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Abstract Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.

Abstract Background Immune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically “hot” tumors. However, immune dynamics in the low T-cell infiltrating “cold” tumor immune microenvironment during ICB remain poorly understood. This study uses molecular imaging to evaluate changes in CD4 + T cells and CD8 + T cells during ICB in breast cancer models and examines biomarkers of response. Methods [89Zr]Zr-DFO-CD4 and [89Zr]Zr-DFO-CD8 radiotracers were used to quantify changes in intratumoral and splenic CD4 T cells and CD8 T cells in response to ICB treatment in 4T1 and MMTV-HER2 mouse models, which represent immunologically “cold” tumors. A correlation between PET quantification metrics and long-term anti-tumor response was observed. Further biological validation was obtained by autoradiography and immunofluorescence. Results Following ICB treatment, an increase in the CD8-specific PET signal was observed within 6 days, and an increase in the CD4-specific PET signal was observed within 2 days in tumors that eventually responded to immunotherapy, while no significant differences in CD4 or CD8 were found at the baseline of treatment that differentiated responders from nonresponders. Furthermore, mice whose tumors responded to ICB had a lower CD8 PET signal in the spleen and a higher CD4 PET signal in the spleen compared to non-responders. Intratumoral spatial heterogeneity of the CD8 and CD4-specific PET signals was lower in responders compared to non-responders. Finally, PET imaging, autoradiography, and immunofluorescence signals were correlated when comparing in vivo imaging to ex vivo validations. Conclusions CD4- and CD8-specific immuno-PET imaging can be used to characterize the in vivo distribution of CD4 + and CD8 + T cells in response to immune checkpoint blockade. Imaging metrics that describe the overall levels and distribution of CD8 + T cells and CD4 + T cells can provide insight into immunological alterations, predict biomarkers of response to immunotherapy, and guide clinical decision-making in those tumors where the kinetics of the response differ.

Under the leadership of the Communist Party of China (CPC), this study aims to explore the relationship between independent directors who are CPC members and firms' ESG (environmental, social, and governance) performance. We use a sample of 30,629 A-share firms in China for the period 2012–2021. Our main results show that CPC membership among independent directors can significantly improve firms' ESG performance, with board meetings serving as an important mechanism for this effect. We also examine the impact of CPC membership on external supervision, attention levels, “full and strict governance over the Party”, and ownership nature. The influence of independent directors' CPC membership on firms' ESG performance is greater in companies lacking external supervision, those with higher attention levels, and in state-owned enterprises (SOEs).

Abstract Background Hyperuricemia and low level of high-density lipoprotein cholesterol (HDL-C) are both risk factors for coronary artery disease (CAD). The uric acid to HDL-C ratio (UHR) has recently been identified as a new inflammatory and metabolic biomarker. However, the relationship between the UHR and coronary culprit plaques has not been fully investigated in patients with acute coronary syndrome (ACS). Methods A total of 346 patients with ACS were enrolled in this study. Culprit lesion characteristics were assessed by optical coherence tomography (OCT). Logistic regression and linear correlation analyses were performed to assess the association between the UHR and culprit plaques. The predictive value of the UHR was investigated by receiver operating characteristic (ROC) curve analysis. Results The percentages of typical culprit plaques, including ruptures, erosions and thrombi, were greater in the high-UHR subgroup than those in the low-UHR subgroup. A positive relationship was also found between the UHR and diameter stenosis (r = 0.160, P = 0.003) and between the UHR and area stenosis (r = 0.145, P = 0.007). The UHR was found to be independently associated with plaque rupture, erosion and thrombus. Furthermore, ROC analysis suggested that the UHR had a better predictive value than low-density lipoprotein cholesterol. Conclusions An elevated UHR level was independently related to the occurrence rate of culprit plaques. The UHR is a simple and easily acquired parameter for detecting culprit plaques in patients with ACS.

ABSTRACTOff-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver. We identified a positive electrostatic patch highly conserved in a germline family very commonly used in the humanization of approved biologics. Neutralization of this patch led to a drastic reduction in the kidney uptake, leading to a biodistribution more favorable to the delivery of highly cytotoxic payloads. Next, we conducted a high throughput study of the electrostatic properties for all combinations of VH and VL germlines. This analysis shows how different VH/VL combinations exhibit varying tendencies to create electrostatic patches, resulting in Fv variants with different isoelectric points. Our work emphasizes the importance of carefully selecting germlines for humanization with optimal electrostatic properties in order to control the unspecific tissue uptake of low molecular weight biologics.

Much research describes gut microbiota in atherosclerotic cardiovascular diseases (ASCVD) for that the composition of the intestinal microbiome or its metabolites can directly participate in the development of endothelial dysfunction, atherosclerosis and its adverse complications. Salidroside, a natural phenylpropane glycoside, exhibits promising biological activity against the progression of ASCVD. Recent studies suggested that the gut microbiota played a crucial role in mediating the diverse beneficial effects of salidroside on health. Here, we describe the protective effects of salidroside against the progression of atherosclerosis. Salidroside regulates the abundance of gut microbiotas and gut microbe-dependent metabolites. Moreover, salidroside improves intestinal barrier function and maintains intestinal epithelial barrier function integrity. In addition, salidroside attenuates the inflammatory responses exacerbated by gut microbiota disturbance. This review delves into how salidroside functions to ameliorate atherosclerosis by focusing on its interaction with gut microbiota, uncovering the potential roles of gut microbiota in the diverse biological impacts of salidroside.

