Morusin suppresses the stemness characteristics of gastric cancer cells induced by hypoxic microenvironment through inhibition of HIF-1α accumulation.

Gastric cancer (GC) is a common, life-threatening malignancy that contributes to the global burden of cancer-related mortality, as conventional therapeutic modalities show limited effects on GC. Hence, it is critical to develop novel agents for GC therapy. Morusin, a typical prenylated flavonoid, possesses antitumor effects against various cancers. The present study aimed to demonstrate the inhibitory effect and mechanism of morusin on the stemness characteristics of human GC in vitro under hypoxia and to explore the potential molecular mechanisms. The effects of morusin on cell proliferation and cancer stem cell-like properties of the human GC cell lines SNU-1 and AGS were assessed by MTT assay, colony formation test, qRT-PCR, flow cytometry analysis, and sphere formation test under hypoxia or normoxia condition through in vitro assays. The potential molecular mechanisms underlying the effects of morusin on the stem-cell-like properties of human GC cells in vitro were investigated by qRT-PCR, western blotting assay, and immunofluorescence assay by evaluating the nuclear translocation and expression level of hypoxia-inducible factor-1α (HIF-1α). The results showed that morusin exerted growth inhibitory effects on SNU-1 and AGS cells under hypoxia in vitro. Moreover, the proportions of CD44+/CD24- cells and the sphere formation ability of SNU-1 and AGS reduced in a dose-dependent manner following morusin treatment. The expression levels of stem cell-related genes, namely Nanog, OCT4, SOX2, and HIF-1α, gradually decreased, and the nuclear translocation of the HIF-1α protein was apparently attenuated. HIF-1α overexpression partially reversed the abovementioned effects of morusin. Taken together, morusin could restrain stemness characteristics of GC cells by inhibiting HIF-1α accumulation and nuclear translocation and could serve as a promising compound for GC treatment.

Brain Pathology in COVID-19: Clinical Manifestations and Potential Mechanisms.

Neurological manifestations of coronavirus disease 2019 (COVID-19) are less noticeable than the respiratory symptoms, but they may be associated with disability and mortality in COVID-19. Even though Omicron caused less severe disease than Delta, the incidence of neurological manifestations is similar. More than 30% of patients experienced "brain fog", delirium, stroke, and cognitive impairment, and over half of these patients presented abnormal neuroimaging outcomes. In this review, we summarize current advances in the clinical findings of neurological manifestations in COVID-19 patients and compare them with those in patients with influenza infection. We also illustrate the structure and cellular invasion mechanisms of SARS-CoV-2 and describe the pathway for central SARS-CoV-2 invasion. In addition, we discuss direct damage and other pathological conditions caused by SARS-CoV-2, such as an aberrant interferon response, cytokine storm, lymphopenia, and hypercoagulation, to provide treatment ideas. This review may offer new insights into preventing or treating brain damage in COVID-19.

CCDC103 as a Prognostic Biomarker Correlated with Tumor Progression and Immune Infiltration in Glioma.

Background: The Coiled-coil domain-containing proteins (CCDCs) are expressed in many cancers, but the role of Coiled-coil domain-containing protein 103 (CCDC103) in cancers remains unclear. Further investigations are necessary to ascertain its diagnostic significance and understand its biological function in cancers. This study aims to elucidate the biological functionalities of CCDC103 in glioma and evaluate the correlation between CCDC103 expression with glioma progression. Methods: Clinical data on glioma patients were acquired from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO). The evaluation encompassed the examination of correlations between CCDC103 expression, pathological characteristics, and clinical outcomes. Furthermore, the analysis included the assessment of the correlations between CCDC103 expression and immune cell infiltration as well as glioma progression. Results: Gliomas have higher levels of CCDC103 expression than the para-carcinoma tissues. Poorer prognosis, unfavorable histological characteristics, the absence of IDH gene mutations, and the absence of chromosome 1p and 19q deletions were all associated with higher expression of CCDC103 in gliomas. In addition to patient age, tumor grade, the absence of IDH mutations, and the absence of chromosome 1p and 19q deletions, univariate and multivariate Cox analyses showed that CCDC103 expression was independently prognostic of overall survival, disease-free survival, and progression-free survival in patients with glioma. Furthermore, tumor infiltration of B cells, neutrophils, macrophages, and dendritic cells were all linked with elevated expression of CCDC103. High CCDC103 expression was linked to immune response-related signaling pathways and cell proliferation, according to gene set enrichment analysis (GSEA). Notably, the knockdown of CCDC103 in glioma cell lines resulted in a significant reduction in cell proliferation and migration. Conclusion: The correlation between CCDC103 expression and both glioma progression and immune cell infiltration implies that CCDC103 expression holds promise as a valuable prognostic biomarker for glioma.

