IL-6 Up-Regulates Expression of LIM-Domain Only Protein 4 in Psoriatic Keratinocytes through Activation of the MEK/ERK/NF-κB Pathway.

Psoriasis is a chronic inflammatory skin disease characterized by the activation of keratinocytes and the infiltration of immune cells. Overexpression of the transcription factor LIM-domain only protein 4 (LMO4) promoted by IL-23 has critical roles in regulating the proliferation and differentiation of psoriatic keratinocytes. IL-6, an autocrine cytokine in psoriatic epidermis, is a key mediator of IL-23/T helper 17-driven cutaneous inflammation. However, little is known about how IL-6 regulates the up-regulation of LMO4 expression in psoriatic lesions. In this study, human immortalized keratinocyte cells, clinical biopsy specimens, and an animal model of psoriasis induced by imiquimod cream were used to investigate the role of IL-6 in the regulation of keratinocyte proliferation and differentiation. Psoriatic epidermis showed abnormal expression of IL-6 and LMO4. IL-6 up-regulated the expression of LMO4 and promoted keratinocyte proliferation and differentiation. Furthermore, in vitro and in vivo studies showed that IL-6 up-regulates LMO4 expression by activating the mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK)/NF-κB signaling pathway. These results suggest that IL-6 can activate the NF-κB signaling pathway, up-regulate the expression of LMO4, lead to abnormal proliferation and differentiation of keratinocytes, and promote the occurrence and development of psoriasis.

A Case Report of Modified Pancreatic Transplantation With a Limited Splenic Arteriovenous Fistula to Elude Thrombosis.

In classic pancreatic transplantation, the splenic artery and vein are ligated at the tail of the pancreas graft. This leads to slowed blood flow in the splenic vein and may cause thrombosis and graft loss. In this study, a patient received a pancreas after kidney transplantation. A modified surgical technique was used in the pancreatic graft preparation. The donor splenic artery and vein were anastomosed end to end at the tail of the pancreas. The splenic artery near the anastomosis was partially ligated, and an effective diameter of 2 mm was reserved to limit arterial blood pressure and flow. The patient recovered very well. Contrasted computed tomography scans on days 11 and 88 after pancreas transplantation indicated sufficient backflow of the splenic vein. We believe that this procedure may avoid the risk of splenic vein thrombosis after pancreas transplantation. This modified technique has not been reported in clinical cases previously and may help reduce the risk of thrombosis after pancreas transplantation.

Associations between indoor air pollution for cooking and heating with muscle and sarcopenia in Chinese older population.

BACKGROUND: Exposure to air pollution brings the advent effect for various diseases, but study about the relationship between air pollution and ageing is scant. We aimed to determine the associations between household air pollution for cooking and heating with muscle and sarcopenia in Chinese older population by a nationally representative study. METHODS: This cross-sectional study included individuals aged 60 and above from the China Health and Retirement Longitudinal Study between 2011 and 2015. The diagnosis of sarcopenia was defined by low muscle mass with low muscle strength and/or reduced physical performance. Generalized additive analyses and dose-dependent analyses with three models were used to assess the effects of different pattern of cooking and heating on muscle and sarcopenia. RESULTS: A total of 8126 Chinese older individuals with predominant male (53.7%) and mean age of 67.3 ± 6.0 years were included in our study. Solid fuel use in cooking showed significant declines in muscle strength (ß = -0.424, 95% CI: -0.767, -0.082, P = 0.01 in model 3) and mass (ß = -0.034, 95% CI: -0.051, -0.017, P < 0.01 in model 3), when compared with clean fuel use in cooking, respectively. Solid fuel for heating was correlated with lower muscle strength (ß = -0.637, 95% CI: -1.033, -0.241, P < 0.01 in model 3) than clean fuel for heating. The joint use of solid fuel for cooking and heating was associated with reduced muscle strength (ß = -0.835, 95% CI: -1.306, -0.365, P < 0.01 in model 3) and mass (ß = -0.038, 95% CI: -0.061, -0.015, P < 0.01 in model 3) than clean fuel for cooking and heating. Solid fuel for cooking was associated with significantly increased risk of low muscle strength (adjusted OR = 1.29, 95% CI: 1.11, 1.50, P < 0.01 in model 3) and mass (adjusted OR = 1.35, 95% CI: 1.11, 1.61, P < 0.01 in model 3), possible sarcopenia (adjusted OR = 1.33, 95% CI: 1.19, 1.48, P < 0.01 in model 3) and sarcopenia (adjusted OR = 1.44, 95% CI: 1.21, 1.72, P < 0.01 in model 3) compared with clean fuel for cooking. Solid fuel for heating had a significant correlation with low muscle strength (adjusted OR = 1.30, 95% CI: 1.09, 1.56, P < 0.01 in model 3) and possible sarcopenia (adjusted OR = 1.49, 95% CI: 1.31, 1.70, P < 0.01 in model 3). Dose-dependent manner was shown in the associations between the number of solid fuel with low muscle strength and possible sarcopenia. Clean fuel for cooking and solid fuel for heating was positively associated with the prevalence of possible sarcopenia than clean fuel for cooking and heating (adjusted OR = 1.34, 95% CI: 1.14, 1.57, P < 0.01 in model 3). CONCLUSIONS: Our findings suggested that solid fuel for cooking and the number of solid fuel use potentially facilitates the onset and progression of muscle loss and sarcopenia.

