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Abstract ER+/HER2- breast cancer is a common subtype of breast cancer. This study aimed to evaluate the prognostic value of ER-to-PR difference (EPD) in ER+/HER2- early breast cancer (EBC). A retrospective cohort study was conducted, including 3,340 ER+/HER2- EBC patients, divided into a training cohort of 2,873 patients and a validation cohort of 467 patients. The optimal EPD cutoff value for stratifying patients was determined using X-tile. Additionally, the prognostic value of EPD, when combined with other clinicopathological factors, was assessed using the Cox proportional hazards model and five traditional machine learning methods. The optimal cutoff value for EPD was determined as 10%, categorizing patients into EPD-low (ER-PR ≤ 10%) and EPD-high (ER-PR > 10%) expression groups. Patients with EPD-high tumors exhibited a poorer prognosis compared to those with EPD-low tumors. In the multivariate Cox model, EPD was identified as an independent prognostic factor for disease-free survival (DFS) (HR: 1.496, P = 0.004). Integrating EPD with clinicopathological parameters into a predictive model effectively predicts DFS in ER+/HER2- EBC patients. In the most effective CoxPH model, the area under the curve (AUC) values for predicting 3-year, 5-year, and 7-year DFS were 0.718, 0.702, and 0.701, respectively, in the WCH cohort, and 0.770, 0.739, and 0.743, respectively, in the FUSCC cohort. EPD may serve as a novel prognostic marker, allowing for the identification of a population with a poor prognosis in ER+/HER2- EBC, thereby aiding clinical decision-making.

Abstract Ischemic stroke is a complex, high-mortality disease with multifactorial etiology and pathogenesis. Currently, drug therapy is mainly used treat ischemic stroke in clinic, but there are still some limitations, such as limited blood-brain barrier (BBB) penetration efficiency, a narrow treatment time window and drug side effects. Recent studies have pointed out that drug delivery systems based on polymeric nanocarriers can effectively improve the insufficient treatment for ischemic stroke. They can provide neuronal protection by extending the plasma half-life of drugs, enhancing the drug’s permeability to penetrate the BBB, and targeting specific structures and cells. In this review, we classified polymeric nanocarriers used for delivering ischemic stroke drugs and introduced their preparation methods. We also evaluated the feasibility and effectiveness and discussed the existing limitations and prospects of polymeric nanocarriers for ischemic stroke treatment. We hoped that this review could provide a theoretical basis for the future development of nanomedicine delivery systems for the treatment of ischemic stroke. Graphical Abstract

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes which primarily affects the sensory nervous system. Pain is the most common complaint that prompts patients to seek medical advice. With various presentations and intricate pathological mechanisms, diabetic peripheral neuropathic pain is currently the most crucial and challenging aspect of managing diabetic complications. As a heterogeneous disorder, there is no medication or treatment modality that is effective for all types of DPN and its associated neuropathic pain. Peripheral nerve decompression provides a new option for treating patients with diabetic peripheral neuropathic pain in the lower extremities. However, the clinical applicability of nerve decompression has been debated since it was first proposed. This review discusses the theoretical basis of nerve decompression, the clinical indications, and the progress of basic research based on the pathological mechanisms and nerve impairment patterns of diabetic peripheral neuropathic pain. The heterogeneity of DPN patients is summarized in terms of three aspects: complex pathophysiological mechanisms, multilevel nervous system involvement, and various nerve impairment properties. Identifying the presence of nerve entrapment among complex pathophysiological mechanisms is the key to successful outcomes. Tinel signs, focal pain, mechanical allodynia, and two-point discrimination were reported to be prognostic factors for good surgical outcomes, and their predictive ability might stem from their association with the early stage of entrapment neuropathy.

