Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

Restoration of CD3+CD56+ NKT-like cell function by TIGIT blockade in inactive carrier and immune tolerant patients of chronic hepatitis B virus infection.

Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT- subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients.

Pathway-based stratification of gliomas uncovers four subtypes with different TME characteristics and prognosis.

Increasing evidences have found that the interactions between hypoxia, immune response and metabolism status in tumour microenvironment (TME) have clinical importance of predicting clinical outcomes and therapeutic efficacy. This study aimed to develop a reliable molecular stratification based on these key components of TME. The TCGA data set (training cohort) and two independent cohorts from CGGA database (validation cohort) were enrolled in this study. First, the enrichment score of 277 TME-related signalling pathways was calculated by gene set variation analysis (GSVA). Then, consensus clustering identified four stable and reproducible subtypes (AFM, CSS, HIS and GLU) based on TME-related signalling pathways, which were characterized by differences in hypoxia and immune responses, metabolism status, somatic alterations and clinical outcomes. Among the four subtypes, HIS subtype had features of immunosuppression, oxygen deprivation and active energy metabolism, resulting in a worst prognosis. Thus, for better clinical application of this acquired stratification, we constructed a risk signature by using the LASSO regression model to identify patients in HIS subtype accurately. We found that the risk signature could accurately screen out the patients in HIS subtype and had important reference value for individualized treatment of glioma patients. In brief, the definition of the TME-related subtypes was a valuable tool for risk stratification in gliomas. It might serve as a reliable prognostic classifier and provide rational design of individualized treatment, and follow-up scheduling for patients with gliomas.

Effects of carbamazepine on BDNF expression in trigeminal ganglia and serum in rats with trigeminal neuralgia. / å¡é©¬è¥¿å¹³å¯¹ä¸‰å‰ç¥žç»ç—›å¤§é¼ ä¸‰å‰ç¥žç»èŠ‚åŠè¡€æ¸ ä¸­BDNF表达变化的影响.

OBJECTIVES: Trigeminal neuralgia (TN) is a severe chronic neuropathic pain that mainly affects the distribution area of the trigeminal nerve with limited treating efficacy. There are numerous treatments for TN, but currently the main clinical approach is to suppress pain by carbamazepine (CBZ). Brain-derived neurotrophic factor (BDNF) is closely related to chronic pain. This study aims to determine the effects of CBZ treatment on BDNF expression in both the trigeminal ganglion (TG) and serum of TN via a chronic constriction injury of the infraorbital nerve (ION-CCI) rat model. METHODS: The ION-CCI models were established in male Sprague-Dawley rats and were randomly divided into a sham group, a TN group, a TN+low-dose CBZ treatment group (TN+20 mg/kg CBZ group), a TN+medium-dose CBZ treatment group (TN+40 mg/kg CBZ group), and a TN+high-dose CBZ treatment group (TN+80 mg/kg CBZ group). The mechanical pain threshold in each group of rats was measured regularly before and after surgery. The expressions of BDNF and tyrosine kinase receptor B (TrkB) mRNA in TGs of rats in different groups were determined by real-time PCR, and the expression of BDNF protein on neurons in TGs was observed by immunofluorescence. Western Blotting was used to detect the protein expression of BDNF, TrkB, extracellular regulated protein kinases (ERK), and phospho-extracellular regulated protein kinases (p-ERK) in TGs of rats in different groups. The expression of BDNF in the serum of rats in different groups was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results of mechanical pain sensitivity showed that there was no significant difference in the mechanical pain threshold in the right facial sensory area of the experimental rats in each group before surgery (all P>0.05). From the 3rd day after operation, the mechanical pain threshold of rats in the TN group was significantly lower than that in the sham group (all P<0.01), and the mechanical pain threshold of rats in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 CBZ mg/kg group was higher than that in the TN group (all P<0.05). The BDNF and TrkB mRNA and protein expressions in TGs of rats in the TN group were higher than those in the sham group (all P<0.05), and those in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than the TN group (all P<0.05). The p-ERK levels in TG of rats in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were significantly decreased compared with the TN group (all P<0.05). The BDNF and neuron-specific nuclear protein (NeuN) were mainly co-expressed in neuron of TGs in the TN group and they were significantly higher than those in the sham group (all P<0.05). The co-labeled expressions of BDNF and NeuN in TGs of the TN+ 80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than those in the TN group (all P<0.05). The results of ELISA showed that the level of BDNF in the serum of the TN group was significantly higher than that in the sham group (P<0.05). The levels of BDNF in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than those in the TN group (all P<0.05). Spearman correlation analysis showed that the BDNF level in serum was negatively correlated with mechanical pain threshold (r=-0.650, P<0.01). CONCLUSIONS: CBZ treatment can inhibit the expression of BDNF and TrkB in the TGs of TN rats, reduce the level of BDNF in serum of TN rats and the phosphorylation of ERK signaling pathway, so as to inhibit TN. The serum level of BDNF can be considered as an indicator for the diagnosis and prognosis of TN.

