The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation is one of the most prevalent activating alterations in cancer. It indicates a poor overall prognosis due to its highly invasive nature. Although several KRAS inhibitors have been developed in recent years, a significant clinical challenge has emerged as a substantial proportion of patients eventually develop resistance to these therapies. Therefore, identifying determinants of drug resistance is critical for guiding treatment strategies. This review provides a comprehensive overview of the mutation landscape and molecular mechanisms of KRAS activity in various cancers. Meanwhile, it summaries the progress and prospects of small molecule KRAS inhibitors undergoing clinical trials. Furthemore, this review explores potential strategies to overcome drug resistance, with the ultimate goal of steering toward patient-centric precision oncology in the foreseeable future.
Humans ; Drug Resistance, Neoplasm/drug effects* ; Proto-Oncogene Proteins p21(ras)/metabolism* ; Mutation/genetics* ; Neoplasms/genetics* ; Antineoplastic Agents/therapeutic use*

Objective:To develop a preoperative CT image segmentation algorithm based on artificial intelligence deep learning technology for total hip arthroplasty (THA) revision surgery, and to verify and preliminarily apply it.Methods:A total of 706 revision cases with clear CT data from April 2019 to October 2022 in Chinese PLA General Hospital were retrospectively analyzed, including 520 males, aged 58.45±18.13 years, and 186 females, aged 52.23±16.23 years. All of them were unilateral, and there were 402 hips on the left and 304 hips on the right. The transformer_unet convolutional neural network was constructed and trained using Tensorflow 1.15 to achieve intelligent segmentation of the revision THA CT images. Based on the developed three-dimensional planning system of total hip arthroplasty, an intelligent planning system for revision hip arthroplasty was preliminarily constructed. Dice overlap coefficient (DOC), average surface distance (ASD) and Hausdorff distance (HD) parameters were used to evaluate the segmentation accuracy of transformer_unet, full convolution network (FCN), 2D U-shaped Net and Deeplab v3 +, and segmentation time was used to evaluate the segmentation efficiency of these networks.Results:Compared with the FCN, 2D U-Net, and Deeplab v3+ learning curves, the transformer_unet network could achieve better training effect with less training amount.The DOC of transformer_unet was 95%±4%, the HD was 3.35±1.03 mm, and the ASD was 1.38±0.02 mm; FCN was 94%±4%, 4.83±1.90 mm, 1.42±0.03 mm; 2D U-Net was 93%±5%, 5.27±2.20 mm, and 1.46±0.02 mm, respectively. Deeplab v3+ was 92%±4%, 6.12±1.84 mm, 1.52±0.03 mm, respectively. The transformer_unet coefficients were better than those of the other three convolutional neural networks, and the differences were statistically significant (all P<0.05). The segmentation time of transformer_unet was 0.031±0.001 s, FCN was 0.038±0.002 s, 2D U-Net was 0.042±0.001 s, Deeplab v3+ was 0.048±0.002 s. The segmentation time of transformer_unet was less than that of the other three convolutional neural networks, and the difference was statistically significant ( P<0.05). Based on the results of previous studies, an artificial intelligence assisted preoperative planning system for THA revision surgery was initially constructed. Conclusion:Compared with FCN, 2D U-Net and Deeplab v3+, the transformer_unet convolutional neural network can complete the segmentation of the revision THA CT image more accurately and efficiently, which is expected to provide technical support for preoperative planning and surgical robots.

