Search

Abstract Background There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. Methods We integrated druggable genome data, cis‐eQTL/cis‐pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia‐related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome‐wide MR (Phe‐MR) approach and investigated actionable drugs for target genes using available databases. Results MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA‐DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up‐regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007–0.018, P = 1.2*10−5) and higher grip strength (OR: 0.96, 95% CI: 0.94–0.98, P = 4.2*10−5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21–0.26, P = 1.8*10−94), higher grip strength (OR: 0.82, 95% CI: 0.75–0.90, P = 2.1*10−5), and faster walking pace (beta: 0.03, 95% CI: 0.02–0.05, P = 8.5*10−6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06–0.11, P = 6.1*10−13; blood pQTL, beta: 0.05, 95% CI: 0.03–0.07, P = 3.8*10−09)], as well as the down‐regulation of HLA‐DRA [lower ALM (beta: ‐0.09, 95% CI: −0.11 to −0.08, P = 5.4*10−36) and lower grip strength (OR: 1.13, 95% CI: 1.07–1.20, P = 1.8*10−5)] and COL15A1 [higher ALM (muscle eQTL, beta: ‐0.07, 95% CI: −0.10 to −0.04, P = 3.4*10−07; blood pQTL, beta: ‐0.05, 95% CI: −0.06 to −0.03, P = 1.6*10−07)], decreased the risk of sarcopenia. AURKA in blood (beta: ‐0.16, 95% CI: −0.22 to −0.09, P = 2.1*10−06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10−05) tissues showed an inverse relationship with sarcopenia risk. The Phe‐MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. Conclusions Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA‐DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

Abstract Objective The pathological features of immune‐mediated necrotizing myopathy (IMNM) are dominated by the infiltration of macrophages. We aimed to perform a histopathologic semiquantitative analysis to investigate the relationship between macrophage markers and prognosis. Methods Semiquantitative analysis of histologic features was performed in 62 samples of IMNM. Independent risk factors were identified through univariate and multivariate regression analysis. Cluster analysis was performed using the partitioning around the medoids (PAM) method. Decision tree modeling was utilized to efficiently determine cluster labels for IMNM patients. The validity of the developmental cohort was assessed by accuracy in comparison with the validation cohort. Results The most enriched groups in patients with IMNM were macrophages expressing CD206 and CD163. In the multivariate logistic regression model, the high density of CD163+ macrophages in perimysial connective tissue increased the risk of unfavorable prognosis (p = 0.025, OR = 1.463, 95% CI: 1.049–2.041). In cluster analysis, patients in Cluster 1, with lower CD163+ macrophage density and inflammatory burden, had a more favorable prognosis. Conversely, patients in Cluster 3, which were enriched for CD163+ macrophages in the perimysial connective tissue, had the most severe clinical features and the worst prognosis. Correlations were found between the density of CD163+ macrophages in connective tissue and symptom duration (R2 = 0.166, p

Abstract Three‐dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D‐RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D‐RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D‐RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor‐dependent and vendor‐independent software platforms were used to analyze the 3D‐RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D‐RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D‐RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D‐RV values should be stratified by sex, age, race, and vendor.

Abstract Background Patients with type 2 diabetes mellitus (T2DM) are predisposed to cardiovascular disease (CVD). Bone mineral density (BMD) is linked to CVD, but most studies focused on women. Our analysis aims to explore the association of BMD and fracture with the prevalence of CVD in men with T2DM. Methods In this retrospective cross‐sectional study, 856 men with T2DM were enrolled. BMDs at the lumbar spine (L2‐4), femoral neck (FN), and total hip (TH) were measured by dual‐energy X‐ray absorptiometry (DXA). The CVD outcome was determined as the sum of the following conditions: congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction, the requirement for coronary artery revascularization, and stroke. The relationship between BMDs and CVD was investigated by restricted cubic spline curves and logistic regression models. Results A total of 163 (19.0%) patients developed CVD. The restricted cubic spline curve revealed a linear and negative association between FN‐BMD, TH‐BMD, and CVD. After full adjustments for confounding covariates, the odds ratios were 1.34 (95% confidence interval [CI] [1.11–1.61], p

