tbuckley/cabot-search huggingface dataset:
Multidrug transporter p‐glycoprotein 170 as a differentiation antigen on normal human lymphocytes and thymocytes: Modulation with differentiation stage and during aging
Authors: Linda M. Pilarski, Darlene Paine, Janet E. McElhaney, Carol E. Cass, Andrew R. Belch
Journal: American Journal of Hematology (1995)

Abstract P‐glycoprotein 170 (P‐gp), the multidrug transport pump, excludes drugs from the interior of cells and is inhibited by agents such as cyclosporin A (CsA), verapamil, and FK‐506, which are also substrates for the P‐gp pump. This work documents the age‐ and differentiation‐related changes in P‐gp on T and B lymphocytes from human blood or spleen, and its absence on most thymus and bone marrow cells. Analysis of rhodamine 123 (Rh123) dye efflux, and its inhibition by cyclosporin A, was used as a quantitative measure of functional P‐gp, and reactivity with MRK‐16 was used as a measure of P‐gp Surface expression. The dye efflux and phenotypic expression of P‐gp+ PBMC appeared equivalent to that of a moderately drug‐resistant cell line, although efflux is prolonged. The sensitivity to inhibition by CsA, cyclosporin G (CsG), and PSC833 of P‐gp on PBMC, thymocytes, or T‐cell lines varied with apparent cell‐type specificity. Normal blood and splenic T‐ or B‐cells included 50‐80% of cells with surface P‐gp (MRK‐16+), which mediated CsA‐sensitive dye export. The proportion of P‐gp+ T‐ and B‐cells was lowest among children under age 10 years, increased in adulthood, and decreased after age 60. Thymus included 30% of P‐gp+ cells mediating CsA‐sensitive dye export, including CD3−4‐8‐ progenitors and mature CD3hi CD4+8‐ or CD4−8+ thymocytes. Mature T‐cells in cord or adult blood, spleen, and bone marrow included a large proportion (50‐60%) with efficient CsA‐sensitive dye export, preferentially among the CD45RA+ subset. Monocytes from all tissue sources, and most bone marrow cells, expressed surface P‐gp but retained Rh123, suggesting the absence of a functional dye export mechanism. In vitro mitogen‐stimu‐lated PBMC T and B lymphocytes lost P‐gp function within 4‐24 hr, consistent with the observation that P‐gp was reduced on antigen‐xperienced CD45RO+ T‐cells in vivo. Drug export by P‐gp may protect lymphocytes from toxic effects of CsA, and may contribute to the immunosuppressive effects of such drugs. The developmentally regulated expression of P‐gp function on lymphocytes, and its modulation on activated T‐ or B‐cells, suggest an important role in normal immune development. © 1995 Wiley‐Liss, Inc.
PHLPP-1 Negatively Regulates Akt Activity and Survival in the Heart
Authors: Shigeki Miyamoto, Nicole H. Purcell, Jeffrey M. Smith, Tianyan Gao, Ross Whittaker, Katherine Huang, Rene Castillo, Chris C. Glembotski, Mark A. Sussman, Alexandra C. Newton, Joan Heller Brown
Journal: Circulation Research (2010)

Rationale: The recently discovered PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) selectively dephosphorylates Akt at Ser473 and terminates Akt signaling in cancer cells. The regulatory role of PHLPP-1 in the heart has not been considered. Objective: To test the hypothesis that blockade/inhibition of PHLPP-1 could constitute a novel way to enhance Akt signals and provide cardioprotection. Methods and Results: PHLPP-1 is expressed in neonatal rat ventricular myocytes (NRVMs) and in adult mouse ventricular myocytes (AMVMs). PHLPP-1 knockdown by small interfering RNA significantly enhances phosphorylation of Akt (p-Akt) at Ser473, but not at Thr308, in NRVMs stimulated with leukemia inhibitory factor (LIF). The increased phosphorylation is accompanied by greater Akt catalytic activity. PHLPP-1 knockdown enhances LIF-mediated cardioprotection against doxorubicin and also protects cardiomyocytes against H 2 O 2 . Direct Akt effects at mitochondria have been implicated in cardioprotection and mitochondria/cytosol fractionation revealed a significant enrichment of PHLPP-1 at mitochondria. The ability of PHLPP-1 knockdown to potentiate LIF-mediated increases in p-Akt at mitochondria and an accompanying increase in mitochondrial hexokinase-II was demonstrated. We generated PHLPP-1 knockout (KO) mice and demonstrate that AMVMs isolated from KO mice show potentiated p-Akt at Ser473 in response to agonists. When isolated perfused hearts are subjected to ischemia/reperfusion, p-Akt in whole-heart homogenates and in the mitochondrial fraction is significantly increased. Additionally in PHLPP-1 KO hearts, the increase in p-Akt elicited by ischemia/reperfusion is potentiated and, concomitantly, infarct size is significantly reduced. Conclusions: These results implicate PHLPP-1 as an endogenous negative regulator of Akt activity and cell survival in the heart.
Caffeine decreases exhaled nitric oxide
Authors: C Bruce
Journal: Thorax (2002)

