Expression and functional implications of YME1L in nasopharyngeal carcinoma.

Mitochondria play a crucial role in the progression of nasopharyngeal carcinoma (NPC). YME1L, a member of the AAA ATPase family, is a key regulator of mitochondrial function and has been implicated in various cellular processes and diseases. This study investigates the expression and functional significance of YME1L in NPC. YME1L exhibits significant upregulation in NPC tissues from patients and across various primary human NPC cells, while its expression remains relatively low in adjacent normal tissues and primary nasal epithelial cells. Employing genetic silencing through the shRNA strategy or knockout (KO) via the CRISPR-sgRNA method, we demonstrated that YME1L depletion disrupted mitochondrial function, leading to mitochondrial depolarization, reactive oxygen species (ROS) generation, lipid peroxidation, and ATP reduction within primary NPC cells. Additionally, YME1L silencing or KO substantially impeded cell viability, proliferation, cell cycle progression, and migratory capabilities, concomitant with an augmentation of Caspase-apoptosis activation in primary NPC cells. Conversely, ectopic YME1L expression conferred pro-tumorigenic attributes, enhancing ATP production and bolstering NPC cell proliferation and migration. Moreover, our findings illuminate the pivotal role of YME1L in Akt-mTOR activation within NPC cells, with Akt-S6K phosphorylation exhibiting a significant decline upon YME1L depletion but enhancement upon YME1L overexpression. In YME1L-silenced primary NPC cells, the introduction of a constitutively-active Akt1 mutant (caAkt1, at S473D) restored Akt-S6K phosphorylation, effectively ameliorating the inhibitory effects imposed by YME1L shRNA. In vivo studies revealed that intratumoral administration of YME1L-shRNA-expressing adeno-associated virus (AAV) curtailed subcutaneous NPC xenograft growth in nude mice. Furthermore, YME1L downregulation, concurrent with mitochondrial dysfunction and ATP reduction, oxidative injury, Akt-mTOR inactivation, and apoptosis induction were evident within YME1L-silenced NPC xenograft tissues. Collectively, these findings shed light on the notable pro-tumorigenic role by overexpressed YME1L in NPC, with a plausible mechanism involving the promotion of Akt-mTOR activation.

Dorsomorphin attenuates ABCG2-mediated multidrug resistance in colorectal cancer.

Colorectal cancer is a common malignant tumor with high mortality, for which chemotherapy resistance is one of the main reasons. The high expression of ABCG2 in the cancer cells and expulsion of anticancer drugs directly cause multidrug resistance (MDR). Therefore, the development of new ABCG2 inhibitors that block the active causes of MDR may provide a strategy for the treatment of colorectal cancer. In this study, we find that dorsomorphin (also known as compound C or BML-275) potently inhibits the transporter activity of ABCG2, thereby preserving the chemotherapeutic agents mitoxantrone and doxorubicin to antagonize MDR in ABCG2-overexpressing colorectal cancer cells. Additionally, dorsomorphin does not alter ABCG2 protein expression. The results of molecular docking studies show that dorsomorphin is bound stably to the ABCG2-binding pocket, suggesting that dorsomorphin is a potent ABCG2 inhibitor that attenuates ABCG2-mediated MDR in colorectal cancer.

Single-center retrospective study of the diagnostic value of double-balloon enteroscopy in Meckel's diverticulum with bleeding.

