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Background: Although immune checkpoint inhibitors (ICIs) have brought survival benefits to non-small cell lung cancer (NSCLC), disease progression still occurs, and there is no consensus on the treatment options for these patients. We designed a network meta-analysis (NMA) to evaluate systemic treatment options for NSCLC after failure of ICIs. Methods: PubMed, Embase, Web of Science and Cochrane Library databases were searched, then literature screening was followed by NMA. We included all Phase II and III randomized controlled trials (RCTs). Progression-free survival (PFS) and overall survival (OS) used hazard ratio (HR) for evaluation. Objective response rate (ORR) and adverse events (AEs) used odds ratio (OR) and relative risk (RR) effect sizes, respectively. R software was applied to compare the Bayesian NMA results. Results: We finally included 6 studies. 1322 patients received ICI plus Chemotherapy (ICI + Chemo), ICI plus Anti-angiogenic monoclonal antibody (ICI + Antiangio-Ab), ICI plus Tyrosine kinase inhibitor (ICI + TKI), Tyrosine kinase inhibitor plus Chemotherapy (TKI + Chemo), Standard of Care (SOC), Chemotherapy (Chemo). TKI + Chemo is associated with longer PFS, higher ORR (surface under cumulative ranking curve [SUCRA], 99.7%, 88.2%), ICI + TKI achieved the longest OS (SUCRA, 82.7%). ICI + Antiangio-Ab was granted the highest safety rating for adverse events (AEs) of any grade, AEs greater than or equal to grade 3 and AEs of any grade leading to discontinuation of treatment (SUCRA, 95%, 82%, 93%). Conclusions: For NSCLC after failure of ICIs, TKI + Chemo was associated with longer PFS and higher ORR, while ICI + TKI was associated with the longest OS. In terms of safety, ICI + Antiangio-Ab was the highest. [ABSTRACT FROM AUTHOR]

Background: Iatrogenic complications of endovascular treatment for central venous stenosis have not yet been reported. Here we present a case of a patient on maintenance hemodialysis who developed catheter-related superior vena cava syndrome and subsequently suffered from hemorrhagic pericardial tamponade after undergoing percutaneous transluminal angioplasty and stenting. Case presentation: A 72-year-old male patient presented with uremia, and had been receiving maintenance hemodialysis for the past five years. The patient initially presented with dysfunction of the dialysis catheter (a cuffed tunneled double-lumen catheter in the right internal jugular vein). Imaging examination revealed a segmental occlusion of the superior vena cava stretching from the distal end of the dialysis catheter up to right atrium entrance, apparent compensatory dilatation of the azygos vein, and abundant subcutaneous collaterals. The patient underwent percutaneous transluminal balloon dilatation and stenting (covered stent) of the superior vena cava in the Cath Lab. During the procedure, with forceful advancement of the guidewire, it was observed to progress for a distance before a "smoke" appeared, and an outward spillage of contrast agent was visible, which suggested a possible vessel puncture leading into the mediastinum. Unfortunately, postoperative hemorrhagic pericardial tamponade occurred and the patient developed cardiogenic shock. He experienced symptoms included chest tightness and breath shortness with a recorded blood pressure of 84/60mmHg. After draining 600 ml of bloody fluid through pericardiocentesis, the patient's symptoms alleviated and his condition improved. Conclusions: The case emphasizes the need for increased attention to iatrogenic endovascular injuries during catheter placement and endovascular treatment, such as causing pericardial hemorrhage leading to cardiac tamponade. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, which is recognized as a hallmark of cancer, refers to the phenomenon by which cancer cells change their metabolism to support their increased biosynthetic demands. Tumor cells undergo substantial alterations in metabolic pathways, such as glycolysis, oxidative phosphorylation, pentose phosphate pathway, tricarboxylic acid cycle, fatty acid metabolism, and amino acid metabolism. Latest studies have revealed that long non-coding RNAs (lncRNAs), a group of non-coding RNAs over 200 nucleotides long, mediate metabolic reprogramming in tumor cells by regulating the transcription, translation and post-translational modification of metabolic-related signaling pathways and metabolism-related enzymes through transcriptional, translational, and post-translational modifications of genes. In addition, lncRNAs are closely related to the tumor microenvironment, and they directly or indirectly affect the proliferation and migration of tumor cells, drug resistance and other processes. Here, we review the mechanisms of lncRNA-mediated regulation of glucose, lipid, amino acid metabolism and tumor immunity in gastrointestinal tumors, aiming to provide more information on effective therapeutic targets and drug molecules for gastrointestinal tumors. [ABSTRACT FROM AUTHOR]

Background: Amphora coffeaeformis, a unicellular diatom, can significantly accumulate lipids under nitrogen (N) limitation. However, the molecular mechanism underlying lipid accumulation in A. coffeaeformis remains unknown and its application development is lagging. Results: This work analyzed the lipid composition of A. coffeaeformis under N deprivation and investigated its mechanism underlying lipid accumulation using RNA-seq. The results showed that the total lipid content of A. coffeaeformis increased from 28.22 to 44.05% after 5 days of N deprivation, while the neutral lipid triacylglycerol (TAG) content increased from 10.41 to 25.21%. The transcriptional profile showed that N deprivation induced wide-ranging reprogramming of regulation and that most physiological activities were repressed, while the upregulation of glycerol-3-phosphate acyltransferase directly determined TAG accumulation. Moreover, we explored the effect of A. coffeaeformis as a food additive on the lipid composition of crucian carp. The results showed that the contents of unsaturated fatty acids in the meat of fish supplemented with A. coffeaeformis were significantly increased, indicating its potential application in animal nutrition for improving meat quality indicators. Conclusion: The findings shed light on the molecular mechanisms of neutral lipid accumulation and revealed the key genes involved in lipid metabolism in A. coffeaeformis. Moreover, we also confirmed that A. coffeaeformis can be used as feed additive for improving the lipid composition of crucian carp meat, which provided evidence for the biotechnology application of this high-oil microalgae. [ABSTRACT FROM AUTHOR]

Background: The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. Methods: This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). Results: Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). Conclusions: In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab. [ABSTRACT FROM AUTHOR]

Microalgal biomass represents a sustainable bioresource for various applications, such as food, nutraceuticals, pharmaceuticals, feed, and other bio-based products. For decades, its mass production has attracted widespread attention and interest. The process of microalgal biomass production involves several techniques, mainly cultivation, harvesting, drying, and pollution control. These techniques are often designed and optimized to meet optimal growth conditions for microalgae and to produce high-quality biomass at acceptable cost. Importantly, mass production techniques are important for producing a commercial product in sufficient amounts. However, it should not be overlooked that microalgal biotechnology still faces challenges, in particular the high cost of production, the lack of knowledge about biological contaminants and the challenge of loss of active ingredients during biomass production. These issues involve the research and development of low-cost, standardized, industrial-scale production equipment and the optimization of production processes, as well as the urgent need to increase the research on biological contaminants and microalgal active ingredients. This review systematically examines the global development of microalgal biotechnology for biomass production, with emphasis on the techniques of cultivation, harvesting, drying and control of biological contaminants, and discusses the challenges and strategies to further improve quality and reduce costs. Moreover, the current status of biomass production of some biotechnologically important species has been summarized, and the importance of improving microalgae-related standards for their commercial applications is noted. [ABSTRACT FROM AUTHOR]

