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Abstract Mitochondria, responsible for cellular energy synthesis and signal transduction, intricately regulate diverse metabolic processes, mediating fundamental biological phenomena such as cell growth, aging, and apoptosis. Tumor invasion and metastasis, key characteristics of malignancies, significantly impact patient prognosis. Tumor cells frequently exhibit metabolic abnormalities in mitochondria, including alterations in metabolic dynamics and changes in the expression of relevant metabolic genes and associated signal transduction pathways. Recent investigations unveil further insights into mitochondrial metabolic abnormalities, revealing their active involvement in tumor cell proliferation, resistance to chemotherapy, and a crucial role in tumor cell invasion and metastasis. This paper comprehensively outlines the latest research advancements in mitochondrial structure and metabolic function. Emphasis is placed on summarizing the role of mitochondrial metabolic abnormalities in tumor invasion and metastasis, including alterations in the mitochondrial genome (mutations), activation of mitochondrial-to-nuclear signaling, and dynamics within the mitochondria, all intricately linked to the processes of tumor invasion and metastasis. In conclusion, the paper discusses unresolved scientific questions in this field, aiming to provide a theoretical foundation and novel perspectives for developing innovative strategies targeting tumor invasion and metastasis based on mitochondrial biology. Graphical Abstract

Abstract Background In China, economic, urbanization, and policy differences between the eastern and western regions lead to uneven healthcare resources. This disparity is more pronounced in the west due to fewer healthcare personnel per thousand individuals and imbalanced doctor-to-nurse ratios, which exacerbates healthcare challenges. This study examines the spatial distribution of human resources in maternal and child healthcare from 2016 to 2021, highlighting regional disparities and offering insights for future policy development. Methods The data were sourced from the “China Health and Family Planning Statistical Yearbook” (2017) and the “China Health and Health Statistics Yearbook” (2018–2022). This study utilized GeoDa 1.8.6 software to conduct both global and local spatial autocorrelation analyses, using China’s administrative map as the base dataset. Results From 2016 to 2021, there was an upward trend in the number of health personnel and various types of health technical personnel in Chinese maternal and child healthcare institutions. The spatial distribution of these personnel from 2016 to 2021 revealed clusters characterized as high-high, low-low, high-low and low-high. Specifically, high-high clusters were identified in Guangxi, Hunan, Jiangxi, and Guangdong provinces; low-low in Xinjiang Uygur Autonomous Region and Inner Mongolia Autonomous Region; high-low in Sichuan province; and low-high in Fujian and Anhui provinces. Conclusions From 2016 to 2021, there was evident spatial clustering of health personnel and various health technical personnel in Chinese maternal and child healthcare institutions, indicating regional imbalances.

Abstract Background Prior studies have suggested a potential relationship between osteoporosis and sarcopenia, both of which can present symptoms of compromised mobility. Additionally, fractures among the elderly are often considered a common outcome of both conditions. There is a strong correlation between fractures in the elderly population, decreased muscle mass, weakened muscle strength, heightened risk of falls, and diminished bone density. This study aimed to pinpoint crucial diagnostic candidate genes for osteoporosis patients with concomitant sarcopenia. Methods Two osteoporosis datasets and one sarcopenia dataset were obtained from the Gene Expression Omnibus (GEO). Differential expression genes (DEGs) and module genes were identified using Limma and Weighted Gene Co-expression Network Analysis (WGCNA), followed by functional enrichment analysis, construction of protein–protein interaction (PPI) networks, and application of a machine learning algorithm (least absolute shrinkage and selection operator (LASSO) regression) to determine candidate hub genes for diagnosing osteoporosis combined with sarcopenia. Receiver operating characteristic (ROC) curves and column line plots were generated. Results The merged osteoporosis dataset comprised 2067 DEGs, with 424 module genes filtered in sarcopenia. The intersection of DEGs between osteoporosis and sarcopenia module genes consisted of 60 genes, primarily enriched in viral infection. Through construction of the PPI network, 30 node genes were filtered, and after machine learning, 7 candidate hub genes were selected for column line plot construction and diagnostic value assessment. Both the column line plots and all 7 candidate hub genes exhibited high diagnostic value (area under the curve ranging from 1.00 to 0.93). Conclusion We identified 7 candidate hub genes (PDP1, ALS2CL, VLDLR, PLEKHA6, PPP1CB, MOSPD2, METTL9) and constructed column line plots for osteoporosis combined with sarcopenia. This study provides reference for potential peripheral blood diagnostic candidate genes for sarcopenia in osteoporosis patients.

Abstract Objective To develop an AI-assisted MRI model to identify surgical target areas in pediatric hip and periarticular infections. Methods A retrospective study was conducted on the pediatric patients with hip and periarticular infections who underwent Magnetic Resonance Imaging(MRI)examinations from January 2010 to January 2023 in three hospitals in China. A total of 7970 axial Short Tau Inversion Recovery (STIR) images were selected, and the corresponding regions of osteomyelitis (label 1) and abscess (label 2) were labeled using the Labelme software. The images were randomly divided into training group, validation group, and test group at a ratio of 7:2:1. A Mask R-CNN model was constructed and optimized, and the performance of identifying label 1 and label 2 was evaluated using receiver operating characteristic (ROC) curves. Calculation of the average time it took for the model and specialists to process an image in the test group. Comparison of the accuracy of the model in the interpretation of MRI images with four orthopaedic surgeons, with statistical significance set at P

Abstract Pulmonary hypertension (PH) is regarded as cardiovascular disease with an extremely poor prognosis, primarily due to irreversible vascular remodeling. Despite decades of research progress, the absence of definitive curative therapies remains a critical challenge, leading to high mortality rates. Recent studies have shown that serious metabolic disorders generally exist in PH animal models and patients of PH, which may be the cause or results of the disease. It is imperative for future research to identify critical biomarkers of metabolic dysfunction in PH pathophysiology and to uncover metabolic targets that could enhance diagnostic and therapeutic strategies. Metabolomics offers a powerful tool for the comprehensive qualitative and quantitative analysis of metabolites within specific organisms or cells. On the basis of the findings of the metabolomics research on PH, this review summarizes the latest research progress on metabolic pathways involved in processes such as amino acid metabolism, carbohydrate metabolism, lipid metabolism, and nucleotide metabolism in the context of PH.

Abstract Background Anesthesia techniques and drug selection may influence tumor recurrence and metastasis. Neutrophil extracellular trapping (NETosis), an immunological process, has been linked to an increased susceptibility to metastasis in individuals with tumors. Furthermore, recurrence may be associated with vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis. This study investigates the impact of lidocaine (combined with sevoflurane or propofol anesthesia ) during breast cancer surgery inhibits the expression of biomarkers associated with metastasis and recurrence (specifically H3Cit, NE, MPO, MMP-9 and VEGF-A). Methods We randomly assigned 120 women undergoing primary or invasive breast tumor resection to receive one of four anesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Blood samples were collected before induction and 3 h after the operation. Biomarkers associated with NETosis (citrullinated histone H3 [H3Cit], myeloperoxidase [MPO], and neutrophil elastase [NE]) and angiogenesis were quantified using enzyme-linked immunosorbent assays. Results Patient and breast tumor characteristics, along with perioperative management, did not differ between study groups. In intra-group comparisons, S and P groups demonstrated a statistically significant increase in post-operative MPO (S group: 10.39[6.89–17.22] vs. 14.31[8.55–20.87] ng ml-1, P = 0.032; P group: 9.45[6.73–17.37] vs. 14.34[9.87–19.75] ng ml-1, P = 0.035)and NE(S group: 182.70[85.66-285.85] vs. 226.20[91.85-391.65] ng ml-1, P = 0.045; P group: 154.22[97.31–325.30] vs. 308.66[132.36-483.57] ng ml-1, P = 0.037) concentrations compared to pre-operative measurements, whereas SL and PL groups did not display a similar increase. H3Cit, MMP-9, and VEGF-A concentrations were not significantly influenced by the anesthesia techniques and drugs. Conclusions Regardless of the specific technique employed for general anesthesia, there was no increase in the postoperative serum concentrations of MPO and NE after perioperative lidocaine infusion compared to preoperative serum concentrations. This supports the hypothesis that intravenous lidocaine during cancer surgery aimed at achieving a cure may potentially decrease the likelihood of recurrence. Further interpretation and discussion of clinical implications are warranted, emphasizing the significance of these findings in the context of cancer surgery and recurrence prevention. Clinical trial registration ChiCTR2300068563.

Abstract Background Olfactory dysfunction occurs frequently in Parkinson’s disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. Methods MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R−) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines. Results Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R− HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis. Conclusions This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.