Utilization of treatment effect on a surrogate endpoint for planning a study to evaluate treatment effect on a final endpoint.

To design a phase III study with a final endpoint and calculate the required sample size for the desired probability of success, we need a good estimate of the treatment effect on the endpoint. It is prudent to fully utilize all available information including the historical and phase II information of the treatment as well as external data of the other treatments. It is not uncommon that a phase II study may use a surrogate endpoint as the primary endpoint and has no or limited data for the final endpoint. On the other hand, external information from the other studies for the other treatments on the surrogate and final endpoints may be available to establish a relationship between the treatment effects on the two endpoints. Through this relationship, making full use of the surrogate information may enhance the estimate of the treatment effect on the final endpoint. In this research, we propose a bivariate Bayesian analysis approach to comprehensively deal with the problem. A dynamic borrowing approach is considered to regulate the amount of historical data and surrogate information borrowing based on the level of consistency. A much simpler frequentist method is also discussed. Simulations are conducted to compare the performances of different approaches. An example is used to illustrate the applications of the methods.

Diosmetin inhibits subchondral bone loss and indirectly protects cartilage in a surgically-induced osteoarthritis mouse model.

Osteoarthritis (OA) is a common degenerative disease characterized by articular cartilage destruction, subchondral bone remodeling, ectopic osteophyte formation and synovitis. It is now recognized that the integrity of the underlying subchondral bone is crucial for the maintenance of the overlying articular cartilage. Therapeutic agents that can prevent subchondral bone loss are demonstrate potential in the prevention and treatment of OA. Diosmetin (DIOS; 3',5,7 -trihydroxy-4'-methoxy flavone), a natural flavonoid, has been shown to exert anti-oxidative, anti-inflammatory, anti-apoptotic and anticancer properties. In this study, we found that diosmetin suppressed the DMM-induced subchondral bone loss and reduced subsequent cartilage degradation in vivo. Cellular-based assays showed that diosmetin inhibited RANKL-induced osteoclast formation and bone resorption,but did not affect IL-1ß-induced chondrocyte hypertrophy. Biochemical analyses demonstrated that the anti-osteoclastic effect of diosmetin was at least in part due to the suppression of RANKL-induced activation of the ERK, p38, and JNK MAPK signaling pathways. Collectively, our results show that diosmetin have potential as a therapeutic agent the treatment of abnormal subchondral bone loss and cartilage degradation associated with the onset of OA.

Identification of six hub genes and two key pathways in two rat renal fibrosis models based on bioinformatics and RNA-seq transcriptome analyses.

Renal fibrosis (RF) is the common pathological manifestation and central treatment target of multiple chronic kidney diseases with high morbidity and mortality. Currently, the molecular mechanisms underlying RF remain poorly understood, and exploration of RF-related hub targets and pathways is urgently needed. In this study, two classical RF rat models (adenine and UUO) were established and evaluated by HE, Masson and immunohistochemical staining. To clear molecular mechanisms of RF, differentially expressed genes (DEGs) were identified using RNA-Seq analysis, hub targets and pathways were screened by bioinformatics (functional enrichment analyses, PPI network, and co-expression analysis), the screening results were verified by qRT-PCR, and potential drugs of RF were predicted by network pharmacology and molecular docking. The results illustrated that renal structures were severely damaged and fibrotic in adenine- and UUO-induced models, as evidenced by collagen deposition, enhanced expressions of biomarkers (TGF-ß1 and α-SMA), reduction of E-cadherin biomarker, and severe renal function changes (significantly decreased UTP, CREA, Ccr, and ALB levels and increased UUN and BUN levels), etc. 1189 and 1253 RF-related DEGs were screened in the adenine and UUO models, respectively. Two key pathways (AGE-RAGE and NOD-like receptor) and their hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) were identified by PPI networks, co-expressed relationships, and qRT-PCR verification. Furthermore, various reported herbal ingredients (curcumin, resveratrol, honokiol, etc.) were considered as important drug candidates due to the strong binding affinity with these hub targets. Overall, this study mainly identified two key RF-related pathways (AGE-RAGE and NOD-like receptor), screened hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) that involved inflammation, ECM formation, myofibroblasts generation, and pyroptosis, etc., and provided referable drug candidates (curcumin, resveratrol, honokiol, etc.) in basic research and clinical treatment of RF.

