Search

Background/objective: Coronavirus disease 2019 (COVID-19) is a disaster in human medical history and glucocorticoids remain the most promising therapy. Osteonecrosis is a disease caused by reduced intraosseous blood flow to bones in the joints, which will rapidly induce joint destruction. Approximately one-third patients with severe acute respiratory syndrome (SARS) who received high cumulative doses and long treatment durations of glucocorticoids occurred osteonecrosis. Considering the similarity of SARS and COVID-19 on their pathogen, clinical characteristics, and therapeutic strategies, it is particularly desirable to investigate whether osteonecrosis will become a common sequela among convalescent COVID-19 patients. Methods: This multi-strategy study was designed by integrating different research methods, such as meta-analysis, systematic review, and cross-sectional investigations to address above study objectives. At first, two meta-analyses were performed on the osteonecrosis incidence among SARS patients and the clinical data of glucocorticoid exposure among COVID-19 patients. Then, a systematic review of low-dosage glucocorticoid associated osteonecrosis and a cross-sectional investigation of glucocorticoid exposure of COVID-19 patients in Wuhan city of China were also conducted. Moreover, the pathogenesis, diagnosis, prevention, and treatment options for osteonecrosis patients with COVID-19 infection were further presented and discussed. Results: Our meta-analysis showed that 32% of SARS patients had developed osteonecrosis after receiving glucocorticoid treatment with high dose, and our system review supported that low level glucocorticoid exposure might also lead to the occurrence of osteonecrosis. Similarly, 40% of COVID-19 patients had undergone glucocorticoid treatment according to our meta-analysis. The cross-sectional investigation in Wuhan city of China found that the average of cumulative glucocorticoid exposure level was 504 ​mg calculated by the dosage of methylprednisolone. Notably, a confirmed osteonecrosis case was identified from 1406 patients with COVID-19 during our cross-sectional investigation, implying that preventive management of osteonecrosis should be better started with regular clinical follow-up observation. Conclusion: Growing evidence of the glucocorticoid therapy for COVID-19 patients prompts us to establish risk-classification-based early screening and to introduce early prevention protocol of its associated osteonecrosis that will be of clinical significance in favor of improved prognosis of this disease. The translational potential of this article: To establish risk-classification-based early screening and to introduce early prevention protocol of glucocorticoid-induced osteonecrosis will be of clinical significance in favor of improved prognosis of COVID-19.

Abstract Repositioning approved antitumor drugs for different cancers is a cost-effective approach. Gilteritinib was FDA-approved for the treatment of FLT3-mutated acute myeloid leukemia in 2018. However, the therapeutic effects and mechanism of Gilteritinib on other malignancies remain to be defined. In this study, we identified that gilteritinib has an inhibitory effect on lung cancer cells (LCCs) without FLT3 mutation in vitro and in vivo. Unexpectedly, we found that gilteritinib induces cholesterol accumulation in LCCs via upregulating cholesterol biosynthetic genes and inhibiting cholesterol efflux. This gilteritinib-induced cholesterol accumulation not only attenuates the antitumor effect of gilteritinib but also induces gilteritinib-resistance in LCCs. However, when cholesterol synthesis was prevented by squalene epoxidase (SQLE) inhibitor NB-598, both LCCs and gilteritinib-resistant LCCs became sensitive to gilteritinib. More importantly, the natural cholesterol inhibitor 25-hydroxycholesterol (25HC) can suppress cholesterol biosynthesis and increase cholesterol efflux in LCCs. Consequently, 25HC treatment significantly increases the cytotoxicity of gilteritinib on LCCs, which can be rescued by the addition of exogenous cholesterol. In a xenograft model, the combination of gilteritinib and 25HC showed significantly better efficacy than either monotherapy in suppressing lung cancer growth, without obvious general toxicity. Thus, our findings identify an increase in cholesterol induced by gilteritinib as a mechanism for LCC survival, and highlight the potential of combining gilteritinib with cholesterol-lowering drugs to treat lung cancer.

