A Randomized,Placebo-Controlled Study of SRT2104, a SIRT1 Activator,in Patients with Moderate to Severe Psoriasis

Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84 but was not consistently in agreement with PASI. Improvement in histology was associated with modulation of IL-17 and TNF-α signaling pathways and keratinocyte differentiation target genes. 27 subjects (69%) across all treatment groups, including placebo, experienced at least one treatment emergent adverse event. The majority of AEs were either mild or moderate. Most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%), and psoriatic arthropathy (8%). Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51–89%). Given the interesting signals of clinical activity, impact on gene expression and the generally favorable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted.

Trial Registration

Clinicaltrials.gov NCT01154101     

High HIV Burden in Men Who Have Sex with Men across Colombia’s Largest Cities: Findings from an Integrated Biological and Behavioral Surveillance Study

Background

Among Latin America’s concentrated HIV epidemics, little is known about men who have sex with men (MSM) in Colombia, the region’s third largest country. To date, surveillance studies have been limited to Bogota, while 80% of HIV cases and deaths originate from Colombia’s other cities and departments. The extent to which interventions should prioritize MSM outside of Bogota is unknown.

Methods

We recruited 2603 MSM using respondent-driven sampling from seven of Colombia’s largest cities. HIV prevalence was estimated by site from dried blood spot samples. Behavioral data were collected through face-to-face interviews and risk factors for HIV infection analyzed using weighted, multi-level logistical regression models accounting for recruitment patterns.

Results

Across cities, HIV prevalence averaged 15%, varied from 6% to 24% and was highest in Cali, Bogota, and Barranquilla. In the past 12 months, 65% of MSM had ≥ 5 casual male partners and 23% had a female partner. Across partnerships (i.e., casual, stable, and commercial), the proportion of MSM engaging in unprotected sex was ≥ 52% with male partners and ≥ 66% with female partners. Self-reported history of STI (24%) and past-year illicit drug use (38%) were also common. In multivariate analysis, age ≥ 35 (adjusted odds ratio [AOR], 19.2) and 25–39 (AOR, 5.6) relative to ≤ 18–24 years, identifying as homosexual relative to heterosexual (AOR 0.1), meeting casual partners on the Internet (adjusted odds ratio [AOR], 3.1) and age of sexual debut of ≤ 13 years (AOR, 3.1) predicted HIV infection. HIV testing and prevention messaging reached just 24% of MSM in the past year.

Conclusions

Findings support consistently elevated HIV burden among MSM throughout Colombia’s largest cities and a need for enhanced behavioral prevention and HIV testing, emphasizing men who use the Internet as well as physical venues to meet sex partners.     

Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA

This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.     

Effect of a four-week course of interleukin-10 on cytokine production in a placebo-controlled study of HIV-1-infected subjects

Interleukin (IL)-10 suppresses synthesis of the pro-inflammatory cytokines tumor necrosis factor (TNF)alpha, IL-1beta, and interferon (IFN)gamma. Since pro-inflammatory cytokines have been implicated in the production of human immunodeficiency virus type 1 (HIV-1), cytokine synthesis in whole blood cultures were determined during a 4-week course of subcutaneous IL-10 injections in 33 HIV-1-infected patients. Patients were randomized into four groups: placebo (nine), IL-10 at 1 microg/kg/day (nine), IL-10 at 4 microg/kg/day (six) and IL-10 at 8 microg/kg three times per week (nine). Whole blood was obtained at the beginning and conclusion of the study and was stimulated for 24 hours with the combination of IL-18 plus lipopolysaccharide. TNFalpha production in stimulated whole blood was reduced three and six hours after the first injection of IL-10 compared to subjects injected with the placebo. After four weeks of treatment, production of IFNgamma was suppressed in a greater number of patients in the IL-10 treatment groups compared to subjects in the placebo group. Similarly, IL-1beta production was lower in the IL-10 treatment groups compared to subjects receiving placebo. In contrast, after four weeks of IL-10, circulating levels of the anti-inflammatory TNF soluble receptor p55 increased dose-dependently compared to placebo subjects. Patient heterogeneity and small sample size presented difficulties in establishing statistical significance. Although the cytokine changes in our study did not demonstrate statistically significant changes, the data nevertheless reveal that four weeks of IL-10 therapy in HIV-1 infected subjects produced the anticipated suppression of pro-inflammatory cytokines.     

