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BackgroundTo mitigate the cardiotoxicity of anthracycline antibiotics without compromising their anticancer activities is still an issue to be solved. We previously demonstrated that schisandrin B (Sch B) could protect against doxorubicin (Dox)-induced acute cardiotoxicity via enhancing cardiomyocytic glutathione redox cycling that could attenuate oxidative stress generated from Dox. In this study, we attempted to prove if Sch B could also protect against Dox-induced chronic cardiotoxicity, a more clinically relevant issue, without compromising its anticancer activity.MethodologyRat was given intragastrically either vehicle or Sch B (50 mg/kg) two hours prior to i.p. Dox (2.5 mg/kg) weekly over a 5-week period with a cumulative dose of Dox 12.5 mg/kg. At the 6th and 12th week after last dosing, rats were subjected to cardiac function measurement, and left ventricles were processed for histological and ultrastructural examination. Dox anticancer activity enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, and S180, a sarcoma cell line, in vitro and in vivo.Principal FindingsPretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward S180 in vitro and in vivo in mice, and increased Dox cytotoxcity against 4T1 in vitro. Although we did not observe this enhancement against the implanted 4T1 primary tumor, the spontaneous metastasis to lung was significantly reduced in combined treatment group than Dox alone group.ConclusionSch B is capable of protecting Dox-induced chronic cardiotoxicity and enhancing its anticancer activity. To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a chemotherapeutic sensitizer, which is potentially applicable for cancer treatment.

Introduction The increased use of telehealth to maintain ambulatory care during the COVID-19 pandemic had potential to exacerbate or diminish disparities in access to care. Objective The purpose of this study was to describe patient characteristics associated with successful transition from in-person to virtual care, and video vs audio-only participation. Methods This was a retrospective analysis of electronic health record data from all patients with ambulatory visits from 1 October 2019–30 September 2020 in a large integrated health system in the Northeast USA. The outcome of interest was receipt of virtual care, and video vs audio-only participation. We matched home addresses with census-tract level area social vulnerability index (SVI) and Internet access. Among ambulatory care patients, we used logistic regression to identify characteristics associated with virtual participation. Among virtual participants, we identified characteristics associated with video vs audio-only visits. Results Among 1,241,313 patients, 528,542 (42.6%) were virtual participants. Relative to in-person only, virtual participants were older, more often English-proficient and with activated patient portal. Characteristics associated with virtual participation included patients with: only behavioural health visits, COVID patients, highest quartile of visit frequency, and multiple visit types. Characteristics associated with video participation (relative to audio-only) included being younger and patients with: only behavioural health visits, highest quartile of visit frequency, non-Hispanic black race, limited English proficiency and inactivated portal account. Discussion In our regional healthcare system, the transition to virtual care during COVID was vital for continued access to care, but substantial inequity remained. Without audio-only visits, access to care would have been even more limited for our most vulnerable patients.

Heat stress seriously threatens the growth of Pleurotus ostreatus. Various studies have been performed to study the resistance of P. ostreatus to heat stress. Here, the metabolome was evaluated to determine the response of P. ostreatus mycelia to heat stress at different times (6, 12, 24, 48 h). More than 70 differential metabolites were detected and enriched in their metabolic pathways. Dynamic metabolites changes in enrichment pathways under heat stress showed that heat stress enhanced the degradation of unsaturated fatty acids and nucleotides, increased the content of amino acids and vitamins, and accelerated glycolysis and the tricarboxylic acid cycle in P. ostreatus. The time course changes of P. ostreatus metabolites under continuous heat stress demonstrated that amino acids continuously changed with heat stress, nucleotides clearly changed with heat stress at 12 and 48 h, and lipids exhibited an increasing trend with prolonged heat stress, while few types saccharides and vitamins changed under heat stress. Additionally, heat-treated P. ostreatus produced salicylic acid and other stress-resistant substances that were reported in plants. This study first reported the metabolites changes in P. ostreatus mycelia during 48 h of heat stress. The metabolic pathways and substances that changed with heat stress in this research will aid future studies on the resistance of P. ostreatus and other edible fungi to heat stress.

The link between carcinogen exposure and cancer immunogenicity is unclear. Single exposure to 12-dimethylbenz[a]anthracene (DMBA) at puberty accelerated spontaneous breast carcinogenesis in mouse mammary tumor virus-polyoma middle tumor-antigen transgenic (MMTV-PyMTtg or PyMT) and MMTV-Her2/neutg (Her2) mice. Paradoxically, DMBA-treated PyMT and Her2 animals were protected from metastasis. CD8+ T cells significantly infiltrated DMBA-exposed breast cancers. CD8+ T cell depletion resulted in severe lung and liver metastasis in DMBA-treated PyMT mice. Besides increasing tumor mutational burden, DMBA exposure up-regulated Chemokine (C-C motif) ligand 21 (CCL21) in cancer cells and heightened antigen presentation. CCL21 injection suppressed breast cancer growth, and CCL21 receptor deletion attenuated T cell immunity against cancer metastasis in DMBA-treated PyMT animals. CCL21 expression correlated with increased mutational burden and cytolytic activity across human cancers. Higher CCL21 levels correlated with increased CD8+ T cell infiltrates in human breast cancer and predicted lower breast cancer distant recurrence rate. Collectively, carcinogen exposure induces immune-activating factors within cancer cells that promote CD8+ T cell immunity against metastasis.

