A Cell for the Ages: Human γδ T Cells across the Lifespan.

The complexity of the human immune system is exacerbated by age-related changes to immune cell functionality. Many of these age-related effects remain undescribed or driven by mechanisms that are poorly understood. γδ T cells, while considered an adaptive subset based on immunological ontogeny, retain both innate-like and adaptive-like characteristics. This T cell population is small but mighty, and has been implicated in both homeostatic and disease-induced immunity within tissues and throughout the periphery. In this review, we outline what is known about the effect of age on human peripheral γδ T cells, and call attention to areas of the field where further research is needed.

Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion.

PURPOSE: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. METHODS: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. RESULTS: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). CONCLUSION: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.

COX2 induction: a mechanism of endocrine breast cancer resistance?

PURPOSE: Urine prostaglandin E2 (PGE2) levels have shown to be a risk factor of breast cancer, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to be beneficial in preventing breast cancer risk and/or recurrence with or without aromatase inhibitors. We hypothesized that the use of an aromatase inhibitor triggers the activation of the inflammatory pathway via release of PGE2. METHODS: A single oral 25 mg dose of an aromatase inhibitor (exemestane) was given to 14 healthy postmenopausal female volunteers. Blood and urine samples were collected between 0 and 72 h post-dosing for pharmacokinetic and pharmacodynamic analysis. RESULTS: Our findings showed that urine PGE2 levels were markedly increased 72 h after exemestane administration (average pre-dosing PGE2 levels, 4061.1 pg/mL vs. post-dosing average PGE2 levels, 10732.5 pg/mL, P = 0.001, Wilcoxon Rank Test). Out of 14 subjects enrolled in the study, one subject showed no change in PGE2; another showed a 23-fold decreased in PGE2; and the remaining 12 showed an average of 8.4-fold increase in PGE2 levels (range 1.3-30.5, standard deviation 9.2) after exemestane administration. We found no statistically significant correlations between fold increase in urine PGE2 levels and the pharmacokinetics of either exemestane or 17-hydroexemestane (major in vivo metabolite of exemestane). CONCLUSION: Our results indicate that one of the pharmacological effects to aromatase inhibitors (e.g., exemestane) involves the activation of the inflammatory pathway via release of PGE2. Further in vitro mechanistic and in vivo translational studies designed to elucidate the role of this newly discovered effect are now warranted.

Long-Term Behavior of Simulated Partial Lead Service Line Replacements.

In this 48-month pilot study, long-term impacts of copper:lead galvanic connections on lead release to water were assessed without confounding differences in pipe exposure prehistory or disturbances arising from cutting lead pipe. Lead release was tracked from three lead service line configurations, including (1) 100% lead, (2) traditional partial replacement with 50% copper upstream of 50% lead, and (3) 50% lead upstream of 50% copper as a function of flow rate, connection types, and sampling methodologies. Elevated lead from galvanic corrosion worsened with time, with 140% more lead release from configurations representing traditional partial replacement configurations at 14 months compared to earlier data in the first 8 months. Even when sampled consistently at moderate flow rate (8 LPM) and collecting all water passing through service lines, conditions representing traditional partial service line configurations were significantly worse (≈40%) when compared to 100% lead pipe. If sampled at a high flow rate (32 LPM) and collecting 2 L samples from service lines, 100% of samples collected from traditional partial replacement configurations exceeded thresholds posing an acute health risk versus a 0% risk for samples from 100% lead pipe. Temporary removal of lead accumulations near Pb:Cu junctions and lead deposits from other downstream plastic pipes reduced risk of partial replacements relative to that observed for 100% lead. When typical brass compression couplings were used to connect prepassivated lead pipes, lead release spiked up to 10 times higher, confirming prior concerns raised at bench and field scale regarding adverse impacts of crevices and service line disturbances on lead release. To quantify semirandom particulate lead release from service lines in future research, whole-house filters have many advantages compared to other approaches.

Profile sampling to characterize particulate lead risks in potable water.

Traditional lead (Pb) profiling, or collecting sequential liters of water that flow from a consumer tap after a stagnation event, has recently received widespread use in understanding sources of Pb in drinking water and risks to consumer health, but has limitations in quantifying particulate Pb risks. A new profiling protocol was developed in which a series of traditional profiles are collected from the same tap at escalating flow rates. The results revealed marked differences in risks of Pb exposure from one consumer home to another as a function of flow rate, with homes grouped into four risk categories with differing flushing requirements and public education to protect consumers. On average, Pb concentrations detected in water at high flow without stagnation were at least three to four times higher than in first draw samples collected at low flow with stagnation, demonstrating a new "worst case" lead release scenario, contrary to the original regulatory assumption that stagnant, first draw samples contain the highest lead concentrations. Testing also revealed that in some cases water samples with visible particulates had much higher Pb than samples without visible particulates, and tests of different sample handling protocols confirmed that some EPA-allowed methods would not quantify as much as 99.9% of the Pb actually present (avg. 27% of Pb not quantified).

NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

Electrochemistry of free chlorine and monochloramine and its relevance to the presence of Pb in drinking water.

The commonly used disinfectants in drinking water are free chlorine (in the form of HOCl/OCl-) and monochloramine (NH2Cl). While free chlorine reacts with natural organic matter in water to produce chlorinated hydrocarbon byproducts, there is also concern that NH2Cl may react with Pbto produce soluble Pb(II) products--leading to elevated Pb levels in drinking water. In this study, electrochemical methods are used to compare the thermodynamics and kinetics of the reduction of these two disinfectants. The standard reduction potential for NH2Cl/Cl- was estimated to be +1.45 V in acidic media and +0.74 V in alkaline media versus NHE using thermodynamic cycles. The kinetics of electroreduction of the two disinfectants was studied using an Au rotating disk electrode. The exchange current densities estimated from Koutecky-Levich plots were 8.2 x 10(-5) and 4.1 x 10(-5) A/cm2, and by low overpotential experiments were 7.5 +/- 0.3 x 10(-5) and 3.7 +/- 0.4 x 10(-5) A/cm2 for free chlorine and NH2Cl, respectively. The rate constantforthe electrochemical reduction of free chlorine at equilibrium is approximately twice as large as that for the reduction of NH2Cl. Equilibrium potential measurements show that free chlorine will oxidize Pb to PbO2 above pH 1.7, whereas NH2Cl will oxidize Pb to PbO2 only above about pH 9.5, if the total dissolved inorganic carbon (DIC) is 18 ppm. Hence, NH2Cl is not capable of producing a passivating PbO2 layer on Pb, and could lead to elevated levels of dissolved Pb in drinking water.