Objective:To investigate the effects of fluoride exposure on proliferation, apoptosis and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in mice.Methods:BMSCs were isolated and cultured from femur bone marrow of C57BL/6 mice (6 - 8 weeks). The cells in passage 3 were used to detect the surface markers of stem cells by flow cytometry. The cells were cultured in media with a final fluoride concentration of 0.0, 0.1, 1.0, 5.0, 10.0, 15.0, 20.0 and 40.0 mg/L, respectively. The effects of different fluoride concentrations on BMSCs cell proliferation (CCK8 method), apoptosis (flow cytometry analysis), osteogenic differentiation ability [alizarin red and alkaline phosphatase (ALP) staining] were detected. Western blot was applied to detect the levels of apoptosis-related proteins [poly ADP-ribose polymerase (PARP)], mitogen-activated protein kinase (MAPK) pathway member proteins [extracellular regulated protein kinase 1/2 (ERK1/2), c-Jun amino-terminal kinase (JNK), p38 and phosphorylated ERK, JNK, p38 (p-ERK, p-JNK, p-p38)], osteogenic differentiation-related protein [Runt-related transcription factor 2 (Runx2), ALP] and Wnt/β-catenin pathway member proteins [glycogen synthase kinase-3β (GSK3β), phosphorylated GSK3β (p-GSK3β) and β-catenin]. Immunocytofluorescense staining was applied to evaluate the expression levels of p-GSK3β and β-catenin. The two pathways (MAPK and Wnt/β-catenin) were blocked by SP600125 and DKK-1, respectively, to testify their involvement in mechanisms of apoptosis and osteogenic differentiation.Results:The mouse BMSCs were successfully isolated and cultured. Flow cytometry analysis showed that the mesenchymal stem cell surface biomarkers (CD73, CD90 and CD105) were positively expressed. The comparison of cell proliferation at three time points (24, 48 and 72 h) in each concentration group was statistically significant ( F = 65.36, 160.04 and 365.32, P < 0.001), and the comparison of early apoptosis (24 h) in each concentration group was statistically significant ( F = 214.04, P < 0.001); compared with the 0.0 mg/L group, the cell proliferation in 15.0, 20.0 and 40.0 mg/L groups decreased, and the early apoptosis rate in 10.0, 15.0 and 20.0 mg/L groups increased ( P < 0.05). When cells were treated with 15.0 mg/L fluoride for 0 - 24 h, the p-JNK/JNK ratio was higher at 2, 4, 8, 12, 18 and 24 h compared with that at 0 min ( P < 0.05); compared with the fluoride group (15.0 mg/L), the early apoptosis rate of cells after SP600125 block decreased ( P < 0.05), and the protein expression levels of PARP and p-JNK decreased ( P < 0.05). After osteogenic induction, compared with the 0.0 mg/L group, in 0.1 and 1.0 mg/L groups ALP staining was enhanced and the number of calcified nodules increased, and the protein expression levels of Runx2 and ALP in the 0.1 and 1.0 mg/L groups were higher ( P < 0.05). After osteogenic induction, compared with the 0.0 mg/L group, the p-GSK3β/GSK3β ratio and β-catenin protein level were significantly higher in the 0.1 and 1.0 mg/L groups ( P < 0.05); and compared with the fluoride group (1.0 mg/L), addition of DKK-1 significantly decreased the protein expression levels of p-GSK3β and β-catenin and reduced the nuclear entry of β-catenin, and ALP staining decreased and the number of calcified nodules decreased. Conclusions:High concentration of fluoride (> 10.0 mg/L) inhibits the proliferation and promotes apoptosis of BMSCs, while low concentration of fluoride (0.1, 1.0 mg/L) promotes osteogenic differentiation. The MAPK/JNK pathway and the classical Wnt pathway are involved in the above cellular processes, respectively.

Objective:To evaluate the effect of evidence-based nursing practice for functional rehabilitation of post-stroke neurogenic bladder (PSNB) .Methods:From October 2020 to July 2021, 136 PSNB patients admitted to the Department of Neurology, Jiangyin People's Hospital were selected by convenience sampling as the research object. According to the random number table method, the patients were divided into the study group and the control group, with 68 cases in each group. The control group received routine rehabilitation nursing, while the study group was given evidence-based rehabilitation nursing based on the control group. The urodynamics, rates of bladder balance, urinary incontinence and urinary retention after intervention were compared between the two groups.Results:After three months of intervention, bladder compliance and bladder balance rate in the study group were higher than those in the control group, and the residual urine volume was less than that in the control group, with statistical differences ( P<0.05) . After three months of intervention, urinary retention rate in the study group was lower than that in the control group, and the difference was statistically significant ( P<0.05) . Conclusions:Evidence-based rehabilitation nursing can help to promote the rapid recovery of bladder balance in PSNB patients and improve the prognosis of patients.

