Exploring the Osteogenic Effects of Simiao Wan through Activation of the PI3K/AKT Pathway in Osteoblasts.

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoporosis (OP) is a degenerative bone disease commonly associated with reduced bone density and increased fracture risk. AIM OF THE STUDY: This study aimed to validate the therapeutic effects of Simiao wan (SMW) on OP and explore the underlying mechanism, particularly focusing on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. MATERIALS AND METHODS: The chemical components of SMW were identified using UPLC-Q-TOF-MS/MS. The obtained compounds were then input into the TCMSP, TargetNet, and SwissTargetPrediction databases to predict potential targets. OP-related targets were collected from the GeneCards and DisGeNET databases, and intersecting targets were identified through a Venn diagram. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the intersecting targets using the Database for Annotation, Visualization and Integrated Discovery (DAVID). SMW extract was subsequently used to treat osteoblasts in vitro, and its toxicity on osteoblasts was assessed using Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. Osteoblast differentiation and activity were further evaluated using alizarin red staining, alkaline phosphatase staining, and western blot analyses to validate the activation of network pharmacological signaling pathways. RESULTS: A total of 121 potential targets were identified for SMW in the treatment of OP, with AKT1 as the primary target. The PI3K/AKT pathway emerged as a key signaling pathway potentially involved in SMW's therapeutic effects o OP. Toxicity assessments showed no significant toxicity of SMW on osteoblasts. Additionally, SMW promoted osteoblast proliferation, alkaline phosphatase activity, calcium nodule deposition, and the expression of osteogenic markers (osteocalcin (OCN), runt-related transcription factor 2 (RunX2), and collagen I), and activated the PI3K/AKT signaling pathway. The PI3K/AKT pathway inhibitor LY294002 partially reversed the SMW-induced mineral deposition and expression of OCN, RunX2, and collagen I. CONCLUSION: SMW demonstrated effective multi-target and multi-pathway therapeutic potential in the treatment of OP, with a significant impact on the PI3K/AKT signaling pathway.

Psychometric Properties of Chinese Version of the Barriers to Error Disclosure Assessment (C-BEDA) Tool.

Aim: The Barriers to Error Disclosure Assessment (BEDA) tool is used to measure barriers to the disclosure of medical errors by healthcare professionals. This study aimed to evaluate the psychometric properties of the Chinese version of the BEDA (C-BEDA). Background: The culture of disclosure and transparency in response to medical errors has been recommended in recent years. However, there are no relevant assessment tools for measuring barriers to disclosing medical errors in China. Methods: The C-BEDA tool underwent translation, back translation, cross-cultural adaptation in a pilot study. It was tested with 1254 healthcare professionals in Guizhou and Sichuan Provinces, China. The content validity index (CVI) was used to evaluate the content validity of the C-BEDA, and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to evaluate its structural validity. The Cronbach's α coefficient and test-retest reliability were evaluated to determine its reliability. Results: Three factors were extracted by EFA that explained 65.892% of the total variance of the C-BEDA tool. CFA showed a good fit for a three-factor structure with acceptable values: goodness-of-fit index=0.939; adjusted goodness-of-fit index=0.911; incremental fit index=0.967; comparative fit index=0.967; partial least squares path modeling for confirmatory factor analysis=0.735; and root mean square error of approximation=0.058. The item-level content validity index ranged from 0.86 to 1.00, and the average scale-level content validity index was 0.98. The Cronbach's α coefficient (0.909) and test-retest reliability (0.86) were acceptable. Conclusion: The C-BEDA toolis a valid and reliable tool for assessing the extent of barriers to error disclosure among Chinese healthcare professionals.

FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.

Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [68Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.

Divergent Evolution in Bilateral Prostate Cancer: a Case Study.

