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Abstract Background Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance. Methods This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. Results Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). Conclusions Belumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. Trial registration ClinicalTrials.gov identifier NCT04930562.

Sleep can affect nonalcoholic fatty liver disease (NAFLD). We investigated the association between sleep duration, sleep quality, and NAFLD. From January to December 2018, 1,073 patients (age: 37.94 ± 10.88, Body Mass Index (BMI): 22.85 ± 3.27) were enrolled. Pittsburgh Sleep Quality Index Questionnaire and Munich Chronotype Questionnaire were used to assess sleep duration, quality, and habits. Ultrasonography was used to diagnose NAFLD. Multivariate logistic regression models were used to calculate the odds ratio (OR) and 95% confidence interval (CI) of the risk of NAFLD by different types of sleep duration and sleep quality. No significant differences in sleep time, sleep quality, and sleep habits between the NAFLD and the non-NAFLD groups were observed (P > 0.05). There was no correlation between sleep duration and NAFLD in the whole cohort. After adjusting for age, exercise, fasting plasma glucose, and BMI, the group with long sleep duration showed a decreased risk of NAFLD in men (OR = 0.01, 95% CI: 0.001–0.27, P = 0.032). However, in all four adjusted models, no correlation between sleep duration, quality, and NAFLD was found in women. In conclusion, sleep duration was significantly and negatively associated with NAFLD in men but not women. Prospective studies are required to confirm this association.

Aim: This analysis compared the impact of laparoscopic appendicectomy (LA) and open appendicectomy (OA) on treating adult perforated appendicitis (PA). Methods: Articles relating to LA and OA in treating PA were retrieved from databases including PubMed, Cochrane Library and Embase since their founding to January 2022. These articles were independently filtered based on the inclusion and exclusion criteria by two investigators. The quality of these articles was assessed and article data were extracted. Dichotomous data were presented in the form of odd's ratio (OR), whereas continuous data were in the form of weighted mean difference (WMD). The included articles reported at least one of the following outcomes: intra-abdominal abscess (IAA), wound infection, operative time, hospital stay and complications. Results: Three randomised control trials (198 LA cases vs. 205 OA cases) and 12 case − control trials (914 LA cases vs. 2192 OA cases) were included. This analysis revealed that although the IAA formation rate was similar in the LA and OA groups (OR: 1.28, 95% confidence interval [CI]: 0.87–1.88), the wound infection rate was lower in the LA group (OR: 0.38, 95% CI: 0.28–0.51). Furthermore, LA was associated with shorter hospital stay (WMD: −1.43 days, 95% CI: −2.33–−0.52) and fewer complications than OA (OR: 0.40, 95% CI: 0.28–0.57). Conclusion: LA has significant benefits in treating PA and is associated with better post-operative outcomes such as shorter hospital stay, lower incidence of wound infection and other complications. However, more studies with randomised and large-sample populations are still required to determine the clinical benefit of LA in treating PA.

Explosive emission cathodes are extensively used in high power microwave sources. Growing requirements are highlighted in the performance of the explosive emission cathode with the development of the high power microwave technology. In order to improve the emission properties of the graphite cathode, modifications using SiC particles or whiskers are carried out by the in situ chemical vapor reaction method. The experiments demonstrate that SiC whiskers accelerate the explosive emission turn-on speed of the graphite cathode for large field enhancement factors and improve the emission uniformity due to the surface flashover plasma generation mechanism. SiC particles increase the emission capability of the graphite cathode, possibly corresponding to the dielectric properties of SiC particles. These results suggest that the SiC whiskers modified graphite cathode is suitable for applications under low magnetic field and large emission area conditions, while the SiC particles modified graphite cathode has a brighter application prospect in the long-time stable operation.

