tbuckley/cabot-search huggingface dataset:
New Genes Originated via Multiple Recombinational Pathways in the -Globin Gene Family of Rodents
Authors: F. G. Hoffmann, J. C. Opazo, J. F. Storz
Journal: Molecular Biology and Evolution (2008)

Species differences in the size or membership composition of multigene families can be attributed to lineage-specific additions of new genes via duplication, losses of genes via deletion or inactivation, and the creation of chimeric genes via domain shuffling or gene fusion. In principle, it should be possible to infer the recombinational pathways responsible for each of these different types of genomic change by conducting detailed comparative analyses of genomic sequence data. Here, we report an attempt to unravel the complex evolutionary history of the β-globin gene family in a taxonomically diverse set of rodent species. The main objectives were: 1) to characterize the genomic structure of the β-globin gene cluster of rodents; 2) to assign orthologous and paralogous relationships among duplicate copies of β-like globin genes; and 3) to infer the specific recombinational pathways responsible for gene duplications, gene deletions, and the creation of chimeric fusion genes. Results of our comparative genomic analyses revealed that variation in gene family size among rodent species is mainly attributable to the differential gain and loss of later expressed β-globin genes via unequal crossing-over. However, two distinct recombinational mechanisms were implicated in the creation of chimeric fusion genes. In muroid rodents, a chimeric γ/ε fusion gene was created by unequal crossing-over between the embryonic ε- and γ-globin genes. Interestingly, this γ/ε fusion gene was generated in the same fashion as the "anti-Lepore" 5′-δ-(β/δ)-β-3′ duplication mutant in humans (the reciprocal exchange product of the pathological hemoglobin Lepore deletion mutant). By contrast, in the house mouse, Mus musculus, a chimeric β/δ fusion pseudogene was created by a β-globin → δ-globin gene conversion event. Although the γ/ε and β/δ fusion genes share a similar chimeric gene structure, they originated via completely different recombinational pathways.
Bone‐ and Cartilage‐Protective Effects of a Monoclonal Antibody Against Colony‐Stimulating Factor 1 Receptor in Experimental Arthritis
Authors: Myew‐Ling Toh, Jean‐Yves Bonnefoy, Nathalie Accart, Sandrine Cochin, Sandy Pohle, Hélène Haegel, Micael De Meyer, Christophe Zemmour, Xavier Preville, Christine Guillen, Christine Thioudellet, Philippe Ancian, Anja Lux, Bettina Sehnert, Falk Nimmerjahn, Reinhard E. Voll, Georg Schett
Journal: Arthritis & Rheumatology (2014)

Objective Colony‐stimulating factor 1 receptor (CSF‐1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF‐1R expression in human RA as well as the efficacy of a specific anti–CSF‐1R monoclonal antibody (AFS98) in 2 different animal models of RA. Methods CSF‐1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen‐induced arthritis (CIA) and serum‐transfer arthritis. Results CSF‐1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast‐like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF‐1R+. In mice, blockade of CSF‐1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF‐1R did not affect inflammation in passive serum‐transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr‐1− monocytes. Conclusion CSF‐1R was broadly expressed in human RA. Blockade of CSF‐1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF‐1R as a therapeutic target in RA.
Hepatitis B-associated polyarteritis nodosa in alaskan eskimos: Clinical and epidemiologic features and long-term follow-up
Authors: Brian J. McMahon, William L. Heyward, David W. Templin, David Clement, Anne P. Lanier
Journal: Hepatology (1989)

We analyzed the demographic, clinical, laboratory and histologic features of 13 patients who were diagnosed as having polyarteritis nodosa associated with hepatitis B virus infection over a 12-year period, 1974 to 1985. All 13 patients were Yupik Eskimos and resided in southwest Alaska, an area hyperendemic for hepatitis B virus infection. The annual incidence of hepatitis B virus-associated polyarteritis nodosa for this population is 7.7 cases per 100,000 population. All patients presented with multisystem disease, and all had biopsy or angiographic findings consistent with polyarteritis nodosa. All 13 were positive for hepatitis B surface antigen and hepatitis B e antigen at diagnosis. Two untreated patients and two of five patients who received corticosteroids died, vs. none of six who received corticosteroids plus cyclophosphamide. None of the patients who survived the initial bout of polyarteritis nodosa has relapsed after a mean follow-up of 55 months, but all have become chronic HBsAg carriers. In eight patients, clinical or serologic evidence indicated that polyarteritis nodosa followed recent hepatitis B virus infection. We concluded that hepatitis B virus-associated polyarteritis nodosa is a serious, life-threatening complication that occurs early in the course of hepatitis B virus infection, is ameliorated by immunosuppressive therapy and can be prevented by hepatitis B vaccine.
Myxoma Virus Is a Novel Oncolytic Virus with Significant Antitumor Activity against Experimental Human Gliomas
Authors: Xueqing Lun, Wenqing Yang, Tommy Alain, Zhong-Qiao Shi, Huong Muzik, John W. Barrett, Grant McFadden, John Bell, Mark G. Hamilton, Donna L. Senger, Peter A. Forsyth
Journal: Cancer Research (2005)

