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 investigate the feasibility of the ultrasound "triangular method" in evaluating the morphology of the aortic arch in normal mid-to-late trimester fetuses，establish the gestational age-specific reference ranges for its morphological parameters，and to analyze their correlations with gestational age（GA）and cardiac valve annulus diameters.Methods:A prospective study was conducted on 317 normal singleton fetuses at 20-38 +6 weeks of gestation from the Second Xiangya Hospital of Central South University. Morphological parameters including arch length（a+b），arch width（w），arch height（h）and arch angle（θ）were measured using the "triangular method" in the aortic arch long-axis view. Arch tortuosity（a+b/w）and height-to-width ratio（h/w）were calculated. Linear regression was used to analyze correlations between arch length，width，height and GA，the reference intervals were established. Pearson correlation was applied to assess relationships between angle，tortuosity，height-to-width ratio and GA，cardiac valve annulus diameters（aortic，pulmonary，mitral，tricuspid）. Results:Aortic arch length，width and height showed strong positive correlations with GA（ r = 0.88，0.88，0.85；all P < 0.001）. The arch angle，tortuosity，and height-to-width ratio were independent of GA（all P > 0.05），with reference values of（69.2 ± 6.1）°，1.7 ± 0.1，and 0.7 ± 0.1，respectively. These parameters also showed no significant correlations with cardiac valve annulus diameters（all P > 0.05）. Conclusions:The ultrasound "triangular method" systematically quantifies fetal aortic arch morphology. The stability of arch angle，tortuosity and height-to-width ratio during mid-to-late gestation may provide a morphological benchmark for prenatal screening of aortic arch anomalies.

Objective:To study the relationship between the polarization state of hippocampal microglia and depression-like behavior in mice and the regulatory effect of Xiaoyaosan.Methods:Sixty female BALB/C mice were randomly divided into control group, model group, Xiaoyaosan group and fluoxetine group according to the random number method with 15 in each group. Except for control group, the mice in the other 3 groups received chronic restraint stress for 21 days to establish the depressive model. The mice in the Xiaoyaosan group and fluoxetine group were gavaged with Xiaoyaosan(28.06 g/kg) and fluoxetine(3.03 mg/kg) respectively, while the mice in control and model groups received the same volume of 0.9% NaCl solution. Mouse behaviors were evaluated by sucrose preference test and elevated plus maze test.ELISA was used to detect the contents of 5-hydroxytryptamine(5-HT), dopamine(DA) in serum and transforming growth factor-β1(TGF-β1), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) in the hippocampus. Immunohistochemistry was used to detect inducible nitric oxide synthase(iNOS) and arginase-1(Arg-1) expression.Western blot was used to detect the protein levels of iNOS, Arg-1, CD86 and CD206. The mRNA expression of iNOS and Arg-1 in hippocampus was detected by qRT-PCR. The pathological changes of hippocampus were observed by HE staining.SPSS 27.0 software was used to analyze the data. One-way ANOVA was used for comparison among multiple groups, and LSD test was used for pairwise comparison.Results:(1) There were significant differences in sucrose preference among the 4 groups ( F=46.62, P<0.05).The sucrose preference of model group was lower than that of the control group ( P<0.05), while the sucrose preference of Xiaoyaosan group was higher than that of the model group ( P<0.05).There were significant differences in the number of open arm entries and residence time in the elevated plus maze test among the 4 groups ( F=24.63, 26.94, both P<0.05). The number of open arm entries and residence time in model group ((1.80±1.48)times, (6.19±1.67)s) were lower than those of the control group ((9.80±1.64)times, (56.81±2.75)s)) (both P<0.05). The number of open arm entries and residence time in Xiaoyaosan group ((6.80±0.84)times, (29.59±7.72)s) were significantly higher than model group(both P<0.05).(2) There were significant differences in serum 5-HT and DA levels among the 4 groups ( F=33.27, 76.03, both P<0.05). The serum 5-HT and DA levels in the model group were lower than those of the control group (both P<0.05).The serum 5-HT and DA levels in the Xiaoyaosan group were higher than those of model group (both P<0.05).(3)There were significant differences in the contents of TGF-β1, IL-10, TNF-α and IL-6 in the hippocampus of 4 groups ( F=31.93, 64.01, 25.74, 28.14, all P<0.05). The contents of TGF-β1 and IL-10 in the model group were lower than those of the control group, while the contents of TNF-α and IL-6 were higher (all P<0.05). Compared with the model group, the contents of TGF-β1 and IL-10 in Xiaoyaosan group ( TGF-β1: (30.40±1.56)pg/mL vs (23.77±2.24) pg/mL; IL-10: ((233.94±11.38)pg/mL) vs (130.46±15.34) pg/mL) were higher, and the contents of TNF-α ((73.35±1.51)ng/mL vs (85.89±4.52)pg/mL) and IL-6 (66.15±2.96)pg/mL vs (76.01±1.59)pg/mL) )were lower (all P<0.05).(4)The results of qRT-PCR, immunohistochemistry and Western blot all showed that there were significant differences in mRNA and protein levels of iNOS ( F=41.92, 20.78, 9.27, all P<0.05) and Arg-1 ( F=27.24, 24.23, 6.49, all P<0.05) in the hippocampus among the 4 groups of mice. The mRNA and protein levels of iNOS of the model group were higher than those in the control group (both P<0.05), while the mRNA and protein levels of Arg-1 were lower than those in the control group(both P<0.05).The mRNA and protein levels of iNOS in the Xiaoyaosan group were lower than those in the model group (both P<0.05), while the mRNA and protein levels of Arg-1 were higher than model group(both P<0.05).(5) The expressions of CD206 and CD86 in hippocampus of the 4 groups were significantly different ( F=86.14, 24.02, both P<0.05). Compared with the control group, the model group had a higher expression of CD86 in the hippocampus and a lower expression of CD206 (both P<0.05).Compared with the model group, the CD86 of Xiaoyaosan group was lower, while CD206 was higher (both P<0.05). (6) The HE staining results showed that the cells in the hippocampal CA1 region of the model group mice exhibited disordered arrangement, fewer cells, larger intercellular space, unclear boundary and other changes.The morphology of the cells in the Xiaoyaosan group was improved compared to the model group. Conclusion:Xiaoyaosan can inhibit M1 activation of microglia and neuronal damage in the hippocampus of mice caused by chronic restraint stress, exerting neuroprotective effects and improving depressive behavior in mice.

