Integrated genetic analysis of diabetic complications: Bioinformatics insights into foot ulcers, neuropathy and peripheral artery disease.

Diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) are common complications of diabetes mellitus, while diabetic peripheral neuropathy and peripheral arterial disease contribute to the pathogenesis of diabetic foot ulcers, and the pathogenic mechanisms between these three diseases still need further investigation. The keywords 'diabetic foot ulcer', 'diabetic peripheral neuropathy' and 'atherosclerosis' were used to search for related gene sets in the GEO database. Differentially expressed genes (DEGs) were screened and analysed for GO, KEGG and enrichR functional enrichment. Potential three disease biomarkers were identified by SVM-SVM-RFE and LASSO regression analysis. The results were also validated using external datasets and discriminability was measured by area under the ROC curve (AUC). Finally, biomarkers and co-upregulated genes were analysed through the GSEA and Attie Laboratories diabetes databases. A total of 11 shared genes (KRT16, CD24, SAMD9L, SRGAP2, FGL2, GPR34, DDIT4, NFE2L3, FBLN5, ANXA3 and CPA3), two biomarkers (SAMD9L and FGL2) and one co-upregulated gene (CD24) were screened. GO and KEGG pathway analysis of DEGs, enrichr enrichment analysis of shared differential genes and GSEA analysis of biomarkers showed that these significant genes were mainly focused on vasoregulatory, inflammatory-oxidative stress and immunomodulatory pathways. In this study, we used bioinformatics to investigate the intrinsic relationship and potential mechanisms of three common lower extremity complications of diabetes and identified two pivotal genes using the LASSO model and the SVM-RFE algorithm, which will further help clinicians to understand the relationship between diabetic complications, improve the diagnosis and treatment of diabetic foot problems and help doctors to identify the potential risk factors of diabetic foot.

Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer.

Lysosome dysfunction has been shown to play an important role in cancer progression. However, few research studies have reported the role of lysosomes in head and neck squamous cell carcinoma (HNSCC) progression. Lysosome-related genes (LRGs) were collected from the Molecular Signatures Database. Differentially expressed lysosome-related genes (DELRGs) were identified from the TCGA-HNSCC dataset. The least absolute shrinkage and selection operator and multivariate Cox regression analysis were used to identify the prognostic genes. The prognostic values and expression of hub DELRGs were further validated by GEO datasets. Estimation of STromal and Immune cells in MAlignant Tumors using Expression data and the single-sample gene set enrichment analysis were applied to evaluate the correlation between cathepsin G (CTSG) and immune infiltrates. Twenty-two DELRGs were identified. Among them, CTSG was an independent prognostic biomarker for HNSCC patients. Gene set enrichment analysis indicated that the potential mechanism of CTSG in regulating HNSCC was associated with the immune- and inflammation-related pathways. CTSG expression was highly correlated with immune cell infiltration. Finally, two potential compounds (CH and MAN) targeting CTSG protein were identified, and their reliability was validated through molecular docking analysis. CTSG was associated with immune infiltration and had prognostic value in HNSCC patients, which may be a potential biomarker for predicting the outcome of immunotherapy.

Prognostic value of inflammatory markers for in-hospital mortality in intensive care patients with acute ischemic stroke: a retrospective observational study based on MIMIC-IV.