[Objective] To address the issue of the highly integrated internal structure of the EP2002 valve system, which hinders internal fault injection, a metro train braking simulation control system that accurately reflects the functioning mechanism of the EP2002 braking system is designed. The system is intended for fault simulation and personnel training in metro train braking systems. [Method] The air circuit structure and operating mechanism of the EP2002 valve system are introduced, and the overall scheme of the metro train braking simulation control system based on EP2002 is elaborated separately for the electrical and pneumatic components. Using AMESim simulation software, common and emergency braking experiments are conducted to simulate the air circuit of the EP2002 braking system and the metro train braking simulation control system respectively, and the consistency of their braking characteristics is verified. [Result & Conclusion] The overall scheme of the metro train braking simulation control system based on EP2002 utilizes basic air circuit components to construct an equivalent unit circuit with properties identical to the EP2002 valve. For the more complex parts of the air circuit, a mathematical model based on chamber air filling and venting is employed using time-stepping simulation in the software for equivalence. The control unit based on the STM32F107 microcontroller is used for monitoring and controlling the pneumatic section, as well as managing communication between various equivalent EP2002 valve units. The metro train braking simulation control system adopts networking structure similar to EP2002 braking system, with multiple equivalent EP2002 valve units interconnected through a CAN bus and vehicle bus to establish a braking simulation control system based on the EP2002 braking system, achieving cost-effective simulation of the entire train braking system. AMESim model simulation results indicate that the metro train braking simulation control system can maintain brake cylinder pressure at the target value with faster response speed and higher control precision, exhibiting external braking characteristics completely consistent with the EP2002 braking system.

ObjectiveTo explore the effect impact of ferroptosis on macrophage polarization and patient prognosis in glioblastoma.MethodsWe screened ferroptosis-related risk from the public datasets of primary and recurrent glioblastoma, combined with reported ferroptosis genes, calculated the risk genes among the ferroptosis-related genes using the LASSO Cox regression model, and investigated the relationship between these ferroptosis-related risk genes in the tumor and the spectrum of infiltrating M1/M2 macrophages. Macrophages were analyzed using the CIBERSORTx deconvolution algorithm. Samples from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and a single-cell RNA sequencing dataset (GSE84465) were included. The expression levels of ferroptosis-related risk genes and molecular markers of M1 and M2 macrophages were detected by qPCR and western blot.ResultsA total of fourteen ferroptosis-related risk genes were obtained and the patients’ risk scores were calculated. Compared with patients in the low-risk group, patients in the high-risk group had worse prognosis. The M1/M2 macrophage ratio and risk score were negatively correlated, indicating that the tumor microenvironment of glioblastoma in the high-risk group contained more M2 than M1 macrophages. In the single-cell RNA sequencing dataset, the risk score of ferroptosis-related genes in tumor cells was positively correlated with the proportion of high M2 macrophages. The expression of eight ferroptosis-related risk genes was increased in glioblastoma cell, which promoted the polarization of M1 macrophages to M2.ConclusionWe investigated the fourteen ferroptosis-related risk genes in glioblastoma for the first time, and clarified the impact of ferroptosis-related risk genes on M1/M2 macrophage polarization and patient prognosis.

BackgroundThe pathogenesis of concomitant continuous pain remains unclear and is worthy of further study. In this clinical study, we aimed to explore the potential role of a narrow foramen ovale in the development of concomitant continuous pain.MethodsA total of 108 patients with classical trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy individuals were enrolled in this study. Three-dimensional reconstructed computerized tomography images of all participants were collected, and the morphometric features of the foramen ovale were examined by two investigators who were blinded to the clinical data of the patients.ResultsIn this cohort, patients with concomitant continuous pain suffered from more sensory abnormalities (18.4% vs. 2.9%, p = 0.015) and responded more poorly to medication (74.3% vs. 91.9%, p = 0.018) than patients without concomitant continuous pain. While no significant differences regarding the mean length (5.02 mm vs. 5.36 mm, p > 0.05) and area (22.14 mm2 vs. 23.80 mm2, p > 0.05) were observed between patients with and without concomitant continuous pain, the mean width of the foramen ovale on the affected side in patients with concomitant continuous pain was significantly narrower than that in patients without concomitant continuous pain (2.01 mm vs. 2.48 mm, p = 0.003).ConclusionThis neuroimaging and clinical study demonstrated that the development of concomitant continuous pain was caused by the compression of the trigeminal nerve owing to a narrow foramen ovale rather than responsible vessels in classical trigeminal neuralgia.

Background: Interleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous. Methods: An inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study. Results: The selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results. Conclusion: Therefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.

