CRISPR/Cas9-based therapeutics face significant challenges in penetrating the dense microenvironment of solid tumors, resulting in insufficient gene editing and compromised treatment efficacy. Current nanostrategies, which mainly focus on the paracellular pathway attempted to improve gene editing performance, whereas their efficiency remains uneven in the heterogenous extracellular matrix. Here, the nanoCRISPR system is prepared with self-cascading mechanisms for gene editing-mediated robust apoptosis and transcellular penetration. NanoCRISPR unlocks its self-cascade capability within the matrix metallopeptidase 2-enriched tumor microenvironment, initiating the transcellular penetration. By facilitating cellular uptake, nanoCRISPR triggers robust apoptosis in edited malignancies, promoting further transcellular penetration and amplifying gene editing in neighboring tumor cells. Benefiting from self-cascade between robust apoptosis and transcellular penetration, nanoCRISPR demonstrates continuous gene transfection/tumor killing performance (transfection/apoptosis efficiency: 1st round: 85%/84.2%; 2nd round: 48%/27%) and homogeneous penetration. In xenograft tumor-bearing mice, nanoCRISPR treatment achieves remarkable anti-tumor efficacy (∼83%) and significant survival benefits with minimal toxicity. This strategy presents a promising paradigm emphasizing transcellular penetration to enhance the effectiveness of CRISPR-based antitumor therapeutics.

Objective:To summarize the best evidence for exercise intervention in elderly patients with sarcopenia in intensive care unit (ICU) through literature search, and provide a reference for clinical implementation of early exercise intervention in this population through evidence-based practice.Methods:① Summary of best evidence: relevant literature on exercise intervention for elderly patients with sarcopenia in ICU, including guideline, evidence summary, expert consensus, systematic review, and original study [quasi-experiment and randomized controlled trial (RCT)] from UpToDate Clinical Advisor, Ovid database, National Guideline Clearinghouse (NGC), National Institute for Health and Care Excellence (NICE), Cochrane Library, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed/Medline, SinoMed, CNKI, Wanfang Database, VIP, and Yimai Tong Guideline Network were systematically searched. The search period covered from the establishment of these databases up to August 24, 2023. The quality of the literature was evaluated by two researchers with methodological expertise in evidence-based medicine, and the evidences were extracted and summarized. ② Evidence-based practice: the elderly patients with high risk of sarcopenia who had been hospitalized in the ICU for more than 7 days from January to April 2024 were enrolled as the research subjects, and they were divided into a control group and an intervention group using convenience sampling method. The control group received routine intensive care nursing. The intervention group implemented exercise intervention based on the actual situation of the patients, the baseline review was conducted before evidence application, and the effectiveness of evidence application at 7 days and 14 days was evaluated.Results:① A total of 19 pieces of literature were included, including 4 guidelines, 1 summary of evidence, 4 expert consensuses, 4 systematic reviews, and 6 original studies (1 quasi-experiment, 5 RCT). After literature quality evaluation, all 19 articles were enrolled. Finally, 31 pieces of best evidence were extracted from eight aspects, including assessment and diagnosis, multidisciplinary cooperation, indication, preparation before intervention, intervention program, safety monitoring, post-intervention evaluation, and special task. ② Finally, a total of 30 patients were enrolled in the intervention group, of which 17 completed 14 days of rehabilitation exercise, and 13 completed 7 days of rehabilitation exercise. Twenty-seven patients were enrolled in the control group, of which 17 completed 14 days of monitoring, and 10 completed 7 days of monitoring. Clinical evidence application results showed that the patients in the intervention group did not experience adverse events such as increased heart rate, extubation, or physical discomfort. The skeletal muscle mass index (SMI) in both groups was gradually decreased with the prolongation of intervention duration, but the 7-day SMI in the intervention group was significantly higher than that in the control group (kg/m 2: 8.61±2.66 vs. 6.65±1.50, P < 0.01). Conclusion:By summarizing the best evidence and evidence-based practice of exercise intervention for elderly patients with sarcopenia in ICU, this study confirmed the feasibility due to safe and effective of implementing early exercise intervention for elderly sarcopenia patients in ICU.