Background: Acute ischemic stroke (AIS) is a primary cause of death and disability worldwide. Four markers that can be readily determined from peripheral blood, namely, the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and total bilirubin, were measured in this study. We examined the relationship between the SII and in-hospital mortality after AIS and evaluated which of the above four indicators was most accurate for predicting in-hospital mortality after AIS. Methods: We selected patients from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database who were aged >18 years and who were diagnosed with AIS on admission. We collected the patients' baseline characteristics, including various clinical and laboratory data. To investigate the relationship between the SII and in-hospital mortality in patients with AIS, we employed the generalized additive model (GAM). Differences in in-hospital mortality between the groups were summarized by the Kaplan-Meier survival analysis and the log-rank test. The receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of the four indicators (SII, NLR, PLR, and total bilirubin) for predicting in-hospital mortality in patients with AIS. Results: The study included 463 patients, and the in-hospital mortality rate was 12.31%. The GAM analysis showed a positive correlation between the SII and in-hospital mortality in patients with AIS, but the correlation was not linear. Unadjusted Cox regression identified a link between a high SII and an increased probability of in-hospital mortality. We also found that patients with an SII of >1,232 (Q2 group) had a considerably higher chance of in-hospital mortality than those with a low SII (Q1 group). The Kaplan-Meier analysis demonstrated that patients with an elevated SII had a significantly lower chance of surviving their hospital stay than those with a low SII. According to the results of the ROC curve analysis, the in-hospital mortality of patients with AIS predicted by the SII had an area under the ROC curve of 0.65, which revealed that the SII had a better discriminative ability than the NLR, PLR, and total bilirubin. Conclusion: The in-hospital mortality of patients with AIS and the SII were positively correlated, but not linearly. A high SII was associated with a worse prognosis in patients with AIS. The SII had a modest level of discrimination for forecasting in-hospital mortality. The SII was slightly better than the NLR and significantly better than the PLR and total bilirubin for predicting in-hospital mortality in patients with AIS.

[Anatomical study and clinical application of thoracoacromial artery perforator flap].

Objective:To study the anatomical characteristics of thoracoacromial artery perforator flap（TAAP）, and to explore the advantages and disadvantages of TAAP in head and neck reconstruction. Methods: Four fresh cadavers （8 hemichests） were collected for anatomical observation, the blood supply of chest skin was observed through autopsy, the presence, number, location, caliber, and landmark on the chest surface of all thoracoacromial artery perforators per hemichest were recorded, including the distance of each from the midpoint of the clavicle. The diameters of the thoracoacromial artery and perforating vessels were measured with vernier calipers （accuracy 0.05 mm）, the pedicle length and thickness were measured with a cm scale （accuracy: 1 mm） after the flap was obtained, and the retained photos were recorded. Results:No perforating branch （12.5%） was found on one side of the 8 hemichests, two perforating branches （12.5%） were found on one hemichest, and one perforating branches （75.0%） were found on the rest of the hemichests. The perforating point was about between the clavicular head of pectoralis major （clavicular part） and the sternocostal head （sternocostal part）. The vessels at the beginning of perforation were generally bulky, with an average diameter of 2.25 mm, however, the vessel diameter was significantly reduced after the perforation of the flap. The pedicle length of thoracoacromial artery perforator flap ranged from 5.43 cm to 9.03 cm, with an average length of 7.14 cm. The pedicle length from the exit point of perforator muscle gap to the flap was 2.32-4.63 cm, with an average length of 3.28 cm. The distance between the exit point of perforator muscle space and the lower edge of the midpoint of the clavicle was 3.31-4.52 cm, with an average distance of 3.77 cm. Conclusion:The thoracoacromial artery perforator flap has some advantages such as similar color as head, neck and maxillofacial region, stable blood supply, relatively consistent vascular pedicle length and caliber size, relatively larger flap, less damage to pectoralis major muscle, and protection of chest shape, thoracic movement and shoulder joint movement function. Although the clinical application of this flap is limited by the uncertainty of perforating vessels, postoperative asymmetry of the nipple and residual chest scar, it still has a broad application prospect in head and neck reconstruction.

Electro-optic chaotic system based on time delay feature hiding and key space enhancement based on chaotic post-processing.

To improve the output performance of the classical all-optical chaotic system and solve the security problems of its key exposure and small key space, a new chaotic system, to the best of our knowledge, based on logistic map post-processing is proposed. In terms of the general output performance of the system, the spectrum of the proposed system is flatter than the classical system. Through a bifurcation diagram and permutation entropy analysis, it is found that the output of the system is extremely complex. In terms of security, the simulation results show that, with a reasonable selection of system parameters, key hiding can be achieved under a large parameter range. Moreover, through the sensitivity analysis of logistic parameters, it can be seen that the introduction of logistic parameters can improve the key space of the system and further improve the security of the system.

NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer.

Background: Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear. Methods: A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively. Results: To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients. Conclusions: Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.

Transcranial direct current stimulation for the treatment of post-stroke depression: A systematic review.

Background: Post-stroke depression (PSD) is not only a frequent neuropsychiatric manifestation secondary to stroke but is also associated with disability, poor rehabilitation outcomes, sleep disorders, cognitive impairment, and increased mortality. Transcranial direct current stimulation (tDCS), a primary modality of non-invasive brain stimulation (NIBS), has shown promising clinical results in the rehabilitation of patients with PSD recently. The primary aim of this systematic review is to assess the effects of tDCS on PSD. Methods: PubMed and Cochrane databases were used for paper identification up to May 2022. Only English language studies and published data were taken into consideration. The methodological quality of selected studies was assessed according to the modified Sackett Scale, based on Physiotherapy Evidence Database (PEDro) scores. Results: Six experimental studies were included for the PSD treatment of tDCS and all of them reported that, following the intervention of tDCS, the experimental group shows a statistically significant decrease in the depression level in accordance with different assessment scales. Conclusion: This article simply aims at providing a comprehensive overview of the raw data reported in this field to date. Based on the current evidence, tDCS presents promising results for the treatment of PSD. Moreover, tDCS is also effective in PSD patients with aphasia or CPSP. However, an optimal stimulation protocol is needed to formulate. Thus, the development of robustly controlled, randomized, and high-quality clinical trials to further assess the utility of tDCS as a therapeutic tool for the treatment of PSD survivors is encouraged. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023322076, identifier: CRD42023322076.

Genomic landscape and tumor mutation burden analysis of Chinese patients with sarcomatoid carcinoma of the head and neck.

BACKGROUND: Sarcomatoid carcinoma (SC) of the head and neck (HN) is a rare disease that has both sarcomatoid and cancerous components. The genetic background and mechanisms of tumorigenesis remain largely unrevealed, and the progress of precision therapy has been limited. METHODS: Targeted DNA-based next-generation sequencing (NGS) was performed by a 539 genes panel of pan-cancer in 12 patients with SC of the HN to identify their genetic alterations and investigate clinically actionable mutations for use in precision treatment. RESULTS: TP53 was identified as the most frequently mutated gene. Genes related to the cell cycling, chromatin remodeling and histone modification were found to be frequently mutated in patients with SC of the HN. Alterations in receptor tyrosine kinases (RTKs) were also found in six patients. In addition, four patients had mutations in members of the downstream RAS and PI3-kinase pathways, PIK3CA was identified as the most frequently mutated gene in this pathway. The tumor mutation burden (TMB) value ranged from 0.71 to 14.71 per megabase, with a median of 4.34. The TMB value of PIK3CA mutation patients was significantly higher than that of PIK3CA wild-type patients. CONCLUSIONS: This was the first study to investigate genomic alterations specifically in Chinese patients with SC of the HN. Our research results showed that 10 out of 12 patients can match the targeted therapies or immunotherapy currently available in clinical practice or active clinical trials, suggesting precision therapy has the potential utility to improve the long-term prognosis for patients with the rare disease. Due to the small number of patients in this study, the findings need to be validated in a larger cohort.

[Analysis of efficacy of coblation assisted endoscope system for the treatment of parapharyngeal space tumors with transoral approach].

