Meta-analysis study on anesthetic sedation recovery and onset times in pediatric and elderly patients undergoing CT and MRI.

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are crucial diagnostic modalities that require patients to remain immobile for extended periods, with anesthesia sometimes used for comfort and image quality enhancement. The study compares dexmedetomidine and propofol in reducing recovery time and sedation onset in pediatric and elderly patients undergoing CT and MRI procedures. A meta-analysis of fifteen studies assessing recovery time, sedation onset, and failed sedation between dexmedetomidine and propofol in pediatric and elderly patients during CT and MRI was conducted. The study indicated that the administration of anaesthesia markedly improved patient compliance and reduced motion artefacts in both CT and MRI (P<0.00001, I2=94%). The meta-analysis indicated that the mean difference (MD) in the onset of sedation was significantly faster in the control group (P<0.00001, I2=96%). The study reveals that dexmedetomidine and propofol anesthesia can improve patient image quality during CT and MRI procedures by reducing motion artefacts. Dexmedetomidine sedated people more quickly than propofol, but no significant differences in sedation duration were observed.

Chitosan, a Natural Polymer, is an Excellent Sustained-Release Carrier for Amide Local Anesthetics.

Local anesthetics, particularly amide types, play a crucial role in perioperative anesthesia to alleviate pain and manage chronic, long-term pain, with their brief effect period remaining a universal challenge that needs resolution. There is a high anticipation for creating materials that maintain prolonged effectiveness of local anesthetics through a straightforward administration technique. Chitosan is the most typical natural amino polymer, which is highly reactive and easy to modify. It has been widely and deeply used in the field of medicine. At present, it is mainly used in tissue regeneration and repair, hemostasis and wound healing, antibacterial and anti-infection, disease diagnosis and treatment detection, and drug delivery. In the field of anesthesia, chitosan is regarded as a potential perfect carrier for the sustained release of amide local anesthetics. This document aims to analyze the current application of chitosan as a prolonged-release substance in amide-type local anesthetics, encapsulate the associated research advancements, and subsequently investigate the practicality and prospects of its medical uses.

Developmentally controlled subcellular remodeling and VND-initiated vacuole-executed PCD module shape xylem-like cells in peat moss.

Peat moss (Sphagnum) is a non-vascular higher plant with unique xylem-like hyaline (H) cells that are accompanied by photosynthetic chlorophyllous cells. These cellular structures play crucial roles in water storage and carbon sequestration. However, it is largely unknown how peat moss develops the H cells. This study systematically explored the Sphagnum Developmental Cell Atlas and Lineage and classified leaf cell development into two lineages with six stages (S0-S5) based on changes in key cellular traits, including the formation of spiral secondary cell walls (S4) and the presence of water pores (S5). Cell lineage-specific subcellular remodeling was transcriptionally regulated during leaf development, and vacuole-mediated clearance of organelles and cell death led to mature dead H cells. Interestingly, expression of land plant conserved Vascular-related NAC Domain (VND) genes correlated with H cell formation. Overall, these results suggest that the origination of xylem-like H cells is related to VND, likely through the neofunctionalization of vacuole-mediated cell death to attempt xylem formation in peat moss, suggesting potential uncoupling of xylem and phloem cell origins. This study positions peat moss as a potential model organism for studying integrative evolutionary cell biology.

Prediction of hemoptysis in patients with anomalous systemic arterial supply to normal basal segments of the lower lobe using a combination of CT features and clinical materials.

