Inactivated cGAS-STING Signaling Facilitates Endocrine Resistance by Forming a Positive Feedback Loop with AKT Kinase in ER+HER2- Breast Cancer.

Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.

Dynamic safety information modeling of underground cavern groups in the entire construction process.

The construction of underground cavern groups represents a particularly challenging task in current subsurface engineering due to a multitude of variable and often unknown factors, including diverse geological conditions. This study introduces a four-dimensional spatiotemporal model and formulates a dynamic safety information model for these underground systems. Developed using C# and Python, the model integrates the finite element analysis software ABAQUS and Microsoft SQL Server database. The framework allows for real-time visual management of monitoring data, dynamic coupling of construction phases with safety metrics, and continual updates correlating with construction progress. The theoretical findings offer valuable insights for enhancing the safety and efficiency of underground cavern group construction while also supplying methods for real-time safety feedback and control throughout the construction process.

Haemophilus aphrophilus and Eikenella corrodens Coinfection of Brain: An Unusual Case from China.

Background: The HACEK group comprises Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, are Gram-negative bacteria that are slow-growing and fastidious. These organisms are common causes of culture-negative endocarditis. However, brain abscesses caused by Haemophilus aphrophilus and E. corrodens have been rarely reported. The case we describe, which was promptly identified and successfully treated, will be meaningful for the diagnosis and treatment of such infectious diseases. Case Presentation: Herein, we report a case of brain abscess in a young man who was infected with Haemophilus aphrophilus and E. corrodens. The patient was admitted to the hospital with sudden onset of vomiting, coma, and fever. Magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid cell counts suggested cerebral abscess, he underwent drainage of the abscess and empirical antimicrobial therapy of meropenem (2 g every 8 hours) and linezolid (0.6 g every 12 hours) for more than 10 days without significant improvement. Metagenomic next-generation sequencing (mNGS) of drainage fluid and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) detection for isolated bacteria from samples suggested the presence of H. aphrophilus and E. corrodens. After 7 weeks of ceftriaxone (2 g every 12 hours) and meropenem (2 g every 8 hours) intravenously, the patient was discharged with a normal temperature and brain MRI showed improvement of the lesion. Conclusion: Similar cases reported in previous studies were always associated with bacterial blood dissemination after dental surgery or myocarditis; however, the patient in our case had no any associated risk factors. As far as we know, this is the only case of central nervous system infection caused by H. aphrophilus and E. corrodens that has utilized combined mNGS and MALDI-TOF MS in the diagnosis.

Magnetic resonance imaging features for differentiating tuberculous from pyogenic spondylitis: a meta-analysis.

OBJECTIVE: To perform a meta-analysis comparing the MRI features of tuberculous and pyogenic spondylitis, using histopathological results and/or blood culture as the standard reference. MATERIALS AND METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched for English-language studies on the MRI features of tuberculous and pyogenic spondylitis published between January 2010 and February 2023. Risk for bias and concerns regarding applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled MRI features' proportions were calculated using a bivariate random-effects model. RESULTS: Thirty-two studies met the inclusion criteria: 21 for tuberculous spondylitis, three for pyogenic spondylitis, and eight for both. Of the nine informative MRI features comparing tuberculous spondylitis to pyogenic spondylitis, involvement of ≥ 2 vertebral bodies (92% vs. 88%, P = .004), epidural extension (77% vs. 25%, P < .001), paravertebral collection (91% vs. 84%, P < .001), subligamentous spread (93% vs. 24%, P < .001), thin and regular abscess wall (94% vs. 18%, P < .001), vertebral collapse (68% vs. 24%, P < .001), and kyphosis (39% vs. 3%, P < .01) were more suggestive of tuberculous spondylitis, while disc signal change (82% vs. 95%, P < .001) and disc height loss (22% vs. 59%, P < .001) were more suggestive of pyogenic spondylitis. CONCLUSION: Involvement of ≥ 2 vertebral vertebral bodies, soft tissue attribution, thin and regular abscess wall, vertebral collapse, and kyphosis were MRI features more common in tuberculous spondylitis, while disc signal change and height loss were more common in pyogenic spondylitis.

