tbuckley/cabot-search huggingface dataset:
The Ews/Fli-1 Fusion Gene Changes the Status of p53 in Neuroblastoma Tumor Cell Lines
Authors: Checo J. Rorie, Bernard E. Weissman
Journal: Cancer Research (2004)

Abstract One hallmark of Ewing’s sarcoma/peripheral neuroectodermal tumors is the presence of the Ews/Fli-1 chimeric oncogene. Interestingly, infection of neuroblastoma tumor cell lines with Ews/Fli-1 switches the differentiation program of neuroblastomas to Ewing’s sarcoma/peripheral neuroectodermal tumors. Here we examined the status of cytoplasmically sequestered wt-p53 in neuroblastomas after stable expression of Ews/Fli-1. Immunofluorescence revealed that in the neuroblastoma-Ews/Fli-1 infectant cell lines, p53 went from a punctate-pattern of cytoplasmic sequestration to increased nuclear localization. Western blot analysis revealed that PARC was down-regulated in one neuroblastoma cell line but not expressed in the second. Therefore, decreased PARC expression could not fully account for relieving p53 sequestration in the neuroblastoma tumor cells. Neuroblastoma-Ews/Fli-1 infectant cell lines showed marked increases in p53 protein expression without transcriptional up-regulation. Interestingly, p53 was primarily phosphorylated, without activation of its downstream target p21WAF1. Western blot analysis revealed that whereas MDM2 gene expression does not change, p14ARF, a negative protein regulator of MDM2, increases. These observations suggest that the downstream p53 pathway may be inactivated as a result of abnormal p53. We also found that p53 has an extended half-life in the neuroblastoma-Ews/Fli-1 infectants despite the retention of a wild-type sequence in neuroblastoma-Ews/Fli-1 infectant cell lines. We then tested the p53 response pathway and observed that the neuroblastoma parent cells responded to genotoxic stress, whereas the neuroblastoma-Ews/Fli-1 infectants did not. These results suggest that Ews/Fli-1 can directly abrogate the p53 pathway to promote tumorigenesis. These studies also provide additional insight into the relationship among the p53 pathway proteins.
Male Circumcision for the Prevention of HSV-2 and HPV Infections and Syphilis
Authors: Aaron A.R. Tobian, David Serwadda, Thomas C. Quinn, Godfrey Kigozi, Patti E. Gravitt, Oliver Laeyendecker, Blake Charvat, Victor Ssempijja, Melissa Riedesel, Amy E. Oliver, Rebecca G. Nowak, Lawrence H. Moulton, Michael Z. Chen, Steven J. Reynolds, Maria J. Wawer, Ronald H. Gray
Journal: New England Journal of Medicine (2009)

Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men.We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2-seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months.At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P=0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P=0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P=0.44).In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure. (ClinicalTrials.gov numbers, NCT00425984 and NCT00124878.)
Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes
Authors: Shamir R Mehta, Jean-Pierre Bassand, Susan Chrolavicius, Rafael Diaz, John W Eikelboom, Keith A A Fox, Christopher B Granger, Sanjit Jolly, Campbell D Joyner, Hans-Jurgen Rupprecht, Petr Widimsky, Rizwan Afzal, Janice Pogue, Salim Yusuf
Journal: New England Journal of Medicine (2010)

Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent.We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days.The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90).In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)
Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway
Authors: Shinya Hayami, Masanori Yoshimatsu, Abhimanyu Veerakumarasivam, Motoko Unoki, Yukiko Iwai, Tatsuhiko Tsunoda, Helen I. Field, John D Kelly, David E. Neal, Hiroki Yamaue, Bruce A. J. Ponder, Yusuke Nakamura, Ryuji Hamamoto
Journal: Molecular Cancer (2010)

Abstract Background Although an increasing number of histone demethylases have been identified and biochemically characterized, their biological functions largely remain uncharacterized, particularly in the context of human diseases such as cancer. We investigated the role of KDM5B, a JmjC histone demethylase, in human carcinogenesis. Quantitative RT-PCR and microarray analyses were used to examine the expression profiles of histone demethylases in clinical tissue samples. We also examined the functional effects of KDM5B on the growth of cancer cell lines treated with small interfering RNAs (siRNAs). Downstream genes and signal cascades induced by KDM5B expression were identified from Affymetrix Gene Chip experiments, and validated by real-time PCR and reporter assays. Cell cycle-dependent characteristics of KDM5B were identified by immunofluorescence and FACS. Results Quantitative RT-PCR analysis confirmed that expression levels of KDM5B are significantly higher in human bladder cancer tissues than in their corresponding non-neoplastic bladder tissues ( P &lt; 0.0001). The expression profile analysis of clinical tissues also revealed up-regulation of KDM5B in various kinds of malignancies. Transfection of KDM5B-specific siRNA into various bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells and increased the number of cells in sub-G 1 phase. Microarray expression analysis indicated that E2F1 and E2F2 are downstream genes in the KDM5B pathway. Conclusions Inhibition of KDM5B may affect apoptosis and reduce growth of cancer cells. Further studies will explore the pan-cancer therapeutic potential of KDM5B inhibition.
Incidence of Treatment for End-Stage Renal Disease Among Individuals With Diabetes in the U.S. Continues to Decline
Authors: Nilka Ríos Burrows, Yanfeng Li, Linda S. Geiss
Journal: Diabetes Care (2009)