Diversity and biogeography of bacterial assemblages in surface sediments across the San Pedro Basin, Southern California Borderlands

Sediment bacteria play important roles in the biogeochemistry of ocean sediments; however, factors influencing assemblage composition have not been extensively studied. We examined extractable sediment bacterial abundance, the composition of bacterial assemblages using a high-throughput molecular fingerprinting approach, and several sediment biogeochemical parameters (organic matter content and alkaline phosphatase activity), along a 35 km transect from Point Fermin, Southern California, to Santa Catalina Island, across the approximately 900-m-deep San Pedro Basin. Automated rRNA intergenic spacer analysis (ARISA) demonstrated that in two spatially isolated shallow (approximately < 60 m, on opposite sides of the channel) sediment environments, assemblages were more similar to each other than to deeper communities. Distinct communities existed in deeper and shallower sediments, and stations within the deep basin over 2 km apart contained remarkably similar assemblage fingerprints. The relative contribution to total amplified DNA fluorescence of operational taxonomic units (OTUs) was significantly correlated to that of other OTUs in few comparisons (2.7% of total), i.e. few bacterial types were found together or apart consistently. The relative proportions within assemblages of only a few OTU were significantly correlated to measured physicochemical parameters (organic matter content and wet/dry weight ratio of sediments) or enzyme (alkaline phosphatase) activities. A low percentage of shared OTU between shallow and deep sediments, and the presence of similar, but spatially isolated assemblages suggests that bacterial OTU may be widely dispersed over scales of a few kilometres, but that environmental conditions select for particular assemblages.     

SHOULD RAPID TESTS FOR HIV INFECTION NOW BE MANDATORY DURING PREGNANCY? GLOBAL DIFFERENCES IN SCARCITY AND A DILEMMA OF TECHNOLOGICAL ADVANCE

Since testing for HIV infection became possible in 1985, testing of pregnant women has been conducted primarily on a voluntary, 'opt-in' basis. Faden, Geller and Powers, Bayer, Wilfert, and McKenna, among others, have suggested that with the development of more reliable testing and more effective therapy to reduce maternal-fetal transmission, testing should become either routine with 'opt-out' provisions or mandatory. We ask, in the light of the new rapid tests for HIV, such as OraQuick, and the development of antiretroviral treatment that can reduce maternal-fetal transmission rates to <2%, whether that time is now. Illustrating our argument with cases from the United States (US), Kenya, Peru, and an undocumented Mexican worker in the US, we show that when testing is accompanied by assured multi-drug therapy for the mother, the argument for opt-out or mandatory testing for HIV in pregnancy is strong, but that it is problematic where testing is accompanied by adverse events such as spousal abuse or by inadequate intrapartum or follow-up treatment. The difference is not a 'double standard', but reflects the presence of conflicts between the health interests of the mother and the fetus--conflicts that would be abrogated by the assurance of adequate, continuing multi-drug therapy. In light of these conflicts, where they still occur, careful processes of informed consent are appropriate, rather than opt-out or mandatory testing.     

Rapid identification of functionally critical amino acids in a G protein-coupled receptor

G protein-coupled receptors (GPCRs) comprise one of the largest protein families found in nature. Here we describe a new experimental strategy that allows rapid identification of functionally critical amino acids in the rat M(3) muscarinic acetylcholine receptor (M3R), a prototypic class I GPCR. This approach involves low-frequency random mutagenesis of the entire M3R coding sequence, followed by the application of a new yeast genetic screen that allows the recovery of inactivating M3R single point mutations. The vast majority of recovered mutant M3Rs also showed substantial functional impairments in transfected mammalian (COS-7) cells. A subset of mutant receptors, however, behaved differently in yeast and mammalian cells, probably because of the specific features of the yeast expression system used. The screening strategy described here should be applicable to all GPCRs that can be expressed functionally in yeast.     

Transgene-coded chimeric proteins as reporters of intracellular proteolysis: Starvation-induced catabolism of a lacZ fusion protein in muscle cells of Caenorhabditis elegans

The product of an integrated transgene provides a convenient and cell-specific reporter of intracellular protein catabolism in 103 muscle cells of the nematode Caenorhabditis elegans. The transgene is an in-frame fusion of a 5′-region of the C. elegans unc-54 (muscle myosin heavy-chain) gene to the lacZ gene of Escherichia coli [Fire and Waterston (1989): EMBO J 8:3419–3428], encoding a 146-kDa fusion polypeptide that forms active β-galactosidase tetramers. The protein is stable in vivo in well-fed animals, but upon removal of the food source it is inactivated exponentially (t_1/2 = 17 h) following an initial lag of 8 h. The same rate constant (but no lag) is observed in animals starved in the presence of cycloheximide, implying that inactivation is catalyzed by pre-existing proteases. Both the 146-kDa fusion polypeptide (t_1/2 = 13 h) and a major 116-kDa intermediate (t_1/2 = 7 h) undergo exponential physical degradation after a lag of 8 h. Degradation is thus paradoxically faster than inactivation, and a number of characteristic immunoreactive degradation intermediates, some less than one-third the size of the parent polypeptide, are found in affinity-purified (active) protein. Some of these intermediates are conjugated to ubiquitin. We infer that the initial proteolytic cleavages occur in the cytosol, possibly by a ubiquitin-mediated proteolytic pathway and do not necessarily inactivate the fusion protein tetramer. J. Cell. Biochem. 67:143–153, 1997. © 1997 Wiley-Liss, Inc.