tbuckley/cabot-search huggingface dataset:
Inhibition of DNA Methylation and Reactivation of Silenced Genes by Zebularine
Authors: J. C. Cheng, C. B. Matsen, F. A. Gonzales, W. Ye, S. Greer, V. E. Marquez, P. A. Jones, E. U. Selker
Journal: JNCI Journal of the National Cancer Institute (2003)

Gene silencing by abnormal methylation of promoter regions of regulatory genes is commonly associated with cancer. Silenced tumor suppressor genes are obvious targets for reactivation by methylation inhibitors such as 5-azacytidine (5-Aza-CR) and 5-aza-2'-deoxycytidine (5-Aza-CdR). However, both compounds are chemically unstable and toxic and neither can be given orally. We characterized a new demethylating agent, zebularine [1-(beta-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one], which is a chemically stable cytidine analog.We tested the ability of zebularine to reactivate a silenced Neurospora crassa gene using a hygromycin gene reactivation assay. We then analyzed the ability of zebularine to inhibit DNA methylation in C3H 10T1/2 Cl8 (10T1/2) mouse embryo cells as assayed by induction of a myogenic phenotype and in T24 human bladder carcinoma cells, using the methylation-sensitive single nucleotide primer extension (Ms-SNuPE) assay. We also evaluated the effects of zebularine (administered orally or intraperitoneally) on growth of EJ6 human bladder carcinoma cells grown in BALB/c nu/nu mice (five mice per group) and the in vivo reactivation of a methylated p16 gene in these cells. All statistical tests were two-sided.In N. crassa, zebularine inhibited DNA methylation and reactivated a gene previously silenced by methylation. Zebularine induced the myogenic phenotype in 10T1/2 cells, which is a phenomenon unique to DNA methylation inhibitors. Zebularine reactivated a silenced p16 gene and demethylated its promoter region in T24 bladder carcinoma cells in vitro and in tumors grown in mice. Zebularine was only slightly cytotoxic to T24 cells in vitro (1 mM zebularine for 48 hours decreased plating efficiency by 17% [95% confidence interval (CI) = 12.8% to 21.2%]) and to tumor-bearing mice (average maximal weight change in mice treated with 1000 mg/kg zebularine = 11% [95% CI = 4% to 19%]). Compared with those in control mice, tumor volumes were statistically significantly reduced in mice treated with high-dose zebularine administered by intraperitoneal injection (P<.001) or by oral gavage (P<.001).Zebularine is a stable DNA demethylating agent and the first drug in its class able to reactivate an epigenetically silenced gene by oral administration.
Cancer death rates in US congressional districts
Authors: Rebecca L. Siegel, Liora Sahar, Kenneth M. Portier, Elizabeth M. Ward, Ahmedin Jemal
Journal: CA A Cancer Journal for Clinicians (2015)

Knowledge of the cancer burden is important for informing and advocating cancer prevention and control. Mortality data are readily available for states and counties, but not for congressional districts, from which representatives are elected and which may be more influential in compelling legislation and policy. The authors calculated average annual cancer death rates during 2002 to 2011 for each of the 435 congressional districts using mortality data from the National Center for Health Statistics and population estimates from the US Census Bureau. Age‐standardized death rates were mapped for all sites combined and separately for cancers of the lung and bronchus, colorectum, breast, and prostate by race/ethnicity and sex. Overall cancer death rates vary by almost 2‐fold and are generally lowest in Mountain states and highest in Appalachia and areas of the South. The distribution is similar for lung and colorectal cancers, with the lowest rates consistently noted in districts in Utah. However, for breast and prostate cancers, while the highest rates are again scattered throughout the South, the geographic pattern is less clear and the lowest rates are in Hawaii and southern Texas and Florida. Within‐state heterogeneity is limited, particularly for men, with the exceptions of Texas, Georgia, and Florida. Patterns also vary by race/ethnicity. For example, the highest prostate cancer death rates are in the West and north central United States among non‐Hispanic whites, but in the deep South among African Americans. Hispanics have the lowest rates except for colorectal cancer in Wyoming, eastern Colorado, and northern New Mexico. These data can facilitate cancer control and stimulate conversation about the relationship between cancer and policies that influence access to health care and the prevalence of behavioral and environmental risk factors. CA Cancer J Clin 2015;65:339–344. © 2015 American Cancer Society.
Consumption of Salted Fish and Other Risk Factors for Nasopharyngeal Carcinoma (NPC) in Tianjin, a Low-Risk Region for NPC in the People's Republic of China
Authors: J.-P. Ning, M. C. Yu, Q.-S. Wang, B. E. Henderson
Journal: JNCI Journal of the National Cancer Institute (1990)