Background: Anomalous systemic arterial supply to the normal basal segments of the lower lobe (ASALL) is a rare anomaly with a common complication of hemoptysis. To estimate the risk of hemoptysis, this study aims to investigate the value of contrast-enhanced computed tomography (CT) and construct a risk-scoring model based on radiological features and clinical materials of patients with ASALL. Methods: Forty-three eligible individuals (17 women and 26 males), who underwent multiphase contrast-enhanced CT, were included in this study. Hemoptysis was predicted by combined systemic arterial features (CD-A) and combined demographic and radiological features (CD-R). Potential hemoptysis predictors were identified using multivariate regression analysis. A receiver operating characteristic (ROC) curve analysis was used to assess the prediction efficiency. The coefficient of regression model was used to build a combined risk scoring (CRS) model for hemoptysis. The decision curve analysis (DCA) was performed to evaluate the clinical usefulness of the risk-scoring model. Results: Hemoptysis was present in 17 (39.5%) ASALL patients. The areas under the curve (AUCs) for the predicted performance of CD-A and CD-R were 0.869 and 0.890, respectively. Independent predictors generated a scoring model using the formula CRS = 3 × age + 3 × sex + 4 × [ground glass opacity (GGO)] + 3 × (CD-A >0.522). The prediction performance of this model was displayed with an AUC of 0.939. This scoring model was demonstrated to be significantly preferable to CD-A (P=0.046) and CD-R (P=0.02) by the Hanley and McNeil test. The DCA showed that the CRS model was more beneficial when the threshold probability was between 5% and 92%. Conclusions: The scoring model offers a viable method for evaluating the risk of hemoptysis in patients with ASALL by combining radiological and clinical data.

BLUPmrMLM: A Fast mrMLM Algorithm in Genome-wide Association Studies.

Multilocus genome-wide association study has become the state-of-the-art tool for dissecting the genetic architecture of complex and multiomic traits. However, most existing multilocus methods require relatively long computational time when analyzing large datasets. To address this issue, in this study, we proposed a fast mrMLM method, namely, best linear unbiased prediction multilocus random-SNP-effect mixed linear model (BLUPmrMLM). First, genome-wide single-marker scanning in mrMLM was replaced by vectorized Wald tests based on the best linear unbiased prediction (BLUP) values of marker effects and their variances in BLUPmrMLM. Then, adaptive best subset selection (ABESS) was used to identify potentially associated markers on each chromosome to reduce computational time when estimating marker effects via empirical Bayes. Finally, shared memory and parallel computing schemes were used to reduce the computational time. In simulation studies, BLUPmrMLM outperformed GEMMA, EMMAX, mrMLM, and FarmCPU as well as the control method (BLUPmrMLM with ABESS removed), in terms of computational time, power, accuracy for estimating quantitative trait nucleotide positions and effects, false positive rate, false discovery rate, false negative rate, and F1 score. In the reanalysis of two large rice datasets, BLUPmrMLM significantly reduced the computational time and identified more previously reported genes, compared with the aforementioned methods. This study provides an excellent multilocus model method for the analysis of large-scale and multiomic datasets. The software mrMLM v5.1 is available at BioCode (https://ngdc.cncb.ac.cn/biocode/tool/BT007388) or GitHub (https://github.com/YuanmingZhang65/mrMLM).

Study on the role of Dihuang Yinzi in regulating the AMPK/SIRT1/PGC-1α pathway to promote mitochondrial biogenesis and improve Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Dihuang Yinzi (DHYZ) is a classic prescription in traditional Chinese medicine. Its therapeutic effect on Alzheimer's disease (AD) has been widely validated. However, the underlying molecular mechanisms of DHYZ in AD treatment remain unclear and require further research. AIM OF THE STUDY: Elucidating DHYZ's promotion of mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α pathway improves neuronal loss, mitochondrial damage, and memory deficits in AD. MATERIALS AND METHODS: Administering DHYZ by gavage to SAMP8 mice, after completing behavioral tests, the effects of DHYZ on hippocampal neuron loss and mitochondrial structural damage in AD model mice were assessed using Nissl staining and transmission electron microscopy. Western blot was used to detect the expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, mitochondrial fusion protein MFN2, and mitochondrial fission proteins DRP1 and FIS1. At the same time, immunofluorescence (IF) was employed to measure the relative fluorescence intensity of mitochondrial fusion protein MFN1. After determining the optimal dose of DYHZ for treating AD, we conducted mechanistic studies. By intraperitoneally injecting SAMP8 mice with the AMPK inhibitor (Compound C) to inhibit AMPK protein expression and subsequently treating them with DHYZ, the impact of DHYZ on hippocampal neurons in AD model mice was evaluated using Nissl and hematoxylin-eosin staining. Western blot was used to detect the protein expression of AMPK, p-AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In contrast, IF was used to measure the relative fluorescence intensity of PGC-1α, NRF1, and TFAM proteins in the hippocampal CA1 region. RESULTS: DHYZ significantly improved AD model mice's cognitive impairment and memory deficits and mitigated hippocampal neuron loss and degeneration. Additionally, it ameliorated mitochondrial morphological structures. DHYZ upregulated the protein expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, and mitochondrial fusion proteins MFN1 and MFN2 while inhibiting the expression of mitochondrial fission proteins DRP1 and FIS1. Further studies revealed that DHYZ could upregulate the expression of the AMPK/SIRT1/PGC-1α pathway proteins and their downstream proteins NRF1 and TFAM. CONCLUSION: DHYZ promotes mitochondrial biogenesis by activating the AMPK/SIRT1/PGC-1α signaling pathway, thereby improving memory deficits, neuronal loss, and mitochondrial dysfunction in AD.