For comprehensive studies of the brain structure and function, fluorescence imaging of the whole brain is essential. It requires large-scale volumetric imaging in cellular or molecular resolution, which could be quite challenging. Recent advances in tissue clearing technology (e.g. CLARITY, PACT) provide new solutions by homogenizing the refractive index of the samples to create transparency. However, it has been difficult to acquire high quality results through immunofluorescence (IF) staining on the cleared samples. To address this issue, we developed TSA-PACT, a method combining tyramide signal amplification (TSA) and PACT, to transform samples into hydrogel polymerization frameworks with covalent fluorescent biomarkers assembled. We show that TSA-PACT is able to reduce the opacity of the zebrafish brain by more than 90% with well-preserved structure. Compared to traditional method, TSA-PACT achieves approximately tenfold signal amplification and twofold improvement in signal-to-noise ratio (SNR). Moreover, both the structure and the fluorescent signal persist for at least 16 months with excellent signal retention ratio. Overall, this method improves immunofluorescence signal sensitivity, specificity and stability in the whole brain of juvenile and adult zebrafish, which is applicable for fine structural analysis, neural circuit mapping and three-dimensional cell counting. [ABSTRACT FROM AUTHOR]

Background: Knee osteoarthritis (KOA) is a common musculoskeletal condition affecting millions of people worldwide and posing a significant challenge to clinicians and researchers. Emerging evidence suggests that the multifaceted symptomatology of KOA may be alleviated by diacerein. With this in mind, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of diacerein in patients with KOA. Methods: We systematically searched Embase, PubMed, Cochrane Library, Web of Science, Chinese Biomedical Literature Database (CBM), Wanfang Database (WanFang), China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (VIP) from their inception to August 2022 for randomized controlled trials (RCTs) of diacerein intervention on patients with KOA. Two reviewers independently performed the selection of eligible studies and the extraction of relevant data. The meta-analysis was performed using RevMan 5.4 and R 4.1.3 software tools. Depending on the type of outcome indicator selected, summary measures were expressed as mean differences (MD), standardized mean differences (SMD), or odds ratio (OR) with 95% confidence intervals (CI). Results: Twelve RCTs with 1732 patients were included. The results revealed that diacerein had comparable efficacy to non-steroidal anti-inflammatory drugs (NSAIDs) in reducing pain indicators such as Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (SMD = 0.09, 95% CI [−0.10, 0.28], P = 0.34) and visual analogue scale (VAS) (SMD = −0.19, 95% CI [−0.65, 0.27], P = 0.42). However, diacerein outperformed NSAIDs in terms of global efficacy assessment by both patients and investigators (patients: 1.97, 95% CI [1.18, 3.29], P = 0.01; investigator: 2.18, 95% CI [0.99, 4.81], P = 0.05) at the end of treatment and sustained effectiveness in reducing WOMAC score and VAS score at four weeks after treatment. Moreover, there was no significant difference in adverse events incidence between the diacerein and NSAID groups. However, the GRADE evaluation indicated that the majority of the evidence quality was low. Conclusions: The results of this study suggest that diacerein could potentially be considered as a pharmacological agent with significant efficacy for the treatment of patients suffering from KOA, offering a potential alternative treatment strategy for those patients contraindicated to NSAIDs. However, further high-quality studies with longer follow-up are needed to make more informed decisions about its efficacy in the treatment of KOA. [ABSTRACT FROM AUTHOR]

Introduction: The results of laboratory testing are crucial basis for clinicians to prescribe antimicrobial. Laboratory testing is a highly complex process, and increasing evidence suggests that errors and obstacles in the pre-analytical process (PP) will affect reasonable antimicrobial use. However, PP was an easily neglected link in hospital infection management and the current situation of it and the influencing factors of management are not clear. Methods: A cross-sectional survey was conducted in the department of clinical, specimen collection, transportation, and inspection in 109 secondary and tertiary hospitals in Central China. The rate of antimicrobial susceptibility test request (AST) and related indexes of above departments were calculated to describe the situation. Management characteristics (frequency of training etc.) were described as proportions and fractional probit regression analysis was used to determine the influencing factors. Results: The average rate of non restricted-use antimicrobial was 63%, the restricted-use was 86%, the special-use was 95%. The zero obstacle rate of specimen collection was 27.3%, of specimen transportation was 19.4% and of inspection feedback was 61.7%. There was a difference between the secondary and tertiary hospitals on non restricted-use (X2 = 22.968, P < 0.001); restricted-use (X2 = 29.466, P < 0.001); special-use (X2 = 27.317, P < 0.001). Taking non restricted-use as an example, training (OR = 0.312, 95%CI: 0.148,0.429), low-frequency appraisal (OR = 0.153, 95%CI: 0.082,0.224), guidance (OR = 0.32, 95%CI: 0.237,0.403) and information technology (OR = 0.104, 95%CI: 0.009,0.199) were positive factors. Conclusions: There were substantial differences in the rate of AST request in clinical department between secondary and tertiary hospitals. The zero obstacle rate in collection, transportation and inspection department were still low. In most departments, training and performance appraisal were positive factors, guidance and information technology were positive supporting factors. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. Results: We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. Conclusions: These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy. [ABSTRACT FROM AUTHOR]

Background: Clinical diagnosis based on machine learning usually uses case samples as training samples, and uses machine learning to construct disease prediction models characterized by descriptive texts of clinical manifestations. However, the problem of sample imbalance often exists in the medical field, which leads to a decrease in classification performance of the machine learning. Methods: To solve the problem of sample imbalance in medical dataset, we propose a hybrid sampling algorithm combining synthetic minority over-sampling technique (SMOTE) and edited nearest neighbor (ENN). Firstly, the SMOTE is used to over-sampling missed abortion and diabetes datasets, so that the number of samples of the two classes is balanced. Then, ENN is used to under-sampling the over-sampled dataset to delete the "noisy sample" in the majority. Finally, Random forest is used to model and predict the sampled missed abortion and diabetes datasets to achieve an accurate clinical diagnosis. Results: Experimental results show that Random forest has the best classification performance on missed abortion and diabetes datasets after SMOTE-ENN sampled, and the MCC index is 95.6% and 90.0%, respectively. In addition, the results of pairwise comparison and multiple comparisons show that the SMOTE-ENN is significantly better than other sampling algorithms. Conclusion: Random forest has significantly improved all indexes on the missed abortion dataset after SMOTE-ENN sampled. [ABSTRACT FROM AUTHOR]