Objective:To investigate and analysis of the occurrence and influencing factors of sarcopenia in elderly critically ill patients in the intensive care unit (ICU).Methods:A prospective cohort study was conducted. Elderly patients (aged ≥ 60 years) admitted to the ICU of Tianjin Medical University General Hospital from November 2023 to June 2024 were enrolled. Clinical records were collected, and conduct muscle mass and strength measurements, as well as upper arm circumference and calf circumference were measured. Appendicular skeletal muscle index (ASMI) of less than 7.0 kg/m 2 for males and less than 5.7 kg/m 2 for females was defined as reduced muscle mass, grip strength of less than 28 kg for males and less than 18 kg for females was defined as decreased muscle strength, patients meeting both low muscle mass and low muscle strength criteria were diagnosed with sarcopenia. According to the diagnostic criteria for sarcopenia, patients were divided into sarcopenia group and non-sarcopenia group. Multivariate Logistic regression analysis was applied to identify risk factors for sarcopenia in the elderly and to develop a predictive model for the occurrence of sarcopenia. The predictive value of various risk factors for sarcopenia in elderly critically ill patients were evaluated by receiver operator characteristic curve (ROC curve). The Kaplan-Meier curve for the length of ICU stay of two groups patients were drawn. Results:Finally, 540 elderly critically ill patients were included, including 43 patients with sarcopenia, and the incidence of sarcopenia was 8.0%. Univariate analysis showed that there were significantly differences in body mass index (BMI), number of hospitalizations in the past year, the length of ICU stay, ventilation mode, duration of mechanical ventilation, pre-admission exercise habits, nutritional support methods, upper arm circumference, calf circumference, and albumin infusion between the sarcopenia group and the non-sarcopenia group. Multivariate Logistic regression analysis showed that BMI [odds ratio ( OR) = 0.79, 95% confidence interval (95% CI) was 0.67-0.93, P = 0.004], calf circumference ( OR = 0.64, 95% CI was 0.54-0.76, P < 0.001), and duration of mechanical ventilation ( OR = 1.06, 95% CI was 1.01-1.12, P = 0.034) were associated with an increased risk of sarcopenia in elderly critically ill patients. The ROC curve results showed that the area under the curve (AUC) and 95% CI of BMI, calf circumference, and duration of mechanical ventilation for predicting sarcopenia in elderly critically ill patients were 0.828 (0.767-0.888), 0.889 (0.844-0.933), and 0.397 (0.299-0.496), respectively, with cut-off values of 22.95 kg/m 2, 28.25 cm, and 50.50 days, respectively. The Kaplan-Meier curve showed that the cumulative survival rate of patients with sarcopenia was significantly lower than that of the non-sarcopenia group (Log-Rank test: χ 2 = 5.619, P = 0.018). Conclusion:Lower BMI, smaller calf circumference, and longer duration of mechanical ventilation are associated with an increased risk of sarcopenia in critically ill elderly patients.

Fibroblast growth factors (FGF) are a group of structurally related polypeptides which constitute an elaborate signaling system with their receptors. Evidence accumulated in the years suggests that the FGF family plays a key role in the repair of central nervous system injury. The main protective mechanisms include activating the expression of PI3K-Akt, peroxisome proliferator-activated receptor (PPARγ) and other signals; inhibiting NF-κB-mediated inflammatory response, oxidative stress and apoptosis; regulating neuronal differentiation and neuronal excitability as well as participating in protection of neurovascular units and nerve function repair. This paper comprehensively summarizes the latest research progress in FGF signaling related to diseases of the central nervous system such as cerebral infarction, cerebral hemorrhage, traumatic brain injury, Alzheimer's disease, Parkinson's disease, epilepsy and depression, aiming to provide scientific basis and reference for the development of innovative FGF drugs for the prevention and treatment of neurological diseases.
Humans ; Fibroblast Growth Factors ; Phosphatidylinositol 3-Kinases/metabolism* ; Central Nervous System/metabolism* ; Signal Transduction/physiology* ; Alzheimer Disease