[Autosomal recessive polycystic kidney disease in a girl]. / å¸¸æŸ“è‰²ä½“éšæ€§é—ä¼ æ€§å¤šå›Šè‚¾1例.

A 5-year-old girl was admitted due to one episode of melena and one episode of hematemesis. Upon admission, gastroscopy revealed esophageal and gastric varices. Abdominal CT scan, MRI, and color Doppler ultrasound suggested cirrhosis, intrahepatic bile duct dilation, and bilateral kidney enlargement. Genetic testing identified compound heterozygous mutations in the PKHD1 gene: c.2264C>T (p.Pro755Leu) and c.1886T>C (p.Val629Ala). The c.2264C>T (p.Pro755Leu) mutation is a known pathogenic variant with previous reports, while c.1886T>C (p.Val629Ala) is a novel mutation predicted to have pathogenic potential according to Mutation Taster and PolyPhen2. The child was diagnosed with autosomal recessive polycystic kidney disease. In children presenting with gastrointestinal bleeding without obvious causes, particularly those with liver or kidney disease, consideration should be given to the possibility of autosomal recessive polycystic kidney disease, and genetic testing should be conducted for definitive diagnosis when necessary.

Nucleolin malonylation as a nuclear-cytosol signal exchange mechanism to drive cell proliferation in Hepatocarcinoma by enhancing AKT translation.

Cancer cells undergo metabolic reprogramming that is intricately linked to malignancy. Protein acylations are especially responsive to metabolic changes, influencing signal transduction pathways and fostering cell proliferation. However, as a novel type of acylations, the involvement of malonylation in cancer remains poorly understood. In this study, we observed a significant reduction in malonyl-CoA levels in hepatocellular carcinoma (HCC), which correlated with a global decrease in malonylation. Subsequent nuclear malonylome analysis unveiled nucleolin (NCL) malonylation, which was notably enhanced in HCC biopsies. we demonstrated that NCL undergoes malonylation at lysine residues 124 and 398. This modification triggers the translocation of NCL from the nucleolus to nucleoplasm and cytoplasm, binding to AKT mRNA, and promoting AKT translation in HCC. Silencing AKT expression markedly attenuated HCC cell proliferation driven by NCL malonylation. These findings collectively highlight nuclear signaling in modulating AKT expression, suggesting NCL malonylation as a novel mechanism through which cancer cells drive cell proliferation.

Cognitive impairment induced by sevoflurane anesthesia is mediated by the cholinergic system after gastrointestinal surgery in older patients: A randomized, controlled trial.

