tbuckley/cabot-search huggingface dataset:
The GSK-3 Family as Therapeutic Target for Myocardial Diseases
Authors: Hind Lal, Firdos Ahmad, James Woodgett, Thomas Force
Journal: Circulation Research (2014)

Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer disease, aging, inflammation, and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review, we will focus on its expanding role in the heart, concentrating primarily on recent studies that have used cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis, and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3α specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction after myocardial infarction by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3β as a regulator of myocardial fibrosis will also be discussed. We will review our recent findings that specific deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3β is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature.
Class Switching in B Cells Lacking 3′ Immunoglobulin Heavy Chain Enhancers
Authors: John P. Manis, Nienke van der Stoep, Ming Tian, Roger Ferrini, Laurie Davidson, Andrea Bottaro, Frederick W. Alt
Journal: The Journal of Experimental Medicine (1998)

The 40-kb region downstream of the most 3' immunoglobulin (Ig) heavy chain constant region gene (Calpha) contains a series of transcriptional enhancers speculated to play a role in Ig heavy chain class switch recombination (CSR). To elucidate the function of this putative CSR regulatory region, we generated mice with germline mutations in which one or the other of the two most 5' enhancers in this cluster (respectively referred to as HS3a and HS1,2) were replaced either with a pgk-neor cassette (referred to as HS3aN and HS1,2N mutations) or with a loxP sequence (referred to as HS3aDelta and HS1,2Delta, respectively). B cells homozygous for the HS3aN or HS1,2N mutations had severe defects in CSR to several isotypes. The phenotypic similarity of the two insertion mutations, both of which were cis-acting, suggested that inhibition might result from pgk-neor cassette gene insertion rather than enhancer deletion. Accordingly, CSR returned to normal in B cells homozygous for the HS3aDelta or HS1,2Delta mutations. In addition, induced expression of the specifically targeted pgk-neor genes was regulated similarly to that of germline CH genes. Our findings implicate a 3' CSR regulatory locus that appears remarkably similar in organization and function to the beta-globin gene 5' LCR and which we propose may regulate differential CSR via a promoter competition mechanism.
Reduction in Heart Rate Variability with Traffic and Air Pollution in Patients with Coronary Artery Disease
Authors: Antonella Zanobetti, Diane R. Gold, Peter H. Stone, Helen H. Suh, Joel Schwartz, Brent A. Coull, Frank E. Speizer
Journal: Environmental Health Perspectives (2009)

