjects. The antigens originated from cow's milk (alpha-lactalbumin, beta-lactoglobulin, casein), cereals, hen's egg (ovalbumin), cod fish, and pork meat.In intestinal fluid of many RA patients, all three immunoglobulin classes showed increased food specific activities. Except for IgM activity against beta-lactoglobulin, all other IgM activities were significantly increased irrespective of the total IgM level. The RA associated serum IgM antibody responses were relatively much less pronounced. Compared with IgM, the intestinal IgA activities were less consistently raised, with no significant increase against gliadin and casein. Considerable cross reactivity of IgM and IgA antibodies was documented by absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in RA patients. Three of the five RA patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies; these became normalised after treatment, but clinical improvement was better reflected in a reduced erythrocyte sedimentation rate.The production of cross reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints.
Allograft Biopsies
Authors: Isaac E. Stillman, Martha Pavlakis
Journal: Journal of the American Society of Nephrology (2009)

Advances in short-term renal allograft survival, as a result in large part of the use of calcineurin inhibitors (CNIs), have not translated into increased organ longevity.1 For decades, researchers have tried to uncover the pathogenesis of chronic graft failure using histopathologic examination of human biopsies. Despite these efforts, biopsy evaluation in the setting of chronic graft failure is often a frustrating experience for nephrologist and nephropathologist alike. There is consensus that the most frequent biopsy findings in long-term graft failure (censored for death) result from cumulative injuries to the graft, which produce a pathologic pattern of scarring involving all renal compartments.2 Controversy over the term used to describe these findings (chronic allograft nephropathy versus interstitial fibrosis and tubular atrophy (IF/TA) is less important than the recognition that the dominant changes seen by routine microscopy represent a nonspecific common injury pathway, not a diagnosis, and that in most of those biopsies we lack the ability to determine the underlying cause.3

There are many reasons for this imprecision, such as preexisting structural damage, the effects of comorbid conditions, and the structure/function interdependence of the renal compartments. Furthermore, comparisons across time and place are limited by the fact that every biopsy bears the imprint of the patient's individual immunosuppression protocol. Nevertheless, significant progress has been made in identifying many of the underlying processes, and donor age and chronic CNI toxicity both emerge as major nonimmunologic factors.4–6 Distinguishing the histopathology of these two processes from other causes of chronic injury, as well as from each other, is difficult, particularly in …
Response to Letter Regarding Article, “Myocardial Injury After Noncardiac Surgery and Its Association With Short-Term Mortality”
Authors: Judith A.R. van Waes, Hendrik M. Nathoe, Jurgen C. de Graaff, Hans Kemperman, Gert Jan de Borst, Linda M. Peelen, Wilton A. van Klei
Journal: Circulation (2014)
Longitudinal Stability of Genetic and Environmental Influences on Irritability: From Childhood to Young Adulthood
Authors: Roxann Roberson-Nay, Ellen Leibenluft, Melissa A. Brotman, John Myers, Henrik Larsson, Paul Lichtenstein, Kenneth S. Kendler
Journal: American Journal of Psychiatry (2015)

Little is known about genetic influences on juvenile irritability and whether such influences are developmentally stable and/or dynamic. This study examined the temporal pattern of genetic and environmental effects on irritability using data from a prospective, four-wave longitudinal twin study.Parents and their twin children (N=2,620 children) from the Swedish Twin Study of Child and Adolescent Development reported on the children's irritability, defined using a previously identified scale from the Child Behavior Checklist.Genetic effects differed across the sexes, with males exhibiting increasing heritability from early childhood through young adulthood and females exhibiting decreasing heritability. Genetic innovation was also more prominent in males than in females, with new genetic risk factors affecting irritability in early and late adolescence for males. Shared environment was not a primary influence on irritability for males or females. Unique, nonshared environmental factors suggested strong effects early for males followed by an attenuating influence, whereas unique environmental factors were relatively stable for females.Genetic effects on irritability are developmentally dynamic from middle childhood through young adulthood, with males and females displaying differing patterns. As males age, genetic influences on irritability increase while nonshared environmental influences weaken. Genetic contributions are quite strong in females early in life but decline in importance with age. In girls, nonshared environmental influences are fairly stable throughout development.
Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase–Transgenic Mice
Authors: Anne Garnier, Jennifer K. Bendall, Sebastien Fuchs, Brigitte Escoubet, Francesca Rochais, Jacqueline Hoerter, Johnny Nehme, Marie-Lory Ambroisine, Noeleen De Angelis, Gilles Morineau, Pauline d’Estienne, Rodolphe Fischmeister, Christophe Heymes, Florence Pinet, Claude Delcayre
Journal: Circulation (2004)

Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear.Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the alpha-myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT1 and AT2 receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (-55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production.Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.
Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial
Authors: Thomas Elter, Liana Gercheva-Kyuchukova, Halyna Pylylpenko, Tadesuz Robak, Branimir Jaksic, Grigoriy Rekhtman, Sławomira Kyrcz-Krzemień, Mykola Vatutin, Jingyang Wu, Cynthia Sirard, Michael Hallek, Andreas Engert
Journal: The Lancet Oncology (2011)
Nutlin3 Blocks Vascular Endothelial Growth Factor Induction by Preventing the Interaction between Hypoxia Inducible Factor 1α and Hdm2
Authors: Gretchen A. LaRusch, Mark W. Jackson, James D. Dunbar, Robert S. Warren, David B. Donner, Lindsey D. Mayo
Journal: Cancer Research (2007)

Abstract Hdm2 is elevated in numerous types of malignancies and is thought to impede the function of wild-type p53. Reactivation of p53 by disrupting the association with Hdm2 was the impetus for the development of Nutlin3. Although regulation of p53 has been the central focus of Hdm2 activity, it also binds other proteins through its p53-binding domain. Here, we show that hypoxia-inducible factor 1α (HIF1α) binds to Hdm2 in the domain designated to bind p53. HIF1α and p53 share a conserved motif that is required to bind Hdm2. Distinct complexes form between Hdm2-HIF1α and Hdm2-p53 as determined by immunoprecipitation of nuclear extracts and in vitro. The Hdm2 antagonist Nutlin3 prevents the association between Hdm2 and HIF1α. The vascular endothelial growth factor (VEGF) gene is a transcriptional target of HIF1α, and under normoxic or hypoxic conditions, Hdm2 increases HIF1α activity to induce VEGF production. Blocking the association of Hdm2 and HIF1α by Nutlin3, or ablating Hdm2 expression, diminished the level of VEGF under conditions of normoxia or hypoxia. Our findings establish a unique role for Nutlin3 in attenuating VEGF induction by preventing the association of Hdm2 with HIF1α. [Cancer Res 2007;67(2):450–4]
Randomised, blinded, placebo controlled trial of doxycycline for chronic seronegative arthritis
Authors: M Smieja
Journal: Annals of the Rheumatic Diseases (2001)

To determine whether long term doxycycline improves symptoms in patients with chronic seronegative or reactive arthritis.A randomised, triple blind, controlled clinical trial of three months' treatment with doxycycline or placebo of patients with chronic reactive or seronegative arthritis was conducted. The primary study end points were three month pain and functional status measured by a self administered Arthritis Impact Measurement Scales version 2 (AIMS2) quality of life questionnaire. Secondary end points were pain and functional status at 6-12 months, three month rheumatologist assessed joint count, pain, and arthritis activity, and treatment efficacy in those with previous exposure to chlamydia.Of 60 patients randomly allocated to receive doxycycline or placebo, results from 37 were evaluable at three months. Groups were well balanced for major prognostic variables. Doxycycline had no detectable effect at three months on pain change scores (mean difference 1.5, 95% CI -1.2 to 4.2, p=0.25) or composite functional change scores (mean difference 0.8, 95% CI -5.6 to 7.1, p=0.81). Furthermore, there were no differences in secondary study end points, and no apparent treatment effect in patients with previous chlamydia infection.Three months' treatment with doxycycline did not improve pain or functional status in patients with chronic reactive or seronegative arthritis.