A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy.

The abnormal activation of epidermal growth factor receptor (EGFR) drives the development of non-small cell lung cancer (NSCLC). The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR mutation. However, free osimertinib administration exhibits an inadequate response in vivo, with only ∼3% patients demonstrating a complete clinical response. Consequently, we designed a biomimetic nanoparticle (CMNP@Osi) comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery, thereby supporting a dual-target strategy for enhancing osimertinib efficacy. After intravenous injection, CMNP@Osi accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous targeting. Osimertinib is subsequently released into the cytoplasm, where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC cells. Thus, this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.

Personalized Bacteria Loaded with Autoantigens for the Enhancement of Tumor Immunotherapy.

Currently, tumor immunotherapy is becoming a new revolution in tumor treatment. Generated from tumor cell lysate (TCL) or irradiated tumor cells, the whole tumor antigen-based vaccines have the possibility to enhance antitumor immune response without survival from immune surveillance in personalized immunotherapy. Here, polydopamine nanoparticles (PDA NPs) after self-polymerization are covalently coated with TCL to form PDA@CL. Engineered Salmonella (EnS) wrapped with PDA@CL (EnS@PDA@CL) is targeted the localization of the tumor site by intravenous administration. EnS@PDA@CL delivered autologous antigen-containing nanoparticles to tumor hypoxia regions through blood circulation. The PDA@CL particles promote the maturation of dendritic cells (DCs), thus eliciting the infiltration of whole tumor antigens specific cytotoxic T lymphocytes, significantly triggering antitumor immunity. The tumor regression in the Panc02 mice confirms the therapeutic potential of EnS@PDA@CL in clinical personalized immunotherapy.

The effect and relative importance of sleep disorders for all-cause mortality in middle-aged and older asthmatics.

BACKGROUND: Previous studies observed that sleep disorders potentially increased the risk of asthma and asthmatic exacerbation. We aimed to examine whether excessive daytime sleepiness (EDS), probable insomnia, objective short sleep duration (OSSD), and obstructive sleep apnea (OSA) affect all-cause mortality (ACM) in individuals with or without asthma. METHODS: We extracted relevant data from the Sleep Heart Health Study established in 1995-1998 with an 11.4-year follow-up. Multivariate Cox regression analysis with a proportional hazards model was used to estimate the associations between ACM and four sleep disorders among asthmatic patients and individuals without asthma. Dose-response analysis and machine learning (random survival forest and CoxBoost) further evaluated the impact of sleep disorders on ACM in asthmatic patients. RESULTS: A total of 4538 individuals with 990 deaths were included in our study, including 357 asthmatic patients with 64 deaths. Three multivariate Cox regression analyses suggested that OSSD (adjusted HR = 2.67, 95% CI: 1.23-5.77) but not probable insomnia, EDS or OSA significantly increased the risk of ACM in asthmatic patients. Three dose-response analyses also indicated that the extension of objective sleep duration was associated with a reduction in ACM in asthmatic patients compared to very OSSD patients. Severe EDS potentially augmented the risk of ACM compared with asthmatics without EDS (adjusted HR = 3.08, 95% CI: 1.11-8.56). Machine learning demonstrated that OSSD of four sleep disorders had the largest relative importance for ACM in asthmatics, followed by EDS, OSA and probable insomnia. CONCLUSIONS: This study observed that OSSD and severe EDS were positively associated with an increase in ACM in asthmatic patients. Periodic screening and effective intervention of sleep disorders are necessary for the management of asthma.