Ambient particulate pollution and traffic have been linked to myocardial infarction and cardiac death risk. Possible mechanisms include autonomic cardiac dysfunction.In a repeated-measures study of 46 patients 43-75 years of age, we investigated associations of central-site ambient particulate pollution, including black carbon (BC) (a marker for regional and local traffic), and report of traffic exposure with changes in half-hourly averaged heart rate variability (HRV), a marker of autonomic function measured by 24-hr Holter electrocardiogram monitoring. Each patient was observed up to four times within 1 year after a percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease (4,955 half-hour observations). For each half-hour period, diary data defined whether the patient was home or not home, or in traffic.A decrease in high frequency (HF; an HRV marker of vagal tone) of 16.4% [95% confidence interval (CI), 20.7 to 11.8%] was associated with an interquartile range of 0.3-microg/m3 increase in prior 5-day averaged ambient BC. Decreases in HF were independently associated both with the previous 2-hr averaged BC (10.4%; 95% CI, 15.4 to 5.2%) and with being in traffic in the previous 2 hr (38.5%; 95% CI, 57.4 to 11.1%). We also observed independent responses for particulate air matter with aerodynamic diameter < or = 2.5 microm and for gases (ozone or nitrogen dioxide).After hospitalization for coronary artery disease, both particulate pollution and being in traffic, a marker of stress and pollution, were associated with decreased HRV.
Meniscal pathology on MRI increases the risk for both incident and enlarging subchondral bone marrow lesions of the knee: the MOST Study
Authors: Martin Englund, Ali Guermazi, Frank W Roemer, Mei Yang, Yuqing Zhang, Michael C Nevitt, John A Lynch, Cora E Lewis, James Torner, David T Felson
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To investigate the association between meniscal pathology and incident or enlarging bone marrow lesions (BML) in knee osteoarthritis. <h3>Methods</h3> The authors studied subjects from the Multicenter Osteoarthritis Study aged 50–79 years either with knee osteoarthritis or at high risk of the disease. Baseline and 30-months magnetic resonance images of knees (n=1344) were scored for subchondral BML. Outcome was defined as an increase in BML score in either the tibial or femoral condyle in medial and lateral compartments, respectively. The authors defined meniscal pathology at baseline as the presence of either meniscal lesions or meniscal extrusion. The risk of an increase in BML score in relation to meniscal status in the same compartment was estimated using a log linear regression model adjusted for age, sex, body mass index, physical activity level and mechanical axis. In secondary analyses the investigators stratified by ipsilateral tibiofemoral cartilage status at baseline and compartments with pre-existing BML. <h3>Results</h3> The adjusted relative risk of incident or enlarging BML ranged from 1.8; 95% CI 1.3 to 2.3 for mild medial meniscal pathology to 5.0; 95% CI 3.2 to 7.7 for major lateral meniscal pathology (using no meniscal pathology in the same compartment as reference). Stratification by cartilage or BML status at baseline had essentially no effect on these estimates. <h3>Conclusions</h3> Knee compartments with meniscal pathology have a substantially increased risk of incident or enlarging subchondral BML over 30 months. Higher relative risks were seen in those with more severe and with lateral meniscal pathology.
TCT-595 Pantera Lux Drug Coated Balloon: Twelve-Month Results On 1'064 Patients Of The International DELUX Registry
Authors: Ralph Toelg, Andrejs Erglis, Gert Richardt, Kristof Graf, Bernhard Witzenbichler, Christoph Naber, Ton Slagboom, Ran Kornowski, Bruno Huret, Stefan Hoffmann, Béla Merkely
Journal: Journal of the American College of Cardiology (2012)
Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties
Authors: Mélanie Chesneau, Laure Michel, Emilie Dugast, Alexis Chenouard, Daniel Baron, Annaïck Pallier, Justine Durand, Faouzi Braza, Pierrick Guerif, David-Axel Laplaud, Jean-Paul Soulillou, Magali Giral, Nicolas Degauque, Elise Chiffoleau, Sophie Brouard
Journal: Journal of the American Society of Nephrology (2015)

Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4(+)CD25(-) T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4(+)CD25(-) effector T cell response in a dose-dependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB(+) B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21(+) T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.
<i>SUMO-1</i> Gene Transfer Improves Cardiac Function in a Large-Animal Model of Heart Failure
Authors: Lisa Tilemann, Ahyoung Lee, Kiyotake Ishikawa, Jaume Aguero, Kleopatra Rapti, Carlos Santos-Gallego, Erik Kohlbrenner, Kenneth M. Fish, Changwon Kho, Roger J. Hajjar
Journal: Science Translational Medicine (2013)