Objective:To study the relationship between the polarization state of hippocampal microglia and depression-like behavior in mice and the regulatory effect of Xiaoyaosan.Methods:Sixty female BALB/C mice were randomly divided into control group, model group, Xiaoyaosan group and fluoxetine group according to the random number method with 15 in each group. Except for control group, the mice in the other 3 groups received chronic restraint stress for 21 days to establish the depressive model. The mice in the Xiaoyaosan group and fluoxetine group were gavaged with Xiaoyaosan(28.06 g/kg) and fluoxetine(3.03 mg/kg) respectively, while the mice in control and model groups received the same volume of 0.9% NaCl solution. Mouse behaviors were evaluated by sucrose preference test and elevated plus maze test.ELISA was used to detect the contents of 5-hydroxytryptamine(5-HT), dopamine(DA) in serum and transforming growth factor-β1(TGF-β1), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) in the hippocampus. Immunohistochemistry was used to detect inducible nitric oxide synthase(iNOS) and arginase-1(Arg-1) expression.Western blot was used to detect the protein levels of iNOS, Arg-1, CD86 and CD206. The mRNA expression of iNOS and Arg-1 in hippocampus was detected by qRT-PCR. The pathological changes of hippocampus were observed by HE staining.SPSS 27.0 software was used to analyze the data. One-way ANOVA was used for comparison among multiple groups, and LSD test was used for pairwise comparison.Results:(1) There were significant differences in sucrose preference among the 4 groups ( F=46.62, P<0.05).The sucrose preference of model group was lower than that of the control group ( P<0.05), while the sucrose preference of Xiaoyaosan group was higher than that of the model group ( P<0.05).There were significant differences in the number of open arm entries and residence time in the elevated plus maze test among the 4 groups ( F=24.63, 26.94, both P<0.05). The number of open arm entries and residence time in model group ((1.80±1.48)times, (6.19±1.67)s) were lower than those of the control group ((9.80±1.64)times, (56.81±2.75)s)) (both P<0.05). The number of open arm entries and residence time in Xiaoyaosan group ((6.80±0.84)times, (29.59±7.72)s) were significantly higher than model group(both P<0.05).(2) There were significant differences in serum 5-HT and DA levels among the 4 groups ( F=33.27, 76.03, both P<0.05). The serum 5-HT and DA levels in the model group were lower than those of the control group (both P<0.05).The serum 5-HT and DA levels in the Xiaoyaosan group were higher than those of model group (both P<0.05).(3)There were significant differences in the contents of TGF-β1, IL-10, TNF-α and IL-6 in the hippocampus of 4 groups ( F=31.93, 64.01, 25.74, 28.14, all P<0.05). The contents of TGF-β1 and IL-10 in the model group were lower than those of the control group, while the contents of TNF-α and IL-6 were higher (all P<0.05). Compared with the model group, the contents of TGF-β1 and IL-10 in Xiaoyaosan group ( TGF-β1: (30.40±1.56)pg/mL vs (23.77±2.24) pg/mL; IL-10: ((233.94±11.38)pg/mL) vs (130.46±15.34) pg/mL) were higher, and the contents of TNF-α ((73.35±1.51)ng/mL vs (85.89±4.52)pg/mL) and IL-6 (66.15±2.96)pg/mL vs (76.01±1.59)pg/mL) )were lower (all P<0.05).(4)The results of qRT-PCR, immunohistochemistry and Western blot all showed that there were significant differences in mRNA and protein levels of iNOS ( F=41.92, 20.78, 9.27, all P<0.05) and Arg-1 ( F=27.24, 24.23, 6.49, all P<0.05) in the hippocampus among the 4 groups of mice. The mRNA and protein levels of iNOS of the model group were higher than those in the control group (both P<0.05), while the mRNA and protein levels of Arg-1 were lower than those in the control group(both P<0.05).The mRNA and protein levels of iNOS in the Xiaoyaosan group were lower than those in the model group (both P<0.05), while the mRNA and protein levels of Arg-1 were higher than model group(both P<0.05).(5) The expressions of CD206 and CD86 in hippocampus of the 4 groups were significantly different ( F=86.14, 24.02, both P<0.05). Compared with the control group, the model group had a higher expression of CD86 in the hippocampus and a lower expression of CD206 (both P<0.05).Compared with the model group, the CD86 of Xiaoyaosan group was lower, while CD206 was higher (both P<0.05). (6) The HE staining results showed that the cells in the hippocampal CA1 region of the model group mice exhibited disordered arrangement, fewer cells, larger intercellular space, unclear boundary and other changes.The morphology of the cells in the Xiaoyaosan group was improved compared to the model group. Conclusion:Xiaoyaosan can inhibit M1 activation of microglia and neuronal damage in the hippocampus of mice caused by chronic restraint stress, exerting neuroprotective effects and improving depressive behavior in mice.