Abstract Background The therapeutic value of targeted therapies in patients with lung cancer is reduced when tumours acquire secondary resistance after an initial period of successful treatment. However, the molecular events behind the resistance to targeted therapies in lung cancer remain largely unknown. Aims To discover the important role and mechanism of lncRNA BC in promoting tumor metastasis and influencing clinical prognosis of LUAD. Materials & Methods: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in lung cancer cells. The functional role and mechanism of lncRNA were further investigated by gain‐ and loss‐of‐function assays. RNA pull‐down, protein assays, and mass spectrometry were used to identify proteins that interacted with lncRNA. TaqMan PCR was used to measure lncRNA in lung adenocarcinoma and adjacent nontumor tissues from 428 patients. The clinical significance of lncRNA identified was statistically confirmed in this cohort of patients. Results In this study, we show that the long non‐coding RNA BC009639 (BC) is involved in acquired resistance to EGFR‐targeted therapies. Among the 235 long non‐coding RNAs that were differentially expressed in lung cancer cell lines, with different metastatic potentials, BC promoted growth, invasion, metastasis, and resistance to EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), both in vitro and in vivo. BC was highly expressed in 428 patients with lung adenocarcinoma (LUAD) and high BC expression correlated with reduced efficacy of EGFR‐TKI therapy. To uncover the molecular mechanism of BC‐mediated EGFR‐TKI resistance in lung cancer, we screened and identified nucleolin and hnRNPK that interact with BC. BC formed the splicing complex with nucleolin and hnRNPK to facilitate the production of a non‐protein‐coding inositol monophosphatase domain containing 1 (IMPAD1) splice variant, instead of the protein‐coding variant. The BC‐mediated alternative splicing (AS) of IMPAD1 resulted in the induction of the epithelial–mesenchymal transition and resistance to EGFR‐TKI in lung cancer. High BC expression correlated with clinical progress and poor survival among 402 patients with LUAD. Disscussion Through alternative splicing, BC boosted the non‐coding IMPAD1‐203 transcript variant while suppressing the IMPAD1‐201 variant. In order to control the processing of pre‐mRNA, BC not only attracted RNA binding proteins (NCL, IGF2BP1) or splicing factors (hnRNPK), but also controlled the formation of the splicing‐regulator complex by creating RNA‐RNA‐duplexes. Conclusion Our results reveal an important role for BC in mediating resistance to EGFR‐targeted therapy in LUAD through IMPAD1 AS and in implication for the targeted therapy resistance.

A 70-day experiment was conducted to investigate the effects of mulberry leaf extract (MLE) on growth, proximate compositions, antioxidant and plasma biochemical parameters, and indices of non-specific immunity of largemouth bass (Micropterus salmoides) fed a high-starch diet. Two hundred eighty largemouth bass (initial body weight, 68.00 ± 0.19 g) were randomly fed seven diets: basal-starch diet (BSD; 8.88% starch), high-starch diet (HSD; 11.42% starch), and HSD diets supplemented with 0.05%, 0.10%, 0.20%, 0.50%, and 1.00% MLE (MLE1, MLE2, MLE3, MLE4, and MLE5, respectively). The results indicated that HSD and MLE did not significantly affect the growth performance of largemouth bass during the experimental period compared with that of the BSD, but the supplementation with more than 0.20% (MLE3, MLE4, and MLE5) MLE significantly decreased the hepatosomatic index (HSI) values, and 1.00% (MLE5) MLE significantly decreased the viscerosomatic index (VSI) values. The whole-body moisture of fish fed an HSD decreased significantly, while the whole-body lipid content increased significantly in the HSD group compared with the BSD group. Compared with HSD, MLE supplementation significantly decreased the moisture and lipid contents in the whole body. Supplementation with more than 0.20% MLE (MLE3, MLE4, and MLE5) significantly decreased the moisture content in the muscle. Supplementation with 1.00% MLE significantly decreased the content of hepatic and muscle glycogen. The malondialdehyde (MDA) content of the HSD group was significantly increased compared to that of the BSD group, whereas more than 0.10% (MLE2, MLE3, MLE4, and MLE5) MLE significantly decreased the MDA content. Additionally, the total antioxidant capacity (T-AOC), catalase (CAT), and glutathione peroxidase (GSH-Px) activities of MLE5 were significantly higher than those of the HSD group. The complement-3 (C3) content and globulin (GLB) in the plasma of the HSD group were significantly lower than those of the BSD group. Plasma C3 levels in the MLE3, MLE4, and MLE5 groups were significantly higher than those in the HSD group. In addition, glucose (GLU) levels in the MLE3, MLE4, and MLE5 groups were significantly lower than those in the HSD group. Supplementation with 0.50% (MLE4) MLE significantly increased the lysozyme (LYZ) content and decreased the activities of alanine transaminase (ALT) and aspartate transaminase (AST). Supplementation with 1.00% MLE significantly increased complement-4 (C4) and GLB contents and alkaline phosphatase (ALP) activity. Overall, these findings suggest that MLE could improve antioxidant capacity, immune function, and glycolipid metabolism, thereby alleviating the negative effects of a high-starch diet in M. salmoides.