Objective:To summarize and analyze the feasibility, safety and efficacy of parapharyngeal space surgery assisted by coblation and endoscopic system with transoral approach. Methods:The data of 20 patients with parapharyngeal space tumors were retrospectively analyzed. All the patients underwent CT and/or MRI examination before surgery, and all underwent transoral approach assisted by coblation and endoscopic systems. The patients were followed up strictly after the operation, with a follow-up time of 8-56 months and the median follow-up time of 28 months. Results:Among the 20 patients, 18 （90%） were pathologically benign tumors and 2 （10%） were malignant tumors. The maximum tumor diameter was （4.4±1.6） cm, the operative time was （79.00±30.03） min, the intraoperative blood loss was （23.63±22.20） mL, and the postoperative pain VAS score was 2.8±1.4. There were 17 cases complete resection, and 3 cases of relapse, including 1 patient who died after distant metastasis of synovial sarcoma postoperative complications occurred in 2 cases, hoarseness in 1 case of neurofibroma and tongue extension deflection in 1 case of schwannoma. Conclusion:Coblation assisted endoscopic system for the treatment of parapharyngeal space tumors with transoral approach has no cervical scar, which is a satisfaction for the patients, less intraoperative bleeding, short operative time, mild postoperative reaction and quick recovery. However, external approach is still recommended for primary malignant lesions, extensive or highly vascularized lesions, tumors located on the lateral side of the internal carotid artery, less than 2 cm from the skull base, or lateral invasion of the deep lobe of the parotid gland, or a pleomorphic adenoma is considered or is found to be too large to be completely resected preoperatively or intraoperatively.

Neuroprotective effects of ginsenoside Rg1 through the Wnt/ß-catenin signaling pathway in both in vivo and in vitro models of Parkinson's disease.

Ginsenoside Rg1 (Rg1) is a major bioactive ingredient in Panax ginseng that has low toxicity and has been shown to have neuroprotective effects. The objectives of the present study were to explore the potential of the application of Rg1 for the treatment of Parkinson's disease (PD) and to determine whether its neuroprotective effects are exerted through the Wnt/ß-catenin signaling pathway by using in vivo and in vitro models of PD. In the in vivo study, Rg1 treatment ameliorated the behavioral deficits of "Pole test", and reduced dopaminergic cell loss that were induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) in a dose-dependent manner in an in vivo model of PD. In the in vitro study, cell viability was increased and cell apoptosis induced by 1-methyl-4-phenylpyridinium(MPP+) was decreased by Rg1 pretreatment. Rg1 induced protective effects on the protein and mRNA expression levels of markers of the Wnt/ß-catenin signaling pathway in both the in vivo and the in vitro studies, and these neuroprotective effects were blocked by DKK1 in the in vitro study. Our results provide evidence that Rg1 has neuroprotective effects in both in vivo and in vitro PD models, and these effects act through the Wnt/ß-catenin signaling pathway. Taken together, these results indicate that Rg1 may exert therapeutic effects on PD via the Wnt/ß-catenin signaling pathway and may therefore provide a novel approach for the treatment of PD.

Rat hippocampal proteomic alterations following intrahippocampal injection of amyloid beta peptide (1-40).

Amyloid beta peptide 1-40 (Aß(1-40)) is closely associated with the progressive neuronal loss and cognitive decline observed in Alzheimer's disease (AD). This study aimed to establish a proteomic strategy for the profiling of AD tissues for disease-specific changes in protein abundance. Intrahippocampal injection of Aß(1-40) induced spatial memory and learning decline in rats. Proteomic analysis revealed the changes in protein expression in the rat hippocampus treated with Aß(1-40). Four proteins of interest which was in abundance was significantly altered in Aß(1-40)-treated rats were identified by peptide mass fingerprint (PMF). These proteins corresponded to synapsin Ib, protein disulfide-isomerase A3 precursor, tubulin ß chain and ATP synthase ß subunit. Our results provide new insights into the relationship between Aß and the pathogenesis of AD, and suggest potential targets for the therapy of AD.

Decreased expression of spine-associated Rap guanosine triphosphatase-activating protein (SPAR) in glutamate-treated primary hippocampal neurons.

