Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting.

Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs.

Plasma cell survival: The intrinsic drivers, migratory signals, and extrinsic regulators.

Antibody-secreting cells (ASC) are the effectors of protective humoral immunity and the only cell type that produces antibodies or immunoglobulins in mammals. In addition to their formidable capacity to secrete massive quantities of proteins, ASC are terminally differentiated and have unique features to become long-lived plasma cells (LLPC). Upon antigen encounter, B cells are activated through a complex multistep process to undergo fundamental morphological, subcellular, and molecular transformation to become an efficient protein factory with lifelong potential.

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19.

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings.

Dominant extrafollicular B cell responses in severe COVID-19 disease correlate with robust viral-specific antibody production but poor clinical outcomes.

A wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings.

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters.

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: (multidrug resistance 3) rs2302387 and [bile salt export pump (BSEP)] rs4668115 reduce transporter expression ( < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; < 0.

Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx.

Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of expression of the steroid hormone transporter OATP1B3 (). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 ( = 23.

Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats.

Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression.

Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells.

Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance.

Structural studies reveal thalidomide's mechanism of action and clinical effects: crystal clear or clearly complexed?

Another piece of the thalidomide puzzle is unraveled through structural studies of thalidomide and its derivatives bound to its protein target cereblon. Two recent studies published in Nature (Fischer et al.) and Nature Structural & Molecular Biology (Chamberlain et al.

Genetic variation: effect on prostate cancer.

The crucial role of androgens in the development of prostate cancer is well established. The aim of this review is to examine the role of constitutional (germline) and tumor-specific (somatic) polymorphisms within important regulatory genes of prostate cancer. These include genes encoding enzymes of the androgen biosynthetic pathway, the androgen receptor gene, genes that encode proteins of the signal transduction pathways that may have a role in disease progression and survival, and genes involved in prostate cancer angiogenesis.

Pharmacogenetics of membrane transporters: a review of current approaches.

This chapter provides a review of the pharmacogenetics of membrane transporters, including ABC transporters and OATPs. Membrane transporters are heavily involved in drug disposition, by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have a significant effect on the absorption, distribution, metabolism, excretion, and activity of compounds.