We examined trends in incidence of treatment for diabetes-related end-stage renal disease (ESRD) in the U.S.Using the U.S. Renal Data System, we obtained the number of individuals having diabetes listed as primary diagnosis who initiated ESRD treatment between 1990 and 2006. Incidence was calculated using the estimated U.S. population with diabetes from the National Health Interview Survey and then was age adjusted based on the 2000 U.S. standard population. Trends were analyzed using joinpoint regression.The number of individuals who began diabetes-related ESRD treatment increased from 17,727 in 1990 to 48,215 in 2006. From 1990 to 1996, the age-adjusted diabetes-related ESRD incidence increased somewhat from 299.0 to 343.2 per 100,000 diabetic population (P = 0.45). However, from 1996 to 2006, the age-adjusted diabetes-related ESRD incidence decreased by 3.9% per year (P < 0.01) from 343.2 to 197.7 per 100,000 diabetic population. Among individuals with diabetes aged <45 years, diabetes-related ESRD incidence decreased by 4.3% per year (P < 0.01) from 1990 to 2006. Among older individuals, incidence increased during the 1990s but decreased in later years, by 3.9% per year (P < 0.01) among individuals aged 45-64, by 3.4% per year (P < 0.01) among individuals aged 65-74 years, and by 2.1% per year (P = 0.02) among individuals aged > or =75 years.Diabetes-related ESRD incidence in the diabetic population has declined in all age-groups, probably because of a reduction in the prevalence of ESRD risk factors, improved treatment and care, and other factors.
Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation
Authors: Aritro Sen, Ismary De Castro, Donald B. DeFranco, Fang-Ming Deng, Jonathan Melamed, Payel Kapur, Ganesh V. Raj, Randall Rossi, Stephen R. Hammes
Journal: Journal of Clinical Investigation (2012)

In prostate cancer, the signals that drive cell proliferation change as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, characterization of common signaling components that regulate both stages of prostate cancer proliferation is important for developing effective treatment strategies. Here, we demonstrate that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and EGF-induced nuclear signaling. We show that androgen and EGF promoted MAPK-dependent phosphorylation of paxillin, resulting in nuclear translocation of paxillin. We found nuclear paxillin could then associate with androgen-stimulated androgen receptor (AR). This complex bound AR-sensitive promoters, retaining AR within the nucleus and regulating AR-mediated transcription. Nuclear paxillin also complexed with ERK and ELK1, mediating c-FOS and cyclin D1 expression; this was followed by proliferation. Thus, paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer. Accordingly, paxillin was required for normal growth of human prostate cancer cell xenografts, and its expression was elevated in human prostate cancer tissue microarrays. Paxillin is therefore a potential biomarker for prostate cancer proliferation and a possible therapeutic target for prostate cancer treatment.
Secretoneurin, an Angiogenic Neuropeptide, Induces Postnatal Vasculogenesis
Authors: Rudolf Kirchmair, Margot Egger, Dirk H. Walter, Wolfgang Eisterer, Andreas Niederwanger, Ewald Woell, Markus Nagl, Michael Pedrini, Toshinori Murayama, Silke Frauscher, Allison Hanley, Marcy Silver, Marianne Brodmann, Wolfgang Sturm, Reiner Fischer-Colbrie, Douglas W. Losordo, Josef R. Patsch, Peter Schratzberger
Journal: Circulation (2004)

