The phosphatidylinositol 3-kinase/akt cassette regulates purine nucleotide synthesis.

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is highly conserved throughout evolution and regulates cell size and survival and cell cycle progression. It regulates the latter by stimulating procession through G(1) and the G(1)/S phase transition. Entry into S phase requires an abundant supply of purine nucleotides, but the effect of the PI3K/Akt pathway on purine synthesis has not been studied.

Stromal control of oncogenic traits expressed in response to the overexpression of GLI2, a pleiotropic oncogene.

Hedgehog signaling is often activated in tumors, yet it remains unclear how GLI2, a transcription factor activated by this pathway, acts as an oncogene. We show that GLI2 is a pleiotropic oncogene. The overexpression induces genomic instability and blocks differentiation, likely mediated in part by enhanced expression of the stem cell gene SOX2.

Mortality and time to extubation in severe hospital-acquired pneumonia.

Background: This study examined predictors of in-hospital mortality and time to extubation among patients with acute, severe hospital-acquired pneumonia (HAP) managed in the intensive care unit (ICU).

Methods: Patients with HAP prospectively identified between June 2001 and May 2003 were included in the study if they (1) met the Centers for Disease Control and Prevention's definition for HAP, (2) were treated in the ICU within 1 day of the HAP diagnosis, and (3) required intubation acutely or had a bloodstream infection within 48 hours of the HAP diagnosis.

Results: The cohort included 219 patients, 83 of whom died (37.

Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial.

Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women. The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion.

Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.

To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X 2 or a 3,5-X 2-4-OH phenyl substructure (X = Br or CH 3).

Temperature effects on survival and DNA repair in four freshwater cladoceran Daphnia species exposed to UV radiation.

The biological responses of four freshwater daphniid species, Daphnia middendorffiana, D. pulicaria, D. pulex and D.

Asymmetric synthesis of inhibitors of glycinamide ribonucleotide transformylase.

Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors and has emerged as a productive target for antineoplastic therapeutic intervention. The asymmetric synthesis and evaluation of the two diastereomers of 10-methylthio-DDACTHF (10R-3 and 10S-3) and related analogues as potential inhibitors of GAR Tfase are reported. This work, which defines the importance of the C10 stereochemistry for this class of inhibitors of GAR Tfase, revealed that both diastereomers are potent inhibitors of rhGAR Tfase (10R-3 Ki = 210 nM, 10S-3 Ki = 180 nM) that exhibit effective cell growth inhibition (CCRF-CEM IC50 = 80 and 50 nM, respectively), which is dependent on intracellular polyglutamation by folylpolyglutamate synthetase (FPGS) but not intracellular transport by the reduced folate carrier.

Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative.

Objective: Experimental and epidemiologic studies suggest that calcium and vitamin D may reduce the risk of developing diabetes. We examined the effect of calcium plus vitamin D supplementation on the incidence of drug-treated diabetes in postmenopausal women.

Research Design And Methods: The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned postmenopausal women to receive 1,000 mg elemental calcium plus 400 IU of vitamin D3 daily, or placebo, in a double-blind fashion.

Day-case Karydakis flap for pilonidal sinus.

Purpose: The Karydakis flap for pilonidal sinus is associated with primary wound healing and infrequent recurrence. Previous studies had reported in-patient protocols. This cohort study was designed to assess the feasibility, safety, and practicalities of day-case Karydakis flap surgery.

Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors.

To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding.

Personality and ethical decision-making in research: the role of perceptions of self and others.

THIS STUDY EXAMINED BASIC PERSONALITY characteristics, narcissism, and cynicism as predictors of ethical decision-making among graduate students training for careers in the sciences. Participants completed individual difference measures along with a scenario-based ethical decision-making measure that captures the complex, multifaceted nature of ethical decision-making in scientific research. The results revealed that narcissism and cynicism (individual differences influencing self-perceptions and perceptions of others) showed consistently negative relationships with aspects of ethical decision-making, whereas more basic personality characteristics (e.

Natural methods of protein stabilization: thermostable biocatalysts.

Enzymes that are naturally found in thermophilic and hyperthermophilic organisms are being used as robust biocatalysts in the fine chemical and pharmaceutical industries. They have important use in these industries due to their increased stability which is often required during commercial reaction conditions. The approach used in these studies is to learn how nature has managed to stabilize these proteins using a detailed knowledge of their biochemical properties and three-dimensional structures.