Objective:To investigate the feasibility of the ultrasound "triangular method" in evaluating the morphology of the aortic arch in normal mid-to-late trimester fetuses，establish the gestational age-specific reference ranges for its morphological parameters，and to analyze their correlations with gestational age（GA）and cardiac valve annulus diameters.Methods:A prospective study was conducted on 317 normal singleton fetuses at 20-38 +6 weeks of gestation from the Second Xiangya Hospital of Central South University. Morphological parameters including arch length（a+b），arch width（w），arch height（h）and arch angle（θ）were measured using the "triangular method" in the aortic arch long-axis view. Arch tortuosity（a+b/w）and height-to-width ratio（h/w）were calculated. Linear regression was used to analyze correlations between arch length，width，height and GA，the reference intervals were established. Pearson correlation was applied to assess relationships between angle，tortuosity，height-to-width ratio and GA，cardiac valve annulus diameters（aortic，pulmonary，mitral，tricuspid）. Results:Aortic arch length，width and height showed strong positive correlations with GA（ r = 0.88，0.88，0.85；all P < 0.001）. The arch angle，tortuosity，and height-to-width ratio were independent of GA（all P > 0.05），with reference values of（69.2 ± 6.1）°，1.7 ± 0.1，and 0.7 ± 0.1，respectively. These parameters also showed no significant correlations with cardiac valve annulus diameters（all P > 0.05）. Conclusions:The ultrasound "triangular method" systematically quantifies fetal aortic arch morphology. The stability of arch angle，tortuosity and height-to-width ratio during mid-to-late gestation may provide a morphological benchmark for prenatal screening of aortic arch anomalies.

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 effect of exclusive enteral nutrition (EEN) on plasma amino acid levels in patients with Crohn′s disease (CD) .Methods:Adult patients with moderate to severe active CD in the Sixth Affiliated Hospital of Sun Yat-sen University from December 1, 2020 to December 31, 2021 were prospectively recruited. All the participants received nasogastric EEN monotherapy for 8 weeks. Patients were divided into clinical response group and non-response group according to CD activity index (CDAI). Clinical data were collected from all the participants before and after EEN. Targeted metabolomics was used to detect and analyze the changes of 25 amino acids levels in plasma in CD patients before and after EEN, as well as the differences between response group and non-response group.Results:Thirteen patients were included in the study. The clinical remission rate reached 69.2% (9/13) after 8 weeks of EEN treatment. Compared with pre-treatment, the plasma levels of tryptophan, threonine, alanine, proline and cysteine in CD patients were significantly higher after EEN treatment. At week 8 after EEN, tryptophan metabolites including indole acetic acid and indole acetamide were significantly lower in patients with clinical remission compared to patients without remission. Correlation analysis showed the plasma levels of tryptophan was negatively correlated with CDAI and erythrocyte sedimentation rate (ESR), and the level of kynurenine was negatively correlated with ESR.Conclusion:EEN therapy is an effective way to induce clinical remission in active CD patients. After EEN, plasma levels of tryptophan, threonine, alanine, proline and cysteine are significantly increased. Tryptophan and cysteine metabolisms may be the key pathways leading to the efficacy of EEN treatment.

