Mysteriously rapid rise in Legionnaires' disease incidence correlates with declining atmospheric sulfur dioxide.

Legionnaires' disease (LD) is a severe form of pneumonia (∼10-25% fatality rate) caused by inhalation of aerosols containing Legionella, a pathogenic gram-negative bacteria. These bacteria can grow, spread, and aerosolize through building water systems. A recent dramatic increase in LD incidence has been observed globally, with a 9-fold increase in the United States from 2000 to 2018, and with disproportionately higher burden for socioeconomically vulnerable subgroups. Despite the focus of decades of research since the infamous 1976 outbreak, substantial knowledge gaps remain with regard to source of exposure and the reason(s) for the dramatic increase in LD incidence. Here, we rule out factors indicated in literature to contribute to its long-term increases and identify a hitherto unexplored explanatory factor. We also provide an epidemiological demonstration that the occurrence of LD is linked with exposure to cooling towers (CTs). Our results suggest that declining sulfur dioxide air pollution, which has many well-established health benefits, results in reduced acidity of aerosols emitted from CTs, which may prolong the survival duration of Legionella in contaminated CT droplets and contribute to the increase in LD incidence. Mechanistically associating decreasing aerosol acidity with this respiratory disease has implications for better understanding its transmission, predicting future risks, and informed design of preventive and interventional strategies that consider the complex impacts of continued sulfur dioxide changes.

Exploring Biopharmaceutical Analysis with Compact Capillary Liquid Chromatography Instrumentation.

A recent trend in the design of liquid chromatography (LC) instrumentation is the move towards miniaturized and portable systems. These smaller platforms provide wider flexibility in operation, with the opportunity for conducting analysis directly at the point of sample collection rather than transporting the sample to a centralized laboratory facility. For the manufacturing of pharmaceutical and biopharmaceutical products, these platforms can be implemented for process monitoring and product characterization directly in manufacturing environments. This article describes a portable, miniaturized LC instrument coupled to a mass spectrometer (MS) for characterization of a biopharmaceutical monoclonal antibody (mAb).

Retinoic Acid Signaling Modulates Recipient Gut Barrier Integrity and Microbiota After Allogeneic Hematopoietic Stem Cell Transplantation in Mice.

Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). An impaired intestinal epithelial barrier is an important component of GVHD pathogenesis. However, contributing host factors that modulate mucosal barrier integrity during GVHD are poorly defined. We hypothesized that vitamin A and retinoic acid (RA) exert positive impacts on maintaining intestinal barrier function after HSCT, thus preventing or dampening GVHD severity. Unexpectedly, we found that exogenous RA increased intestinal permeability of recipient mice after allogeneic HSCT. Serum bacterial endotoxin levels were significantly higher in GVHD mice fed a vitamin A-high (VAH) diet compared to those fed a vitamin A-normal (VAN) diet, indicating a more compromised intestinal barrier function. Furthermore, VAH mice showed more severe lung GVHD with increased donor T cell infiltration in this tissue and died significantly faster than VAN recipients. 16S rRNA sequencing of fecal samples revealed significant differences in the diversity and composition of gut microbiota between VAN and VAH transplant recipients. Collectively, we show that retinoic acid signaling may negatively impact intestinal barrier function during GVHD. Mild vitamin A supplementation is associated with increased lung GVHD and more profound gut dysbiosis. Micronutrients such as vitamin A could modulate complications of allogeneic HSCT, which may be mediated by shaping gut microbiota.

T cells localized to the androgen-deprived prostate are TH1 and TH17 biased.

BACKGROUND: T cells infiltrate the prostates of prostate cancer patients undergoing neoadjuvant androgen deprivation. These prostate-infiltrating T cells have an oligoclonal phenotype, suggesting the development of an antigen-specific T-cell response. We hypothesized that androgen deprivation might elicit a prostate tissue-specific T-cell response that could potentially be combined with other immune-active therapies, and consequently sought to investigate the nature and timing of this T-cell response following castration. METHODS: We investigated the phenotype and cytokine expression of T cells at various time points in the prostates of Lewis rats following surgical castration, and used adoptive transfer of prostate-infiltrating lymphocytes (PILs) to determine whether the infiltration by T cells was mediated by effects of castration on the prostate or lymphocytes. RESULTS: Prostate T-cell infiltration shortly after castration was T(H) 1 biased up to approximately 30 days, followed by a predominance of T(H) 17-type cells, which persisted until at least 90 days post castration. PILs from sham-treated or castrate rats localized to the prostates of castrate animals. CONCLUSIONS: These observations suggest castration elicits a time-dependent prostate-specific T-cell infiltration, and this infiltration is likely mediated by effects of castration on prostate tissue rather than T-cells. These findings have implications for the timing of immunotherapies combined with androgen deprivation as treatments for prostate cancer.

Prostate cancer patients on androgen deprivation therapy develop persistent changes in adaptive immune responses.

Prostate cancer is a significant cause of morbidity and mortality among men worldwide. The cornerstone treatment for metastatic prostate cancer is androgen deprivation, which has known effects on prostate tissue apoptosis and thymic regrowth. These findings, together with interest in developing immune-based treatments for prostate cancer, lead us to question whether androgen deprivation causes changes in the adaptive immune responses of prostate cancer patients, and whether the timing of changes has implications for the sequencing of immunotherapies in combination with androgen deprivation. Peripheral blood mononuclear cells were obtained from patients before beginning androgen deprivation therapy (ADT) and at several time points thereafter. These cells were analyzed for the frequency of specific lymphocyte populations and their response to stimulation. The development of prostate antigen-specific immune responses was assessed using SEREX (serological identification of antigens by recombinant expression). Patients developed expansion of the naive T-cell compartment persisting over the course of androgen deprivation, together with an increase in effector-cell response to stimulation, and the generation of prostate tissue-associated IgG antibody responses, implying a potential benefit to the use of ADT in combination with prostate cancer-directed immunotherapies. The optimal timing and sequence of androgen deprivation with immune-based therapies awaits future experimental evaluation.