Abstract Myxoma virus, a poxvirus previously considered rabbit specific, can replicate productively in a variety of human tumor cells in culture. The purpose of this study was to determine if there was efficacy or toxicities of this oncolytic virus against experimental models of human malignant gliomas in vitro, in vivo, and ex vivo in malignant glioma specimens. In vitro, the majority of glioma cell lines tested (7 of 8, 87.5%) were fully permissive for myxoma virus replication and killed by infection. In vivo, intracerebral (i.c.) myxoma virus inoculation was well tolerated and produced only minimal focal inflammatory changes at the site of viral inoculation. U87 and U251 orthotopic xenograft models were used to assess myxoma virus efficacy in vivo. A single intratumoral injection of myxoma virus dramatically prolonged median survival compared with treatment with UV-inactivated myxoma virus. Median survival was not reached in myxoma virus-treated groups versus 47.3 days (U87; P = 0.0002) and 50.7 days (U251; P = 0.0027) in UV-inactivated myxoma virus-treated groups. Most myxoma virus-treated animals (12 of 13, 92%) were alive and apparently “cured” when the experiment was finished (&amp;gt;130 days). Interestingly, we found a selective and long-lived myxoma virus infection in gliomas in vivo. This is the first demonstration of the oncolytic activity of myxoma virus in vivo. The nonpathogenic nature of myxoma virus outside of the rabbit host, its capacity to be genetically modified, its ability to produce a long-lived infection in human tumor cells, and the lack of preexisting antibodies in the human population suggest that myxoma virus may be an attractive oncolytic agent against human malignant glioma.
Hypereosinophilic syndrome with multiple organ dysfunction treated by allogeneic bone marrow transplantation
Authors: Eric Archimbaud, Denis Guyotat, Christian Guillaume, Jean Godard, Denis Fiere
Journal: American Journal of Hematology (1988)

Abstract A 26‐year‐old man with hypereosinophilic syndrome who had initial neurologic, cardiac, and pulmonary dysfunction, high eosinophil count, thrombocytopenla, and bone marrow fibrosis had only a transient response to conventional treatment with corticosteroids and hydroxyurea. He therefore received human lymphocyte antigen‐identical allogeneic bone marrow transplantation (BMT) after conditioning with cytoxan and fractionated total body irradiation. Hematologic recovery was prompt, with normalization of blood counts and bone marrow. The patient died less than 3 months after transplantation from diffuse cytomegalovirus infection. Potential interest of BMT in patients with resistant hypereosinophilic syndrome and features of poor prognosis is discussed.
Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study
Authors: R. Skjaerven, A. J. Wilcox, K. Klungsoyr, L. M. Irgens, B. E. Vikse, L. J. Vatten, R. T. Lie
Journal: BMJ (2012)