Background: In the context of biomedical and epidemiological research, gene-environment (G-E) interaction is of great significance to the etiology and progression of many complex diseases. In high-dimensional genetic data, two general models, marginal and joint models, are proposed to identify important interaction factors. Most existing approaches for identifying G-E interactions are limited owing to the lack of robustness to outliers/contamination in response and predictor data. In particular, right-censored survival outcomes make the associated feature screening even challenging. In this article, we utilize the overlapping group screening (OGS) approach to select important G-E interactions related to clinical survival outcomes by incorporating the gene pathway information under a joint modeling framework. Results: Simulation studies under various scenarios are carried out to compare the performances of our proposed method with some commonly used methods. In the real data applications, we use our proposed method to identify G-E interactions related to the clinical survival outcomes of patients with head and neck squamous cell carcinoma, and esophageal carcinoma in The Cancer Genome Atlas clinical survival genetic data, and further establish corresponding survival prediction models. Both simulation and real data studies show that our method performs well and outperforms existing methods in the G-E interaction selection, effect estimation, and survival prediction accuracy. Conclusions: The OGS approach is useful for selecting important environmental factors, genes and G-E interactions in the ultra-high dimensional feature space. The prediction ability of OGS with the Lasso penalty is better than existing methods. The same idea of the OGS approach can apply to other outcome models, such as the proportional odds survival time model, the logistic regression model for binary outcomes, and the multinomial logistic regression model for multi-class outcomes. [ABSTRACT FROM AUTHOR]

Developing novel photosensitizers for deep tissue imaging and efficient photodynamic therapy (PDT) remains a challenge because of the poor water solubility, low reactive oxygen species (ROS) generation efficiency, serve dark cytotoxicity, and weak absorption in the NIR region of conventional photosensitizers. Herein, cyclometalated iridium (III) complexes (Ir) with aggregation-induced emission (AIE) feature, high photoinduced ROS generation efficiency, two-photon excitation, and mitochondria-targeting capability were designed and further encapsulated into biocompatible nanoparticles (NPs). The Ir-NPs can be used to disturb redox homeostasis in vitro, result in mitochondrial dysfunction and cell apoptosis. Importantly, in vivo experiments demonstrated that the Ir-NPs presented obviously tumor-targeting ability, excellent antitumor effect, and low systematic dark-toxicity. Moreover, the Ir-NPs could serve as a two-photon imaging agent for deep tissue bioimaging with a penetration depth of up to 300 μm. This work presents a promising strategy for designing a clinical application of multifunctional Ir-NPs toward bioimaging and PDT. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) is a widely used herbicide and a common cause of poisoning that leads to pulmonary fibrosis with a high mortality rate. However, the underlying mechanisms of PQ-induced pulmonary fibrosis and whether pulmonary epithelial cell senescence is involved in the process remain elusive. In this study, PQ-induced pulmonary epithelial cell senescence and Hippo-YAP/TAZ activation were observed in both C57BL/6 mice and human epithelial cells. PQ-induced senescent pulmonary epithelial cells promoted lung fibroblast transformation through secreting senescence-associated secretory phenotype (SASP) factors. Yap/Taz knockdown in mice lungs significantly decreased the expression of downstream profibrotic protein Ctgf and senescent markers p16 and p21, and alleviated PQ-induced pulmonary fibrosis. Interfering YAP/TAZ in senescent human pulmonary epithelial cells resulted in decreased expression of the anti-apoptosis protein survivin and elevated level of apoptosis. In conclusion, our findings reveal a novel mechanism by which the involvement of Hippo-YAP/TAZ activation in pulmonary epithelial cell senescence mediates the pathogenesis of PQ-induced pulmonary fibrosis, thereby offering novel insights and potential targets for the clinical management of PQ poisoning as well as providing the mechanistic insight of the involvement of Yap/Taz activation in cell senescence in pulmonary fibrosis and its related pulmonary disorders. The YIN YANG balance between cell senescence and apoptosis is important to maintain the homeostasis of the lung, the disruption of which will lead to disease. [ABSTRACT FROM AUTHOR]

Background: Numerous signaling pathways have been demonstrated experimentally to affect the pathogenesis of cerebral cavernous malformations (CCM), a disease that can be caused by CCM3 deficiency. However, the understanding of the CCM progression is still limited. The objective of the present work was to elucidate the role of CCM3 by RNA-seq screening of CCM3 knockout mice. Results: We found that ATPIF1 was decreased in siCCM3-treated Human Umbilical Vein Endothelial Cells (HUVECs), and the overexpression of ATPIF1 attenuated the changes in cell proliferation, adhesion and migration caused by siCCM3. The probable mechanism involved the conserved ATP concentration in mitochondria and the elongated morphology of the organelles. By using the CRISPR-cas9 system, we generated CCM3-KO Endothelial Progenitor Cells (EPCs) and found that the knockout of CCM3 destroyed the morphology of mitochondria, impaired the mitochondrial membrane potential and increased mitophagy. Overexpression of ATPIF1 contributed to the maintenance of normal structure of mitochondria, inhibiting activation of mitophagy and other signaling proteins (e.g., KLF4 and Tie2). The expression of KLF4 returned to normal in CCM3-KO EPCs after 2 days of re-overexpression of CCM3, but not other signaling proteins. Conclusion: ATPIF1 maintains the normal structure of mitochondria, inhibiting the activation of mitophagy and other signaling pathway in endothelial cells. Loss of CCM3 leads to the destruction of mitochondria and activation of signaling pathways, which can be regulated by KLF4. [ABSTRACT FROM AUTHOR]