Progress and prospect of inhaled biological agents in asthma / 中国临床药理学与治疗学

More than 300 million people worldwide suffer from asthma, and the incidence is increasing year by year. As one of the most common chronic diseases, asthma is an immune-mediated inflammatory disease with complex triggering mechanisms and strong heterogeneity. With the in-depth study of physiological and pathological mechanisms, therapeutic small molecule and hormone drugs have been introduced to control and treat most patients, but about 5% - 10% of patients still suffer from various subtypes of difficult to control and treat asthma, that is, severe asthma. In the past decade, with the rapid development of bio-pharmaceutical research, protein and antibody have become the key drugs for the treatment of severe asthma with high efficacy, high specificity and high safety. However, biological drugs are usually administered by injection, they cannot be noninvasive and directly delivered into the lung to quickly absorb and take effect. Therefore, there is an urgent need for the introduction of inhaled biologics with quick effectiveness, convenience, economy and safety in clinical. The review summarizes the existing small molecule, hormone and biological therapy drugs, and summarizes the development of inhalable biological agents of asthma, and analyzes the future prospects of the inhalable biological drugs, which is designed to deepen the perception of the direction of the inhalable biological drugs research, and update the information of the field, in order to provide reference for the development of more inhalable biologics.

Generation of induced pluripotent stem cell lines from South Asian ethnicity.

South Asians, which represent around 25% of the world's population, have a disproportionately high risk of cardiometabolic disease, two-fold higher risk of myocardial infarction, and 4- to 6-fold higher risk for diabetes compared to Caucasians. We generated two induced pluripotent stem cell (iPSC) lines from healthy South Asian donors and validated the pluripotency and ability of these cell lines to differentiate into three germ layers. These iPSC lines can be applied to generate many cardiovascular cell types such as cardiomyocytes, endothelial cells, and mural cells to investigate different cardiovascular disease mechanisms triggered by environmental risk factors or drugs in vitro.

Clinical efficacy of total laparoscopic splenectomy for portal hypertension and its influence on hepatic hemodynamics and liver function.

BACKGROUND: The liver hemodynamic changes caused by portal hypertension (PH) are closely related to various complications such as gastroesophageal varices and portosys-temic shunts, which may lead to adverse clinical outcomes in these patients, so it is of great clinical significance to find treatment strategies with favorable clinical efficacy and low risk of complications. AIM: To study the clinical efficacy of total laparoscopic splenectomy (TLS) for PH and its influence on hepatic hemodynamics and liver function. METHODS: Among the 199 PH patients selected from October 2016 to October 2020, 100 patients [observation group (OG)] were treated with TLS, while the remaining 99 [reference group (RG)] were treated with open splenectomy (OS). We observed and compared the clinical efficacy, operation indexes [operative time (OT) and intraoperative bleeding volume], safety (intraperitoneal hemorrhage, ascitic fluid infection, eating disorders, liver insufficiency, and perioperative death), hepatic hemodynamics (diameter, velocity, and flow volume of the portal vein system), and liver function [serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and serum total bilirubin (TBil)] of the two groups. RESULTS: The OT was significantly longer and intraoperative bleeding volume was significantly lesser in the OG than in the RG. Additionally, the overall response rate, postoperative complications rate, and liver function indexes (ALT, AST, and TBil) did not differ significantly between the OG and RG. The hepatic hemodynamics statistics showed that the pre- and postoperative blood vessel diameters in the two cohorts did not differ statistically. Although the postoperative blood velocity and flow volume reduced significantly when compared with the preoperative values, there were no significant inter-group differences. CONCLUSION: TLS contributes to comparable clinical efficacy, safety, hepatic hemodynamics, and liver function as those of OS in treating PH, with a longer OT but lesser intraoperative blood loss.

