tbuckley/cabot-search huggingface dataset:
MicroRNA-22 Regulates Cardiac Hypertrophy and Remodeling in Response to Stress
Authors: Zhan-Peng Huang, Jinghai Chen, Hee Young Seok, Zheng Zhang, Masaharu Kataoka, Xiaoyun Hu, Da-Zhi Wang
Journal: Circulation Research (2013)

The adult heart is composed primarily of terminally differentiated, mature cardiomyocytes that express signature genes related to contraction. In response to mechanical or pathological stress, the heart undergoes hypertrophic growth, a process defined as an increase in cardiomyocyte cell size without an increase in cell number. However, the molecular mechanism of cardiac hypertrophy is not fully understood.To identify and characterize microRNAs that regulate cardiac hypertrophy and remodeling.Screening for muscle-expressed microRNAs that are dynamically regulated during muscle differentiation and hypertrophy identified microRNA-22 (miR-22) as a cardiac- and skeletal muscle-enriched microRNA that is upregulated during myocyte differentiation and cardiomyocyte hypertrophy. Overexpression of miR-22 was sufficient to induce cardiomyocyte hypertrophy. We generated mouse models with global and cardiac-specific miR-22 deletion, and we found that cardiac miR-22 was essential for hypertrophic cardiac growth in response to stress. miR-22-null hearts blunted cardiac hypertrophy and cardiac remodeling in response to 2 independent stressors: isoproterenol infusion and an activated calcineurin transgene. Loss of miR-22 sensitized mice to the development of dilated cardiomyopathy under stress conditions. We identified Sirt1 and Hdac4 as miR-22 targets in the heart.Our studies uncover miR-22 as a critical regulator of cardiomyocyte hypertrophy and cardiac remodeling.
Docosahexaenoic Acid and Smoking-Related Chronic Obstructive Pulmonary Disease
Authors: EYAL SHAHAR, LORI L. BOLAND, AARON R. FOLSOM, MELVYN S. TOCKMAN, PAUL G. McGOVERN, JOHN H. ECKFELDT
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

If the inflammatory response to inhalation of cigarette smoke causes chronic obstructive pulmonary disease (COPD), suppression of that natural response might be beneficial. We hypothesized that a smoker's risk of developing COPD is inversely related to physiologic levels of two fatty acids that have antiinflammatory properties: eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6). The proportion of each fatty acid in plasma lipids was measured in 2,349 current or former smokers. COPD was identified and defined by clinical symptoms and/or spirometry. After adjustment for smoking exposure and other possible confounders, the prevalence odds of COPD were inversely related to the DHA (but not to the EPA) content of plasma lipid components in most of the models. For example, as compared with the first quartile of the DHA distribution, the prevalence odds ratios (ORs) for chronic bronchitis were 0.98, 0.88, and 0.69 for the second, third, and fourth quartiles, respectively (p for linear trend = 0.09). The corresponding ORs for COPD as defined spirometrically, were 0.65, 0.51, and 0.48 (p < 0.001). Among 543 current heavy smokers, adjusted mean values of FEV1 (lowest to highest DHA quartile) were 2,706, 2,785, 2,801, and 2,854 ml. DHA may have a role in preventing or treating COPD and other chronic inflammatory conditions of the lung. Pilot testing of that hypothesis in experimental models seems warranted.
Mutations in<i>VANGL1</i>Associated with Neural-Tube Defects
Authors: Zoha Kibar, Elena Torban, Jonathan R. McDearmid, Annie Reynolds, Joanne Berghout, Melissa Mathieu, Irena Kirillova, Patrizia De Marco, Elisa Merello, Julie M. Hayes, John B. Wallingford, Pierre Drapeau, Valeria Capra, Philippe Gros
Journal: New England Journal of Medicine (2007)

Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting. In a protein-protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3. These findings implicate VANGL1 as a risk factor in human neural-tube defects.
Sleep Duration and Breast Cancer: A Prospective Cohort Study
Authors: Pia K. Verkasalo, Kirsi Lillberg, Richard G. Stevens, Christer Hublin, Markku Partinen, Markku Koskenvuo, Jaakko Kaprio
Journal: Cancer Research (2005)