Abstract Heart failure (HF) is a disease with high mortality and morbidity rate. Autophagy is critically implicated in HF progression. The current research was designed to investigate the function of Dioscin on oxidative stress, autophagy, and apoptosis in HF. In this study, doxorubicin (Dox) was employed to induce HF model and HL‐1 cell damage model. Echocardiography implied that Dioscin could dramatically relieve heart function in vivo. Western blotting determined that Dioscin treatment reversed the promotive effect of autophagy caused by Dox through modulating levels of key autophagy‐associated molecules, including Atg5 and Beclin1. Dioscin also impaired apoptosis by regulating apoptosis‐related protein, including Bcl‐2 and cleaved caspase‐3 following Dox treatment in vivo and in vitro. Furthermore, the impacts of Dioscin were mediated by upregulation of PDK1‐mediated Akt/mTOR signaling. The mTOR inhibitor (rapamycin) could counteract the therapeutic impact of Dioscin in vitro. Taken together, Dioscin could relieve cardiac function through blocking apoptosis and autophagy by activating the PDK1‐elicited Akt/mTOR pathway.

Abstract Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti‐inflammatory macrophages, there are few researches on targeting pro‐inflammatory macrophages, which is partially attributed to their non‐s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro‐inflammatory macrophages via antigen recognition, which is named AnCar‐ExoLaIMTS. The data indicate that the phagocytosis efficiencies of pro‐inflammatory macrophages for different AnCar‐ExoLaIMTS show obvious differences. The AnCar‐ExoLaIMTS3 has the best targeting ability for pro‐inflammatory macrophages in vitro and in vivo. Mechanically, AnCar‐ExoLaIMTS3 can specifically recognize the leucine‐rich repeat domain of the TLR4 receptor, and then enter into pro‐inflammatory macrophages via the TLR4‐mediated receptor endocytosis pathway. Moreover, AnCar‐ExoLaIMTS3 can efficiently deliver therapeutic cargo to pro‐inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF‐1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro‐inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases.

Abstract Background and aim Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains. Methods A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini–mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test–revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation. Results Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p

Abstract Background Predictive biomarkers for oesophageal squamous cell carcinoma (ESCC) immunotherapy are lacking, and immunotherapy resistance remains to be addressed. The role of long noncoding RNA (lncRNA) in ESCC immune escape and immunotherapy resistance remains to be elucidated. Methods The tumour‐associated macrophage‐upregulated lncRNAs and the exosomal lncRNAs highly expressed in ESCC immunotherapy nonresponders were identified by lncRNA sequencing and polymerase chain reaction assays. CRISPR‐Cas9 was used to explore the functional roles of the lncRNA. RNA pull‐down, MS2‐tagged RNA affinity purification (MS2‐TRAP) and RNA‐binding protein immunoprecipitation (RIP) were performed to identify lncRNA‐associated proteins and related mechanisms. In vivo, the humanized PBMC (hu‐PBMC) mouse model was established to assess the therapeutic responses of specific lncRNA inhibitors and their combination with programmed cell death protein 1 (PD‐1) monoclonal antibody (mAb). Single‐cell sequencing, flow cytometry, and multiplex fluorescent immunohistochemistry were used to analyze immune cells infiltrating the tumour microenvironment. Results We identified a lncRNA that is involved in tumour immune evasion and immunotherapy resistance. High LINC02096 (RIME) expression in plasma exosomes correlates with a reduced response to PD‐1 mAb treatment and poor prognosis. Mechanistically, RIME binds to mixed lineage leukaemia protein‐1 (MLL1) and prevents ankyrin repeat and SOCS box containing 2 (ASB2)‐mediated MLL1 ubiquitination, improving the stability of MLL1. RIME‐MLL1 increases H3K4me3 levels in the promoter regions of programmed death‐ligand 1 (PD‐L1) and indoleamine 2,3‐dioxygenase 1 (IDO‐1), constitutively increasing the expression of PD‐L1/IDO‐1 in tumour cells and inhibiting CD8+ T cells infiltration and activation. RIME depletion in huPBMC‐NOG mice significantly represses tumour development and improves the effectiveness of PD‐1 mAb treatment by activating T‐cell‐mediated antitumour immunity. Conclusions This study reveals that the RIME‐MLL1‐H3K4me3 axis plays a critical role in tumour immunosuppression. Moreover, RIME appears to be a potential prognostic biomarker for immunotherapy and developing drugs that target RIME may be a new therapeutic strategy that overcomes immunotherapy resistance and benefits patients with ESCC.