Background: Caffeine is known to inhibit phosphodiesterases, to mobilise intracellular calcium, and to act as an antagonist at adenosine receptors, all of which can potentially alter nitric oxide (NO) production. It was therefore hypothesised that caffeine may alter exhaled NO (eNO) levels. Methods: In a randomised, single blind, crossover manner, 12 normal subjects consumed either (1) coffee and a placebo capsule, (2) decaffeinated coffee and a capsule of 200 mg caffeine, or (3) decaffeinated coffee and a placebo capsule. Serum caffeine levels were measured at baseline and 1 hour later. Exhaled NO levels were also measured at baseline and each hour for 4 hours. Results: A significant percentage fall in mean (SE) eNO from baseline was seen 1 hour after either caffeinated coffee or a caffeine capsule when compared with placebo (13.5 (4.0)%, p=0.009 and 19.0 (3.8)%, p=0.001, respectively). Conclusion: Caffeine causes a significant decrease in eNO which will need to be considered when designing trials to measure eNO levels. The mechanism may be via adenosine receptor antagonism or by altering levels of cGMP.
Engineering the gut microbiota to treat hyperammonemia
Authors: Ting-Chin David Shen, Lindsey Albenberg, Kyle Bittinger, Christel Chehoud, Ying-Yu Chen, Colleen A. Judge, Lillian Chau, Josephine Ni, Michael Sheng, Andrew Lin, Benjamin J. Wilkins, Elizabeth L. Buza, James D. Lewis, Yevgeny Daikhin, Ilana Nissim, Marc Yudkoff, Frederic D. Bushman, Gary D. Wu
Journal: Journal of Clinical Investigation (2015)

Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.
Cost-Effectiveness of Services for Mentally Ill Homeless People: The Application of Research to Policy and Practice
Authors: Robert Rosenheck
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: About one-quarter of homeless Americans have serious mental illnesses. This review synthesizes research findings on the cost-effectiveness of services for this population and their relevance for policy and practice. METHOD: Service interventions for seriously mentally ill homeless people were grouped into three overlapping categories: 1) outreach, 2) case management, and 3) housing placement and transition to mainstream services. Data were reviewed both from experimental studies with high internal validity and from observational studies, which better reflect typical community practice. RESULTS: In most studies, specialized interventions are associated with significantly improved outcomes, most consistently in the housing domain, but also in mental health status and quality of life. These programs are also associated with increased use of many types of health service and housing assistance, resulting in increased costs in most cases. The value of these programs to the public thus depends on whether their greater effectiveness is deemed to be worth their additional cost. CONCLUSIONS: Innovative programs for seriously mentally ill homeless people are effective and are also likely to increase costs in many cases. Their value ultimately depends on the moral and political value society places on caring for its least-well-off members.
Aberrant Silencing of Cancer-Related Genes by CpG Hypermethylation Occurs Independently of Their Spatial Organization in the Nucleus
Authors: Hariharan P. Easwaran, Leander Van Neste, Leslie Cope, Subhojit Sen, Helai P. Mohammad, Gayle J. Pageau, Jeanne B. Lawrence, James G. Herman, Kornel E. Schuebel, Stephen B. Baylin
Journal: Cancer Research (2010)