Background and Purpose: Patient care-seeking has likely changed during the coronavirus disease 2019 (COVID-19) pandemic. In stroke, delayed or avoided care may translate to substantial morbidity. We sought to determine the effect of the pandemic on patterns of stroke patient presentation and quality of care. Methods: We analyzed data from 25 New England hospitals: one urban, academic comprehensive stroke center and telestroke hub, and 24 spoke hospitals in the telestroke network. We included all telestroke consultations from the 24 spokes, and all stroke admissions to the comprehensive stroke center hub from November 1, 2019 through April 30, 2020. We compared rates of presentation, timeliness presentation, and quality of care pre- versus post-March 1, 2020. We examined trends in patient demographics, stroke severity, timeliness, diagnoses including large vessel occlusion, alteplase use, and endovascular thrombectomy among eligible subjects. We compared proportions and bivariate comparisons to examine for changes pre- versus post-March 1, 2020 and used linear regression to examine trends over time. Results: Among 1248 patient presentations (844 telestroke consultations, 404 comprehensive stroke center admissions), telestroke consultations and ischemic stroke patient admissions decreased among the spokes and hub. Age and stroke severity were unchanged over the study period. We found no change in alteplase administration at telestroke spoke hospitals but did note a decrease in both alteplase use and thrombectomy at our comprehensive stroke center. Time metrics for patient presentation and care delivery were unchanged; however, rates of adherence for the quality measures dysphagia screening, early antithrombotic initiation, and early venous thromboembolism prophylaxis were reduced during the pandemic. Conclusions: In this regional analysis, we found decreasing telestroke consultations and ischemic stroke admissions, and reduced performance on stroke quality of care measures during the COVID-19 pandemic. Contrary to prior reports, we did not find an increase in thrombectomy nor decrease in clinical severity that might be expected if patients with milder symptoms avoided hospitalization.

Background Trehalose, an intracellular protective agent reported to mediate defense against many stresses, can alleviate high-temperature-induced damage in Pleurotus ostreatus. In this study, the mechanism by which trehalose relieves heat stress was explored by the addition of exogenous trehalose and the use of trehalose-6-phosphate synthase 1 (tps1) overexpression transformants. Results The results suggested that treatment with exogenous trehalose or overexpression of tps1 alleviated the accumulation of lactic acid under heat stress and downregulated the expression of the phosphofructokinase (pfk) and pyruvate kinase (pk) genes, suggesting an ameliorative effect of trehalose on the enhanced glycolysis in P. ostreatus under heat stress. However, the upregulation of hexokinase (hk) gene expression by trehalose indicated the involvement of the pentose phosphate pathway (PPP) in heat stress resistance. Moreover, treatment with exogenous trehalose or overexpression of tps1 increased the gene expression level and enzymatic activity of glucose-6-phosphate dehydrogenase (g6pdh) and increased the production of both the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), confirming the effect of trehalose on alleviating oxidative damage by enhancing PPP in P. ostreatus under heat stress. Furthermore, treatment with exogenous trehalose or overexpression of tps1 ameliorated the decrease in the oxygen consumption rate (OCR) caused by heat stress, suggesting a relationship between trehalose and mitochondrial function under heat stress. Conclusions Trehalose alleviates high-temperature stress in P. ostreatus by inhibiting glycolysis and stimulating PPP activity. This study may provide further insights into the heat stress defense mechanism of trehalose in edible fungi from the perspective of intracellular metabolism.

The skin provides the first line of physical and immunological defense against environmental insults. However, the age-related changes in the immune function of human skin are unclear. Here, we investigated the agerelated changes in epidermal Langerhans cells (LCs), which play a sentinel role in the initiation of the immune responses in the skin. We found a significant reduction in the number of epidermal LCs in sun-protected skin with age. Among the possible explanations for this reduction, the number of CD14 þ CD207 þ CCR6 þ dermal-resident monocytes that can differentiate into epidermal LCs was markedly reduced with age (P ¼ 0.0057). Among the chemokines that can recruit these cells into the skin, the expression of CXCL14 was significantly down-regulated in epidermal keratinocytes with age. In addition, we discovered that young skin recruited a significantly higher number of monocytic THP-1 cells compared with old skin ex vivo. This recruitment was blocked by CXCL14 neutralizing antibody and conversely promoted by CXCL14 treatment. Collectively, our findings indicate that decreased CXCL14-mediated recruitment of CD14 þ monocytes in human skin results in the reduction of epidermal LCs with age, and CXCL14 may provide a therapeutic target for the prevention of age-related reduction in LCs.