Multifocal prostate cancer is a prevalent phenomenon, with most cases remaining uncharacterized from a genomic perspective. A patient presented with bilateral prostate cancer. On systematic biopsy, two indistinguishable clinicopathologic lesions were detected. Whole-genome sequencing displayed somatically unrelated tumours with distinct driver CNA regions, suggesting independent origins of the two tumors. We demonstrated that similar clinicopathologic multifocal tumours, which might be interpreted as clonal disease, can in fact represent independent cancers. Genetic prognostics can prevent mischaracterization of multifocal disease to enable optimal patient management.

RETRACTED: Development and evaluation of a second victim training course for nursing managers.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. The Journal was alerted to legal and ethical concerns regarding the publication of this paper. Neither the use of the copyrighted Jefferson Scale of Empathy© nor the adaptation was authorized by the copyright holders at Thomas Jefferson University. The Editor-in-Chief has therefore determined that the paper should be retracted. The corresponding author acknowledged the notice reporting the outcome of this retraction.

FAM134B deletion exacerbates apoptosis and epithelial-to-mesenchymal transition in rat lungs exposed to hyperoxia.

Oxygen therapy is widely used in clinical practice; however, prolonged hyperoxia exposure may result in hyperoxic acute lung injury (HALI). In this study, we investigated the role of FAM134B in hyperoxia-induced apoptosis, cell proliferation, and epithelial-to-mesenchymal transition (EMT) using RLE-6TN cells and rat lungs. We also studied the effect of CeO2-NPs on RLE-6TN cells and lungs following hyperoxia exposure. FAM134B was inhibited in RLE-6TN cells and rat lungs following hyperoxia exposure. Overexpressing FAM134B promoted cell proliferation, and reduced EMT and apoptosis following hyperoxia exposure. FAM134B activation increased ER-phagy, decreased apoptosis, improved lung structure damage, and decreased collagen fiber deposition to limit lung injury. These effects could be reversed by PI3K/AKT pathway inhibitor LY294002. Additionally, CeO2-NPs protected RLE-6TN cells and lung damage following hyperoxia exposure by ameliorating impaired ER-phagy. Therefore, FAM134B restoration is a potential therapeutic target for the HALI. Moreover, CeO2-NPs can be used for the treatment of HALI.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Methylobacterium nigriterrae sp. nov., isolated from black soil.

An aerobic, Gram-stain-negative, motile rod bacterium, designated as SYSU BS000021T, was isolated from a black soil sample in Harbin, Heilongjiang province, China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belongs to the genus Methylobacterium, and showed the highest sequence similarity to Methylobacterium segetis KCTC 62267 T (98.51%) and Methylobacterium oxalidis DSM 24028 T (97.79%). Growth occurred at 20-37℃ (optimum, 28 °C), pH 6.0-8.0 (optimum, pH 7.0) and in the presence of 0% (w/v) NaCl. Polar lipids comprised of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminolipid and one unidentified polar lipid. The major cellular fatty acids (> 5%) were C18:0 and C18:1 ω7c and/or C18:1 ω6c. The predominant respiratory quinone was Q-10. The genomic G + C content was 68.36% based on the whole genome analysis. The average nucleotide identity (≤ 83.5%) and digital DNA-DNA hybridization (≤ 27.3%) values between strain SYSU BS000021T and other members of the genus Methylobacterium were all lower than the threshold values recommended for distinguishing novel prokaryotic species. Based on the results of phenotypic, chemotaxonomic and phylogenetic analyses, strain SYSU BS000021T represents a novel species of the genus Methylobacterium, for which the name Methylobacterium nigriterrae sp. nov. is proposed. The type strain of the proposed novel species is SYSU BS000021T (= GDMCC 1.3814 T = KCTC 8051 T).

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Spatial transcriptomics reveals prognosis-associated cellular heterogeneity in the papillary thyroid carcinoma microenvironment.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. METHODS: In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. RESULTS: The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. CONCLUSIONS: The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.

CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: CD70 is commonly overexpressed in renal cell carcinoma and is minimally expressed in normal human tissue, making it a potential therapeutic target for patients with advanced renal cell carcinoma. The expression frequency of CD70 in metastatic renal cell carcinoma is not well established. MATERIALS AND METHODS: We assessed CD70 immunohistochemistry in 391 primary renal tumors and 72 metastatic renal cell carcinomas on a tissue microarray including 26 sets of paired primary and metastatic tumors. RESULTS: CD70 was frequently overexpressed in clear cell carcinoma, with a significantly lower expression rate in papillary renal cell carcinoma (P < .0001). No expression of CD70 was detected in other types of renal tumors and normal renal parenchyma. In clear cell renal cell carcinoma, CD70 expression was significantly correlated with hypoxia pathway proteins, corroborating with a recent study suggesting that CD70 is a downstream target gene of hypoxia-inducible factor. While higher expression levels were observed in males and non-Caucasians, CD70 expression was not associated with tumor grade, sarcomatoid differentiation, stage, or cancer-specific survival. Further, analysis of 26 paired primary and metastatic tumors from same individuals revealed a concordance rate of 85%. CONCLUSION: Our findings validated CD70 as a promising therapeutic target for patients with metastatic clear cell renal cell carcinoma. The utility of primary tumor tissue as surrogate samples for metastatic clear cell carcinoma awaits future CD70-targeted clinical trials.

Limbic system plasticity after electroacupuncture intervention in knee osteoarthritis rats.

Knee osteoarthritis (KOA) is characterized by debilitating pain. Electroacupuncture (EA), a traditional Chinese medical therapy, has shown promise in KOA pain management. This study investigated the therapeutic potential of EA in KOA and its impact on limbic system neural plasticity. Sixteen rats were randomly assigned into two groups: EA group and sham-EA group. EA or sham-EA interventions were administered at acupoints ST32 (Futu) and ST36 (Zusanli) for three weeks. Post-intervention resting-state fMRI was scanned, assessing parameters including Amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC) and nodal characterizations of network within limbic system. The results showed that EA was strategically directed towards the limbic system, resulting in discernible alterations in neural activity, FC, and network characteristics. Our findings demonstrate that EA had a significant impact on the limbic system neural plasticity in rats with KOA, presenting a novel nonpharmacological approach for KOA treatment.

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

[Excess Oxygen Supply for Different Time Periods Affect Energy Metabolism in Rat Alveolar Epithelial Type â ¡ Cells].

Objective To observe the effect of excess oxygen supply for different time periods on the mitochondrial energy metabolism in alveolar epithelial type Ⅱ cells. Methods Rat RLE-6TN cells were assigned into a control group (21% O2 for 4 h) and excess oxygen supply groups (95% O2 for 1,2,3,and 4 h,res-pectively).The content of adenosine triphosphate (ATP),the activity of mitochondrial respiratory chain complex V,and the mitochondrial membrane potential were determined by luciferase assay,micro-assay,and fluorescent probe JC-1,respectively.Real-time fluorescence quantitative PCR was employed to determine the mRNA levels of NADH dehydrogenase subunit 1 (ND1),cytochrome b (Cytb),cytochrome C oxidase subunit I (COXI),and adenosine triphosphatase 6 (ATPase6) in the core subunits of mitochondrial respiratory chain complexes Ⅰ,Ⅲ,Ⅳ,and Ⅴ,respectively. Results Compared with the control group,excess oxygen supply for 1,2,3,and 4 h down-regulated the mRNA levels of ND1 (q=24.800,P<0.001;q=13.650,P<0.001;q=9.869,P<0.001;q=20.700,P<0.001),COXI (q=16.750,P<0.001;q=10.120,P<0.001;q=8.476,P<0.001;q=14.060,P<0.001),and ATPase6 (q=22.770,P<0.001;q=15.540,P<0.001;q=12.870,P<0.001;q=18.160,P<0.001).Moreover,excess oxygen supply for 1 h and 4 h decreased the ATPase activity (q=9.435,P<0.001;q=11.230,P<0.001) and ATP content (q=5.615,P=0.007;q=5.029,P=0.005).The excess oxygen supply for 2 h and 3 h did not cause significant changes in ATPase activity (q=0.156,P=0.914;q=3.197,P=0.116) and ATP content (q=0.859,P=0.557;q=1.273,P=0.652).There was no significant difference in mitochondrial membrane potential among the groups (F=0.303,P=0.869). Conclusion Short-term excess oxygen supply down-regulates the expression of the core subunits of mitochondrial respiratory chain complexes and reduces the activity of ATPase,leading to the energy metabolism disorder of alveolar epithelial type Ⅱ cells.