Abstract Chryseobacterium arthrosphaerae strain FS91703 was isolated from Rana nigromaculata in our previous study. To investigate the genomic characteristics, pathogenicity-related genes, antimicrobial resistance, and phylogenetic relationship of this strain, PacBio RS II and Illumina HiSeq 2000 platforms were used for the whole genome sequencing. The genome size of strain FS91703 was 5,435,691 bp and GC content was 37.78%. A total of 4,951 coding genes were predicted; 99 potential virulence factors homologs were identified. Analysis of antibiotic resistance genes revealed that strain FS91703 harbored 10 antibiotic resistance genes in 6 categories and 2 multidrug-resistant efflux pump genes, including adeG and farA. Strain FS91703 was sensitive to β-lactam combination drugs, cephem, monobactam and carbapenems, intermediately resistant to phenicol, and resistant to penicillin, aminoglycosides, tetracycline, fluoroquinolones, and folate pathway inhibitors. Phylogenetic analysis revealed that strain FS91703 and C. arthrosphaerae CC-VM-7T were on the same branch of the phylogenetic tree based on 16 S rRNA; the ANI value between them was 96.99%; and the DDH values were 80.2, 72.2 and 81.6% by three default calculation formulae. These results suggested that strain FS91703 was a species of C. arthrosphaerae. Pan-genome analysis showed FS91703 had 566 unique genes compared with 13 other C. arthrosphaerae strains, and had a distant phylogenetic relationship with the other C. arthrosphaerae strains of the same branch in phylogenetic tree based on orthologous genes. The results of this study suggest that strain FS91703 is a multidrug-resistant and highly virulent bacterium, that differs from other C. arthrosphaerae strains at the genomic level. The knowledge about the genomic characteristics and antimicrobial resistance of strain FS91703 provides valuable insights into this rare species, as well as guidance for the treatment of the disease caused by FS91703 in Rana nigromaculata.

Abstract Gastrointestinal cancer, one of the most common cancers, continues to be a major cause of mortality and morbidity globally. Accumulating evidence has shown that alterations in mitochondrial energy metabolism are involved in developing various clinical diseases. NADH dehydrogenase 1 alpha subcomplex 4 (NDUFA4), encoded by the NDUFA4 gene located on human chromosome 7p21.3, is a component of mitochondrial respiratory chain complex IV and integral to mitochondrial energy metabolism. Recent researchers have disclosed that NDUFA4 is implicated in the pathogenesis of various diseases, including gastrointestinal cancer. Aberrant expression of NDUFA4 leads to the alteration in mitochondrial energy metabolism, thereby regulating the growth and metastasis of cancer cells, indicating that it might be a new promising target for cancer intervention. This article comprehensively reviews the structure, regulatory mechanism, and biological function of NDUFA4. Of note, the expression and roles of NDUFA4 in gastrointestinal cancer including colorectal cancer, liver cancer, gastric cancer, and so on were discussed. Finally, the existing problems of NDUFA4-based intervention on gastrointestinal cancer are discussed to provide help to strengthen the understanding of the carcinogenesis of gastrointestinal cancer, as well as the development of new strategies for clinical intervention.

Abstract Background Kawasaki disease shock syndrome (KDSS), though rare, has increased risk for cardiovascular complications. Early diagnosis is crucial to improve the prognosis of KDSS patients. Our study aimed to identify risk factors and construct a predictive model for KDSS. Methods This case-control study was conducted from June, 2015 to July, 2023 in two children’s hospitals in China. Children initially diagnosed with KDSS and children with Kawasaki disease (KD) without shock were matched at a ratio of 1:4 by using the propensity score method. Laboratory results obtained prior to shock syndrome and treatment with intravenous immunoglobulin were recorded to predict the onset of KDSS. Univariable logistic regression and forward stepwise logistic regression were used to select significant and independent risk factors associated with KDSS. Results After matching by age and gender, 73 KDSS and 292 KD patients without shock formed the development dataset; 40 KDSS and 160 KD patients without shock formed the validation dataset. Interleukin-10 (IL-10) > reference value, platelet counts (PLT) 80 mg/ml, procalcitonin (PCT) > 1ng/ml, and albumin (Alb)

Abstract Tumor-infiltrating T cells recognize, attack, and clear tumor cells, playing a central role in antitumor immune response. However, certain immune cells can impair this response and help tumor immune escape. Therefore, exploring the factors that influence T-cell infiltration is crucial to understand tumor immunity and improve therapeutic effect of cancer immunotherapy. The use of single-cell RNA sequencing (scRNA-seq) allows the high-resolution analysis of the precise composition of immune cells with different phenotypes and other microenvironmental factors, including non-immune stromal cells and the related molecules in the tumor microenvironment of various cancer types. In this review, we summarized the research progress on T-cell infiltration and the crosstalk of other stromal cells and cytokines during T-cell infiltration using scRNA-seq to provide insights into the mechanisms regulating T-cell infiltration and contribute new perspectives on tumor immunotherapy.

Abstract Objective This study aimed to explore the characteristics of carbapenem-resistant Enterobacterales (CRE) patients in the intensive care unit (ICU) in different regions of Henan Province to provide evidence for the targeted prevention and treatment of CRE. Methods This was a cross-sectional study. CRE screening was conducted in the ICUs of 78 hospitals in Henan Province, China, on March 10, 2021. The patients were divided into provincial capital hospitals and nonprovincial capital hospitals for comparative analysis. Results This study involved 1009 patients in total, of whom 241 were CRE-positive patients, 92 were in the provincial capital hospital and 149 were in the nonprovincial capital hospital. Provincial capital hospitals had a higher rate of CRE positivity, and there was a significant difference in the rate of CRE positivity between the two groups. The body temperature; immunosuppressed state; transfer from the ICU to other hospitals; and use of enemas, arterial catheters, carbapenems, or tigecycline at the provincial capital hospital were greater than those at the nonprovincial capital hospital (P

Abstract Objective Hypertension caused by vascular Behcet’s disease (BD) is an important prognostic factor of paediatric BD. However, much less is known about its clinical features. The objective of this study was to investigate the clinical characteristics of paediatric vascular BD complicated by hypertension. Methods A retrospective study was carried out in paediatric BD patients complicated by hypertension treated in the Children’s Hospital Capital Institute of Paediatrics from Jan 2009 to Dec 2022. Results Of 65 BD patients, 6 (9.2%) were complicated by hypertension, 5 patients were female, and the median ages of onset and diagnosis were 9.8 years and 11.3 years, respectively. Three patients were found to have cardiac involvement and hypertensive retinopathy secondary to hypertension. Five of the 6 patients with hypertension had right renal artery involvement, and all of them were treated with glucocorticoids and immunosuppressants. Four patients were treated with biological agents. One patient with severe renal artery stenosis underwent unsuccessful vascular interventional therapy. After 3–6 years of follow-up, five patients were found to have renal atrophy, and one patient was at stable condition. Conclusion Hypertension in paediatric BD is mainly caused by renal artery involvement. Early recognition and treatment of vascular involvement in BD is important to prevent poor prognosis.

Abstract Background Abnormal blood potassium levels are associated with an increased risk of cardiometabolic diseases and mortality in the general population; however, evidence regarding the association between dyskalemia and mortality among patients with cardiovascular disease (CVD) remains inconclusive. This study aimed to evaluate the association of potassium levels with all-cause and cardiovascular mortality among patients with CVD. Methods PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to August 2023 to identify relevant cohort studies among patients with CVD, such as myocardial infarction, stroke, and heart failure. Abnormal potassium levels were considered as hypokalemia or hyperkalemia. The primary outcomes were all-cause mortality based on follow-up length (including in-hospital, short-term and long-term mortality) and cardiovascular mortality. The methodological quality of included studies was assessed by using the Newcastle-Ottawa Scale. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Restricted cubic splines were applied to explore the dose-response relationship. Results Thirty-one cohort studies involving 227,645 participants with an average age of 68.3 years were included in the meta-analysis, all of which achieved moderate to high quality. Hyperkalemia was significantly associated with an approximately 3.0-fold increased risk of all-cause in-hospital mortality (RR:2.78,95CI%:1.92,4.03), 1.8-fold of all-cause short-term mortality (RR:1.80, 95CI%:1.44,2.27), 1.3-fold of all-cause long-term mortality (RR:1.33, 95CI%:1.19,1.48) and 1.2-fold of cardiovascular mortality (RR:1.19, 95CI%:1.04,1.36). Similar positive associations were also observed between hypokalemia and risk of all-cause mortality and cardiovascular mortality. The RRs of all-cause in-hospital, short-term, long-term mortality and cardiovascular mortality with hyperkalemia were attenuated to 2.21 (95CI%:1.60,3.06), 1.46(95CI%:1.25,1.71), 1.23 (95CI%:1.09,1.39) and 1.13 (95CI%:1.00,1.27) when treating hypokalemia together with normokalemia as the reference group. A U-shaped association was observed between potassium levels and mortality, with the lowest risk at around 4.2 mmol/L. Conclusions Both hypokalemia and hyperkalemia were positively associated with the risk of mortality in patients with CVD. Our results support the importance of potassium homeostasis for improving the CVD management. Registration PROSPERO, CRD42022324337.

