A high reticulocyte count is a risk factor for the onset of metabolic dysfunction-associated steatotic liver disease: Cross-sectional and prospective studies of data of 310,091 individuals from the UK Biobank.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a considerable health risk. Nevertheless, its risk factors are not thoroughly comprehended, and the association between the reticulocyte count and MASLD remains uncertain. This study aimed to explore the relationship between reticulocyte count and MASLD. Methods: A total of 310,091 individuals from the UK Biobank were included in this cross-sectional study, and 7,316 individuals were included in this prospective study. The cross-sectional analysis categorized reticulocyte count into quartiles, considering the sample distribution. Logistic regression models examined the connection between reticulocyte count and MASLD. In the prospective analysis, Cox analysis was utilized to investigate the association. Results: Our study findings indicate a significant association between higher reticulocyte count and an elevated risk of MASLD in both the cross-sectional and prospective analyses. In the cross-sectional analysis, the adjusted odds ratios (ORs) of MASLD increased stepwise over reticulocyte count quartiles (quartile 2: OR 1.22, 95% CI 1.17-1.28, p < 0.001; quartile 3: OR 1.44; 95% CI 1.38-1.51, p < 0.001; quartile 4: OR 1.66, 95% CI 1.59-1.74, p < 0.001). The results of prospective analyses were similar. Conclusion: Increased reticulocyte count was independently associated with a higher risk of MASLD. This discovery offers new insights into the potential of reticulocytes as biomarkers for MASLD.

Research on coronavirus disease 2019 and the kidney: A bibliometric analysis.

Background: In addition to damage to the lungs, coronavirus disease 2019 (COVID-19) can damage multiple organs, including the kidney. Our purpose was to analyze the research hotspots and trends in COVID-19 and kidney diseases using bibliometrics to help clarify the development direction of this field. Methods: We selected and extracted all relevant publications related to COVID-19 and the kidney from the Web of Science from December 1, 2019, to July 24, 2022. VOSviewer, RStudio, CiteSpace, and other software were used to visualize keywords, publishing trends, authors and their countries, and institutions in this field and perform the statistical analysis. Results: A total of 645 articles published in 220 journals were included in this study. The United States and China contributed the most publications and were most active in international cooperation. In addition to COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acute kidney injury (AKI), kidney transplant and mortality were the three keywords with the highest frequencies. In the initial stage of the COVID-19 outbreak, research focused on the clinical symptoms of COVID-19 and other macrocharacteristics, while in a later stage, the associations between SARS-CoV-2 infection and CKD and AKI, as well as the prognosis of patients with kidney disease or those who underwent kidney transplantation, gained more attention. The immune response and vaccines were also recent research hotspots. Conclusions: This bibliometric analysis provides a comprehensive overview of research on COVID-19 and kidney disease, which has received continuous, global attention. AKI, CKD, kidney transplantation, immune response and vaccines are among the hotspots in this field.

Delta opioid receptor expression correlates to skin ageing and melanin expression in Asian women.

While the evidence for the implication of opioid receptors (OPr) in ageing is growing, there is, to our knowledge, no study focusing directly on changes in vivo cutaneous OPr expression with increasing age. We thus investigated OPr expression in 30 healthy female Asian volunteers in Southern China whose ages range from the early 20s to the early 60s. Excisional biopsies were taken from the sun-exposed extensor area of the lower arm and the photo-protected area of the upper inner arm. The thickness of the epidermal layers, melanin content, as well as expression of mu-opioid receptors (MOPr) and delta-opioid receptors (DOPr) were compared between different age ranges and photo-exposure status. Significant increased epidermal hypertrophy on the extensor surface was observed. There was significant reduction of DOPr in the epidermis with increasing age, independent of photo-ageing. The increase of melanin was significantly correlated with epidermal DOPr expression, not with MOPr expression. DOPr expression could thus serve as a marker for real biological ageing unaffected by chronic photo-exposure. Additionally, DOPr expression was inversely correlated with the deposition of melanin. Based on these results, we hypothesise that regulation of DOPr expression could be used to improve aged skin, including hyperpigmentation.

Intraoperative rapid molecular diagnosis aids glioma subtyping and guides precise surgical resection.