Background: Selenium (Se) in soil mainly consists of selenite, selenate, and elemental Se. However, little is known about the mechanism involved in the uptake and biotransformation of elemental Se by plants. Results: In this study, the uptake, translocation, subcellular distribution and biotransformation of selenium nanoparticles (SeNPs) in rice (Oryza sativa L.), and a comparison with selenite and selenate, were investigated through hydroponic experiments. The study revealed that SeNPs could be absorbed by rice plants; and aquaporin inhibitor was responsible for a 60.4% inhibition of SeNP influx, while metabolic inhibitor was ineffective. However, the SeNPs uptake rate of rice roots was approximately 1.7 times slower than that of selenite or selenate. Under the SeNPs or selenite treatment, Se was primarily accumulated in roots rather than in shoots, whereas an opposite trend was observed with selenate treatment. Additionally, most of the absorbed Se was distributed in cell wall of the SeNPs or selenite treated-rice plants, while its proportion was the highest in soluble cytosol of the selenate treated-rice plants. The absorbed SeNPs or selenite was rapidly assimilated to organic forms, with SeMet being the most predominant species in both shoots and roots of the rice plants. However, following selenate treatment, Se(VI) remained as the most predominant species, and only a small amount of it was converted to organic forms. Conclusion: Therefore, this study provides a deeper understanding of the mechanisms associated SeNPs uptake and biotransformation within plants. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) remains a predominant form of malignant tumor globally, necessitating innovative non-surgical therapeutic approaches. This investigation aimed to delineate the expression landscape of macrophage-associated genes in GC and to evaluate their prognostic significance and influence on immunotherapeutic responsiveness. Utilizing the CellMarker2.0 database, we identified 69 immune cell markers with prognostic relevance in GC, including 12 macrophage-specific genes. A Weighted Gene Co-Expression Network Analysis (WGCNA) isolated 3,181 genes correlated with these macrophage markers. The Cancer Genome Atlas (TCGA-STAD) dataset was employed as the training set, while data from the GSE62254 served as the validation cohort. 13 genes were shortlisted through LASSO-Cox regression to formulate a prognostic model. Multivariable Cox regression substantiated that the calculated risk score serves as an imperative independent predictor of overall survival (OS). Distinct macrophage infiltration profiles, pathway associations, treatment susceptibilities, and drug sensitivities were observed between high- and low-risk groups. The preliminary validation of ANXA5 in predicting the survival rates of GC patients at 1 year, 3 years, and 5 years, as well as its expression levels were higher and role in promoting tumor angiogenesis in GC through immunohistochemistry and angiogenesis experiments. In summary, macrophage-related genes were potentially a novel crosstalk mechanism between macrophages and endothelial cells in the tumor microenvironment, and the interplay between inflammation and angiogenesis might have also offered new therapeutic targets, providing a new avenue for personalized treatment interventions. [ABSTRACT FROM AUTHOR]

Although the incidence of venous thromboembolism (VTE) in Asian populations is lower than in Western countries, the overall burden of VTE in Asia has been considerably underestimated. Factors that may explain the lower prevalence of VTE in Asian populations relative to Western populations include the limited availability of epidemiological data in Asia, ethnic differences in the genetic predisposition to VTE, underdiagnoses, low awareness toward thrombotic disease, and possibly less symptomatic VTE in Asian patients. The clinical assessment, diagnostic testing, and therapeutic considerations for VTE are, in general, the same in Asian populations as they are in Western populations. The management of VTE is based upon balancing the treatment benefits against the risk of bleeding. This is an especially important consideration for Asian populations because of increased risk of intracranial hemorrhage with vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants have shown advantages over current treatment modalities with respect to bleeding outcomes in major phase 3 clinical trials, including in Asian populations. Although anticoagulant therapy has been shown to reduce the risk of postoperative VTE in Western populations, VTE prophylaxis is not administered routinely in Asian countries. Despite advances in the management of VTE, data in Asian populations on the incidence, prevalence, recurrence, risk factors, and management of bleeding complications are limited and there is need for increased awareness. To that end, this review summarizes the available data on the epidemiology, risk stratification, diagnosis, and treatment considerations in the management of VTE in Asia. [ABSTRACT FROM AUTHOR]

Background: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear. Methods: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. Results: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. Conclusions: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate an unsettled issue that whether T4 esophageal cancer could benefit from surgery. Methods: Patients with T4N0-3M0 esophageal cancer from 2004 to 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. Kaplan–Meier method, Cox proportional hazard regression, and propensity score matching (PSM) were used to compare overall survival (OS) between the surgery and no-surgery group. Results: A total of 1822 patients were analyzed. The multivariable Cox regression showed the HR (95% CI) for surgery vs. no surgery was 0.492 (0.427–0.567) (P < 0.001) in T4N0-3M0 cohort, 0.471 (0.354–0.627) (P < 0.001) in T4aN0-3M0 cohort, and 0.480 (0.335–0.689) (P < 0.001) in T4bN0-3M0 cohort. The HR (95% CI) for neoadjuvant therapy plus surgery vs. no surgery and surgery without neoadjuvant therapy vs. no surgery were 0.548 (0.461–0.650) (P < 0.001) and 0.464 (0.375–0.574) (P < 0.001), respectively. No significant OS difference was observed between neoadjuvant therapy plus surgery and surgery without neoadjuvant therapy: 0.966 (0.686–1.360) (P = 0.843). Subgroup analyses and PSM-adjusted analyses showed consistent results. Conclusion: Surgery might bring OS improvement for T4N0-3M0 esophageal cancer patients, no matter in T4a disease or in T4b disease. Surgery with and without neoadjuvant therapy might both achieve better OS than no surgery. [ABSTRACT FROM AUTHOR]

Background: This study analyzes the regulation of and developments in blood donation in China from 1996 to 2019, and demonstrates the government's efforts to improve blood safety.Results: Since the implementation of the Blood Donation Law in 1998, the number of blood donors in China increased by 275% from 1998 to 2018 (from 4 million to 15 million). The principle of no-fault liability was proposed and has been applied since 2010 to the tort liability related to blood transfusion malpractice. In 2015, mutual blood donation accounted for 4.2% of the national collection. However, in some provinces of China, the percentage of mutual blood donation increased from 9.3 to 35.6% in 2016. The National Health Commission canceled mutual blood donation in March of 2018. Since 2015, nucleic acid amplification testing has become a routine test item for screening blood.Conclusions: The Chinese government institutionalized the voluntary non-remunerated donation principle, enacted regulations for the management of blood transfusion, and adopted advanced blood testing technology to sustain blood supply and ensure blood safety. Despite increased blood donation, blood shortages persist. The quality and safety of blood collection can be further improved through the cancellation of mutual blood donation and incentive measures for voluntary non-remunerated donation of blood, which needs facilitation by governmental legislation. [ABSTRACT FROM AUTHOR]

Background: End-stage renal disease (ESRD) is a condition that is characterized by the loss of kidney function. ESRD patients suffer from various endothelial dysfunctions, inflammation, and immune system defects. Lysine malonylation (Kmal) is a recently discovered post-translational modification (PTM). Although Kmal has the ability to regulate a wide range of biological processes in various organisms, its specific role in ESRD is limited. Methods: In this study, the affinity enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have been used to create the first global proteome and malonyl proteome (malonylome) profiles of peripheral blood mononuclear cells (PBMCs) from twenty patients with ESRD and eighty-one controls. Results: On analysis, 793 differentially expressed proteins (DEPs) and 12 differentially malonylated proteins (DMPs) with 16 Kmal sites were identified. The Rap1 signaling pathway and platelet activation pathway were found to be important in the development of chronic kidney disease (CKD), as were DMPs TLN1 and ACTB, as well as one malonylated site. One conserved Kmal motif was also discovered. Conclusions: These findings provided the first report on the Kmal profile in ESRD, which could be useful in understanding the potential role of lysine malonylation modification in the development of ESRD. [ABSTRACT FROM AUTHOR]