Acute kidney injury (AKI) is an important factor for the occurrence and development of CKD. The protective effect of dihydroartemisinin on AKI and and reported mechanism have not been reported. In this study, we used two animal models including ischemia-reperfusion and UUO, as well as a high-glucose-stimulated HK-2 cell model, to evaluate the protective effect of dihydroartemisinin on premature senescence of renal tubular epithelial cells in vitro and in vivo. We demonstrated that dihydroartemisinin improved renal aging and renal injury by activating autophagy. In addition, we found that co-treatment with chloroquine, an autophagy inhibitor, abolished the anti-renal aging effect of dihydroartemisinin in vitro. These findings suggested that activation of autophagy/elimination of senescent cell might be a useful strategy to prevent AKI/UUO induced renal tubular senescence and fibrosis.
Animals ; Kidney ; Acute Kidney Injury/chemically induced* ; Ischemia ; Reperfusion Injury/drug therapy* ; Autophagy ; Reperfusion

Objective To construct a CaME141G fusion protein-expressing plasmid,and to express,purify,and identify the activity of the recombinant protein. Methods The 141st site of the wild type CaM,E (GAG),was mutated to G (GGG),using site-specific mutagenesis technology. Escherichia coli BL-21 was transformed with the mutant plasmid. The GST-CaME141G fusion protein was mass-cultured and induced for expression. Subsequently,the GST-CaME141G fusion protein was purified using GS-4B beads. PreScission protease was applied to remove the GST,the Bradford method used to determine the concentration of purified protein,and SDS-PAGE used to detect its relative molecular weight and purity. The GST pull-down assay was used to study the protein's biological activity. Results The CaME141G protein was successfully purified at a high concentration and purity. The protein could interact with PreIQ protein fragments from the myocardial CaV1. 2 calcium channel C terminal,in a CaME141G concentration-dependent manner. Therefore,CaME141G has the ability to bind with the CaV1. 2 calcium channel. Conclusion This study successfully constructed a CaME141G fusion protein-expressing plasmid and purified the CaME141G protein. This lays a foundation for regulating the function of CaM mutations in the myocardial CaV1. 2 calcium channel,and for the study of its relationship with diseases of the cardiovascular system.

This article reviews studies on the heredity of personality disorders and family environment factors from the population-based studies, and summarizes the interaction between genetic factors and environmental factors. Studies have shown that there is a genetic basis for personality disorders, including family studies, twin studies, and neurophysiological studies. In addition, environmental factors, including social psychological factors, also play an important role in the development of personality disorder. In sum, the occurrence of personality disorder is the result of interactions between genetic factors and environmental factors. This paper snmmarizes sresearch on personality disorders, and investigates the role of interaction between genetic and environmental factors in the development of personality disorders. Such evidence has implications for effective prevention and intervention of personality disorders.

Objective To investigate the effect of ellagic acid extracted from gallnut on multiple myeloma SP2 / 0 cell line and related mechanisms. Methods Multiple myeloma SP2 / 0 cell line was treated for 48 h with different concentrations of ellagic acid in vitro. Cell morphology,proliferation,apoptosis and cell cycle were analyzed with microscope,MTT experiment and flow cytometry,respectively. Tumor cell proliferation and apoptosis-related gene expression of COX-2 were detected by Western blotting. Results Cell cycle was arrested at the G1 phase 48 h after treatment with ellagic acid, the cell in G1 were (55. 21±3. 01)% , (64. 48 ± 0. 43)% , (75. 10 ± 2. 46)% , respectively, with significant difference as compared with control group [(34. 04±1. 74)% ,P<0. 01]. Cell suppression rate (21. 18±5. 92)% ,(44. 58±3. 43)% and (70. 15±2. 90)% ,respectively, in 20,40 and 60 μg·mL-1 ellagic acid treatment groups. Compared with the control group,the differences were significant (P<0. 01). Cell apoptosis rate was (9. 60 ± 0. 56)% , (19. 30 ± 1. 51)% and (35. 10 ± 5. 26)% , respectively, in 20,40 and 60 μg·mL-1 ellagic acid treatment groups,with significant differences as compared with the control group[(3. 23±0. 85)% ,P<0. 01]. With the increase of drug concentration,COX-2 expression was decreased. Conclusion Ellagic acid can inhibit myeloma SP2 / 0 cell proliferation and promote apoptosis.