Induction of postnatal vasculogenesis, the mobilization of bone marrow-derived endothelial progenitor cells and incorporation of these cells into sites of blood vessel formation, is a well-known feature of angiogenic cytokines such as vascular endothelial growth factor. We hypothesized that the angiogenic neuropeptide secretoneurin induces this kind of neovascularization.Secretoneurin induced mobilization of endothelial progenitor cells to sites of vasculogenesis in vivo in the cornea neovascularization assay. Progenitor cells were incorporated into vascular structures or were located adjacent to them. Systemic injection of secretoneurin led to increase of circulating stem cells and endothelial progenitor cells. In vitro secretoneurin induced migration, exerted antiapoptotic effects, and increased the number of these cells. Furthermore, secretoneurin stimulated the mitogen-activated protein kinase system, as shown by phosphorylation of extracellular signal-regulated kinase, and activated the protein kinase B/Akt pathway. Activation of mitogen-activated protein kinase was necessary for increase of cell number and migration, whereas Akt seemed to play a role in migration of endothelial progenitor cells.These data show that the angiogenic neuropeptide secretoneurin stimulates postnatal vasculogenesis by mobilization, migration, and incorporation of endothelial progenitor cells.
Ultrasound detection of knee patellar enthesitis
Authors: R J Wakefield, D McGonagle, A L Tan, A Evangelisto, P Emery
Journal: Annals of the Rheumatic Diseases (2004)

We read with interest the report by Kamel et al who highlighted the use of ultrasound (US) and magnetic resonance imaging (MRI) for the detection of patellar tendon enthesitis in patients with seronegative arthropathies without typical radiographic evidence.1 Their work adds to the growing body of evidence supporting the clinical use of US in rheumatological practice. US has previously been shown to be better than clinical examination for the detection of enthesitis,2,3 but data on MRI are more limited. The authors make interesting observations about the position of the abnormalities in the patellar tendon, when compared with the Achilles tendon, possibly relating to joint biomechanics and lines of force. However, we would like to raise a few points on what we regard as important omissions from the paper.

Firstly, the authors do not include the frequencies of the described US or the technical details of the MRI findings and do not state how the modalities correlated with each other. The authors also do not comment on the presence of bone marrow oedema adjacent to the enthesis on MRI. With regard to the plantar fascia, …
Effects of Excess Weight on Cancer Incidences Depending on Cancer Sites and Histologic Findings Among Men: Korea National Health Insurance Corporation Study
Authors: Sang Woo Oh, Yeong Sook Yoon, Soon-Ae Shin
Journal: Journal of Clinical Oncology (2005)

Purpose The effects of excess weight on the development of cancers are controversial, and little is known for populations outside the United States and Europe. We conducted this study to assess the effects of excess weight with a large cohort of Koreans. Methods We assessed the relationship between body mass index (BMI) and various cancers in a 10-year follow-up cohort of 781,283 Korean men who were free of prior cancer at baseline. Weight and height were measured, and questionnaires related to health behaviors and medical history were completed. Data on newly developed cancers were obtained from two organizations in Korea. A proportional hazards model was used to examine the relationship between BMI and cancer. Results Adenocarcinoma in the colon and rectosigmoid, hepatocellular carcinoma, cholangiocarcinoma, adenocarcinoma in the prostate, renal cell carcinoma, papillary carcinoma in the thyroid, small-cell carcinoma in the lung, non-Hodgkin's lymphoma, and melanoma had positive dose-dependent relationships with BMI (all P &lt; .05). Although no linear trend was found (P = .267), obese men who never smoked with a BMI of ≥ 30 kg/m 2 had an increased risk of developing gastric adenocarcinoma (relative risk = 1.73). Other cancers, such as leukemia, multiple myeloma, and gallbladder and pancreatic cancer, did not show significant associations. Conclusion These findings show that, even in Koreans, obesity clearly increases the risk of many types of cancers and the strength of the associations varies with the organ and histologic type. Because these obesity-related cancers are reported to be rapidly increasing in Korea and many other Asian countries, controlling obesity epidemics could be an effective tool for preventing these cancers in these areas.
Intrathoracic vagus nerve tumours
Authors: B. Strickland, M. K. Wolverson
Journal: Thorax (1974)

<b>Strickland, B. and Wolverson, M. K. (1974).</b><i>Thorax</i>, <b>29</b>, 215-222. <b>Intrathoracic vagus nerve tumours.</b> Three new cases of intrathoracic vagus nerve sheath tumour are presented. Two were neurofibromas associated with generalized neurofibromatosis, the third a neurilemmoma. All three presented as tumours of the superior middle mediastinum on the left in close association with the aortic arch. Previously reported cases are reviewed with special reference to the anatomical position and mode of clinical presentation. The tumours most often occur on the proximal part of the nerve close to the aortic arch and more often on the left than the right. They usually present as an incidental finding on a chest radiograph. To explain this anatomical localization it is suggested that the tumours tend to occur on the bulkiest part of the nerve which is in the upper thorax and where there is room for growth which is below the thoracic inlet. Proximal vagal tumours are more easily seen on a chest radiograph than those occurring distally and are therefore more likely to be detected. Symptoms occur only with proximal lesions.
Abnormal goblet cell glycoconjugates in rectal biopsies associated with an increased risk of neoplasia in patients with ulcerative colitis: early results of a prospective study.
Authors: C R Boland, P Lance, B Levin, R H Riddell, Y S Kim
Journal: Gut (1984)