Identifying the Risk Factors for Postoperative Sore Throat After Endotracheal Intubation for Oral and Maxillofacial Surgery.

Objective: To identify risk factors for postoperative sore throat (POST) after general anesthesia in oral and maxillOfacial surgery. Material and Methods: This study is a retrospective cohort design study. We enrolled patients with oral and maxillofacial surgery who underwent endotracheal intubation under general anesthesia in the Stomatology Hospital, Zhejiang University School Of Medicine between April 2020 and April 2021. They were divided into the POST group and the without POST group. The distribution Of various characteristics in the two groups was firstly analyzed. Then, logistic regression analysis was performed to explore the independent predictors for POST occurrence. Following this, logistic regression and random forest models were constructed and their performance was evaluated to predict POST occurrence. Results: A total of 891 participants were enrolled in the study. Female gender and cough during extubation were significantly associated with increased POST occurrence in multivariate analysis (all P <0.05). Stratified logistic regression analysis results showed that the female gender was an independent predictor for POST occurrence in the 4≤age≤14 and 1460 group after adjusting American Society of Anesthesiologists status and throat and lung disease (all P <0.05). The logistic regression model had a similar effect to the random forest model in predicting POST occurrence. Interestingly, the female gender had a higher important weight compared to the cough during extubation. Conclusion: This research reveals female gender and cough during extubation as potential risk factors for POST occurrence, which may provide guidance for the effective prevention of POST in oral and maxillofacial surgery.

Androgen Drives the Expression of SARS-CoV-2 Entry Proteins in Sinonasal Tissue.

Background and objectives: Men have higher morbidity and mortality from COVID-19 than women, possibly due to androgen receptor-regulated viral entry protein expression. This led to a clinical trial of androgen deprivation therapy (ADT), which has not shown a significant benefit in the outcomes among hospitalized male COVID-19 patients. The aim of this study was to explore biological explanations for the failure of ADT to mitigate clinical outcomes in men with severe COVID-19 by assessing the role of androgen in regulating viral entry protein expression in the upper and lower respiratory tract. Methods: Immunohistochemistry was used to assess the expression of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and how it correlated to androgen receptor expression in the sinonasal epithelium, minor salivary glands of the sinus, lacrimal glands, and lungs from mice pretreated with and without castration and ADT as well as the sinonasal epithelium obtained from healthy human donors and hospitalized COVID-19 patients. Results: In murine models, castration and ADT treatment downregulated the expression of TMPRSS2 and ACE2 in the sinonasal epithelium, minor salivary glands of the sinus, and lacrimal glands, but not in the lungs. Correlative analyses using human tissue also showed a potential role of ADT in men during the early sinonasal phase but not in the later lung phase of SARS-CoV-2 infection. Conclusions: Our study suggests a potential benefit of ADT in male patients with early COVID-19 when the virus enters the nasopharynx, but not in those with advanced disease. The downregulation of viral entry proteins in the upper respiratory system following androgen blockade may be a key mechanism for this effect.

[Demographic features and compliance of children with allergic diseases receiving sublingual immunotherapy]. / èˆŒä¸‹å ç–«æ²»ç–—è¿‡æ•æ€§ç–¾ç— æ‚£å„¿çš„äººå£å­¦ç‰¹å¾ä¸Žä¾ä»Žæ€§åˆ†æž.

