Multi-institutional report on toxicities of concurrent nivolumab and radiation therapy

Purpose: Radiation therapy (RT) and nivolumab are standard therapies for a wide range of advanced and metastatic cancers, yet little is known about the toxicity profile of their combined treatment. The rate of grade ≥3 toxicities from nivolumab monotherapy and radiation-only palliative treatments has been reported at 10% to 18% and 0% to 26%, respectively. We reviewed our experience to assess the acute toxicity profile of concurrent RT-nivolumab. Methods and materials: A retrospective review of all consecutive patients from January 2015 to May 2017 who received concurrent RT-nivolumab was conducted at 4 separate centers. Concurrent RT-nivolumab was defined as RT completed between 3 days prior to initial nivolumab infusion and 28 days after the last nivolumab infusion. Results: Of the 261 patients who received nivolumab, 46 (17.6%) had concurrent RT to 67 treatment sites. The median follow-up was 3.3 months (interquartile range, 1.7-6.1 months) and the 1-year overall survival rate was 22%. For the 11 of 46 patients (24%) who were alive at last analysis, the median follow-up was 12.8 months (interquartile range, 8.3-14.9 months). The most common histology, RT prescription, and treatment site were non-small cell lung cancer (23 of 46 patients; 50%), 30 Gy in 10 fractions (24 of 67 patients; 35.8%), and abdomen/pelvis (16 of 67 patients; 24%), respectively. Four patients with melanoma had concurrent ipilimumab and were removed from the final toxicity analysis of RT-nivolumab. Within 3 months of treatment with RT-nivolumab, 4 of 42 patients (9.5%) experienced grade 3 toxicity and 2 of these patients’ toxicities were attributed specifically to the addition of RT: grade 3 hearing loss after whole brain RT and grade 3 pancreatitis after stereotactic body RT to the left adrenal gland. One death from transaminitis was attributed to nivolumab alone because the RT field did not encompass the liver. Conclusions: Concurrent RT-nivolumab did not appear to increase the toxicity profile from the previously reported toxicity rates from nivolumab or radiation alone

Prescription and Other Medication Use in Pregnancy

OBJECTIVE: To characterize prescription and other medication use in a geographically and ethnically diverse cohort of women in their first pregnancy. METHODS: In a prospective, longitudinal cohort study of nulliparous women followed through pregnancy from the first trimester, medication use was chronicled longitudinally throughout pregnancy. Structured questions and aids were used to capture all medications taken as well as reasons they were taken. Total counts of all medications taken including number in each category and class were captured. Additionally, reasons the medications were taken were recorded. Trends in medications taken across pregnancy and in the first trimester were determined. RESULTS: Of the 9,546 study participants, 9,272 (97.1%) women took at least one medication during pregnancy with 9,139 (95.7%) taking a medication in the first trimester. Polypharmacy, defined as taking at least five medications, occurred in 2,915 (30.5%) women. Excluding vitamins, supplements, and vaccines, 73.4% of women took a medication during pregnancy with 55.1% taking one in the first trimester. The categories of drugs taken in pregnancy and in the first trimester include the following: gastrointestinal or antiemetic agents (34.3%, 19.5%), antibiotics (25.5%, 12.6%), and analgesics (23.7%, 15.6%, which includes 3.6%; 1.4% taking an opioid pain medication). CONCLUSION: In this geographically and ethnically diverse cohort of nulliparous pregnant women, medication use was nearly universal and polypharmacy was common

Non-isothermal thermogravimetric kinetic analysis of the thermochemical conversion of human faeces

The “Reinvent the Toilet Challenge” set by the Bill & Melinda Gates Foundation aims to bring access to adequate sanitary systems to billions of people. In response to this challenge, on-site sanitation systems are proposed and being developed globally. These systems require in-situ thermal treatment, processes that are not well understood for human faeces (HF). Thermogravimetric analysis has been used to investigate the pyrolysis, gasification and combustion of HF. The results are compared to the thermal behaviour of simulant faeces (SF) and woody biomass (WB), along with the blends of HF and WB. Kinetic analysis was conducted using non-isothermal kinetics model-free methods, and the thermogravimetric data obtained for the combustion of HF, SS and WB. The results show that the devolatilisation of HF requires higher temperatures and rates are slower those of WB. Minimum temperatures of 475 K are required for fuel ignition. HF and SF showed similar thermal behaviour under pyrolysis, but not under combustion conditions. The activation energy for HF is 157.4 kJ/mol, relatively higher than SS and WB. Reaction order for HF is lower (n = 0.4) to WB (n = 0.6). In-situ treatment of HF in on-site sanitary systems can be designed for slow progressive burn