Aberrant promoter DNA-hypermethylation and repressive chromatin constitutes a frequent mechanism of gene inactivation in cancer. There is great interest in dissecting the mechanisms underlying this abnormal silencing. Studies have shown changes in the nuclear organization of chromatin in tumor cells as well as the association of aberrant methylation with long-range silencing of neighboring genes. Furthermore, certain tumors show a high incidence of promoter methylation termed as the CpG island methylator phenotype. Here, we have analyzed the role of nuclear chromatin architecture for genes in hypermethylated inactive versus nonmethylated active states and its relation with long-range silencing and CpG island methylator phenotype. Using combined immunostaining for active/repressive chromatin marks and fluorescence in situ hybridization in colorectal cancer cell lines, we show that aberrant silencing of these genes occurs without requirement for their being positioned at heterochromatic domains. Importantly, hypermethylation, even when associated with long-range epigenetic silencing of neighboring genes, occurs independent of their euchromatic or heterochromatic location. Together, these results indicate that, in cancer, extensive changes around promoter chromatin of individual genes or gene clusters could potentially occur locally without preference for nuclear position and/or causing repositioning. These findings have important implications for understanding relationships between nuclear organization and gene expression patterns in cancer.
Preexisting <i>MEK1</i> Exon 3 Mutations in <i>V600E/K</i> <i>BRAF</i> Melanomas Do Not Confer Resistance to BRAF Inhibitors
Authors: Hubing Shi, Gatien Moriceau, Xiangju Kong, Richard C. Koya, Ramin Nazarian, Gulietta M. Pupo, Antonella Bacchiocchi, Kimberly B. Dahlman, Bartosz Chmielowski, Jeffrey A. Sosman, Ruth Halaban, Richard F. Kefford, Georgina V. Long, Antoni Ribas, Roger S. Lo
Journal: Cancer Discovery (2012)

BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced V600E/KBRAF melanomas. Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with V600E/KBRAF may be selected for by BRAFi. We sequenced MEK1/2 exon 3 in melanomas at baseline and upon disease progression. Of 31 baseline V600E/KBRAF melanomas, 5 (16%) carried concurrent somatic BRAF/MEK1 activating mutations. Three of 5 patients with BRAF/MEK1 double-mutant baseline melanomas showed objective tumor responses, consistent with the overall 60% frequency. No MEK1 mutation was found in disease progression melanomas, except when it was already identified at baseline. MEK1-mutant expression in V600E/KBRAF melanoma cell lines resulted in no significant alterations in p-ERK1/2 levels or growth-inhibitory sensitivities to BRAFi, MEK1/2 inhibitor (MEKi), or their combination. Thus, activating MEK1 exon 3 mutations identified herein and concurrent with V600E/KBRAF do not cause BRAFi resistance in melanoma.As BRAF inhibitors gain widespread use for treatment of advanced melanoma, biomarkers for drug sensitivity or resistance are urgently needed. We identify here concurrent activating mutations in BRAF and MEK1 in melanomas and show that the presence of a downstream mutation in MEK1 does not necessarily make BRAF–mutant melanomas resistant to BRAF inhibitors.
PWE-096 The investigation and management of colovesical fistulae in the modern era—a single institutions 12-year experience
Authors: N Ladwa, M Sajid, M McFall, A Miles, P Sains, M K Baig
Journal: Gut (2012)