Abstract Dendritic cells (DCs) serve as a pivotal link connecting innate and adaptive immunity by processing tumor-derived antigens and activating T cells. The advent of single-cell sequencing has revolutionized the categorization of DCs, enabling a high-resolution characterization of the previously unrecognized diversity of DC populations infiltrating the intricate tumor microenvironment (TME). The application of single-cell sequencing technologies has effectively elucidated the heterogeneity of DCs present in the tumor milieu, yielding invaluable insights into their subpopulation structures and functional diversity. This review provides a comprehensive summary of the current state of knowledge regarding DC subtypes in the TME, drawing from single-cell studies conducted across various human tumors. We focused on the categorization, functions, and interactions of distinct DC subsets, emphasizing their crucial roles in orchestrating tumor-related immune responses. Additionally, we delve into the potential implications of these findings for the identification of predictive biomarkers and therapeutic targets. Enhanced insight into the intricate interplay between DCs and the TME promises to advance our comprehension of tumor immunity and, in turn, pave the way for the development of more efficacious cancer immunotherapies.

Abstract Background The establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the development of multiple malignancies. However, its role in hypopharyngeal carcinoma (HPC) progression remains uncharacterized. Methods This study employed bioinformatics to determine the ESCO2 expression in head and neck squamous cell carcinoma (HNSC) and normal tissues. In vitro cell proliferation, migration, apoptosis, and/or cell cycle distribution assays were used to determine the function of ESCO2 and its relationship with STAT1. Xenograft models were established in nude mice to determine ESCO2 in HPC growth in vivo. Co-immunoprecipitation/mass spectrometry (Co-IP/MS) was conducted to identify the potential ESCO2 binding partners. Results We found that ESCO2 expression was elevated in HNSC tissues, and ESCO2 depletion suppressed tumor cell migration in vitro and inhibited tumor growth in vitro and in vivo. Co-IP/MS and immunoblotting assays revealed the interaction between ESCO2 and STAT1 in HPC cells. STAT1-overexpression compromised ESCO2-mediated suppressive effects on HPC cell proliferation, viability, and migration. Conclusions These findings suggest that ESCO2 is crucial in promoting HPC malignant progression through the STAT1 pathway and provides novel therapeutic targets for HPC treatment.

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary vascular remodeling which is associated with the malignant phenotypes of pulmonary vascular cells. Recently, the effects of heat shock protein 110 (Hsp110) in human arterial smooth muscle cells were reported. However, the underlying roles and mechanisms of Hsp110 in human pulmonary arterial endothelial cells (HPAECs) that was disordered firstly at the early stage of PAH remain unknown. Methods In this research, the expression of Hsp110 in PAH human patients and rat models was investigated, and the Hsp110 localization was determined both in vivo and in vitro. The roles and mechanism of elevated Hsp110 in excessive cell proliferation and migration of HPAECs were assessed respectively exposed to hypoxia. Small molecule inhibitors targeting Hsp110-STAT3 interaction were screened via fluorescence polarization, anti-aggregation and western blot assays. Moreover, the effects of compound 6 on HPAECs abnormal phenotypes in vitro and pulmonary vascular remodeling of hypoxia-indued PAH rats in vivo by interrupting Hsp110-STAT3 interaction were evaluated. Results Our studies demonstrated that Hsp110 expression was increased in the serum of patients with PAH, as well as in the lungs and pulmonary arteries of PAH rats, when compared to their respective healthy subjects. Moreover, Hsp110 levels were significantly elevated in HPAECs under hypoxia and mediated its aberrant phenotypes. Furthermore, boosted Hsp110-STAT3 interaction resulted in abnormal proliferation and migration via elevating p-STAT3 and c-Myc in HPAECs. Notably, we successfully identified compound 6 as potent Hsp110-STAT3 interaction inhibitor, which effectively inhibited HPAECs proliferation and migration, and significantly ameliorated right heart hypertrophy and vascular remodeling of rats with PAH. Conclusions Our studies suggest that elevated Hsp110 plays a vital role in HPAECs and inhibition of the Hsp110-STAT3 interaction is a novel strategy for improving vascular remodeling. In addition, compound 6 could serve as a promising lead compound for developing first-in-class drugs against PAH.

Abstract Background Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. Methods We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. Results Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. Conclusion Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection. Graphic abstract

Abstract Background The association between the oxidative stress gene polymorphism and chronic obstructive pulmonary disease (COPD) risk has been extensively studied but the results have been controversial. This study aimed to investigate the overall association between the oxidative stress gene including glutathione S-transferase (GST), epoxide hydrolase exon (EPHX), superoxide dismutase (SOD), catalase (CAT), cytochrome P450 system (CYP) and heme oxygenase (HO-1) polymorphism and the risk of COPD. Methods We searched the PubMed and EMBASE database to identify studies that investigated the association between the oxidative stress gene polymorphism and risk of COPD. The relevant data were extracted and statistical analyses were performed using the Revman 5.4 and STATA 12 software. Dominant genetic model, recessive model, co-dominant model, heterozygote model, and allele model were analyzed. Venice criteria and publication bias were conducted to access the credibility and reliability. Results In total, 63 publications including 14,733 patients and 50,570 controls were included in the meta-analysis.15 genetic variants of 6 genes were analyzed, and 7 SNPs in GSTP1, CAT, CYP, SOD were first analyses until now. In our study, EPHX T113C C allele, GSTM1 null, GSTT1 null, GSTP1 A313G G and C341T T allele, CYP1A1 MspI C allele, SOD3 A213G G allele and L type in Ho-1 showed increased COPD risk, especially in Asians. T allele in CAT C262T and C allele in SOD2 Val 9 Ala were associated with decreased COPD risk. To avoid high heterogeneity and publications bias, subgroups analysis was performed in accord with HWE and ethnicity. Publication bias was assessed by Begg’s funnel plots and Egger’s test, and no publication bias were found for recessive models. 4 variants were identified with strong levels of epidemiological evidence of associations with the COPD risk. Conclusions Our results confirm that oxidative stress gene polymorphism was associated with COPD risk. These finding can improve human understanding of this disease gene molecular level and enable early intervention and prevention of COPD. Well-designed studies with large sample sizes are essential to clarify the association of these significant variants with the susceptibility to COPD.

Abstract Background Human immunodeficiency virus type one (HIV-1) is the leading cause of acquired immunodeficiency syndrome (AIDS). AIDS remains a global public health concern but can be effectively suppressed by life-long administration of combination antiretroviral therapy. Early detection and diagnosis are two key strategies for the prevention and control of HIV/AIDS. Rapid and accurate point-of-care testing (POCT) provides critical tools for managing HIV-1 epidemic in high-risk areas and populations. Methods In this study, a POCT for HIV-1 RNA was developed by CRISPR-Cas13a lateral flow strip combined with reverse transcriptase recombinase-aided amplification (RT-RAA) technology, the results can be directly observed by naked eyes. Results Moreover, with the degenerate base-binding CRISPR-Cas13a system was introduced into the RT-RAA primer designing, the technology developed in this study can be used to test majority of HIV-1 RNA with limit of detection (LOD) 1 copy/μL, while no obvious cross-reaction with other pathogens. We evaluated this method for detecting HIV-1 RNA of clinical samples, the results showed that the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 91.81% (85.03- 96.19%), 100% (92.60–100%), 100% (96.41–100%), 39.14% (25.59–54.60%) and 92.22% (86.89–95.88%), respectively. The lowest viral load detectable by this method was 112copies/mL. Conclusion Above all, this method provides a point-of-care detection of HIV-1 RNA, which is stable, simple and with good sensitivity and specificity. This method has potential to be developed for promoting early diagnosis and treatment effect monitoring of HIV patients in clinical.