BACKGROUND: The study aimed to analyze the characteristic clinical manifestations of patients with intestinal disease Meckel's diverticulum (MD) complicated by digestive tract hemorrhage. Moreover, we aimed to evaluate the value of double-balloon enteroscopy (DBE) in MD diagnosis and the prognosis after laparoscopic diverticula resection. AIM: To evaluate the value of DBE in the diagnosis and the prognosis after laparoscopic diverticula resection for MD with bleeding. METHODS: The study retrospectively analyzed relevant data from 84 MD patients treated between January 2015 and March 2022 and recorded their clinical manifestations, auxiliary examination, and follow-up after laparoscopic resection of diverticula. RESULTS: (1) Among 84 MD patients complicated with hemorrhage, 77 were male, and 7 were female with an average age of 31.31 ± 10.75 years. The incidence was higher in men than in women of different ages; (2) Among the 84 MD patients, 65 (78.40%) had defecated dark red stools, and 50 (58.80%) had no accompanying symptoms during bleeding, indicating that most MD bleeding appeared a dark red stool without accompanying symptoms; (3) The shock index of 71 patients (85.20%) was < 1, suggesting that the blood loss of most MD patients was less than 20%-30%, and only a few patients had a blood loss of > 30%; (4) The DBE-positive rate was 100% (54/54), 99mTc-pertechnetate-positive scanning rate was 78% (35/45) compared with capsule endoscopy (36%) and small intestine computed tomography (19%). These results suggest that DBE and 99mTc-pertechnetate scans had significant advantages in diagnosing MD and bleeding, especially DBE was a highly precise examination method in MD diagnosis; (5) A total of 54 MD patients with hemorrhage underwent DBE examination before surgery. DBE endoscopy revealed many mucosal manifestations including normal appearance, inflammatory changes, ulcerative changes, diverticulum inversion, and nodular hyperplasia, with ulcerative changes being the most common (53.70%). This suggests that diverticular mucosal ulcer was the main cause of MD and bleeding; and (6) Laparoscopic dissection of diverticulae was performed in 76 patients, The patients who underwent postoperative follow-up did not experience any further bleeding. Additionally, follow-up examination of the 8 cases who had declined surgery revealed that 3 of them experienced a recurrence of digestive tract bleeding. These findings indicate that laparoscopic diverticula resection in MD patients complicated by bleeding had a favorable prognosis. CONCLUSION: Bleeding associated with MD was predominantly observed in male adolescents, particularly at a young age. DBE was a highly precise examination method in MD diagnosis. Laparoscopic diverticula resection effectively prevented MD bleeding and had a good prognosis.

Predictive potential of preoperative Naples prognostic score-based nomogram model for the prognosis in surgical resected thoracic esophageal squamous cell carcinoma patients: A retrospective cohort study.

The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all P < .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676-0.795, P < .001) and 0.835 (95% CI 0.786-0.884, P < .001), and 0.734 (95% CI 0.675-0.793, P < .001) and 0.851 (95% CI 0.805-0.896, P < .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681-0.755) and 0.669 (95% CI 0.633-0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558-0.638) for OS and 0.586 (95% CI 0.546-0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639-0.755) vs 0.644 (95% CI 0.589-0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.

Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans.

Background: Peripheral traditional immune cell disorder plays an important role in cancer onset and development. The causal relationships between leukocytes prior to cancer and the risk of digestive system cancer remain unknown. This study assesses the causal correlations between leukocytes and digestive system cancer risk in East Asians and Europeans. Methods: Summary-level data on leukocyte-related genetic variation were extracted from Biobank Japan (107,964 participants) and a recent large-scale meta-analysis (563,946 participants). Summary-level data for the cancers were obtained from Biobank Japan (212,978 individuals) and the FinnGen consortium (178,802 participants). Univariable and multivariable Mendelian randomization (MR) analyses were performed on East Asians and Europeans separately. Results: Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in East Asians (odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.69 - 0.92, P = 0.002) and a suggestive relationship in the European population (OR = 0.86, 95% CI: 0.77 - 0.97, P = 0.013). An inverse suggestive association was observed between levels of basophils and the risk of gastric cancer (GC) in East Asians (OR = 0.83, 95% CI: 0.72 - 0.97, P = 0.019). The multivariable MR analysis showed the independent causal effect of eosinophil count on CRC risk in East Asians (OR = 0.72, 95% CI: 0.57 - 0.92, P = 0.009) and Europeans (OR = 0.80, 95% CI: 0.70 - 0.92, P = 0.002). Circulating basophils served as the negative causal factor in GC risk in East Asians (OR = 0.80, 95% CI: 0.67 - 0.94, P = 0.007). Conclusions: Our MR analyses revealed a genetic causal relationship between reduced blood eosinophils and an increased CRC risk in both Europeans and East Asians. Furthermore, our results suggested a causal association between decreased basophils and an elevated GC risk specifically in East Asians.

A ResNet mini architecture for brain age prediction.