A MCP-Mod approach to designing and analyzing survival trials with potential non-proportional hazards.

Non-proportional hazards have been observed in many studies especially in immuno-oncology clinical trials. Traditional analysis using the combined approach with log-rank test as the significance test and Cox model for treatment effect estimation becomes questionable as this approach relies heavily on the proportional hazards assumption. Inspired by the MCP-Mod (multiple comparisons and modeling approach) that has been widely used in dose-finding studies, we propose a similar approach to handle non-proportional hazards. Using this approach, efficacy signal is first established by a max-combo test, after which hazard ratios across time will be estimated using a logically nested splines model. Simulations studies and real-data examples are used to illustrate the use of this approach.

Bivariate Bayesian hypothesis testing with missing data in components.

Multiple endpoints and historical data borrowing may be simultaneously incorporated for enhancing efficiency and speeding up the new drug development process in the pharmaceutical industry. O'Brien's test is a widely used weighted combination test for multiplicity adjustment on multiple endpoints to control the overall type error rate in a weak sense. In this research, a modification on the O'Brien's test more specifically on the weights is considered for a trial with two primary endpoints to potentially increase power. The method can handle missing data in the current study and in the prior derivation for dynamic historical data borrowing. Simulations are conducted to compare the performances of different methods. A data example is used to illustrate the applications of the methods.

Knowledge Hiding: Current Research Status and Future Research Directions.

This article provides a review of scientific articles addressing the topic of knowledge hiding in organizations. Based on a descriptive analysis, bibliometric analysis, and content analysis of a sample of 81 articles published in the academic journals in the Web of Science from 2012 to 2020, we identify the main areas and current dynamics of knowledge hiding research. Our results show that the central research themes of knowledge hiding include five clusters: concept and dimensions, antecedents, consequences, theories, and influence mechanisms. Based on our findings, we suggest future research should further develop the concept and dimensions of knowledge hiding; probe deeper into the consequences of knowledge hiding; explore multilateral, cross-level, and collective knowledge hiding; employ innovative theoretical perspectives and research methods to study knowledge hiding; and address how cultural and other contextual factors may shape the knowledge hiding behavior.

Depletion of CIP2A inhibits the proliferation, migration, invasion and epithelial-mesenchymal transition of glioma cells.

CIP2A is an oncoprotein that is overexpressed in multiple solid tumours and some malignant haematologic disorders. However, its function in glioma is poorly understood. In this study, our results demonstrated that the expression of CIP2A was higher in glioma tissues than in normal tissues. Using tissue microarrays for immunohistochemistry, we found that the intensity of CIP2A expression was higher in high-grade gliomas (grade III-IV) than in low-grade gliomas (grade I-II). In addition, we found that depletion of CIP2A inhibited glioma cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Taken together, our findings revealed that CIP2A was involved in glioma progression, indicating that CIP2A could be used as a potential therapeutic target in the future.

Joint analysis of recurrence and termination: A Bayesian latent class approach.

Like many other clinical and economic studies, each subject of our motivating transplant study is at risk of recurrent events of non-fatal tissue rejections as well as the terminating event of death due to total graft rejection. For such studies, our model and associated Bayesian analysis aim for some practical advantages over competing methods. Our semiparametric latent-class-based joint model has coherent interpretation of the covariate (including race and gender) effects on all functions and model quantities that are relevant for understanding the effects of covariates on future event trajectories. Our fully Bayesian method for estimation and prediction uses a complete specification of the prior process of the baseline functions. We also derive a practical and theoretically justifiable partial likelihood-based semiparametric Bayesian approach to deal with the analysis when there is a lack of prior information about baseline functions. Our model and method can accommodate fixed as well as time-varying covariates. Our Markov Chain Monte Carlo tools for both Bayesian methods are implementable via publicly available software. Our Bayesian analysis of transplant study and simulation study demonstrate practical advantages and improved performance of our approach.