Plant serine carboxypeptidase-like acyltransferases (SCPL-AT) have similar structural characteristics and high homology compared to the serine carboxypeptidase. They can transfer the acyl from acyl glucose esters to many natural products, participate in the acylation modification of plant secondary metabolites, enrich the structural diversity of natural products, and improve the physicochemical properties such as water solubility and stability of compounds. This review summarizes the structural characteristics, catalytic mechanism, functional characterization, and biocatalytic applications of SCPL-AT from plants. This will help to promote the functional characterization of these acyltransferase genes and the biosynthesis of useful plant secondary metabolites by synthetic biotechnology.
Acylation ; Acyltransferases/metabolism* ; Carboxypeptidases/metabolism* ; Plants/enzymology*

Objective:Serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker of bacterial infection. However, the diagnostic value of sTREM-1 of alveolar fluid in pulmonary infection is still unclear. This article aimed to explore the value of sTREM-1 of alveolar fluid in the early diagnosis of ventilator-associated pneumonia (VAP) by systematic review of relevant literatures.Methods:CNKI, Wanfang, VIP, PubMed/Medline and Embase databases were retrieved. Articles on diagnosis of VAP by sTREM-1 before June 30, 2019 were collected. QUADAS-2 scale provided by Cochrane Collaboration Network was used to evaluate the quality of diagnostic experiments. RevMan 5.3 and Stata 13.0 software were used to complete Meta-analysis. The levels of sTREM-1 between VAP and non-VAP patients were analyzed by Meta-analysis, and then diagnostic test Meta-analysis was conducted. Heterogeneity, sensitivity and publication bias were analyzed.Results:A total of 24 articles were enrolled. QUADAS-2 scale indicated that the selected literature had low bias and high clinical adaptability. ① In Meta-analysis of sTREM-1 level in alveolar fluid, 20 articles were selected and found to have high heterogeneity ( I2 = 94.4%, P = 0.000). The random effects models were used for Meta-analysis. It was indicated that the sTREM-1 level in alveolar fluid of VAP group was significantly higher than that of non-VAP group with significant difference [standardized mean difference ( SMD) was 1.47, 95% confidence interval (95% CI) was 1.00-1.95, Z = 6.14, P = 0.000]. By subgroup analysis and Meta-regression analysis, no source of heterogeneity was found. Sensitivity analysis suggested that the results of this Meta-analysis were robust and credible, and Begg funnel plot analysis showed that there was no significant publication bias ( Z = 1.46, P = 0.143). ② A total of 18 articles were included in the Meta-analysis of diagnostic experiments. Deek funnel plot showed publication bias ( P = 0.012). The combined sensitivity was 0.87 (95% CI was 0.81-0.91), specificity was 0.80 (95% CI was 0.73-0.86), and diagnostic odds ratio ( DOR) was 26 (95% CI was 13-50). Subgroup analysis of three different sources of alveolar fluid (bronchoalveolar lavage fluid, endotracheal aspiration fluid and exhaled ventilator condensate) showed that STREM-1 had a certain value in early diagnosis of VAP. The I2 of combined DOR was 35.4%, and I2 of sensitivity was 79.46%, I2 of specificity was 77.61%, suggesting heterogeneity in the selected literature. Subgroup analysis found that nationality, subject design, sample source, sample size and diagnostic "gold criteria" were related to heterogeneity, but not age. The area under synthetic receiver operating characteristic (SROC) curve (AUC) was 0.90 (95% CI was 0.87-0.92). Conclusions:The detection of sTREM-1 level in alveolar fluid can be used for the early diagnosis of VAP with high sensitivity and specificity. If combined with other biomarkers, it may have more diagnostic value.

Objective To explore the changes of depressive symptoms and serum level of brain derived neurotrophic factor(BDNF)before and after venlafaxine treatment in female patients with depression. Methods 40 perimenopausal women patients with depression received treatment with venlafaxine for 4 weeks. Before and after treatment,the patients were assessed by the Hamilton Depression Scale(table 24 item version)and serum levels of BDNF were measured. The results were compared with those from 40 healthy menopausal women. Results In the treatment group,the depressive symptoms were improved(P < 0.05);and the BDNF level was elevated(P < 0.05). The serum BDNF levels were higher in the effective group than in the non-effective group (P<0.05);the BDNF levels were increased(P<0.05)before and after treatment.Conclusions Treatment with venlafaxine for depression in perimenopausal women,BDNF levels are increased and depression symptoms are mproved significantly.The effect is associated with the level of BDNF.