BackgroundHypertrophic Cardiomyopathy (HCM), a widespread genetic heart disorder, is largely associated with sudden cardiac fatality. Necroptosis, an emerging type of programmed cell death, plays a fundamental role in several cardiovascular diseases.AimThis research utilized bioinformatics analysis to investigate necroptosis's implication in HCM.MethodsThe study retrieved RNA sequencing datasets GSE130036 and GSE141910 from the Gene Expression Omnibus (GEO) database. It detected necroptosis-linked differentially expressed genes (NRDEGs) by reviewing both the gene set for necroptosis and the differently expressed genes (DEGs). The enriched signaling pathway of HCM was assessed using GSEA, while common DEGs were studied through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Concurrently, the Protein-Protein Interaction network (PPI) proved useful for identifying central genes. CIBERSORT facilitated evaluating the correlation between distinct immune cell-type prevalence and NRDEGs by analyzing immune infiltration patterns. Lastly, GSE141910 dataset validated the expression ranks of NRDEGs and immune-cell penetration.ResultsThe investigation disclosed significant enrichment and activation of the necroptosis pathway in HCM specimens. Seventeen diverse genes, including CYBB, BCL2, and JAK2 among others, were identified in the process. PPI network scrutiny classified nine of these genes as central genes. Results from GO and KEGG enrichment analyses showed substantial connections of these genes to pathways pertaining to the HIF-1 signaling track, necroptosis, and NOD-like receptor signaling process. Moreover, an imbalance in M2 macrophage cells in HCM samples was observed. Finally, CYBB, BCL2, and JAK2 emerged as vital genes and were validated using the GSE141910 dataset.ConclusionThese results indicate necroptosis as a probable underlying factor in HCM, with immune cell infiltration playing a part. Additionally, CYBB, BCL2, JAK2 could act as potential biomarkers for recognizing HCM. This information forms crucial insights into the basic mechanisms of HCM and could enhance its diagnosis and management.

IntroductionGlioma is the most common primary intracranial neoplasm with a relatively poor prognosis.Case presentationHere, we present a unique case of a 53-year-old woman with two histopathologically distinct gliomas at the initial diagnosis. She presented with headaches and left limb weakness before admission, and magnetic resonance imaging (MRI) showed right frontal and basal ganglia area involvement combined with hemorrhage. The patient underwent a navigation-guided craniotomy for tumor removal. Pathological examination revealed the right frontal lobe lesion as a WHO grade II IDH-NOS astrocytoma, but the right parietal lobe lesion was a WHO grade IV IDH-mutant diffuse astrocytoma. Molecular detection of the parietal lesion revealed a point mutation at the R132 locus of the IDH1 gene, no mutation in the TERT promoter, amplification of the epidermal growth factor receptor, and a non-homozygous CDKN2A/B deletion.DiscussionIn-depth epigenomic analysis and molecular examination revealed that one patient had two different brain tumors, underscoring the importance of performing a comprehensive brain tumor workup.ConclusionThis unique case confirms that adjacent astrocytomas may have different molecular pathogenesis and provides novel insights into the development of gliomas.

Abstract Background Acute ischemic stroke (AIS) is one of the leading contributors to death and disability in adults. And cuproptosis is a novel type of cell death. Yet, its role in AIS is still unknown. Methods The mRNA, miRNA, and circRNA expression data were downloaded from the Gene Expression Omnibus database. We explored differentially expressed circRNAs (DEcircRNAs), microRNAs (DEmiRNAs), and cuproptosis-related genes (DECuRGs) after AIS. With the target prediction tools, we constructed a cuproptosis-related competitive endogenous RNA (ceRNA) network mediated by circRNAs in AIS. Afterward, functional enrichment analysis, cytoHubba plugin, protein–protein interaction, weighted gene co-expression network analysis, and unsupervised clustering analysis were performed to determine the critical genes and relevant pathways. Machine learning techniques were used to identify the optimal risk model. The CIBERSORT was applied to explore the immune-infiltrating characteristics in AIS samples. Finally, two independent datasets were employed to verify the predictive value of the risk model. Results Altogether, 26 DECuRGs were identified in this study. Enrichment analysis revealed that they participated in the reactive oxygen metabolism, inflammatory responses, and corresponding cuproptosis-related biological processes. Of the DECuRGs, MTF1 and UBE2D2 were included in the ceRNA network, comprising three circRNA-miRNA and two miRNA-mRNA interaction pairs. Hub gene analysis determined the hub regulatory axis in the process of cuproptosis, namely, MTF1-miR-765-circ_0040760/0068531. We finally constructed a 5-gene risk model (C10orf32, NUCB1, AX748267, MRPL28, and PPP1R15A) by multiple analyses, which was validated by two independent datasets (AUC = 0.958 and 0.668). Besides, significant differences in immune cell infiltration were observed between AIS patients and normal controls. The levels of neutrophils were correlated with most of the DECuRGs. The ceRNA axis identified in this study was also associated with the immune microenvironment of AIS patients. Conclusion The findings revealed that cuproptosis might be associated with AIS and that the key nodes, including the regulatory axes, might exert critical roles in the process of AIS. The risk model provided new insights into the early diagnosis and treatment of AIS.