Combining autophagy and immune characterizations to predict prognosis and therapeutic response in lung adenocarcinoma.

Background: Autophagy, a key regulator of programmed cell death, is critical for maintaining the stability of the intracellular environment. Increasing evidence has revealed the clinical importance of interactions between autophagy and immune status in lung adenocarcinoma. The present study evaluated the potential of autophagy-immune-derived biomarkers to predict prognosis and therapeutic response in patients with lung adenocarcinoma. Methods: Patients from the GSE72094 dataset were randomized 7:3 to a training set and an internal validation set. Three independent cohorts, TCGA, GSE31210, and GSE37745, were used for external verification. Unsupervised hierarchical clustering based on autophagy- and immune-associated genes was used to identify autophagy- and immune-associated molecular patterns, respectively. Significantly prognostic autophagy-immune genes were identified by LASSO analysis and by univariate and multivariate Cox regression analyses. Differences in tumor immune microenvironments, functional pathways, and potential therapeutic responses were investigated to differentiate high-risk and low-risk groups. Results: High autophagy status and high immune status were associated with improved overall survival. Autophagy and immune subtypes were merged into a two-dimensional index to characterize the combined prognostic classifier, with 535 genes defined as autophagy-immune-related differentially expressed genes (DEGs). Four genes (C4BPA, CD300LG, CD96, and S100P) were identified to construct an autophagy-immune-related prognostic risk model. Survival and receiver operating characteristic (ROC) curve analyses showed that this model was significantly prognostic of survival. Patterns of autophagy and immune genes differed in low- and high-risk patients. Enrichment of most immune infiltrating cells was greater, and the expression of crucial immune checkpoint molecules was higher, in the low-risk group. TIDE and immunotherapy clinical cohort analysis predicted that the low-risk group had more potential responders to immunotherapy. GO, KEGG, and GSEA function analysis identified immune- and autophagy-related pathways. Autophagy inducers were observed in patients in the low-risk group, whereas the high-risk group was sensitive to autophagy inhibitors. The expression of the four genes was assessed in clinical specimens and cell lines. Conclusions: The autophagy-immune-based gene signature represents a promising tool for risk stratification in patients with lung adenocarcinoma, guiding individualized targeted therapy or immunotherapy.

Associations between sarcopenia with asthmatic prevalence, lung function and comorbidity.

BACKGROUND: Sarcopenia is listed as a treatment trait in behavioral/risk factors for severe asthma, but studies on asthma and sarcopenia are lacking. This study aimed to determine the associations between sarcopenia with asthmatic prevalence, symptoms, lung function and comorbidities. METHODS: Fifteen thousand four hundred four individuals from the China Health and Retirement Longitudinal Study(CHARLS) and 10,263 individuals from the Study on global AGEing and adult health(SAGE) in China were included in this study. Four components of this study were used to assess the bidirectional association in the prevalence between sarcopenia with asthma, and estimate the relationships between sarcopenia with asthmatic symptoms, lung function and comorbidities via generalized additive models. The 10-item Center for Epidemiological Studies-Depression Scale ≥ 12 scores was classified as depression. RESULTS: In the CHARLS and SAGE, the prevalence of sarcopenia in asthmatics was higher than those without asthma. Asthmatics with sarcopenia had a significantly increased prevalence of severe shortness of breath(sarcopenia yes vs. no, adjusted OR = 3.71, 95%CI: 1.43-9.60) and airway obstruction in the SAGE(sarcopenia yes vs. no, adjusted OR = 6.82, 95%CI: 2.54-18.34) and an obvious reduction of PEF in the CHARLS and SAGE(sarcopenia yes vs. no, adjusted RR = 0.86, 95%CI: 0.82-0.91) compared to asthmatics without sarcopenia. The presence of sarcopenia was positively associated with the prevalence of chronic obstructive pulmonary disease(sarcopenia yes vs no, adjusted OR = 5.76, 95%CI:2.01-16.5) and depression(sarcopenia yes vs no, adjusted OR = 1.87, 95%CI:1.11-3.14) in asthmatics. CONCLUSIONS: Our findings indicated that sarcopenia partakes in the development of asthma by affecting lung function and comorbidities and maybe considered a treatable trait of asthma management.