BackgroundObservational epidemiological studies suggested an association between the gut microbiota and breast cancer, but it remains unclear whether the gut microbiota causally influences the risk of breast cancer. We employed two-sample Mendelian randomization (MR) analysis to investigate this association.MethodsWe used summary statistics of the gut microbiome from a genome-wide association study (GWAS) of 18,340 individuals in the MiBioGen study. GWAS summary statistics for overall breast cancer risk and hormone receptor subtype-specific analyses were obtained from the UK Biobank and FinnGen databases, totaling 400,000 individuals. The inverse variance-weighted (IVW) MR method was used to examine the causal relationship between the gut microbiome and breast cancer and its subtypes. Sensitivity analyses were conducted using maximum likelihood, MR-Egger, and MR pleiotropic residual sums and outliers methods.ResultsThe IVW estimates indicated that an increased abundance of Genus_Sellimonas is causally associated with an increased risk of ER+ breast cancer [odds ratio (OR) = 1.09, p = 1.72E−04, false discovery rate (FDR) = 0.02], whereas an increased abundance of Genus_Adlercreutzia was protective against ER+ breast cancer (OR = 0.88, p = 6.62E−04, FDR = 0.04). For Her2+ breast cancer, an increased abundance of Genus_Ruminococcus2 was associated with a decreased risk (OR = 0.77, p = 4.91E−04, FDR = 0.04), whereas an increased abundance of Genus_Erysipelatoclostridium was associated with an increased risk (OR = 1.25, p = 6.58E−04, FDR = 0.04). No evidence of heterogeneity or horizontal pleiotropy was found.ConclusionOur study revealed a gut microbiota–mammary axis, providing important data supporting the potential use of the gut microbiome as a candidate target for breast cancer prevention, diagnosis, and treatment.

IntroductionThe current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood.MethodsNetrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed.ResultsAcross human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted via its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells in vivo during ischemic stroke.ConclusionOur study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.

Introduction To identify proteins and corresponding genes that share sequential and structural similarity with programmed cell death protein-1 (PD-1) in patients with type 1 diabetes mellitus (T1DM) via bioinformatics analysis.Research design and methods All proteins with immunoglobulin V-set domain were screened in the human protein sequence database, and the corresponding genes were obtained in the gene sequence database. GSE154609 was downloaded from the GEO database, which contained peripheral blood CD14+ monocyte samples from patients with T1DM and healthy controls. The difference result and the similar genes were intersected. Analysis of gene ontology and Kyoto encyclopedia of genes and genomes pathways was used to predict potential functions using the R package ‘cluster profiler’. The expression differences of intersected genes were analyzed in The Cancer Genome Atlas pancreatic cancer dataset and GTEx database using t-test. The correlation between the overall survival and disease-free progression of patients with pancreatic cancer was analyzed using Kaplan-Meier survival analysis.Results 2068 proteins with immunoglobulin V-set domain similar to PD-1 and 307 corresponding genes were found. 1705 upregulated differentially expressed genes (DEGs) and 1335 downregulated DEGs in patients with T1DM compared with healthy controls were identified. A total of 21 genes were overlapped with the 307 PD-1 similarity genes, including 7 upregulated and 14 downregulated. Of these, mRNA levels of 13 genes were significantly increased in patients with pancreatic cancer. High expression of MYOM3 and HHLA2 was significantly correlated with shorter overall survival of patients with pancreatic cancer, while high expression of FGFRL1, CD274, and SPEG was significantly correlated with shorter disease-free survival of patients with pancreatic cancer.Conclusions Genes encoding immunoglobulin V-set domain similar to PD-1 may contribute to the occurrence of T1DM. Of these genes, MYOM3 and SPEG may serve as potential biomarkers for the prognosis of pancreatic cancer.

Background: Mechanical allodynia (MA) is one of the leading clinical symptoms of painful diabetic peripheral neuropathy (PDPN), which is a primary reason for non-traumatic amputations, foot ulceration, and gait abnormalities in patients with diabetes. However, the pathogenic mechanisms of MA have not yet been fully elucidated, and there is no effective treatment. This study aims to study the potential pathogenetic mechanisms of MA and to provide targets for the therapy of MA.Methods: A single intraperitoneal injection of streptozotocin induced type 1 diabetes in rat models. Subsequently, rats were divided into the control group, the diabetic group without MA, and the diabetic group with MA based on weekly behavioral assays. The differentially expressed lipids in the sciatic nerve of each group were detected using untargeted lipidomics, and the differentially expressed genes in the sciatic nerve of each group were detected by transcriptomics. The pathogenesis of MA was predicted using integrated analysis and validated by immunofluorescence staining and transmission electron microscopy.Results: Untargeted lipidomics revealed the accumulation of a more severe lipid in MA rats. Transcriptomics results suggested that differentially expressed genes in MA rats were primarily related to lipid droplets and myelin sheath. Integrated analysis results indicated that the downregulation of Cytochrome P450 1A2 (CYP1A2) expression was closely linked to lipid metabolism disorders. Immunofluorescence staining demonstrated that down-regulation of CYP1A2 expression occurred in MA rats. Transmission electron microscopy results showed that more severe lipid droplet accumulation and myelin sheath degeneration occurred in MA rats.Conclusion: Our findings imply that the downregulation of CYP1A2 expression leads to disorders of lipid metabolism and further leads to lipid droplet accumulation and myelin sheath degeneration, which might ultimately lead to the development of MA. Therefore, our study contributes to promoting the understanding of the molecular mechanisms of MA and providing potential targets for the clinical treatment of MA.