Neutrophils, known as an important part of the immune system, are the most abundant leukocyte population in peripheral blood, but excessive recruitment will lead to tissue/organ injury. RNA sequencing showed that ionizing radiation significantly increased the expression of characteristic genes of neutrophils in intestinal tissues compared with liver and lung tissues. By clearing neutrophils with an anti-Ly6G antibody, we found that neutrophil infiltration is critical for irradiation-induced intestinal injury. CXCR2 is a G-protein-coupled receptor that mediates the migration of neutrophils by combining with its ligands. Compared with observations in liver and lung tissues, we found that CXCR2 and its ligands, including CXCL1, CXCL2, CXCL3, and CXCL5, were all significantly upregulated in irradiated intestinal tissues. Further studies showed that SB225002, an inhibitor of CXCR2, could effectively inhibit the chemotaxis of neutrophils and tissue damage mediated by the CXCL-CXCR2 signalling pathway.

It has been widely assumed and proven that a firm’s research and development (R&D) investment is limited if the availability of cash flow is constrained. The purpose of this study is to verify the opposite proposition: whether firms invest heavily in R&D when more cash flow is available. This paper discusses the heterogeneous relationship between cash flow from different sources and the R&D investment of firms. The study divides the firm’s cash flow into three categories according to the business activities that generate firm finance: cash flow from operating activities (CFO), cash flow from investing activities (CFI), and cash flow from financing activities (CFF). On this basis, a dynamic R&D investment model is constructed, and the relevant data for Chinese listed firms are used for the empirical research. The study finds that Chinese listed firms do not necessarily spend more cash on R&D investment, even if the availability of cash flow is not constrained. For young firms, CFO and CFI do not significantly correlate with R&D investment, and CFF significantly negatively correlates with R&D investment. For mature firms, the correlations between cash flow generated from different activities and R&D investment are nonsignificant.

Prior research offers a minimal amount of direct evidence on the effect of gamification features such as top-donor leaderboards on medical crowdfunding, particularly regarding donor engagement, contributions per donor, and total campaign funds. The study analyzes data from 3,415 distinct medical campaigns, leveraging an unannounced change on GoFundMe. The findings reveal a complex scenario that defies simple expectations. The leaderboard is expected to increase donor engagement, but it appears to discourage larger contributions per donor, a phenomenon termed "crowding out." Despite these mixed outcomes, there is a positive correlation between the leaderboard's presence and the funds raised. These findings highlight the potential of leaderboards to increase engagement and total funds raised in medical crowdfunding campaigns. However, the crowding-out effect raises concerns about the Pareto efficiency of this motivation system. This research contributes insights to both practitioners and theorists, shedding light on the complex interplay between gamification features and crowdfunding outcomes in the medical context. [ABSTRACT FROM AUTHOR]