Aldehyde dehydrogenase 2 overexpression inhibits neuronal apoptosis after spinal cord ischemia/reperfusion injury.

Aldehyde dehydrogenase 2 (ALDH2) is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury. Therefore, we hypothesized that ALDH2 could reduce spinal cord ischemia/reperfusion injury. Spinal cord ischemia/reperfusion injury was induced in rats using the modified Zivin's method of clamping the abdominal aorta. After successful model establishment, the agonist group was administered a daily consumption of 2.5% alcohol. At 7 days post-surgery, the Basso, Beattie, and Bresnahan score significantly increased in the agonist group compared with the spinal cord ischemia/reperfusion injury group. ALDH2 expression also significantly increased and the number of apoptotic cells significantly decreased in the agonist group than in the spinal cord ischemia/reperfusion injury group. Correlation analysis revealed that ALDH2 expression negatively correlated with the percentage of TUNEL-positive cells (r = -0.485, P < 0.01). In summary, increased ALDH2 expression protected the rat spinal cord against ischemia/reperfusion injury by inhibiting apoptosis.

Treatment of osteoporosis with eldecalcitol, a new vitamin D analog: a comprehensive review and meta-analysis of randomized clinical trials.

OBJECTIVE: Eldecalcitol (ELD) is an active form of vitamin D analog that has been approved for the treatment of osteoporosis in Japan. Over recent years, a number of multicenter, randomized controlled clinical trials have been conducted. Our goal is to comprehensively summarize the results from these studies. METHODS: We searched the databases MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials up to February 28, 2015. Each database was searched using search terms "Eldecalcitol" and "ED-71" and the results were combined. The retrieved data from three independent clinical trials included a total of 1,332 patients with osteoporosis. After the data were pooled from three trials, RevMan software was used to conduct meta-analyses to determine the effects of ELD on bone mineral density (BMD) and bone turnover marker (BTM) type I collagen amino-terminal telopeptide (NTX). Effects of ELD on some of the bone formation and bone resorption parameters, incidence of vertebral fractures at the lower spine, and health-related quality of life (HRQOL) in patients with osteoporosis were also summarized. RESULTS: With a test for overall effect Z=6.35, ELD could increase lumbar BMD (P<0.00001). In comparison with alphacalcidol, ELD suppressed the NTX level to a greater degree (test for overall effect Z=3.82,P<0.0001). ELD was also found to suppress bone alkaline phosphatase (BALP) by 19% (P<0.01) and osteocalcin by 19% (P<0.01) at the dose of 0.75 µg/day. Compared to alfacalcidol, ELD showed higher potency in suppressing serum BALP (26±9 vs 32±11 U/L,P<0.05) and amino-terminal propeptide of procollagen I (PINP) (42±15 vs 59±23 ng/mL,P<0.05). In addition, ELD was found to be more effective in reducing the incidence of vertebral fractures at the lower spine (P=0.029). CONCLUSION: Our meta-analysis showed that ELD was more potent than alphacalcidol in reducing BTM (NTX). Clinical data together suggest that ELD is efficient in treating osteoporosis by increasing lumbar BMD; suppressing BTMs, including NTX, BALP, osteocalcin, and PINP; resulting in the reduction in the incidence of vertebral fractures at the lower spine; and increasing the HRQOL in patients with osteoporosis.

Histone deacetylase inhibitors repress chondrosarcoma cell proliferation.

