tbuckley/cabot-search huggingface dataset:
An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases
Authors: Jieliang Chen, Wen Zhang, Junyu Lin, Fan Wang, Min Wu, Cuncun Chen, Ye Zheng, Xiuhua Peng, Jianhua Li, Zhenghong Yuan
Journal: Molecular Therapy (2013)

The hepatitis B virus (HBV) is a DNA virus that can cause chronic hepatitis B (CHB) in humans. Current therapies for CHB infection are limited in efficacy and do not target the pre-existing viral genomic DNA, which are present in the nucleus as a covalently closed circular DNA (cccDNA) form. The transcription activator-like (TAL) effector nucleases (TALENs) are newly developed enzymes that can cleave sequence-specific DNA targets. Here, TALENs targeting the conserved regions of the viral genomic DNA among different HBV genotypes were constructed. The expression of TALENs in Huh7 cells transfected with monomeric linear full-length HBV DNA significantly reduced the viral production of HBeAg, HBsAg, HBcAg, and pgRNA, resulted in a decreased cccDNA level and misrepaired cccDNAs without apparent cytotoxic effects. The anti-HBV effect of TALENs was further demonstrated in a hydrodynamic injection-based mouse model. In addition, an enhanced antiviral effect with combinations of TALENs and interferon-α (IFN-α) treatment was observed and expression of TALENs restored HBV suppressed IFN-stimulated response element-directed transcription. Taken together, these data indicate that TALENs can specifically target and successfully inactivate the HBV genome and are potently synergistic with IFN-α, thus providing a potential therapeutic strategy for treating CHB infection. The hepatitis B virus (HBV) is a DNA virus that can cause chronic hepatitis B (CHB) in humans. Current therapies for CHB infection are limited in efficacy and do not target the pre-existing viral genomic DNA, which are present in the nucleus as a covalently closed circular DNA (cccDNA) form. The transcription activator-like (TAL) effector nucleases (TALENs) are newly developed enzymes that can cleave sequence-specific DNA targets. Here, TALENs targeting the conserved regions of the viral genomic DNA among different HBV genotypes were constructed. The expression of TALENs in Huh7 cells transfected with monomeric linear full-length HBV DNA significantly reduced the viral production of HBeAg, HBsAg, HBcAg, and pgRNA, resulted in a decreased cccDNA level and misrepaired cccDNAs without apparent cytotoxic effects. The anti-HBV effect of TALENs was further demonstrated in a hydrodynamic injection-based mouse model. In addition, an enhanced antiviral effect with combinations of TALENs and interferon-α (IFN-α) treatment was observed and expression of TALENs restored HBV suppressed IFN-stimulated response element-directed transcription. Taken together, these data indicate that TALENs can specifically target and successfully inactivate the HBV genome and are potently synergistic with IFN-α, thus providing a potential therapeutic strategy for treating CHB infection.
Severity assessment of healthcare-associated pneumonia and pneumonia in immunosuppression
Authors: Maria Carrabba, Marina Zarantonello, Paola Bonara, Cinzia Hu, Francesca Minonzio, Ivan Cortinovis, Silvano Milani, Giovanna Fabio
Journal: European Respiratory Journal (2012)