Quantum key distribution with continuous-variable (CVQKD) provides an alternative way for the security improvement of underwater optical communication, but facing into the awkward situation of short distance. For this reason, here we exploit photon addition operation at the emitter into enhancing the performance of underwater CVQKD. Based on numerical simulation, it is shown that applying photon-addition non-Gaussian operation between entangled resource and the sender can further enhance both the secure key rate and the transmission distance, compared to apply photon subtraction operation between entangled resource and the receiver. In addition, the influence of seawater quality factors in underwater CVQKD system is also considered, so as to provide technical support for underwater safety communication.

Objective: To design new and effective polyphenol oxidase （PPO） inhibitors and expand their application in the field of aquatic product preservation. Methods: The synthesized H8[P2Mo17Ni（OH2）O61] （P2Mo17Ni） structure was characterized by ultraviolet and infrared spectrum. The inhibitory effect, type and mechanism of P2Mo17Ni on the relative activity of mushroom PPO in vitro was clarified. Then, the preservation effects of P2Mo17Ni on Litopenaeus vannamei Boone were evaluated through studying the index change of shrimps treated with P2Mo17Ni stored at 4 ℃, in which included the sensory score, the value of chromatic aberration L*, the value of total chromatic aberration （ΔE）, the total number of colonies, the value of pH and the value of total volatile basic nitrogen （TVB-N）. Results: The results showed that P2Mo17Ni was synthesized successfully. P2Mo17Ni inhibited the activity of PPO from mushroom in vitro with semi-inhibitory concentration （IC50） of （0.377±0.004） mmol/L. P2Mo17Ni inhibited mushroom PPO in a competitive reversible manner, and the inhibition constant KI was 0.185 mmol/L. Under the cold storage condition of 4 ℃, compared with the control group, P2Mo17Ni could effectively delay the decline of sensory score and the increase of L* and ΔE value in shrimps treated with P2Mo17Ni, and the inhibitory effect was significant. P2Mo17Ni could significantly inhibit the increase of total number of colonies, pH value and TVB-N value. P2Mo17Ni could extend the shelf life of shrimps for 4~5 days. Conclusion: P2Mo17Ni can slow down the blackening of shrimps and prevent its spoilage. P2Mo17Ni possesses a good preservation effect on L. vannamei and can be used in the preservation industry of aquatic products.

Abstract Background The effect of neuroinflammatory cytokines on cognitive deficits in patients with major depressive disorder (MDD) can be altered by selective serotonin reuptake inhibitors (SSRIs). This study aimed to examine serum interleukin-8 (IL-8) levels, cognitive function, and their associations in MDD patients with SSRIs. Methods Thirty SSRI-treated MDD patients and 101 healthy controls were recruited for this study. We examined cognitive performance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-8 levels using the Human Inflammatory Cytokine Cytometric Bead Array in both cases and controls. Results The RBANS test scores were significantly lower in MDD patients with SSRIs than in healthy controls after controlling for covariates (all p

Abstract Background The circular RNA (circRNA) plays a vital role in the pathogenesis of tumors as a competitive endogenous RNA (ceRNA). Given the high aggressiveness and fatality rate of glioblastoma (GBM) as well as poor prognosis, it is necessary to construct a circRNA-related ceRNA network for further studies on the mechanism of GBM and identify possible biomarkers as well as therapeutic drugs. Methods Three datasets from the gene expression omnibus (GEO) database were downloaded to distinguish differential circRNAs, microRNAs, and messenger RNAs respectively in GBM. With the help of GEPIA2, circBank, CSCD, TargetScan, miRDB, and miRTarBase databases, we established a circRNAs-related ceRNA network in GBM. Functional enrichments were employed to profile the most relevant mRNAs to indirectly clarify the mechanisms of the ceRNA network. Based on the expression profile data and survival information of GBM patients from the GEO and the cancer genome atlas (TCGA) databases, we performed survival analysis to select prognostic mRNAs and constructed a novel circRNA-miRNA-mRNA central regulatory subnetwork. The DGIdb database was used to find potential drug–gene interactions. Results The datasets obtained from the GEO and TCGA databases were analyzed, and 504 differentially expressed mRNAs (DEmRNAs), 71 differentially expressed microRNAs (DEmiRNAs), and 270 differentially expressed circRNAs (DEcircRNAs) were screened out. The novel ceRNA regulatory network included 22 circRNAs, 11 miRNAs, and 15 mRNAs. FZD1 and KLF10 were significantly correlated with the overall survival rate of patients with GBM (P