The roles of long noncoding RNAs in the regulation of OCT4 expression.

OCT4 is a major transcription factor that maintains the pluripotency of stem cells, including embryonic stem cells, induced pluripotent stem cells and cancer stem cells. An increasing number of long noncoding RNAs have been reported to participate in the regulation of OCT4 expression through various mechanisms, including binding with the OCT4 gene promoter to regulate local methylation; promoting chromosomal spatial folding to form an inner ring, thereby aggregating OCT4 cis-acting elements scattered in discontinuous sites of the chromosome; competitively binding microRNAs with OCT4 to upregulate OCT4 expression at the posttranscriptional level; and sharing a promoter with OCT4. Moreover, the transcription of some long noncoding RNAs is regulated by OCT4, and certain long noncoding RNAs form feedback regulatory loops with OCT4. In this review, we summarized the research progress of the long noncoding RNAs involved in the regulation of OCT4 expression.

Comparison of Immediate and Sequential Withdrawal of a Systemic Glucocorticoid in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Parallel-Controlled, Open-Label Study.

Patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) were treated with immediate or sequential withdrawal after 5 days of systemic glucocorticoids. The effects of the two withdrawal methods on the prognosis of patients were compared at 30, 90, 180, and 360 days after discharge. A multicenter, randomized, double-blind, parallel-controlled, open-label study was conducted in the respiratory department of tertiary hospitals in Central China. Patients met inclusion criteria for AECOPD and needed to use systemic glucocorticoids. They were randomly assigned to immediate and sequential withdrawal groups at a 1:1 ratio. The study was completed in August 2020 and is registered at the China Clinical Trials Registry (Chictr.org) (ChiCTR1800018894). According to general data and clinical characteristics, there were no statistically significant differences between the 329 patients in the immediate withdrawal group and the 310 patients in the sequential withdrawal group (P > 0.05). At the 30, 90, 180, and 360-days follow-up, the acute exacerbation frequency, rehospitalization rate, mortality, and intensive care unit (ICU) treatment rate were not significantly different between the immediate withdrawal group and sequential withdrawal group (P > 0.05). The modified Medical Research Council (mMRC) and COPD assessment test (CAT) scores were also not significantly different between the two groups. At the 180- and 360-day follow-up, forced expiratory volume in 1 s (FEV1%) and peak expiratory flow (PEF) were not significantly different between the two groups (P > 0.05). The time from discharge to first acute exacerbation was significantly lower in the immediate withdrawal group (46.12 days) than in sequential withdrawal group (49.02 days) (P < 0.05). The time of stay in the hospital for the first time after discharge was not significantly different between the two groups (P > 0.05). Adverse events were not significantly different between the immediate withdrawal group and sequential withdrawal group (P < 0.05). Subgroup analysis was performed according to age, degree of disease, and relevant indicators. At the 30-day follow-up, the acute exacerbation frequency of patients with advanced age, high global strategy for chronic obstructive lung disease (GOLD), and high fractional exhaled nitric oxide was significantly higher in the immediate withdrawal group than in the sequential withdrawal group (P < 0.05). In addition, according to receiver operating characteristic (ROC) curve analysis, the frequency of acute exacerbations at the 30-day follow-up was significantly higher in patients with age > 63.5 years or GOLD > 3 in the immediate withdrawal group than in the sequential withdrawal group, suggesting that the short-term efficacy was poor.

Association between sleep duration and asthma in different weight statuses (CHNS 2009-2015).