BackgroundSystemic Lupus Erythematosus (SLE) is acknowledged for its significant influence on systemic health. This study sought to explore potential crosstalk genes, pathways, and immune cells in the relationship between SLE and moyamoya disease (MMD).MethodsWe obtained data on SLE and MMD from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify common genes. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these shared genes. Hub genes were further selected through the least absolute shrinkage and selection operator (LASSO) regression, and a receiver operating characteristic (ROC) curve was generated based on the results of this selection. Finally, single-sample Gene Set Enrichment Analysis (ssGSEA) was utilized to assess the infiltration levels of 28 immune cells in the expression profile and their association with the identified hub genes.ResultsBy intersecting the important module genes from WGCNA with the DEGs, the study highlighted CAMP, CFD, MYO1F, CTSS, DEFA3, NLRP12, MAN2B1, NMI, QPCT, KCNJ2, JAML, MPZL3, NDC80, FRAT2, THEMIS2, CCL4, FCER1A, EVI2B, CD74, HLA-DRB5, TOR4A, GAPT, CXCR1, LAG3, CD68, NCKAP1L, TMEM33, and S100P as key crosstalk genes linking SLE and MMD. GO analysis indicated that these shared genes were predominantly enriched in immune system process and immune response. LASSO analysis identified MPZL3 as the optimal shared diagnostic biomarkers for both SLE and MMD. Additionally, the analysis of immune cell infiltration revealed the significant involvement of activation of T and monocytes cells in the pathogenesis of SLE and MMD.ConclusionThis study is pioneering in its use of bioinformatics tools to explore the close genetic relationship between MMD and SLE. The genes CAMP, CFD, MYO1F, CTSS, DEFA3, NLRP12, MAN2B1, NMI, QPCT, KCNJ2, JAML, MPZL3, NDC80, FRAT2, THEMIS2, CCL4, FCER1A, EVI2B, CD74, HLA-DRB5, TOR4A, GAPT, CXCR1, LAG3, CD68, NCKAP1L, TMEM33, and S100P have been identified as key crosstalk genes that connect MMD and SLE. Activation of T and monocytes cells-mediated immune responses are proposed to play a significant role in the association between MMD and SLE.

BackgroundCutaneous tuberculosis (CTB) and nontuberculous mycobacteria (NTM) infections present considerable diagnostic and therapeutic challenges. This study aims to provide a comprehensive clinicopathological analysis of CTB and NTM infections.MethodsWe conducted a retrospective analysis of 103 patients diagnosed with cutaneous tuberculosis (CTB) and nontuberculous mycobacteria (NTM) infections at a Beijing dermatology department from January 2000 to January 2024. Demographic, clinical, histological, and laboratory finding data were collected. Diagnostic methods and histopathological examination were recorded. Treatment regimens and outcomes were reviewed. Descriptive statistics were used to summarize demographic and clinical data, and continuous variables expressed as means and standard deviations (SD), and categorical variables as frequencies and percentages. Statistical analyses were conducted using SPSS version 25.0.ResultsThe cohort included 103 patients (40.8% males and 59.2% females), with a mean age of 51.86 years. Common clinical manifestations included nodules (97.1%), erythema (74.8%), and plaques (68.9%). Histological examination revealed hyperkeratosis (68.9%), parakeratosis (23.3%), and extensive neutrophil infiltration (95.1%) were observed. Acid fast bacteria (AFB) stains and nucleic acid tests exhibited respective positivity rates of 39.6% and 52.3%, respectively. Most patients were treated with a combination of three drugs; 77.1% of patients showed improvement, with the cure rate for CTB being 20.0%.DiscussionThis study highlights the diverse clinical and histological presentations of CTB and NTM infections, emphasizing the need for comprehensive diagnostic approaches. The variability in treatment regimens reflects the complex management of these infections.ConclusionThe implementation of advanced molecular techniques and standardized treatment protocols is imperative for enhancing diagnostic precision and therapeutic outcomes.

