Excessive hydrogen sulfide-induced activation of NMDA receptors in the colon participates in anxiety- and compulsive-like behaviors in a rodent model of hemorrhagic shock and resuscitation.

OBJECTIVE: Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H2S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H2S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl-d-Aspartate (NMDA) receptor function. METHODS: Mice were immediately administered dl-propargylglycine (PAG) intragastrically as an H2S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. RESULTS: Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H2S-induced intestinal and cerebral injury. CONCLUSION: This experimental data suggests that H2S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.

The Role of Pyruvate Kinase M2 Posttranslational Modification in the Occurrence and Development of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadly malignant tumors that directly leads to the death of nearly one million people worldwide every year, causing a serious burden on society. In the presence of sufficient oxygen, HCC cells rapidly generate energy through aerobic glycolysis, which promotes tumor cell proliferation, immune evasion, metastasis, angiogenesis, and drug resistance. Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis. In recent years, studies have found that PKM2 not only exerts pyruvate kinase activity in the process of glucose metabolism, but also exerts protein kinase activity in non-metabolic pathways to affect tumor cell processes, and its activity is flexibly regulated by various posttranslational modifications such as acetylation, phosphorylation, lactylation, ubiquitination, SUMOylation, and so forth. This review summarizes the role of posttranslational modifications of PKM2-related sites in the development of HCC.

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.

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.

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.

The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial.

BACKGROUND: The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN. METHODS: Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events. RESULTS: There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29). CONCLUSIONS: In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03062813.

Identification and validation of Osteopontin and receptor for hyaluronic acid-mediated motility (RHAMM, CD168) for potential immunotherapeutic significance of in lung squamous cell carcinoma.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths. Immunotherapy is a promising therapeutic approach, but the population best suited to immunotherapy is yet to be determined. MATERIALS AND METHODS: Lung squamous cell carcinoma (LUSC) was chosen as the object for the present study. Four gene expression profiles were retrieved from the GEO database. 141 differentially expressed genes (DEGs) were detected in LUSC tissues and normal tissues by the GEO2R tool and Venn diagram software. RESULTS: 34 candidate genes were selected for further analysis. A Kaplan-Meier survival plot further isolated 29 of 34 genes and after re-validation using gene expression profiling interactive analysis and pathway enrichment, Bonferroni correction was used to adjust P values, results showed that two genes (CD168 and OPN) were markedly enriched in the extracellular matrix (ECM)-receptor interaction pathway. We believe this pathway and genes may be tightly involved in the LUSC tumor immune microenvironment. We conducted a further cellular study to knock-down OPN in H520 cells using siRNA. The expression of CD168 was reduced in siRNA-OPN H520 cells (P < 0.05). Our results indicate that the arrest of CD168 occurs after the downregulation of the OPN protein, suggesting that OPN participates in ECM-receptor interactions. CONCLUSIONS: By using integrated bioinformatics, we have identified CD168 and OPN as DEGs with poor prognosis in LUSC and have validated their interaction in the ECM receptor pathway. These genes could be potential diagnostic and therapeutic targets for LUSC patients undergoing immunotherapy.

Delayed adjuvant imatinib in patients with high risk of recurrence of gastrointestinal stromal tumor after radical surgery: a retrospective cohort study.

PURPOSE: To investigate the impact of delayed adjuvant imatinib on GIST patients with high risk of recurrence. METHOD: Adult GIST patients were retrospectively collected from our hospital between 2011 and 2018, and patients having high risk of recurrence were included for subsequent analyses. The primary endpoint was recurrence-free survival (RFS). RESULTS: According to the interval between the radical surgery and the beginning of adjuvant imatinib, 222 patients were divided into three groups: group A (≤ 2 months, n = 41), group B (2-≤ 4 months, n = 113), and group C (4-≤ 6 months, n = 68). Univariate, multivariate, and survival analyses all showed that patients in group A had significantly more favorable RFS than those in group C but not group B, and patients taking adjuvant imatinib for over 12 months were also associated with longer RFS comparing to adjuvant imatinib of ≤ 12 months. When stratified by the duration of adjuvant imatinib, no significant differences were found in RFS among groups A, B, and C for adjuvant imatinib of ≤ 12 months. While for adjuvant imatinib of over 12 months, both groups A and B had significantly more favorable RFS than group C, and no significant difference in RFS was found between group A and B. CONCLUSION: Delayed postoperative adjuvant imatinib for over 4 months in patients with high risk of recurrence of GIST may lead to worse RFS, and longer treatment with shorter delay has best results.

NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFß-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.

[Responses of radial growth of Quercus mongolica to stand density and climatic factors in a mountainous area of eastern Liaoning Province, China]. / è¾½ä¸œå±±åŒºè’™å¤æ Žå¾„å‘ç”Ÿé•¿å¯¹æž—åˆ†å¯†åº¦å’Œæ°”å€™å› å­çš„å“åº”.