Abstract Breast cancer incidence has increased during recent decades for reasons that are only partly understood. Prevalence of sleeping difficulties and sleepiness has increased, whereas sleeping duration per night has decreased. We hypothesized that there is an inverse association between sleep duration and breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. This population-based study includes information from women born in Finland before 1958. Sleep duration, other sleep variables, and breast cancer risk factors were assessed by self-administered questionnaires given in 1975 and in 1981. Breast cancer incidence data for 1976 to 1996 was obtained from the Finnish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox proportional hazards models adjusting for potential confounders. Altogether, 242 cases of breast cancer occurred over the study period among the 12,222 women with sleep duration data in 1975. For these women, the HRs for breast cancer in the short (≤6 hours), average (7-8 hours), and long sleep (≥9 hours) duration groups were 0.85 (CI, 0.54-1.34), 1.0 (referent), and 0.69 (CI, 0.45-1.06), respectively. Analysis restricted to the 7,396 women (146 cases) whose sleep duration in 1975 and 1981 were in the same duration group (stable sleepers) yielded HRs of 1.10 (CI, 0.59-2.05), 1.0, and 0.28 (CI, 0.09-0.88), with a decreasing trend (P = 0.03). This study provides some support for a decreased risk of breast cancer in long sleepers.
Trps1 Haploinsufficiency Promotes Renal Fibrosis by Increasing Arkadia Expression
Authors: Zhibo Gai, Gengyin Zhou, Ting Gui, Shunji Itoh, Kosuke Oikawa, Kohsaku Uetani, Yasuteru Muragaki
Journal: Journal of the American Society of Nephrology (2010)

Mutations in <i>TRPS1</i> cause tricho-rhino-pharyngeal syndrome (TRPS). Trps1 is essential for nephron development, acting downstream of Bmp7. Because Bmp7 counteracts epithelial-to-mesenchymal transition (EMT) and reverses chronic renal injury, we examined the function of Trps1 in renal fibrosis. Immunohistochemistry revealed Trps1 expression in proximal tubular epithelial cells of mice. Unilateral ureteral obstruction reduced mRNA and protein expression of Trps1 in wild-type and heterozygous Trps1-knockout (<i>Trps1</i><sup>+/−</sup>) mice. Trps1 haploinsufficiency promoted tubulointerstitial fibrosis via increased phosphorylation of Smad3 and decreased Smad7 protein. In primary culture, Trps1 deficiency promoted TGF-β1-mediated EMT in proximal tubule cells. <i>Trps1</i><sup>+/−</sup>-derived cells had higher levels of phosphorylated Smad3, and TGF-β1 induced a time-dependent decrease in Smad7 protein in wild-type and <i>Trps1</i><sup>+/−</sup> kidneys. In addition, compared with wild-type cells, <i>Trps1</i><sup>+/−</sup> cells had double the amount of the E3 ubiquitin ligase Arkadia, and TGF-β1 induced further Arkadia expression. Furthermore, knockdown of Arkadia inhibited TGF-β1-induced EMT in <i>Trps1</i><sup>+/−</sup> cells. Collectively, these data suggest that Trps1 haploinsufficiency enhances TGF-β1-induced EMT and tubulointerstitial fibrosis by modulating the amount of Smad7 through Arkadia/ubiquitin-mediated degradation.
Anxiety, depression and alexithymia in patients with obstructive sleep apnea syndrome
Authors: Silvia Dumitru, Dionissios Bratis, Sotirios Gyftopoulos, Athanassios Tselebis, Ioannis Xazapis, Katerina Chronopoulou, Epaminondas Kosmas
Journal: European Respiratory Journal (2011)

