tbuckley/cabot-search huggingface dataset:
Mesenchymal Stromal Cells Treatment Attenuates Dry Eye in Patients With Chronic Graft-versus-host Disease
Authors: Jianyu Weng, Chang He, Peilong Lai, Chenwei Luo, Rong Guo, Suijing Wu, Suxia Geng, Andy Xiangpeng, Xialin Liu, Xin Du
Journal: Molecular Therapy (2012)

Cell therapy is a promising approach for the treatment of refractory ocular disease. This study investigated the efficacy of mesenchymal stromal cells (MSCs) for the treatment of dry eye associated with chronic graft-versus-host disease (cGVHD) and assessed the immunomodulatory effects of MSCs on regulatory CD8(+)CD28(-) T lymphocytes. A total of 22 patients with refractory dry eye secondary to cGVHD were enrolled. The symptoms of 12 out of 22 patients abated after MSCs transplantation by intravenous injection, improving in the dry eye scores, ocular surface disease index scores and the Schirmer test results. The clinical improvements were accompanied by increasing level of CD8(+)CD28(-) T cells, but not CD4(+)CD25(+) T cells, in the 12 patients who were treated effectively. They had significantly higher levels of Th1 cytokines (interleukin (IL)-2 and interferon-γ) and lower levels of Th2 cytokines (IL-10 and IL-4). In addition, CD8(+) T cells were prone to differentiation into CD8(+)CD28(-) T cells after co-culture with MSCs in vitro. In conclusion, transfusion of MSCs improved the clinical symptoms in patients (54.55%) with refractory dry eye secondary to cGVHD. MSCs appear to exert their effects by triggering the generation of CD8(+)CD28(-) T cells, which may regulate the balance between Th1 and Th2.
CCAAT/enhancer binding protein α predicts poorer prognosis and prevents energy starvation–induced cell death in hepatocellular carcinoma
Authors: Guo‐Dong Lu, Yang Huey Ang, Jing Zhou, Jegadeesan Tamilarasi, Benedict Yan, Yaw Chyn Lim, Supriya Srivastava, Manuel Salto‐Tellez, Kam M. Hui, Han‐Ming Shen, Long N. Nguyen, Bryan C. Tan, David L. Silver, Shing Chuan Hooi
Journal: Hepatology (2014)

CCAAT enhancer binding protein α (C/EBPα) plays an essential role in cellular differentiation, growth, and energy metabolism. Here, we investigate the correlation between C/EBPα and hepatocellular carcinoma (HCC) patient outcomes and how C/EBPα protects cells against energy starvation. Expression of C/EBPα protein was increased in the majority of HCCs examined (191 pairs) compared with adjacent nontumor liver tissues in HCC tissue microarrays. Its upregulation was correlated significantly with poorer overall patient survival in both Kaplan-Meier survival (P=0.017) and multivariate Cox regression (P=0.028) analyses. Stable C/EBPα-silenced cells failed to establish xenograft tumors in nude mice due to extensive necrosis, consistent with increased necrosis in human C/EBPα-deficient HCC nodules. Expression of C/EBPα protected HCC cells in vitro from glucose and glutamine starvation-induced cell death through autophagy-involved lipid catabolism. Firstly, C/EBPα promoted lipid catabolism during starvation, while inhibition of fatty acid beta-oxidation significantly sensitized cell death. Secondly, autophagy was activated in C/EBPα-expressing cells, and the inhibition of autophagy by ATG7 knockdown or chloroquine treatment attenuated lipid catabolism and subsequently sensitized cell death. Finally, we identified TMEM166 as a key player in C/EBPα-mediated autophagy induction and protection against starvation.The C/EBPα gene is important in that it links HCC carcinogenesis to autophagy-mediated lipid metabolism and resistance to energy starvation; its expression in HCC predicts poorer patient prognosis.
Evolution of erythrocyte sedimentation rate as predictor of early relapse in posttherapy early-stage Hodgkin's disease.
Authors: S Friedman, M Henry-Amar, J M Cosset, P Carde, M Hayat, N Dupouy, M Tubiana
Journal: Journal of Clinical Oncology (1988)