Delayed neurocognitive recovery after surgery is associated with increased morbidity and mortality. However, its mechanism of action remains controversial and complex. A prospective, double-blind, randomized controlled trial was performed at the Affiliated Hospital of Zunyi Medical University. Older patients (aged 65 years and older) who underwent gastrointestinal surgery were randomly divided into sevoflurane-based or propofol-based anesthesia groups. The Mini-Mental State Examination was performed to evaluate cognitive function. Peripheral venous blood was collected to test the levels of choline acetyltransferase and acetylcholinesterase. A total of 75 patients were enrolled and 30 patients in each group completed the study. On Day 1 postoperation, patients in the sevoflurane group showed worse performance on the Mini-Mental State Examination than patients in the propofol group. Lower blood choline acetyltransferase concentrations and higher acetylcholinesterase concentrations were observed in patients who had sevoflurane anesthesia than in patients who had propofol anesthesia 1 day postoperative. At 3 days postoperation, patients with sevoflurane- or propofol-based general anesthesia did not differ regardless of Mini-Mental State Examination score or choline acetyltransferase and acetylcholinesterase levels. Sevoflurane-based anesthesia has short-term delayed neurocognitive recovery in older surgical patients, which may be related to central cholinergic system degeneration.

Genetic Screening of Factors in the Plant Protein Secretion.

The endomembrane system in plants is composed of interconnected membrane organelles that contribute to intracellular structure and function. These organelles include the endoplasmic reticulum (ER), Golgi apparatus, vacuole, trans-Golgi network, and prevacuolar compartment or multivesicular body. Through vesicle-mediated transport, secreted proteins are synthesized in the ER and subsequently transported along the secretory pathway to the vacuole or outside of cells to fulfill specialized functions. Genetic screening is a crucial method for studying plant protein secretion. It entails identifying phenotypic differences resulting from genetic mutations, such as ethyl methanesulfonate, T-DNA insertion, and RNAi, to investigate gene function and discover mutants with specific traits or gene functions. Significant progress has been achieved in the study of plant protein secretion through genetic screening. In this protocol, we provide a step-by-step guide to studying the protein secretion pathway using a genetic screen approach. We use the example of the free 1 suppressor of Arabidopsis thaliana and oil body mutants of Marchantia polymorpha. Additionally, we offer an overview of genetic screening and briefly summarize the emerging technologies in the field of protein secretion research.

Effect of Gegen Qinlian Decoction combined with dietary management on patients with damp-heat Type-2 diabetes mellitus and metabolic syndrome.

Objective: To explore the effect of Gegen Qinlian Decoction (GQD) combined with dietary management in the treatment of patients with Type-2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) (T2DM MetS). Methods: This is a retrospective analysis of 102 cases of T2DM in the Brain Hospital of Hunan Province, China from April 2020 to February 2023. Of them, 49 patients received conventional drug treatment (control group), and 53 patients received GQD combined with dietary management on the basis of conventional drugs (observation group). Treatment efficacy was calculated, and blood glucose levels before and after the treatment, blood lipid-related indicators, tumor necrosis factor-α (TNF-α) and adiponectin (ADP) levels, and incidence of adverse reactions were compared between the two groups. Results: The total efficacy of the observation group (92.45%) was significantly higher than that of the control group (75.51%) (P<0.05). After the treatment, blood glucose and lipid indicators in both groups were significantly improved compared to pretreatment levels, and were significantly better in the observation group than in the control group (P<0.05). After the treatment, TNF-α levels in both groups decreased compared to before the treatment, and were significantly lower in the observation group compared to the control group. Levels of ADP after the treatment increased, and were significantly higher in the observation group compared to the control group (P<0.05). Conclusions: When taken as an adjunct to the conventional drug regimen, GQD combined with dietary management can effectively regulate blood glucose and lipid metabolism in patients with T2DM and MetS (T2DM MetS), improve TNF-α and ADP levels, and enhance disease treatment effectiveness.