The brain presents age-related structural and functional changes in the human life, with different extends between subjects and groups. Brain age prediction can be used to evaluate the development and aging of human brain, as well as providing valuable information for neurodevelopment and disease diagnosis. Many contributions have been made for this purpose, resorting to different machine learning methods. To solve this task and reduce memory resource consumption, we develop a mini architecture of only 10 layers by modifying the deep residual neural network (ResNet), named ResNet mini architecture. To support the ResNet mini architecture in brain age prediction, the brain age dataset (OpenNeuro #ds000228) that consists of 155 study participants (three classes) and the Alzheimer MRI preprocessed dataset that consists of 6400 images (four classes) are employed. We compared the performance of the ResNet mini architecture with other popular networks using the two considered datasets. Experimental results show that the proposed architecture exhibits generality and robustness with high accuracy and less parameter number.

Application and characterization of digital Sallen-Key filter in nuclear spectrum smoothing.

In the nuclear spectrum analysis processing, spectrum smoothing can remove the statistical fluctuation in the spectrum, which is beneficial for peak detection and peak area calculation. In this work, a spectrum smoothing algorithm is proposed based on digital Sallen-Key filter, which contains four parameters (m, n, k, D). The amplitude-frequency response curve of Sallen-Key filter is deduced and the filtering performance is analyzed. Meanwhile, the effects of the four parameters on the shape of the smoothed spectrum are explored: D affects the counts and peak areas of the spectrum, and the peak area can be corrected by the peak area correction function S'. The parameters of m, n and k affect the peak position after smoothing, making the peak position shift to the right, and the peak position correction function P' can be used to correct the peak position, when n¿2, the spectrum data appear negative after smoothing, when k¿2, the smoothed spectrum broadening degree is greater than 20%. Smoothness (R), noise smoothing factor (NSF), spectrum count ratio before and after smoothing (PER), and comprehensive evaluation factor (Q) are used to evaluate the smoothing effect of the algorithm. The parameters of the algorithm are optimally selected: about the gamma spectrum of 137Cs and 60Co, the optimal parameters are m=1.5 n=2 k=2 D=1, about the characteristic X-ray spectrum of Fe and quasi-geological sample (TiMnFeNiCuZn), the optimal parameters are m=1.1 n=1.1 k=1.3 D=1. Based on Sallen-Key smoothing method, Fourier transform method, Gaussian function method, wavelet transformation method, center of gravity method and least squares method, the gamma spectrum of 137Cs is smoothed and denoised in this paper. The results show that the Sallen-Key method has better spectrum denoising effect (R=0.6056) and comprehensive performance indicators (Q=0.6104), which can be further applied for the smoothing of nuclear spectrum data.

Effect of inflammatory response on joint function after hip fracture in elderly patients: A clinical study.

BACKGROUND: Excellent hip joint function facilitates limb recovery and improves the quality of survival. This study aimed to investigate the potential risk factors affecting postoperative joint functional activity and outcomes in elderly hip fractures patients and to provide evidence for patient rehabilitation and clinical management. AIM: To explore the relationship between inflammatory factors and hip function and the interaction between inflammation and health after hip fracture in elderly patients. METHODS: The elderly patients who had hip fracture surgery at our hospital between January 1, 2021, and December 31, 2022 were chosen for this retrospective clinical investigation. Patients with excellent and fair postoperative hip function had their clinical information and characteristics gathered and compared. Age, gender, fracture site, surgical technique, laboratory indices, and other variables that could have an impact on postoperative joint function were all included in a univariate study. To further identify independent risk factors affecting postoperative joint function in hip fractures, risk factors that showed statistical significance in the univariate analysis were then included in a multiple logistic regression analysis. In addition to this, we also compared other outcome variables such as visual analogue scale and length of hospital stay between the two groups. RESULTS: A total of 119 elderly patients with hip fractures were included in this study, of whom 37 were male and 82 were female. The results of univariate logistic regression analysis after excluding the interaction of various factors showed that there was a statistically significant difference in interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP), and complement C1q (C1q) between the fair and excellent joint function groups (P < 0.05). The results of multiple logistic regression analysis showed that IL-6 > 20 pg/mL [(Odds ratio (OR) 3.070, 95%CI: 1.243-7.579], IL-8 > 21.4 pg/ mL (OR 3.827, 95%CI: 1.498-9.773), CRP > 10 mg/L (OR 2.142, 95%CI: 1.020-4.498) and C1q > 233 mg/L (OR 2.339, 95%CI: 1.094-5.004) were independent risk factors for poor joint function after hip fracture surgery (all P < 0.05). CONCLUSION: After hip fractures in older patients, inflammatory variables are risk factors for fair joint function; therefore, early intervention to address these markers is essential to enhance joint function and avoid consequences.