We attempted to investigate anxiety (with Spielberger9s Trait Anxiety), depression (with Beck Depression Inventory) and alexithymia (with Toronto Alexithymia Scale) in patients with newly diagnosed obstructive sleep apnea syndrome (OSAS) with an Apnea-Hypopnea Index (AHI) ≥ 5 events/hour. We present our results from 32 consecutive patients (age 51±9 years, AHI 54±16 events/hour, no significant cardiac or other comorbidities) who have performed full night polysomnography due to symptoms, sucha as snoring, disrupted sleep, witnessed apneas, morning headache, morning fatigue and daily hypersomnolence (estimated by Epworth Scale).We have found that 56.25% of patients had clinically important anxiety, 62.50% depression and 46.87% alexithymia. Apart from a weak correlation between anxiety and sleep latency, there was not any other correlation between the above psychologic parameters and age, AHI, nocturnal oxygenation and sleep efficiency. We found a cut-off level of AHI ≥ 70 events/hour and age ≥ 60 years old in combination, where all 9 patients in that specific subgroup had anxiety, depression and alexithymia. In conclusion, the incidence of anxiety, depression and alexithymia is significantly higher in OSAS patients as compared to the general population.Older age and more severe OSAS are factors predisposing to these psychologic disturbances. However, not any correlation has been found between the psychologic profile and severity of OSAS, abnormal oxygenation or sleep quality. Probably, other factors, unknown as of yet, may play a role.
Chimeric NKG2D–Modified T Cells Inhibit Systemic T-Cell Lymphoma Growth in a Manner Involving Multiple Cytokines and Cytotoxic Pathways
Authors: Tong Zhang, Amorette Barber, Charles L. Sentman
Journal: Cancer Research (2007)

Abstract In this study, the efficacy and mechanisms of chimeric NKG2D receptor (chNKG2D)–modified T cells in eliminating NKG2D ligand–positive RMA/Rae1 lymphoma cells were evaluated. Intravenous injection of RMA/Rae1 cells led to significant tumor formation in spleens and lymph nodes within 2 weeks. Adoptive transfer of chNKG2D-modified T cells after tumor injection significantly reduced tumor burdens in both spleens and lymph nodes, and prolonged the survival of tumor-bearing mice. Multiple treatments with chNKG2D T cells resulted in long-term tumor-free survival. Moreover, these long-term survivors were resistant to rechallenge with RMA tumor cells (NKG2D ligand–negative), and their spleen and lymph node cells produced IFN-γ in response to RMA but not to other tumors in vitro, indicating immunity against RMA tumor antigens. ChNKG2D T cell–derived IFN-γ and granulocyte-macrophage colony–stimulating factor, but not perforin (Pfp), tumor necrosis factor–related apoptosis-inducing ligand, or Fas ligand (FasL) alone were critical for in vivo efficacy. T cells deficient in both Pfp and FasL did not kill NKG2D ligand–positive RMA cells in vitro. Adoptive transfer of Pfp−/−FasL−/− chNKG2D T cells had reduced in vivo efficacy, indicating that chNKG2D T cells used both mechanisms to attack RMA/Rae1 cells. Taken together, these results indicate that chNKG2D T-cell–mediated therapeutic effects are mediated by both cytokine-dependent and cytotoxic mechanisms in vivo. [Cancer Res 2007;67(22):11029–36]
Interplay of RUNX1/MTG8 and DNA Methyltransferase 1 in Acute Myeloid Leukemia
Authors: Shujun Liu, Tiansheng Shen, Lenguyen Huynh, Marko I. Klisovic, Laura J. Rush, Jamie L. Ford, Jianhua Yu, Brian Becknell, Yu Li, Chunhui Liu, Tamara Vukosavljevic, Susan P. Whitman, Kun-Sang Chang, John C. Byrd, Danilo Perrotti, Christoph Plass, Guido Marcucci
Journal: Cancer Research (2005)

