Effect of Systemic Administration of CD4+ T cells and Local Administration of T-cell Stimulants on T-cell Activity in Psoriatic Skin Xenografts on NOG Mice.

Immunodeficient mice engrafted with psoriatic human skin are widely used for the preclinical evaluation of new drug candidates. However, the T-cell activity, including the IL23/IL17 pathway, declines in the graft over time after engraftment, which likely affects the study data. Here, we investigated whether the T-cell activity could be sustained in xenografted psoriatic skin by local stimulation of T cells or systemic injection of autologous CD4 + T cells. We surgically transplanted human psoriatic skin from 5 untreated patients onto female NOG mice. Six days after surgery, mice received an intraperitoneal injection of autologous human CD4+ T cells, a subcutaneous injection under the grafts of a T-cell stimulation cocktail consisting of recombinant human IL2, human IL23, antihuman CD3, and antihuman CD28, or saline. Mice were euthanized 21 d after surgery and spleens and graft biopsies were collected for analysis. Human T cells were present in the grafts, and 60% of the grafts maintained the psoriatic phenotype. However, neither local T-cell stimulation nor systemic injection of autologous CD4+ T cells affected the protein levels of human IL17A, IL22, IFN γ, and TNF α in the grafts. In conclusion, NOG mice seem to accept psoriatic skin grafts, but the 2 approaches studied here did not affect human T-cell activity in the grafts. Therefore, NOG mice do not appear in this regard to be superior to other immunodeficient mice used for psoriasis xenografts.

The effect of music on sleep in hospitalized patients: A systematic review and meta-analysis.

Sleep is often severely disturbed in hospitalized patients due to multiple factors such as noise, pain, and an unfamiliar environment. Since sleep is important for patient recovery, safe strategies to improve sleep in hospitalized patients are warranted. Music interventions have been found to improve sleep in general, and the aim of this systematic review is to assess the effect of music on sleep among hospitalized patients. We searched 5 databases to identify randomized controlled trials evaluating the effect of music interventions on sleep in hospitalized patients. Ten studies including a total of 726 patients matched the inclusion criteria. The sample sizes ranged from 28 to 222 participants per study. The music interventions varied in how the music was chosen as well as duration and time of day. However, in most studies, participants in the intervention group listened to soft music for 30 minutes in the evening. Our meta-analysis showed that music improved sleep quality compared to standard treatment (standardized mean difference 1.55 [95% CI 0.29-2.81], z = 2.41; p = 0.0159). Few studies reported other sleep parameters, and only one study used polysomnography for objective sleep measurement. No adverse events were reported in any of the trials. Hence, music may constitute a safe and low-cost adjunctive intervention to improve sleep in hospitalized patients. Prospero registration number: CRD42021278654.

Transcriptional regulation of Hepatic Stellate Cell activation in NASH.

Non-alcoholic steatohepatitis (NASH) signified by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis is a growing cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Hepatic fibrosis resulting from accumulation of extracellular matrix proteins secreted by hepatic myofibroblasts plays an important role in disease progression. Activated hepatic stellate cells (HSCs) have been identified as the primary source of myofibroblasts in animal models of hepatotoxic liver injury; however, so far HSC activation and plasticity have not been thoroughly investigated in the context of NASH-related fibrogenesis. Here we have determined the time-resolved changes in the HSC transcriptome during development of Western diet- and fructose-induced NASH in mice, a NASH model recapitulating human disease. Intriguingly, HSC transcriptional dynamics are highly similar across disease models pointing to HSC activation as a point of convergence in the development of fibrotic liver disease. Bioinformatic interrogation of the promoter sequences of activated genes combined with loss-of-function experiments indicates that the transcriptional regulators ETS1 and RUNX1 act as drivers of NASH-associated HSC plasticity. Taken together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.

Tumor-Preferential Induction of Immune Responses and Epidermal Cell Death in Actinic Keratoses by Ingenol Mebutate.

UNLABELLED: The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolved skin of 26 patients in a phase I, single-center, open-label, within-patient comparison. As early as 1 day after application, ingenol mebutate induced profound epidermal cell death, along with a strong infiltrate of CD4+ and CD8+ T-cells, neutrophils, and macrophages. Endothelial ICAM-1 activation became evident after 2 days. The reaction pattern was significantly more pronounced in AK compared with uninvolved skin, suggesting a tumor-preferential mode of action. Extensive molecular analyses and transcriptomic profiling of mRNAs and microRNAs demonstrated alterations in gene clusters functionally associated with epidermal development, inflammation, innate immunity, and response to wounding. Ingenol mebutate reveals a unique mode of action linking directly to anti-tumoral effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01387711.

Natural and enhanced anaerobic degradation of 1,1,1-trichloroethane and its degradation products in the subsurface--a critical review.

1,1,1-Trichloroethane (TCA) in groundwater is susceptible to a variety of natural degradation mechanisms. Evidence of intrinsic decay of TCA in aquifers is commonly observed; however, TCA remains a persistent pollutant at many sites and some of the daughter products that accumulate from intrinsic decay of TCA have been determined to be more toxic than the parent compound. Research advances from the past decade indicate that in situ enhanced reductive dechlorination (ERD) offers promise as a cost-effective solution toward the cleanup of groundwater contaminated with TCA and its transformation daughter products. Laboratory studies have demonstrated that pure or mixed cultures containing certain Dehalobacter (Dhb) bacteria can catalyze respiratory dechlorination of TCA and 1,1-dichloroethane (1,1-DCA) to monochloroethane (CA) in groundwater systems. 16S rRNA Dhb gene probes have been used as biomarkers in groundwater samples to both assess ERD potential and quantify growth of Dhb in ERD applications at TCA sites. Laboratory findings suggest that iron-bearing minerals and methanogenic bacteria that co-occur in reduced aquifers may synergistically affect dechlorination of TCA. Despite these advances, a number of significant challenges remain, including an inability of any known cultures to completely dechlorinate TCA to ethane. CA is commonly observed as a terminal product of the biological reductive dechlorination of TCA and 1,1-DCA. Also important is the lack of rigorous field studies demonstrating the utility of bioaugmentation with Dhb cultures for remediation of TCA in the field. In this paper we review the state-of-the-science of TCA degradation in aquifers, examining results from both laboratory experiments and twenty-two field case studies, focusing on the capabilities and limits of ERD technology, and identifying aspects of the technology that warrant further development.