Preclinical anti‐myeloma activity of the novel HDAC‐inhibitor JNJ‐26481585

Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti‐cancer agents and may be useful to enhance the therapeutic efficiency of established anti‐myeloma treatments. This study preclinically evaluated the effects of the ‘second generation’ pan‐HDAC inhibitor JNJ‐26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n = 42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2‐family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl‐1 depletion and Hsp72 induction were the most reliable features observed in JNJ‐26481585‐treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ‐26481585 with anti‐myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC‐inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.     

CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses

Both CD4⁺ T cell help and IL-2 have been postulated to “program” activated CD8⁺ T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8⁺ T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4⁺ T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8⁺ T cells peaked 3–4 days after initial priming and was dependent on CD4⁺ T cell help, likely through a CD28:CD80/86 mediated pathway. CD4⁺ T cell or CD25-deficiency led to normal early effector CD8⁺ T cell differentiation, but a subsequent lack of accumulation of CD8⁺ T cells resulting in overall decreased memory cell generation. Interestingly, in both primary and recall responses KLRG1^high CD127^low short-lived effector cells were drastically diminished in the absence of IL-2 signaling, although memory precursors remained intact. In contrast to previous reports, upon secondary antigen encounter CD25-deficient CD8⁺ T cells were capable of undergoing robust expansion, but short-lived effector development was again impaired. Thus, these results demonstrated that CD4⁺ T cell help and IL-2 signaling were linked via CD25 up-regulation, which controls the expansion and differentiation of antigen-specific effector CD8⁺ T cells, rather than “programming” memory cell traits.     

Bundling occupational safety with harm reduction information as a feasible method for improving police receptiveness to syringe access programs: evidence from three U.S. cities

Introduction  

In light of overwhelming evidence that access to sterile injection equipment reduces incidence of injection-attributable bloodborne disease without encouraging drug use, many localities have authorized sterile syringe access programs (SAPs), including syringe exchange and pharmacy-based initiatives. Even where such interventions are clearly legal, many law enforcement officers are unaware of the public health benefits and legal status of these programs and may continue to treat the possession of injection equipment as illegal and program participation as a marker of illegal behavior. Law enforcement practice can impede SAP utilization and may increase the risk of needlestick injury (NSI) among law enforcement personnel. Many SAPs conduct little or no outreach to law enforcement, in part because they perceive law enforcement actors as unreceptive to health-promotion programs targeting drug users.     

Relationships between adiponectin and the status of glucose metabolism in Koreans

The objective of this study was to assess relationships between adiponectin and the status of glucose metabolism and to investigate whether low adiponectin levels were independently associated with the risk of impaired glucose metabolism and type 2 diabetes in Korean population. A total of 3,508 participants (mean age 56.3±8.0 years; BMI 24.7±3.2 kg/ m²; 41.0% male) were enrolled. Participants with normal glucose metabolism (NGM), impaired glucose metabolism (IGM), and type 2 diabetes were 58.0%, 28.9%, and 13.1%. Adiponectin levels in both men and women were significantly lower in participants with IGM and type 2 diabetes than participants with NGM. Low adiponectin levels in both men and women were strongly associated with the risk of IGM and type 2 diabetes in large population-based cohort of rural adult Koreans.     

Zinc protoporphyrin levels, blood lead levels and neurocognitive deficits in Andean children with chronic lead exposure

OBJECTIVES: To investigate the relationship between blood lead (PbB), zinc protoporphyrin (ZPP) levels and performance on a test of auditory memory in Andean children and adolescents with chronic lead (Pb) exposure. DESIGN AND METHODS: PbB and ZPP levels were measured in blood samples from 166 participants (aged 6-16 yrs.) exposed to Pb in a local ceramic glazing cottage industry in Ecuadorian villages. PbB levels and ZPP/heme ratios were analyzed in relation to performance on the Digit Span subtest of the Wechsler IV intelligence scale, a test of auditory memory. RESULTS: Mean PbB level for the study group was 18.0 microg/dL (S.D.: 15.1; range: 3.0-86.0), and the mean ZPP/heme ratio was 105.7 mumol/mol (S.D.: 100.9; range: 36.0-592.0). There was no significant difference in PbB and ZPP levels between the 84 females and the 82 males. The mean Digit Span scale score (DS SS) for the study group was 6.81 (S.D.: 2.95; range: 1.0-17.0), which is below the average score of 10 for the test, with the females performing significantly better than males (t=2.435; p=0.01). Regression analyses revealed statistically significant inverse associations between DS SS and PbB level (r=0.251, p=0.001), and between DS SS and ZPP/heme ratio (r=0.246, p=0.001). CONCLUSION: Elevated PbB levels, representing acute exposure, and ZPP levels, reflecting chronic Pb exposure in this cohort of Andean inhabitants were associated with poor performance on a test of auditory memory, suggesting that the children and adolescents in the study area have neurocognitive deficits that may affect learning.     

In vitro antimycobacterial activities of capuramycin analogues

Translocase I inhibitor compounds derived from capuramycin demonstrated rapid bactericidal activity against several different mycobacterial species. SQ641 was the most active of the compounds, with a MIC of 0.12 to 8 microg/ml, a postantibiotic effect of 55 h, and interesting synergistic effects with other antitubercular drugs.     

A Comparison of Two Systems for Entering and Assessing Dietary Data for a Research Study

To reduce the cost of analyzing dietary data for research studies, we evaluated the accuracy of an entry and assessment system that could be used by trained food and nutrition professionals who did not routinely perform this type of task. We compared intakes from 24-hour recalls for 175 adult women and 185 schoolchildren using two methods for entry of dietary data. For the standard method, registered dietitians who routinely evaluate dietary data entered the recalls using a professional data entry program, RapidCalc. For the second method, other food and nutrition professionals were trained by the registered dietitians to use the Pacific Tracker program, a consumer-friendly dietary assessment system. Both programs use the same food composition table. Mean food group and nutrient intakes were similar for the two methods, differing by <10% on average for both adults and children. Correlations were also high, ranging from 0.77 to 0.96 for the women and from 0.76 to 0.94 for the children. For adults and children combined, mean energy intakes were remarkably close, at 2,067 kcal/d for RapidCalc and 2,072 kcal/d for Pacific Tracker, although absolute differences in energy intakes were >300 kcal/d for 23% of the women and 30% of the children. Costs are much lower with the Pacific Tracker method, unless the fees for the standard method are subsidized. We conclude that the Pacific Tracker method provides an accurate and cost-effective method of dietary data entry for research purposes.