Abstract A stable and highly active core‐shell heterostructure electrocatalyst is essential for catalyzing oxygen evolution reaction (OER). Here, a dual‐trimetallic core‐shell heterostructure OER electrocatalyst that consists of a NiFeWS2 inner core and an amorphous NiFeW(OH)z outer shell is designed and synthesized using in situ electrochemical tuning. The electrochemical measurements of different as‐synthesized catalysts with a similar mass loading suggest that the core‐shell Ni0.66Fe0.17W0.17S2@amorphous NiFeW(OH)z nanosheets exhibit the highest overall performance compared with that of other bimetallic reference catalysts for the OER. Additionally, the nanosheet arrays were in situ grown on hydrophilic‐treated carbon paper to fabricate an integrated three‐dimensional electrode that affords a current density of 10 mA cm−2 at a small overpotential of 182 mV and a low Tafel slope of 35 mV decade−1 in basic media. The Faradaic efficiency of core‐shell Ni0.66Fe0.17W0.17S2@amorphous NiFeW(OH)z is as high as 99.5% for OER. The scanning electron microscope, transmission electron microscope, and X‐ray photoelectron spectroscopy analyses confirm that this electrode has excellent stability in morphology and elementary composition after long‐term electrochemical measurements. Importantly, density functional theory calculations further indicate that the core‐shell heterojunction increased the conductivity of the catalyst, optimized the adsorption energy of the OER intermediates, and improved the OER activity. This study provides a universal strategy for designing more active core‐shell structure electrocatalysts based on the rule of coordinated regulation between electronic transport and active sites.

Background This study investigated the long‐term clinical and angiographic outcomes of encephaloduroarteriosynangiosis treatment for symptomatic intracranial atherosclerotic arterial steno‐occlusive disease to further evaluate the potential therapeutic role of encephaloduroarteriosynangiosis in this population. Methods and Results A total of 152 adult patients with symptomatic intracranial atherosclerotic arterial steno‐occlusive disease who were treated with encephaloduroarteriosynangiosis and intensive medical management across 3 tertiary centers in China between January 2011 and September 2019 were retrospectively included. The primary outcomes were defined as postoperative cerebrovascular events, including ischemic and hemorrhagic stroke. The postoperative neovascularization was analyzed qualitatively and quantitatively by using angiography. Clinical, radiological, and long‐term follow‐up data were analyzed using Cox regression, logistic regression, and linear regression analyses. Primary outcome rates were 3.2% (5/152) within 30 days, 6.6% (10/152) within 2 years, 9.2% (14/152) within 5 years, and 11.1% (17/152) during a median 9.13 years follow‐up. Initial infarction symptoms were positively associated with recurrent ischemic stroke. Additionally, posterior circulation involvement and coexisting cardiac disease indicated poorer neurological status, whereas encephaloduroarteriosynangiosis neovascularization efficacy was negatively associated with older age and vascular risk factors but positively associated with posterior circulation involvement. Conclusions Encephaloduroarteriosynangiosis plus intensive medical management appears efficacious and safe for symptomatic intracranial atherosclerotic arterial steno‐occlusive disease, with low perioperative risk and favorable long‐term results. Further prospective trials are needed to verify its efficacy and determine the optimal patient selection criteria.