Recently, the impact of small ubiquitin-related modifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2a) function was discovered. The amount of myocardial SUMO-1 is decreased in failing hearts, and its knockdown results in severe heart failure (HF) in mice. In a previous study, we showed that SUMO-1 gene transfer substantially improved cardiac function in a murine model of pressure overload-induced HF. Toward clinical translation, we evaluated in this study the effects of SUMO-1 gene transfer in a swine model of ischemic HF. One month after balloon occlusion of the proximal left anterior descending artery followed by reperfusion, the animals were randomized to receive either SUMO-1 at two doses, SERCA2a, or both by adeno-associated vector type 1 (AAV1) gene transfer via antegrade coronary infusion. Control animals received saline infusions. After gene delivery, there was a significant increase in the maximum rate of pressure rise [dP/dt(max)] that was most pronounced in the group that received both SUMO-1 and SERCA2a. The left ventricular ejection fraction (LVEF) improved after high-dose SUMO-1 with or without SERCA2a gene delivery, whereas there was a decline in LVEF in the animals receiving saline. Furthermore, the dilatation of LV volumes was prevented in the treatment groups. SUMO-1 gene transfer therefore improved cardiac function and stabilized LV volumes in a large-animal model of HF. These results support the critical role of SUMO-1 in SERCA2a function and underline the therapeutic potential of SUMO-1 for HF patients.
Anthracyclines, Mitoxantrone, Radiotherapy, and Granulocyte Colony-Stimulating Factor: Risk Factors for Leukemia and Myelodysplastic Syndrome After Breast Cancer
Authors: Marie-Cécile Le Deley, Florence Suzan, Bruno Cutuli, Suzette Delaloge, Akthar Shamsaldin, Claude Linassier, Stéphanie Clisant, Florent de Vathaire, Pierre Fenaux, Catherine Hill
Journal: Journal of Clinical Oncology (2006)

To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer.We conducted a case-control study among women treated for breast cancer between 1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups.The risk of AML/MDS was increased after topoisomerase-II inhibitor-based chemotherapy (P < 10-16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk [RR] = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately.This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.
Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial
Authors: József Tímár, Andrea Ladányi, Csaba Forster-Horváth, Júlia Lukits, Balázs Döme, Éva Remenár, Mária Gődény, Miklós Kásler, Beáta Bencsik, Gábor Répássy, György Szabó, Norbert Velich, Zsuzsa Suba, János Élő, Zsuzsa Balatoni, Károly Pócza, Béla Zemplén, Paul Chretien, Eyal Talor
Journal: Journal of Clinical Oncology (2005)

Purpose To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins. Patients and Methods Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate. Results Two pathologically complete, two major (&gt; 50%), and four minor responses (&gt; 30% but &lt; 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4 + :CD8 + ratio was low (&lt; 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4 + and a decrease of CD8 + T cells was observed in LI-treated patients, leading to a significantly (P &lt; .05) higher intratumoral CD4 + :CD8 + ratio (&gt; 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P &lt; .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P &lt; .05) increase in tumor stroma of LI-treated patients compared with controls. Conclusion LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4 + :CD8 + ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.
Two family outbreaks of Chlamydia pneumoniae infection
Authors: F Blasi, R Cosentini, F Denti, L Allegra
Journal: European Respiratory Journal (1994)

During autumn 1992, we observed two unrelated family outbreaks of Chlamydia pneumoniae infection. Family A consisted of grandmother (aged 77 yrs), father (aged 41 yrs), mother (aged 38 yrs), daughter (aged 10 yrs), and two sons (aged 6 yrs and 3 months, respectively). The grandmother and daughter suffered from pneumonia, father from pharyngitis and bronchitis and the older son from mild bronchitis. No symptoms were recorded in the mother and younger son. Symptomatic subjects showed a fourfold increase in immunoglobulin G (IgG) titre for Chlamydia pneumoniae, determined by a microimmunofluorescence test with specific antigen (TW-183). Other serological studies against Mycoplasma pneumonia, Legionella pneumophila, influenza virus type A and B, adenovirus and respiratory syncytial virus (RSV) were negative. Sputum culture gave a positive result for Haemophilus influenzae, colony forming units (cfu) = 10(4).ml-1 in the grandmother. No serum positivity was recorded in the mother and younger son, who remained asymptomatic. All symptomatic patients were successfully treated with macrolides. Family B consisted of mother (aged 63 yrs) and daughter (aged 36 yrs). Both suffered from Chlamydia pneumoniae pneumonia. Diagnosis was made by means of serological microimmunofluorescence test, and direct identification using an indirect immunofluorescence test on pharyngeal swab. Sputum culture and other serological tests remained negative. Both patients were successfully treated with macrolides. These observations emphasize the relevance of Chlamydia pneumoniae in family cluster respiratory infections.
Analysis of IgA1 O-Glycans in IgA Nephropathy by Fluorophore-Assisted Carbohydrate Electrophoresis
Authors: ALICE C. ALLEN, ELAINE M. BAILEY, JONATHAN BARRATT, KATHARINE S. BUCK, JOHN FEEHALLY
Journal: Journal of the American Society of Nephrology (1999)