The study compares the ability of the PSI (pneumonia severity index), CURB-65 (confusion, urea &gt;7 mol·L −1 , respiratory rate ≥30 breaths·min −1 , blood pressure &lt;90 mmHg systolic or ≤60 mmHg diastolic, and age ≥65 yrs), CURB and CRB-65 scales and the Severe Community-Acquired Pneumonia (SCAP) score to predict 30-day mortality in healthcare-associated pneumonia (HCAP) patients, and analyses differences in the demographics, aetiology and outcomes of community-acquired pneumonia (CAP), HCAP and pneumonia in immunocompromised patients. 629 consecutive patients admitted to a tertiary care university hospital were prospectively categorised as having CAP (n=322) or HCAP (n=307), and the HCAP patients were further sub-divided into those who were immunocompromised (n=219) or immunocompetent (n=88). The 30-day mortality rate was 9.0% in the CAP group and 24.1% in the HCAP group. In the HCAP group, the PSI and SCAP scores had similar prognostic power (area under the curve (AUC) of 0.68 and 0.67, respectively) and performed better than the CURB-65 score (AUC ≤0.62). Among the immunocompetent HCAP patients, the PSI and CURB-65 scores were more sensitive than the others at every threshold, whereas SCAP was more specific than both of these. In the immunocompromised group, the PSI was highly sensitive but poorly specific at all thresholds. Our results suggest that prognostic tools should be designed for subsets of HCAP patients.
Synergistic <i>In vivo</i> Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma
Authors: Yukihiko Kato, Kiyoshi Yoshimura, Tahiro Shin, Henk Verheul, Hans Hammers, Tolib B. Sanni, Brenda C. Salumbides, Karen Van Erp, Richard Schulick, Roberto Pili
Journal: Clinical Cancer Research (2007)

Abstract Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration–approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase–expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (&amp;gt;80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (∼40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (&amp;gt;90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4+CD25+ T cells and Foxp3+ T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8+ T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.
Enhancement of the Tumorigenicity of Preneoplastic Mammary Nodule Lines by Enzymatic Dissociation2
Authors: Daniel Medina, F. Shepherd, T. Gropp
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Enhancement of the Tumorigenicity of Preneoplastic Mammary Nodule Lines by Enzymatic Dissociation Get access Daniel Medina, Daniel Medina Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Shepherd, F. Shepherd Search for other works by this author on: Oxford Academic PubMed Google Scholar T. Gropp T. Gropp Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 5, May 1978, Pages 1121–1126, https://doi.org/10.1093/jnci/60.5.1121 Published: 01 May 1978 Article history Received: 18 August 1977 Accepted: 29 November 1977 Published: 01 May 1978
Volume-Outcome Relation for Physicians and Hospitals Performing Angioplasty for Acute Myocardial Infarction in New York State
Authors: Babak A. Vakili, Robert Kaplan, David L. Brown
Journal: Circulation (2001)

An inverse relation exists between the number of coronary angioplasty procedures performed by physicians or hospitals and short-term mortality. It is not known, however, whether a similar relation holds for physicians and hospitals that perform primary angioplasty for acute myocardial infarction.We analyzed data from the 1995 New York State Coronary Angioplasty Reporting System Registry to determine the relation between the number of primary angioplasty procedures performed by physicians and hospitals and in-hospital mortality. Patients who underwent angioplasty procedures within 23 hours of onset of acute myocardial infarction without preceding thrombolytic therapy were included (n=1342). In-hospital mortality was reduced 57% among patients who underwent primary angioplasty by high-volume as opposed to low-volume physicians (adjusted relative risk 0.43; 95% CI 0.21 to 0.83). When patients with acute myocardial infarction were treated with primary angioplasty in high-volume hospitals rather than low-volume institutions, the relative risk reduction for in-hospital mortality was 44% (adjusted relative risk 0.56; 95% CI 0.29 to 1.1). Compared with patients treated at low-volume hospitals by low-volume physicians, patients treated at high-volume hospitals by high-volume physicians had a 49% reduction in the risk of in-hospital mortality (adjusted relative risk 0.51; 95% CI 0.26 to 0.99).Among hospitals in New York State, a higher volume of primary angioplasty procedures performed by physicians and/or hospitals was associated with a lower mortality rate.
Loss of Nav1.5 expression and function in murine atria containing the RyR2-P2328S gain-of-function mutation
Authors: James H. King, Chandu Wickramarachchi, Krystine Kua, Yuan Du, Kamalan Jeevaratnam, Hugh R. Matthews, Andrew A. Grace, Christopher L.-H. Huang, James A. Fraser
Journal: Cardiovascular Research (2013)