Artificial UV-B and solar radiation reduce in vitro infectivity of the human pathogen Cryptosporidium parvum.

The potential for solar ultraviolet (UV) radiation to act as a significant abiotic control of Cryptosporidium parvum oocysts in nature is unknown. Infectivity of C. parvum following exposure to artificial UV-B and natural solar radiation, with and without UV wavelengths, was tested under controlled pH and temperature conditions.

Risk factors for surgical site infection complicating laminectomy.

Objective: To examine risk factors for surgical site infection (SSI) following spinal surgery and to analyze the associations between a surgeon's years of operating experience and surgical specialty and patients' SSI risk.

Design: Case-control study.

Setting: A tertiary care facility and a community hospital in Durham, North Carolina.

Impact of zooplankton grazing on the excystation, viability, and infectivity of the protozoan pathogens Cryptosporidium parvum and Giardia lamblia.

Very little is known about the ability of the zooplankton grazer Daphnia pulicaria to reduce populations of Giardia lamblia cysts and Cryptosporidium parvum oocysts in surface waters. The potential for D. pulicaria to act as a biological filter of C.

Validation of the University of California San Francisco Oral Cancer Pain Questionnaire.

Unlabelled: The aim of this study was to validate the published University of California San Francisco (UCSF) Oral Cancer Pain Questionnaire. To test for validity of the questionnaire, 16 patients with oral cancer completed the 8-item questionnaire immediately before and after treatment (surgical resection) of their oral cancer. For all 8 questions, the difference between mean preoperative and mean postoperative responses were statistically significant (P < .

Expression of 25 human ABC transporters in the yeast Pichia pastoris and characterization of the purified ABCC3 ATPase activity.

Human ATP-binding cassette (ABC) transporters comprise a family of 48 membrane-spanning transport proteins, many of which are associated with genetic diseases or multidrug resistance of cancers. In this study, we present a comprehensive approach for the cloning, expression, and purification of human ABC transporters in the yeast Pichia pastoris. We analyzed the expression of 25 proteins and demonstrate that 11 transporters, including ABCC3, ABCB6, ABCD1, ABCG1, ABCG4, ABCG5, ABCG8, ABCE1, ABCF1, ABCF2, and ABCF3, were expressed at high levels comparable to that of ABCB1 (P-glycoprotein).

Role of extracellular charged amino acids in the yeast alpha-factor receptor.

The yeast pheromone receptor, Ste2p, is a G protein coupled receptor that initiates cellular responses to alpha-mating pheromone, a 13 residue peptide that carries a net positive charge at physiological pH. We have examined the role of extracellular charged groups on the receptor in response to the pheromone. Substitutions of Asn or Ala for one extracellular residue, Asp275, affected both pheromone binding and signaling, suggesting that this position interacts directly with ligand.

Racial variation in the relationship of anemia with mortality and mobility disability among older adults.

Anemia is more common among older blacks than older whites. However, it is unclear whether anemia predicts adverse events similarly in both races. Data on 1018 black and 1583 white adults aged 71 to 82 years were analyzed.

AMCP Format dossier requests: manufacturer response and formulary implications for one large health plan.

Background: The Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, a template for health plans to use in developing formulary submission guidelines, has been widely adopted since its initial release in 2000. Many health plans request a dossier (a standardized set of clinical and economic evidence prepared by pharmaceutical manufacturers) to provide information for consideration during the formulary decision-making process. While dossier quality has reportedly improved over time, there is no recent research examining the response rate to dossier requests and the quality of dossiers received.

Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.

A series of benzo-macrolactones of varying ring size and conformation has been prepared by chemical synthesis and evaluated by structural and biological techniques. Thus, 12- to 16-membered lactones were obtained by concise routes, involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-, and 16-membered analogs are good inhibitors, suggesting that they can adopt the required conformation to fit in the ATP-binding site.

Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.

Most studies of the relation between kidney function and physical function have been conducted in persons with advanced kidney disease and have used creatinine-based measures of kidney function. Cystatin C concentration is a measure of kidney function that is independent of muscle mass, unlike creatinine. Using baseline data on 3,043 elderly adults from the Health, Aging, and Body Composition Study (Blacks and Whites recruited from Pittsburgh, Pennsylvania, and Memphis, Tennessee, in 1997-1998), the authors examined the cross-sectional association between cystatin C level and performance on several tests of physical function.