Oncogenic miR-93-5p/Gal-9 axis drives CD8 (+) T-cell inactivation and is a therapeutic target for hepatocellular carcinoma immunotherapy.

Evading immune destruction is an emerging hallmark of cancer and a potential key step in tumorigenesis. Immune checkpoint blocker (ICB)-based combination therapies revolutionize the landscape of systemic therapy for HCC. However, the molecular underpinnings governing immune evasion and responses remain unclear. Our study aims to find new regulatory molecules that drive HCC immune escape and tumorigenesis and find new promising immunotherapeutic approaches for HCC. In our study, laser capture microdissection (LCM) and miRNA sequencing combined with in vitro and in vivo experiments identified miR-93-5p as a crucial initiating oncogene during liver progenitor cell (LPC) malignant transformation and immune escape. Mechanistically, miR-93-5p could directly target canonical tumour suppressors such as APC to promote LPC malignant transformation and hepatocarcinogenesis. More importantly, miR-93-5p could induce deviant GAL-9 augmentation to inactivate infiltrated CD8(+) T cells and induce immune evasion by targeting several epigenetic regulators, such as AEBP2, and then regulating H3K4me3/H3K27me3 bivalency. Experiments in C57BL/6 mice demonstrated that blockade of Gal-9 abrogated miR-93-5p-induced HCC progression and improved their prognosis. Clinically, we identified a unique subtype of HCC closely associated with high GAL-9 expression and anti-PD1 treatment resistance. Our study highlights the pivotal role of the miR-93-5p/Gal-9 axis in driving HCC immune escape and tumorigenesis. Blocking GAL-9 is an effective and promising immunotherapeutic approach for HCC.

Resveratrol improves the cytotoxic effect of CD8 +T cells in the tumor microenvironment by regulating HMMR/Ferroptosis in lung squamous cell carcinoma.

Ferroptosis, an iron-dependent cell death process, is a potential therapeutic strategy for Lung squamous cell carcinoma (LUSC). Resveratrol (RES) is an anti-tumor polyphenol. However, whether and how RES treats LUSC is not yet known. This study aimed to investigate the effect of RES on LUSC and to explore its potential mechanism. This study used a combination of proteomics, bioinformatics, clinical samples, and cell experiments to study the interaction between HMMR and the ferroptosis signaling pathway and investigate the role of RES in regulating tumor immune microenvironment and anti-tumor by cytotoxic CD8 +T cells in LUSC. Ferroptosis signaling pathway and HMMR were involved in the LUSC tumor immune microenvironment and correlated with worse prognosis of LUSC patients. RES+H520 cells induced a higher level of ferroptosis and MDA, mainly by reducing the expression of GPX4 and SLC7A11, inducing the expression of ACSL4 and TFRC. HMMR, GSH, and SOD contents were lower observed than in H520 cells. When HMMR was expressed, SLC7A11 was also highly expressed in LUSC, and there was an interaction between HMMR expression and SLC7A11. In addition, RES increased the TNF-α, IFN-γ, IL-12, and IL-2 expression and increased the cytotoxic effects of CD8 +T cells expressions in LUSC. Resveratrol regulates SLC7A11-HMMR interaction, activates ferroptosis, enhances the cytotoxic effect of CD8 +T cells, and regulates the tumor immune microenvironment. Based on the pathogenesis of LUSC and the clinical efficacy of RES, this study explored the influence of RES on LUSC, clarified its biological effects, and further provided cell biological basis for the clinical application of RES, which could guide clinical combination and personalized medicine, improve the response rate of immunotherapy and benefit more patients with LUSC.