A group of 18 patients with stable ulcerative colitis involving the entire colon for at least eight years was subjected to a biopsy of normal appearing rectal mucosa and followed prospectively over four years for the development of either dysplasia or cancer. Goblet cell glycoconjugate structure was examined in the rectal biopsies using fluorescein conjugated lectins. At the beginning of the study, 13 of the 18 patients had abnormalities of goblet cell mucin or cytoplasmic glycoconjugates in the rectal biopsies. Dysplasia subsequently developed in six and carcinoma in one of these patients. Among the five patients with normal lectin binding studies in the initial rectal biopsies, colonic dysplasia has subsequently developed in one. The abnormalities seen in the rectal goblet cells resembled in part those previously seen in immature and neoplastic colonic cells. The dysplastic tissues all contained the form of mucin which has been found in other neoplastic colonic tissues. This preliminary report after four years of prospective study suggests that abnormalities of glycoconjugate structure may be associated with, and may precede, neoplastic events in the setting of chronic ulcerative colitis.
Commitment of Common T/Natural Killer (Nk) Progenitors to Unipotent T and Nk Progenitors in the Murine Fetal Thymus Revealed by a Single Progenitor Assay
Authors: Tomokatsu Ikawa, Hiroshi Kawamoto, Shinji Fujimoto, Yoshimoto Katsura
Journal: The Journal of Experimental Medicine (1999)

We have established a new clonal assay system that can evenly support the development of T and natural killer (NK) cells. With this system, we show that all T cell progenitors in the earliest CD44+CD25−FcγRII/III− fetal thymus (FT) cell population retain NK potential, and that the NK lineage–committed progenitors (p-NK) also exist in this population. T cell lineage–committed progenitors (p-T), which are unable to generate NK cells, first appear at the CD44+CD25− FcγRII/III+ stage in day 12 FT. The proportion of p-T markedly increases during the transition from the CD44+CD25− stage to the CD44+CD25+ stage in day 14 FT. On the other hand, p-NK preferentially increase in number at the CD44+CD25− stage between days 12 and 14 of gestation. The production of p-NK continues up to the CD44+CD25+ stage, but ceases before the rearrangement of T cell receptor β chain genes. It was further shown that the CD44+CD25− CD122+ population of day 14 FT exclusively contains p-NK. These results indicate that the earliest T cell progenitor migrating into the FT is T/NK bipotent, and strongly suggest that the bipotent progenitor continuously produces p-NK and p-T until the CD44+CD25+ stage.
Increased Incidence of Fractures in Recipients of Hematopoietic Stem-Cell Transplantation
Authors: Xerxes N. Pundole, Andrea G. Barbo, Heather Lin, Richard E. Champlin, Huifang Lu
Journal: Journal of Clinical Oncology (2015)

Purpose The number of long-term survivors after hematopoietic stem-cell transplantation (HSCT) for malignant and nonmalignant disorders is increasing, and late effects are gaining importance. Osteoporosis and fractures can worsen the quality of life of HSCT survivors, but the burden of the disease is unknown. Patients and Methods We conducted a retrospective study of patients older than age 18 years who underwent an HSCT at The University of Texas MD Anderson Cancer Center from January 1, 1997, to December 31, 2011, and were observed until December 31, 2013, to ascertain occurrence of fractures. Cumulative incidence rates of fractures were calculated with death as a competing risk. Age- and sex-specific incidence rates per person-year of fracture were compared with those of the US general population by using estimated rates from the 1994 National Health Interview Survey and the 2004 National Hospital Discharge Survey. Results A total of 7,620 patients underwent an HSCT from 1997 to 2011 at the MD Anderson Cancer Center of whom 602 (8%) developed a fracture. Age, underlying disease, and HSCT type were significantly associated with fracture. Age- and sex-specific fracture incidence rates after HSCT were significantly greater than those of the US general population in almost all subgroups. The striking difference was an approximately eight times greater risk in females and approximately seven to nine times greater risk in males age 45 to 64 years old when compared with the National Health Interview Survey and National Hospital Discharge Survey fracture rates. Conclusion The incidence of fractures is compellingly higher after HSCT.