Comprehensive analysis of the clinical and biological significances of cholesterol metabolism in lower-grade gliomas.

BACKGROUND: As a component of membrane lipids and the precursor of oxysterols and steroid hormones, reprogrammed cholesterol metabolism contributes to the initiation and progression of multiple cancers. Thus, we aim to further investigate the significances of cholesterol metabolism in lower-grade gliomas (LGGs). METHODS: The present study included 413 LGG samples from TCGA RNA-seq dataset (training cohort) and 172 LGG samples from CGGA RNA-seq dataset (validation cohort). The cholesterol metabolism-related signature was identified by the LASSO regression model. Bioinformatics analyses were performed to explore the functional roles of this signature in LGGs. Kaplan-Meier and Cox regression analyses were enrolled to estimate prognostic value of the risk signature. RESULTS: Our findings suggested that cholesterol metabolism was tightly associated clinicopathologic features and genomic alterations of LGGs. Bioinformatics analyses revealed that cholesterol metabolism played a key role in immunosuppression of LGGs, mainly by promoting macrophages polarization and T cell exhaustion. Kaplan-Meier curve and Cox regression analysis showed that cholesterol metabolism was an independent prognostic indicator for LGG patients. To improve the clinical application value of the risk signature, we also constructed a nomogram model to predict the 1-, 3- and 5-year survival of LGG patients. CONCLUSION: The cholesterol metabolism was powerful prognostic indicator and could serve as a promising target to enhance personalized treatment of LGGs.

Molecular and clinical characterization of PTRF in glioma via 1,022 samples.

Polymerase I and transcript release factor (PTRF) plays a role in the regulation of gene expression and the release of RNA transcripts during transcription, which have been associated with various human diseases. However, the role of PTRF in glioma remains unclear. In this study, RNA sequencing (RNA-seq) data (n = 1022 cases) and whole-exome sequencing (WES) data (n = 286 cases) were used to characterize the PTRF expression features. Gene ontology (GO) functional enrichment analysis was used to assess the biological implication of changes in PTRF expression. As a result, the expression of PTRF was associated with malignant progression in gliomas. Meanwhile, somatic mutational profiles and copy number variations (CNV) revealed the glioma subtypes classified by PTRF expression showed distinct genomic alteration. Furthermore, GO functional enrichment analysis suggested that PTRF expression was associated with cell migration and angiogenesis, particularly during an immune response. Survival analysis confirmed that a high expression of PTRF is associated with a poor prognosis. In summary, PTRF may be a valuable factor for the diagnosis and treatment target of glioma.

Long non-coding RNA MSTRG.81401 short hairpin RNA relieves diabetic neuropathic pain and behaviors of depression by inhibiting P2X4 receptor expression in type 2 diabetic rats.

Patients with diabetic neuropathic pain (DNP) experience immense physical and mental suffering, which is comorbid with other mental disorders, including major depressive disorder (MDD). P2X4 receptor, one of the purinergic receptors, is a significant mediator of DNP and MDD. The present study aimed to identify the roles and mechanisms of MSTRG.81401, a long non-coding RNA (lncRNA), in alleviating DNP and MDD-like behaviors in type 2 diabetic rats. After administration with MSTRG.81401 short hairpin RNA (shRNA), the model + MSTRG.81401 shRNA group demonstrated increased mechanical withdrawal threshold, thermal withdrawal latency, open-field test, and sucrose preference test; however, immobility time on the forced swimming test decreased. MSTRG.81401 shRNA administration significantly decreased the expression of the P2X4 receptor, tumor necrosis factor-α, and interleukin-1ß in the hippocampus and spinal cord in the model + MSTRG.81401 shRNA group. Simultaneously, MSTRG.81401 shRNA administration downregulated phosphorylation of ERK1/2 in the hippocampus and spinal cord. Thus, lncRNA MSTRG.81401 shRNA can alleviate DNP and MDD-like behaviors in type 2 diabetic rats and may downregulate the expression of P2X4 receptors in the hippocampus and spinal cord of rats.