Genus Pseudomonas bacteria mainly consume glucose through the Entner–Doudoroff (ED) route due to a lack of a functional Embden–Meyerhof–Parnas (EMP) pathway. In the present study, a 6-phosphogluconate dehydratase (edd) operon in the ED route was well investigated to find its structural characteristics and roles in the regulation of glucose consumption and 2-ketogluconic acid (2KGA) metabolism in the industrial 2KGA-producer P. plecoglossicida JUIM01. The edd operon contained four structural genes of edd, glk, gltR, and gtrS, encoding 6-PG dehydratase Edd, glucokinase Glk, response regulatory factor GltR, and histidine kinase GtrS, respectively. A promoter region was observed in the 5′-upstream of the edd gene, with a transcriptional start site located 129 bp upstream of the edd gene and in a pseudo-palindromic sequence of 5′-TTGTN7ACAA-3′ specifically binding to the transcription factor HexR. The knockout of the edd gene showed a remarkably negative effect on cell growth and re-growth using 2KGA as a substrate, beneficial to 2KGA production, with an increase of 8%. The deletion of glk had no significant effect on the cell growth or glucose metabolism, while showing an adverse impact on the 2KGA production, with a decrease of 5%. The outputs of the present study would provide a theoretical basis for 2KGA-producer improvement with metabolic engineering strategies and the development and optimization of P. plecoglossicida as the chassis cells.

Abstract Background The pathogenesis of moyamoya disease (MMD) is unclear. Inflammation and immune imbalance have been identified as potential factors contributing to the occurrence and progression of MMD. However, the specific proteins and metabolites responsible for triggering this process are yet to be established. The purpose of this study is to identify differentially expressed proteins and metabolites in patients with MMD and perform Kyoto Encyclopedia of Genes and Genomes pathway integration analysis to pinpoint crucial proteins and metabolites involved in the disease. Methods We performed untargeted metabolomic and data‐independent acquisition proteomic analyses on the serum samples of individuals with MMD and healthy controls (HC). Results In patients with MMD versus HC, 24 proteins and 60 metabolites, including 21 anionic metabolites and 39 cationic metabolites, which were significantly different, were identified. In patients with MMD, several proteins involved in inflammation and immune metabolism, such as tubulin beta‐6 and complement C4, were found to have significantly altered levels. Similarly, many metabolites involved in inflammation and immune metabolisms, such as dimethyl 4‐hydroxyisophthalate, beta‐nicotinamide mononucleotide, 2‐(3‐(4‐pyridyl)‐1H‐1,2,4‐triazol‐5‐yl)pyridine, and PC (17:1/18:2), were significantly altered. Intriguingly, these proteins and metabolites are involved in the progression of atherosclerosis through immune and inflammatory pathways, although some have never been reported in MMD. Moreover, integrated proteomics and metabolomics studies were conducted to determine shared pathways involving cholesterol metabolism, vitamin digestion, fat digestion, and absorption pathways of proteins and metabolites, which warrant further investigation. Conclusions Significant increases in pro‐inflammatory and immunosuppressive abilities have been observed in patients with MMD, accompanied by significant reductions in anti‐inflammatory and immune regulation. Various metabolites and proteins implicated in these processes have been identified for the first time. These findings hold immense significance for comprehending the pathogenesis of MMD and for the development of future drug therapies.

The nitrogen application rate (NAR) has a significant effect on the contents of wheat grain protein and its composition. There is still no consensus regarding the appropriate NAR, given the differences in studied conditions and influence of factors such as geographical location, climate, and soil nutrient contents. In this study, 66 papers related to wheat grain protein and its composition published from 1984 to 2021 were selected for meta-analysis in comprehensively evaluating the response of wheat grain protein content and composition to NAR in China. The results reveal that NAR significantly increased total protein content by 9.49–28.6%, gliadin by 9.13–30.5%, glutenin by 12.9–45.4%, albumin by 5.06–15.8%, and globulin by 8.52–24.0% of wheat grain in China, respectively, compared to no nitrogen application. The optimal NAR is 240–300 kg ha−1 when specific planting conditions are not being considered. Under different growing conditions, the NAR that provided the greatest increase in wheat grain protein and its composition varied as follows: 180–240 kg ha−1 in Northwest China and at >100 m altitudes; >300 kg ha−1 in North China and at −1 in Southeast China, with higher soil nutrients levels and for all average annual temperatures and precipitation ranges. In conclusion, the results of the present study reveal that it is feasible to systematically enhance the contents of wheat grain protein and its related fractions by appropriate NAR under different cropping conditions.