BackgroundThis study explores the risk factors associated with viral shedding time in elderly Chinese patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron.MethodsParticipants infected with SARS-CoV-2 omicron were enrolled in a retrospective study, and divided into two groups according to shedding time (≥10 days, “late clearance group” and

ObjectivesPainful diabetic peripheral neuropathy (DPN) is often refractory to conventional medications. Triple-nerve decompression was proposed for painful DPN due to the frequent involvement of multiple nerve entrapments in diabetes. However, the role of decompressive surgery remains controversial. This trial aims to assess the efficacy of triple-nerve decompression for patients with painful DPN suggestive of nerve entrapment using a randomized controlled trial (RCT) design.Methods and analysisThis trial is a single-center RCT and will be conducted in Shanghai Ninth People's Hospital. Enrolled subjects (n = 74) with painful DPN due to nerve compression, which can be detected by nerve conduction studies, will be randomly allocated at a 1:1 ratio into surgical and non-surgical groups. The primary outcome will be measured by 50% responder rates, which is defined as the proportion of subjects with at least 50% reduction of the mean weekly visual analog score (VAS) of pain from baseline after 6 months of treatment. Mean weekly VAS will be additionally evaluated 1 week (W1), 1 month (M1), and 3 months (M3) after treatment to monitor the changes in pain intensity. The secondary outcomes include two-point discrimination (TPD), Toronto clinical scoring system (TCSS), electrophysiological indexes, hospital anxiety and depression scale (HADS), and the medical outcome study short-form 36-item questionnaire (SF-36). A quantitative analgesic questionnaire (QAQ) will be used as a secondary outcome to quantify the analgesic medication weekly. TPD and TCSS will be conducted at W1, M1, M3, and M6 after treatment. Electrophysiological tests, HADS, and SF-36 will be performed at M3 and M6.Ethics and disseminationEthics approval has been obtained from the Ethics Committee of Shanghai Ninth People's Hospital (SH9H-2-21-T323-2). It was registered on the Chinese Clinical Trial Registry website (http://www.chictr.org.cn) on 16 August 2021 with the number ChiCTR2100050049. Written informed consent will be obtained from all participants. The results of this trial will be disseminated via peer-reviewed journals, mass media, and presentations at national and international academic conferences.

Evidence supports associations between gut microbiota and cardiovascular protein levels in plasma. However, it is unclear whether these associations reflect a causal relationship. To reveal the causal relationship between gut microbiota and cardiovascular protein levels in plasma, we estimated their causal effects using two-sample Mendelian randomization (MR) analysis. Sensitivity analysis was also performed to assess the robustness of our results. Genome-wide association study (GWAS) of microbiomes in the MiBioGen study included 211 bacterial taxa (18,473 individuals), and GWAS of 90 cardiovascular proteins included 30,931 individuals. There were 196 bacterial taxa from five levels available for analysis. The following 14 causal relationships were identified: phylum Euryarchaeota and carbohydrate antigen 125 (β = 0.289), order Bacillales and CSF-1 (β = -0.211), genus Dorea and HSP-27 (β = 0.465), phylum Actinobacteria and IL-8 (β = 0.274), order Enterobacteriales and KIM-1 (β = -0.499), class Actinobacteria, genus Bifidobacterium, phylum Actinobacteria and LEP (β = -0.219, β = -0.201, and β = -0.221), genus Methanobrevibacter and NT-proBNP (β = 0.371), family Peptostreptococcaceae and SRC (β = 0.191), order Verrucomicrobiales, phylum Verrucomicrobia and TNF-R2 (β = 0.251 and β = 0.233), family Veillonellaceae and t-PA (β = 0.271), and class Erysipelotrichia and VEGF-D (β = 0.390). Sensitivity analysis showed no evidence of pleiotropy or heterogeneity. The results of the reverse MR analysis showed no reverse causality for any of the 13 gut microbes and 11 cardiovascular proteins. Mendelian randomization estimates provide strong evidence for a causal effect of gut microbiota-mediated alterations on cardiovascular protein expression.