Abstract Background Currently, there is a lack of research investigating the feasibility of employing anterograde lag screw fixation through the iliac crest for minimally invasive percutaneous treatment of the posterior acetabular column, which encompasses retrograde and anterograde screw fixation in posterior acetabular lag screw fixation. And consequently, the purpose of this study was to examine the anatomical parameters of anterograde lag screw fixation of the posterior column of the pelvis through the iliac crest as well as to investigate the intraoperative fluoroscopy technique, to furnish a scientific rationale supporting the practical utilization of this method within clinical settings. Methods In this study, pelvic CT data of 60 healthy adults, including 30 males and 30 females, were accumulated. The mimics 21.0 software was developed to reconstruct the three-dimensional pelvis model, simulate the anterograde lag screw fixation of the posterior column of the acetabulum through use of the iliac crest, and precisely identify the insertion point: Utilizing the widest iliac tubercle as the starting point, the insertion point was moved toward the anterior superior iliac spine by 1.0 cm at a time until it reached 4.0 cm. With a total of five insertion points, all oriented toward the lesser sciatic notch, the initial diameter of the virtual screw measured 5.0 mm, and it was progressively enlarged by 1.0 mm increments until reaching a final diameter of 8.0 mm. Besides, the longest lengths of virtual screws with distinct diameters at divergent entry points were measured and compared. At the same time, the intraoperative fluoroscopy technique for optimal access was analyzed. Results The cross-section from the iliac crest to the lesser sciatic notch was irregular, with multiple curved shapes. Furthermore, the diameter of the screw was determined by the anteroposterior radians and width of the iliac crest plate, while the screw length was determined by the curvature of the square body. On the condition that the screw diameter of the D channel (3.0 cm outward from the widest part of the iliac tubercle to the lesser sciatic notch) was 5 mm, 6 mm as well as 7 mm, the longest screw lengths were (145.6 ± 12.8) mm, (143.6 ± 14.4) mm and (139.9 ± 16.6) mm, correspondingly, indicating statistically substantial distinctions from other channels (P

Abstract Background The coronavirus disease 2019 outbreak has hit Beijing since mid-Nov, 2022, with soaring growth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children. Therefore, it is vital to determine the clinical manifestations of epidemic SARS-CoV-2 strains in paediatric patients. Methods In this study, nucleic acid tests (NATs) for SARS-CoV-2 were performed in paediatric outpatients with symptoms of acute respiratory tract infection during 18 Nov–6 Dec, 2022. Half of the outpatients positive for SARS-CoV-2 were randomly selected to screen for other respiratory pathogens, whereas those with low cycle threshold values in SARS-CoV-2 NATs were amplified and sequenced to determine the SARS-CoV-2 variants. Finally, children positive for SARS-CoV-2 with clinical information in detail were enrolled in a follow-up study to identify potential factors significantly associated with long recovery. Results Among 9625 paediatric outpatients tested for nucleic acid of SARS-CoV-2, 733 (7.62%, 733/9625) were identified as SARS-CoV-2 NAT positive, with only three (0.82%, 3/366) co-infected with other pathogens among 366 randomly selected patients, and 71 (62.83%) determined as Omicron subvariant BF.7 and 42 (37.22%) as BA.5.2 among 113 successfully sequenced. Among the 681 patients with complete clinical information, fever was the most common symptom (96.8%). In a follow-up study of 592 patients, 46.96% became asymptomatic on the third day and 65.71% on the fifth day. Only 1.7% of infected children experienced febrile seizures. Combined with abnormal C-reactive protein, a higher percentage of antibiotics administration was observed. More co-living members and longer duration of first symptoms served as independent risk factors for long-term recovery, especially in children vaccinated for SARS-CoV-2. Conclusions BF.7 and BA.5.2 were the dominate Omicron subvariants and caused milder infections during the SARS-CoV-2 outbreak in Beijing. The number of co-living members and duration of first symptoms were independent risk factors for long-term recovery.

Abstract Background Despite multiple attempts have been made to develop risk stratification within high-risk neuroblastoma (NB) patients (age of diagnosis ≥ 18 month-old with metastatic NB), the definition of “ultra high-risk NB” is still lack of consensus, and indicators for identifying this subgroup are still unclear. This study aimed to develop a nomogram based on easy-to-obtain blood-derived biofactors for identifying ultra high-risk NB patients with highest risk of death within 3 or 5 years. Methods One hundred sixty-seven NB patients who treated at Sun Yat-sen University Cancer Center between 2015 and 2023 were recruited and clustered randomly into training and validation cohorts (116 and 51 cases, respectively). Univariate and multivariate Cox analysis were performed in training set to screen independent prognostic indicators for constructing nomogram model of predicting 1-, 3- and 5-year overall survival (OS). The discrimination power of the nomogram in training and validation sets were assessed by concordance index (C-index) and calibration plot. Based on the risk score obtained from nomogram model, the prognostic accuracy of 1-, 3- and 5-year OS rates in training and validation cohorts were further evaluated using the area under receiver operating characteristic (ROC) curves (AUC). Results Through univariate and multivariate Cox analysis, independent prognostic indicators, including serum lactate dehydrogenase (LDH) and albumin (ALB), were identified in training set, and used to establish a nomogram model. The model showed good discrimination power with C-index in training cohort being 0.706 (95%CI: 0.633—0.788). According to the cut-point calculated based on the established nomogram, patients with a nomogram score > 34 points could be stratified to ultra high-risk NB subgroup, and this subgroup had poorer OS than those in non-ultra one (p

Abstract Background Postoperative cognitive dysfunction (POCD) is a common postoperative disorder that is frequently observed after general anesthesia, which seriously threatens the quality of patients’ life. Existing studies have demonstrated that S-ketamine plays an important role in improving neuroinflammation. This trial aimed to explore the effects of S-ketamine on quality of recovery and cognitive function in patients following modified radical mastectomy (MRM). Methods Ninety patients aged 45 to 70 years with ASA grades of I or II, who underwent MRM, were selected. Patients were randomly assigned to the S-ketamine or control group. In the S-ketamine group, patients were induced with S-ketamine instead of sufentanil and maintained with S-ketamine and remifentanil. In the control group, patients were induced with sufentanil and maintained with remifentanil. The primary outcome was the Mini-Mental State Examination (MMSE) and Quality of Recovery-15 (QoR-15) score. Secondary outcomes including visual analog scale (VAS) score, cumulative propofol and opioids consumption, post anesthesia care unit (PACU) recovery time, occurrence of remedial analgesia, postoperative nausea and vomiting (PONV), other adverse events, as well as patient satisfaction. Results The global QoR-15 scores at postoperative day 1 (POD1) were significantly higher in the S-ketamine group than in the control group (124 [119.5–128.0] vs. 119 [114.0–123.5], P = 0.002), with a median difference of 5 points (95% confidence interval [CI] [-8 to -2]). Similarly, the global QoR-15 scores at postoperative day 2 (POD2) in the S-ketamine group were significantly higher than in the control group (140.0 [133.0–145.0] vs. 132.0 [126.5–141.5], P = 0.004). In addition, among the five subcomponents of the 15-item scale, S-ketamine group had a higher score in terms of physical comfort, pain, and emotional state both at POD1 and POD2. In terms of MMSE score, S-ketamine could promote the recovery of postoperative cognitive function at POD1, but not at POD2. Furthermore, the consumption of opioids, VAS score, and remedial analgesia in the S-ketamine group decreased significantly. Conclusions Collectively, our findings support that general anesthesia with S-ketamine as a potential strategy showed high safety and could not only improve the quality of recovery mainly through improving pain, physical comfort, and emotional state but also promote the recovery of cognitive function on POD1 in patients undergoing MRM. Trial registration The study was registered in the Chinese Clinical Trial Registry (registration No:ChiCTR2200057226, Date of registration: 04/03/2022).

Abstract Background We have previously demonstrated that ginsenoside compound K can attenuate the formation of atherosclerotic lesions. Therefore, ginsenoside compound K has potential for atherosclerosis therapy. How to improve the druggability and enhance the antiatherosclerotic activity of ginsenoside compound K are the core problems in the prevention and treatment of atherosclerosis. CKN is a ginsenoside compound K derivative that was previously reported to have excellent antiatherosclerotic activity in vitro, and we have applied for international patents for it. Methods Male C57BL/6 ApoE−/− mice were fed a high-fat and high-choline diet to induce atherosclerosis and were subjected to in vivo studies. In vitro, the CCK-8 method was applied to evaluate cytotoxicity in macrophages. Foam cells were utilized, and cellular lipid determination was performed for in vitro studies. The area of atherosclerotic plaque and fatty infiltration of the liver were measured by image analysis. Serum lipid and liver function were determined by a seralyzer. Immunofluorescence and western blot analysis were conducted to explore the alterations in the expression levels of lipid efflux-related proteins. Molecular docking, reporter gene experiments and cellular thermal shift assays were used to verify the interaction between CKN and LXRα. Results After confirming the therapeutic effects of CKN, molecular docking, reporter gene experiments and cellular thermal shift assays were used to predict and investigate the antiatherosclerotic mechanisms of CKN. CKN exhibited the greatest potency, with a 60.9% and 48.1% reduction in en face atherosclerotic lesions on the thoracic aorta and brachiocephalic trunk, reduced plasma lipid levels and decreased foam cell levels in the vascular plaque content in HHD-fed ApoE−/− mice. Moreover, CKN in the present study may exert its antiatherosclerotic effects through activated ABCA1 by promoting LXRα nuclear translocation and reducing the adverse effects of LXRα activation. Conclusions Our results revealed that CKN prevented the formation of atherosclerosis in ApoE−/− mice by activating the LXRα pathway.