A retrospective study was undertaken at the Institut Gustave Roussy (IGR) to determine the predictive ability of changes in the erythrocyte sedimentation rate (ESR) during posttherapy periods for early relapse (within 18 months from start of therapy) and long-term survival in Hodgkin's disease (HD). Three hundred one patients with clinical stages (CS) I or II HD entered in the European Organization for Research and Treatment of Cancer (EORTC) clinical trials were included in this study. All relevant data and long-term follow-up were available for these patients. A stepwise logistic regression was performed to assess the prognostic value of ESR changes independent of other prognostic parameters and treatment. The incidence of early relapse was found to be significantly increased in patients in whom ESR remained elevated (greater than 30 mm at one hour) after completion of therapy, regardless of the value before therapy. This was true whether the ESR was elevated in plateau fashion, oscillating between normal and abnormal, or was lower than at onset, but still abnormal. Moreover, early relapse predicted by elevated ESR posttherapy was associated with poor survival despite subsequent initiation of combination chemotherapy. Thus, the persistence of an abnormal ESR appears to be a reliable indicator for high probability of early relapse and subsequent poor prognosis. This might be introduced as a prognostic variable in the design of future therapy programs for HD.
ON THE ROLE OF VIRUS SULFHYDRYL GROUPS IN THE ATTACHMENT OF ENTEROVIRUSES TO ERYTHROCYTES
Authors: Lennart Philipson, Purnell W. Choppin
Journal: The Journal of Experimental Medicine (1960)

Many animal viruses possess the ability to agglutinate erythrocytes. In most but not all cases hemagglutination is due to the virus particle itself, and appears to result from the mechanical bridging of two or more erythrocytes by virus particles which attach to receptor sites on each erythrocyte (1, 2). Thus, attachment of virus particles to erythrocytes is a prerequisite for hemagglutination, and prevention of absorption of virus prevents hemagglutination. Among the enteroviruses, many ECHO viruses and some strains of Coxsackie B3 virus agglutinate human erythrocytes (3-7), and the evidence indicates that hemagglutination is due to the virus particle itself (3, 5, 6). The precise mechanism of attachment of enteroviruses to cells is unknown. Chymotrypsin treatment of erythrocytes prevents the absorption of some ECHO viruses (8). This suggests that the receptor sites on the erythrocyte may be at least in part protein in nature. The present communication is concerned with the mechanism of attachment of enteroviruses to cells. It is shown that sulfhydryl reagents block the hemagglutinating activity of enteroviruses. Treated virus fails to absorb to erythrocytes. Thiol compounds restore the hemagglutinating activity of enteroviruses treated with mercaptide-forming sulfhydryl reagents. The effect of sulfhydryl reagents on the infectivity of some enteroviruses is also described.
NICE is urged to make drug companies supply all trial data
Authors: A. O'Dowd
Journal: BMJ (2012)

The drug regulator the National Institute for Health and Clinical Excellence should put more pressure on drug companies to produce all data in trials, MPs have said.

MPs on the parliamentary health select committee challenged the leaders of NICE to take action to tackle the issue of unpublished data from drug trials at an evidence session on Tuesday 4 December.

Michael Rawlins, NICE’s chairman, who will retire from the post next April, and its chief executive, Andrew Dillon, appeared before the Health Committee as part of its inquiry into the institute.

In October the BMJ published an open letter from its editor in chief, Fiona Godlee, to the drug company Roche saying that researchers were still denied …
Supernatural agents may have provided adaptive social information
Authors: Jesse M. Bering, Todd K. Shackelford
Journal: Behavioral and Brain Sciences (2004)

Atran &amp; Norenzayan's (A&amp;N's) target article effectively combines the insights of evolutionary biology and interdisciplinary cognitive science, neither of which alone yields sufficient explanatory power to help us fully understand the complexities of supernatural belief. Although the authors' ideas echo those of other researchers, they are perhaps the most squarely grounded in neo-Darwinian terms to date. Nevertheless, A&amp;N overlook the possibility that the tendency to infer supernatural agents' communicative intent behind natural events served an ancestrally adaptive function.
Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus
Authors: G. Döring, S.P. Conway, H.G.M Heijerman, M.E Hodson, N Høiby, A Smyth, D.J Touw, for the Consensus Committee
Journal: European Respiratory Journal (2000)