Clinical benefit analysis of PD-1 inhibitors in patients with advanced, recurrent or metastatic cervical cancer: a meta-analysis and systematic review.

Purpose: This study aims to comprehensively evaluate the efficacy and safety of programmed cell death protein-1 (PD-1) in patients with advanced, recurrent, or metastatic cervical cancer (ARMCC) and identify the population that may benefit the most. Methods: We conducted a search of PubMed, EMBASE, and the Cochrane Collaboration Library from their inception to September 2023. We extracted and analyzed the results related to the efficacy and safety of PD-1 in patients with ARMCC. The primary endpoints included the overall objective response rate (ORR) and adverse events (AEs), while the secondary endpoints encompassed the 1-year overall survival (OS) rate, 1-year progression-free survival (PFS) rate, as well as OS and PFS. We used a random effects model to conduct a meta-analysis on single-group rates, and the Mantel-Haenszel method was utilized to compare the ORR and the incidence of AEs. Results: Our study included a total of 21 trials involving 2,097 patients. The ORR of the combination of PD-1 inhibitors with chemotherapy was 56.36%, the combination of PD-1 inhibitors with anti-angiogenic agents was 38.72%, the combination of PD-1 inhibitors with Cytotoxic T-lymphocyte antigen 4 inhibitors was 25.60%, and PD-1 inhibitor monotherapy was 15.99%. The subgroup analysis showed that the group of patients with squamous cell carcinoma (SCC) exhibited a significantly higher ORR compared to the non-SCC group in patients who received PD-1 inhibitors combined with other anti-tumor drugs (Odds Ratio =2.43, P=0.002). Additionally, the group of patients with a programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥1 exhibited a significantly higher ORR compared to the PD-L1 CPS <1 group in patients who received PD-1 inhibitor monotherapy (OR=4.14, P=0.02). PD-1 inhibitor monotherapy or PD-1 inhibitors combined with chemotherapy did not significantly increase the incidence of all grades of adverse events (Relative Risk=0.99, p=0.788) or the incidence of serious adverse events (RR=0.99, p=0.788) compared to chemotherapy alone. Conclusion: PD-1 inhibitors demonstrate outstanding efficacy in the treatment of patients with ARMCC. Patients with SCC may benefit more from treatments including PD-1 inhibitors in combination with other anti-tumor drugs, and PD-L1 CPS ≥1 can be considered a favorable indicator of immune therapy response. Importantly, the use of PD-1 inhibitor monotherapy or PD-1 inhibitors in combination with chemotherapy did not lead to an increased incidence of AEs compared with chemotherapy alone, indicting safety during treatment. Systematic Review Registration: PROSPERO (CRD42023457945).

Comprehensive analysis of anoikis-related genes in diagnosis osteoarthritis: based on machine learning and single-cell RNA sequencing data.

Osteoarthritis (OA) is a degenerative disease closely associated with Anoikis. The objective of this work was to discover novel transcriptome-based anoikis-related biomarkers and pathways for OA progression.The microarray datasets GSE114007 and GSE89408 were downloaded using the Gene Expression Omnibus (GEO) database. A collection of genes linked to anoikis has been collected from the GeneCards database. The intersection genes of the differential anoikis-related genes (DEARGs) were identified using a Venn diagram. Infiltration analyses were used to identify and study the differentially expressed genes (DEGs). Anoikis clustering was used to identify the DEGs. By using gene clustering, two OA subgroups were formed using the DEGs. GSE152805 was used to analyse OA cartilage on a single cell level. 10 DEARGs were identified by lasso analysis, and two Anoikis subtypes were constructed. MEgreen module was found in disease WGCNA analysis, and MEturquoise module was most significant in gene clusters WGCNA. The XGB, SVM, RF, and GLM models identified five hub genes (CDH2, SHCBP1, SCG2, C10orf10, P FKFB3), and the diagnostic model built using these five genes performed well in the training and validation cohorts. analysing single-cell RNA sequencing data from GSE152805, including 25,852 cells of 6 OA cartilage.