BackgroundThe etiology of primary trigeminal neuralgia remains unclear and is worthy of further study; In this study, the morphometric characteristics of ovale foramina between various groups were compared and analyzed to explore the novel cause of primary trigeminal neuralgia.MethodsHigh-resolution three-dimensional reconstruction images from head computed tomography of 109 patients with primary trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy controls were retrospectively reviewed. Among the 109 primary trigeminal neuralgia patients, 79 patients with apparent neurovascular compression (not simply contact) demonstrated on MRI or during surgery were divided into the classical trigeminal neuralgia group and 30 patients with MRI showing no significant abnormalities were divided into idiopathic trigeminal neuralgia group. The morphometric parameters including the area, width and length of ovale foramina were examined through the use of radiologic methods.ResultsIn this study, the average minimum area, width and length of 79 ovale foramina on the affected and unaffected sides in the classical trigeminal neuralgia group were 21.83 ± 8.45, 21.94 ± 7.93 mm2, 2.32 ± 0.91, 2.58 ± 0.81, 5.32 ± 1.29, and 5.26 ± 1.21 mm, respectively. No significant difference in these parameters was observed (p > 0.05). However, in the idiopathic trigeminal neuralgia group, the average minimum area, width and length of 30 ovale foramina were 21.33 ± 8.21, 22.85 ± 8.36 mm2, 2.25 ± 0.90, 2.79 ± 0.96, 5.20 ± 1.27, and 5.28 ± 1.19 mm, respectively. The width on the symptomatic side was significantly smaller (p = 0.03) than that on the asymptomatic side. No significant difference in area (p = 0.48) or length (p = 0.79) was observed. In addition, when compared with the healthy control group, the area and width of ovale foramina on the symptomatic side in both groups were significantly smaller. No significant difference in length was observed.ConclusionsBy comparing and analyzing the statistical data, it can be inferred that a narrow foramen ovale is associated with primary trigeminal neuralgia, as well as its recurrence after microvascular decompression.

Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated that dysregulated ERV transcription level is associated with immune cell infiltration in cancers, but the association between ERV expression and programmed cell death protein 1 (PD-1) blockade response is currently unraveled for solid cancers, such as advanced clear cell renal cell carcinoma (ccRCC). Methods: ERV mRNA profiles were obtained from three clinical trials of ccRCC where the patients were treated with anti-PD-1 (CM-009, CM-010, CM-025, and TCGA-KIRC data). Patients treated with nivolumab were divided into training and test cohort, while the TCGA-KIRC cohort was used as an external validation. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were used to establish the signature. Immune cell infiltration analysis and gene set enrichment analysis were performed to explore potential biological mechanisms. Results: An ERV signature was established based on nine ERV expression patterns. In the training cohort, the median overall survival in the low- and high-risk group was 45.2 and 19.6 months [hazard ratio (HR) = 0.49, 0.32–0.75, p

ObjectiveTo evaluate the efficacy of Paxlovid in treating Chinese elder patients infected with SARS-CoV-2 omicron variants.Materials and methodsWe performed a non-randomized, controlled trial in Shanghai, China. Participants infected with SARS-CoV-2 omicron variants were enrolled. All patients were divided into the Paxlovid group or the control group according to the Chinese guideline (version 9). The nucleic acid shedding time was the primary endpoint.ResultsAccording to the inclusion criteria, 142 patients infected with omicron variants were enrolled, 36 patients who did not receive paxlovid were assigned to the control group, and 106 were in the Paxlovid group. The baseline characteristics were similar in either group. No significant difference in BMI, age, time from onset to patient enrollment, the severity on first admission, vaccination status, comorbidity, first symptoms, and laboratory results were recorded. Compared to the control group, participants in the Paxlovid group had a shorter viral shedding time [11.11 (2.67) vs. 9.32 (2.78), P = 0.001].ConclusionIn Chinese elder patients infected with the variant of SARS-CoV-2 omicron, our data suggest that Paxlovid can significantly reduce the nucleic acid shedding time.