Cystic fibrosis (CF) is the most common lethal hereditary disorder with autosomal recessive heredity in caucasians. The majority of CF patients suffer from chronic respiratory infection with the opportunistic bacterial pathogen Pseudomonas aeruginosa. No consensus among clinicians has been reached so far concerning antibiotic treatment against P. aeruginosa in CF patients. Consensus answers to 24 important questions in this context, based on current evidence, are presented, given by a panel of 34 European experts. Questions addressed and answered are: The diagnosis of P. aeruginosa lung colonization in CF; The impact of P. aeruginosa on the clinical state of CF patients; The assessment of P. aeruginosa susceptibility against antibiotics and the importance of these results for the clinician; The use of monotherapy versus combination therapy; The development of microbial resistance; The achievement of optimal airway concentrations; The effects of subinhibitory concentrations of antibiotics on P. aeruginosa; Statements on the pharmacokinetics of antibiotics in CF patients; Recommendations for doses and dosing intervals and length of treatment regimens; and Toxic side effects due to repeated antibiotic therapy was addressed. The expert panel answered further questions on the use of fluoroquinolones in children with CF, on the administration of nebulized antibiotics and whether prevention of P. aeruginosa lung colonization is possible in CF using antibiotic therapy. Problems of antibiotic therapy at home and in the hospital were addressed, a consensus statement on regular maintenance treatment, or treatment on demand, was given and different routes of administration of antibiotics were recommended for different clinical situations. Finally, the factors which determine the choice of the antibiotic, the dosage, and the duration of the treatment in cystic fibrosis patients were addressed and the design of future antibiotic studies in the context of Pseudomonas aeruginosa lung infection in cystic fibrosis patients were recommended.
Long term suppressive therapy with pegylated interferon for chronic hepatitis C associated membranoproliferative glomerulonephritis
Authors: I H Y Cua
Journal: Gut (2006)

Long term suppressive therapy with pegylated interferon for chronic hepatitis C associated membranoproliferative glomerulonephritisRenal disease secondary to chronic hepatitis C virus (HCV) infection is infrequent but often life threatening and difficult to treat.Management is directed towards eradication of the virus.Combination therapy with interferon a or pegylated interferon a and ribavirin has been used successfully to induce recovery from membranoproliferative glomerulonephritis (MPGN), cryoglobulinaemia, and vasculitis, if viral clearance is achieved. [1]][3][4][5][6][7][8] Unfortunately, symptoms recur in the absence of a sustained virological response.Long term suppressive maintenance therapy may be an alternative, but has not been reported previously.
Endoplasmic reticulum aminopeptidase 1 (ERAP1) exhibits functionally significant interaction with HLA-B27 and relates to subtype specificity in ankylosing spondylitis
Authors: Nigil Haroon, Florence W Tsui, Barbara Uchanska-Ziegler, Andreas Ziegler, Robert D Inman
Journal: Annals of the Rheumatic Diseases (2012)

The functional interaction of endoplasmic reticulum aminopeptidase 1 (ERAP1) with human leucocyte antigen (HLA)-B*27 could be important in the pathogenesis of ankylosing spondylitis (AS). AS is associated with B*27:04 and B*27:05, but not with B*27:06 and B*27:09. The authors studied the surface expression of peptide-HLA(pHLA)-B27 complexes and HLA class-I free heavy chains (FHCs) on peripheral blood mononuclear cells of patients with AS with different ERAP1 single nucleotide polymorphisms. The effects of ERAP1 suppression on HLA-B*27 subtypes were tested.Peripheral blood mononuclear cells were collected from Caucasian patients with AS for flow cytometry and were stained for pHLA and FHCs. Genotyping was performed for two ERAP1 single nucleotide polymorphisms (rs27044(C/G) and rs30187(C/T)). C1R cells transfected with different HLA-B27 subtypes (B*27:04, B*27:05, B*27:06 and B*27:09) were subjected to ERAP1 suppression by small interfering RNA and stained using the monoclonal antibody (mAb) MARB4 as well as antibodies for pHLA, FHC, intracellular FHC (IC-FHC). MARB4 has been reported to bind to HLA-B27 with extended peptides.The authors found variations in FHC expression on the monocytes of patients with AS, depending on different ERAP1 variants. Subsequently, using Hmy2.C1R cells in vitro, the authors show that ERAP1 suppression leads to increased IC-FHC and surface pHLA that react with the monoclonal antibody MARB4. The functional interaction between ERAP1 and HLA-B27 molecules appears to be subtype-specific, since ERAP1 suppression leads to changes only in cells expressing B*27:04 or B*27:05, but not B*27:06 or B*27:09.Direct or indirect alterations in the ERAP1-HLA-B27 interaction could be crucial by causing changes in peptide presentation or FHC formation by HLA-B27 molecules, as well as by contributing to differential subtype association in spondyloarthropathies.
Genetic Evidence for the Convergent Evolution of Light Skin in Europeans and East Asians
Authors: H. L. Norton, R. A. Kittles, E. Parra, P. McKeigue, X. Mao, K. Cheng, V. A. Canfield, D. G. Bradley, B. McEvoy, M. D. Shriver
Journal: Molecular Biology and Evolution (2006)