Abstract Background Concealed accessory pathway (AP) may cause atrial ventricular reentrant tachycardia impacting the health of patients. However, it is asymptomatic and undetectable during sinus rhythm. Methods To detect concealed AP with electrocardiography (ECG) images, we collected normal sinus rhythmic ECG images of concealed AP patients and healthy subjects. All ECG images were randomly allocated to the training and testing datasets, and were used to train and test six popular convolutional neural networks from ImageNet pre‐training and random initialization, respectively. Results We screened 152 ECG recordings in concealed AP group and 600 ECG recordings in control group. There were no statistically significant differences in ECG characteristics between control group and concealed AP group in terms of PR interval and QRS interval. However, the QT interval and QTc were slightly higher in control group than in concealed AP group. In the testing set, ResNet26, SE‐ResNet50, MobileNetV3_large_100, and DenseNet169 achieved a sensitivity rate more than 87.0% with a specificity rate above 98.0%. And models trained from random initialization showed similar performance and convergence with models trained from ImageNet pre‐training. Conclusion Our study suggests that deep learning could be an effective way to predict concealed AP with normal sinus rhythmic ECG images. And our results might encourage people to rethink the possibility of training from random initialization on ECG image tasks.

Abstract Aims We aim to investigate the additive effect of B‐lines on lung ultrasound (LUS) for predicting outcome in patients with heart failure (HF) when combined with conventional assessment of clinical congestion. Methods and results This study prospectively enrolled 117 hospitalized HF patients (61 ± 16 years, 70.1% males) who underwent congestion assessment by the ‘wet/dry’ status, clinical congestion score (CCS), and B‐lines on LUS. The primary endpoint was all‐cause mortality or hospitalization for HF during the 180‐day follow‐up after discharge. The ‘Wet’, CCS ≥ 3, and B‐lines >5, indicators of congestion positive (+), were observed in 83.8%, 76.1%, and 70.1% of the patients on admission, respectively; and the numbers significantly decreased to 41.9%, 41.9%, and 35.9% at discharge, respectively. The agreement between the ‘wet/dry’ status and B‐lines (58.1%) or between CCS and B‐lines (56.4%) was moderate at discharge, in terms of both positive and both negative. By incorporating the B‐lines with assessment of clinical congestion, the patients at discharge were divided into three phenotypes as clinical congestion (+), clinical congestion (−) with B‐lines (+), and clinical congestion (−) with B‐lines (−). The Kaplan–Meier analysis showed a better survival in the both (−) group (‘wet/dry’ with B‐lines: Chi‐square 10.591, P = 0.005; CCS with B‐lines: χ2 6.239, P = 0.031). When the ‘wet’ patients (n = 49) being taken as the reference, the ‘dry’ patients with B‐lines (+) (n = 21) had an identical risk of the composite endpoint (hazard ratio [HR] adjusted for clinical covariates 1.021, 95% confidence interval [CI] 0.480–2.134, P = 0.974), while the ‘dry’ patients with B‐lines (−) (n = 47) had a lower risk (HR 0.264, 95% CI 0.113–0.617, P = 0.002). When the CCS (+) patients (n = 49) being regarded as the reference, similar results were obtained in the patients with CCS (−) but B‐lines (+) (n = 22) (HR 1.348, 95% CI 0.627–2.896, P = 0.444) as well as in those with both CCS (−) and B‐lines (−) (n = 46) (HR 0.447, 95% CI 0.202–0.992, P = 0.048). Conclusions The combination of B‐lines on LUS and conventional assessment helped to identify new phenotypes of congestion that aid in the risk stratification of discharged HF patients. Further investigation is warranted to determine whether this strategy could be adopted as a guide for decongestion therapy.