Acute 1,2-Dichloropropane Poisoning due to Ingestion of Rubber Cement: An Autopsy Case Report and Review.

ABSTRACT: 1,2-Dichloropropane (1,2-DCP) is a common industrial solvent and chemical intermediate that can cause acute poisoning to humans through exposure during its production and industrial use. The target organs of 1,2-DCP include the eyes, respiratory system, liver, kidney, central nervous system, and skin. Forensic identification of 1,2-DCP poisoning is difficult because of the lack of characteristic pathological changes. This article reports an autopsy case of acute 1,2-DCP poisoning caused by self-ingestion of rubber cement. A woman developed seizures and coagulation dysfunction after ingesting approximately 10 mL of rubber cement and died 43 hours later. Autopsy revealed generalized subcutaneous hemorrhage, cardiopulmonary multifocal hemorrhage, bronchopneumonia, severe cerebral edema, focal hepatic necrosis, granular deposition in the glomerular capsule and renal tubules, and delipidation of the adrenal cortex. These findings indicate that 1,2-DCP poisoning can induce central nervous system dysfunction, respiratory system damage, liver and kidney function damage, hemolytic anemia, disseminated intravascular coagulation, and adrenal damage. This case may provide useful perspectives for forensic identification of 1,2-DCP poisoning in the future.

Integrated analysis of the genomic and transcriptional profile of high-grade gliomas in different age groups.

BACKGROUND: Age is a powerful prognostic factor of high-grade glioma (HGG). However, the underlying genetic mechanisms of the discrepant prognosis among different age groups remain elusive. METHODS: A total of 953 and 559 HGG patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts were enrolled and assigned as young, intermediate, elderly groups. The data of clinicopathological characteristics, mRNA, mutation, copy number alteration was analyzed. RESULTS: Transcriptomic analysis revealed that diverse biological processes including immune response are altered between the young and elderly groups. Combined with the analysis of infiltrating immune cells and immune checkpoints, our results suggest an immune suppression status in the elderly group. Patients from different age groups exhibit different mutation and copy number alteration profiles. CONCLUSIONS: A multi-omics analysis is conducted to explore the biological basis of HGG patients of different age groups. This study suggests an immune-suppressive environment in elderly patients.

Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.

Identification of an ATP metabolism-related signature associated with prognosis and immune microenvironment in gliomas.

As the core element of material and energy metabolism pathways, the biological functions and prognostic significance of ATP metabolism in diffuse gliomas have so far remained unclear. Based on comprehensive analysis of ATP metabolism-related gene expression profiles, we constructed an ATP metabolism-related risk signature to determine the role of ATP metabolism. We found that this ATP metabolism-related gene expression profile could divide patients into 2 robust groups with distinct clinical characteristics and prognosis. Patients in the high-risk group tended to be predicted as malignant entities, indicating that the activation of ATP metabolism may promote the malignant progress of diffuse gliomas. Cox regression and Kaplan-Meier analyses suggested that this risk signature was an independent predictor for prognosis. Furthermore, we constructed an individualized prognosis prediction model through nomogram and time-dependent receiver operating characteristic (ROC) curve analyses. Functional analysis suggested that, in addition to material and energy metabolism, ATP metabolism also played an essential role in the regulation of the tumor immune microenvironment. In brief, the ATP metabolism-related signature was tightly associated with regulation of the tumor immune microenvironment and could serve as an independent prognostic biomarker in diffuse gliomas.

A Soft Sensor Approach Based on an Echo State Network Optimized by Improved Genetic Algorithm.