RNA guanine-7 methyltransferase (RNMT), in complex with FAM103A1, plays an important role in tumorigenesis and development. The aim of this study was to establish a prognostic model of RNMT and FAM103A1-based upstream microRNAs and explore its correlation with immune cell infiltration in breast cancer (BC) while investigating its potential prognostic value and verify the model by quantitative real-time polymerase chain reaction (qRT-PCR). The miRNA expression data upstream of the m7G methyltransferase complex RNMT/FAM103A1 in BC was obtained from The Cancer Genome Atlas and TargetScan databases. We performed univariate Cox regression, LASSO regression, Kaplan-Meier survival, and principal component analyses, along with risk prognostic modelling. Based on multivariate Cox regression analysis, a total of 12 m7G methyltransferase-related miRNAs were found. The model showed good accuracy for predicting the 1-, 3-,5-, and 10-year survival rates, and the areas under the curve were almost >0.7. To characterize the risk-level model constructed from 12 miRNAs, 12 differentially expressed mRNAs related to prognosis and immune infiltration were obtained. The prognosis of BC patients is well predicted by the risk model we constructed. This model is also closely related to immune infiltration, and new immunotherapy targets can be explored from this field.

Mechanical allodynia (MA) is the main reason that patients with diabetic peripheral neuropathy (DPN) seek medical advice. It severely debilitates the quality of life. Investigating hyperglycemia-induced changes in neural transcription could provide fundamental insights into the complex pathogenesis of painful DPN (PDPN). Gene expression profiles of physiological dorsal root ganglia (DRG) have been studied. However, the transcriptomic changes in DRG neurons in PDPN remain largely unexplored. In this study, by single-cell RNA sequencing on dissociated rat DRG, we identified five physiological neuron types and a novel neuron type MAAC (Fxyd7+/Atp1b1+) in PDPN. The novel neuron type originated from peptidergic neuron cluster and was characterized by highly expressing genes related to neurofilament and cytoskeleton. Based on the inferred gene regulatory networks, we found that activated transcription factors Hobx7 and Larp1 in MAAC could enhance Atp1b1 expression. Moreover, we constructed the cellular communication network of MAAC and revealed its receptor-ligand pairs for transmitting signals with other cells. Our molecular investigation at single-cell resolution advances the understanding of the dynamic peripheral neuron changes and underlying molecular mechanisms during the development of PDPN.

Time is infinite movement in constant motion. We are glad to see that Neurorestoratology, a new discipline, has grown into a rich field involving many global researchers in recent years. In this 2019 yearbook of Neurorestoratology, we introduce the most recent advances and achievements in this field, including findings on the pathogenesis of neurological diseases, neurorestorative mechanisms, and clinical therapeutic achievements globally. Many patients have benefited from treatments involving cell therapies, neurostimulation/neuromodulation, brain–computer interface, neurorestorative surgery or pharmacy, and many others. Clinical physicians can refer to this yearbook with the latest knowledge and apply it to clinical practice.

A hybrid model integrating chaos theory, support vector machine (SVM) and the difference evolution grey wolf optimization (DEGWO) algorithm is developed to analyze and predict dam deformation. Firstly, the chaotic characteristics of the dam deformation time series will be identified, mainly using the Lyapunov exponent method, the correlation dimension method and the kolmogorov entropy method. Secondly, the hybrid model is established for dam deformation forecasting. Taking SVM as the core, the deformation time series is reconstructed in phase space to determine the input variables of SVM, and the GWO algorithm is improved to realize the optimization of SVM parameters. Prior to this, the effectiveness of DEGWO algorithm based on the fusion of the difference evolution (DE) and GWO algorithm has been verified by 15 sets of test functions in CEC 2005. Finally, take the actual monitoring displacement of Jinping I super-high arch dam as examples. The engineering application examples show that the PSR-SVM-DEGWO model established performs better in terms of fitting and prediction accuracy compared with existing models.