Clinical characteristics, diagnosis and management of nivolumab-induced myocarditis.

Nivolumab can cause fatal myocarditis. We aimed to analyze the clinical characteristics of nivolumab-induced myocarditis and provide evidence for clinical diagnosis, treatment, and prevention. Studies involving nivolumab-induced myocarditis were identified in electronic databases from 2000 to 2023 for retrospective analysis. A total of 66 patients were included, with a median age of 68 years. The median onset time of myocarditis is 11.5 days. The main organs affected in persons presented with myocarditis are heart (100.0%) and skeletal muscle (22.7%). The main clinical manifestations are dyspnea (49.2%), fatigue (47.6%), and myalgias (25.4%). The levels of troponin, troponin T, troponin I, creatine kinase, creatine kinase myocardial band, creatine phosphokinase, C-reactive protein, brain natriuretic peptide, and N-terminal brain natriuretic peptide precursor were significantly increased. Histopathology often shows lymphocyte infiltration, myocardial necrosis, and fibrosis. Myocardial immunological parameters usually present positive. Cardiac imaging often suggests complete heart block, intraventricular conduction delay, arrhythmia, myocardial infarction, edema, left ventricular ejection fractions reduction, ventricular dysfunction, and other symptoms of myocarditis. Forty-two (63.6%) patients achieved remission within a median time of 8 days after discontinuation of nivolumab and treatment with systemic corticosteroids, immunoglobulins, plasmapheresis, and immunosuppressant. Thirty-five patients eventually died attributed to myocarditis (68.6%), cancer (20.0%), respiratory failure (5.7%), and other reasons (5.7%). Nivolumab-induced myocarditis should be comprehensively diagnosed based on clinical symptoms, histopathological manifestations, immunological parameters, and cardiac function imaging examinations. Nivolumab should be discontinued immediately, plasmapheresis and systemic corticosteroids combined with immunoglobulins or immunosuppressants may be an effective treatment.

A clinical predictive model for pre-transplantation Klebsiella pneumoniae colonization and relevance for clinical outcomes in patients receiving allogeneic hematopoietic stem cell transplantation.

The purpose of this study is to establish a clinical prediction model to discriminate patients at high risk of Klebsiella pneumoniae (KP) colonization before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and evaluate the impact of KP colonization on clinical outcomes after allo-HSCT. We retrospectively collected data from 2,157 consecutive patients receiving allo-HSCT between January 2018 and March 2022. KP colonization was defined as a positive test for KP from a pharyngeal or anal swab before allo-HSCT. Logistic regression was used to build a clinical prediction model. Cox regression analyses were performed to explore the effect of KP colonization on clinical outcomes. Among all the inpatients, 166 patients had KP colonization and 581 with no positive pathogenic finding before transplantation. Seven candidate predictors were entered into the final prediction model. The prediction model had an area under the curve of 0.775 (95% CI 0.723-0.828) in the derivation cohort and 0.846 (95% CI: 0.790-0.902) in the validation cohort. Statistically significantly different incidence rates were observed among patient groups with clinically predicted low, medium, and high risk for KP infection (P < 0.001). The presence of KP colonization delayed platelet engraftment (P < 0.001) and patients with KP colonization were more likely to develop KP bloodstream infections within 100 days after allo-HSCT (P < 0.0001). Patients with KP colonization had higher non-relapse mortality (P = 0.032), worse progression-free survival (P = 0.0027), and worse overall survival within 100 days after allo-HSCT (P = 0.013). Our findings suggest that increased awareness of risks associated with pre-transplantation bacterial colonization is warranted.IMPORTANCESeveral studies have identified that Klebsiella pneumoniae (KP) is among the most common and deadly pathogens for patients in hospital intensive care units and those receiving transplantation. However, there are currently no studies that evaluate the impact of KP colonization to patients undergoing allogeneic hematopoietic stem cell transplantation. Our results confirm that pre-existing KP colonization is relatively common in a hematology transplant ward setting and negatively affects post-transplantation prognosis. Our clinical prediction model for KP colonization can support early intervention in patients at high risk to avoid subsequent bloodstream infections and improve survival outcomes. Altogether, our data suggest that increased awareness of risks associated with pre-transplantation bacterial colonization is warranted. Future studies are needed to confirm these findings and to test early intervention strategies for patients at risk of complications from KP infection.