OBJECTIVE: The molecular era of glioma diagnosis and treatment has arrived, and a single rapid histopathology is no longer sufficient for surgery. This study sought to present an automatic integrated gene detection system (AIGS), which enables rapid intraoperative detection of IDH/TERTp mutations. METHODS: A total of 78 patients with gliomas were included in this study. IDH/TERTp mutations were detected intraoperatively using AIGS in 41 of these patients, and they were guided to surgical resection (AIGS detection group). The remaining 37 underwent histopathology-guided conventional surgical resection (non-AIGS detection group). The clinical utility of this technique was evaluated by comparing the accuracy of glioma subtype diagnosis before and after TERTp mutation results were obtained by pathologists and the extent of resection (EOR) and patient prognosis for molecular pathology-guided glioma surgery. RESULTS: With NGS/Sanger sequencing and chromosome detection as the gold standard, the accuracy of AIGS results was 100%. And the timing was well matched to the intraoperative rapid pathology report. After obtaining the TERTp mutation detection results, the accuracy of the glioma subtype diagnosis made by the pathologists increased by 19.51%. Molecular pathology-guided surgical resection of gliomas significantly increased EOR (99.06% vs. 93.73%, p < 0.0001) and also improved median OS (26.77 vs. 13.47 months, p = 0.0289) and median PFS (15.90 vs. 10.57 months, p = 0.0181) in patients with glioblastoma. INTERPRETATION: Using AIGS intraoperatively to detect IDH/TERTp mutations to accurately diagnose glioma subtypes can help achieve maximum safe resection of gliomas, which in turn improves the survival prognosis of patients.

Global burden of non-communicable diseases attributable to kidney dysfunction with projection into 2040.

BACKGROUND: Spatiotemporal disparities exist in the disease burden of non-communicable diseases (NCDs) attributable to kidney dysfunction, which has been poorly assessed. The present study aimed to evaluate the spatiotemporal trends of the global burden of NCDs attributable to kidney dysfunction and to predict future trends. METHODS: Data on NCDs attributable to kidney dysfunction, quantified using deaths and disability-adjusted life-years (DALYs), were extracted from the Global Burden of Diseases Injuries, and Risk Factors (GBD) Study in 2019. Estimated annual percentage change (EAPC) of age-standardized rate (ASR) was calculated with linear regression to assess the changing trend. Pearson's correlation analysis was used to determine the association between ASR and Sociodemographic Index (SDI) for 21 GBD regions. A Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2040. RESULTS: Between 1990 and 2019, the absolute number of deaths and DALYs from NCDs attributable to kidney dysfunction increased globally. The death cases increased from 1,571,720 (95% uncertainty interval [UI]: 1,344,420-1,805,598) in 1990 to 3,161,552 (95% UI: 2,723,363-3,623,814) in 2019 for both sexes combined. Both the ASR of death and DALYs increased in Andean Latin America, the Caribbean, Central Latin America, Southeast Asia, Oceania, and Southern Sub-Saharan Africa. In contrast, the age-standardized metrics decreased in the high-income Asia Pacific region. The relationship between SDI and ASR of death and DALYs was negatively correlated. The BAPC model indicated that there would be approximately 5,806,780 death cases and 119,013,659 DALY cases in 2040 that could be attributed to kidney dysfunction. Age-standardized death of cardiovascular diseases (CVDs) and CKD attributable to kidney dysfunction were predicted to decrease and increase from 2020 to 2040, respectively. CONCLUSION: NCDs attributable to kidney dysfunction remain a major public health concern worldwide. Efforts are required to attenuate the death and disability burden, particularly in low and low-to-middle SDI regions.

The Opioid Receptor Influences Circadian Rhythms in Human Keratinocytes through the ß-Arrestin Pathway.

The recent emphasis on circadian rhythmicity in critical skin cell functions related to homeostasis, regeneration and aging has shed light on the importance of the PER2 circadian clock gene as a vital antitumor gene. Furthermore, delta-opioid receptors (DOPrs) have been identified as playing a crucial role in skin differentiation, proliferation and migration, which are not only essential for wound healing but also contribute to cancer development. In this study, we propose a significant association between cutaneous opioid receptor (OPr) activity and circadian rhythmicity. To investigate this link, we conducted a 48 h circadian rhythm experiment, during which RNA samples were collected every 5 h. We discovered that the activation of DOPr by its endogenous agonist Met-Enkephalin in N/TERT-1 keratinocytes, synchronized by dexamethasone, resulted in a statistically significant 5.6 h delay in the expression of the core clock gene PER2. Confocal microscopy further confirmed the simultaneous nuclear localization of the DOPr-ß-arrestin-1 complex. Additionally, DOPr activation not only enhanced but also induced a phase shift in the rhythmic binding of ß-arrestin-1 to the PER2 promoter. Furthermore, we observed that ß-arrestin-1 regulates the transcription of its target genes, including PER2, by facilitating histone-4 acetylation. Through the ChIP assay, we determined that Met-Enkephalin enhances ß-arrestin-1 binding to acetylated H4 in the PER2 promoter. In summary, our findings suggest that DOPr activation leads to a phase shift in PER2 expression via ß-arrestin-1-facilitated chromatin remodeling. Consequently, these results indicate that DOPr, much like its role in wound healing, may also play a part in cancer development by influencing PER2.

Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy.

BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.

Dual mutations in the whitefly nicotinic acetylcholine receptor ß1 subunit confer target-site resistance to multiple neonicotinoid insecticides.

Neonicotinoid insecticides, which target insect nicotinic acetylcholine receptors (nAChRs), have been widely and intensively used to control the whitefly, Bemisia tabaci, a highly damaging, globally distributed, crop pest. This has inevitably led to the emergence of populations with resistance to neonicotinoids. However, to date, there have been no reports of target-site resistance involving mutation of B. tabaci nAChR genes. Here we characterize the nAChR subunit gene family of B. tabaci and identify dual mutations (A58T&R79E) in one of these genes (BTß1) that confer resistance to multiple neonicotinoids. Transgenic D. melanogaster, where the native nAChR Dß1 was replaced with BTß1A58T&R79E, were significantly more resistant to neonicotinoids than flies where Dß1 were replaced with the wildtype BTß1 sequence, demonstrating the causal role of the mutations in resistance. The two mutations identified in this study replace two amino acids that are highly conserved in >200 insect species. Three-dimensional modelling suggests a molecular mechanism for this resistance, whereby A58T forms a hydrogen bond with the R79E side chain, which positions its negatively-charged carboxylate group to electrostatically repulse a neonicotinoid at the orthosteric site. Together these findings describe the first case of target-site resistance to neonicotinoids in B. tabaci and provide insight into the molecular determinants of neonicotinoid binding and selectivity.

Regulatory mechanism and promising clinical application of exosomal circular RNA in gastric cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide and the leading cause of cancer-related deaths. Exosomes are nanoscale extracellular vesicles secreted by a variety of cells and play an important role in cellular communication and epigenetics by transporting bioactive substances in the tumor microenvironment (TME). Circular RNA (circRNA) is a type of non-coding RNA (ncRNA) with a specific structure, which is widely enriched in exosomes and is involved in various pathophysiological processes mediated by exosomes. Exosomal circRNAs play a critical role in the development of GC by regulating epithelial-mesenchymal transition (EMT), angiogenesis, proliferation, invasion, migration, and metastasis of GC. Given the biological characteristics of exosomal circRNAs, they have more significant diagnostic sensitivity and specificity in the clinic and may become biomarkers for GC diagnosis and prognosis. In this review, we briefly describe the biogenesis of exosomes and circRNAs and their biological functions, comprehensively summarize the mechanisms of exosomal circRNAs in the development of GC and chemotherapy resistance, and finally, we discuss the potential clinical application value and challenges of exosomal circRNAs in GC.

Total flavonoids of Cynomorium songaricum attenuates cognitive defects in an Aß 1-42 -induced Alzheimer's disease rat model by activating BDNF/TrkB signaling transduction.

Alzheimer's disease (AD) is a degenerative disorder characterized by cognitive dysfunction and BDNF/TrkB is a well-conceived anti-AD signaling. Cynomorium songaricum Rupr. ( C. songaricum ) is a herb with promising neuroprotective effects and the function is majorly attributed to flavonoids. The current study attempted to explore the effects of total flavonoids of C. songaricum (CS) on AD model by focusing on changes in BDNF/TrkB axis. AD model was induced in rats via transcranial injection of Aß 1-42 and AD symptoms treated with CS of three doses. Donepezil was used as the positive control. Changes in rat memory and learning abilities, brain histological, apoptosis, production of neurotransmitters, BDNF/TrkB axis, and apoptosis-related markers were measured. The injection of Aß 1-42 induced cognitive dysfunction in AD rats. The integrity of brain tissue structure was destructed and apoptosis was induced in AD rats, in which was found the increased production of AChE and Aß 1-42 , and decreased production of ChAT, ACH. At the molecular level, the expression of BDNF, TrkB, and Bcl-2 was suppressed, while the expression of Bax, caspase-3, and caspase-9 was induced. After the administration of CS, the memory and learning abilities of rats were improved, the production of neurotransmitter was restored, ordered arrangement of pyramidal cells was retained, and neuron apoptosis was inhibited. The attenuation of Aß 1-42 -indcued impairments was associated with the activation of BDNF/TrkB axis and blockade of apoptosis-related pathways. Collectively, CS can improve learning and memory abilities in Aß 1-42 -induced AD model rats. which may depend on the activation of the hippocampal BDNF/TrkB signaling pathway.