Functional Differences in Engineered Myocardium from Embryonic Stem Cell-Derived versus Neonatal Cardiomyocytes

Stem cell-derived cardiomyocytes represent unique tools for cell- and tissue-based regenerative therapies, drug discovery and safety, and studies of fundamental heart-failure mechanisms. However, the degree to which stem cell-derived cardiomyocytes compare to mature cardiomyocytes is often debated. We reasoned that physiological metrics of engineered cardiac tissues offer a means of comparison. We built laminar myocardium engineered from cardiomyocytes that were differentiated from mouse embryonic stem cell-derived cardiac progenitors or harvested directly from neonatal mouse ventricles, and compared their anatomy and physiology in vitro. Tissues assembled from progenitor-derived myocytes and neonate myocytes demonstrated similar cytoskeletal architectures but different gap junction organization and electromechanical properties. Progenitor-derived myocardium had significantly less contractile stress and slower longitudinal conduction velocity than neonate-derived myocardium, indicating that the developmental state of the cardiomyocytes affects the electromechanical function of the resultant engineered tissue. These data suggest a need to establish performance metrics for future stem cell applications

Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A

Ubc13, a ubiquitin-conjugating enzyme (Ubc), requires the presence of a Ubc variant (Uev) for polyubiquitination. Uevs, although resembling Ubc in sequence and structure, lack the active site cysteine residue and are catalytically inactive. The yeast Uev (Mms2) incites noncanonical Lys63-linked polyubiquitination by Ubc13, whereas the increased diversity of Uevs in higher eukaryotes suggests an unexpected complication in ubiquitination. In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2. Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains. Functionally, we describe that Ubc13–Mms2 is required for DNA damage repair but not nuclear factor κB (NF-κB) activation, whereas Ubc13–Uev1A is involved in NF-κB activation but not DNA repair. Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination

Reduction of hexavalent chromium by fasted and fed human gastric fluid. II. Ex vivo gastric reduction modeling

AbstractTo extend previous models of hexavalent chromium [Cr(VI)] reduction by gastric fluid (GF), ex vivo experiments were conducted to address data gaps and limitations identified with respect to (1) GF dilution in the model; (2) reduction of Cr(VI) in fed human GF samples; (3) the number of Cr(VI) reduction pools present in human GF under fed, fasted, and proton pump inhibitor (PPI)-use conditions; and (4) an appropriate form for the pH-dependence of Cr(VI) reduction rate constants. Rates and capacities of Cr(VI) reduction were characterized in gastric contents from fed and fasted volunteers, and from fasted pre-operative patients treated with PPIs. Reduction capacities were first estimated over a 4-h reduction period. Once reduction capacity was established, a dual-spike approach was used in speciated isotope dilution mass spectrometry analyses to characterize the concentration-dependence of the 2nd order reduction rate constants. These data, when combined with previously collected data, were well described by a three-pool model (pool 1 = fast reaction with low capacity; pool 2 = slow reaction with higher capacity; pool 3 = very slow reaction with higher capacity) using pH-dependent rate constants characterized by a piecewise, log-linear relationship. These data indicate that human gastric samples, like those collected from rats and mice, contain multiple pools of reducing agents, and low concentrations of Cr(VI) (<0.7 mg/L) are reduced more rapidly than high concentrations. The data and revised modeling results herein provide improved characterization of Cr(VI) gastric reduction kinetics, critical for Cr(VI) pharmacokinetic modeling and human health risk assessment

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

Background ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.Methods In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A–B (n=20) or B–A (n=20). The primary efficacy end-point was change in cough frequency assessed over 24 h. The primary safety end-point was frequency and severity of adverse events (AEs).Results 37 patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg: 25% (90% CI 11.5–36.5%); p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41–49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5–21% with eliapixant; all were mild.Conclusions Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC

Modeling of GE Appliances in GridLAB-D: Peak Demand Reduction

The widespread adoption of demand response enabled appliances and thermostats can result in significant reduction to peak electrical demand and provide potential grid stabilization benefits. GE has developed a line of appliances that will have the capability of offering several levels of demand reduction actions based on information from the utility grid, often in the form of price. However due to a number of factors, including the number of demand response enabled appliances available at any given time, the reduction of diversity factor due to the synchronizing control signal, and the percentage of consumers who may override the utility signal, it can be difficult to predict the aggregate response of a large number of residences. The effects of these behaviors can be modeled and simulated in open-source software, GridLAB-D, including evaluation of appliance controls, improvement to current algorithms, and development of aggregate control methodologies. This report is the first in a series of three reports describing the potential of GE's demand response enabled appliances to provide benefits to the utility grid. The first report will describe the modeling methodology used to represent the GE appliances in the GridLAB-D simulation environment and the estimated potential for peak demand reduction at various deployment levels. The second and third reports will explore the potential of aggregated group actions to positively impact grid stability, including frequency and voltage regulation and spinning reserves, and the impacts on distribution feeder voltage regulation, including mitigation of fluctuations caused by high penetration of photovoltaic distributed generation and the effects on volt-var control schemes

Wharton’s jelly-derived mesenchymal stromal cells and fibroblast-derived extracellular matrix synergistically activate apoptosis in a p21-dependent mechanism in WHCO1 and MDA MB 231 cancer cells in vitro

The tumour microenvironment plays a crucial role in tumour progression and comprises tumour stroma which is made up of different cell types and the extracellular matrix (ECM).Mesenchymal stromal cells (MSCs) are part of the tumour stroma and may have conflicting effects on tumour growth. In this study we investigated the effect of Wharton’s Jelly-derived MSCs (WJ-MSCs) and a fibroblast-derived ECM (fd-ECM) on esophageal (WHCO1) and breast (MDAMB 231) cancer cells in vitro. BothWJ-MSCs and the fd-ECM, alone or in combination, downregulate PCNA, cyclin D1, Bcl-2, Bcl-xL, and MMPs and upregulate p53 and p21. p21 induction resulted in G2 phase cell cycle arrest and induced apoptosis in vitro. Our data suggest that p21 induction is via p53- dependent and p53-independent mechanisms inWHCO1 andMDA MB 231 cells, respectively. Vascular endothelial growth factor, Akt, and Nodal pathways were downregulated in cancer cells cocultured with WJ-MSCs. We also demonstrate that WJ-MSCs effects on cancer cells appear to be short-lived whilst the fd-ECM effect is long-lived. This study shows the influence of tumour microenvironment on cancer cell behaviour and provides alternative therapeutic targets for potential regulation of tumour cells.The International Centre for Genetic Engineering and Biotechnology (ICGEB), the South African Medical Research Council, the National Research Foundation (NRF) of South Africa, theUniversity of Pretoria, and the University of Cape Town. Karlien Kallmeyer and Michael S. Pepper’s work was funded by the South African Medical Research Council (University Flagship award and Extramural Stem Cell Unit).http://www.hindawi.com/journals/sci/am2016Immunolog

Wharton’s Jelly-Derived Mesenchymal Stromal Cells and Fibroblast-Derived Extracellular Matrix Synergistically Activate Apoptosis in a p21-Dependent Mechanism in WHCO1 and MDA MB 231 Cancer Cells In Vitro

The tumour microenvironment plays a crucial role in tumour progression and comprises tumour stroma which is made up of different cell types and the extracellular matrix (ECM).Mesenchymal stromal cells (MSCs) are part of the tumour stroma and may have conflicting effects on tumour growth. In this study we investigated the effect of Wharton’s Jelly-derived MSCs (WJ-MSCs) and a fibroblast-derived ECM (fd-ECM) on esophageal (WHCO1) and breast (MDAMB 231) cancer cells in vitro. BothWJ-MSCs and the fd-ECM, alone or in combination, downregulate PCNA, cyclin D1, Bcl-2, Bcl-xL, and MMPs and upregulate p53 and p21. p21 induction resulted in G2 phase cell cycle arrest and induced apoptosis in vitro. Our data suggest that p21 induction is via p53- dependent and p53-independent mechanisms inWHCO1 andMDA MB 231 cells, respectively. Vascular endothelial growth factor, Akt, and Nodal pathways were downregulated in cancer cells cocultured with WJ-MSCs. We also demonstrate that WJ-MSCs effects on cancer cells appear to be short-lived whilst the fd-ECM effect is long-lived. This study shows the influence of tumour microenvironment on cancer cell behaviour and provides alternative therapeutic targets for potential regulation of tumour cells.The International Centre for Genetic Engineering and Biotechnology (ICGEB), the South African Medical Research Council, the National Research Foundation (NRF) of South Africa, theUniversity of Pretoria, and the University of Cape Town. Karlien Kallmeyer and Michael S. Pepper’s work was funded by the South African Medical Research Council (University Flagship award and Extramural Stem Cell Unit).http://www.hindawi.com/journals/sci/am2016Immunolog