[Mechanism of Shikonin on spinal cord injury in rats based on TNFR/RIPK1 pathway].

OBJECTIVE: To explore the effect of shikonin on the recovery of nerve function after acute spinal cord injury(SCI) in rats. METHODS: 96 male Sprague-Dawley(SD)rats were divided into 4 groups randomly:sham operation group (Group A), sham operation+shikonin group (Group B), SCI+ DMSO(Group C), SCI+shikonin group (Group D).The acute SCI model of rats was made by clamp method in groups C and D . After subdural catheterization, no drug was given in group A. rats in groups B and D were injected with 100 mg·kg-1 of shikonin through catheter 30 min after modeling, and rats in group C were given with the same amount of DMSO, once a day until the time point of collection tissue. Basso-Beattie-Bresnahan(BBB) scores were performed on 8 rats in each group at 6, 12, and 3 d after moneling, and oblique plate tests were performed on 1, 3, 7 and 14 d after modeling, and then spinal cord tissues were collected. Eight rats were intraperitoneally injected with propidine iodide(PI) 1 h before sacrificed to detection PI positive cells at 24 h in each group. Eight rats were sacrificed in each group at 24 h after modeling, the spinal cord injury was observed by HE staining.The Nissl staining was used to observe survivor number of nerve cells. Western-blot technique was used to detect the expression levels of Bcl-2 protein and apoptosis related protein RIPK1. RESULTS: After modeling, BBB scores were normal in group A and B, but in group C and D were significantly higher than those in group A and B. And the scores in group D were higher than those in group C in each time point (P<0.05). At 12 h after modeling, the PI red stained cells in group D were significantly reduced compared with that in group C, and the disintegration of neurons was alleviated(P<0.05). HE and Nissl staining showed nerve cells with normal morphology in group A and B at 24h after operation. The degree of SCI and the number of neuronal survival in group D were better than those in group C, the difference was statistically significant at 24h (P<0.05). The expression of Bcl-2 and RIPK1 proteins was very low in group A and B;The expression of RIPK1 was significantly increased in Group C and decreased in Group D, with a statistically significant difference (P<0.05);The expression of Bcl-2 protein in group D was significantly higher than that in group C (P<0.05). CONCLUSION: Shikonin can alleviate the pathological changes after acute SCI in rats, improve the behavioral score, and promote the recovery of spinal nerve function. The specific mechanism may be related to the inhibition of TNFR/RIPK1 signaling pathway mediated necrotic apoptosis.

Intrathecal or intraventricular antimicrobial therapy for post-neurosurgical Gram-negative bacillary meningitis or ventriculitis: a systematic review and meta-analysis.

PURPOSE: Extensively-drug-resistant Gram-negative bacteria (XDR GNB)-related post-neurosurgical infection is closely related to mortality, which represents a major challenge for neurosurgeons. There is an urgent need to review and evaluate methods to reduce mortality. METHODS: Both international and Chinese databases were searched independently from their inception to 15 June 2023. A meta-analysis was conducted using RevMan 5.4 to compare the efficacy and safety of intravenous (IV) treatment in combination with intrathecal or intraventricular (ITH/IVT) treatment with IV treatment alone for post-neurosurgical meningitis or ventriculitis due to GNB. Mortality, microbiological clearance and adverse events were considered as primary outcomes. RESULTS: In total, 18 eligible studies involving 602 patients were included in the meta-analysis. The IV + ITH/IVT group was associated with significantly lower mortality (especially in the XDR GNB subgroup) and acceptable safety. In terms of microbiological clearance, a significant decrease was shown in the XDR GNB subgroup. Significant benefits were shown in laboratory parameters and clinical symptoms after patients were treated with ITH/IVT. CONCLUSION: Additional ITH/IVT treatment may promote XDR GNB clearance and reduce mortality. In addition, ITH/IVT administration can improve clinical symptoms and cerebrospinal fluid indicators of patients with post-neurosurgical infections. Significantly, ITH/IVT treatment does not increase the incidence of adverse events at the recommended dose.