In the process of fault diagnosis and the health and safety operation evaluation of modern industrial processes, it is crucial to measure important state variables, which cannot be directly detected due to limitations of economy, technology, environment and space. Therefore, this paper proposes a data-driven soft sensor approach based on an echo state network (ESN) optimized by an improved genetic algorithm (IGA). Firstly, with an ESN, a data-driven model (DDM) between secondary variables and dominant variables is established. Secondly, in order to improve the prediction performance, the IGA is utilized to optimize the parameters of the ESN. Then, the immigration strategy is introduced and the crossover and mutation operators are changed adaptively to improve the convergence speed of the algorithm and address the problem that the algorithm falls into the local optimum. Finally, a soft sensor model of an ESN optimized by an IGA is established (IGA-ESN), and the advantages and performance of the proposed method are verified by estimating the alumina concentration in an aluminum reduction cell. The experimental results illustrated that the proposed method is efficient, and the error was significantly reduced compared with the traditional algorithm.

Expression profile analysis of antisense long non-coding RNA identifies WDFY3-AS2 as a prognostic biomarker in diffuse glioma.

BACKGROUND: Increasing evidence has shown that long non-coding RNAs (lncRNAs) are important prognostic biomarkers and epigenetic regulators with critical roles in cancer initiation and progression. However, the expression and clinical prognostic value of antisense lncRNAs in diffuse glioma patients remain unknown. METHODS: Here, we profiled differentially expressed antisense lncRNAs in glioma using RNA sequencing data from Chinese Glioma Genome Atlas database. Cox regression was performed to evaluate the prognostic value. Gene oncology (GO) and gene set enrichment analysis (GSEA) were used for functional analysis of antisense LncRNAs. RESULTS: Expression profiling identified 169 aberrantly expressed antisense lncRNAs between lower grade glioma (LGG) (grade II and III) and glioblastoma multiforme (GBM), 113 antisense lncRNAs between LGG IDH-wt and IDH-mut samples, and 70 antisense lncRNAs between GBM IDH-wt and IDH-mut samples, respectively. Among them, three antisense lncRNAs (WDFY3-AS2, MCM3AP-AS1 and LBX2-AS1) were significantly associated with prognosis and malignant progression of patients. WDFY3-AS2, the top one of downregulated antisense lncRNAs in GBM with fold change of 0.441 (P < 0.001), showed specific decreased expression in classical, mesenchymal, LGG IDH-wt, GBM IDH-wt or MGMT promoter unmethylated stratified patients. Chi square test found that WDFY3-AS2 was significantly associated with the clinical and molecular features of glioma. Univariate and multivariate Cox regression analysis indicated that WDFY3-AS2 was independently correlated with overall survival (OS) of patients. Kaplan-Meier analysis found that patients with high WDFY3-AS2 expression had longer OS than the low expression ones in the stratified cohorts. Additionally, GO and GSEA showed that gene sets correlated with WDFY3-AS2 expression were involved in regulation of synaptic transmission, glutamate receptor and TNF signaling pathway. CONCLUSION: Our findings provided convincing evidence that WDFY3-AS2 is a novel valuable prognostic biomarker for diffuse glioma.

ADAR3 expression is an independent prognostic factor in lower-grade diffuse gliomas and positively correlated with the editing level of GRIA2Q607R.