Incidence and risk factors for acute kidney injury after traumatic hemorrhagic shock: A 10-year retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is a common complication of traumatic hemorrhagic shock. The risk factors for AKI after traumatic hemorrhagic shock remain unclear. The aim of this study was to investigate the risk factors for AKI after traumatic hemorrhagic shock. METHODS: This was a ten-year retrospective cohort study of patients who experienced traumatic hemorrhagic shock between January 2013 and April 2023. Patient characteristics and clinical data were recorded for 417 patients. The outcome was the occurrence of AKI, defined as a serum creatinine increase of ≥ 0.3 mg/dL (≥ 26.5 µmol/L) within 48 h, or an increase to 1.5 times the baseline, or a urine volume of < 0.5 mL/(kg h.). Risk factors for AKI were tested by logistic regression models. RESULTS: The incidence of AKI after traumatic hemorrhagic shock was 29.3% (122/417 patients). Multivariable analysis revealed that the independent risk factors for AKI included age (OR, 1.048; 95% CI, 1.022-1.074; p < 0.001), B-type natriuretic peptide (OR, 1.002; 95% CI, 1.000-1.004; p = 0.041), sepsis (OR, 4.536; 95% CI, 1.651-12.462; p = 0.030) and acute myocardial injury (OR, 2.745; 95% CI, 1.027-7.342; p = 0.044). Road traffic accidents (OR, 0.202; 95% CI, 0.076-0.541; p = 0.001), mean arterial pressure (OR, 0.972; 95% CI, 0.950-0.995; p = 0.017), and base excess (OR, 0.842; 95% CI, 0.764-0.929; p = 0.001) were negatively correlated with AKI. The area under the receiver operating characteristic (ROC) curve for prediction by this model was 0.85 (95% CI, 0.81-0.90). CONCLUSION: The incidence of AKI after traumatic hemorrhagic shock was 29.3% in our series. Indicators of blood perfusion, sepsis and acute myocardial injury may be independent risk factors for AKI after traumatic hemorrhagic shock. Early detection and effective intervention on these risk factors could reduce the occurrence of AKI and improve outcomes.

Supportive Psychotherapy Combined with Analgesic Management can Effectively Improve Pain and Quality of Life in Patients with Advanced Prostate Cancer: A Retrospective Study.

OBJECTIVE: Patients with advanced prostate cancer commonly experience psychological issues and have a low quality of life. This study aims to analyse the application of supportive psychotherapy combined with analgesic management on the pain and quality of life of patients with advanced prostate cancer. METHODS: Patients with advanced prostate cancer admitted to our hospital from February 2018 to December 2022 were continuously selected as the research objects. In accordance with the different management methods recorded in the medical record system, the patients were divided into a control group (routine nursing + analgesic management) and an observation group (routine nursing + analgesic management + supportive psychotherapy). The Athens Insomnia Scale (AIS), State Anxiety Scale (S-AI), Trait Anxiety Scale (T-AI), Numeric Rating Scale (NRS) and 36-Item Short-Form Health Survey (SF-36) scores between the two groups were compared. RESULTS: A total of 125 patients with advanced prostate cancer participated in this study, with 60 patients in the control group and 65 patients in the observation group. No significant difference was found in the scores of the AIS, S-AI, T-AI, NRS and SF-36 of the two groups before management (p > 0.05). After management, the AIS (4.00 vs. 5.00, p = 0.002), S-AI (38.88 vs. 41.12, p = 0.002), T-AI (39.17 vs. 41.65, p = 0.001) and NRS (3.00 vs. 3.00, p < 0.001) scores of the observation group were lower than those of the control group. However, the SF-36 scores of the observation group were higher than those of the control group in the dimensions of physiological enginery (75.85 vs. 68.75, p < 0.001), physiological function (71.85 vs. 67.75, p = 0.004), body pain (73.15 vs. 69.33, p = 0.006), social function (73.88 vs. 69.85, p = 0.004), emotional function (72.92 vs. 68.98, p = 0.006), mental health (73.52 vs. 69.83, p = 0.008), vitality (72.09 vs. 69.52, p = 0.044) and general health (70.65 vs. 66.23, p = 0.002). CONCLUSIONS: Supportive psychotherapy combined with analgesic management for patients with advanced prostate cancer may help improve the pain, anxiety and quality of sleep and life of patients.