Abstract Backgroud To summarize the clinical characteristics and identify the risk factors for pediatric Takayasu arteritis (TAK) with coronary artery lesions (CALs). Methods Clinical data of pediatric TAK patients in our center were retrospectively assessed. Independent risk factors for CALs were identified using multivariate logistic regression analysis. Survival analysis was used to compare differences in survival rates between the groups. Results Among the 66 pediatric TAK cases, the incidence of accompanying CALs was 39.4%. In the CAL group, 19 (73.1%) cases started within 36 months. None of the patients had symptoms of angina or ischemia on electrocardiogram (ECG), the CALs were detected using coronary ultrasound. The CALs most commonly were the left main and right coronary arteries. The lesions were mostly small or middle coronary artery aneurysms; some children may have giant coronary aneurysmal dilations, thrombosis and heart failure. The age of onset and symptom onset to diagnosis in TAK patients with CAL were lower than those in TAK patients without CAL(P

Abstract Background Mitochondrial quality control (MQC) plays a critical role in the progression of tubulointerstitial injury in diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt), which is an important MQC process, is activated to maintain mitochondrial protein homeostasis in response to mitochondrial stress. Activating transcription factor 5 (ATF5) is critical in the mammalian UPRmt via mitochondria-nuclear translocation. However, the role of ATF5 and UPRmt in tubular injury under DKD conditions is unknown. Methods ATF5 and UPRmt-related proteins including heat shock protein 60 (HSP60) and Lon peptidase 1 (LONP1), in DKD patients and db/db mice were examined by immunohistochemistry (IHC) and western blot analysis. Eight-week-old db/db mice were injected with ATF5-shRNA lentiviruses via the tail vein, and a negative lentivirus was used as a control. The mice were euthanized at 12 weeks, and dihydroethidium (DHE) and TdT-mediated dUTP nick end labeling (TUNEL) assays were performed to evaluate reactive oxygen species (ROS) production and apoptosis in kidney sections, respectively. In vitro, ATF5-siRNA, ATF5 overexpression plasmids or HSP60-siRNA were transfected into HK-2 cells to evaluate the effect of ATF5 and HSP60 on tubular injury under ambient hyperglycemic conditions. Mitochondrial superoxide (MitoSOX) staining was used to gauge mitochondrial oxidative stress levels, and the early stage of cell apoptosis was examined by Annexin V-FITC kits. Results Increased ATF5, HSP60 and LONP1 expression was observed in the kidney tissue of DKD patients and db/db mice and was tightly correlated with tubular damage. The inhibition of HSP60 and LONP1, improvements in serum creatinine, tubulointerstitial fibrosis and apoptosis were observed in db/db mice treated with lentiviruses carrying ATF5 shRNA. In vitro, the expression of ATF5 was increased in HK-2 cells exposed to high glucose (HG) in a time-dependent manner, which was accompanied by the overexpression of HSP60, fibronectin (FN) and cleaved-caspase3 (C-CAS3). ATF5-siRNA transfection inhibited the expression of HSP60 and LONP1, which was accompanied by reduced oxidative stress and apoptosis in HK-2 cells exposed to sustained exogenous high glucose. ATF5 overexpression exacerbated these impairments. HSP60-siRNA transfection blocked the effect of ATF5 on HK-2 cells exposed to continuous HG treatment. Interestingly, ATF5 inhibition exacerbated mitochondrial ROS levels and apoptosis in HK-2 cells in the early period of HG intervention (6 h). Conclusions ATF5 could exert a protective effect in a very early stage but promoted tubulointerstitial injury by regulating HSP60 and the UPRmt pathway under DKD conditions, providing a potential target for the prevention of DKD progression.

Abstract Background IgA nephropathy (IgAN) has become the leading cause of end-stage renal disease in young adults. Nevertheless, the current diagnosis exclusively relies on invasive renal biopsy, and specific treatment is deficient. Thus, our study aims to identify potential crucial genes, thereby providing novel biomarkers for the diagnosis and therapy of IgAN. Methods Three microarray datasets were downloaded from GEO official website. Differentially expressed genes (DEGs) were identified by limma package. GO and KEGG analysis were conducted. Tissue/organ-specific DEGs were distinguished via BioGPS. GSEA was utilized to elucidate the predominant enrichment pathways. The PPI network of DEGs was established, and hub genes were mined through Cytoscape. The CTD database was employed to determine the association between hub genes and IgAN. Infiltrating immune cells and their relationship to hub genes were evaluated based on CIBERSORT. Furthermore, the diagnostic effectiveness of hub markers was subsequently predicted using the ROC curves. The CMap database was applied to investigate potential therapeutic drugs. The expression level and diagnostic accuracy of TYROBP was validated in the cell model of IgAN and different renal pathologies. Results A total of 113 DEGs were screened, which were mostly enriched in peptidase regulator activity, regulation of cytokine production, and collagen-containing extracellular matrix. Among these DEGs, 67 genes manifested pronounced tissue and organ specificity. GSEA analysis revealed that the most significant enriched gene sets were involved in proteasome pathway. Ten hub genes (KNG1, FN1, ALB, PLG, IGF1, EGF, HRG, TYROBP, CSF1R, and ITGB2) were recognized. CTD showed a close connection between ALB, IGF, FN1 and IgAN. Immune infiltration analysis elucidated that IGF1, EGF, HRG, FN1, ITGB2, and TYROBP were closely associated with infiltrating immune cells. ROC curves reflected that all hub genes, especially TYROBP, exhibited a good diagnostic value for IgAN. Verteporfin, moxonidine, and procaine were the most significant three therapeutic drugs. Further exploration proved that TYROBP was not only highly expressed in IgAN, but exhibited high specificity for the diagnosis of IgAN. Conclusions This study may offer novel insights into the mechanisms involved in IgAN occurrence and progression and the selection of diagnostic markers and therapeutic targets for IgAN.

Abstract Background Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. Methods First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. Results Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. Conclusions Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.

Abstract Background Frailty has been considered to be associated with major mortality and increased length of stay after cardiac surgery. This study aimed to explore the predictive potential of frailty assessment in the prognosis of elderly patients undergoing bypass surgery. Methods This study assessed the preoperative frailty according to the Fried’s frailty phenotype, and included 150 frail and 150 non-frail elderly patients (≥ 65 y) who underwent bypass surgery. The present study evaluated the prognosis of elderly patients based on sequential organ failure assessment (SOFA) score, and collected clinical indicators to construct logistic regression models with the prognosis as the dependent variable, to explore the potential predictive ability of preoperative frailty. Moreover, this study focused on the complications and analyzed the relationship between preoperative frailty and postoperative complications. Results In the present study, 244 patients were divided into the favorable prognosis group and 56 patients were divided into the unfavorable prognosis group. Logistic regression analysis showed that increased myoglobin and high cardiac function classification were independent risk factors for unfavorable prognosis in elderly patients undergoing bypass surgery. The discrimination of the clinical prediction model was determined by the receiver operating characteristic (ROC) curve, and the area under curve (AUC) was 0.928. After adding preoperative frailty assessment, the AUC was improved to 0.939. This study found a significant correlation between preoperative frailty and postoperative complications, mainly in the circulatory system. Conclusion Preoperative frailty assessment could be a predictive factor for the prognosis of elderly patients undergoing coronary artery bypass grafting. According to our study, frailty assessment and appropriate intervention before bypass surgery may be beneficial to the enhanced recovery after cardiac surgery. Trial registration The clinical study was approved by the Medical Ethics Committee of The First Affiliated Hospital of Nanjing Medical University (2021-SR-393). All patients signed an informed consent form.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Background The age of glioma plays a unique role in prognosis. We hypothesized that age is not positively correlated with survival prognosis and explored its exact relationship. Methods Glioma was identified from the SEER database (between 2000 and 2018). A multivariate Cox proportional regression model and restricted cubic spline (RCS) plot were used to assess the relationship between age and prognosis. Results A total of 66465 patients with glioma were included. Hazard ratios (HR) for ten-year by age: 0–9 years, HR 1.06 (0.93–1.20); 10–19 years: reference; 20–29 years, HR 0.90 (0.82–1.00); 30–39 years, HR 1.14 (1.04–1.25); 40–49 years, HR 2.09 (1.91–2.28); 50–59 years, HR 3.48 (3.19–3.79); 60–69 years, HR 4.91 (4.51–5.35);70–79 years, HR 7.95 (7.29–8.66); 80–84 years, HR 12.85 (11.74–14.06). After adjusting for covariates, the prognosis was not positively correlated with age. The smooth curve of RCS revealed this non-linear relationship: HR increased to 10 years first, decreased to 23 years, reached its lowest point, and became J-shaped. Conclusion The relationship between age and glioma prognosis is non-linear. These results challenge the applicability of current age groupings for gliomas and advocate the consideration of individualized treatment guided by precise age.