Recent studies reported slowed conduction velocity (CV) in murine hearts homozygous for the gain-of-function RyR2-P2328S mutation (RyR2S/S) and associated this with an increased incidence of atrial and ventricular arrhythmias. The present experiments determined mechanisms contributing to the reduced atrial CV. The determinants of CV were investigated in murine RyR2S/S hearts and compared with those in wild-type (WT) and slow-conducting Scn5a+/− hearts. Picrosirius red staining demonstrated increased fibrosis only in Scn5a+/− hearts. Immunoblot assays showed similar expressions of Cx43 and Cx40 levels in the three genotypes. In contrast, Nav1.5 expression was reduced in both RyR2S/S and Scn5a+/− atria. These findings correlated with intracellular microelectrode and loose-patch-clamp studies. Microelectrode measurements showed reduced maximum rates of depolarization in Scn5a+/− and RyR2S/S atria compared with WT, despite similar diastolic membrane potentials. Loose-patch-clamp measurements demonstrated reduced peak Na+ currents (INa) in the Scn5a+/− and RyR2S/S atria relative to WT, with similar normalized current–voltage relationships. In WT atria, reduction in INa could be produced by treatment with high extracellular Ca2+, caffeine, or cyclopiazonic acid, each expected to produce an acute increase in [Ca2+]i. RyR2S/S atria show reduced levels of Nav1.5 expression and Na+ channel function. Reduced Na+ channel function was also observed in WT atria, following acute increases in [Ca2+]i. Taken together, the results suggest that raised [Ca2+]i produces both acute and chronic inhibition of Na+ channel function. These findings may help explain the relationship between altered Ca2+ homeostasis, CV, and the maintenance of common arrhythmias such as atrial fibrillation.
What patients account for the post-socialist increase in pulmonary tuberculosis?
Authors: Alan Altraja, Piret Viiklepp, Kai Kliiman, Heinart Sillastu, Lea Pehme
Journal: European Respiratory Journal (2011)

Background:  After a steady decline in tuberculosis (TB) from 1954 (417/10 5 /yr) to 1992 (21/10 5 /yr), along with the overwhelming societal and health care changes after independence was declared in 1991, Estonia experienced a resurgence of TB incidence since 1993, which peaked at 47.5/10 5 /yr in 1998, without immigration playing a major role.   Aims:  To reveal whether patients with particular characteristics accounted for the increasing incidence of pulmonary TB (PTB) in the changed societal conditions (1995–2003) compared to the “low incidence period with a decrease” (1985–1991) to determine the populations under significant risk in such circumstances.   Methods:  TB-related characteristics of all PTB cases diagnosed during 1985–1991 (n=362, median age 43.0 yr) and 1995–2003 (n=668, median age 44 yr) in Tartu city and county in Estonia were subjected to logistic regression analysis to find determinants of PTB characteristic of the independence period.   Results:  During independence, there were significantly more smear-positive patients (OR 2.39, 95%CI 1.57-3.64), those who sought help because of symptoms (OR 2.40, 95%CI 1.73-3.31), and those who had had TB contact (OR 5.03, 95%CI 3.68-6.88), but significantly less alcohol abusers (OR 0.60, 95%CI 0.42-0.87), smokers (OR 0.57, 95%CI 0.41-0.81), and those with a cavitary (OR 0.66, 95%CI 0.46-0.96) and a limited disease (OR 0.55, 95%CI 0.31-0.95).   Conclusions:  Despite continuously free access to care for TB, the common social groups like non-alcoholics and non-smokers more often fall ill with culture-confirmed non-limited PTB and account for the increased incidence of TB after the post-socialist changes.  Funded by an ESF grant No. 8118.
Radioimmunoassay for Measurement of Thyroglobulin in Human Serum
Authors: A. J. Van Herle, R. P. Uller, N. L. Matthews, Josiah Brown
Journal: Journal of Clinical Investigation (1973)