Abstract The translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) results in the expression of the fusion protein RUNX1/MTG8, which in turn recruits histone deacetylases (HDAC) to silence RUNX1 target genes [e.g., interleukin-3 (IL-3)].We previously reported that expression of the RUNX1/MTG8 target gene IL-3 is synergistically restored by the combination of inhibitors of HDACs (i.e., depsipeptide) and DNA methyltransferases (DNMT; i.e., decitabine) in RUNX1/MTG8-positive Kasumi-1 cells. Thus, we hypothesized that DNMT1 is also part of the transcriptional repressor complex recruited by RUNX1/MTG8. By a chromatin immunoprecipitation assay, we identified a RUNX1/MTG8-DNMT1 complex on the IL-3 promoter in Kasumi-1 cells and in primary RUNX1/MTG8-positive AML blasts. The physical association of RUNX1/MTG8 with DNMT1 was shown by coimmunoprecipitation experiments. Furthermore, RUNX1/MTG8 and DNMT1 were concurrently released from the IL-3 promoter by exposure to depsipeptide or stabilized on the promoter by decitabine treatment. Finally, we proved that RUNX1/MTG8 and DNMT1 were functionally interrelated by showing an enhanced repression of IL-3 after coexpression in 293T cells. These results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML.
Regulation of Metabolism and Body Fat Mass by Leptin
Authors: Clifton A. Baile, Mary Anne Della-Fera, Roy J. Martin
Journal: Annual Review of Nutrition (2000)

The relative stability of body weight over the long term and under a variety of environmental conditions that alter short-term energy intake and expenditure provides strong evidence for the regulation of body energy content. The lipostatic theory of energy balance regulation proposed 40 years ago that circulating factors, generated in proportion to body fat stores, acted as signals to the brain, eliciting changes in energy intake and expenditure. The discovery of leptin and its receptors has now provided a molecular basis for this theory. Leptin functions as much more than an adipocyte-derived signal of lipid stores, however. Although suppression of food intake is an important centrally mediated effect of leptin, considerable evidence indicates that leptin also functions both directly and indirectly, via the brain, to orchestrate complex metabolic changes in a number of organs and tissues, altering nutrient flux to favor energy expenditure over energy storage.
Estimates of benefits and harms of prophylactic use of aspirin in the general population
Authors: J. Cuzick, M.A. Thorat, C. Bosetti, P.H. Brown, J. Burn, N.R. Cook, L.G. Ford, E.J. Jacobs, J.A. Jankowski, C. La Vecchia, M. Law, F. Meyskens, P.M. Rothwell, H.J. Senn, A. Umar
Journal: Annals of Oncology (2014)

BackgroundAccumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population.MethodsThe effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer.ResultsThe effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50–65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period.ConclusionsProphylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit–harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening–eradication before starting aspirin prophylaxis.
622 SAFETY AND EFFICACY OF YTTRIUM-90 MICROSPHERES FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA: A SINGLE CENTER EXPERIENCE
Authors: F. Abaalkhail, W. Al-Hamoudi, M. Al Sebayel, H. Alsuhaibani, Y. Kamel, H. Khalaf, H. Al-Bahili, A. Abdo
Journal: Journal of Hepatology (2011)
Enigma in cardiac hypertrophy
Authors: A. M. Lompre
Journal: Cardiovascular Research (2010)

The Enigma subfamily belongs to the PDZ- (for PSD-95, DLG, ZO-1) and LIM- (for LIN-11, Isl-1, MEC-3) encoding protein family. This family is composed of at least four different members: Enigma (also called PD-LIM7; LMP-1), Enigma homologue (ENH), ZASP/Cypher/Oracle, and LMP-4. All members of the PDZ–LIM Enigma family, including ENH, are cytoplasmic proteins that bind to the cytoskeleton through a direct interaction between their PDZ domain and α-actinin,1 thus localizing the protein to the Z-disk of cardiac myocytes.2 The LIM domain is a cysteine-rich domain, composed of two independent zinc-coordinated fingers, that has been proposed to participate in protein–protein interactions. ENH1 was first identified as an adaptor for protein kinase C (PKC) by using a yeast two-hybrid system. PKC binds to any of the three LIM domains of ENH1 in an isoform-specific manner.3 In neurons, ENH1 recruits PKCe to the N-type voltage-gated Ca2+ channel.4 The LIM2 motif of ENH1 has also been shown to bind protein kinase … 

*Corresponding author. Tel: +33 1 4077 9681; fax: +33 1 4077 9645, Email: anne-marie.lompre{at}upmc.fr
Evolution of Ultrasmall Spliceosomal Introns in Highly Reduced Nuclear Genomes
Authors: C. H. Slamovits, P. J. Keeling
Journal: Molecular Biology and Evolution (2009)