Congenital pulmonary lymphatic duct hypoplasia in a fetus with hydrops fetalis found at delivery: A case report.

Objective: To elaborate the clinical characteristics of congenital pulmonary lymphangiectasia in a neonate with hydrops fetalis. This could be an alert in considering it as a differential diagnosis for neonates with acute respiratory failure. Methods: We reviewed and analyzed single-center registry patients who underwent cadaveric autopsies in the Department of Pathology at Children's Hospital from January 1, 2010 to December 31, 2021. We aimed to explore the perinatal clinical manifestations associated with congenital pulmonary lymphangiectasis (CPL). Literature was reviewed to summarize the common features of CPL in pregnancy from individual cases, and to facilitate prenatal and intrapartum diagnosis prognosis, and assessment of medical emergencies. Results: Thirty-four patients were included, and the main causes of death were intrauterine infection (n = 6), severe pneumonia (n = 11), spontaneous pneumothorax (n = 3), hemorrhagic shock (n = 2), CPL (n = 1), and other non-respiratory failure manifestations (n = 12). The manifestations of respiratory distress in CPL were different from those of intrauterine infections and respiratory failure due to parenchymal lung lesions. These include prenatal presentation of fetal edema, postnatal presentation of uncorrectable respiratory failure with severe hypoproteinemia, pneumothorax and interstitial emphysema on imaging, and poor response to treatment with surfactant-like substances. Thus, when the pregnancy tests reveal fetal edema and postnatal presentation of acute, respiratory distress, the diagnosis of CPL should be considered first, and corresponding medical care should be implemented to improve the survival rate. Conclusions: CPL is a rare pulmonary defect, and its perinatal clinical manifestations can often be neglected. For children with prenatal fetal edema who die after birth due to progressive respiratory distress, a timely autopsy is of utmost importance to clarify the etiology, improve understanding of CPL, and diagnose early to allow for proper prenatal and postnatal care.

Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression.

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.

Monolithic Saturable Absorber with Gallium Arsenide Nanowires Integrated on the Flexible Substrate for Optical Pulse Generation.

In this work, we demonstrated a kind of flexibly monolithic saturable absorber (SA) with GaAs nanowires (NWs) on polyimide (PI) plastic substrate for broadband optical modulation at 1.0 and 1.5 µm, separately. The monolithic SA sample was prepared by the metalorganic vapor phase epitaxy (MOVPE) method. The crystal structure and element analysis were examined carefully by high-resolution scanning transmission electron microscopy (HRSTEM) and energy-dispersive X-ray spectroscopy (EDX). We observed a high-density distribution of NWs on the flexible substrate by scanning electron microscopy (SEM). In addition, linear and nonlinear optical properties of the sample were examined by testing the photoluminescence and absorption properties, which showed its potential application as an optical switch due to the pure semiconducting properties. After the characterizations, we experimentally demonstrated this monolithic SA for laser modulation at 1.0 and 1.5 µm, which yielded the minimum optical pulse widths of 1.531 and 6.232 µs, respectively. Our work demonstrated such a kind of monolithic flexible NW substrate-integrated device used for broadband optical modulation, which not only eased the integration process of NWs onto the fiber endface, but also proved the potential of easily integrating with more semiconducting nanomaterials (e.g., graphene, MoS2, …) to realize monolithic active flexible photonic systems, such as a microscale phase modulator, delay-line, and so on, paving an easy avenue for the development of both active and flexible photonic devices.

Efficacy and safety of different PD-1 inhibitors in combination with lenvatinib in the treatment of unresectable primary liver cancer: a multicentre retrospective study.