Background: A growing body of research has revealed the connection of metabolism reprogramming and tumor progression, yet how metabolism reprogramming affects inter-patient heterogeneity and prognosis in head and neck squamous cell carcinoma (HNSCC) still requires further explorations. Methods: A cellular hierarchy framework based on metabolic properties discrepancy, METArisk, was introduced to re-analyze the cellular composition from bulk transcriptomes of 486 patients through deconvolution utilizing single-cell reference profiles from 25 primary and 8 metastatic HNSCC sample integration of previous studies. Machine learning methods were used to identify the correlations between metabolism-related biomarkers and prognosis. The functions of the genes screened out in tumor progression, metastasis and chemotherapy resistance were validated in vitro by cellular functional experiments and in vivo by xenograft tumor mouse model. Results: Incorporating the cellular hierarchy composition and clinical properties, the METArisk phenotype divided multi-patient cohort into two classes, wherein poor prognosis of METArisk-high subgroup was associated with a particular cluster of malignant cells with significant activity of metabolism reprogramming enriched in metastatic single-cell samples. Subsequent analysis targeted for phenotype differences between the METArisk subgroups identified PYGL as a key metabolism-related biomarker that enhances malignancy and chemotherapy resistance by GSH/ROS/p53 pathway, leading to poor prognosis of HNSCC. Conclusion: PYGL was identified as a metabolism-related oncogenic biomarker that promotes HNSCC progression, metastasis and chemotherapy resistance though GSH/ROS/p53 pathway. Our study revealed the cellular hierarchy composition of HNSCC from the cell metabolism reprogramming perspective and may provide new inspirations and therapeutic targets for HNSCC in the future. [ABSTRACT FROM AUTHOR]

Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. Methods: Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. Results: Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24–0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03–0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1–3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8–37.3) months and 16.0 (95% CI 10.8–21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3–17.8) months and 7.6 (95% CI 3.6–11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. Conclusion: The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy. Highlights: Baseline serum AFP > 400 ng/mL and NLR > 2.77 were independent prognostic factors associated with worse OS and PFS in unresectable HCC patients treated with immune checkpoint inhibitors. A scoring system based on these two variables predicts survival outcomes and treatment response in patients with unresectable HCC undergoing immunotherapy. [ABSTRACT FROM AUTHOR]

Glyco-quantum dots (glyco-QDs) have attracted significant interest in bioimaging applications, notably in cancer imaging, because they effectively combine the glycocluster effect with the exceptional optical properties of QDs. The key challenge now lies in how to eliminate the high heavy metal toxicity originating from traditional toxic Cd-based QDs for in vivo bioimaging. Herein, we report an eco-friendly pathway to prepare nontoxic Cd-free glyco-QDs in water by the "direct" reaction of thiol-ending monosaccharides with metal salts precursors. The formation of glyco-CuInS2 QDs could be explained by a nucleation-growth mechanism following the LaMer model. As-prepared four glyco-CuInS2 QDs were water-soluble, monodispersed, spherical in shape and exhibited size range of 3.0–4.0 nm. They exhibited well-separated dual emission in the visible region (500–590 nm) and near-infrared range (~ 827 nm), which may be attributable to visible excitonic emission and near-infrared surface defect emission. Meanwhile, the cell imaging displayed the reversibly distinct dual-color (green and red) fluorescence in tumor cells (HeLa, A549, MKN-45) and excellent membrane-targeting properties of glyco-CuInS2 QDs based on their good biorecognition ability. Importantly, these QDs succeed in penetrating uniformly into the interior (the necrotic zone) of 3D multicellular tumor spheroids (MCTS) due to their high negative charge (zeta potential values ranging from − 23.9 to − 30.1 mV), which overcame the problem of poor penetration depth of existing QDs in in vitro spheroid models. So, confocal analysis confirmed their excellent ability to penetrate and label tumors. Thus, the successful application in in vivo bioimaging of these glyco-QDs verified that this design strategy is an effective, low cost and simple procedure for developing green nanoparticles as cheap and promising fluorescent bioprobes. [ABSTRACT FROM AUTHOR]

Purpose: Proximal humerus fractures (PHFs) are common. With the development of locking plates, open reduction and internal fixation (ORIF) of the proximal humerus can provide excellent clinical outcomes. The quality of fracture reduction is crucial in the locking plate fixation of proximal humeral fractures. The purpose of this study was to determine the impact of 3-dimensional (3D) printing technology and computer virtual technology assisted preoperative simulation on the reduction quality and clinical outcomes of 3-part and 4-part proximal humeral fractures. Method: A retrospective comparative analysis of 3-part and 4-part PHFs undergoing open reduction internal fixation was performed. Patients were divided into 2 groups according to whether computer virtual technology and 3D printed technology were used for preoperative simulation: the simulation group and the conventional group. Operative time, intraoperative bleeding, hospital stay, quality of fracture reduction, Constant scores, American Society for Shoulder and Elbow Surgery (ASES) scores, shoulder range of motion, complications, and revision surgeries were assessed. Results: This study included 67 patients (58.3%) in the conventional group and 48 patients (41.7%) in the simulation group. The patient demographics and fracture characteristics were comparable in these groups. Compared with the conventional group, the simulation group had shorter operation time and less intraoperative bleeding (P < 0.001, both). Immediate postoperative assessment of fracture reduction showed a higher incidence of greater tuberosity cranialization of < 5 mm, neck-shaft angle of 120° to 150°, and head shaft displacement of < 5 mm in the simulation group. The incidence of good reduction was 2.6 times higher in the simulation group than in the conventional group (95% CI, 1.2–5.8). At the final follow-up, the chance of forward flexion > 120° (OR 5.8, 95% CI 1.8–18.0) and mean constant score of > 65 (OR 3.4, 95% CI 1.5–7.4) was higher in the simulation group than the conventional group, as well as a lower incidence of complications in the simulation group was obtained (OR 0.2, 95% CI 0.1–0.6). Conclusions: This study identified that preoperative simulation assisted by computer virtual technology and 3D printed technology can improve reduction quality and clinical outcomes in treatment of 3-part and 4-part PHFs. [ABSTRACT FROM AUTHOR]