PURPOSE: Due to the high resistance to conventional therapy, there is still no convincingly effective treatment for chondrosarcoma. As a promising new treatment strategy, histone deacetylase inhibitors (HDACIs) have been reported to induce cell arrest, apoptosis and differentiation in some kinds of malignancies, but how HDACi exert their effects on chondrosarcoma is not well understood yet. METHODS: We investigated the effects of HDACIs trichostatin A (TSA) and sodium valproate (VPA) on chondrosarcoma cells in vitro and in vivo. The cell proliferation and cell cycle were examined in two chondrosarcoma cell lines, SW1353 and JJ012, by MTS and flow cytometry assays, respectively. The in vivo effects of HDACIs were investigated by assessing the chondrosarcoma growth in a mouse xenograft model. RESULTS: Our results showed that TSA and VPA significantly repressed the proliferation of chondrosarcoma cells in a concentration-dependent manner. Flow cytometry indicated that TSA arrested the cell cycle in G2/M phase and VPA arrested the cell cycle in G1 phase. The tumor growth was markedly suppressed in mice treated with TSA and VPA. CONCLUSIONS: HDACIs significantly repress the proliferation of chondrosarcoma cells in vitro and in vivo. Our findings imply that HDACIs may provide a novel therapeutic target for the treatment of chondrosarcoma.

Associations between the cytotoxic T lymphocyte antigen 4 polymorphisms and risk of bone sarcomas.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) genetic polymorphisms are implicated to be associated with susceptibility to bone sarcomas, but published studies have reported inconclusive results. The objective of our study was to conduct a meta-analysis investigating the associations between CTLA-4 gene polymorphisms and risk of bone sarcomas. PubMed and Embase databases were searched for all articles published up to June 2, 2013. Odds ratio (OR) with a 95 % confidence interval (95 % CI) was used to assess the association. Finally, 11 individual studies with a total of 2,951 cases with bone sarcomas and 3,396 controls were included in the meta-analysis. There were four studies on the CTLA-4 49G/A polymorphism, three studies on CTLA-4 318C/T polymorphism, two studies on CTLA-4 1661A/G polymorphism, and two studies on CTLA-4 60A/G polymorphism. Overall, CTLA-4 49G/A polymorphism was obviously associated with risk of bone sarcomas (A vs. G: OR = 1.36, 95 % CI = 1.20-1.54; AA vs. GG: OR = 2.24, 95 % CI = 1.67-2.99; AA vs. AG/GG: OR = 2.00, 95 % CI = 1.53-2.62; AA/GA vs. GG: OR = 1.35, 95 % CI = 1.14-1.61). However, CTLA-4 318C/T, 1661A/G, and 60A/G polymorphisms were not associated with risk of bone sarcomas. The current meta-analysis suggests that CTLA-4 49G/A polymorphism is obviously associated with risk of bone sarcomas. More studies are needed to further evaluate the associations between CTLA-4 polymorphisms and risk of bone sarcomas.

No genetic tradeoffs between hygienic behaviour and individual innate immunity in the honey bee, Apis mellifera.

Many animals have individual and social mechanisms for combating pathogens. Animals may exhibit short-term physiological tradeoffs between social and individual immunity because the latter is often energetically costly. Genetic tradeoffs between these two traits can also occur if mutations that enhance social immunity diminish individual immunity, or vice versa. Physiological tradeoffs between individual and social immunity have been previously documented in insects, but there has been no study of genetic tradeoffs involving these traits. There is strong evidence that some genes influence both innate immunity and behaviour in social insects--a prerequisite for genetic tradeoffs. Quantifying genetic tradeoffs is critical for understanding the evolution of immunity in social insects and for devising effective strategies for breeding disease-resistant pollinator populations. We conducted two experiments to test the hypothesis of a genetic tradeoff between social and individual immunity in the honey bee, Apis mellifera. First, we estimated the relative contribution of genetics to individual variation in innate immunity of honey bee workers, as only heritable traits can experience genetic tradeoffs. Second, we examined if worker bees with hygienic sisters have reduced individual innate immune response. We genotyped several hundred workers from two colonies and found that patriline genotype does not significantly influence the antimicrobial activity of a worker's hemolymph. Further, we did not find a negative correlation between hygienic behaviour and the average antimicrobial activity of a worker's hemolymph across 30 honey bee colonies. Taken together, our work indicates no genetic tradeoffs between hygienic behaviour and innate immunity in honey bees. Our work suggests that using artificial selection to increase hygienic behaviour of honey bee colonies is not expected to concurrently compromise individual innate immunity of worker bees.