Identification of QTNs and Their Candidate Genes for Boll Number and Boll Weight in Upland Cotton.

Genome-wide association study (GWAS) has identified numerous significant loci for boll number (BN) and boll weight (BW), which play an essential role in cotton (Gossypium spp.) yield. The North Carolina design II (NC II) genetic mating population exhibits a greater number of genetic variations than other populations, which may facilitate the identification of additional genes. Accordingly, the 3VmrMLM method was employed for the analysis of upland cotton (Gossypium hirsutum L.) in an incomplete NC II genetic mating population across three environments. A total of 204 quantitative trait nucleotides (QTNs) were identified, of which 25 (24.75%) BN and 30 (29.13%) BW QTNs were of small effect (<1%) and 24 (23.76%) BN and 20 (19.42%) BW QTNs were rare (<10%). In the vicinity of these QTNs, two BN-related genes and two BW-related genes reported in previous studies were identified, in addition to five BN candidate genes and six BW candidate genes, which were obtained using differential expression analysis, gene function annotation, and haplotype analysis. Among these, six candidate genes were identified as homologs of Arabidopsis genes. The present study addresses the limitation of heritability missing and uncovers several new candidate genes. The findings of this study can provide a basis for further research and marker-assisted selection in upland cotton.

Discovery of hepatitis B virus subviral particle biogenesis inhibitors from a bioactive compound library.

High levels of hepatitis B virus (HBV) surface antigen (HBsAg) in the blood of chronic HBV carriers are considered to drive the exhaustion of antigen-specific T and B lymphocytes and thus responsible for the persistence of infection. Accordingly, therapeutic elimination of HBsAg may facilitate the activation of adaptive antiviral immune responses against HBV and achieve a functional cure of chronic hepatitis B. We discovered recently that an amphipathic alpha helix spanning W156 to R169 of HBV small envelope (S) protein plays an essential role in the morphogenesis of subviral particles (SVPs) and metabolism of S protein. We thus hypothesized that pharmacological disruption of SVP morphogenesis may induce intracellular degradation of S protein and reduce HBsAg secretion. To identify inhibitors of SVP biogenesis, we screened 4417 bioactive compounds with a HepG2-derived cell line expressing HBV S protein and efficiently secreting small spherical SVPs. The screen identified 24 compounds that reduced intracellular SVPs and secreted HBsAg in a concentration-dependent manner. However, 18 of those compounds inhibited the secretion of HBsAg and HBeAg in HBV replicon transfected HepG2 cells at similar efficiency, suggesting each of those compounds may disrupt a common cellular function required for the synthesis and/or secretion of these viral proteins. Interestingly, lycorine more efficiently inhibited the secretion of HBsAg in HepG2 cells transfected with HBV replicons, HepG2.2.15 cells and HBV infected - HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). The structure activity relationship and antiviral mechanism of lycorine against HBV have been determined.

Peripheral inflammation as a potential mechanism and preventive strategy for perioperative neurocognitive disorder under general anesthesia and surgery.

General anesthesia, as a commonly used medical intervention, has been widely applied during surgical procedures to ensure rapid loss of consciousness and pain relief for patients. However, recent research suggests that general anesthesia may be associated with the occurrence of perioperative neurocognitive disorder (PND). PND is characterized by a decline in cognitive function after surgery, including impairments in attention, memory, learning, and executive functions. With the increasing trend of population aging, the burden of PND on patients and society's health and economy is becoming more evident. Currently, the clinical consensus tends to believe that peripheral inflammation is involved in the pathogenesis of PND, providing strong support for further investigating the mechanisms and prevention of PND.

Mechanism research on microRNA-669f-5p/deoxycytidylate deaminase axis mediating sevoflurane-induced cognitive dysfunction in aged mice.