Background: Apis cerana is widely distributed in China and, prior to the introduction of western honeybees, was the only bee species kept in China. During the long-term natural evolutionary process, many unique phenotypic variations have occurred among A. cerana populations in different geographical regions under varied climates. Understanding the molecular genetic basis and the effects of climate change on the adaptive evolution of A. cerana can promote A. cerana conservation in face of climate change and allow for the effective utilization of its genetic resources. Result: To investigate the genetic basis of phenotypic variations and the impact of climate change on adaptive evolution, A. cerana workers from 100 colonies located at similar geographical latitudes or longitudes were analyzed. Our results revealed an important relationship between climate types and the genetic variation of A. cerana in China, and a greater influence of latitude compared with longitude was observed. Upon selection and morphometry analyses combination for populations under different climate types, we identified a key gene RAPTOR, which was deeply involved in developmental processes and influenced the body size. Conclusion: The selection of RAPTOR at the genomic level during adaptive evolution could allow A. cerana to actively regulate its metabolism, thereby fine-tuning body sizes in response to harsh conditions caused by climate change, such as food shortages and extreme temperatures, which may partially elucidate the size differences of A. cerana populations. This study provides crucial support for the molecular genetic basis of the expansion and evolution of naturally distributed honeybee populations. [ABSTRACT FROM AUTHOR]

Background: The sesquiterpene germacrene D is a highly promising product due to its wide variety of insecticidal activities and ability to serve as a precursor for many other sesquiterpenes. Biosynthesis of high value compounds through genome mining for synthases and metabolic engineering of microbial factories, especially Saccharomyces cerevisiae, has been proven to be an effective strategy. However, there have been no studies on the de novo synthesis of germacrene D from carbon sources in microbes. Hence, the construction of the S. cerevisiae cell factory to achieve high production of germacrene D is highly desirable. Results: We identified five putative sesquiterpene synthases (AcTPS1 to AcTPS5) from Acremonium chrysogenum and the major product of AcTPS1 characterized by in vivo, in vitro reaction and NMR detection was revealed to be (–)-germacrene D. After systematically comparing twenty-one germacrene D synthases, AcTPS1 was found to generate the highest amount of (–)-germacrene D and was integrated into the terpene precursor-enhancing yeast strain, achieving 376.2 mg/L of (–)-germacrene D. Iterative engineering was performed to improve the production of (–)-germacrene D, including increasing the copy numbers of AcTPS1, tHMG1 and ERG20, and downregulating or knocking out other inhibitory factors (such as erg9, rox1, dpp1). Finally, the optimal strain LSc81 achieved 1.94 g/L (–)-germacrene D in shake-flask fermentation and 7.9 g/L (–)-germacrene D in a 5-L bioreactor, which is the highest reported (–)-germacrene D titer achieved to date. Conclusion: We successfully achieved high production of (–)-germacrene D in S. cerevisiae through terpene synthase mining and metabolic engineering, providing an impressive example of microbial overproduction of high-value compounds. [ABSTRACT FROM AUTHOR]

Background: Due to the high cost of data collection for magnetization detection of media, the sample size is limited, it is not suitable to use deep learning method to predict its change trend. The prediction of physical and chemical properties of magnetized water and fertilizer (PCPMWF) by meta-learning can help to explore the effects of magnetized water and fertilizer irrigation on crops. Method: In this article, we propose a meta-learning optimization model based on the meta-learner LSTM in the field of regression prediction of PCPMWF. In meta-learning, LSTM is used to replace MAML's gradient descent optimizer for regression tasks, enables the meta-learner to learn the update rules of the LSTM, and apply it to update the parameters of the model. The proposed method is compared with the experimental results of MAML and LSTM to verify the feasibility and correctness. Results: The average absolute percentage error of the meta-learning optimization model of meta-learner LSTM is reduced by 0.37% compared with the MAML model, and by 4.16% compared with the LSTM model. The loss value of the meta-learning optimization model in the iterative process drops the fastest and steadily compared to the MAML model and the LSTM model. In cross-domain experiments, the average accuracy of the meta-learning optimized model can still reach 0.833. Conclusions: In the case of few sample, the proposed model is superior to the traditional LSTM model and the basic MAML model. And in the training of cross-domain datasets, this model performs best. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) are increasingly recognized as important regulators in cancer including ovarian cancer (OC). This work focuses on the effects of circ_0000745 on the OC development of and molecules involved. Methods: Expression of circ_0000745 in collected OC tissues and the acquired OC cell lines was examined by RT-qPCR. The stability of circ_0000745 in cells was examined by RNase R treatment. The target transcripts interacted with circ_0000745 were predicted using bioinformatic systems. Gain- and loss-of-function studies of circ_0000745, microRNA (miR)-3187-3p and erb-b2 receptor tyrosine kinase 4 (ERBB4) were conducted to determine their functions on proliferation, migration, invasion and stem cell property of OC cells. Results: Circ_0000745 and ERBB4 were abundantly expressed while miR-3187-3p was poorly expressed in OC tissues and cells. Circ_0000745 sequestered miR-3187-3p and blocked its repressive effect on ERBB4. Downregulation of circ_0000745 reduced proliferation, aggressiveness, epithelial-mesenchymal transition, and stemness of SK-OV-3 cells, but this reduction was blocked upon miR-3187-3p inhibition or ERBB4 upregulation. By contrast, artificial induction of circ_0000745 upregulation, miR-3187-3p upregulation and ERBB4 downregulation led to inverse trends in ES-2 cells. ERBB4 promoted the phosphorylation of the PI3K/AKT signaling pathway. An RNA binding protein IGF2BP2 was found to circ_0000745 bind to and promote its expression and stability. Conclusion: This study demonstrated that circ_0000745 upregulated by IGF2BP2 promotes aggressiveness and stemness of OC cells through a miR-3187-3p/ERBB4/PI3K/AKT axis. Circ_0000745 may serve as a promising target for OC treatment. [ABSTRACT FROM AUTHOR]

Background: Anti-GABABR encephalitis is a rare type of autoimmune encephalitis, which often presents with memory impairments, behavioral changes and seizures. This case series describes the neuropsychological function recovery pattern in five adult patients with anti-GABABR encephalitis.Case Presentation: We recruited five patients with clinically confirmed anti-GABABR encephalitis without any accompanying malignancy. Comprehensive neuropsychological evaluation was conducted on each patient. All the five patients were evaluated in the chronic phase. Five age and gender matched healthy adults were recruited as control group. Our study demonstrated that the neuropsychological function of the patients with anti-GABABR encephalitis was no different with respect to the control group during the chronic phase (more than 6 months after onset). Moreover, one patients with neuropsychological evaluation at acute (within 2 months after onset of symptoms), post-acute (2 to 6 months after onset) and chronic phases respectively, presented neuropsychological function recovered as early as in the post-acute phase and only showed cognition impairment in the acute phase.Conclusions: The results of this retrospective study indicate a favorable long-term neuropsychological function outcome in adult patients with anti-GABABR encephalitis, despite severe memory deficits occurring during the acute phase. These findings improve our understanding related to the prognosis of neuropsychological function in anti-GABABR encephalitis. [ABSTRACT FROM AUTHOR]