A specific and reproducible double antibody radioimmunoassay for the measurement of thyroglobulin (HTg) in human serum has been developed. Since antithyroglobulin autoantibodies combine with the [131I] HTg tracer, antibody-positive sera were rejected for measurement. Specificity is demonstrated in that thyroid analogous such as thyroxine (T4), triiodothyronine (T2) monoiodotyrosine (MIT) and diiodotyrosine (DIT) did not crossreact. Sera previously reacted with anti-HTg-Sepharose contained no immunoassayable HTg. Finally, sera obtained from patients after total thyroid ablation for thyroid carcinoma did not contain demonstrable HTg. The sensitivity of the assay is 1.6 ng/ml, and HTg was detectable in 74% of 95 normal subjects. The mean concentration was 5.1 ng/ml ±0.49 SEM (range <1.6-20.7 ng/ml). Day to day variation in HTg levels is large in some euthyroid subjects and nearly absent in others. HTg was detectable in 90% of the sera obtained in 23 pregnant women at delivery in whom a mean concentration of 10.1 ng/ml ±1.3 SEM was observed. The mean level for the corresponding newborn infants at birth was 29.3 ng/ml ±4.7 SEM a value significantly higher than the mean maternal HTg concentration (P <0.01). A group of 17 thyrotoxic individuals all had elevated HTg levels; the mean for this group was 344.8 ng/ml ±90.7 SEM. In the acute phase of subacute thyroiditis HTg was also elevated in all of 12 patients, and the mean for this group was 136.8 ng/ml ±74.6 SEM.
Susceptible Stages in Schwann Cells for NF1-Associated Plexiform Neurofibroma Development
Authors: Lu Q. Le, Chiachi Liu, Tracey Shipman, Zhiguo Chen, Ueli Suter, Luis F. Parada
Journal: Cancer Research (2011)

Stem cells are under strict regulation by both intrinsic factors and the microenvironment. There is increasing evidence that many cancers initiate through acquisition of genetic mutations (loss of intrinsic control) in stem cells or their progenitors, followed by alterations of the surrounding microenvironment (loss of extrinsic control). In neurofibromatosis type 1 (NF1), deregulation of Ras signaling results in development of multiple neurofibromas, complex tumors of the peripheral nerves. Neurofibromas arise from the Schwann cell lineage following loss of function at the NF1 locus, which initiates a cascade of interactions with other cell types in the microenvironment and additional cell autonomous modifications. In this study, we sought to identify whether a temporal "window of opportunity" exists during which cells of the Schwann cell lineage can give rise to neurofibromas following loss of NF1. We showed that acute loss of NF1 in both embryonic and adult Schwann cells can lead to neurofibroma formation. However, the embryonic period when Schwann cell precursors and immature Schwann cells are most abundant coincides with enhanced susceptibility to plexiform neurofibroma tumorigenesis. This model has important implications for understanding early cellular events that dictate neurofibroma development, as well as for the development of novel therapies targeting these tumors.
Guidelines of tuberculosis preventive therapy for HIV-infected persons: a prospective, multicentre study
Authors: G. Antonucci, E. Girardi, M. Raviglione, P. Vanacore, G. Angarano, A. Chirianni, G. Pagano, F. Suter, F.N. Lauria, G. Ippolito
Journal: European Respiratory Journal (2001)

The aim of this study was to assess the degree of implementation of national guidelines for isoniazid preventive therapy (IPT) among human immunodeficiency virus (HIV)-infected individuals and factors affecting the impact of the programme. Twenty-eight infectious disease hospital units in Italy participated in this observational, multicentre, prospective cohort study. A number of HIV-infected subjects, (n=1,705) seen for the first time as outpatients, were included in this analysis. Of the subjects considered, 1,215 out of the 1,705 completed purified protein derivative (PPD) screening. Variables independently associated with offering and completion of PPD screening included having acquired immune deficiency syndrome (AIDS), higher educational levels and currently receiving therapy. Overall, 103 subjects were identified as candidates for IPT. Of these subjects, five had tuberculosis and 15 had contraindications to IPT. Forty subjects agreed to start IPT, and 29 completed a full-course regimen. The incidence of tuberculosis among IPT candidates who either did not begin or discontinued IPT was 6.1 per 100 person-yrs, while no cases of tuberculosis were observed in subjects completing IPT. Several factors may limit the implementation of an isoniazid preventive therapy programme for human immunodeficiency virus-infected persons. Physicians fail to offer purified protein derivative screening to patients with high degrees of immunodeficiency, and those with a more intense workload seem to pay less attention to this test. The high number of contraindications among patients and their low level of acceptance further affects the impact of isoniazid preventive therapy.
Prevention of Syncope Trial (POST)
Authors: Robert Sheldon, Stuart Connolly, Sarah Rose, Thomas Klingenheben, Andrew Krahn, Carlos Morillo, Mario Talajic, Teresa Ku, Fetnat Fouad-Tarazi, Debbie Ritchie, Mary-Lou Koshman
Journal: Circulation (2006)

Previous studies that assessed the effects of beta-blockers in preventing vasovagal syncope provided mixed results. Our goal was to determine whether treatment with metoprolol reduces the risk of syncope in patients with vasovagal syncope.The multicenter Prevention of Syncope Trial (POST) was a randomized, placebo-controlled, double-blind, trial designed to assess the effects of metoprolol in vasovagal syncope over a 1-year treatment period. Two prespecified analyses included the relationships of age and initial tilt-test results to any benefit from metoprolol. All patients had >2 syncopal spells and a positive tilt test. Randomization was stratified according to ages <42 and > or =42 years. Patients received either metoprolol or matching placebo at highest-tolerated doses from 25 to 200 mg daily. The main outcome measure was the first recurrence of syncope. A total of 208 patients (mean age 42+/-18 years) with a median of 9 syncopal spells over a median of 11 years were randomized, 108 to receive metoprolol and 100 to the placebo group. There were 75 patients with > or =1 recurrence of syncope. The likelihood of recurrent syncope was not significantly different between groups. Neither the age of the patient nor the need for isoproterenol to produce a positive tilt test predicted subsequent significant benefit from metoprolol.Metoprolol was not effective in preventing vasovagal syncope in the study population.
Influence of Igh-linked gene products on the generation of T helper cells in the response to sheep erythrocytes.
Authors: N Nutt, J Haber, H H Wortis
Journal: The Journal of Experimental Medicine (1981)

The role of Igh-linked loci in the generation and expression of T cell help for antibody responses to sheep erythrocytes (SRBC) was investigated. The production of IgM, IgG3, IgG1, IgG2b, and IgG2a antibody to SRBC was shown to be T cell dependent. The Igh-congenic mouse pair CBA/Tufts (Ighj) and CBA.Ighb gave equivalent responses to SRBC. CBA.nude mice (Ighj) supplemented with peripheral T cells of either Ighj or Ighb genotype produced equivalent, high responses. Therefore, T cell-B cell mismatching for the Igh haplotype is not in itself a bar to the generation or expression of help. In contrast, T cells primed in an environment that lacks Ighj-linked products are inefficient helpers for Ighj B cells. These results suggest that antigen-primed B cells or their products prime a set of T cells that can help B cells that bear matching, Igh-linked gene products.
Truncation of Titin’s Elastic PEVK Region Leads to Cardiomyopathy With Diastolic Dysfunction
Authors: Henk L. Granzier, Michael H. Radke, Jun Peng, Dirk Westermann, O. Lynne Nelson, Katharina Rost, Nicholas M.P. King, Qianli Yu, Carsten Tschöpe, Mark McNabb, Douglas F. Larson, Siegfried Labeit, Michael Gotthardt
Journal: Circulation Research (2009)

The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region.The purpose of this study was to investigate the contribution of titin's proline-glutamate-valine-lysine (PEVK) region to biomechanics and growth of the heart.We removed a portion of the PEVK segment (exons 219 to 225; 282 aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element.Titin's PEVK region contributes to the elastic properties of the cardiac ventricle. Our findings are consistent with a model in which strain of the N2B spring element and expression of FHL proteins trigger cardiac hypertrophy. These novel findings provide a molecular basis for the future differential therapy of isolated diastolic dysfunction versus more complex cardiomyopathies.