Abstract Background The prognosis of non-small cell lung cancer (NSCLC) with brain metastases (BMs) had been researched in some researches, but the combination of clinical characteristics and serum inflammatory indexes as a noninvasive and more accurate model has not been described. Methods We retrospectively screened patients with BMs at the initial diagnosis of NSCLC at Sun Yat-Sen University Cancer Center. LASSO-Cox regression analysis was used to establish a novel prognostic model for predicting OS based on blood biomarkers. The predictive accuracy and discriminative ability of the prognostic model was compared to Adjusted prognostic Analysis (APA), Recursive Partition Analysis (RPA), and Graded Prognostic Assessment (GPA) using concordance index (C-index), time-dependent receiver operating characteristic (td-ROC) curve, Decision Curve Analysis(DCA), net reclassification improvement index (NRI), and integrated discrimination improvement index (IDI). Results 10-parameter signature's predictive model for the NSCLC patients with BMs was established according to the results of LASSO-Cox regression analysis. The C-index of the prognostic model to predict OS was 0.672 (95% CI = 0.609 ~ 0.736) which was significantly higher than APA,RPA and GPA. The td-ROC curve and DCA of the predictive model also demonstrated good predictive accuracy of OS compared to APA, RPA and GPA. Moreover, NRI and IDI analysis indicated that the prognostic model had improved prediction ability compared with APA, RPA and GPA. Conclusion The novel prognostic model demonstrated favorable performance than APA, RPA, and GPA for predicting OS in NSCLC patients with BMs.

Abstract Background Although eukaryotic initiation factor 6 (eIF6) is a novel therapeutic target, data on its importance in the development of esophageal carcinoma (ESCA) remains limited. This study evaluated the correlation between eIF6 expression and metabolic analysis using fluorine-18 fluorodeoxyglucose (18F-FDG) -Positron emission tomography (PET) and immune gene signatures in ESCA. Methods This study employed The Cancer Genome Atlas (TCGA) to analyze the expression and prognostic value of eIF6, as well as its relationship with the immune gene signatures in ESCA patients. The qRT-PCR and Western blot analyses were used to profile the expression of eIF6 in ESCA tissues and different ESCA cell lines. The expression of tumor eIF6 and glucose transporter 1 (GLUT1) was examined using immunohistochemical tools in fifty-two ESCA patients undergoing routine 18F-FDG PET/CT before surgery. In addition, the cellular responses to eIF6 knockdown in human ESCA cells were assessed via the MTS, EdU, flow cytometry and wound healing assays. Results Our data demonstrated that compared with the normal esophageal tissues, eIF6 expression was upregulated in ESCA tumor tissues and showed a high diagnostic value with an area under curve of 0.825 for predicting ESCA. High eIF6 expression was significantly correlated with shorter overall survival of patients with esophagus adenocarcinoma (p = 0.038), but not in squamous cell carcinoma of the esophagus (p = 0.078). In addition, tumor eIF6 was significantly associated with 18F-FDG PET/CT parameters: maximal and mean standardized uptake values (SUVmax and SUVmean) and total lesion glycolysis (TLG) (rho = 0.458, 0.460, and 0.300, respectively, p

Abstract Background Cryptosporidium parvum is a zoonotic parasite and member of the phylum Apicomplexa with unique secretory organelles, including a rhoptry, micronemes and dense granules that discharge their contents during parasite invasion. The mucin-like glycoprotein GP900 with a single transmembrane domain is an immunodominant antigen and micronemal protein. It is relocated to the surface of excysted sporozoites and shed to form trails by sporozoites exhibiting gliding motility (gliding sporozoites). However, the biological process underlying its relocation and shedding remains unclear. The primary aim of this study was to determine whether GP900 is present as a transmembrane protein anchored to the plasma membrane on the surface of sporozoites and whether it is cleaved before being shed from the sporozoites. Methods Two anti-GP900 antibodies, a mouse monoclonal antibody (mAb) to the long N-terminal domain (GP900-N) and a rabbit polyclonal antibody (pAb) to the short C-terminal domain (GP900-C), were produced for the detection of intact and cleaved GP900 proteins in sporozoites and other parasite developmental stages by microscopic immunofluorescence assay and in discharged molecules by enzyme-linked immunosorbent assay. Results Both anti-GP900 antibodies recognized the apical region of unexcysted and excysted sporozoites. However, anti-GP900-N (but not anti-GP900-C) also stained both the pellicles/surface of excysted sporozoites and the trails of gliding sporozoites. Both antibodies stained the intracellular meronts, both developing and developed, but not the macro- and microgamonts. Additionally, the epitope was recognized by anti-GP900-N (but not anti-GP900-C) and detected in the secretions of excysted sporozoites and intracellular parasites. Conclusions GP900 is present in sporozoites and intracellular meronts, but absent in sexual stages. It is stored in the micronemes of sporozoites, but enters the secretory pathway during excystation and invasion. The short cytoplasmic domain of GP900 is cleaved in the secretory pathway before it reaches the extracellular space. The molecular features and behavior of GP900 imply that it plays mainly a lubrication role. Graphical Abstract

Abstract Background Both obesity and subclinical hypothyroidism (SCH) have adverse effects on human body, but the relationship between these two conditions remains inconsistent. The presence of thyroid autoantibodies influences thyroid hormone levels, and may further mediate the interaction between obesity and SCH. This study aimed to explore the association among obesity, SCH and thyroid autoantibodies. Methods This study was a cross-sectional survey of 2505 subjects. Obesity was defined as a body mass index ≥28 kg/m2. Serum concentrations of thyroid hormones, thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) were examined. Logistic analysis was used to explore the relation among obesity, SCH and thyroid autoantibodies. Results A proportion of 11.54% (289/2505) subjects were obese, and 165 subjects had SCH. The positive rates of thyroid autoantibodies, TPO-Ab and Tg-Ab were 17.64% (442/2505), 11.02% (276/2505) and 14.13% (354/2505), respectively. The proportion of SCH was significantly higher in obese than nonobese subjects among those with positive thyroid autoantibodies [22.41% (13/58) vs. 11.72% (45/384), p = 0.025, χ2 test]. Moreover, obesity was significantly associated with SCH in the presence of thyroid autoantibodies after adjusting for confounding factors (OR 2.212, 95% CI 1.103 to 4.433, p = 0.025). A higher proportion of subjects with obesity had Tg-Ab positivity [17.99% (52/289) vs. 13.63% (302/2216), p = 0.045, χ2 test], and obesity remained significantly associated with Tg-Ab positivity by multiple logistic analysis (OR 1.504, 95% CI 1.077 to 2.101, p = 0.017). Conclusions Obesity was associated with SCH in the presence of thyroid autoantibodies. Examination of SCH is recommended in obese subjects with thyroid autoantibody positivity.

Abstract Background Inflammation markers have an important effect on tumor proliferation, invasion, and metastasis. Oligometastatic disease (OMD) is an intermediate state between widespread metastases and locally confined disease, where curative strategies may be effective for some patients. We aimed to explore the predictive value of inflammatory markers in patients with oligometastatic colorectal cancer (OMCC) and build a nomogram to predict the prognosis of these patients. Methods Two hundred nine patients with OMCC were retrospectively collected in this study. The Kaplan-Meier survival curves and Cox regression analysis were used to estimate overall survival (OS) and progression-free survival (PFS). A multivariate Cox analysis model was utilized to establish the nomogram. The concordance index (C-index), calibration curve, and receiver operating characteristics (ROC) were established to verify the validity and accuracy of the prediction model. Results According to the multivariate analysis, decreased platelet-to-lymphocyte ratio (PLR) might independently improve OS in patients with OMCC (HR = 2.396, 95% CI 1.391–4.126, P = 0.002). Metastases of extra-regional lymph nodes indicated poor OS (HR = 2.472, 95% CI 1.247–4.903, P = 0.010). While the patients with early N stage had better OS (HR = 4.602, 95% CI 2.055–10.305, P = 0.001) and PFS (HR = 2.100, 95% CI 1.364–3.231, P = 0.007). Primary tumor resection (HR = 0.367, 95% CI 0.148–0.908, P = 0.030) and lower fibrinogen (HR = 2.254, 95% CI 1.246–4.078, P = 0.007) could significantly prolong the OS in patients with OMCC. PLR, metastases of extra-regional lymph nodes, N stage, primary tumor resection, and fibrinogen were used to make up the nomogram. The C-index and area under the curve (AUC) of the ROC in nomogram were 0.721 and 0.772 respectively for OS, showed good consistency between predictive probability of OS and actual survival. Conclusions Decreased PLR could predict a good prognosis in patients with OMCC. The nomogram including inflammatory factors and clinicopathological markers was credible and accurate to predict survivals in patients with OMCC.