Background: Ultra-processed foods have now become dominant in the global food system. Whether their consumption is associated with cardiovascular mortality remains controversial. Moreover, data on ultra-processed foods and cardiovascular outcomes are scarce in the US population. We aimed to examine the association of ultra-processed food consumption with cardiovascular mortality in a US population. Methods: A population-based cohort of 91,891 participants was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary data were collected through a validated 137-item food frequency questionnaire. Ultra-processed foods were defined by the NOVA classification. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular mortality. Restricted cubic spline regression was used to test nonlinearity. Subgroup analyses were conducted to identify the potential effect modifiers. Results: After an average follow-up of 13.5 years (1,236,049.2 person-years), 5490 cardiovascular deaths were documented, including 3985 heart disease deaths and 1126 cerebrovascular deaths. In the fully adjusted model, participants in the highest vs. the lowest quintiles of ultra-processed food consumption had higher risks of death from cardiovascular disease (HRquintile 5 vs. 1, 1.50; 95% CI, 1.36–1.64) and heart disease (HRquintile 5 vs. 1, 1.68; 95% CI, 1.50–1.87) but not cerebrovascular disease (HRquintile 5 vs. 1, 0.94; 95% CI, 0.76–1.17). A nonlinear dose–response pattern was observed for overall cardiovascular and heart disease mortality (all Pnonlinearity < 0.05), with a threshold effect observed at ultra-processed food consumption of 2.4 servings/day and 2.3 servings/day, respectively; below the thresholds, no significant associations were observed for these two outcomes. Subgroup analyses showed that the increased risks of mortality from ultra-processed foods were significantly higher in women than in men (all Pinteraction < 0.05). Conclusions: High consumption of ultra-processed foods is associated with increased risks of overall cardiovascular and heart disease mortality. These harmful associations may be more pronounced in women. Our findings need to be confirmed in other populations and settings. [ABSTRACT FROM AUTHOR]

Background: Novel non-invasive biomarkers for gastric cancer (GC) are needed, because the present diagnostic methods for GC are either invasive or insensitive and non-specific in clinic. The presence of stable circulating microRNAs (miRNAs) in plasma suggested a promising role as GC biomarkers.Methods: Based on the quantitative droplet digital PCR (ddPCR), four miRNAs (miR-21, miR-93, miR-106a and miR-106b) related to the presence of GC were identified in plasma from a training cohort of 147 participants and a validation cohort of 28 participants.Results: All circulating miRNA levels were significantly higher in the plasma of GC patients compared to healthy controls (P < 0.05). Through a combination of four miRNAs by logistic regression model, receiver operating characteristic (ROC) analyses yielded the highest AUC value of 0.887 in discriminating GC patients from healthy volunteers. Furthermore, miR-21, miR-93 and miR-106b levels were significantly related to an advanced TNM stage in GC patients. ROC analyses of the combined miRNA panel also showed the highest AUC value of 0.809 in discriminating GC patients with TNM stage I and II from stage III and IV. Through combining four miRNAs and clinical parameters, a classical random forest model was established in the training stage. In the validation cohort, it correctly discriminated 23 out of 28 samples in the blinded phase (false rate, 17.8%).Conclusions: Using the ddPCR technique, circulating miR-21, miR-93, miR-106a and miR-106b could be used as diagnostic plasma biomarkers in gastric cancer patients. [ABSTRACT FROM AUTHOR]

Background: No consensus treatment has been reached for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Hepatic resection (HR) and transarterial chemoembolization (TACE) have been recommended as effective options, but which is better remains unclear. This meta-analysis is to compare the effectiveness of HR and TACE for HCC with PVTT patients.Methods: The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched for comparing HR and TACE treating PVTT.Results: Twelve retrospective studies with 3129 patients were included. A meta-analysis of 11 studies suggested that the 1-, 2-, 3-, and 5-year overall survival (OS) rates (OR = 0.48, 95% CI = 0.41-0.57, I2 = 37%, P < 0.00001; OR = 0.21, 95% CI = 0.12-0.38, I2 = 43%, P < 0.00001; OR = 0.35, 95% CI = 0.28-0.44, I2 = 53%, P < 0.00001; OR = 0.28, 95% CI = 0.14-0.54, I2 = 72%, P = 0.0001, respectively) favored HR over TACE. In a subgroup analysis, HR had better 1-, 2-,3, 5-year OS for type I PVTT (OR = 0.33, 95% CI = 0.17-0.64, I2 = 20%, P = 0.001; OR = 0.32, 95% CI = 0.16-0.63, I2 = 0%, P = 0.001; OR = 0.18, 95% CI = 0.09-0.36, I2 = 0%, P < 0.00001; OR = 0.07, 95% CI = 0.01-0.32, I2 = 0%, P = 0.0006, respectively) and better 1-, 3-, and 5-year OS for type II PVTT (OR = 0.37, 95% CI = 0.20-0.70, I2 = 59%, P = 0.002; OR = 0.22, 95% CI = 0.13-0.39, I2 = 0%, P < 0.00001; OR = 0.16; 95% CI = 0.03-0.91; I2 = 51%, P = 0.04, respectively). There was no difference in 1-, 3-, or 5-year OS between HR and TACE for type III PVTT (OR = 0.86, 95% CI = 0.61-1.21, I2 = 0%, P = 0.39; OR = 0.83, 95% CI = 0.42-1.64, I2 = 0%, P = 0.59; OR = 0.59, 95% CI = 0.06--6.04, I2 = 65%, P = 0.66, respectively).Conclusions: HR may lead to longer OS for some selected HCC patients with PVTT than TACE, especially for type I or II PVTT, with less difference being observed for type III or IV PVTT. [ABSTRACT FROM AUTHOR]