Immune checkpoint inhibitors (ICIs) are safe and efficacious treatments for advanced primary liver cancer (PLC). The efficacy of different ICIs in the treatment of liver cancer remains unclear. The purpose of this study was to explore whether there is a difference in the efficacy and safety of various programmed cell death protein 1 (PD-1) inhibitors in combination with lenvatinib in the treatment of unresectable PLC. Patients with PLC treated with lenvatinib in combination with PD-1 inhibitors (camrelizumab, tislelizumab, sintilimab, or pembrolizumab) between January 2018 and December 2021 were retrospectively enrolled. Tumor response, adverse events, and grades were evaluated. Kaplan-Meier analysis and log-rank test were used to compare the overall survival and progression-free survival of patients treated with different PD-1 inhibitors. Cox regression analysis was used for univariate and multivariate analyses to identify clinical variables related to treatment efficacy. This study included a total of 176 patients who received a combination of lenvatinib and PD-1 inhibitors. Of these, 103 patients received camrelizumab, 44 received tislelizumab, 20 received sintilimab, and 9 received pembrolizumab. There was no significant difference in the pairwise comparison of camrelizumab, tislelizumab, sintilimab, and pembrolizumab using Kaplan-Meier survival analysis. Adverse events occurred in 40 (22.7%) patients (grade ≥ 3, 2.3%). The incidence of grade 3 adverse events among the four PD-1 inhibitor groups was below 5%. Camrelizumab, tislelizumab, sintilimab, and pembrolizumab are viable options for patients with unresectable PLC. These PD-1 inhibitors in combination with lenvatinib showed good safety profiles. The results guide selecting treatment for patients with unresectable PLC.

Transcriptomics and systems network-based molecular mechanism of herbal formula Huosu-Yangwei inhibited gastric cancer in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: The efficacy of the herbal formula Huosu-Yangwei (HSYW) in the treatment of advanced gastric cancer and chronic atrophic gastritis with precancerous lesions has been reported in clinical trials. However, the molecular mechanisms underlying its inhibition of gastric tumor are not well-understood. AIM OF THE STUDY: Combined with transcriptomics and systems network-based molecular mechanism to explore the potential circRNA-miRNA-mRNA network of HSYW in the treatment of gastric cancer. MATERIALS AND METHODS: Animal experiments were conducted to investigate the effect of HSYW on tumor growth in vivo. RNA sequencing (RNA-seq) was implemented to identify the differentially expressed (DE) genes. Predictive miRNA targets and mRNA were used to construct circRNA-miRNA-mRNA networks and protein-protein interaction (PPI) networks. Quantitative real-time PCR (qRT-PCR) was utilized to verify the accuracy of the proposed circRNA-miRNA-mRNA networks. Additionally, the differentially expressed target proteins between gastric cancer (GC) and normal patients were assessed using data from the TCGA (The Cancer Genome Atlas) and HPA (The Human Protein Atlas) databases. RESULTS: We demonstrate HSYW significantly inhibits tumor growth of N87 cell-bearing Balb/c mice. Transcriptomic analysis revealed the existence of 119 differentially expressed (DE) circRNAs and 200 DE mRNAs between HSYW-treated and model mice. By associating predicted circRNA-miRNA pairs and miRNA-mRNA pairs, we constructed a circRNA-miRNA-mRNA (CMM) network. Furthermore, a protein-protein interaction (PPI) network was developed using the differential expressed mRNAs. Consequently, the reconstructed core CMM network and qRT-PCR validation indicated that 4 circRNAs, 5 miRNAs and 6 mRNAs could potentially serve as biomarkers to assess the therapeutic effects of HSYW-treated N87-bearing Balb/c mice. The TCGA and HPA databases also demonstrated that mRNA KLF15 and PREX1 had substantial differences between gastric cancer (GC) and healthy controls. CONCLUSIONS: By combining the experimental and bioinformatics analysis, this study confirms that the circRNA_00240/hsa-miR-642a-5p/KLF15 and circRNA_07980/hsa-miR-766-3p/PREX1 pathways play critical roles in HSYW-treated gastric cancer.

Systematic analysis identifies REST as an oncogenic and immunological biomarker in glioma.