Abstract Background Aberrant alternative splicing plays critical role in aging and age-related diseases. Heterogeneous nuclear ribonucleoproteins (hnRNPs) reportedly regulate RNA splicing process. Whether and how hnRNPs contribute to age-related neurodegenerative diseases, especially Alzheimer’s disease (AD), remain elusive. Methods Immunoblotting and immunostaining were performed to determine expression patterns and cellular/subcellular localization of the long isoform of hnRNP D-like (L-DL), which is a hnRNP family member, in mouse hippocampus. Downregulation of L-DL in WT mice was achieved by AAV-mediated shRNA delivery, followed by memory-related behavioural tests. L-DL interactome was analysed by affinity-precipitation and mass spectrometry. Alternative RNA splicing was measured by RNA-seq and analyzed by bioinformatics-based approaches. Downregulation and upregulation of L-DL in APP/PS1 mice were performed using AAV-mediated transduction. Results We show that L-DL is specifically localized to nuclear speckles. L-DL levels are decreased in the hippocampus of aged mouse brains and downregulation of L-DL impairs cognition in mice. L-DL serves as a structural component to recruit other speckle proteins, and regulates cytoskeleton- and synapse-related gene expression by altering RNA splicing. Mechanistically, these splicing changes are modulated via L-DL-mediated interaction of SF3B3, a core component of U2 snRNP, and U2AF65, a U2 spliceosome protein that guides U2 snRNP’s binding to RNA. In addition, L-DL levels are decreased in APP/PS1 mouse brains. While downregulation of L-DL deteriorates memory deficits and overexpression of L-DL improves cognitive function in AD mice, by regulating the alternative splicing and expression of synaptic gene CAMKV. Conclusions Our findings define a molecular mechanism by which hnRNP L-DL regulates alternative RNA splicing, and establish a direct role for L-DL in AD-related synaptic dysfunction and memory decline.

Abstract Background Patients with spinal muscular atrophy (SMA) are at risk of decreased bone mineral density (BMD). The bone health status of Chinese patients with SMA has been poorly studied. We aimed to evaluate the BMD of children with SMA types 2 and 3 in mainland China and investigate its influencing factors. Methods Forty patients with a mean age of 5.5 years affected by SMA types 2 and 3 (n = 22 and n = 18, respectively) were enrolled between September 2017 and May 2019. Total body less head (TBLH) BMD, lumbar spine (LS) BMD, and body composition were measured using dual-energy X-ray absorptiometry (DXA). Serum bone metabolism markers and complete spinal radiographs were assessed. We utilized a linear regression model to explore the correlations between BMD and its related factors. Results A total of 67.5% (27/40) of patients were diagnosed with low BMD and 2.5% (1/40) were diagnosed with osteoporosis. The TBLH BMD and LS BMD Z-scores in children with SMA type 2 were significantly lower than those with SMA type 3. Both TBLH and LS BMD Z-scores tended to increase with the change of SMA subtypes from 2a-3b. Vitamin D insufficiency and deficiency were found in 37.5% (15/40) of the patients. Serum Ca, phosphorus (P), alkaline phosphatase (ALP) and parathormone (PTH) levels were normal. There were no significant differences among the four subtypes in terms of all the serum bone metabolism markers. Phenotype was significantly associated with TBLH BMD and LS BMD Z-scores, and serum PTH levels were significantly associated with TBLH BMD Z-scores. Conclusions Low BMD and osteoporosis were highly prevalent in mainland Chinese children with SMA types 2 and 3. Phenotype and serum PTH level might be the influencing factors of BMD. Regular monitoring of BMD by DXA scan and taking active interventions aim to SMA children with different types are important.

Abstract Background Arterial stiffness is an independent cardiovascular risk factor. However, the association between sodium/potassium intake and vascular stiffness was inconsistent. Therefore, a large community-based cross-sectional study was performed to try and achieve more definitive conclusion. Methods Urinary sodium, potassium, and creatinine levels were tested in spot urine samples during physical examinations of each recruited participant. The 24-h estimated urinary sodium excretion (eUNaE) and estimated urinary potassium excretion (eUKE) levels were determined using the Kawasaki formula (used as a surrogate for intake). Carotid intima-media thickness (IMT) and plaques were measured using ultrasound. Results In 13,523 subjects aged 18–80 years, the relationships between carotid plaques and IMT with eUNaE, eUKE and their ratios were analyzed. Overall, 30.2% of participants were diagnosed with carotid artery plaques. The ratio of estimated sodium vs. potassium excretion (Na/K ratio) of the individuals with carotid artery plaques was significantly higher than that of participants without plaque (2.14 ± 0.73 vs. 2.09 ± 0.61, P

Abstract Background Tuberous sclerosis complex 1 (Tsc1) is known to regulate the development and function of various cell types, and RORγt is a critical transcription factor in the immune system. However, whether Tsc1 participates in regulating RORγt-expressing cells remains unknown. Methods We generated a mouse model in which Tsc1 was conditionally deleted from RORγt-expressing cells (Tsc1 RORγt ) to study the role of RORγt-expressing cells with Tsc1 deficiency in brain homeostasis. Results Type 3 innate lymphoid cells (ILC3s) in Tsc1 RORγt mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1 RORγt mice exhibited spontaneous tonic-clonic seizures and died between 4 and 6 weeks after birth. At the age of 4 weeks, mice in which Tsc1 was specifically knocked out in RORγt-expressing cells had cortical neuron defects and hippocampal structural abnormalities. Notably, over-activation of neurons and astrogliosis were observed in the cortex and hippocampus of Tsc1 RORγt mice. Moreover, expression of the γ-amino butyric acid (GABA) receptor in the brains of Tsc1 RORγt mice was decreased, and GABA supplementation prolonged the lifespan of the mice to some extent. Further experiments revealed the presence of a group of rare RORγt-expressing cells with high metabolic activity in the mouse brain. Conclusions Our study verifies the critical role of previously unnoticed RORγt-expressing cells in the brain and demonstrates that the Tsc1 signaling pathway in RORγt-expressing cells is important for maintaining brain homeostasis.

Abstract Background To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM). Methods Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed. Results Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21). Conclusions All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.

Abstract Background Monocyte/macrophage-targeting delivery systems (MTDSs) have been focused upon as an emerging routine for delivering drugs to treat various macrophage-related diseases. However, the ability of MTDSs to distinguish different macrophage-related diseases and their impact on macrophage function and disease progression have not been systematically revealed, which is important for actively targeted therapeutic or diagnostic strategies. Results Herein, we used dextran-modified polystyrene nanoparticles (DEX-PS) to demonstrate that modification of nanoparticles by dextran can specifically enhance their recognition by M2 macrophages in vitro, but it is obstructed by monocytes in peripheral blood according to in vivo assays. DEX-PS not only targeted and became distributed in tumors, an M2 macrophage-related disease, but was also highly distributed in an M1 macrophage-related disease, namely acute peritonitis. Thus, DEX-PS acts as a double-edged sword in these two different diseases by reeducating macrophages to a pro-inflammatory phenotype. Conclusions Our results suggest that MTDSs, even those designed based on differential expression of receptors on specific macrophage subtypes, lack the ability to distinguish different macrophage subtype-related diseases in vivo. In addition to the potential impact of these carrier materials on macrophage function, studies of MTDSs should pay greater attention to the distribution of nanoparticles in non-target macrophage-infiltrated disease sites and their impact on disease processes.

Abstract Background The management of papillary lesions of the breast remains controversial, and thus, we assessed the value of vacuum-assisted excision (VAE)-guided ultrasound in the diagnosis and treatment of breast papillary lesions. Methods We retrospectively reviewed the data of 108 patients with papillary lesions diagnosed using VAE between August 2014 and January 2019. Cases without postoperative breast imaging in the follow-up were excluded, and 85 cases were eligible for the study. The follow-up period ranged from 6 to 53 months, with 38 months on average. All the papillary lesions were located away from the skin or nipple with a size less than or equal to 30 mm, and the lesions categorized as C2-4b were completely excised using VAE. All VAEs were performed using an 8-gauge vacuum-assisted biopsy needle under the guidance of ultrasound using a 10 MHz linear probe. Results Most patients with breast papillary lesions were asymptomatic (56.5%), and when the size of the breast papillary lesion was more than 20 mm on ultrasound imaging, atypical hyperplasia may have been concomitant. Breast lesions might have been pathologically diagnosed as papilloma after biopsy when they were categorized as BI-RADS 4a on ultrasound images. The rate of underestimation was 7.7% in papillary lesions diagnosed with VAE, and the recurrence rate of papilloma after VAE was low. Conclusions Breast papilloma was a common lesion on ultrasonographic screening, and VAE was applicable for completely excising small papillomas, even papillomas with atypical hyperplasia, to obtain an accurate diagnosis with a low rate of underestimation and recurrence. We believe that papilloma diagnosed by VAE might not require immediate excision, and imaging follow-up may be safe for at least 3 years.