Application of back-forward Bending CT localization image in the prediction of proximal junctional kyphosis after spinal deformity surgery in adults / 中国修复重建外科杂志

OBJECTIVE@#To investigate the feasibility of predicting proximal junctional kyphosis (PJK) in adults after spinal deformity surgery based on back-forward Bending CT localization images and related predictive indicators.@*METHODS@#A retrospective analysis was performed for 31 adult patients with spinal deformity who underwent posterior osteotomy and long-segment fusion fixation between March 2017 and March 2020. There were 5 males and 26 females with an average age of 62.5 years (range, 30-77 years). The upper instrumented vertebrae (UIV) located at T 5 in 1 case, T 6 in 1 case, T 9 in 13 cases, T 10 in 12 cases, and T 11 in 4 cases. The lowest instrumented vertebrae (LIV) located at L 1 in 3 cases, L 2 in 3 cases, L 3 in 10 cases, L 4 in 7 cases, L 5 in 5 cases, and S 1 in 3 cases. Based on the full-length lateral X-ray film of the spine in the standing position before and after operation and back-forward Bending CT localization images before operation, the sagittal sequence of the spine was obtained, and the relevant indexes were measured, including thoracic kyphosis (TK), lumbar lordosis (LL), local kyphosis Cobb angle (LKCA) [the difference between the different positions before operation (recovery value) was calculated], kyphosis flexibility, hyperextension sagittal vertical axis (hSVA), T 2-L 5 hyperextension C 7-vertebral sagittal offset (hC 7-VSO), and pre- and post-operative proximal junctional angle (PJA). At last follow-up, the patients were divided into PJK and non-PJK groups based on PJA to determine whether they had PJK. The gender, age, body mass index (BMI), number of fusion segments, number of cases with coronal plane deformity, bone mineral density (T value), UIV position, LIV position, operation time, intraoperative blood loss, osteotomy grading, and related imaging indicators were compared between the two groups. The hC 7-VSO of the vertebral body with significant differences between groups was taken, and the receiver operating characteristic curve (ROC) was used to evaluate its accuracy in predicting the occurrence of PJK.@*RESULTS@#All 31 patients were followed up 13-52 months, with an average of 30.0 months. The patient's PJA was 1.4°-29.0° at last follow-up, with an average of 10.4°; PJK occurred in 8 cases (25.8%). There was no significant difference in gender, age, BMI, number of fusion segments, number of cases with coronal plane deformity, bone mineral density (T value), UIV position, LIV position, operation time, intraoperative blood loss, and osteotomy grading between the two groups ( P>0.05). Imaging measurements showed that the LL recovery value and T 8-L 3 vertebral hC 7-VSO in the PJK group were significantly higher than those in the non-PJK group ( P>0.05). There was no significant difference in hyperextension TK, hyperextension LL, hyperextension LKCA, TK recovery value, LL recovery value, kyphosis flexibility, hSVA, and T 2-T 7, L 4, L 5 vertebral hC 7-VSO ( P>0.05). T 8-L 3 vertebral hC 7-VSO was analyzed for ROC curve, and combined with the area under curve and the comprehensive evaluation of sensitivity and specificity, the best predictive index was hC 7-L 2, the cut-off value was 2.54 cm, the sensitivity was 100%, and the specificity was 60.9%.@*CONCLUSION@#Preoperative back-forward Bending CT localization image can be used to predict the occurrence of PJK after posterior osteotomy and long-segment fusion fixation in adult spinal deformity. If the patient's T 8-L 2 vertebral hC 7-VSO is too large, it indicates a higher risk of postoperative PJK. The best predictive index is hC 7-L 2, and the cut-off value is 2.54 cm.

Projection-Specific Heterogeneity of the Axon Initial Segment of Pyramidal Neurons in the Prelimbic Cortex / 神经科学通报·英文版

The axon initial segment (AIS) is a highly specialized axonal compartment where the action potential is initiated. The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons (PyNs), which likely contributes to their unique spiking properties. However, whether the various characteristics of AISs can be linked to specific PyN subtypes remains unknown. Here, we report that in the prelimbic cortex (PL) of the mouse, two types of PyNs with axon projections either to the contralateral PL or to the ipsilateral basal lateral amygdala, possess distinct AIS properties reflected by morphology, ion channel expression, action potential initiation, and axo-axonic synaptic inputs from chandelier cells. Furthermore, projection-specific AIS diversity is more prominent in the superficial layer than in the deep layer. Thus, our study reveals the cortical layer- and axon projection-specific heterogeneity of PyN AISs, which may endow the spiking of various PyN types with exquisite modulation.