BACKGROUND: RNA editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines (A-to-I) in RNA, that alters gene expression and generates protein diversity. Dysregulation of A-to-I editing has been found associated with a number of nervous system diseases. However, the role of ADAR3, a brain specific high expression adenosine deaminase, in gliomas has rarely been investigated. In this study we illuminated the clinical significance and molecular features of ADAR3 in patients with glioma. METHODS: 309 glioma samples from Chinese Glioma Genome Atlas were enrolled into this study. In validation sets, 601 glioma samples in TCGA, 410 glioma samples in REMBRANDT and 258 glioma samples in GSE16011 were obtained. Relationships between ADAR3 expression and prognosis-related genomic alteration, outcome and gene ontology analysis were investigated. Moreover, the characteristic of GRIA2Q607R editing in gliomas has been investigated. Graphpad Prism 5.0, SPSS 16.0 and R language were used to perform statistical analysis and graphical work. RESULTS: ADAR3 expression was down regulated along with glioma grade progression in CGGA dataset. ADAR3 was characteristically highly expressed in neural subtype and IDH1/2 mutant preference. Moreover, high expression of ADAR3 predicted a better prognosis in lower-grade glioma (LGG) patients and multivariate analysis suggested ADAR3 expression was an independent prognostic indicator. The results of the three other validation datasets showed similar findings. Bioinformatics analyses suggested that ADAR3 may play a role in the malignant transformation of glioma cells by affecting cell proliferation, angiogenesis or cell adhesion. Furthermore, the editing level of GRIA2Q607R was significantly correlated with ADAR3 expression. CONCLUSIONS: Our study demonstrated the clinical and molecular characterization of ADAR3 in glioma development and progression. ADAR3 expression was negatively associated with tumor malignant in the overall glioma patients. And it was a favorable independent prognostic indicator of LGG patients. ADAR3 appeared to act as a tumor suppressor in glioma cells. Therefore, ADAR3 represented a potential therapeutic target and useful prognostic factor for glioma patients.

PVT1 promotes proliferation and macrophage immunosuppressive polarization through STAT1 and CX3CL1 regulation in glioblastoma multiforme.

AIMS: This study aimed to investigate the role of plasmacytoma variant translocation 1 (PVT1), a long non-coding RNA, in glioblastoma multiforme (GBM) and its impact on the tumor microenvironment (TME). METHODS: We assessed aberrant PVT1 expression in glioma tissues and its impact on GBM cell growth in vitro and in vivo. Additionally, we investigated PVT1's role in influencing glioma-associated macrophages. To understand PVT1's role in cell growth and the immunosuppressive TME, we performed a series of comprehensive experiments. RESULTS: PVT1 was overexpressed in GBM due to copy number amplification, correlating with poor prognosis. Elevated PVT1 promoted GBM cell proliferation, while its downregulation inhibited growth in vitro and in vivo. PVT1 inhibited type I interferon-stimulated genes (ISGs), with STAT1 as the central hub. PVT1 correlated with macrophage enrichment and regulated CX3CL1 expression, promoting recruitment and M2 phenotype polarization of macrophages. PVT1 localized to the cell nucleus and bound to DHX9, enriching at the promoter regions of STAT1 and CX3CL1, modulating ISGs and CX3CL1 expression. CONCLUSION: PVT1 plays a significant role in GBM, correlating with poor prognosis, promoting cell growth, and shaping an immunosuppressive TME via STAT1 and CX3CL1 regulation. Targeting PVT1 may hold therapeutic promise for GBM patients.

Efforts to promote osteogenesis-angiogenesis coupling for bone tissue engineering.

Repair of bone defects exceeding a critical size has been always a big challenge in clinical practice. Tissue engineering has exhibited great potential to effectively repair the defects with less adverse effect than traditional bone grafts, during which how to induce vascularized bone formation has been recognized as a critical issue. Therefore, recently many studies have been launched to attempt to promote osteogenesis-angiogenesis coupling. This review summarized comprehensively and explored in depth current efforts to ameliorate the coupling of osteogenesis and angiogenesis from four aspects, namely the optimization of scaffold components, modification of scaffold structures, loading strategies for bioactive substances, and employment tricks for appropriate cells. Especially, the advantages and the possible reasons for every strategy, as well as the challenges, were elaborated. Furthermore, some promising research directions were proposed based on an in-depth analysis of the current research. This paper will hopefully spark new ideas and approaches for more efficiently boosting new vascularized bone formations.

TRAIP suppresses bladder cancer progression by catalyzing K48-linked polyubiquitination of MYC.

TRAF-interacting protein (TRAIP), an E3 ligase containing a RING domain, has emerged as a significant contributor to maintaining genome integrity and is closely associated with cancer. Our study reveals that TRAIP shows reduced expression in bladder cancer (BLCA), which correlates with an unfavorable prognosis. In vitro and in vivo, TRAIP inhibits proliferation and migration of BLCA cells. MYC has been identified as a novel target for TRAIP, wherein direct interaction promotes K48-linked polyubiquitination at neighboring K428 and K430 residues, ultimately resulting in proteasome-dependent degradation and downregulation of MYC transcriptional activity. This mechanism effectively impedes the progression of BLCA. Restoring MYC expression reverses suppressed proliferation and migration of BLCA cells induced by TRAIP. Moreover, our results suggest that MYC may bind to the transcriptional start region of TRAIP, thereby exerting regulatory control over TRAIP transcription. Consequently, this interaction establishes a negative feedback loop that regulates MYC expression, preventing excessive levels. Taken together, this study reveals a mechanism that TRAIP inhibits proliferation and migration of BLCA by promoting ubiquitin-mediated degradation of MYC.