Abstract Background The data on the association between the microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) during pregnancy and risk of preeclampsia (PE) is limited. Methods We, therefore, conducted a prospective nested case control study during Sep 2017 to Dec 2018 to examine the association between plasma TMAO measured during pregnancy and the risk of PE. Total of 17 patients diagnosed with early onset PE (EOPE), 49 with late onset PE (LOPE) and 198 healthy controls were enrolled. Blood samples were collected at 15–23 weeks gestation and time at delivery. The Logistic regression model was used to assess the odds ratio (OR) and 95% confidence interval (CI) for TMAO and risk of PE, EOPE, LOPE, mild PE, and severe PE. Results We found that the mean TMAO levels of overall subjects in the second trimester (T2) and at the time of delivery (TD) were 90.39 μg/m3 (standard deviation (SD) =45.91) and 175.01 μg/m3 (SD = 160.97), respectively. No significant spearman correlation was found between the TMAO in those two periods (p > 0.05). T2 TMAO was not significantly associated with risk of PE or risk of any PE subtypes (p > 0.05). However, TD TMAO was significant associated with risk of PE, EOPE and severe PE (adjusted OR and 95%CI were 1.24(1.09, 1.40), 1.62(1.29, 2.03), and 1.41(1.17, 1.70)) per 50 μg/m3 increment, respectively). Conclusion Our study found that plasma TMAO level would alter over the course of pregnancy. The major role of TMAO in PE development might be in the accelerating process not in the initiation.

Abstract Background Fecal microbiota transplantation may contribute to disease remission in ulcerative colitis; however, the factors that determine the effects of treatment remain unknown. The aim of the present study was to prospectively investigate the clinical efficacy of fecal microbiota transplantation in patients with ulcerative colitis and identify the bacterial signatures associated with clinical remission. Methods A total of 20 patients with ulcerative colitis were included in this prospective and uncontrolled study. All patients underwent gastroscopy five times, once every 3 weeks. Clinical indices were used to assess the efficacy of fecal microbiota transplantation, as well as the Mayo score, a score used to evaluate the extent of intestinal mucosal lesions in patients with ulcerative colitis. The changes in intestinal flora were detected by 16S ribosomal RNA-sequencing, and the relationship between ulcerative colitis and intestinal flora was analyzed. Results After treatment, clinical index scores for diarrhea, abdominal pain, and blood stool decreased significantly (p

Abstract Background White smoke inhalation (WSI) is an uncommon but potentially deadly cause of acute lung injury and acute respiratory distress syndrome for which no effective pharmaceutical treatment has been developed. This study aimed to determine the protective effects of human amnion-derived mesenchymal stem cells (hAMSCs) against WSI-induced lung injury in rats. Methods hAMSCs were injected into rats via the tail vein 4 h after WSI. At 1, 3, 7, 14, and 28 days after cell injection, hAMSCs labeled with PKH26 in lung, heart, liver, and kidney tissues were observed by fluorescence microscopy. The lung injury score was determined by hematoxylin and eosin staining. Lung fibrosis was assessed by Masson’s trichrome staining. The computed tomography (CT) score was assessed by CT scanning. The wet/dry weight ratio was calculated. The levels of interleukin (IL)-1β, IL-6, and IL-10 were determined by enzyme-linked immunosorbent assays. The expression of surfactant protein (SP)-A, SP-C, and SP-D was measured by Western blotting. Results The injected hAMSCs were primarily distributed in the lung tissues in WSI-induced rats. Compared with the model and phosphate-buffered saline (PBS) group, hAMSC treatment led to reduced lung injury, lung fibrosis, CT score, and inflammation levels in WSI-induced mice. hAMSC treatment also resulted in increased cell retention in the lung, partial pressure of oxygen (PaO2), and PaO2/fraction of inspired oxygen (FiO2) levels, and pulmonary SP-A, SP-C, and SP-D expression compared with that in the model and PBS group. Conclusions hAMSCs are a potential cell-based therapy for WSI-induced lung injury.

Abstract Long noncoding RNA HOTTIP plays important roles in the generation and progression of human cancers. Exosomes participate in cellular communication by transmitting moleculars between cells and are regarded as suitable candidates for non-invasive diagnosis. However, the existence of HOTTIP in the circulating exosomes and the potential roles of exosomal HOTTIP in gastric cancer (GC) was poorly understood. This study aims at investigating the clinical roles of exosomal HOTTIP in GC. Serum exosomal HOTTIP from 246 subjects (126 GC patients and 120 healthy people) were detected by reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR). Our results showed that expression levels of exosomal HOTTIP were typically upregulated in GC than in normal control (P

Abstract Background Malignant obstructive jaundice is a common problem in the clinic. Currently, the generally applied treatment methods are percutaneous transhepatic biliary drainage (PTBD) and endoscopic biliary drainage (EBD). Nevertheless, there has not been a uniform conclusion published on either efficacy of the two types of drainage or the incidence rate of complications. Therefore, we conducted a systematic review and meta-analysis of studies comparing endoscopic versus percutaneous biliary drainage in malignant obstructive jaundice, to determine whether there is any difference between percutaneous and endoscopic biliary drainage, with respect to efficacy and incidence rate of overall complications. Methods The enrolled studies contain a total of three randomized controlled trials and eleven retrospective studies, which together encompass 2246 patients with PTBD and 8100 patients with EBD. Results Our analysis indicates that there is no difference between PTBD and EBD with regard to therapeutic success rate (%), overall complication (%), intraperitoneal bile leak, 30-day mortality, sepsis, or duodenal perforation (%). Cholangitis and pancreatitis after PTBD were lower than after EBD, with odds ratios (OR) of 0.48 (95% confidence interval (CI), 0.31 to 0.74) and 0.16 (95% CI, 0.05 to 0.52), respectively. Incidences of bleeding and tube dislocation for PTBD were higher than EBD, OR of 1.81 (95% CI, 1.35 to 2.44) and 3.41 (95% CI, 1.10 to 10.60). Conclusions This meta-analysis indicates certain advantages for both PTBD and EBD. In the clinical practice, it is advised to choose specifically either PTBD or EBD, based on location of obstruction, purpose of drainage (as a preoperative procedure or a palliative treatment) and level of experience in biliary drainage at individual treatment centers.

Abstract Background PCSK9 rs505151 and rs11591147 polymorphisms are identified as gain- and loss-of-function mutations, respectively. The effects of these polymorphisms on serum lipid levels and cardiovascular risk remain to be elucidated. Methods In this meta-analysis, we explored the association of PCSK9 rs505151 and rs11591147 polymorphisms with serum lipid levels and cardiovascular risk by calculating the standardized mean difference (SMD) and odds ratios (OR) with 95% confidence intervals (CI). Results Pooled results analyzed under a dominant genetic model indicated that the PCSK9 rs505151 G allele was related to higher levels of triglycerides (SMD: 0.14, 95% CI: 0.02 to 0.26, P = 0.021, I2 = 0) and low-density lipoproteins cholesterol (LDL-C) (SMD: 0.17, 95% CI: 0.00 to 0.35, P = 0.046, I2 = 75.9%) and increased cardiovascular risk (OR: 1.50, 95% CI: 1.19 to 1.89, P = 0.0006, I2 = 48%). The rs11591147 T allele was significantly associated with lower levels of total cholesterol (TC) and LDL-C (TC, SMD: -0.45, 95% CI: -0.57 to −0.32, P = 0.000, I2 = 0; LDL-C, SMD: -0.44, 95% CI: -0.55 to −0.33, P = 0.000, I2 = 0) and decreased cardiovascular risk (OR: 0.77, 95% CI: 0.60 to 0.98, P = 0.031, I2 = 59.9) in Caucasians. Conclusions This study indicates that the variant G allele of PCSK9 rs505151 confers increased triglyceride (TG) and LDL-C levels, as well as increased cardiovascular risk. Conversely, the variant T allele of rs11591147 protects carriers from cardiovascular disease susceptibility and lower TC and LDL-C levels in Caucasians. These findings provide useful information for researchers interested in the fields of PCSK9 genetics and cardiovascular risk prediction not only for designing future studies, but also for clinical and public health applications.