Silent mutations within the RAS  gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies. Kirsten-RAS ( KRAS ) mutations, predominantly oncogenic, are pivotal drivers in various cancers. While extensive research has elucidated the molecular mechanisms and biological consequences of active KRAS  mutations, the functional significance of silent mutations remains relatively understudied. This review synthesizes current knowledge on KRAS  silent mutations, highlighting their impact on cancer development. Silent mutations, which do not alter protein sequences but can affect RNA stability and translational efficiency, pose intriguing questions regarding their contribution to tumor biology. Understanding these mutations is crucial for comprehensively unraveling KRAS -driven oncogenesis and exploring novel therapeutic avenues. Moreover, investigations into the clinical implications of silent mutations in KRAS -mutant tumors suggest potential diagnostic and therapeutic strategies. Despite being in early stages, research on KRAS  silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments. In conclusion, this review underscores the evolving landscape of KRAS  silent mutations, advocating for further exploration to bridge fundamental biology with clinical applications in oncology.
Humans ; Mutation/genetics* ; Neoplasms/genetics* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Animals

Objective:Explore the protective effect and mechanism of methyl badosolone (CDDO-Me) on rats with traumatic brain injury (TBI).Methods:A total of 72 SPF-grade SD rats aged 8 weeks were randomly (random number) divided into 4 groups ( n=18) using the random number table method: Sham, TBI, TBI+Vehicle, and TBI+CDDO-Me. The rat TBI model was established using the hydraulic impact head injury method. The TBI+CDDO-Me group was administered CDDO-Me (dissolved in 1% DMSO, at a dose of 10 mg/kg) via intraperitoneal injection 30 minutes after modeling, twice a day for a total of 3 days. On the third day after modeling, brain tissue was collected for pathological and water content detection after mNSS scoring. Immunofluorescence double staining was used to detect the expression of nuclear factor erythroid2 related factor 2 (Nrf2); immunohistochemical staining was used to detect the expression of ionized calcium binding adapter molecule-1(Iba-1); ELISA was used to detect the levels of tumor necrosis factor-α(TNF-α), interleukin (IL)-1β, and IL-18 in serum; kits were used to detect the levels of malondialdehyde (MDA) and reactive oxygen species (ROS); Western blot was used to detect the expression of the Nrf2 pathway, B-cell lymphoma-2 (BCL-2), and BCL-2 associated X protein (BAX). Results:(1) Compared with the Sham group, the mNSS scores and water content in the injured cortex of the TBI group rats were significantly increased (both P<0.05), and both significantly decreased after CDDO-Me intervention (both P<0.05). (2) Compared with the Sham group, the proportion of Nissl-stained injured neurons and apoptotic positive cells in the TBI group rats were significantly increased (both P<0.05), and both significantly decreased after CDDO-Me intervention (both P<0.05), accompanied by a decrease in BAX protein expression and upregulation of BCL-2 protein expression (both P<0.05). (3) Immunofluorescence and Western blot results showed that compared with the Sham group, the expression of total Nrf2, nuclear Nrf2, HO-1, and NQO1 proteins in the TBI group were all increased (all P<0.05), and the increase was more significant after CDDO-Me intervention (all P<0.05). (4) Immunohistochemistry and ELISA results showed that compared with the Sham group, the levels of MDA, ROS, Iba-1 in brain tissue and the levels of TNF-α, IL-1β, and IL-18 in serum in the TBI group rats were all significantly increased (all P<0.05), and all significantly decreased after CDDO-Me intervention (all P<0.05). Conclusion:CDDO-Me helps to reduce oxidative stress and inflammatory responses in TBI rats, and the mechanism may be related to the activation of the Nrf2/HO-1 antioxidant stress pathway.

Background::Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms. Methods::Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-cateninΔ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer. Results::MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer. Conclusion::MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.

Objective To establish a scientific training program that takes into account both anaerobic and aerobic training for pilots,and to explore the appropriate ratio of aerobic and anaerobic training.Methods According to the physical examination standards for pilots,a total of 16 healthy subjects aged 18-24 were selected from two batches.The two batches of subjects were trained with different aerobic and anaerobic ratios.Training period was 3 months.The changes in cardiopulmonary function of the subjects before and after training were evaluated using the cardiopulmonary function exercise testing system(CPET),and the changes in anaerobic capacity were evaluated using changes in strength as an indicator.Results After training,the weight load of the subjects in the two training programs,including barbell squats,leg flexion and hard pull,and barbell under 10RM and 3RM,was significantly increased(P<0.001),and there was no statistically significant difference in anaerobic strength growth between the two groups.The results of CPET showed that the maximum load,maximum heart rate,and respiratory quotient in the two groups were significantly increased after than before the training(P<0.01).The maximum load(Experiment group 1:29.12±19.69,Experiment group 2:72.00±46.24)and respiratory quotient(Experiment grouop 1:0.11±0.09,Experiment group 2:0.28±0.16)of the subjects in experiment group 2 before and after training were greater than those in experiment group 1.The difference was statistically significant(P<0.05).Conclusion The anaerobic and aerobic capacities of the subjects in the experiment group 2 are effectively improved,indicating that ratio of aerobic and anaerobic of the training scheme is better.