<b>Objective</b> To assess the association of pre-eclampsia with later cardiovascular death in mothers according to their lifetime number of pregnancies, and particularly after only one child. <b>Design</b> Prospective, population based cohort study. <b>Setting</b> Medical Birth Registry of Norway. <b>Participants</b> We followed 836 147 Norwegian women with a first singleton birth between 1967 and 2002 for cardiovascular mortality through linkage to the national Cause of Death Registry. About 23 000 women died by 2009, of whom 3891 died from cardiovascular causes. Associations between pre-eclampsia and cardiovascular death were assessed by hazard ratios, estimated by Cox regression analyses. Hazard ratios were adjusted for maternal education (three categories), maternal age at first birth, and year of first birth <b>Results</b> The rate of cardiovascular mortality among women with preterm pre-eclampsia was 9.2% after having only one child, falling to 1.1% for those with two or more children. With term pre-eclampsia, the rates were 2.8% and 1.1%, respectively. Women with pre-eclampsia in their first pregnancy had higher rates of cardiovascular death than those who did not have the condition at first birth (adjusted hazard ratio 1.6 (95% confidence interval 1.4 to 2.0) after term pre-eclampsia; 3.7 (2.7 to 4.8) after preterm pre-eclampsia). Among women with only one lifetime pregnancy, the increase in risk of cardiovascular death was higher than for those with two or more children (3.4 (2.6 to 4.6) after term pre-eclampsia; 9.4 (6.5 to 13.7) after preterm pre-eclampsia). The risk of cardiovascular death was only moderately elevated among women with pre-eclamptic first pregnancies who went on to have additional children (1.5 (1.2 to 2.0) after term pre-eclampsia; 2.4 (1.5 to 3.9) after preterm pre-eclampsia). There was little evidence of additional risk after recurrent pre-eclampsia. All cause mortality for women with two or more lifetime births, who had pre-eclampsia in first pregnancy, was not elevated, even with preterm pre-eclampsia in first pregnancy (1.1 (0.87 to 1.14)). <b>Conclusions</b> Cardiovascular death in women with pre-eclampsia in their first pregnancy is concentrated mainly in women with no additional births. This association might be due to health problems that discourage or prevent further pregnancies rather than to pre-eclampsia itself. As a screening criterion for cardiovascular disease risk, pre-eclampsia is a strong predictor primarily among women with only one child—particularly with preterm pre-eclampsia.
Protection against reperfusion injury with ITF-1697 in acute myocardial infarction: The PARI-MI trial
Authors: Maurits T. Dirksen, Arnoud W. van 't Hof, G. Guagliumi, H.R. Michels, M.L. Simoons, L. Tavazzi, G.J. Laarman
Journal: Journal of the American College of Cardiology (2003)
Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise
Authors: Nadia C Whitelaw, Suyinn Chong, Daniel K Morgan, Colm Nestor, Timothy J Bruxner, Alyson Ashe, Eleanore Lambley, Richard Meehan, Emma Whitelaw
Journal: Genome biology (2010)

Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans.
Practice Patterns and Clinical Outcomes After Hybrid Coronary Revascularization in the United States
Authors: Ralf E. Harskamp, J. Matthew Brennan, Ying Xian, Michael E. Halkos, John D. Puskas, Vinod H. Thourani, James S. Gammie, Bradley S. Taylor, Robbert J. de Winter, Sunghee Kim, Sean O’Brien, Eric D. Peterson, Jeffrey G. Gaca
Journal: Circulation (2014)

Hybrid coronary revascularization (HCR) involves a combination of surgical and percutaneous techniques, which in selected patients may present an alternative to conventional coronary artery bypass grafting (CABG). Patients were included who underwent HCR (staged/concurrent) or isolated CABG in the Society of Thoracic Surgeons Adult Cardiac Surgery Database (July 2011 to March 2013). HCR represented 0.48% (n=950; staged=809, concurrent=141) of the total CABG volume (n=198,622) during the study period, and was performed in one-third of participating centers (n=361). Patients who underwent HCR had higher cardiovascular risk profiles in comparison with patients undergoing CABG. In comparison with CABG, median sternotomy (98.5% for CABG, 61.1% for staged HCR, and 52.5% for concurrent HCR), direct vision harvesting (98.9%, 66.0%, and 68.1%) and cardiopulmonary bypass (83.4%, 45%, and 36.9%) were less frequently used for staged and concurrent HCR, whereas robotic assistance (0.7%, 33.0%, and 30.5%) was more common. After adjustment, no differences were observed for the composite of in-hospital mortality and major morbidity (odds ratio, 0.93; 95% confidence interval, 0.75-1.16; P=0.53 for staged HCR, and odds ratio, 0.94; 95% confidence interval, 0.56-1.56; P=0.80 for concurrent HCR in comparison with CABG). There was no statistically significant association between operative mortality and either treatment group (odds ratio, 0.74; 95% confidence interval, 0.42-1.30; P=0.29 for staged HCR, and odds ratio, 2.26; 95% confidence interval, 0.99-5.17; P=0.053 for concurrent HCR in comparison with CABG). HCR, either as a staged or concurrent procedure, is performed in one-third of US hospitals and is reserved for a highly selected patient population. Although HCR may appear to be an equally safe alternative for CABG surgery, further randomized study is warranted.
Myc Regulates Embryonic Vascular Permeability and Remodeling
Authors: Enikö Kokai, Florian Voss, Frank Fleischer, Sybille Kempe, Dragan Marinkovic, Hartwig Wolburg, Frank Leithäuser, Volker Schmidt, Urban Deutsch, Thomas Wirth
Journal: Circulation Research (2009)