Difference and its clinical significance of peripheral blood lymphocyte subsets between elderly and non-elderly patients with rheumatoid arthritis / 中华老年医学杂志

Objective:To investigate the difference of lymphocyte subsets between elderly patients with rheumatoid arthritis and non-elderly patients and its clinical significance.Methods:A total of 124 patients with rheumatoid arthritis in Affiliated Hospital of Nantong University from January, 2017 to December, 2019 were enrolled.The patients were divided into elderly group(≥60 years old, 34 cases)and non-elderly group(<60 years old, 90 cases). Rheumatoid arthritis activity(DAS-28)scoring was performed for each patient.Peripheral blood mononuclear cells(PBMCs)were extracted by Ficoll density centrifugation.Lymphocytes were labeled and detected by 18-color flowcytometry with more than 30 fluorescent antibodies.Results:DAS-28 scoring showed that the disease activity score of the elderly group(4.56±1.89)was higher than that of the non-elderly group(3.37±1.49)( t=3.633, P<0.001). Flow cytometry showed that MAIL%T(mucus-associated lymphoid tissue T cell subset)( Z=-2.798, P=0.005), Tn%CD8 T cells(initial CD8 T cells)( Z=-2.179, P=0.029), VD2% T(Vδ2+ T, γδT cell subtype)( Z=-2.806, P=0.005), PD1-CD28-%Th( Z=-2.050, P=0.040)and IGM+ D-%B( Z=-2.376, P=0.017)were lower in the elderly group than in the non-elderly group.While, CD45+ CD27+ %CD8 T cells( Z=-3.069, P=0.002), abT%T cell(αβT cells)( Z=-2.103, P=0.035), CD27-CD28+ %T cells( Z=-2.341, P=0.019), ASC%PBMC( Z=-2.341, P=0.019)and ASC%CD19+ ( Z=-2.000, P=0.046)subgroup expression were higher in the elderly group than in the non-elderly group. Conclusions:The disease activity of elderly patients with rheumatoid arthritis is significantly higher than that of younger patients.The expressions of abT%T and CD4% abT in effector T cells of elderly patients with rheumatoid arthritis are higher than those of younger patients, while the expression of VD2% T is lower.The expression level of CD45RA+ CD27+ %CD8 T with cytotoxic effect is higher; However, the expression level of Tn%CD8 T in naive cells is lower.

Efficacy of autologous peripheral blood nucleated cell therapy on periocular wrinkles / 中华医学美学美容杂志

Objective:To explore the clinical effect of dermal and subcutaneous injection of autologous peripheral blood nucleated cells in improving periocular wrinkles.Methods:Eighteen cases of beauty seekers who planned to improve periocular wrinkles were selected as the research objects of this study. Autologous nucleated cells and blood active components were isolated and purified by negative collection mixed method and evenly injected into the periocular skin of patients. VISIA image analysis system, and satisfactory score were used to detect and evaluate the related characteristics of periocular skin at different stages before and after treatment. The scores were compared and analyzed, and the complications after treatment were recorded.Results:The 18 patients were followed up. The score of VISIA periorbital static wrinkles decreased from (22.09±8.21) before treatment to (18.31±7.84) one month after treatment, and the difference was statistically significant ( t=-7.495, P<0.05). 17 patients were satisfied; After 3 months of follow-up, 15 cases were satisfied. The texture, consistency and pore state of periorbital skin were improved in some patients (10 cases). Conclusions:Autologous peripheral blood nucleated cell therapy can improve periorbital wrinkles, especially skin fine lines, and geta high satisfactory rate. There are almost no adverse reactions after the treatment, which is worthy of clinical application.