Human skin pigmentation shows a strong positive correlation with ultraviolet radiation intensity, suggesting that variation in skin color is, at least partially, due to adaptation via natural selection. We investigated the evolution of pigmentation variation by testing for the presence of positive directional selection in 6 pigmentation genes using an empirical F(ST) approach, through an examination of global diversity patterns of these genes in the Centre d'Etude du Polymorphisme Humain (CEPH)-Diversity Panel, and by exploring signatures of selection in data from the International HapMap project. Additionally, we demonstrated a role for MATP in determining normal skin pigmentation variation using admixture mapping methods. Taken together (with the results of previous admixture mapping studies), these results point to the importance of several genes in shaping the pigmentation phenotype and a complex evolutionary history involving strong selection. Polymorphisms in 2 genes, ASIP and OCA2, may play a shared role in shaping light and dark pigmentation across the globe, whereas SLC24A5, MATP, and TYR have a predominant role in the evolution of light skin in Europeans but not in East Asians. These findings support a case for the recent convergent evolution of a lighter pigmentation phenotype in Europeans and East Asians.
Histone Demethylase RBP2 Promotes Lung Tumorigenesis and Cancer Metastasis
Authors: Yu-Ching Teng, Cheng-Feng Lee, Ying-Shiuan Li, Yi-Ren Chen, Pei-Wen Hsiao, Meng-Yu Chan, Feng-Mao Lin, Hsien-Da Huang, Yen-Ting Chen, Yung-Ming Jeng, Chih-Hung Hsu, Qin Yan, Ming-Daw Tsai, Li-Jung Juan
Journal: Cancer Research (2013)

Abstract The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-β1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role. Cancer Res; 73(15); 4711–21. ©2013 AACR.
Dendritic Cells Enhance Growth and Differentiation of CD40-activated B Lymphocytes
Authors: Bertrand Dubois, Béatrice Vanbervliet, Jérome Fayette, Catherine Massacrier, Cees Van Kooten, Francine Brière, Jacques Banchereau, Christophe Caux
Journal: The Journal of Experimental Medicine (1997)

After antigen capture, dendritic cells (DC) migrate into T cell–rich areas of secondary lymphoid organs, where they induce T cell activation, that subsequently drives B cell activation. Here, we investigate whether DC, generated in vitro, can directly modulate B cell responses, using CD40L-transfected L cells as surrogate activated T cells. DC, through the production of soluble mediators, stimulated by 3- to 6-fold the proliferation and subsequent recovery of B cells. Furthermore, after CD40 ligation, DC enhanced by 30–300-fold the secretion of IgG and IgA by sIgD− B cells (essentially memory B cells). In the presence of DC, naive sIgD+ B cells produced, in response to interleukin-2, large amounts of IgM. Thus, in addition to activating naive T cells in the extrafollicular areas of secondary lymphoid organs, DC may directly modulate B cell growth and differentiation.
Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity
Authors: Roland Lang, Andrew L. Gundlach, Fiona E. Holmes, Sally A. Hobson, David Wynick, Tomas Hökfelt, Barbara Kofler
Journal: Pharmacological Reviews (2014)