Background: Peripheral nerve decompression microsurgery can relieve nerve entrapment and improve the symptoms of DPN. However, postoperative tissue adhesion will produce new pressure on the nerves, affecting the surgical efficacy. In this study, a nerve conduit was used in the peripheral nerve decompression microsurgery to prevent postoperative adhesions, and the role of the nerve conduit in surgical nerve decompression was explored. Methods: A total of 69 patients with DPN were recruited and randomly divided into three groups: the nerve conduit group, conventional surgery group, and control group. Two weeks before surgery and 6 months after surgery, patients in each group were clinically tested using the visual analog scale (VAS) score, neurophysiological test, Toronto clinical scoring system (TCSS) score, and two-point discrimination (2-PD) test. Results: The patients’ symptoms in the nerve conduit group were relieved to varying degrees, and the relief rate reached 90.9%; the treatment efficacy was higher than that in the other groups. The postoperative nerve conduction velocity (NCV) in the two surgical groups was significantly higher than that before the surgery, and the difference between the nerve conduit group and the conventional surgery group was statistically significant (p < 0.05). For the 2-PD test, there was a statistically significant difference between the two surgical groups (p < 0.05). The TCSS score in the two surgical groups was significantly higher than that in the control group (p < 0.01). There was a significant difference in the TCSS scores between the nerve conduit group and the conventional surgery group (p < 0.05). Conclusions: The nerve conduit could further improve the efficacy of peripheral nerve decompression microsurgery in the treatment of DPN.

Graph neural networks (GNNs) have garnered significant attention for their ability to effectively process graph-related data. Most existing methods assume that the input graph is noise-free; however, this assumption is frequently violated in real-world scenarios, resulting in impaired graph representations. To address this issue, we start from the essence of graph structure learning, considering edge discovery and removal, reweighting of existing edges, and differentiability of the graph structure. We introduce virtual nodes and consider connections with virtual nodes to generate optimized graph structures, and subsequently utilize Gumbel-Softmax to reweight edges and achieve differentiability of the Graph Structure Learning (VN-GSL for abbreviation). We conducted a thorough evaluation of our method on a range of benchmark datasets under both clean and adversarial circumstances. The results of our experiments demonstrate that our approach exhibits superiority in terms of both performance and efficiency. Our implementation will be made available to the public.

Recent studies have revealed that neurons can promote glioma growth through activity‐dependent secretion of neurotrophins, especially neuroligin‐3. It has therefore been suggested that blocking neuron‐derived neurotrophins may serve as a therapeutic intervention for gliomas. Carbonic anhydrase‐related proteins 11 and 10 (CA11 and CA10) are secreted synaptic proteins which function as neurexin ligands, and the gene‐encoding CA11 is part of a gene signature associated with radiotherapy and prognosis in gliomas. We therefore hypothesized that CA11/CA10 might participate in the neuronal activity‐dependent regulation of glioma growth. In this study, we report that CA11 secreted by depolarized cultured neurons within conditioned medium (CM) inhibited the growth of glioma cell lines. CM from depolarized neurons inhibited CA11 expression in glioma cell lines via the Akt signaling pathway. Consistently, CA11 expression was also reduced in clinical glioma samples and negatively associated with high histological grade. Low CA11 expression of gliomas was associated with short survival in four independent datasets [repository of brain neoplasia data (REMBRANDT), The Cancer Genome Atlas (TCGA) lower grade glioma (LGG), GSE4271, and GSE42669]. CA11 knockdown promoted cell growth, clone formation, and migration; inhibited apoptosis; and increased tumor size in xenografted nude mice. Similarly, CA10 and CA10 secreted by depolarized cultured neurons also inhibited the growth of glioma cell lines. Low CA10 expression was associated with short survival in REMBRANDT, TCGA LGG, and GEO GSE4271 datasets. Our results suggest that CA11 and CA10 negatively regulate neuronal activity‐dependent glioma growth and inhibit glioma aggression. Thus, CA11/CA10 may represent a potential therapeutic target for the treatment of gliomas.

To investigate the effect of surgical decompression on painful diabetic peripheral neuropathy (DPN) patients and discuss the role which pain distribution and characterization play in the management of painful DPN as well as the underlying mechanism involved.A total of 306 patients with painful diabetic lower-extremity neuropathy were treated with Dellon surgical nerve decompression in our department. Clinical evaluation including Visual analogue scale (VAS), Brief Pain Inventory Short Form for diabetic peripheral neuropathy (BPI-DPN) questionnaire, two-point discrimination (2-PD), nerve conduction velocity (NCV) and high-resolution ultrasonography (cross-sectional area, CSA) were performed in all cases preoperatively, and at 6 month intervals for 2 years post-decompression. The patients who underwent surgery were retrospectively assigned into two subgroups (focal and diffuse pain) according to the distribution of the diabetic neuropathic pain. The control group included 92 painful DPN patients without surgery.The levels of VAS, scores in BPI-DPN, 2-PD, NCV results and CSA were all improved in surgical group when compared to the control group (P