PURPOSE: Inadequate sleep duration affects asthma and weight. The associations among sleep duration, asthma, and different weight statuses in the Chinese population need to be further determined. METHODS: The study included 32,776 Chinese adults from the China Health and Nutrition Survey during 2009-2015. Self-reported sleep duration was classified into three groups: ≤ 6 h (short), 7 to 8 h (optimal), and ≥ 9 h (long). Age, sex, smoking, drinking alcohol, and residence location were adjusted as potential confounding factors in a generalized estimating equations model. RESULTS: The prevalence of asthma in the Chinese population was approximately 1.17% (383/32,776). Asthmatics were associated with shorter sleep duration and higher indices of central obesity (mean waist circumference, waist to height ratio, and conicity index) than the population without asthma. After adjusting for potential confounding factors, odds ratios (ORs) indicated positive associations between sleep duration and asthma (short vs optimal, adjusted OR = 1.74, 95%CI 1.33, 2.26; and long vs optimal, adjusted OR = 1.51, 95%CI 1.18, 1.93). When stratified by weight status, the participants with central obesity showed highest prevalence of asthma among the three sleep duration groups. With the adjustment of confounding factors, underweight and obesity grouped by waist to height ratio and conicity index remained associated with higher risk of asthma among short and long sleepers than in optimal sleepers. CONCLUSIONS: Short and long sleepers with central obesity and underweight status were associated with significantly higher prevalence of asthma than optimal sleepers in Chinese adults.

A cascade dual-targeted nanocarrier for enhanced alectinib delivery to ALK-positive lung cancer.

Alectinib is a highly efficacious inhibitor for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in the clinic; however, serious adverse events (AEs) occurred in 44.0% of patients. Herein, we explored magnetic/TAT dual-targeted nanocarriers as delivery systems for alectinib. Magnetic targeting efficiently enhanced the extravasation of alectinib-loaded nanoparticles from vessels into the tumor tissue, while the TAT targeting reactivated in the tumor tissue significantly improved the tumor cellular uptake of the nanocarrier. As a result, this dual-targeted polymeric nanocarrier exhibited superior therapeutic effects and induced tumor shrinkage in vivo. Meanwhile, this dual-targeted nanocarrier also minimized alectinib-induced hepatotoxicity, providing an efficient strategy to extend the application of alectinib for NSCLC patients.

Role of selected criteria and preventive chemotherapy in tumor recurrence after liver transplantation.

BACKGROUND: Long-term survival after liver transplantation (LT) for hepatocellular carcinoma (HCC) patients remains poor because of tumor recurrence. To improve the prognosis of HCC patients after LT, we aimed to identify different transplantation criteria and risk factors related to tumor recurrence and evaluate the effect of preventive chemotherapy in a single center. METHODS: In total, data on 20 variables and the survival of 199 patients with primary HCC who underwent LT between 2005 and 2015 were included for analysis. The patients were divided into the following three groups: Group 1, within the Milan and Hangzhou criteria (n = 51); Group 2, beyond the Milan but within the Hangzhou criteria (n = 36); and Group 3, beyond the Milan and Hangzhou criteria (n = 112). Survival probabilities for the three groups were calculated using multivariate Cox regression analysis. The association between preventive therapy and HCC-recurrence after LT was analyzed by multiple logistic regression analysis. RESULTS: Child-Pugh stage C and hepatitis B virus (HBV) infection were independent risk factors for patients with tumor recurrence who did not meet the Milan criteria. The overall survival rates of the 199 patients showed statistically significant differences among the three groups (P < 0.001). Moreover, no significant difference was noted in the survival rate between Group 1 and Group 2 (P > 0.05). Multivariate logistic regression analysis showed that postoperative prophylactic chemotherapy reduced the risk of tumor recurrence in patients who did not meet the Hangzhou and Milan criteria (OR = 0.478; 95% CI: 0.308-0.741; P = 0.001). CONCLUSIONS: Child-Pugh classification and HBV infection were the independent risk factors of tumor recurrence in HCC patients with LT. The Hangzhou criteria were effective and analogous compared with the Milan criteria. Preventive chemotherapy significantly reduced the risk of recurrence and prolonged the survival time for HCC patients beyond the Milan and Hangzhou criteria after LT.

Clinical course and treatment efficacy of COVID-19 near Hubei Province, China: A multicentre, retrospective study.