<h3>Introduction</h3> This aim of this study is to review how investigation and management of colovesical fistulae has progressed in our institution over a 12-year period and to propose a clear protocol to ensure prompt diagnosis and treatment in the future. <h3>Methods</h3> A retrospective case note review was conducted of all patients with colovesical fistulae who underwent definitive surgery over a 12-year period. Variables collected include patient demographics, symptoms, investigations, operative data, histology, complications and length of stay. <h3>Results</h3> 56 patients (38 male) underwent operative intervention for colovesical fistula. The most common symptoms are pneumaturia (69%), faecaluria (32%) and symptoms associated with recurrent UTIs (68%). Cystoscopy was the most accurate test to identify fistulae (91%) followed by CT (60%) and barium enema (31%). Two patients were unfit for major surgery and underwent palliative loop colostomies. The most common pathology was diverticular disease. Of the 54 remaining patients, 45% underwent laparoscopic resection with a conversion rate of 33% (due to adhesions or multiple abscesses). Sigmoid colectomy, (52%) anterior resection (30%) and hartmanns (9%) are the most common procedures performed. Bladder repair was required in 25% of cases with a further 16% requiring partial resection. All patients received a postoperative cystogram to ensure bladder had healed and 70% of patients were defunctioned to protect the anastomosis. There was no mortality reported peri-operatively; the anastomotic leak rate was 5% and recurrence rate was 5%. Median postoperative stay was 12.5 days (range 4–91) in the laparoscopic group and 16 days (range 6–62) in the open group. <h3>Conclusion</h3> Surgical management for colovesical fistulae is effective and safe. Laparoscopic resections are increasing in popularity and deliver encouraging results comparable to open resection. A large multi-centre randomised controlled trial is required to validate its potential benefits over open surgery. <h3>Competing interests</h3> None declared.
Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies
Authors: Gabrielle M. Siegers, Mahima Swamy, Edgar Fernández-Malavé, Susana Minguet, Sylvia Rathmann, Alberto C. Guardo, Verónica Pérez-Flores, Jose R. Regueiro, Balbino Alarcón, Paul Fisch, Wolfgang W.A. Schamel
Journal: The Journal of Experimental Medicine (2007)

The γδ T cell receptor for antigen (TCR) comprises the clonotypic TCRγδ, the CD3 (CD3γe and/or CD3δe), and the ζζ dimers. γδ T cells do not develop in CD3γ-deficient mice, whereas human patients lacking CD3γ have abundant peripheral blood γδ T cells expressing high γδ TCR levels. In an attempt to identify the molecular basis for these discordant phenotypes, we determined the stoichiometries of mouse and human γδ TCRs using blue native polyacrylamide gel electrophoresis and anti-TCR–specific antibodies. The γδ TCR isolated in digitonin from primary and cultured human γδ T cells includes CD3δ, with a TCRγδCD3e2δγζ2 stoichiometry. In CD3γ-deficient patients, this may allow substitution of CD3γ by the CD3δ chain and thereby support γδ T cell development. In contrast, the mouse γδ TCR does not incorporate CD3δ and has a TCRγδCD3e2γ2ζ2 stoichiometry. CD3γ-deficient mice exhibit a block in γδ T cell development. A human, but not a mouse, CD3δ transgene rescues γδ T cell development in mice lacking both mouse CD3δ and CD3γ chains. This suggests important structural and/or functional differences between human and mouse CD3δ chains during γδ T cell development. Collectively, our results indicate that the different γδ T cell phenotypes between CD3γ-deficient humans and mice can be explained by differences in their γδ TCR composition.
HPV DNA Testing of Self-collected Vaginal Samples Compared With Cytologic Screening to Detect Cervical Cancer
Authors: Thomas C. Wright, Jr
Journal: JAMA (2000)

MPLEMENTATION OF CYTOLOGICscreening programs has been associated with a 5-fold reduction in the incidence of invasive cervical cancer in North America over the last 4 decades. 1 However, cytologic screening programs have been difficult to implement in many resource-poor regions of the world.Approximately 360 000 cases of cervical cancer were diagnosed in 1990 worldwide, accounting for approximately 190 000 deaths. 2 Even in countries where cytologic screening is routinely performed, cervical cancer continues to be a health problem.This year approximately 12 800 women will be diagnosed as having invasive cervical cancer in the United States and 4800 women will die of this disease. 36][7] This is especially a problem for older women.
Lentiviral vectors pseudotyped with a modified RD114 envelope glycoprotein show increased stability in sera and augmented transduction of primary lymphocytes and CD34+ cells derived from human and nonhuman primates
Authors: Virginie Sandrin, Bertrand Boson, Patrick Salmon, Wilfried Gay, Didier Nègre, Roger Le Grand, Didier Trono, François-Loı̈c Cosset
Journal: Blood (2002)
The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy.
Authors: P Romagnoli, R N Germain
Journal: The Journal of Experimental Medicine (1994)