Galanin was first identified 30 years ago as a "classic neuropeptide," with actions primarily as a modulator of neurotransmission in the brain and peripheral nervous system. Other structurally-related peptides—galanin-like peptide and alarin—with diverse biologic actions in brain and other tissues have since been identified, although, unlike galanin, their cognate receptors are currently unknown. Over the last two decades, in addition to many neuronal actions, a number of nonneuronal actions of galanin and other galanin family peptides have been described. These include actions associated with neural stem cells, nonneuronal cells in the brain such as glia, endocrine functions, effects on metabolism, energy homeostasis, and paracrine effects in bone. Substantial new data also indicate an emerging role for galanin in innate immunity, inflammation, and cancer. Galanin has been shown to regulate its numerous physiologic and pathophysiological processes through interactions with three G protein–coupled receptors, GAL<sub>1</sub>, GAL<sub>2</sub>, and GAL<sub>3</sub>, and signaling via multiple transduction pathways, including inhibition of cAMP/PKA (GAL<sub>1</sub>, GAL<sub>3</sub>) and stimulation of phospholipase C (GAL<sub>2</sub>). In this review, we emphasize the importance of novel galanin receptor–specific agonists and antagonists. Also, other approaches, including new transgenic mouse lines (such as a recently characterized GAL<sub>3</sub> knockout mouse) represent, in combination with viral-based techniques, critical tools required to better evaluate galanin system physiology. These in turn will help identify potential targets of the galanin/galanin-receptor systems in a diverse range of human diseases, including pain, mood disorders, epilepsy, neurodegenerative conditions, diabetes, and cancer.
Quantitative PCR to diagnose<i>Pneumocystis</i>pneumonia in immunocompromised non-HIV patients
Authors: K. Mühlethaler, K. Bögli-Stuber, S. Wasmer, C. von Garnier, P. Dumont, A. Rauch, K. Mühlemann, C. Garzoni
Journal: European Respiratory Journal (2011)

The utility of quantitative Pneumocystis jirovecii PCR in clinical routine for diagnosing Pneumocystis pneumonia (PCP) in immunocompromised non-HIV patients is unknown. We analysed bronchoalveolar lavage fluid with real-time quantitative P. jirovecii PCR in 71 cases with definitive PCP defined by positive immunofluorescence (IF) tests and in 171 randomly selected patients with acute lung disease. In those patients, possible PCP cases were identified by using a novel standardised PCP probability algorithm and chart review. PCR performance was compared with IF testing, clinical judgment and the PCP probability algorithm. Quantitative P. jirovecii PCR values &gt;1,450 pathogens·mL −1 had a positive predictive value of 98.0% (95% CI 89.6–100.0%) for diagnosing definitive PCP. PCR values of between 1 and 1,450 pathogens·mL −1 were associated with both colonisation and infection; thus, a cut-off between the two conditions could not be identified and diagnosis of PCP in this setting relied on IF and clinical assessment. Clinical PCP could be ruled out in 99.3% of 153 patients with negative PCR results. Quantitative PCR is useful for diagnosing PCP and is complementary to IF. PCR values of &gt;1,450 pathogens·mL −1 allow reliable diagnosis, whereas negative PCR results virtually exclude PCP. Intermediate values require additional clinical assessment and IF testing. On the basis of our data and for economic and logistical limitations, we propose a clinical algorithm in which IF remains the preferred first test in most cases, followed by PCR in those patients with a negative IF and strong clinical suspicion for PCP.
Long-term Exercise and Atherogenic Activity of Blood Mononuclear Cells in Persons at Risk of Developing Ischemic Heart Disease
Authors: J. Kelly Smith
Journal: JAMA (1999)

LTHOUGH THE AGE-ADJUSTEDdeath rate due to cardiovascular disease (CVD) has declined in the past 25 years, heart disease remains the leading cause of death in the United States, accounting for 733 834 deaths, or 31.6% of total mortality, in 1996. 1 A number of studies have shown that moderate-intensity physical activity reduces the incidence of all-cause mortality, particularly deaths due to CVD. [2][3][4][5][6][7][8][9] The accumulated evidence on the health benefits of physical activity prompted participants in a National Institutes of Health Consensus Conference to recommend that "children and adults alike should set a goal of accumulating at least 30 minutes of moderate-intensity physical activity on most, and preferably all, days of the week." 10 Despite the documented health benefits, the mechanism whereby physical activity prevents CVD is incompletely understood, although it is probably multifactoral.Risk factors such as hypertension, 11 obesity, 12 hyperlipidemia, 13 and insulin resistance 14 may respond favorably to moderate levels of physical activity, thereby protecting against CVD.However, because exercise also protects against CVD in smokers and in persons