University of Texas Southwestern Medical Center

About: University of Texas Southwestern Medical Center is a healthcare organization based out in Dallas, Texas, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 39107 authors who have published 75242 publications receiving 4497256 citations. The organization is also known as: UT Southwestern & UT Southwestern Medical School.

Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a.

Abstract: The NH2-terminal domain of sterol-regulatory element binding protein-1a (SREBP-1a) activates transcription of genes encoding enzymes of cholesterol and fatty acid biosynthesis in cultured cells. This domain is synthesized as part of a membrane-bound precursor that is attached to the nuclear envelope and endoplasmic reticulum. In sterol-depleted cells a two-step proteolytic process releases this NH2-terminal domain, which enters the nucleus and activates transcription. Proteolysis is suppressed by sterols, thereby suppressing transcription. In the current experiments we produce transgenic mice that overexpress a truncated version of human SREBP-1a that includes the NH2-terminal domain but lacks the membrane attachment site. This protein enters the nucleus without a requirement for proteolysis, and therefore it cannot be down-regulated. Expression was driven by the phosphoenolpyruvate carboxykinase (PEPCK) promoter, which gives high level expression in liver. When placed on a low carbohydrate/high protein diet to induce the PEPCK promoter, the transgenic mice developed progressive and massive enlargement of the liver, owing to the engorgement of hepatocytes with cholesterol and triglycerides. The mRNAs encoding 3-hydroxy-3-methylglutaryl CoA (HMG CoA) synthase, HMG CoA reductase, squalene synthase, acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase-1 were all elevated markedly, as was the LDL receptor mRNA. The rates of cholesterol and fatty acid synthesis in liver were elevated 5- and 25-fold, respectively. Remarkably, plasma lipid levels were not elevated. The amount of white adipose tissue decreased progressively as the liver enlarged. These studies indicate that the NH2-terminal domain of SREBP-1a can produce major effects on lipid synthesis and storage in the liver.

Longitudinal Growth of Hospitalized Very Low Birth Weight Infants

Abstract: Background. The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies. Objectives. To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis). Design. Large, multicenter, prospective cohort study. Methods. Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol. Results. Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4–16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings. Conclusions. These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes.

Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis

Abstract: Liver cirrhosis is a major yet largely preventable and underappreciated cause of global health loss. Variations in cirrhosis mortality at the country level reflect differences in prevalence of risk factors such as alcohol use and hepatitis B and C infection. We estimated annual age-specific mortality from liver cirrhosis in 187 countries between 1980 and 2010. We systematically collected vital registration and verbal autopsy data on liver cirrhosis mortality for the period 1980 to 2010. We corrected for misclassification of deaths, which included deaths attributed to improbable or nonfatal causes. We used ensemble models to estimate liver cirrhosis mortality with uncertainty by age, sex, country and year. We used out-of-sample predictive validity to select the optimal model. Global liver cirrhosis deaths increased from around 676,000 (95% uncertainty interval: 452,863 to 1,004,530) in 1980 to over 1 million (1,029,042; 670,216 to 1,554,530) in 2010 (about 2% of the global total). Over the same period, the age-standardized cirrhosis mortality rate decreased by 22%. This was largely driven by decreasing cirrhosis mortality rates in China, the US and countries in Western Europe. In 2010, Egypt, followed by Moldova, had the highest age-standardized cirrhosis mortality rates, 72.7 and 71.2 deaths per 100,000, respectively, while Iceland had the lowest. In Egypt, almost one-fifth (18.1%) of all deaths in males 45- to 54-years old were due to liver cirrhosis. Liver cirrhosis mortality in Mexico is the highest in Latin America. In France and Italy, liver cirrhosis mortality fell by 50% to 60%; conversely, in the United Kingdom, mortality increased by about one-third. Mortality from liver cirrhosis was also comparatively high in Central Asia countries, particularly Mongolia, Uzbekistan and Kyrgyzstan, and in parts of sub-Saharan Africa, notably Gabon. Liver cirrhosis is a significant cause of global health burden, with more than one million deaths in 2010. Our study identifies areas with high and/or rapidly increasing mortality where preventive measures to control and reduce liver cirrhosis risk factors should be urgently strengthened. Please see related commentary: http://www.biomedcentral.com/1741-7015/12/159/abstract .

Metabolic reprogramming and cancer progression

Abstract: Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.