Glutathione (GSH), a non-protein thiol product with various biological activities, has been widely used in pharmaceutical and food industries. Recently, genetic engineering becomes an important strategy for obtaining GSH-high-producing strains. However, auxotrophic selection markers used may result in reduced cell growth or GSH production. In the present study, clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9-associated-system (CRISPR-Cas), in which gRNA expression constructs and homologous DNA fragments of target genes were co-transformed into Saccharomyces cerevisiae cells, was used for the construction of the prototrophic strain derived from the engineered auxotrophic strain W303-1b/FGP. As a result, the prototrophic strain W303-1b/FGPPT showed a significantly shorter culture cycle compared with the auxotrophic strain. Furthermore, chemically defined medium could be used to culture strain W303-1b/FGPPT that might have great interests in industrial fermentation.

Objective To analyze the influencing factors of extra uterine growth retardation (EUGR) in premature very low birth weight infants.Methods A total of 61 EUGR premature very low birth weight infants survived in intensive care unit of our hospital were enrolled into EUGR group,and at the same time another 50 non-EUGR premature very low birth weight infants were selected into non-EUGR group.The clinical related medical records in the two groups were compared and analyzed,and the influencing factors of EUGR was analyzed by Logistic regression analysis.Results The birth gestational age of EUGR group was (31.29±1.56)weeks,which was significantly lower than (33.98±1.35)weeks of the non-EUGR group (t=9.60,P<0.05).The birth weight of the EUGR group was (1 206.76±212.14)g,which was significantly lower than (1 341.55±103.26)g of the non-EUGR group (t=4.11,P<0.05).The hospital stay,return to birth weight time,start enteral nutrition time and total parenteral nutrition time in the EUGR group were (27.77±5.00)d,(15.36±5.91)d,(3.36±1.91)d,(16.93±4.02)d respectively,which were significantly longer than those in the non-EUGR group[22.69±3.97)d,(10.61±4.57)d,(2.61±1.37)d,(9.43±3.11)d](t=3.53,4.65,2.33,10.80,all P<0.05).The incidence rates of complications such as respiratory system,digestive system and metabolic disorder in the EUGR group were 26.23%,19.67% and 67.21%,respectively,which were significantly higher than those of the non-EUGR group(8.00%,6.00% and 40.00%)(x2=6.18,4.39,8.22,all P<0.05).Logistic regression analysis showed that low birth gestational age and birth weight,long hospital stay,later return to birth weight and total parenteral nutrition time,intrauterine growth retardation,and respiratory system,digestive system and metabolic disorder were independent risk factors for the occurrence of EUGR(all P<0.05).Conclusion The influencing factors of EUGR in very low birth weight infants were mainly low gestational age and birth weight,long hospital stay,later return to birth weight and total parenteral nutrition time,intrauterine growth retardation,and respiratory system,digestive system and metabolic disorder.Therefore,in order to prevent EUGR,active symptomatic measures should be given in clinic.

Objective: To investigate the current status of brucella infection in major occupational groups in Bayannur, China, and to analyze the risk factors for brucellosis. Methods: From January to March, 2015, a questionnaire survey and the serological testing were performed to investigate the current status of brucella infection in 649 workers in 13 slaughter and breeding plants in 7 counties in Bayannur, China. The items in the questionnaire survey included general information, related occupational information, living habits, medical history, and awareness of related knowledge. Results: A total of 112 workers (17.26%) had brucella infection. Brucella infection was associated with sex, age, years of exposure to hazardous substances, job, educational background, usage of protective equipment, the presence or absence of a wound at the exposure site, and whether to smoke during the work clearance (P<0.05) . The multivariate analysis showed that the risk factors for brucellosis were meat processing work (OR=1.812) , >5 years of exposure to hazardous substances (OR=1.363) , improper use or nonuse of protective equipment (OR=1.957) , smoke during work (OR=2.027) , and the presence of a woundat the exposure site (OR= 1.231) ; the protective factors for brucellosis were high school and college education and above (OR=0.521) and high rate of awareness of brucella-related knowledge (OR=0.648) . Conclusion The brucella infection rate is high in the major occupational groups in Bayannur, China. The main influencing factors for brucellosis are job, years of exposure to hazardous substances, usage of protective equipment, whether to smoke during work, and the presence or absence of a wound at the exposure site.