Intron reduction and loss is a significant component of genome compaction in many eukaryotic lineages, including yeasts, microsporidia, and some nucleomorphs. Nucleomorphs are the extremely reduced relicts of algal endosymbiont nuclei found in two lineages, cryptomonads and chlorarachniophytes. In cryptomonads, introns are rare or even lost altogether. In contrast, the nucleomorph of the chlorarachniophyte Bigelowiella natans contains the smallest nuclear genome known but paradoxically also retained over 800 tiny spliceosomal introns, ranging from 18 to 21 nt in length. Because introns have not been described in any other chlorarachniophyte nucleomorph, we do not know when these introns were reduced or whether they have been lost in other lineages. To gain insight into the evolution of these unique introns, we sequenced more than 150 spliceosomal introns in the nucleomorph of the chlorarachniophyte Gymnochlora stellata and compared size distribution, sequence features, and patterns of gain/loss. To clarify the possible relationship between intron size and splicing efficiency, we also analyzed the outcome of 580 splicing events. Overall, these data indicate that the radical intron size reduction took place in the ancestor of all extant chlorarachniophytes and that although most introns have been retained through this reductive process, intron loss has also occurred. We also show that intron size is not static, and splicing is not determined strictly by size, but that size does play a strong role in splicing efficiency, likely as part of a combination of sequence features and size.
Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma
Authors: Ranjana Advani, Andres Forero-Torres, Richard R. Furman, Joseph D. Rosenblatt, Anas Younes, Hong Ren, Kate Harrop, Nancy Whiting, Jonathan G. Drachman
Journal: Journal of Clinical Oncology (2009)

To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.
Effects of Estrogen plus Progestin on Health-Related Quality of Life
Authors: Jennifer Hays, Judith K. Ockene, Robert L. Brunner, Jane M. Kotchen, JoAnn E. Manson, Ruth E. Patterson, Aaron K. Aragaki, Sally A. Shumaker, Robert G. Brzyski, Andrea Z. LaCroix, Iris A. Granek, Barbara G. Valanis
Journal: New England Journal of Medicine (2003)

The Women's Health Initiative (WHI) and other clinical trials indicate that significant health risks are associated with combination hormone use. Less is known about the effect of hormone therapy on health-related quality of life.
CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of <i>Leishmania major</i> infection favors pathogen persistence
Authors: Ekaterina Yurchenko, Michael Tritt, Valerie Hay, Ethan M. Shevach, Yasmine Belkaid, Ciriaco A. Piccirillo
Journal: The Journal of Experimental Medicine (2006)

Pathogen persistence after clinical cure is a hallmark of many chronic infections. Previously, we showed that naturally occurring CD4+CD25+ regulatory T (nTreg) cells rapidly accumulate within chronic dermal sites of Leishmania major infection where they suppress anti-pathogen CD4+ T cell responses, favor parasite persistence and dermal pathology, and consequently control concomitant immunity. Here, we postulated that chemokines might direct nTreg cell homing in sites of infection and show that CD4+CD25+ nTreg cells, compared with normal CD4+ T cells, preferentially express the CCR5 chemokine receptor, which enables them to migrate in response to CCR5 ligands in vitro. We show that in contrast to their wild-type (WT) counterparts, CCR5-/- CD4+CD25+ nTreg cells resulted in an increased magnitude of parasite-specific, interferon gamma-producing CD4+ T cells within infection sites, dramatically reduced parasite numbers, and potent resistance to infection, a finding consistent with the clinical outcome of infected CCR5-/- mice. Interestingly, this resistance was related to an inefficient migration of CCR5-/- nTreg cells to infected dermal sites compared with WT nTreg cells. Thus, this study shows that CCR5 directs the homing of CD4+CD25+ nTreg cells to L. major-infected dermal sites where they promote the establishment of infection and long-term survival of the parasite in the immune host.
Sympathetic denervation in patients following acute myocardial infarction: relationship to myocardial perfusion and metabolism
Authors: Erica D. Engelstein, Stephen G. Sawada, Gary D. Hutchins, Susan Straka, Ruchir Sehra, Richard L. Fain, Ratnakar Amaravadi, Douglas P. Zipes
Journal: Journal of the American College of Cardiology (1998)