Abnormal O-glycosylation of IgA1 may contribute to pathogenic mechanisms in IgA nephropathy (IgAN). Observations of altered lectin binding to IgA1 in IgAN suggest that the O-glycan chains may be undergalactosylated, but precise structural definition of the defect has proved technically difficult, and it remains unconfirmed. This is the first study using fluorophore-assisted carbohydrate electrophoresis (FACE) to analyze IgA1 O-glycans in IgAN and controls. IgA1 was purified from serum, and the intact O-glycans were released by hydrazinolysis at 60 degrees C. After re-N-acetylation, the glycans were fluorophore-labeled and separated by polyacrylamide gel electrophoresis. Sequential exoglycosidase digestions of IgA1 allowed identification of the different O-glycan bands on FACE gels, and their relative frequencies in IgA1 samples were measured by ultraviolet densitometry. Lectin binding of the IgA1 samples was also measured. In some patients with IgAN, FACE analysis demonstrated a significant increase in the percentage of IgA1 O-glycan chains consisting of single N-acetyl galactosamine (GalNAc) units rather than the more usual galactosylated and sialylated forms. This finding was confirmed using both desialylated IgA1 and enzymatically released O-glycans. Good correlation was also found between O-glycan agalactosylation on FACE analysis and IgA1 lectin binding in IgAN, supporting the value of lectins as tools for detection of this abnormality. This is the first study in which all of the predicted O-glycan forms of IgA1 have been analyzed simultaneously, and demonstrates that in IgAN, the IgA1 Oglycan chains are truncated, with increased terminal GalNAc. This abnormality has the potential to significantly affect IgA1 behavior and handling with pathogenic consequences in IgAN.
Difficulties in the Use of Risk Factors to Screen for Gestational Diabetes Mellitus
Authors: David Simmons, Marion C. Devers, Louise Wolmarans, Elizabeth Johnson
Journal: Diabetes Care (2008)

Hyperglycemia and pregnancy complications are strongly associated (1), so managing gestational diabetes mellitus (GDM) reduces complications (2) and preventing progression from GDM to type 2 diabetes reduces diabetes prevalence (3). The questions of whether and how to screen for GDM, including risk-factor screening, have been widely debated (3). We hypothesized that, in New Zealand, limited use of risk factors by those undertaking screening (midwives) could contribute to the underscreening of high-risk women (3). We therefore sent to 131 midwives of the Waikato region a one-page open questionnaire about screening with a stamped, addressed envelope as well as a reminder postcard after 14 days. When appropriate, we then also followed up by telephone.

Of the 83 (63%) respondents, 75% worked full-time and 70% trained in New Zealand. Some …
DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer
Authors: Malcolm V. Brock, Craig M. Hooker, Emi Ota-Machida, Yu Han, Mingzhou Guo, Stephen Ames, Sabine Glöckner, Steven Piantadosi, Edward Gabrielson, Genevieve Pridham, Kristen Pelosky, Steven A. Belinsky, Stephen C. Yang, Stephen B. Baylin, James G. Herman
Journal: New England Journal of Medicine (2008)

Despite optimal and early surgical treatment of non-small-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor.Fifty-one patients with stage I NSCLC who underwent curative resection but who had a recurrence within 40 months after resection (case patients) were matched on the basis of age, NSCLC stage, sex, and date of surgery to 116 patients with stage I NSCLC who underwent curative resection but who did not have a recurrence within 40 months after resection (controls). We investigated whether the methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence.In a multivariate model, promoter methylation of the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of p16 and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an odds ratio of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC.Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence.