tbuckley/cabot-search huggingface dataset:
326. Zinc Finger Protein Targeted Epigenetic Gene Regulation: Toward Directed Long-Term Gene Control
Authors: Andrew R. McNamara, Andrew W. Snowden, Philip D. Gregory
Journal: Molecular Therapy (2004)

Zinc finger protein transcription factors (ZFP TFs) are capable of regulating the expression of any endogenous gene, potentially providing direct therapeutics for the treatment of disease. To extend this approach we have coupled the versatility and specificity of the ZFP DNA binding domain with non-classical effector domains implicated in long-term, epigenetic control of gene expression. The use of epigenetic mechanisms of gene regulation has multiple applications in ZFP TF-driven gene therapy, including: (i) long-term correction of the disease state (beyond the duration of expression of the ZFP TF), (ii) heritable, stable modification of gene expression in stem cells for cell-based therapies and regenerative medicine and (iii) the direct application to disease caused by the mis-regulation of epigenetic states such as cancer progression. Using a designed ZFP DNA binding domain that recognizes a defined site in the promoter of the VEGF-A gene (a gene often over-expressed in cancer) we have shown that targeting of the catalytic domain from human DNA methyltransferase 3A (DNMT3A) resulted in potent, gene-specific transcriptional repression. Crucially, this repression function was lost when an enzymatically inactive mutant of the DNMT3a domain was employed. To determine directly whether DNA methylation was concomitant with repression of the target gene, stable cell lines expressing the ZFP-DNMT3A or the catalytically null mutant version were analyzed for VEGF-A promoter specific DNA methylation within the vicinity of the ZFP binding site. Expression of the wild type ZFP-DNMT3A fusion resulted in both DNA methylation of the VEGF-A promoter, as detected by methylation-sensitive restriction enzyme analysis, and it's transcriptional repression. Significantly, expression of the mutant DNMT fusion did not influence the methylation status of the promoter, and no repression function was observed. Thus, an engineered ZFP is shown to be able to specifically address a catalytically active DNA methylation domain to a predetermined target gene, and result in both the methylation of the promoter and its transcriptional silencing. These data demonstrate that epigenetic modifications can be targeted using ZFP TFs, and raise the possibility of long term, and potentially heritable gene expression changes for therapeutic use.
Association of glucocorticoid receptor gene polymorphisms of R23K and R477H and steroid-resistant asthma in Chinese Han population
Authors: Feng Zhao, Haofeng Ouyang, Changgui Wu, Zhikui Li
Journal: European Respiratory Journal (2012)

Some previous studies have shown that steroid resistance in asthma is associated with the mutation of glucocorticoid receptor (GR) gene. Other studies, however, have reached the opposite conclusion. The aim of this study was to detect the GR polymorphisms of R23K and R477H in steroid-resistant (SR) asthma patients and steroid-sensitive (SS) asthma patients in Chinese Han population, and to elucidate the association between GR polymorphisms and steroid resistance in asthma. Sixty-four SR patients and 68 SS patients were recruited for the detection of R23K and R477H variants, using polymerase chain reaction-sequence specific primers. Cortisol contents in serum were examined. The equilibrium dissociation constants ( K  d ) were calculated by dexamethasone radioligand-binding assay and Scatchard analysis to determine GR affinity to glucocorticoids. No statistically significant difference was found in the distribution of R23K polymorphism between SR patients and SS patients. In R477H, the wild genotype GG and AA frequencies were significantly lower in SR patients than in SS patients ( P =0.043). The cortisol content in serum was found no significant difference between SR patients and SS patients, and among different genotypes. No significant differences in  K  d  were found between GG genotype and GA genotype of R23K variant, GG genotype and GA+GG genotype of R477H variant. In SR patients, the  K  d  values were significant higher than in SS patients ( P
Structure and Function of Renal Macrophages and Dendritic Cells From Lupus‐Prone Mice
Authors: Ranjit Sahu, Ramalingam Bethunaickan, Satwinder Singh, Anne Davidson
Journal: Arthritis & Rheumatology (2014)

Objective To characterize renal macrophages and dendritic cells (DCs) in 2 murine models of lupus nephritis. Methods We used a bead‐based enrichment step followed by cell sorting to isolate populations of interest from young mice and nephritic mice. Cell morphology was examined by microscopy. Arginase and nitrite production was examined using biochemical assays. The antigen‐presenting functions of the cells were determined using mixed lymphocyte reactions. Selected cytokine, chemokine, and Toll‐like receptor (TLR) profiles were examined using real‐time quantitative polymerase chain reaction. Results We identified 2 populations of macrophages and 3 populations of DCs in both of our murine models of lupus (NZB/NZW and [NZW × BXSB]F1 mice). F4/80 high macrophages, which were resident in normal kidneys and found to be increased in number during nephritis, did not produce either arginase or nitrite upon cytokine stimulation and acquired a mixed proinflammatory and antiinflammatory functional phenotype during nephritis that resembles the constitutively activated phenotype of gut F4/80 high macrophages. The various cell types differed in their expression of chemokine receptors and TLRs, consistent with variability in their renal location. Resident renal CD103+ DCs were the best antigen‐presenting cells and could easily be distinguished from CD11c high myeloid DCs that accumulated in large numbers during nephritis. Conclusion Our study highlights the heterogeneity of the macrophage/DC infiltrate in chronic lupus nephritis and provides an initial phenotypic and functional analysis of the different cellular components that can now be used to define the role of each cell subset in nephritis progression or amelioration. Of note, the dominant macrophage population that accumulates during nephritis has an acquired phenotype that is neither M1 nor M2 and may reflect failure of resolution of inflammation.
Treatment of intersex needs open discussion
Authors: M. Cull
Journal: BMJ (2002)

EDITOR—It is excellent to see surgery for ambiguous genitalia and intersex being openly discussed.1 2 3 4 5 These articles prove what patients have been saying for years, that surgery can, and does, cause damage to sexual function. This research is long overdue and most welcomed by patients and parents. I agree that cosmetic genital surgery needs to be reassessed.

Parents and patients need to have all the facts explained before opting for irreversible …
Abstract 16836: Continued Remodeling Despite Cardiac Resynchronization Therapy in Mildly Symptomatic Heart Failure Identifies Subjects at Increased Mortality: Long Term Follow-Up Results From REVERSE
Authors: Michael R Gold, Claude Daubert, William T Abraham, Stefano Ghio, Martin St. John Sutton, J Harrison Hudnall, Jeffrey Cerkvenik, Cecilia Linde
Journal: Circulation (2014)

BACKGROUND:  Adverse remodeling with left ventricular dilation is associated with increased mortality in heart failure (HF). Multiple drug and device therapies are directed at reversing the remodeling process. In this regard, Cardiac Resynchronization Therapy (CRT) is one of the most effective therapies for reverse remodeling. However, little is known regarding long term prognosis when continued LV dilation occurs despite CRT.   METHODS:  The REVERSE study randomized 419 patients (pts) with NYHA I/II HF to receive CRT with a prospectively planned 5-year long-term follow-up phase with core lab adjudicated endpoints. Of these pts, 353 had paired left ventricular end systolic volume index (LVESVi) measurements at baseline and 6 months post-implant. Pts were divided into two groups based on LVESVi change to examine their mortality rates: LVESVi increased or decreased after 6 months of CRT.   RESULTS:  Pts in whom LVESVi increased with CRT (n=89) had 29.8% mortality 4.5 years later. This was significantly higher than the 8.0% mortality rate among pts (n=264) with a reduction of LVESVi (Figure, p   CONCLUSIONS:  Continued adverse remodeling despite CRT was observed in 25% of subjects, and this was associated with tripling of long term mortality. Simple clinical factors can help identify these high risk pts in whom alternative therapies should be considered.
Abstract 15089: Relationship between Paradoxical Decrease in High-Density Lipoprotein Cholesterol Levels Following Statin Therapy and Severe Cardiovascular Event in Patients with Acute Myocardial Infarction
Authors: Tomoyuki Ota, Hideki Ishii, Susumu Suzuki, Akihito Tanaka, Naohiro Osugi, Yoshihiro Kawamura, Yohei Shibata, Yosuke Tatami, Kengo Maeda, Takahisa Kondo, Toyoaki Murohara
Journal: Circulation (2014)

Introduction: Low levels of high-density lipoprotein-cholesterol (HDL-C) are well known as an important risk factor for cardiovascular disease. In addition to lowering low-density lipoprotein-cholesterol (LDL-C), statin therapy increase HDL-C moderately. Contrary to this expectation, we sometimes have experience to paradoxical decrease in HDL-C following statin therapy. The purpose of our study was to analyze the relation between the paradoxical HDL-C decrease following statin therapy and adverse cardiovascular event in patients with acute myocardial infarction (AMI). Methods: Total of 724 AMI patients who started statins newly after initial coronary intervention were analyzed. Change in HDL-C levels (ΔHDL) was calculated as HDL-C levels at follow-up coronary angiography minus baseline HDL-C levels. These patients were divided into two groups according toΔHDL; 620 patients with ΔHDL≥0 (increase HDL group) and 104 patients with ΔHDL&lt;0 (decrease HDL group). Severe cardiovascular events were defined as all cause death, myocardial infarction and stroke. Results: Change in lipid profile and clinical outcomes were shown in table. Event-free survival curves for severe cardiovascular events appeared in figure. Multivariate analysis showed that decrease HDL and reperfusion time per hour were the independent predictor of severe cardiovascular event (hazard ratio [HR]: 2.138; 95% confidence interval [CI]: 1.106 - 4.132 and HR: 1.070; 95% CI: 1.026 - 1.117, respectively). Conclusions: Paradoxical decrease in serum HDL-C levels following statin therapy might be an independent predictor of long-term severe cardiovascular disease in patients with AMI.
Abstract 4204: Isatin analog as bruton tyrosine kinase inhibitor: A promising novel agent for multiple myeloma treatment
Authors: Krishne Gowda, Manoj K. Pandey, Arun K. Sharma, Shantu Amin
Journal: Cancer Research (2014)

Abstract Multiple myeloma (MM) is a clonal malignancy of plasma cells accumulating in the bone marrow. MM cells are highly dependent on the bone marrow (BM) microenvironment for growth and survival through interactions particularly with BM stromal cells (BMSCs), which secrete important MM growth factors and cytokines. Understanding and defining these BM factors are critical to provide the rationale to functionally target these factors and/or kinases as novel biologically based therapeutics for MM. Bruton tyrosine kinase (Btk), a non-receptor tyrosine kinase resembling the Src family, plays a key role in the development and function of normal B cells through activation of the B-cell antigen receptor signaling pathway on binding to antigens. Btk further phosphorylates PLC-γ, leading to activation of MAPK, NF-κB, and AKT signaling pathways. Earlier our group synthesized a novel series of 5,7-dibromoisatin analogs. Analogs 6, 11 and 13 were potential anti-cancer agents. In the present study, through docking studies we predicted that bromo isatin analog-11 directly interacts with Btk. We found that Isatin-11 inhibits Btk activity in a dose- and time-dependent manner. Isatin-11 down-regulates the expression of Bcl-2, Bcl-xL on MM cells. Isatin-11 also activates caspase-3 and PARP-cleavage in MM cells. Taken together, these results suggest that targeting of Btk by Isatin-11 may represent a new therapeutic strategy to treat MM. Citation Format: Krishne Gowda, Manoj K. Pandey, Arun K. Sharma, Shantu Amin. Isatin analog as bruton tyrosine kinase inhibitor: A promising novel agent for multiple myeloma treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2014-4204
Abstract 3148: Atrial Fibrillation Is Associated With Increased Risk Of Fatal And Non-fatal Cardiovascular Events In Patients With Heart Failure And Preserved Ejection Fraction - Findings From The Irbesartan In Heart Failure With Preserved Systolic Function Trial (I-PRESERVE)
Authors: Michael R Zile, Michel Komajda, Robert McKelvie, John McMurray, Mark Donovan, Agata Ptaszynska, Peter Carson, Barry M Massie
Journal: Circulation (2007)

Background: Atrial fibrillation (AF, documented by ECG) is present in 15% of patients with heart failure and a reduced LV ejection fraction (HF-REF) and is an independent predictor of cardiovascular (CV) events. The prevalence of AF in patients with HF and preserved EF (HF-PEF) and whether AF is an independent predictor of CV outcomes in HF-PEF have not been defined. Methods: The Irbesartan in Heart Failure with Preserved Systolic Function Trial (I-PRESERVE) randomized 4128 patients with an EF ≥ 45% to receive Irbesartan or placebo. The prevalence of AF was established by ECG at randomization. The “ primary” outcome (475 events/3796 patients) of all-cause mortality or CV hospitalization (myocardial infarction, stroke, worsening heart failure, atrial or ventricular arrhythmia, unstable angina) and a “ secondary” outcome (294 events/3796 patients) of HF mortality and HF hospitalizations were compared over one year of follow-up between patients with and without AF. The independent predictive role of AF was examined in a multivariable model (including symptoms, clinical history, CV examination, biochemistry, hematology). Results: In I-PRESERVE, 16% of patients had AF by ECG at randomization. Patients with AF, compared to patients without AF, were older (74 ± 0.3 vs 71 ± 0.1 yrs, mean ± SEM), less often female (54% vs 62%), had lower EF (58 ± 0.4% vs 60 ± 0.2%), lower eGFR (68 ± 0.8 vs 73 ± 0.4), higher incidence of previous HF hospitalization (61% vs 41%), less frequent history of hypertension and MI (84 &amp; 17% vs 89 &amp; 25%), lower systolic BP (134 ± 0.6 vs 137 ± 0.3 mmHg), higher heart rate (76 ± 0.5 vs 71 ± 0.2 BPM), all p &lt; 0.05. The primary and secondary outcomes occurred in 19 &amp; 15% of patients with AF and 12 &amp; 6% of patients without AF at 1 year. In a multivariate analysis AF remained a significant predictor of increased risk of the primary (Hazard Ratio, HR 1.33 [95% CI 1.07, 1.65]) and secondary (HR 1.81 [95% CI 1.40, 2.33]) outcomes. Conclusions: At randomization to I-PRESERVE, the prevalence of AF by ECG in HF-PEF patients was similar to patients with HF-REF in previous studies. HF-PEF patients with AF had a significantly worse outcome than those without AF and this increased risk of fatal and non-fatal CV events was independent of other factors associated with a worse prognosis.
Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update
Authors: Chunquan Sheng, Wannian Zhang
Journal: Medicinal Research Reviews (2012)

Abstract Fragment‐based drug design ( FBDD ) is a promising approach for the discovery and optimization of lead compounds. Despite its successes, FBDD also faces some internal limitations and challenges. FBDD requires a high quality of target protein and good solubility of fragments. Biophysical techniques for fragment screening necessitate expensive detection equipment and the strategies for evolving fragment hits to leads remain to be improved. Regardless, FBDD is necessary for investigating larger chemical space and can be applied to challenging biological targets. In this scenario, cheminformatics and computational chemistry can be used as alternative approaches that can significantly improve the efficiency and success rate of lead discovery and optimization. Cheminformatics and computational tools assist FBDD in a very flexible manner. Computational FBDD can be used independently or in parallel with experimental FBDD for efficiently generating and optimizing leads. Computational FBDD can also be integrated into each step of experimental FBDD and help to play a synergistic role by maximizing its performance. This review will provide critical analysis of the complementarity between computational and experimental FBDD and highlight recent advances in new algorithms and successful examples of their applications. In particular, fragment‐based cheminformatics tools, high‐throughput fragment docking, and fragment‐based de novo drug design will provide the focus of this review. We will also discuss the advantages and limitations of different methods and the trends in new developments that should inspire future research.
Abstract 19349: Blood Pressure Control in Community Dwelling Patients with Atrial Fibrillation: Results from the ORBIT-AF Registry
Authors: Sreekanth Vemulapalli, Sunghee Kim, Laine Thomas, Jonathan P Piccini, Manesh R Patel, Paul Chang, Gregg C Fonarow, Michael D Ezekowitz, Peter R Kowey, Kenneth W Mahaffey, Bernard J Gersh, Eric D Peterson
Journal: Circulation (2014)

Background:  Hypertension (HTN) is a risk factor for stroke and bleeding in Atrial Fibrillation (AF). We assessed the quality of systolic blood pressure (SBP) control among outpatients with AF in community practice.   Methods:  The study population included 10,132 outpatients with AF enrolled in the ORBIT-AF registry from 176 practices. Baseline SBP and history of HTN were determined and categorized as follows: 1) no history of HTN 2) controlled HTN 3) stage 1 uncontrolled HTN (SBP 140-160 mmHg) and 4) stage 2 uncontrolled HTN (SBP >160 mmHg). Among patients with a history of HTN, pooled logistic regression models were constructed to generate odds ratios for predictors of uncontrolled SBP over discrete follow-up visits.   Results:  Among 8383 patients with AF and HTN, 75.8% had their SBP controlled at baseline while 19.6% had stage 1 uncontrolled HTN, and 392 (4.7%) had stage 2 uncontrolled HTN. Over 2 years of follow-up, there was a mild improvement in SBP control rates; at 2 years of follow-up 79% of patients had controlled HTN, 17% had stage 1 uncontrolled HTN, and 4% had stage 2 uncontrolled HTN. Among those with baseline controlled HTN, 17% developed uncontrolled HTN of any stage and 66% of those with any baseline uncontrolled HTN achieved control. After adjusting for baseline SBP, factors associated with a failure to achieve follow-up SBP control include uncontrolled SBP at baseline (OR 3.04; 95% CI 2.69-3.43, p    Conclusion:  One quarter of patients with AF have uncontrolled blood pressure at baseline with only minimal improvement in overall rates of control over two years of follow-up. Females, diabetic patients, and those with a history of PCI are less likely to achieve BP control. These data suggest that opportunities remain to improve blood pressure control among those with AF in the community.
Abstract 2615: Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells
Authors: Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara
Journal: Cancer Research (2014)

Abstract Introduction: Humanized anti-HER2 monoclonal antibody, trastuzumab, has provided survival benefit to patients with HER2 positive breast cancer and advanced gastric cancer. However, the treatment with trastuzumab was limited due to low or heterogeneous HER2 positivity, insufficient effects as single agent and acquisition of resistance. To overcome these problems, we employed the adenoviral vector expressing HER2-extracellular domain (HER2-ECD), Ad/ HER2-ECD, which is designed to tag cancer cells with HER2-ECD and to sensitize them to trastuzumab, and a novel photoimmunotherapy (PIT). PIT consists of trastuzumab-conjugated with a photosensitizer, IR700 (Tmab-IR700) and irradiation with near-infrared light, induces a strong cytotoxicity on HER2 positive cancer cells. We assessed the effect of Ad/HER2-ECD and Tmab-IR700 mediated PIT in HER2 negative cancer cells. Methods: HER2 negative breast cancer cells (MCF7, MDA-MB-231) and gastric cancer cells (MKN1 and MKN45) were infected with Ad/ HER2-ECD. They were treated with Tmab-IR700 mediated PIT. We evaluated the HER2-ECD expression induced by Ad/ HER2-ECD and the cytotoxic effects of Tmab-IR700 mediated PIT. Results: Ad/HER2-ECD efficiently expressed HER2 protein on the surface of the cancer cells. HER2-ECD expressing cells were selectively and rapidly killed by Tmab-IR700 mediated PIT, which was morphologically captured as bleb formation of cellular membrane. Conclusions: We demonstrated that Ad/ HER-ECD combined with Tmab-IR700 mediated PIT could induce target-selective, immediate cell death in HER2 negative cancer cells. The combination therapy of adenoviral gene transfer of HER2-ECD and the molecular-target PIT is effective for cancer cells regardless of HER2 expression. Citation Format: Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara. Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2615. doi:10.1158/1538-7445.AM2014-2615
Mental Health Drugs Exempt
Authors: Mike Mitka
Journal: JAMA (2006)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Full House: The Spread of Excellence from Plato to Darwin., by Stephen Jay Gould
Authors: C. Weijer
Journal: BMJ (1997)

Stephen Jay Gould / Harmony Books, $25, pp 244 ISBN 0 517 70394 7

The median is not the message, and neither, says evolutionary biologist Stephen Jay Gould, is the mean or the maximum. To avoid erroneous conclusions about a “biological system”–be it baseball, life on earth, or cancer—you must examine the total variation within a system, the “full house” of all cases, and not merely one narrow aspect of it. Gould challenges two widely accepted claims. Firstly, that the decline this century of very …