To explore the effects of stand density and climatic factors on radial growth of Quercus mongolica, we used tree ring chronology to examine the radial growth changes in a secondary Q. mongolica forest under different levels of stand density (thinning). The meteorological data combined with the driving factors of Q. mongolica growth were analyzed. The results showed that the radial growth of Q. mongolica was significantly affected by stand density. The mean annual radial growth of Q. mongolica was 3.12 mm in low-density virgin forest, 1.55 and 1.42 mm in the two medium-density secondary forests, respectively, and 0.96 mm in high-density secondary forest. The thinning intensity of 20% had a limited effect on promoting the radial growth recovery of high-density forest (1900 trees·hm-2), but had a significant effect on medium-density forest (1600 trees·hm-2). The radial growth of Q. mongolica was sensitive to the precipitation changes in January and February of the current year. Thinning reduced the sensitivity of Q. mongolica radial growth to climate. Under scenarios of climate warming and drying, density regulation could be beneficial in mitigating the adverse effects of climate change on the growth of Q. mongolica.

MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis.

The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy ability during hypoxia. As a result, the accumulation of damaged, ROS-generating mitochondria leads to activation of the NLRP3 inflammasome, which induces abnormal soluble cytokines secretion, then promotes the differentiation and maturation of osteoclasts, and ultimately results in bone metastasis. Notably, phosphorylation of ULK1 by MAPK1/ERK2-MAPK3/ERK1 kinase triggers its interaction with BTRC and subsequent K48-linked ubiquitination and proteasome degradation. Also, a clearly negative correlation between the expression levels of ULK1 and p-MAPK1/3 was observed in human breast cancer tissues. The MAP2K/MEK inhibitor trametinib is sufficient to restore mitophagy function via upregulation of ULK1, leading to inhibition of NLRP3 inflammasome activation, thereby reduces bone metastasis. These results indicate that ULK1 knockout-mediated mitophagy defect promotes breast cancer bone metastasis and provide evidence to explore MAP2K/MEK- MAPK1/3 pathway inhibitors for therapy, especially in cancers displaying low levels of ULK1.Abbreviations: ATG: autophagy-related; Baf A1: bafilomycin A1; BTRC/ß-TrCP: beta-transducin repeat containing E3 ubiquitin protein ligase; CHX: cycloheximide; CM: conditioned media; FBXW7/FBW7: F-box and WD repeat domain containing 7; MAPK1: mitogen-activated protein kinase 1; MTDR: MitoTracker Deep Red; mtROS: mitochondrial reactive oxygen species; microCT: micro-computed tomography; mtROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; SQSTM1: sequestosome 1; ACP5/TRAP: acid phosphatase, tartrate resistant; ULK1: unc-51 like autophagy activating kinase 1.

[Network Meta-analysis of oral Chinese patent medicine in treatment of acute cerebral infarction].

The efficacy of oral Chinese patent medicine in the treatment of acute cerebral infarction was systematically evaluated by network Meta-analysis. The literature search was conducted in three English databases(Medline, EMbase and Cochrane Library) and four Chinese databases(CNKI, VIP, WanFang and SinoMed) from inception to June 2018, and the randomized controlled trials of acute cerebral infarction were screened out according to the pre-set criteria. Two reviewers independently screened out the literature by using pre-specified eligibility criteria, and assessed the quality of included studies according to the risk of bias tool of Cochrane Handbook 5.1.0. Data analysis was conducted by using Stata 13.0 and WinBUGS 1.4.3 software. Finally, 52 RCT were included, involving 11 kinds of oral Chinese patent medicines. The results of the network Meta-analysis showed that in terms of the total effective rate, the order of efficacy was as follows: Naomaitai Capsules>Xiaoshuan Changrong Capsules>Angong Niuhuang Pills>Yangxue Qingnao Granules>Compound Danshen Dripping Pills>Naoxintong Capsules>Tongxinluo Capsules>Naoxueshu Oral Liquid>Zhuyu Tongmai Capsules>Yinxingye Tablets>Compound Danshen Tablets; in terms of neurological deficit scores, the order of efficacy was: Tongxinluo Capsules>Angong Niuhuang Pills>Compound Danshen Dripping Pills>Xiaoshuan Changrong Capsules>Yangxue Qingnao Granules>Zhuyu Tongmai Capsules>Naoxintong Capsules>Naoxueshu Oral Liquid; in terms of Barthel index score, the order of efficacy was: Xiaoshuan Changrong Capsules>Naomaitai Capsules>Naoxueshu Oral Liquid>Angong Niuhuang Pills>Tongxinluo Capsules>Zhuyu Tongmai Capsules. Although different oral Chinese patent medicines can improve these outcomes, the difference in efficacy ranking was relatively large. Because of the small number and low quality of research literature, the conclusion still needs to be proved by multi-center, large-sample, and double-blind randomized trials.

A new multimodal, image-guided, robot-assisted, interstitial brachytherapy for the treatment of head and neck tumors-A preliminary study.

BACKGROUND: Interstitial brachytherapy (BT) is becoming an accepted treatment option for head and neck cancer patients for whom surgery poses high risks. Multimodal, image-guided, robotic surgery has the potential to allow precise seed implantation into tumors. Our aim was to introduce a new multimodal, image-guided surgical robot during the performance of interstitial BT for the treatment of tumors in the head and neck regions. METHODS: Clinical data for three patients were analyzed, retrospectively; patients had received 125 I seed implantations from July 2019 to October 2019. Multimodal, image-guided, robotic surgery was performed in all patients. Postoperative computed tomography data were imported to software to evaluate the accuracy of the seed position and the operation times. RESULTS: The mean placement error of the 125 I seed was 1.9 ± 0.74 mm. The mean operation time is 47 minutes. CONCLUSION: The experimental results showed that the Remebot has promise for use during BT for the head and neck.