Biomaterial-mediated strategies for accurate and convenient diagnosis, and effective treatment of diabetes: advantages, current progress and future perspectives.

As a kind of widespread chronic disease, diabetes potentially triggers serious complications, thereby severely threatening patients' life and health. To achieve the goal of more accurate and convenient diagnosis, and effective treatment of diabetes that what could be achieved based on traditional methods, many biomaterial-mediated strategies have been launched in recent studies, and have shown promising application potentials. In this review, we have systematically summarized the biomaterial-mediated diagnosis strategies in three parts including combined use of biomedical nanomaterials or organometallic compounds and Raman spectroscopy, utilization of gas sensors made of biomedical metal-oxides to detect glucose in exhaled gas, and detection of glucose by wearable sensors made of biomaterials with high sensitivity and conductivity, and the biomaterial-mediated treatment strategies in four parts including antidiabetic drug delivery by nanoparticles, transdermal drug delivery systems, gels and vesicles, and achieving insulin secretion by transplantation of pancreatic endocrine cells or tissue engineered islets. In particular, advantages of every strategy, current research progress, as well as the challenges and perspectives are elaborated. This review will certainly help to spark new ideas and possibilities for accurate and convenient diagnosis, and effective treatment of diabetes.

The Impact of Living Arrangements and Social Capital on the Well-Being of the Elderly.

This study examines the impact of living arrangements and social capital on the subjective well-being of the elderly, as well as the mutual effects and relationships between the well-being and self-rated health status of the elderly. A total of 369 questionnaires were administered, and the effective recovery rate was 98.10%. The results indicate three key findings: (1) the current location for aging in place, social support, social activities, house ownership, and self-rated health status are indispensable factors affecting the well-being of the elderly. The best location for aging in place was the community, where the elderly's sense of well-being was highest-the next best options were aging at home and institutional care. (2) Elderly people with sole ownership of their homes were more likely to have higher levels of well-being than those owning jointly or who were tenants. (3) There was significant interaction between subjective well-being and self-rated health status.

Effect of Nanoscale in Situ Interface Welding on the Macroscale Thermal Conductivity of Insulating Epoxy Composites: A Multiscale Simulation Investigation.

Insulating thermally conductive polymer composites are in great demand in integrated-circuit packages, for efficient heat dissipation and to alleviative short-circuit risk. Herein, the continuous oriented hexagonal boron nitride (h-BN) frameworks (o-BN@SiC) were prepared via self-assembly and in situ chemical vapor infiltration (CVI) interface welding. The insulating o-BN@SiC/epoxy (o-BN@SiC/EP) composites exhibited enhanced thermal conductivity benefited from the CVI-SiC-welded BN-BN interface. Further, multiscale simulation, combining first-principles calculation, Monte Carlo simulation, and finite-element simulation, was performed to quantitatively reveal the effect of the welded BN-BN interface on the heat transfer of o-BN@SiC/EP composites. Phonon transmission in solders and phonon-phonon coupling of filler-solder interfaces enhanced the interfacial heat transfer between adjacent h-BN microplatelets, and the interfacial thermal resistance of the dominant BN-BN interface was decreased to only 3.83 nK·m2/W from 400 nK·m2/W, plunging by over 99%. This highly weakened interfacial thermal resistance greatly improved the heat transfer along thermal pathways and resulted in a 26% thermal conductivity enhancement of o-BN@SiC/EP composites, compared with physically contacted oriented h-BN/EP composites, at 15 vol % h-BN. This systematic multiscale simulation broke through the barrier of revealing the heat transfer mechanism of polymer composites from the nanoscale to the macroscale, which provided rational cognition about the effect of the interfacial thermal resistance between fillers on the thermal conductivity of polymer composites.