Previous work has shown that c-Myc is required for adequate vasculogenesis and angiogenesis. To further investigate the contribution of Myc to these processes, we conditionally expressed c-Myc in embryonic endothelial cells using a tetracycline-regulated system. Endothelial Myc overexpression resulted in severe defects in the embryonic vascular system. Myc-expressing embryos undergo widespread edema formation and multiple hemorrhagic lesions. They die between embryonic days 14.5 and 17.5. The changes in vascular permeability are not caused by deficiencies in vascular basement membrane composition or pericyte coverage. However, the overall turnover of endothelial cells is elevated as is revealed by increased levels of both proliferation and apoptosis. Whole-mount immunohistochemical analysis revealed alterations in the architecture of capillary networks. The dermal vasculature of Myc-expressing embryos is characterized by a reduction in vessel branching, which occurs despite upregulation of the proangiogenic factors vascular endothelial growth factor-A and angiopoietin-2. Thus, the net outcome of an excess of vascular endothelial growth factor-A and angiopoietin-2 in the face of an elevated cellular turnover appears to be a defect in vascular integrity.
Progesterone Receptor Isoform-Specific Promoter Methylation: Association of<i>PRA</i>Promoter Methylation with Worse Outcome in Breast Cancer Patients
Authors: Thushangi N. Pathiraja, Priya B. Shetty, Jaroslav Jelinek, Rong He, Ryan Hartmaier, Astrid L. Margossian, Susan G. Hilsenbeck, Jean-Pierre J. Issa, Steffi Oesterreich
Journal: Clinical Cancer Research (2011)

ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.
The <i>p53</i> Codon 72 <i>Proline</i> Allele Is Associated with <i>p53</i> Gene Mutations in Non–Small Cell Lung Cancer
Authors: Yingchuan Hu, Michael P. McDermott, Steven A. Ahrendt
Journal: Clinical Cancer Research (2005)

Abstract The p53 gene plays a critical role in cell cycle control, the initiation of apoptosis, and in DNA repair. An Arg/Pro polymorphism at codon 72 of the p53 gene alters the ability of the p53 protein to induce apoptosis, influences the behavior of mutant p53, decreases DNA repair capacity, and may be linked with an increased risk of lung cancer. To further define the role of the p53 codon 72 polymorphism on DNA repair, lung cancer risk, and mutant p53 function, we examined the effect of this polymorphism on mutation of the p53 gene and patient survival in non–small cell lung cancer (NSCLC). Tumor and nonneoplastic (lung or lymphocyte) samples were collected from 182 patients with NSCLC. p53 mutations were detected by direct sequencing and/or the Gene Chip p53 assay in 93 of 182 (51%) tumors. p53 codon 72 polymorphisms were identified by PCR/RFLP analysis. p53 mutations were significantly (P = 0.01) associated with the number of codon 72 Pro alleles: Pro/Pro homozygotes, 17 of 26 (65%); Arg/Pro heterozygotes, 45 of 79 (57%); and Arg/Arg homozygotes, 31 of 77 (40%). The number of codon 72 Pro alleles was independently associated with p53 mutations (odds ratio, 1.97; 95% confidence interval, 1.14-3.40; P = 0.01) in a multiple logistic regression model. The codon 72 polymorphism did not influence patient survival in either the entire patient group or among patients with p53 mutant tumors. In summary, the p53 Pro allele is associated with an increased frequency of p53 mutations in NSCLC.
Serum from achalasia patients alters neurochemical coding in the myenteric plexus and nitric oxide mediated motor response in normal human fundus
Authors: S Bruley des Varannes
Journal: Gut (2005)

Achalasia is a disease of unknown aetiology. An immune mechanism has been suggested on the basis of previous morphological observations. The objective of this study was to test whether the serum of achalasia patients could reproduce the phenotype and functional changes that occur with disease progression in an ex vivo human model.Specimens of normal human fundus were maintained in culture in the presence of serum from patients with achalasia, gastro-oesophageal reflux disease (GORD), or healthy subjects (controls). Immunohistochemical detection of choline acetyltransferase (ChAT), neurone specific enolase (NSE), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), and substance P was carried out in whole mounts of gastric fundus myenteric plexus. In addition, the effects of achalasia serum on electrical field stimulation (EFS) induced contractions were measured in circular muscle preparations.Serum from achalasia patients did not affect the number of myenteric neurones. Tissues incubated with serum from achalasia patients showed a decrease in the proportion of NOS (-26% of NSE positive neurones; p=0.016) and VIP (-54%; p=0.09) neurones, and a concomitant increase in ChAT neurones (+16%; p<0.001) compared with controls. In contrast, GORD serum did not modify the phenotype of myenteric neurones. Area under the curve of EFS induced relaxations (abolished by N-nitro-L-arginine methyl ester) was significantly decreased following incubation with serum from achalasia patients compared with controls (-7.6 (2.6) v -14.5 (5.0); p=0.036).Serum from achalasia patients can induce phenotypic and functional changes which reproduce the characteristics of the disease. Further identification of putative seric factors and mechanisms involved could lead to the development of novel diagnostic and/or therapeutic strategies in achalasia.