Objective:To investigate the differences in programmed death-ligand 1 (PD-L1) expression and immune cell infiltration characteristics in different molecular subtypes of endometrial cancer.Methods:A retrospective case series study was conducted. Ninety primary treated EC patients who underwent surgery without preoperative neoadjuvant therapy at the Second Hospital of Tianjin Medical University from November 2016 to May 2022 were collected. The surgical paraffin-embedded tissues were selected, and the molecular subtypes of endometrial cancer were classified according to 2020 World Health Organization (WHO) molecular subtypes using POLE gene Sanger sequencing and immunohistochemical staining. The expression of PD-L1, CD3, CD4, CD8, CD68, and CD20 proteins were detected by immunohistochemistry. Stained slides were digitally scanned for quantitative analysis of PD-L1 and immune cell infiltration density. The PD-L1-related scores were evaluated, including tumor cell score (TCS, the percentage of PD-L1 positive tumor cells among total tumor cells ≥1% was TCS positive, <1% was TCS negative), immune cell score (ICS, the percentage of PD-L1 positive tumor-associated lymphocytes and macrophages among total tumor-associated lymphocytes and macrophages ≥1% was ICS positive, <1% was ICS negative) and combined positive score [CPS, PD-L1 positive stained cells (including tumor cells, lymphocytes and macrophages)/total number of viable tumor cells ×100 ≥ 1 was CPS positive, < 1 was CPS negative]. Clinicopathological characteristics, PD-L1 scores and immune cell infiltration densities among different molecular subtypes were analyzed. Kaplan-Meier method was used to plot disease-free survival (DFS) curves for molecular subtypes, PD-L1 scores and immune cell infiltration densities, with subgroup comparisons using log-rank test. Cox proportional hazards models were used for univariate and multivariate analyses of poor DFS in endometrial cancer patients.Results:The median age of 90 patients was 58 years old (range: 33-72 years old); endometrioid carcinoma was present in 78 cases (86.7%), and non-endometrioid carcinoma was present in 12 cases (13.3%). Molecular subtyping identified POLE-mutated subtype in 6 cases (6.7%), mismatch repair deficient (MMRd) subtype in 23 cases (25.6%), p53 abnormal subtype in 14 cases (15.6%), and non-specific molecular profile (NSMP) subtype in 47 cases (52.2%). Significant differences were observed among the 4 molecular subtypes in International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, morphological subtype, tertiary lymphoid structures, estrogen receptor expression, and progesterone receptor expression (all P < 0.05). Among the 90 cases, 18 cases (20.0%) were positive for TCS, 31 cases (34.4%) were positive for ICS, and 39 cases (43.3%) were positive for CPS. Significant differences were found among the 4 molecular subtypes in PD-L1 + cell density, distribution of patients with ICS positivity, and distribution of patients with CPS positivity (all P < 0.01), but not in distribution of patients with TCS positivity ( P = 0.090); compared to NSMP subtype, the proportions of ICS-positive patients in POLE-mutated and MMRd subtypes were higher, the proportion of CPS-positive patients and PD-L1 + cell density in MMRd and p53 abnormal subtypes were higher, and the differences were statistically significant (all P < 0.05). Significant differences in immune cell densities were observed among the 4 molecular subtypes (all P < 0.01); compared to NSMP subtype, POLE-mutated, MMRd and p53 abnormal subtypes had higher densities of CD3 + and CD8 + cells, MMRd subtype had higher CD4 + cell density, and POLE-mutated and MMRd subtypes had higher CD68 + and CD20 + cell densities (all P < 0.05). The median follow-up was 43 months (range: 7-75 months). Among the molecular subtypes, p53 abnormal patients had the worst DFS, and POLE-mutated patients had the best DFS, and the difference in DFS among the 4 subtypes was statistically significant ( P = 0.046). Grouping according to the median density of immune cells in the entire group, patients with high CD8 + cell density (45 cases) had better DFS than those with low density (45 cases) ( P = 0.010), PD-L1 ICS-positive patients had worse DFS than negative patients ( P = 0.019), and NSMP subtype patients with high CD4 + cell density (24 cases) had better DFS than those with low density (23 cases) ( P < 0.001). There was no statistically significant difference in DFS among patients grouping with other PD-L1 scoring modes and other immune cell infiltration density (all P > 0.05). Cox regression analysis indicated that high CD8 + cell density ( HR = 0.335, 95% CI: 0.113-0.990, P = 0.048) was an independent protective factor for poor DFS in endometrial cancer patients, and high CD4 + cell density was an independent protective factor for poor DFS in NSMP subtype patients ( HR = 0.035, 95% CI: 0.003-0.345, P = 0.004). Conclusions:There are significant differences in PD-L1 expression and immune cell infiltration density among the different molecular subtypes of endometrial cancer, which are correlated with the prognosis of patients, and may provide reference for the selection of immunotherapy strategies and prognosis judgment.