The protein kinase A signaling pathway mediates the effect of electroacupuncture on excessive contraction of the bladder detrusor in a rat model of neurogenic bladder.

BACKGROUND: Neurogenic bladder (NB) is a form of neurological bladder dysfunction characterized by excessive contraction of the bladder detrusor. Protein kinase A (PKA) signaling is involved in the contraction of the detrusor muscle. AIMS: To investigate whether PKA signaling mediates the effect of electroacupuncture (EA) on the excessive contraction of the bladder detrusor in NB. METHODS: Sixty rats were randomly divided into control, sham, NB, NB + EA, and NB + EA + H89 (a PKA receptor antagonist) groups. The modified Hassan Shaker spinal cord transection method was used to generate a NB model. After EA intervention for one week, urodynamic tests were used to evaluate bladder function, hematoxylin and eosin staining was conducted to assess morphological changes, enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentration of PKA, and Western blotting was conducted to measure the protein levels of phosphorylated myosin light chain kinase (p-MLCK)/p-MLC. RESULTS: The results showed that NB resulted in morphological disruption, impairment of urodynamics, and decreases in the concentration of PKA and the protein levels of p-MLCK/p-MLC. EA reversed the changes induced by NB dysfunction. However, the improvement in urodynamics and the increases in the concentration of PKA and the protein levels of p-MLCK/p-MLC were inhibited by H89. CONCLUSION: Our findings indicate that the PKA signaling pathway mediates the beneficial effect of EA on excessive contraction of the bladder detrusor in a rat model of NB.

Mechanism of Shikonin on spinal cord injury in rats based on TNFR/RIPK1 pathway / 中国骨伤

OBJECTIVE@#To explore the effect of shikonin on the recovery of nerve function after acute spinal cord injury(SCI) in rats.@*METHODS@#96 male Sprague-Dawley(SD)rats were divided into 4 groups randomly:sham operation group (Group A), sham operation+shikonin group (Group B), SCI+ DMSO(Group C), SCI+shikonin group (Group D).The acute SCI model of rats was made by clamp method in groups C and D . After subdural catheterization, no drug was given in group A. rats in groups B and D were injected with 100 mg·kg-1 of shikonin through catheter 30 min after modeling, and rats in group C were given with the same amount of DMSO, once a day until the time point of collection tissue. Basso-Beattie-Bresnahan(BBB) scores were performed on 8 rats in each group at 6, 12, and 3 d after moneling, and oblique plate tests were performed on 1, 3, 7 and 14 d after modeling, and then spinal cord tissues were collected. Eight rats were intraperitoneally injected with propidine iodide(PI) 1 h before sacrificed to detection PI positive cells at 24 h in each group. Eight rats were sacrificed in each group at 24 h after modeling, the spinal cord injury was observed by HE staining.The Nissl staining was used to observe survivor number of nerve cells. Western-blot technique was used to detect the expression levels of Bcl-2 protein and apoptosis related protein RIPK1.@*RESULTS@#After modeling, BBB scores were normal in group A and B, but in group C and D were significantly higher than those in group A and B. And the scores in group D were higher than those in group C in each time point (P<0.05). At 12 h after modeling, the PI red stained cells in group D were significantly reduced compared with that in group C, and the disintegration of neurons was alleviated(P<0.05). HE and Nissl staining showed nerve cells with normal morphology in group A and B at 24h after operation. The degree of SCI and the number of neuronal survival in group D were better than those in group C, the difference was statistically significant at 24h (P<0.05). The expression of Bcl-2 and RIPK1 proteins was very low in group A and B;The expression of RIPK1 was significantly increased in Group C and decreased in Group D, with a statistically significant difference (P<0.05);The expression of Bcl-2 protein in group D was significantly higher than that in group C (P<0.05).@*CONCLUSION@#Shikonin can alleviate the pathological changes after acute SCI in rats, improve the behavioral score, and promote the recovery of spinal nerve function. The specific mechanism may be related to the inhibition of TNFR/RIPK1 signaling pathway mediated necrotic apoptosis.