The dietary habits, occupational exposures, use of tobacco and alcohol, and medical history were compared among 100 patients with histologically confirmed nasopharyngeal carcinoma (NPC) in Tianjin City, People's Republic of China, and 300 neighborhood controls who were individually matched to the patients with regard to age (within 5 yr), sex, and race (Han). Exposure to salted fish was significantly associated with an increased risk of NPC. Four characteristics of exposure to salted fish independently contributed to the increased risk: (a) earlier age at first exposure, (b) increasing duration of consumption, (c) increasing frequency of consumption, and (d) cooking the fish by steaming it rather than frying, grilling, or boiling it. In addition, significant associations were observed for consumption in childhood of salted shrimp paste (increased risk) and carrots (reduced risk), and the three dietary effects (i.e., those from consumption of salted fish, salted shrimp paste, and carrots) were independent of each other. None of the non-dietary factors studied were significantly associated with NPC risk.
Medroxyprogesterone Acetate Elevation of Nm23-H1 Metastasis Suppressor Expression in Hormone Receptor–Negative Breast Cancer
Authors: Diane Palmieri, Douglas O. Halverson, Taoufik Ouatas, Christine E. Horak, Massimiliano Salerno, Jennifer Johnson, W. Douglas Figg, Melinda Hollingshead, Stephen Hursting, David Berrigan, Seth M. Steinberg, Maria J. Merino, Patricia S. Steeg
Journal: JNCI Journal of the National Cancer Institute (2005)

Reestablishment of metastasis suppressor gene expression may constitute a therapeutic strategy for high-risk breast cancer patients. We previously showed that medroxyprogesterone acetate (MPA), a progestin that has been tested as treatment for advanced breast cancer, elevates expression of the Nm23-H1 metastasis suppressor gene in hormone receptor-negative metastatic human breast carcinoma cell lines in vitro via a glucocorticoid receptor-based mechanism. Here, we tested whether MPA treatment inhibits metastatic colonization of a hormone receptor-negative breast cancer cell line in vivo.We tested the soft-agar colony-forming efficiency of untransfected MDA-MB-231T human breast carcinoma cells and MDA-MB-231T cells transfected with antisense Nm23-H1 in the presence and absence of MPA. Pharmacokinetic studies were used to establish dose and injection schedules that led to MPA serum levels in mice similar to those achievable in humans. For in vivo studies, nude mice were injected intravenously with MDA-MB-231T cells. After 4 weeks, mice were randomized to control or MPA arms. Endpoints included incidence, number, and size of gross pulmonary metastases; Nm23-H1 protein expression in gross metastases; and side effects. All statistical tests were two-sided.MPA reduced colony formation of MDA-MB-231T cells by 40%-50% but had no effect on colony formation of Nm23-H1 antisense transfectants. Metastases developed in 100% (95% confidence interval [CI] = 78% to 100% and 77% to 100%, respectively) of control mice injected with MDA-MB-231T cells. In two independent experiments, only 73% (95% CI = 45% to 92%) and 64% (95% CI = 35% to 87%) of mice injected with 2 mg of MPA developed metastases. Mice injected with 2 mg of MPA showed reductions in the mean numbers, per mouse, of all metastases and of large (>3 mm) metastases (P = .04 and .013, respectively). Nm23-H1 was expressed at high levels in 43% of pulmonary metastases in MPA-treated mice but only 13% of metastases in untreated mice. Mice receiving at least 1-mg doses of MPA gained more weight than control-treated mice but exhibited no bone density alterations or abnormal mammary fat pad histology.Our preclinical results show that MPA appears to elevate Nm23-H1 metastasis suppressor gene expression, thereby reducing metastatic colonization. The data suggest a new use for an old agent in a molecularly defined subset of breast cancer patients.
Ly and Ia antigen phenotypes of T cells involved in delayed-type hypersensitivity and in suppression.
Authors: M A Vadas, J F Miller, I F McKenzie, S E Chism, F W Shen, E A Boyse, J R Gamble, A M Whitelaw
Journal: The Journal of Experimental Medicine (1976)

The Ly and Ia phenotypes of T lymphocytes involved in different functions were characterized by the use of specific antisera. T cells responsible for delayed-type hypersensitivity (DTH) and for helper functions were found to be Ly-1+,2- in contrast to cytotoxic T cells and T cells responsible for suppression of antibody responses which were Ly-1-,2+. Unlike some primed helper cells, T cells involved in DTH were Ia-. Suppressor cells in the system were Ia+.
Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells
Authors: Nima Abbasian, James O. Burton, Karl E. Herbert, Barbara-Emily Tregunna, Jeremy R. Brown, Maryam Ghaderi-Najafabadi, Nigel J. Brunskill, Alison H. Goodall, Alan Bevington
Journal: Journal of the American Society of Nephrology (2015)

Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.
Autoimmune conditions v lifestyle diseases
Authors: A. Jain
Journal: BMJ (2014)

The management of autoimmune diseases takes on a different dimension when compared with diseases attributed to factors in an individual’s lifestyle. Not just the medical community but also public health policy planners, individuals, and their families tend to view these conditions differently, which translates into a different approach towards the disease. This is exemplified through the conditions of coeliac disease and obesity that we cover on bmj.com this month.