Objective Aiming at solving the problem of poor accuracy for numerical solution of traditional finite element method (FEM) in numerical analysis on piezoelectric effects of bone remodelling, a model with an edge-based smoothed FEM (ES-FEM) was proposed. Methods The bone model was discretized by triangular elements, and the smoothing domain was constructed based on edges of the existing mesh element. Based on gradient smoothing technique, the smoothed strain gradient and the smoothed electric field gradient were obtained, and the discrete equations of the system were constructed under the framework of smoothed Galerkin weakform. Results The changes of bone mineral density (BMD) and the distributions of electric potential under piezoelectric effects in the process of bone remodelling were reflected by using the above model. Compared with FEM, ES-FEM could improve the accuracy of simulation result for bone remodelling to a certain extent. Conclusions The proposed ES-FEM can simulate the process of bone remodelling more accurately. The accurate prediction for piezoelectric effect of bone reconstruction by this method provides an effective theoretical basis for clinical research of bone diseases.

ObjectiveTo clarify the accumulation and distribution characteristics of dry matter and mineral elements in Artemisia argyi var. argyi cv. Qiai， and to provide technical support for the high yield of and efficient utilization of nutrients in this medicinal species. MethodTwo cultivars of this species， Qiqing 1 and Qihuang 1 were selected， and the composition of dry matter in different organs， the content， accumulation， and distribution of mineral elements in each organ of the two cultivars， and the dynamic changes of volatile oil content and index components eucalyptol and borneol in leaves of the two cultivars were monitored at different growth stages. ResultThe period from February to March marked the early growth stage of Qiai， and the dry matter was mainly distributed in the leaves. It accelerated the growth in April， and the period from April to mid-June witnessed the vigorous vegetative growth of Qiai， during which the dry matter was mainly found in the stems and leaves. It began the reproductive growth from late June and the dry matter was mainly distributed in the stems. In the flowering stage in August， no dry matter accumulation occurred. As for the volatile oil， the content was high （> 1.10%） at the vigorous vegetative growth stage and peaked on June 14 （1.33% in Qiqing 1， and 1.23% in Qihuang 1）. The relative mass fraction of eucalyptol was the maximum at the vegetative growth stage （8.67% in Qiqing 1， and 13.07% in Qihuang 1）. The relative mass fraction of borneol peaked at the early growth stage （2.63% in Qiqing 1， and 5.94% in Qihuang 1）. The content of nitrogen， phosphorus， potassium， and zinc in leaves was in significantly positive correlation with the content of volatile oil and the relative content of eucalyptol and borneol. The content of macroelements nitrogen， phosphorus， potassium， and calcium and trace elements iron and zinc peaked at the early growth stage， and the content was the highest in stem and leaf. The content of macroelement magnesium and trace elements manganese and copper was the highest at vegetative growth stage when the content of other elements decreased and the nutrients were gradually transferred to the buds， flowers and other organs. In the whole growth period， the distribution of potassium， calcium， and zinc was in the order of leaf > stem > root， and the distribution of nitrogen， phosphorus， copper， magnesium， and manganese followed the order of leaf > root > stem. The distribution of iron was in the order of root > leaf > stem. There was a significantly positive correlation between the total amount of dry matter and the absorption of nutrients in 'Qiai'. The absorption of macroelements by Qiai was in the order of potassium > nitrogen > calcium > phosphorus > magnesium， and the ratio of absorbed elements was about 2.66∶2.51∶0.6∶0.11∶0.04. The absorption of trace elements followed the order of manganese > iron > zinc > copper， and the ratio of absorbed elements was about 0.25∶0.17∶0.05∶0.04. In terms of the production of medicinal materials， 'Qiai' needed about 4.11 kg potassium， 3.58 kg nitrogen， 0.91 kg phosphorus， 0.18 kg calcium， 0.06 kg magnesium， about 6.64 g manganese， 2.56 g iron， 1.30 g zinc， and 0.92 g copper to produce 100 kg medicinal materials. ConclusionEnough organic fertilizer and phosphorus and potassium fertilizers should be applied as base fertilizers for Qiai. The vegetative growth stage （April-June） marks the high accumulation of dry matter and large demand of nutrients， during which topdressing should be conducted timely and early， especially nitrogen fertilizer， and appropriate amount of micro-element fertilizer should be added. Qiai needs a large amount of calcium and magnesium fertilizers from the mid-vegetative growth stage， and they should be applied in time in the late stage to ensure the vegetative growth of the plants for seeds and the quality of the medicinal material of Qiai.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.