Changes of corneal nerve fiber and the correlation analysis with visual acuity in demyelinating optical neuritis patients / 中华眼底病杂志

Objective:To investigate the changes in the nerve fiber layer of the cornea in patients with demyelinating optic neuritis (DON) and its correlation with visual acuity.Methods:A cross-sectional study. From March 2021 to July 2022, 27 cases (39 eyes) of DON patients diagnosed in the Department of Neurology and Ophthalmology of Beijing Tongren Hospital Affiliated to Capital Medical University were enrolled in this study. According to the serological test results, the patients were divided into aquaporin 4 antibody associated optic neuritis (AQP4-ON group) and myelin oligodendrocyte glycoprotein antibody associated optic neuritis (MOG-ON group), with 15 cases (19 eyes) and 12 cases (20 eyes) respectively. According to previous history of glucocorticoid treatment, the patients were divided into glucocorticoid treated group and non-glucocorticoid treated group, with 17 cases (27 eyes) and 10 cases (12 eyes) respectively. Twenty healthy volunteers (20 eyes) with age- and gender-matched were selected as the control group. All eyes underwent best corrected visual acuity (BCVA) and in vivo confocal microscopy (IVCM) examinations. BCVA was performed using Snellen's standard logarithmic visual acuity chart, which was converted into logarithmic minimum angle resolution (logMAR) visual acuity during statistics. The corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve fiber branch length (CNBL), corneal nerve fiber branch density (CNBD) and the density of corneal dendritic cells (DC) were detected by IVCM examination. Parameter comparison between groups by t-test and Kruskal-Wallis rank sum test. The correlation between logMAR BCVA and pamameters of corneal nerve fibers were analyzed using Spearman analysis. Results:The CNFL, CNFD, and CNBL of the DON group and the control group were (10.67±2.55) mm/mm 2, (57.78±12.35) root/mm 2, (3.27±1.34) mm/mm 2, and (13.74±3.05) mm/mm 2, (70.95±13.14) root/mm 2, and (4.22±1.03) mm/mm 2, respectively; the difference in CNFL, CNFD, and CNBL between the two groups were statistically significant ( t=4.089, 3.795, 2.773; P<0.05). The CNFL, CNBL, and CNBD of the affected eyes in the MOG-ON group and AQP4-ON group were (12.02±2.13) mm/mm 2, (3.80±1.19) mm/mm 2, (47.97±8.86) fibers/mm 2, and (9.25±2.19) mm/mm 2, (2.72±1.19) mm/mm 2, (39.43±13.86) fibers/mm 2, respectively; the differences in CNFL, CNBL, and CNBD between the two groups were statistically significant ( t=-4.002, -2.706, -2.306; P<0.05). The corneal DC density of the patients in the hormone treated group and the non-hormone treated group was (24.43±8.32) and (41.22±9.86) cells/mm 2, respectively. The difference in corneal DC density between the two subgroups was statistically significant ( P<0.001). Correlation analysis showed that there was a significant negative correlation between logMAR BCVA and CNBL and CNFL in patients with DON ( r=-0.422, -0.456; P<0.05). Conclusions:There are different degrees of corneal nerve fiber damage in patients with different types of DON. There was a negative correlation between BCVA and the length of corneal nerve fibers.

Discovery and bioassay of disubstituted β-elemene-NO donor conjugates: synergistic enhancement in the treatment of leukemia / 中国天然药物

Natural products are essential sources of antitumor drugs. One such molecule, β-elemene, is a potent antitumor compound extracted from Curcuma wenyujin. In the present investigation, a series of novel 13,14-disubstituted nitric oxide (NO)-donor β-elemene derivatives were designed, with β-elemene as the foundational compound, and subsequently synthesized to evaluate their therapeutic potential against leukemia. Notably, the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. In vivo studies indicated that compound 13d could effectively inhibit tumor growth, exhibiting no discernible toxic manifestations. Specifically, a significant tumor growth inhibition rate of 62.9% was observed in the K562 xenograft tumor mouse model. The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.

Peripheral BDNF Regulates Somatosensory-Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain / 神经科学通报·英文版

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.

