The Function of Hypoxia-Inducible Factor (HIF) Is Independent of the Endoplasmic Reticulum Protein OS-9

The protein “amplified in osteosarcoma-9” (OS-9) has been shown previously to interact with the prolyl hydroxylases PHD2 and PHD3. These enzymes initiate oxygen-dependent degradation of the α-subunit of hypoxia-inducible factor (HIF), a transcription factor that adapts cells to insufficient oxygen supply (hypoxia). A new model has been proposed where OS-9 triggers PHD dependent degradation of HIF-α. It was the aim of our study to define the molecular mode of action of OS-9 in the regulation of PHD and HIF activity. Although initial co-immunoprecipitation experiments confirmed physical interaction between OS-9 and PHD2, neither overexpression nor lentiviral inhibition of OS-9 expression affected HIF regulation. Subcellular localization experiments revealed a distinct reticular staining pattern for OS-9 while PHD2 was mainly localized in the cytoplasm. Further cell fractionation experiments and glycosylation tests indicated that OS-9 is a luminal ER protein. In vivo protein interaction analysis by fluorescence resonance energy transfer (FRET) showed no significant physical interaction of overexpressed PHD2-CFP and OS-9-YFP. We conclude that OS-9 plays no direct functional role in HIF degradation since physical interaction of OS-9 with oxygen sensing HIF prolyl hydroxylases cannot occur in vivo due to their different subcellular localization

Hospitalization due to Adverse Drug Reactions and Drug Interactions before and after HAART

OBJECTIVE: To characterize and compare the rates of adverse drug reactions (ADRs) and interactions on admission in two, one-year periods: pre-highly active antiretroviral therapy (HAART) (phase 1) and post-HAART (phase 2)

Hospitalization due to Adverse Drug Reactions and Drug Interactions before and after HAART

OBJECTIVE: To characterize and compare the rates of adverse drug reactions (ADRs) and interactions on admission in two, one-year periods: pre-highly active antiretroviral therapy (HAART) (phase 1) and post-HAART (phase 2).DESIGN: Retrospective chart review.SETTING:University-affiliated tertiary care centre.POPULATION STUDIED: HIV-positive patients admitted to hospital.MAIN RESULTS: In phase 1, 436 of 517 admissions, and, in phase 2, 323 of 350 admissions were analyzed. Over 92% of patients were male, with a mean age of 38 years. Significant differences (Pud_less_than0.05) in the mean length of stay (12.08 versus 10.02 days), the CD4 counts (99.25 versus 129.45) and the number of concurrent diseases (4.20 versus 3.63) were found between phase 1 and 2, respectively. The mean number of medications taken (5.52 versus 5.94) and the rates of hospitalization with ADRs (20.4% versus 21.4%) or interactions (2.5% versus 2.16%) were similar between the two phases. Antiretrovirals were more common in ADR admissions post-HAART (21.3% versus 36.2%), while antiparasitics, psychotherapeutics and antineoplastics were more common pre-HAART. Other classes of drugs involved in both phases were sulphonamides, narcotics, ganciclovir, foscarnet, antimycobacterials and antifungals. ADR causality was possible or probable in more than 80% of cases. Over 60% of ADRs were grades 3 to 4, and about 85% were either the main or contributing reason for admission. About 65% of patients had at least partial recovery at the time of discharge. In phases 1 and 2, 8.9% and 2.9% of admissions,respectively, with ADRs were fatal.CONCLUSIONS: Although hospitalizations with ADRs and interactions were similar in both phases, HAART therapy has had a significant impact on the incidence and nature of ADRs at St Michael?s Hospital, Wellesley Central Site, Toronto, Ontario.Peer Reviewe

TORC1 regulates the transcriptional response to glucose and developmental cycle via the Tap42-Sit4-Rrd1/2 pathway in Saccharomyces cerevisiae

Target of Rapamycin Complex 1 (TORC1) is a highly conserved eukaryotic protein complex that couples the presence of growth factors and nutrients in the environment with cellular proliferation. TORC1 is primarily implicated in linking amino acid levels with cellular growth in yeast and mammals. Although glucose deprivation has been shown to cause TORC1 inactivation in yeast, the precise role of TORC1 in glucose signaling and the underlying mechanisms remain unclear.Agency for Science, Technology and Research (A*STAR)Published versionWe would like to acknowledge A*STAR (Singapore)’s core funding provided to Bioinformatics Institute

Safety and Tolerability of Varenicline Tartrate (Champix®/Chantix®) for Smoking Cessation in HIV-Infected Subjects: A Pilot Open-Label Study

The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix®, Pfizer, Saint-Laurent, QC, Canada or Chantix®, Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p=0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9–12 was 42% (95% confidence interval [CI]: 26–58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline

Pathways From HIV-Related Stigma to Antiretroviral Therapy Measures in the HIV Care Cascade for Women Living With HIV in Canada

Associations between HIV-related stigma and reduced antiretroviral therapy (ART) adherence are widely established, yet the mechanisms accounting for this relationship are underexplored. There has been less attention to HIV-related stigma and its associations with ART initiation and current ART use. We examined pathways from HIV-related stigma to ART initiation, current ART use, and ART adherence among women living with HIV in Canada