Background: The role of stress signals in regulating gastric cancer initiation and progression is not quite clear. It is known that stress signals modulate multiple processes such as immune function, cell migration and angiogenesis. However, few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis.Methods: Here, we used β2-adrenergic receptor (β2-AR) agonist isoprenaline to imitate a stress signal and demonstrated the molecular mechanism underlying stress's influence on tumor angiogenesis.Results: We found that isoprenaline stimulated vascular endothelial growth factor (VEGF) secretion in gastric cancer cells and plexin-A1 expression was induced by human recombinant VEGF165 in both gastric cancer cells and vascular endothelial cells. Furthermore, interfere with plexin-A1 expression in gastric cancer cells influence HUVEC tube formation, migration and tumor growth in vivo.Conclusions: These findings suggest that isoprenaline stimulate VGEF secretion and subsequently up-regulate the expression of plexin-A1 and VEGFR2 in gastric cancer cells, which form a positive impetus to promote tumor angiogenesis. This study reveals a novel molecular mechanism that a stress signal like isoprenaline may enhance angiogenesis via activating plexin-A1/VEGFR2 signaling pathway in gastric cancer, which may be a potential target in development of an anti-angiogenic therapy for gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Associations between adipokines and bone mineral density (BMD) in knee osteoarthritis (OA) remain indistinct. The aim of this study was to investigate the cross-sectional associations between serum levels of adipokines and BMD in patients with knee OA.Methods: This study included 164 patients with symptomatic knee OA from the Anhui Osteoarthritis study. Serum levels of leptin, adiponectin, and resistin were measured using an enzyme-linked immunosorbent assay (ELISA). BMD at total body, spine, hip, and femur were measured by dual-energy X-ray absorptiometry (DXA).Results: In multivariable analyses, serum levels of leptin were significantly associated with reduced BMD at total body, hip, total femur, femoral neck, and femoral shaft (β = - 0.019, 95% CI -0.034 to - 0.005; β = - 0.018, 95% CI -0.034 to - 0.003; β = - 0.018, 95% CI -0.034 to - 0.002; β = - 0.016, 95% CI -0.032 to 0.000; β = - 0.026, 95% CI -0.046 to - 0.006; respectively). Serum levels of adiponectin were significantly and negatively associated with BMD at total femur and femoral shaft (β = - 0.007, 95% CI -0.013 to 0.000; β = - 0.011, 95% CI -0.018 to - 0.003; respectively). However, no significant associations were found between serum levels of resistin and BMD at any site measured.Conclusions: Serum levels of leptin and adiponectin were significantly and negatively associated with BMD, suggesting potentially detrimental effects of leptin and adiponectin on BMD in knee OA patients. [ABSTRACT FROM AUTHOR]

Background: The rapid determination of pathogenic agent is very important to clinician for guiding their clinical medication. However, current diagnostic methods are of limitation in many aspects, such as detecting range, time-consuming, specificity and sensitivity. In this report, we apply our new-developing pathogen detection method to clarify that Propionibacterium acnes is the causative agent of a two-year-old boy with juvenile myelomonocytic leukemia presenting clinical symptoms including serious rash and hyperpyrexia while traditional clinical methods of diagnosis fail to detect the pathogenic agent and multiple antimicrobial drugs are almost ineffective Propionibacterium acnes is confirmed to be the infectious agent by quantitative real-time polymerase chain reaction.Case Presentation: After haploidentical hematopoietic stem cell transplantation, a two-year-old boy with juvenile myelomonocytic leukemia presented to a pediatrist in a medical facility with hyperpyrexia and red skin rash which later changed to black skin rash all over his body. Traditional diagnostic assays were unrevealing, and several routine antimicrobial treatments were ineffective, including the vancomycin, meropenem, tobramycin, cefepime and rifampin. In this case, pediatrist resorted to the next-generation sequencing technology for uncovering potential pathogens so as to direct their use of specific drugs against pathogenic bacteria. Therefore, based on the BGISEQ100 (Ion Proton System) which performed sequencing-by-synthesis, with electrochemical detection of synthesis, and each such reaction coupled to its own sensor, which are in turn organized into a massively parallel sensor array on a complementary metal-oxidesemiconductor chip, we detect and identify the potential pathogens. As a result, we detected a significantly higher abundance of skin bacteria Propionibacterium acnes in patient's blood than controls. It had been reported that patients infected by Propionibacterium acnes almost always had history of immunodeficiency, trauma or surgery. Considering this possible cause, antimicrobial treatment was adjusted to target this rare opportunistic pathogen. Fever and black skin rashes were rapidly reduced after administrating specific drugs against Propionibacterium acnes.Conclusion: This case showed our new-developing pathogen detection method was a powerful tool in assisting clinical diagnosis and treatment. And it should be paid more attention to Propionibacterium acnes infection in clinical cases. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a common chronic disease in older adults. Currently, there are no effective therapies to reduce disease severity and progression of knee OA (KOA), particularly in mid- to late-stages. This study aims to examine the effect of methotrexate (MTX) on knee effusion-synovitis and pain in symptomatic patients with mid- to late-stage KOA.Methods/design: This protocol describes a multicentre randomised placebo-controlled clinical trial aiming to recruit 200 participants with mid- to late-stage symptomatic KOA and with effusion-synovitis grade of ≥ 2. Participants will be randomly allocated to the MTX group (start from 5 mg per week for the first 2 weeks and increase to 10 mg per week for the second 2 weeks and 15 mg per week for the remaining period if tolerated) or the placebo group. Primary outcomes are effusion-synovitis size measured by magnetic resonance imaging (MRI) and knee pain assessed by visual analogue scale (VAS). Secondary outcomes are signal intensity alteration within infrapatellar fat pad (IPFP) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and subscores, and the Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders. Both intention-to-treat and per-protocol analyses will be performed.Discussion: If MTX intervention can relieve symptoms and reduce inflammation in patients with mid- to late-stage KOA, it has the potential for significant clinical and public health impact as this low-cost and commonly used intervention would delay the time to knee replacement, leading to substantial cost savings and improve quality of life.Trial Registration: ClinicalTrials.gov NCT03815448 . Registered on 21 January 2019. [ABSTRACT FROM AUTHOR]

Background: To evaluate the clinical significance of low-frequency electrical stimulation in preventing urinary retention after radical hysterectomy. Methods: A total of 91 women with stage IA2–IB2 cervical cancer, who were treated with radical hysterectomy and lymphadenectomy from January 2009 to December 2012, were enrolled into this study and were randomly divided into two groups: trail group (48 cases) and control group (43 cases). Traditional bladder function training and low-frequency electrical stimulation were conducted in the trail group, while patients in the control group were only treated by traditional bladder training. The general condition, rate of urinary retention, and muscle strength grades of pelvic floor muscle in the perioperative period were compared between these two groups. Results: The incidence of postoperative urinary retention in the electrical stimulation group was 10.41%, significantly lower than that in the control group (44.18%), and the difference was statistically significant (P < 0.01). The duration of postoperative fever and use of antibiotics were almost the same between these two groups. Eleven days after surgery, the difference in grades of the pelvic floor muscle between these two groups was not statistically significant. However, 14 days after the operation, grades of the pelvic floor muscle were significantly higher in the trail group than in the control group, and the difference was statistically significant (P < 0.01). In addition, although there was no significant difference between the two groups with different parameters (P = 0.782), the incidence of urinary retention was lower in the endorphins analgesia program group than in the neuromuscular repair program group (9.09% < 11.54%). Conclusion: Low-frequency electrical stimulation is more effective than conventional intervention in preventing urinary retention after radical hysterectomy. It also intensifies the recovery of pelvic muscle strength. [ABSTRACT FROM AUTHOR]