Ventilation Heterogeneity Is a Treatable Trait in Severe Asthma.

BACKGROUND: Ventilation heterogeneity (VH) is a feature of asthma and indicates small airway disease. Nuclear imaging methods assess VH, which can facilitate clinical diagnosis and further our understanding of disease aetiology. OBJECTIVE: We sought to assess VH in severe eosinophilic asthma (SEA) using ventilation/perfusion single-photon emission computed tomography (V/P SPECT), and to assess its use as an objective test of the effect of biologic treatment for ventilation defects in SEA. METHODS: Adults (≥18 y) with severe asthma were recruited to participate in a cross-sectional observational study. Participants underwent a clinical assessment and V/P SPECT CT using Technegas as the ventilation agent. Measures were repeated for a nested before-after treatment study in people with SEA commencing biologics. RESULTS: A total of 62 participants with severe asthma were recruited. From this, 38 participants with SEA were included in the before-after study. The VH was associated with clinical variables such as lung function impairment and significantly improved after monoclonal antibody treatment in the severe asthma group. The changes in VH correlated with change in post bronchodilator forced expiratory volume in 1 second (FEV1) %predicted (r = -0.503; P = .001) and post bronchodilator FEV1/FVC (forced vital capacity) (r = -0.415; P = .01). CONCLUSIONS: The VH is clinically significant, measurable, and treatable, which establishes VH as a treatable trait in severe asthma.

Measuring the density and viscosity of culture media for optimized computational fluid dynamics analysis of in vitro devices.

Culture medium is frequently modelled as water in computational fluid dynamics (CFD) analysis of in vitro culture systems involving flow, such as bioreactors and organ-on-chips. However, culture medium can be expected to have different properties to water due to its higher solute content. Furthermore, cellular activities such as metabolism and secretion of ECM proteins alter the composition of culture medium and therefore its properties during culture. As these properties directly determine the hydromechanical stimuli exerted on cells in vitro, these, along with any changes during culture must be known for CFD modelling accuracy and meaningful interpretation of cellular responses. In this study, the density and dynamic viscosity of DMEM and RPMI-1640 media supplemented with typical concentrations of foetal bovine serum (0, 5, 10 and 20% v/v) were measured to serve as a reference for computational design analysis. Any changes in the properties of medium during culture were also investigated with NCI-H460 and HN6 cell lines. The density and dynamic viscosity of the media increased proportional to the % volume of added foetal bovine serum (FBS). Importantly, the viscosity of 5% FBS-supplemented RPMI-1640 was found to increase significantly after 3 days of culture of NCI-H460 and HN6 cell lines, with distinct differences between magnitude of change for each cell line. Finally, these experimentally-derived values were applied in CFD analysis of a simple microfluidic device, which demonstrated clear differences in maximum wall shear stress and pressure between fluid models. Overall, these results highlight the importance of characterizing model-specific properties for CFD design analysis of cell culture systems.

LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression.

Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479-90. ©2017 AACR.

Nutritional issues and body weight in long-term survivors of allogeneic blood and marrow transplant (BMT) in NSW Australia.

PURPOSE: The aims of this study were to describe the long-term nutrition, body weight and body image issues facing survivors of Allogeneic Blood and Marrow Transplant (BMT) and their impact on quality of life. It also describes survivors' perception of enteral feeding during BMT. METHODS: Four hundred and forty-one survivors who had undergone a BMT in NSW, Australia between 2000 and 2012 (n = 441/583) completed the Sydney Post BMT Study Survey (SPBS). RESULTS: Forty-five percent of survivors less than 2-year post-transplant reported a dry mouth, 36 % reported mouth ulcers and 19 % had diarrhoea. This was consistent across all survivor groups, regardless of time since transplant. Patients with one or more gastrointestinal (GI) symptoms had significantly lower quality of life scores. There was a significant difference in quality of life scores when comparing those with no GI symptoms to those with one or more symptoms (P = <0.0001). Quality of life was significantly higher in those who once again enjoyed mealtimes (P < 0.0001). Males were more likely to be satisfied with their body weight compared to females (P = 0.009). The median body mass index (BMI) for all patients reporting body weight satisfaction was significantly lower (BMI 23.5) than those reporting dissatisfaction (BMI 27.5) (P = <0.0001). Survivors who had a normal BMI had significantly higher rates of body weight satisfaction compared to underweight, overweight and obese survivors (P = <0.0001). Those survivors who were overweight or obese were significantly more likely to be diabetic (P = 0.008). CONCLUSION: This study revealed an important relationship between gastrointestinal symptoms, body weight and body image and survivor's quality of life. It provides further support for the importance of nutrition therapy post-BMT.

Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer.

Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate lncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation.

A dynamic perfusion bioreactor approach for engineering respiratory tissues in-vitro.

In vitro culture of respiratory tissues poses many challenges due to the intrinsic complexity of the respiratory system. Multiple cellular phenotypes comprise the respiratory epithelium and operate under dynamic, gas-interchanging conditions that should be replicated for near-physiologic cultivation of functional tissues in vitro. A novel biomimetic perfusion bioreactor system has been proposed to reconstitute key functional conditions of the human lung. This portable system consists of several biologically-inspired components: (i) a 3-dimensional (3-D) elastomeric soft tissue scaffold construct, (ii) a mechanical actuator, (iii) a perfusion system and (iv) gaseous exchange capabilities. These integrated components operate synergistically to create a unique, dynamic air-liquid interface (ALI) environment that allows controlled application of physiological and pathological strain while complementing standard cell culture techniques. This system holds potential for engineering 3-D tissues to meet growing demand for a range of applications, from more ethical and efficient pharmaceutical screening to clinical graft transplants.

Radiation exposure during standing voiding cystourethrography in women.

OBJECTIVES: To calculate the total radiation exposure and effective organ doses from standard protocol voiding cystourethrography (VCUG). METHODS: A prospective series of consecutive, non-neurogenic women underwent a standardized VCUG protocol by the same technologist using a Siemens Sireskop Fluorospot radiographic/fluoroscopic unit. Only studies that followed the protocol were included. The effective dose was calculated using a commercially available dose-modeling program (PCXMC, version 1.5) for risk assessment. RESULTS: A total of 119 studies in 118 women (mean age 60 +/- 13 years, range 30 to 93) were included. Only 15 patients (13%) were premenopausal with in situ reproductive organs. The mean number of images and fluoroscopic time per study was 12.8 +/- 1.4 (lateral images 7.5 +/- 1.3) and 35.8 +/- 11.2 seconds, respectively. The mean effective dose for a single VCUG study was calculated to be 4.3 mSv, of which 26% was from fluoroscopy (1.1 mSv). The dose to the gonads accounted for 50% of the total effective organ dose. Using whole population radiologic risk factors, the total risk detriment, cancer and hereditary, was about 3 per 10,000 patients or a 99.997% chance of no detriment incurred from the study. The genetic and malignant risks were reduced in this cohort of patients, who were older, with most (87%) having no reproductive potential. CONCLUSIONS: Using a standard protocol for adult women, a VCUG study is associated with an acceptable radiation risk.