Currently, COVID-19 has been reported in nearly all countries globally. To date, little is known about the viral shedding duration, clinical course and treatment efficacy of COVID-19 near Hubei Province, China. This multicentre, retrospective study was performed in 12 hospitals in Henan and Shaanxi Provinces from 20 January to 8 February 2020. Clinical outcomes were followed up until 26 March 2020. The viral shedding duration, full clinical course and treatment efficacy were analysed in different subgroups of patients. A total of 149 COVID-19 patients were enrolled. The median age was 42 years, and 61.1% (91) were males. Of them, 133 (89.3%) had fever, 131 of 144 (91%) had pneumonia, 27 (18.1%) required intensive care unit (ICU) management, 3 (2%) were pregnant, and 3 (2%) died. Two premature newborns were negative for SARS-CoV-2. In total, the median SARS-CoV-2 shedding period and clinical course were 12 (IQR: 9-17; mean: 13.4, 95% CI: 12.5, 14.2) and 20 (IQR: 16-24; mean: 21.2, 95% CI: 20.1, 22.3) days, respectively, and ICU patients had longer median viral shedding periods (21 [17-24] versus 11 [9-15]) and clinical courses (30 [22-33] vs. 19 [15.8-22]) than non-ICU patients (both p < .0001). SARS-CoV-2 clearances occurred at least 2 days before fatality in 3 non-survivors. Current treatment with any anti-viral agent or combination did not present the benefit of shortening viral shedding period and clinical course (all p > .05) in real-life settings. In conclusion, the viral shedding duration and clinical course in Henan and Shaanxi Provinces were shorter than those in Hubei Province, and current anti-viral therapies were ineffective for shortening viral shedding duration and clinical course in real-world settings. These findings expand our knowledge of the SARS-CoV-2 infection and may be helpful for management of the epidemic outbreak of COVID-19 worldwide. Further studies concerning effective anti-viral agents and vaccines are urgently needed.

The Association Between Sleep Duration, Asthma-Related Episodes/Attacks and Emergency Department Visits.

BACKGROUND: Inadequate sleep duration potentially increases the risk of allergic asthma; yet, the effect of different sleep duration on asthma-related episodes/attacks and emergency department (ED) visits has remained unclear. The purpose of this study is to evaluate the association between sleep duration, asthma-related episodes/attacks and ED visits. METHODS: This study included 1526 asthma participants from the Behavioral Risk Factor Surveillance System Questionnaire during 2013-2017. Self-reported sleep duration was classified into three groups: ≤6 h (short), 7 h to 8 h (optimal) and ≥9 h (long). Generalized additive model with binomial or Poisson regression was used to complete all statistical analyses. RESULTS: During a 12-month period, 857 participants reported acute episodes/attacks of asthma, and 279 participants reported asthma-related ED visits. Asthmatics with ED visits harbored significantly lower mean sleep duration (6.50 h vs 7.01 h, adjusted OR=0.93, 95% CI: 0.88-0.98) than those without episodes/attacks. After adjusting the potential confounding factors, the participants with long sleep duration were associated with lower risk of asthma-related episodes/attacks (adjusted OR=0.59, 95% CI: 0.41-0.86) than those with short sleep duration. The prevalence (adjusted OR=0.67, 95% CI: 0.47-0.94) and frequency (adjusted OR=0.83, 95% CI: 0.69-0.9996) of asthma-related ED visits among short sleepers were significantly higher than that among optimal sleepers. The differences of asthma-related episodes/attacks and ED visits between long and optimal sleepers were statistically insignificant. CONCLUSION: Our study demonstrated that asthmatics with short sleep duration were associated with highest prevalence of asthma-related episodes/attacks and ED visits among the three sleep duration groups.

Successful treatment of severe COVID-19 pneumonia in a liver transplant recipient.

Coronavirus disease 2019 (COVID-19) pandemic spreads rapidly and may be an increasing challenge for transplant community. Clinical data on COVID-19 infection in transplant population is very limited. Herein we presented the clinical course and outcome of a 50-year-old male post liver transplantation who contracted COVID-19, with subsequent infection of his wife. The process of illness was representative. A therapeutic regime with temporary immunosuppression withdrawal and systemic low-dose corticosteroid as principle was involved in the management of the patient which made him recover from severe COVID-19 pneumonia.