In a personal view (doi:10.1136/bmj.g2046), Pankaj Vohra, a paediatric gastroenterologist, shares his insights into managing coeliac disease in India, and laments the problems of underdiagnosis and overdiagnosis. A lack of awareness of coeliac disease in the general public, and of its varied manifestations among doctors often results in a missed diagnosis and inappropriate treatment. On the other hand, he …
Baseline status of paediatric oncology care in ten low-income or mid-income countries receiving My Child Matters support: a descriptive study
Authors: Raul C Ribeiro, Eva Steliarova-Foucher, Ian Magrath, Jean Lemerle, Tim Eden, Caty Forget, Isabel Mortara, Isabelle Tabah-Fisch, Jose Julio Divino, Thomas Miklavec, Scott C Howard, Franco Cavalli
Journal: The Lancet Oncology (2008)
Targeting of HER2 Antigen for the Treatment of Disseminated Peritoneal Disease
Authors: Diane E. Milenic, Kayhan Garmestani, Erik D. Brady, Paul S. Albert, Dangshe Ma, Alia Abdulla, Martin W. Brechbiel
Journal: Clinical Cancer Research (2004)

The studies reported herein demonstrate the efficacy of alpha-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker, Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts, a low but uniform HER2 expressing, human colon carcinoma, with a single dose of (213)Bi-CHX-A"-Herceptin, proved disappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with alpha-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P = 0.009) was observed, and although a maximum-tolerated dose was not determined, a dose of 500 to 750 muCi was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 59 days with 500 and 750 muCi, respectively. The therapeutic effectiveness of (213)Bi-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model, and higher doses were required to obtain an increase in survival of the mice (P = 0.001).
Cerebrospinal Fluid Hormone Concentration in the Evaluation of Pituitary Tumors
Authors: RICHARD M. JORDAN
Journal: Annals of Internal Medicine (1976)

Cerebrospinal fluid (CSF) concentrations of corticotropin, growth hormone, thyrotropin, prolactin, luteinizing hormone, and follicle stimulating hormone were measured in 28 patients with various neurologic disorders, in 49 patients with pituitary tumors of whom 22 had suprasellar extension, and in 6 patients with craniopharyngiomas. With the exception of 1 patient with pseudotumor cerebri, CSF adenohypophyseal hormone concentrations were low in patients with neurologic disease and in patients with pituitary tumor without suprasellar extension. In marked contrast, 21 to 22 patients with suprasellar extension of a pituitary tumor and 2 of 6 patients with a craniopharyngioma had elevations of one or more CSF adenohypophyseal hormones. Posttreatment CSF adenohypophyseal hormone levels fell from previously elevated levels in 4 of 5 patients. These data suggest that an elevated CSF adenohypophyseal hormone concentration is a sensitive indicator of suprasellar extension of a pituitary tumor, and posttreatment measurements are useful in determining efficacy of therapy.
WATERBORNE OUTBREAK OF ROTAVIRUS DIARRHOEA IN ADULTS IN CHINA CAUSED BY A NOVEL ROTAVIRUS
Authors: Hung Tao, Wang Changan, Fang Zhaoying, Chou Zinyi, Chang Xuejian, Liong Xiaoquang, Chen Guangmu, Yao Henli, Chao Tungxin, Ye Weiwe, Den Shuasen, Chang Weicheng
Journal: The Lancet (1984)
Maspin Retards Cell Detachment via a Novel Interaction with the Urokinase-Type Plasminogen Activator/Urokinase-Type Plasminogen Activator Receptor System
Authors: Shuping Yin, Jaron Lockett, Yonghong Meng, Hector Biliran, Grant E. Blouse, Xiaohua Li, Neelima Reddy, Zimin Zhao, Xinli Lin, John Anagli, Michael L. Cher, Shijie Sheng
Journal: Cancer Research (2006)