OBJECTIVE: To investigate the role of the microRNA (miRNA)-669f-5p/deoxycytidylate deaminase (Dctd) axis in sevoflurane inducing cognitive dysfunction in aged mice. METHODS: Sixty-six C57BL/6J mice were used in the experiment model and were randomly divided into the sevoflurane group and the control group. The mice in the sevoflurane group were anesthetised with 3.4% sevoflurane, whereas those in the control group were air-treated for the same period. The study was then performed using bioinformatics sequencing, as well as in vitro and in vivo validation. RESULTS: The mice in the sevoflurane group showed significant cognitive impairments in terms of a decrease in both spatial learning and memory abilities. Experimental doses of miR-669f-5p agonist exhibited no obvious effect on cognitive function following sevoflurane inhalation, but inhibiting the expression of miR-669f-5p could alleviate the impairments. Based on the results of the bioinformatics sequencing, miR-669f-5p/Dctd and the toll-like receptor (TLR) signalling pathway could be the key miRNA, gene and pathway leading to postoperative cognitive dysfunction following sevoflurane inhalation. The aged mice showed significantly increased expression of miR-669f-5p in the hippocampus following sevoflurane inhalation, and upregulating/inhibiting its expression could increase/decrease TLR expression in the hippocampus. Furthermore, miR-669f-5p could reduce the expression of the Dctd gene by binding to its 3'untranslated region. CONCLUSION: The miR-669f-5p/Dctd axis plays an important role in sevoflurane inducing cognitive dysfunction in aged mice, providing a new direction for further development of therapeutic strategies concerning the prevention and treatment of cognitive dysfunction associated with sevoflurane anaesthesia.

Current status and perspectives of clinical trials for tumor-infiltrating lymphocyte therapy.

Immunotherapies, mainly immune checkpoint inhibitors (ICIs), have revolutionized cancer treatment strategies over the past decade, but their limitations have limited clinical applications. Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy (ACT), which collects infiltrating lymphocytes at the tumor site and expands them in vitro to obtain TIL final products cloned by various T-cell receptors, subsequently reinfused TIL into the patient, which is effective for the treatment of solid tumors. The approval of Lifileucel for commercialization marks the success of TIL therapy. This review summarizes the current status of clinical trials of TIL treatment. In addition, it is suggested that the current research trend of TIL should focus on improving the survival time of TIL in vivo, reducing drug toxicity, and searching for prognostic markers. Finally, it is expected that TIL therapy can be applied to a more wide range of clinical treatments.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

ß-elemene promotes microglial M2-like polarization against ischemic stroke via AKT/mTOR signaling axis-mediated autophagy.

BACKGROUND: Resident microglia- and peripheric macrophage-mediated neuroinflammation plays a predominant role in the occurrence and development of ischemic stroke. Microglia undergo polarization to M1/M2-like phenotype under stress stimulation, which mediates intracellular inflammatory response. ß-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of ß-elemene in ischemic stroke from the perspective of balancing microglia M1/M2-like polarization. METHODS: The middle cerebral artery occlusion (MCAO) model and photothrombotic stroke model were established to explore the regulation effect of ß-elemene on the cerebral ischemic injury. The LPS and IFN-γ stimulated BV-2 cells were used to demonstrate the anti-inflammatory effects and potential mechanism of ß-elemene regulating M1/M2-like polarization in vitro. RESULTS: In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, ß-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. ß-elemene promoted the phenotype transformation of microglia from M1-like to M2-like, which prevented neurons from oxygen and glucose deprivation/reoxygenation (OGD/R) injury by inhibiting inflammatory factor release, thereby reducing neuronal apoptosis. Mechanically, ß-elemene prevented the activation of TLR4/NF-κΒ and MAPK signaling pathway and increased AKT/mTOR mediated-autophagy, thereby promoting M2-like polarization of microglia. CONCLUSIONS: These results indicated that ß-elemene improved cerebral ischemic injury and promoted the transformation of microglia phenotype from M1-like to M2-like, at least in part, through AKT/mTOR-mediated autophagy. This study demonstrated that ß-elemene might serve as a promising drug for alleviating ischemic stroke injury.