Searching for potential biomarkers reflecting early injury and progressive of podocytes in nephropathy based on cellular metabolomics combined with ROC analysis / 药学学报

The pathogenesis of the nephrotic syndrome is complex and the pathological types are diverse, so the minor symptoms in its early phases are difficult to detect. Renal biopsy is the gold indicator for the diagnosis of renal pathology and progression, but poor patient compliance shows, and the optimal treatment time is often delayed. Therefore, the discovery of biomarkers for early diagnosis and disease progression monitoring is of great clinical significance. In this study, doxorubicin-injured podocyte models were used to simulate human kidney disease at different stages of progression. LC-MS-based metabolomic technology combined with statistical methods was used to screen and identify the potential biomarkers associated with early injury or progression of podocytes. The results of cell viability, apoptosis tests and podocyte structural protein analysis showed that the model was successfully constructed, and the degree of podocyte injury was significantly different between the two modeling methods. According to VIP > 1 and P < 0.05 based on the orthogonal partial least squares discriminant analysis (OPLS-DA) model, nine differential metabolites reflecting early podocyte injury and twelve differential metabolites reflecting the injury progression were screened, respectively. ROC analysis was adopted to focus on the potential biomarkers that can reflecting the early podocyte injury including L-tryptophan, guanosine triphosphate (GTP), 5′-thymidylic acid (dTMP) and thymidine, and the biomarkers reflecting the injury progression of podocytes composed of L-phenylalanine, L-tyrosine acid, uridine 5′-diphosphate (UDP) and guanosine 5′-diphosphate (GDP) AUC > 0.85. It indicated that these eight metabolites may have high sensitivity and diagnostic ability. This study provides a reference for the research on biomarkers of progressive diseases.

Study on the correlation between meibomian gland dysfunction and sleep quality / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To study the correlation between meibomian gland dysfunction(MGD)patients and their sleep quality.METHODS: Retrospective case-control study. A total of 150 MGD patients treated in our hospital from January 2021 to October 2022 were selected and divided into sleep disorder group(75 cases, PSQI&#x003E;10 points)and control group(75 cases, PSQI≤10 points)according to the Pittsburgh sleep quality index(PSQI). Both groups were scored using the ocular surface disease index(OSDI), underwent meibomian gland-related examinations(eyelid margin morphology, meibomian gland secretion ability, meibomian gland secretion quality score), corneal fluorescein staining(FL)score, Schirmer Ⅰ test(SⅠt), tear film break-up time(BUT)was measured, and sleep indicators(sleep quality, sleep latency, subjective sleep quality, sleep time)were evaluated.RESULTS: There were significant differences in OSDI score, FL score, SⅠt, BUT, eyelid margin morphology score, meibomian gland secretion ability score, and meibomian gland secretion quality score between the two groups(P&#x003C;0.05). In the sleep disorder group, PSQI score, sleep latency score, subjective sleep quality score, and sleep time score were significantly positively correlated with OSDI score, FL score, meibomian gland secretion ability score, and meibomian gland secretion quality score(P&#x003C;0.05); PSQI score, subjective sleep quality score, and sleep time score were significantly positively correlated with eyelid margin morphology score(P&#x003C;0.05); PSQI score, sleep latency score, and subjective sleep quality score were significantly negatively correlated with BUT and SⅠt(P&#x003C;0.05); sleep time score was significantly negatively correlated with BUT(P&#x003C;0.05); sleep latency score was not significantly correlated with eyelid margin morphology score(P&#x003E;0.05); sleep time score was not significantly correlated with SⅠt(P&#x003E;0.05).CONCLUSION:The ocular surface condition of MGD patients is correlated with multiple sleep quality indicators, and a decline in sleep quality may increase the risk of MGD.

Therapeutic effect of two methods on avulsion fracture of tibial insertion of anterior cruciate ligament.