Transforming growth factor‐β (TGF‐β) and programmed death ligand 1 (PD‐L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial‐to‐mesenchymal transition, and angiogenesis. Meanwhile, PD‐L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti‐PD‐L1 therapies have been approved for the treatment of various cancers, but TGF‐β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF‐β and PD‐L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual‐targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual‐targeting agent is bintrafusp alfa. This drug is a first‐in‐class bifunctional fusion protein that consists of the extracellular domain of the TGF‐βRII receptor (a TGF‐β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD‐L1. Given the immunosuppressive effects of the TGF‐β and PD‐L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

Abstract Manoeuvering target tracking is a challenging problem for filter design in a variety of tracking systems. However, how to quantify the complexity of this problem is seldom studied. In this paper, a normalised complexity metric for manoeuvering target tracking called relative difficulty to Kalman filter is defined as the ratio between maximum tolerance error of positional estimation and its requirement precision of positional measurement. It can be employed as an indicator of the difficulty of designing an advanced filter to satisfy the tracking requirement. Analytical expression of RD2KF in three‐dimensional space is derived. Two typical tracking examples show that RD2KF is affected by manoeuver intensity, data rate and the required precision of the tracking mission.

Abstract Hereditary spherocytosis (HS) is often misdiagnosed due to lack of specific diagnostic methods. Our study summarized clinical characteristics and described the diagnostic workflow for mild and moderate HS in Chinese individuals, using data from 20 adults, 8 of whom presented a familial history for HS. We used scanning electron microscopy (SEM) to diagnose HS. We observed reduced eosin maleimide fluorescence activity (5.50 mean channel fluorescence (MCF) units) in the 10 cases of HS, which differed significantly when compared with 10 normal adults (15.50 units), iron deficiency anemia (15.50 MCF units), and megaloblastic anemia (12.00 MCF units) values (P

Abstract Background Promising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC. Methods Clinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80–100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups. Results A total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19–0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14–0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P

Background The study was conducted to examine changes in diagnostic and staging imaging methods for lung cancer in China over a 10‐year period and to determine the relationships between such changes and socioeconomic development. Methods This was a hospital‐based, nationwide, multicenter retrospective study of primary lung cancer cases. The data were extracted from the 10‐year primary lung cancer databases at eight tertiary hospitals from various geographic areas in China. The chi‐squared test was used to assess the differences and the Cochran–Armitage trend test was used to estimate the trends of changes. Results A total of 7184 lung cancer cases were analyzed. Over the 10‐year period, the utilization ratio of diagnostic imaging methods, such as chest computed tomography (CT) and chest magnetic resonance imaging (MRI), increased from 65.79% to 81.42% and from 0.73% to 1.96%, respectively, while the utilization ratio of chest X‐ray declined from 50.15% to 30.93%. Staging imaging methods, such as positron emission tomography‐CT, neck ultrasound, brain MRI, bone scintigraphy, and bone MRI increased from 0.73% to 9.29%, 22.95% to 47.92%, 8.77% to 40.71%, 42.40% to 62.22%, and 0.88% to 4.65%, respectively; abdominal ultrasound declined from 83.33% to 59.9%. These trends were more notable in less developed areas than in areas with substantial economic development. Conclusion Overall, chest CT was the most common radiological diagnostic method for lung cancer in China. Imaging methods for lung cancer tend to be used in a diverse, rational, and regionally balanced manner.

Moxibustion is a treatment in traditional Chinese medicine that can promote human health. In order to study the effect of moxibustion on cardiovascular function, photoplethysmogram signals were obtained from acupoints at st 36 (zusanli), sp 6 (sanyinjiao), and li 11 (quchi) during moxibustion. The test data were collected from six volunteers of average weight for 6 days of treatment. The effect of moxibustion treatment was determined by comparing amplitude–frequency characteristics of the instantaneous frequency in the power spectrum after Hilbert–Huang transformation of the pulse signal before and after treatment. It was found that after moxibustion, the maximum energy frequency of the photoplethysmogram would increase, but the amplitude would decrease. The results show that moxibustion therapy has the dual benefit of the infrared effect and acupoint stimulation, which can improve cardiovascular health and has a positive effect on metabolism.