Invariant chain (Ii) contributes in a number of distinct ways to the proper functioning of major histocompatibility complex (MHC) class II molecules. These include promoting effective association and folding of newly synthesized MHC class II alpha and beta subunits, increasing transit of assembled heterodimers out of the endoplasmic reticulum (ER), inhibiting class II peptide binding, and facilitating class II movement to or accumulation in endosomes/lysosomes. Although the cytoplasmic tail of Ii makes a key contribution to the endocytic localization of class II, the relationship between the structure of Ii and its other diverse functions remains unknown. We show here that two thirds of the lumenal segment of Ii can be eliminated without affecting its contributions to the secretory pathway events of class II folding, ER to Golgi transport, or inhibition of peptide binding. These same experiments reveal that a short (25 residue) contiguous internal segment of Ii (the CLIP region), frequently found associated with purified MHC class II molecules, is critical for all three functions. Together with other recent findings, these results raise the possibility that the contributions of Ii to the early postsynthetic behavior of class II may depend on its interaction with the class II binding site. This would be consistent with the intracellular behavior of unoccupied MHC class I and class II molecules as incompletely folded proteins and imply a related structural basis for the similar contributions of Ii to class II and of short peptides to class I assembly and transport.
Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung.
Authors: M E Rothenberg, A D Luster, C M Lilly, J M Drazen, P Leder
Journal: The Journal of Experimental Medicine (1995)

Eotaxin is a member of the C-C family of chemokines and is related during antigen challenge in a guinea pig model of allergic airway inflammation (asthma). Consistent with its putative role in eosinophilic inflammation, eotaxin induces the selective infiltration of eosinophils when injected into the lung and skin. Using a guinea pig lung cDNA library, we have cloned full-length eotaxin cDNA. The cDNA encodes a protein of 96 amino acids, including a putative 23-amino acid hydrophobic leader sequence, followed by 73 amino acids composing the mature active eotaxin protein. The protein-coding region of this cDNA is 73, 71, 50, and 48% identical in nucleic acid sequence to those of human macrophage chemoattractant protein (MCP) 3, MCP-1, macrophage inflammatory protein (MIP) 1 alpha, and RANTES, respectively. Analysis of genomic DNA suggested that there is a single eotaxin gene in guinea pig which is apparently conserved in mice. High constitutive levels of eotaxin mRNA expression were observed in the lung, while the intestines, stomach, spleen, liver, heart, thymus, testes, and kidney expressed lower levels. To determine if eotaxin mRNA levels are elevated during allergen-induced eosinophilic airway inflammation, ovalbumin (OVA)-sensitized guinea pigs were challenged with aerosolized antigen. Compared with the lungs from saline-challenged animals, eotaxin mRNA levels increased sixfold within 3 h and returned to baseline by 6 h. Thus, eotaxin mRNA levels are increased in response to allergen challenge during the late phase response. The identification of constitutive eotaxin mRNA expression in multiple tissues suggests that in addition to regulating airway eosinophilia, eotaxin is likely to be involved in eosinophil recruitment into other tissues as well as in baseline tissue homing.
Restriction molecules involved in the interaction of T cells with allogeneic antigen-presenting cells.
Authors: N Ishii, Z A Nagy, J Klein
Journal: The Journal of Experimental Medicine (1982)

The proliferative responses of T cells, depleted of alloreactive cells, were tested upon stimulation by antigens presented on allogeneic antigen-presenting cells (APC). Restriction molecules involved in these responses were identified by inhibition of T cell proliferation with monoclonal antibodies against A(A alpha A beta) and E(E alpha E beta) molecules of the APC. The responses to all three antigens tested [Poly(Glu40Ala60) (GA), lactate dehydrogenase B (LDHB), and poly(Glu51, Lys34, Tyr15) (GLT)] were A plus E restricted when the allogeneic APC expressed both molecules, and only A restricted when the APC did not express cell surface E molecules. In contrast, when T cells and APC are syngeneic, the same antigens are recognized only in the context of either A molecules (GA and LDHB) or E molecules (GLT). The data indicate that the immune response gene control of these responses is not associated with either a failure of antigen presentation, or the lack of certain T cell specificities from the germ line repertoire, but probably with selective somatic elimination (tolerance) of certain clones from the T cell repertoire.