Objective To understand the Helicobacter pylori ( Hp) infection eradication rate of standard tri-ple therapy in Guangdong Meizhou and the drug resistance situation for metronidazole ,clarithromycin ,amoxicillin and levofloxacin ,in order to look for the treatment countermeasures in Hp eradication failure .Methods 297 cases of Hp positive patients because of gastrointestinal symptoms to our hospital examined from April 2011 and March 2013,were randomly assigned into three standard triple therapy groups:A ( OCA ) group and B ( OCM ) group and C ( OCL ) group.The Hp eradication rate was analyzed .Patients with primary treatment failure were selected as group D (OBAL),proceed to (PPl+B+A+L)7 d therapy,the Hp eradication rate was analyzed .230 Hp strains were isola-ted and cultured from 297 cases received the first eradication therapy and 87 cases received again eradication therapy . The minimum inhibitory concentration (MIC) of metronidazole,clarithromycin,amoxicillin and levofloxacin were tested by E-test,in order to determine the resistance of these four antibiotics in clinical isolated Hp strains .Results With intention-to-treat(ITT) analysis,the Hp eradication rates of group A (OCA),group B(OCM) and group C(OCL) were 72.0%(72/100),63.0%(63/100) and 72.2%(70/97),respectively.With per-protocol(PP) analysis,the Hp eradication rates of group A (OCA),group B(OCM) and group C(OCL) were 72.7%(72/99),64.3%(63/98),73.7%(70/95),respectively.The eradication rate among three standard triple therapy groups had no obvi-ous difference (ITT:P=0.278,PP:P=0.288,P>0.05).With ITT analysis,the Hp eradication rate in the quadrup-le therapy group D(OBAL) was 92.0%(80/87).With per-protocol(PP) analysis,the Hp eradication rate in the quadruple therapy group D(OBAL) was 97.6%(80/82),which was higher than that of the three standard triple ther-apy groups(ITT:P=0.000,PP:P=0.000).In 230 clinical isolated Hp strains,the resistant rates of levofloxacin,amoxicillin,clarithromycin and metronidazole were 6.08%(14/230),6.52%(15/230),25.65%(59/230), 70.87%(163/230),respectively.Of those 37 strains were mixed resistance,the mixed resistant rate was 16.09%(37/230).The resistant rate of metronidazole was higher than levofloxacin , amoxicillin and clarithromycin ( P =0.000,P<0.01),the resistant rate of clarithromycin was higher than levofloxacin and amoxicillin (P=0.000),no statistically significant difference between amoxicillin and levofloxacin (P=0.848).Conclusion The Hp resistance is similar to the national average in Guangdong Meizhou ,the eradication rate of standard triple therapy is lower than 80%,contain bismuth agent of quadruple therapy is good rescue therapy .

Objective Inflammatory response is an important part in pathological change of traumatic arthritis(TA).Studies show that hydrogen has antioxidate and anti-inflammatory properties, however, there are few reports on treating TA with it.So this research aimed to investigate curative effects of curing traumatic arthritis in rabbits with intraperitoneal injection of saturated hydrogen saline solution . Methods A total of 26 New Zealand white rabbits were divided into three groups:normal control group (n=6), model experimental group (n=10), and model control group (n=10).Rabbits in model experimental group were intraperitoneally injected with 8 ml /kg saturated hy-drogen saline, once every three day;equivalent saline was injected in rabbits of model control group;while no treatment was done on normal control group.The treatment lasted for 6 weeks.Before and after the treatment, the serum and joint fluid of the rabbits in the three groups were respectively taken to determine the content of nitric oxide (NO) and hyaluronic acid (HA), which was used to evaluate therapeutic effect in combination with the behavioral performance of the rabbits . Results Significant improvement in behavior was found in model ex-perimental group after the treatment (P<0.05).No statistical differences were found in knee swelling scores of the three groupsbefore the treatment(P>0.05), but model experimental group was superior to model control group in knee swelling scores after the treatment (P<0.05).The contents of NO both in serum ([79.58 ±13.46] vs [76.23 ±12.15]) and joint fluid ([89.45 ±14.98] vs [80.36 ±12.78]) in two model groups increased before the treatment, which was of statistical difference (P<0.05), but the NO content decreased dramatically in model experimental group after the treatment ([436.82 ±60.91] vs [340.21 ±40.57],P<0.05), and no obvious changes were observed in model control group (P>0.05).The content of serum HA in model experimental group declined dramatically (P<0.05) and the joint fluid increased after the treatment ([1.72 ±0.37] vs [2.47 ±0.62],P<0.05), while no significant changes were found in model control group before and after the treatment. Conclusion The intraperitoneal injec-tion of saturated hydrogen saline may be effective in the treatment of trau-matic arthritis.