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Objective: To investigate the occurrence and risk factors of deep venous thrombosis (DVT) in adult burn patients. Methods: The clinical data of 1 219 adult burn patients admitted to the Department of Burns of Zhengzhou First People′s Hospital from January 1, 2015 to August 31, 2016, conforming to the study criteria, were analyzed retrospectively by the method of case-control study, including 811 males and 408 females, aged 18-102 years. According to whether DVT occurred during hospitalization or not, the patients were divided into group DVT (n=12) and non-DVT group (n=1 207). The incidence of DVT, the diagnosis time of DVT, affected limbs, and DVT classification were counted and recorded. The gender, age, total burn area, D-dimer, lower limb burn, full-thickness burn, femoral vein indwelling central venous catheter (CVC) , inhalation injury, sepsis/infection shock, surgical operation, and infusion of concentrated red blood cells of patients between the two groups were compared with chi-square test, and then the indicators with statistically significant differences between the two groups were processed by multivariate binary logistic regression analysis to screen the independent risk factors of DVT in the adult burn patients. Results: (1) The incidence of DVT of adult burn patients was 0.98% (12/1 219), and DVT was diagnosed 24-138 days after injury, with a median of 61.5 days. DVT occurred in the right lower limb of 2 patients, left lower limb of 8 patients, and bilateral lower limbs of 2 patients, and DVT classification included 6 cases of mixed type and 6 cases of peripheral type. (2) There were no statistically significant differences in gender, age, and full-thickness burn of patients between the two groups ( χ²=1.524, 0.021, 3.115, P>0.05). There were statistically significant differences in total burn area, lower limb burn, inhalation injury, sepsis/infection shock, D-dimer, femoral vein indwelling CVC, surgical operation, and infusion of concentrated red blood cells among patients between the two groups (χ²=17.975, 6.206, 3.987, 8.875, 5.447, 15.124, 10.735, 14.031, P<0.05 or P<0.01). (3) Total burn area, D-dimer, and femoral vein indwelling CVC were independent risk factors for DVT in adult burn patients (odds ratio=10.927, 4.762, 9.394, 95% confidence interval=3.078-38.789, 1.197-18.934, 2.631-33.540, P<0.05 or P<0.01). Conclusions The incidence of DVT in adult burn patients is relatively low, and the diagnosis time of DVT is 3 weeks after burn, with DVT classification of mixed type and peripheral type. The total burn area, femoral vein indwelling CVC, and D-dimer are independent risk factors for predicting DVT in adult burn patients.

Objective:To prepare nanosilver-hybridized polylactic acid-glycolic acid copolymer (PLGA) microspheres loaded with simvastatin (SIM), and to evaluate its sustained release effect in vitro. Methods:The emulsification-solvent evaporation method was used to prepare SIM-loaded PLGA microspheres. Silk fibroin (SF) was used to modify the surface of SIM-loaded PLGA microspheres by hydrophobic interaction. Then, the microspheres were continually modified by electrostatic adsorption to chitosan (CTS) and nano-silver (AgNPs) to prepare SF-AgNPs-CTS-SF-SIM-PLGA microspheres. Scanning electron microscope, Fourier transform infrared spectrometer, energy spectrometer, Zeta potential meter were used to analyze the SIM-loaded microspheres. The external release properties of the SIM-loaded microspheres were also investigated.Results:The average diameter of the prepared PLGA microspheres was about 9.67 μm. The results of Fourier transform infrared spectroscopy and energy spectroscopy showed that the AgNPs-CTS-SF-SIM-PLGA microspheres have been successfully constructed. The Zeta potential results indicated that the SIM-loaded microspheres were all in a stable state. The in vitro release results showed that the SF-AgNPs-CTS-SF-SIM-PLGA microspheres had a good in vitro release effect, could delay the drug release rate and prolong the drug release time. Conclusions:The SF-AgNPs-CTS-SF-SIM-PLGA microspheres have antibacterial and osteogenic effects, and exhibit a good in vitro release effect. They can be used for local sustained-release administration in the oral cavity, which make makes them potentially useful in the treatment of periodontitis.