The repressor element 1 silencing transcription factor (REST) has been proposed to function as a transcription factor to silence gene transcription by binding to repressor element 1 (RE1), a highly conserved DNA motif. The functions of REST in various tumors have been studied, but its role and correlation with immune cell infiltration remains uncertain in gliomas. REST expression was analyzed in datasets of The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) and validated by the Gene Expression Omnibus and Human Protein Atlas databases. The clinical prognosis of REST was evaluated by clinical survival data of TCGA cohort and validated by Chinese Glioma Genome Atlas cohort. MicroRNAs (miRNAs) contributing to REST overexpression in glioma were identified by a combination of a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. The correlations between immune cell infiltration level and REST expression were analyzed by TIMER2 and GEPIA2 tools. Enrichment analysis of REST was performed using STRING and Metascape tools. The expression and function of predicted upstream miRNAs at REST and their association with glioma malignancy and migration were also confirmed in glioma cell lines. REST was highly expressed and associated with poorer overall survival and disease-specific survival in glioma and some other tumors. MiR-105-5p and miR-9-5p were identified as the most potential upstream miRNAs of REST in glioma patient cohort and experiments in vitro. REST expression was positively correlated with infiltration of immune cells and the expression of immune checkpoints such as PD1/PD-L1 and CTLA-4 in glioma. Furthermore, histone deacetylase 1 (HDAC1) was a potential REST-related gene in glioma. Enrichment analysis of REST found chromatin organization and histone modification were the most significant enriched terms, and Hedgehog-Gli pathway might be involved in the effect of REST on the pathogenesis of glioma. Our study suggests REST to be an oncogenic gene and the biomarker of poor prognosis in glioma. High REST expression might affect the tumor microenvironment of glioma. More basic experiments and large clinical trials aimed at the carcinogenetic study of REST in glioma will be needed in the future.

Application of Intraoperative Rapid Molecular Diagnosis in Precision Surgery for Glioma: Mimic the World Health Organization CNS5 Integrated Diagnosis.

BACKGROUND: With the advent of the molecular era, the diagnosis and treatment systems of glioma have also changed. A single histological type cannot be used for prognosis grade. Only by combining molecular diagnosis can precision medicine be realized. OBJECTIVE: To develop an automatic integrated gene detection system (AIGS) for intraoperative detection in glioma and to explore its positive role in intraoperative diagnosis and treatment. METHODS: We analyzed the isocitrate dehydrogenase 1 (IDH1) mutation status of 105 glioma samples and evaluated the product's potential value for diagnosis; 37 glioma samples were detected intraoperatively to evaluate the feasibility of using the product in an actual situation. A blinding method was used to evaluate the effect of the detection technology on the accuracy of intraoperative histopathological diagnosis by pathologists. We also reviewed the current research status in the field of intraoperative molecular diagnosis. RESULTS: Compared with next-generation sequencing, the accuracy of AIGS in detecting IDH1 was 100% for 105 samples and 37 intraoperative samples. The blind diagnostic results were compared between the 2 groups, and the molecular information provided by AIGS increased the intraoperative diagnostic accuracy of glioma by 16.2%. Using the technical advantages of multipoint synchronous detection, we determined the tumor molecular margins for 5 IDH-positive patients and achieved accurate resection at the molecular level. CONCLUSION: AIGS can quickly and accurately provide molecular information during surgery. This methodology not only improves the accuracy of intraoperative pathological diagnosis but also provides an important molecular basis for determining tumor margins to facilitate precision surgery.

A trio of tumor suppressor miRNA downregulates CREB5 dependent transcription to modulate neoadjuvant hormonal therapy sensitivity.

Neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy (RP) is an approach that can potentially maximize survival outcomes in prostate cancer (PCa) patients with high-risk disease. Unfortunately, subsets of patients do not respond well to such hormonal therapy. We previously identified several pathological parameters in predicting differences in response to NHT of PCa. However, little is known about the potential role and mechanism of miRNAs mediated NHT resistance (NHT-R) in PCa. Here we demonstrate that miR-l42-3p, miR-150-5p and miR-342-3p are the top downregulated miRNAs in PCa tissues with NHT-R. Functional analysis reveals that the three miRNAs inhibit cell proliferation in vitro. Transfection of miRNAs mimics strengthens the inhibitory effects of bicalutamide and enzalutamide to PCa cells. Luciferase reporter assay reveals that CREB5 is the common target of these three miRNAs. Clinically, high expression level of CREB5 correlates with high Gleason score, advanced tumor stage and NHT-R in PCa tissues. CREB5 expression promotes antiandrogen therapy resistance in LNCaP cells and IL6 signaling pathway may be involved in this process. In all, our findings highlight an important role of miR-142-3p, miR-150-5p, and miR-342-3p in contributing NHT-R by targeting CREB5 in PCa.