OBJECTIVES: To study the demographic features of children with allergic diseases receiving standardized sublingual immunotherapy (SLIT) and the influencing factors for the compliance with SLIT. METHODS: A retrospective analysis was performed on the demographic features and follow-up data of 1 789 children with allergic diseases who received SLIT in Children's Hospital of Jiangxi Province from January 1, 2018 to December 31, 2020. The compliance with SLIT and its influencing factors were analyzed. RESULTS: A total of 1 789 children received SLIT, among whom there were 1 271 boys (71.05%) and 518 girls (28.95%), with an age range of 4-14 years. Among these children, 777 (43.43%) had complete compliance with SLIT and 1 012 (56.57%) withdrew from the treatment within one year. Among the 1 012 children, 354 (34.98%) withdrew from the treatment due to self-conscious inconvenient use, 346 (34.19%) withdrew due to unsatisfactory treatment outcome, 253 (25.00%) stopped the treatment due to the improvement in symptoms, and 59 (5.83%) terminated the treatment due to adverse reactions. Withdrawal was mainly observed within 1-4 months after treatment (74.31%, 752/1 012). Girls tended to have a lower compliance rate than boys, and the children with a single disease had a lower compliance rate than those with multiple diseases (P<0.05). The multivariate analysis showed that compared with boys, girls had an increased risk of withdrawal (OR=0.811, 95%CI: 0.658-0.998, P<0.05), and compared with the children with multiple diseases, the children with a single disease were more likely to withdraw from the treatment (OR=1.313, 95%CI: 1.005-1.715, P<0.05). CONCLUSIONS: Children with allergic diseases tend to have poor compliance with SLIT, which is associated with sex and the number of diseases, and the main reasons for withdrawal are self-conscious inconvenient use and unsatisfactory treatment outcome.

Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy.

Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.

Comparison of different sedatives in children before general anaesthesia for selective surgery: A network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: It is estimated that 60% of children undergoing anaesthesia develop severe preoperative anxiety. The anxiety is associated with adverse reactions. Sedatives such as dexmedetomidine, midazolam, clonidine, ketamine, and melatonin can be used as premedication against preoperative anxiety. However, no consensus has been reached on the choice of pre-anaesthetic sedatives in children before selective surgery. Therefore, the current network meta-analysis (NMA) was carried out to evaluate different sedatives in children aged between 1 and 7 before general anaesthesia for selective surgery. METHODS: Randomized clinical trials (RCTs) were retrieved from Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases from inception to October 22, 2021. Primary outcomes showed satisfactory sedation at parent separation and also at induction or mask acceptance. Secondary outcomes were those related to added benefits and side effects. The present NMA was conducted using the R software. Results of the study were reported as Relative Risk (RR) or Mean Difference (MD) at a 95% credible intervals (CrIs). RESULTS AND DISCUSSION: A total of 48 trials were included in the present study. It was found that the effectiveness of dexmedetomidine, midazolam, clonidine, and ketamine were superior to that of placebo in satisfactory sedation at parent separation and induction or mask acceptance. There was no significant difference between melatonin and placebo in satisfactory sedation at induction or mask acceptance. Dexmedetomidine, ketamine, clonidine, and melatonin were superior to placebo in reducing emergence delirium (ED). In addition, midazolam prolonged the length of stay in the post anaesthesia care unit (PACU) as compared with placebo. Dexmedetomidine caused a significant reduction in systolic blood pressure (SBP) and heart rate (HR). Nevertheless, it was noted that the hemodynamic changes were roughly within safety limits. WHAT IS NEW AND CONCLUSION: It was evident that the studied drugs can provide effective sedation with exception of melatonin and placebo. However, it was found that midazolam, ketamine, and clonidine lead to several side effects. The findings of the present study supported that dexmedetomidine, especially intranasal administration, has potential in the optimal selection of the sedatives for premedication in children. This is because the drug has effective sedation, reduced incidence of ED, side effects, and onset time.