Interleukin-1ß-Induced Senescence Promotes Osteoblastic Transition of Vascular Smooth Muscle Cells.

INTRODUCTION: Interleukin (IL)-1ß, as a key biomarker and mediator of vascular calcification in patients with end-stage renal disease (ESRD), may be involved in the process of premature senescence of vascular smooth muscle cells (VSMCs). This work sought to investigate whether IL-1ß-induced premature senescence contributes to the process of osteoblastic transition and vascular calcification in VSMCs. METHODS: Eighty-eight patients with ESRD (aged 25-81 years), 11 healthy individuals, and 15 cases of lesion-free distal radial arteries from dialysis ESRD patients with angiostomy were collected in this study. Immunohistochemical analysis was performed to detect expression of IL-1ß, p21, and bone morphogenetic protein-2 (BMP2) in the distal radial arteries. Primary human VSMCs from healthy neonatal umbilical cords were incubated with test agents for 1-3 days. Intracellular levels of reactive oxygen species (ROS) and senescence-associated-ß-galactosidase (SA-ß-gal) staining were used to detect senescent cells. Alizarin red staining and the calcium content of the cell layer were used to detect mineral deposition in VSMCs. RESULTS: Coincident with positive staining of IL-1ß, p21, and BMP2 in the lesion-free distal radial arteries, 66.67% patients showed mineral deposition. Serum IL-1ß was 0.24 ± 0.57, 1.20 ± 2.95, and 9.41 ± 40.52 pg/mL in 11 healthy individuals, 20 patients without calcification, and 53 patients with calcification, respectively. Analysis of the cross-table chi-square test showed cardiovascular calcification is not correlated with levels of serum IL-1ß in patients with ESRD (p = 0.533). In response to IL-1ß, VSMCs showed a senescence-like phenotype, such as flat and enlarged morphology, increased expression of p21, an increased activity of SA-ß-gal, and increased levels of ROS. IL-1ß-induced senescence of VSMCs was required for the activation of IL-1ß/NF-κB/p53/p21 signaling pathway. IL-1ß-induced senescent VSMCs underwent calcification due to osteoblastic transition mainly depending upon the upregulation of BMP2. Resveratrol, an activator of sirtuin-1, postponed the IL-1ß-induced senescence through blocking the NF-κB/p53/p21 pathway and attenuated the osteoblastic transition and calcification in VSMCs. CONCLUSIONS: High levels of IL-1ß in medial smooth muscles of arteries may play roles in inducing senescence-associated calcification. IL-1ß-induced senescence depending on the activation of the NF-κB/p53/p21 signaling pathway and contributing to osteoblastic transition of VSMCs.

A polymeric nanocarrier with a tumor acidity-activatable arginine-rich (R9) peptide for enhanced drug delivery.

Cell-penetrating peptides (CPPs) have been considered as a powerful tool to improve the intracellular and nuclear delivery efficiency of nanocarriers. However, their clinical application is limited because of their nonspecific targeting function, short half-life, and severe system toxicity. Herein, we have developed a polymeric nanocarrier with a tumor acidity-activatable arginine-rich (R9) peptide for targeted drug delivery. The nanocarrier is fabricated with a R9-conjugated amphiphilic diblock polymer of poly(ethylene glycol) (PEG) and poly(hexyl ethylene phosphate) (PHEP), and then further coated with tumor acidity-activatable polyanionic polyphosphoester through electrostatic interaction in order to block the nonspecific targeting function of the R9 peptide. In the slightly acidic tumor extracellular environment (∼pH 6.5), tumor acidity-activatable polyanionic polyphosphoester would be deshielded from the nanoparticles, resulting in the re-exposure of the R9 peptide to enhance tumor cellular uptake. As a result, intracellular concentration of payload in 4T1 tumor cells significantly increased at pH 6.5. And, we further demonstrate that such a delivery system remarkably promoted the anti-tumor efficiency of chemotherapeutic drugs in tumor-bearing mice, offering great potential for drug delivery and cancer therapy.