Abstract It is well documented that tumor suppressive maspin inhibits tumor cell invasion and extracellular matrix remodeling. Maspin is a cytosolic, cell surface–associated, and secreted protein in the serine protease inhibitor superfamily. Although several molecules have been identified as candidate intracellular maspin targets, the extracellular maspin target(s) remains elusive. Although maspin does not directly inhibit urokinase-type plasminogen activator (uPA) activity, we have shown evidence that maspin may block the pericellular proteolysis mediated by cell surface–associated uPA. In the current study, maspin significantly inhibited the Ca2+ reduction–induced detachment of DU145 cells. This maspin effect was associated with increased and sustained levels of mature focal adhesion contacts (FAC). We noted that maspin (a) colocalized with uPA and uPA receptor (uPAR), (b) enhanced the interaction between uPAR and low-density lipoprotein receptor related protein, and (c) induced rapid internalization of uPA and uPAR. The maspin effects on surface-associated uPA and uPAR required the interaction between uPA and uPAR. Further biochemical and biophysical analyses revealed that maspin specifically bound to pro-uPA with a deduced Kd of 270 nmol/L and inhibited the plasmin-mediated pro-uPA cleavage. Interestingly, substitution of maspin p1′ site Arg340 in the reactive site loop (RSL) with alanine not only abolished the binding to pro-uPA but also diminished the maspin effects on pro-uPA cleavage and cell detachment. These data show an important role of maspin RSL in regulating the uPA/uPAR–dependent cell detachment. Together, our data led to a new hypothesis that maspin may stabilize mature FACs by quenching localized uPA/uPAR complex before uPA activation. (Cancer Res 2006; 66(8): 4173-81)
Abstract P252: Prevalence and Trend of Dyslipidemia from 1996 to 2006 among Adolescents in Taiwan
Authors: Nain-Feng Chu, Philip Kou, Ju-Ting Shu, Isabel Tzou
Journal: Circulation (2013)

Background: Cardiovascular diseases are the leading causes of death in Taiwan. We try to evaluate the prevalence and trend of dyslipidemia from 1996 to 2006 and examine its relationship with weight...
Possible health impact of animal oestrogens in food
Authors: Andreas Daxenberger, Dolores Ibarreta, Heinrich H.D. Meyer
Journal: Human Reproduction Update (2001)

Oestrogens govern reproductive functions in vertebrates, and are present in all animal tissues. The theoretical maximum daily intake (TMDI) of oestradiol-17β by consumption of cattle meat is calculated to be 4.3 ng. Following the use of oestradiol-containing growth-promoting agents, TMDI is increased by a factor of 4.6 to 20 ng oestradiol-17β, assuming that single dosage and 'good animal husbandry' are observed. Pork and poultry probably contain similar amounts of oestrogens as untreated cattle. The mean concentration of oestradiol-17β in whole milk is estimated at 6.4 pg/ml. Scarce data available on eggs report up to 200 pg/g oestradiol-17β. The risk evaluation of oestrogenic growth-promoting agents is limited by analytical uncertainties. Residues of oestradiol-17α and the importance of oestrogen conjugates are widely unknown. The performance of mass spectrometry still needs to be improved for confirmation of oestrogen concentrations in most food. At present, the potential relevance of oestradiol acyl esters, the actual daily production rate of oestradiol in prepubertal children, and the role of oestradiol metabolites in cancer are obscure. The presence of different cytoplasmic oestrogen receptor subtypes and potential oestradiol effects in non-reproductive functions require further examination.
The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002
Authors: Gregory L. Armstrong, Annemarie Wasley, Edgar P. Simard, Geraldine M. McQuillan, Wendi L. Kuhnert, Miriam J. Alter
Journal: Annals of Internal Medicine (2006)

Defining the primary characteristics of persons infected with hepatitis C virus (HCV) enables physicians to more easily identify persons who are most likely to benefit from testing for the disease.To describe the HCV-infected population in the United States.Nationally representative household survey.U.S. civilian, noninstitutionalized population.15,079 participants in the National Health and Nutrition Examination Survey between 1999 and 2002.All participants provided medical histories, and those who were 20 to 59 years of age provided histories of drug use and sexual practices. Participants were tested for antibodies to HCV (anti-HCV) and HCV RNA, and their serum alanine aminotransferase (ALT) levels were measured.The prevalence of anti-HCV in the United States was 1.6% (95% CI, 1.3% to 1.9%), equating to an estimated 4.1 million (CI, 3.4 million to 4.9 million) anti-HCV-positive persons nationwide; 1.3% or 3.2 million (CI, 2.7 million to 3.9 million) persons had chronic HCV infection. Peak prevalence of anti-HCV (4.3%) was observed among persons 40 to 49 years of age. A total of 48.4% of anti-HCV-positive persons between 20 and 59 years of age reported a history of injection drug use, the strongest risk factor for HCV infection. Of all persons reporting such a history, 83.3% had not used injection drugs for at least 1 year before the survey. Other significant risk factors included 20 or more lifetime sex partners and blood transfusion before 1992. Abnormal serum ALT levels were found in 58.7% of HCV RNA-positive persons. Three characteristics (abnormal serum ALT level, any history of injection drug use, and history of blood transfusion before 1992) identified 85.1% of HCV RNA-positive participants between 20 and 59 years of age.Incarcerated and homeless persons were not included in the survey.Many Americans are infected with HCV. Most were born between 1945 and 1964 and can be identified with current screening criteria. History of injection drug use is the strongest risk factor for infection.