Dynamic foraging strategy adaptation to heterogeneous environments contributes to social aggregation in snub-nosed monkeys.

The dynamics of animal social structures are heavily influenced by environmental patterns of competition and cooperation. In folivorous colobine primates, prevailing theories suggest that larger group sizes should be favored in rainforests with a year-round abundance of food, thereby reducing feeding competition. Yet, paradoxically, larger groups are frequently found in high-altitude or high-latitude montane ecosystems characterized by a seasonal scarcity of leaves. This contradiction is posited to arise from cooperative benefits in heterogeneous environments. To investigate this hypothesis, we carried out a six-year field study on two neighboring groups of golden snub-nosed monkey ( Rhinopithecus roxellana), a species representing the northernmost distribution of colobine primates. Results showed that the groups adjusted their movement and habitat selection in response to fluctuating climates and spatiotemporal variability of resources, indicative of a dynamic foraging strategy. Notably, during the cold, resource-scarce conditions in winter, the large group occupied food-rich habitats but did not exhibit significantly longer daily travel distances than the smaller neighboring group. Subsequently, we compiled an eco-behavioral dataset of 52 colobine species to explore their evolutionary trajectories. Analysis of this dataset suggested that the increase in group size may have evolved via home range expansion in response to the cold and heterogeneous climates found at higher altitudes or latitudes. Hence, we developed a multi-benefits framework to interpret the formation of larger groups by integrating environmental heterogeneity. In cold and diverse environments, even smaller groups require larger home ranges to meet their dynamic survival needs. The spatiotemporal distribution of high-quality resources within these expanded home ranges facilitates more frequent interactions between groups, thereby encouraging social aggregation into larger groups. This process enhances the benefits of collaborative actions and reproductive opportunities, while simultaneously optimizing travel costs through a dynamic foraging strategy.

Overexpressed Gαi1 exerts pro-tumorigenic activity in nasopharyngeal carcinoma.

The current study tested the expression and potential functions of Gαi1 in nasopharyngeal carcinoma (NPC). The Cancer Genome Atlas (TCGA) database results demonstrate that Gαi1 transcripts' number in NPC tissues is significantly higher than that in the normal nasal epithelial tissues. Its overexpression correlates with poor survival in certain NPC patients. Moreover, Gαi1 is significantly upregulated in NPC tissues of local primary patients and in different primary human NPC cells. Whereas its expression is relatively low in cancer-surrounding normal tissues and in primary nasal epithelial cells. Genetic silencing (via shRNA strategy) or knockout (via CRISPR-sgRNA method) of Gαi1 substantially suppressed viability, proliferation, cell cycle progression, and migration in primary NPC cells, causing significant caspase-apoptosis activation. Contrarily, ectopic Gαi1 expression exerted pro-tumorigenic activity and strengthened cell proliferation and migration in primary NPC cells. Gαi1 is important for Akt-mTOR activation in NPC cells. Akt-S6K phosphorylation was downregulated after Gαi1 shRNA or KO in primary NPC cells, but strengthened following Gαi1 overexpression. In Gαi1-silenced primary NPC cells, a S473D constitutively-active mutant Akt1 (caAkt1) restored Akt-S6K phosphorylation and ameliorated Gαi1 shRNA-induced proliferation inhibition, migration reduction and apoptosis. Bioinformatics analyses proposed zinc finger protein 384 (ZNF384) as a potential transcription factor of Gαi1. In primary NPC cells, ZNF384 shRNA or knockout (via CRISPR-sgRNA method) decreased Gαi1 mRNA and protein expression, whereas ZNF384 overexpression upregulated it. Importantly, there was an increased binding between ZNF384 protein and the Gαi1 promoter in human NPC tissues and different NPC cells. In vivo studies showed that intratumoral injection of Gαi1-shRNA-expressing adeno-associated virus (AAV) impeded subcutaneous NPC xenograft growth in nude mice. Gαi1 downregulation, Akt-mTOR inactivation, and apoptosis induction were detected in Gαi1-silenced NPC xenograft tissues. Gαi1 KO also effectively inhibited the growth of NPC xenografts in nude mice. Together, overexpressed Gαi1 exerts pro-tumorigenic activity in NPC possibly by promoting Akt-mTOR activation.