Spine-associated Rap guanosine triphosphatase-activating protein (SPAR) is an important regulator of activity-dependent remodeling of synapses. It is also critically involved in both mature dendritic spine formation and the maintenance of spine maturity. Glutamate is a major neurotransmitter of the brain, and is involved in all aspects of cognitive function, as it is the primary transmitter utilized by the cortical and hippocampal pyramidal neurons. Glutamate has also been associated with neuronal dendritic spine damage. The precise molecular mechanisms underlying dendritic spine damage following glutamate-induced neurotoxicity remain unknown. In the current study, we measured mRNA and protein expression levels of SPAR and serum-inducible kinase (SNK) in primary hippocampal neurons following glutamate treatment. Expression of SPAR and SNK was altered by glutamate treatment, indicating that the SPAR and SNK signaling pathways may be involved in the damage to dendritic spines in hippocampal neurons following excitotoxicity induced by glutamate.

Role of the SNK-SPAR pathway in the development of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of senile plaques and neurofibrillary tangles in the brain. The beta-amyloid peptide (Abeta) is the primary constituent of the senile plaques, and has been proposed to be a key contributor to the neurodegeneration observed in AD. The molecular mechanisms underlying dendritic spine damage that is induced by Abeta toxicity in AD patients remain largely unknown. It has been suggested previously that the SNK-SPAR signaling pathway is involved in activity-dependent remodeling of synapses. The relationship between the SNK-SPAR pathway and Abeta-induced excitotoxicity, however, is poorly understood. The present study investigated the effects of bilateral intrahippocampal injection of Abeta peptide 1-40 (Abeta(1-40)) on learning and memory in the rat, and explored the mechanisms underlying the effects of this injection. We reported that bilateral injection of Abeta(1-40) in rats resulted in impaired performance in the step-down passive avoidance and Morris water maze tasks. Then we examined mRNA and protein expression levels in the different brain regions one week after injection with Abeta(1-40) and found that the SNK-SPAR signaling pathway was possibly involved in dendritic spine damage in the different brain regions of Abeta-treated rats. These results demonstrate that the SNK-SPAR pathway may possibly play a crucial role in Abeta-induced excitotoxic damage in the central nervous system by regulating synaptic stability.

Protective effect of spleen-yin-nourishing recipe on amyloid beta-peptide-induced damage of primarily cultured rat hippocampal neurons and its mechanism.

OBJECTIVE: To observe the relationship among amyloid beta-peptide (Abeta)-induced neurotoxicity, serum-inducible kinase (SNK)-spine-associated Rap guanosine triphosphatase activating protein (SPAR) pathway and N-methyl-D-aspartate receptor (NMDAR), and to explore the mechanism of the protective effect of spleen-yin nourishing recipe (Zibu Piyin Recipe, ZBPYR) in hippocampal neurons against Abeta-induced neurotoxicity. METHODS: The Abeta(1-40) powder was dissolved in 1 x PBS and incubated at 37 degrees centigrade, and then aggregated fibrillar Abeta(1-40) was obtained 72 h later. We used rat primary hippocampal neurons as cell model. ZBPYR-containing serum was gained by the method of serum pharmacology. ZBPYR-containing serum was added to the culture 1 h before Abeta(1-40) (5 micromol/L) exposure. Cells were harvested 2 h after Abeta(1-40) exposure for total RNA extracting. Then the mRNA expression levels of SNK, SPAR and NMDAR subunits NR1, NR2A and NR2B were detected by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: After 2-hour Abeta(1-40) exposure, we found that the expression level of SNK mRNA was up-regulated and the expression levels of SPAR, NR1, NR2A and NR2B mRNAs were down-regulated in hippocampal neurons as compared with control group (P < 0.01, P < 0.05). While with ZBPYR-containing serum pretreatment, the expression level of SNK mRNA was down-regulated and the levels of SPAR, NR1, NR2A and NR2B were up-regulated as compared with Abeta(1-40) exposure, and 2% ZBPYR-containing serum showed the best effect (P < 0.05). CONCLUSION: Abeta-induced neurotoxicity was related to SNK-SPAR pathway and NMDAR; ZBPYR-containing serum can protect neurons from Abeta-induced neurotoxicity, and this protective effect may be performed by regulating the expression of NMDAR and blocking of the SNK-SPAR pathway.