BACKGROUND: The tibial stop of anterior cruciate ligament (ACL) is fan-shaped and attached to the medial groove in front of the intercondylar spine, which is located between the anterior horn of the medial and lateral meniscus. The incidence of this fracture is low previously reported, which is common in children and adolescents. With the increase of sports injury and traffic injury and the deepening of under-standing, it is found that the incidence of the disease is high at present. AIM: To explore the difference between open reduction and internal fixation with small incision and high-intensity non-absorbable suture under arthroscopy in the treatment of tibial avulsion fracture of ACL. METHODS: Seventy-six patients with tibial avulsion fracture of anterior cruciate ligament diagnosed and treated in Guanyun County People's Hospital from April 2018 to June 2020 were retrospectively analyzed. According to the surgical methods, they were divided into group A (40 cases) and group B (36 cases). Patients in group A were treated with arthroscopic high-strength non-absorbable suture, and patients in group B were treated with small incision open reduction and internal fixation. The operation time, fracture healing time, knee joint activity and functional score before and after operation, and surgical complications of the two groups were compared. RESULTS: The operation time of group A was higher than that of group B, and the difference was statistically significant (P < 0.05); the fracture healing time of group A was compared with that of group B, and the difference was not statistically significant (P > 0.05); The knee joint function activity was compared between two groups before operation, 3 mo and 6 mo after operation, and the difference was not statistically significant (P > 0.05); the knee joint function activity of group A and group B at 3 mo and 6 mo after operation was significantly higher than that before operation (P < 0.05); the limp, support, lock, instability, swelling, upstairs, squatting, pain and Lysholm score were compared between the two groups before and 6 mo after operation, and the difference was not statistically significant (P > 0.05); the scores of limp, support, lock, instability, swelling, upstairs, squatting, pain and Lysholm in group A and group B at 6 mo after operation were significantly higher than those before operation (P > 0.05); the surgical complication rate of group A was 2.63%, which was lower than 18.42% of group B, and the difference was statistically significant (P > 0.05). CONCLUSION: Both small incision open reduction and internal fixation and arthroscopic high-strength non-absorbable sutures can achieve good results in the treatment of anterior cruciate ligament tibial avulsion fractures. The operation time of arthroscopic high-strength non-absorbable sutures is slightly longer, but the complication rate is lower.

Baseline blood pressure does not modify the effect of intravenous thrombolysis in successfully revascularized patients.

Background: Studies indicate a trajectory relationship between baseline blood pressure (BP) and outcome in patients with acute ischemic stroke (AIS) eligible for both intravenous thrombolysis (IVT) with alteplase and endovascular treatment (EVT). We determined whether baseline BP modified the effect of IVT in successfully revascularized AIS patients who participated in the Direct Intra-Arterial Thrombectomy to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIECT-MT) trial. Methods: The association of baseline systolic BP, trichotomized as high (141-185 mmHg), middle (121-140 mmHg), and low (91-120 mmHg), and the outcomes of any intracerebral hemorrhage (ICH), symptomatic ICH (sICH), and mortality and functional outcome on the modified Rankin scale at 90 days were explored. Logistic regression models determined the interaction between clinical outcomes and baseline systolic and diastolic BP, and mean arterial pressure (MAP), at 10 mmHg intervals. Data are reported as odds ratios (OR) and 95% CI. Results: A post-hoc analysis of DIRECT-MT, in 510 of the 656 randomized participants with successful revascularization underwent MT. The overall adjusted common OR of IVT and baseline BP on any ICH, sICH, and 90-day mortality and functional outcome were 0.884 (95%CI 0.613-1.274), 0.643 (95%CI 0.283-1.458), 0.842 (95%CI 0.566-1.252), and 1.286 (95%CI 0.772-2.142), respectively. No significant interaction between baseline blood pressure and intravenous thrombolysis with clinical outcome was observed. Conclusions: In patients with baseline SBP under 185 mmHg, baseline blood pressure does not alter the risk of hemorrhagic transformation and clinicaloutcome in successfully revascularized patients, regardless of intravenous alteplase usage. Future studies are needed to confirm our findings. Registration: URL: http://www.clinicaltrials.gov, Identifier: NCT03469206.