Objective:To investigate the effect of exclusive enteral nutrition (EEN) on plasma amino acid levels in patients with Crohn′s disease (CD) .Methods:Adult patients with moderate to severe active CD in the Sixth Affiliated Hospital of Sun Yat-sen University from December 1, 2020 to December 31, 2021 were prospectively recruited. All the participants received nasogastric EEN monotherapy for 8 weeks. Patients were divided into clinical response group and non-response group according to CD activity index (CDAI). Clinical data were collected from all the participants before and after EEN. Targeted metabolomics was used to detect and analyze the changes of 25 amino acids levels in plasma in CD patients before and after EEN, as well as the differences between response group and non-response group.Results:Thirteen patients were included in the study. The clinical remission rate reached 69.2% (9/13) after 8 weeks of EEN treatment. Compared with pre-treatment, the plasma levels of tryptophan, threonine, alanine, proline and cysteine in CD patients were significantly higher after EEN treatment. At week 8 after EEN, tryptophan metabolites including indole acetic acid and indole acetamide were significantly lower in patients with clinical remission compared to patients without remission. Correlation analysis showed the plasma levels of tryptophan was negatively correlated with CDAI and erythrocyte sedimentation rate (ESR), and the level of kynurenine was negatively correlated with ESR.Conclusion:EEN therapy is an effective way to induce clinical remission in active CD patients. After EEN, plasma levels of tryptophan, threonine, alanine, proline and cysteine are significantly increased. Tryptophan and cysteine metabolisms may be the key pathways leading to the efficacy of EEN treatment.

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.

Objective:To investigate the clinical efficacy of dual growing rods (DGR) in the treatment of early onset scoliosis (EOS), and to evaluate the safety of its clinical application.Methods:From March 2015 to August 2021, a total of 20 EOS patients with onset age within 10 years old who were treated with dual growth rod technique were retrospectively analyzed, including 8 males and 12 females. The mean age of patients at first surgery was 9.0±1.4 years (range, 6.3-10.8 years); the preoperative Cobb angle was 59.0°±16.8° (range, 41.2°-103°). The Cobb angle, thoracic kyphosis angle, lumbar lordosis angle, T 1-T 12 height, T 1-S 1 height, coronal plane imbalance, sagittal vertical axis (SVA), apical vertebral translation (AVT) and Campbell's space available for lung ratio (SAL) were recorded and analyzed while surgery-related complications were also recorded. Results:The average follow-up time of 20 patients was 28.07±14.30 months. The average initial hospital stay was 20.56±8.28 days, the average initial operation time was 211.70±39.80 min, the average blood loss in the initial operation was 255.00±149.50 ml, and the average surgical distraction was 1.60±0.51 times per person. The Cobb angle of the main curve in the coronal plane decreased from 59.00°±16.80° before operation to 33.40°±11.80° after the initial operation, which was 29.67°±11.67° at 1 year and 29.40°±11.30° at the last follow-up. Preoperative thoracic kyphosis angle was 41.39°±6.06°, decreased to 31.72°±3.56° after the initial operation, was 30.32°±4.26° at 1-year and 30.24°±4.23° at the last follow-up; preoperative lumbar lordosis angle was 45.90°±8.03°, decreased to 42.65°±9.05° after initial operation, 41.55°±7.84° at 1-year follow-up, and 41.53°±8.21° at the last follow-up; preoperative T 1-S 1 height was 31.76±4.42 cm, initial after operation, it increased to 34.64±3.96 cm, 36.73±3.87 cm at 1 year, and 37.28±4.36 cm at the last follow-up; preoperative T 1-T 12 height was 17.38±2.76 cm. increased to 19.39±2.86 cm after the initial operation, 21.77±2.71 cm at 1 year, and 21.91±2.74 cm at the last follow-up; Preoperative coronal balance was 1.52±0.73 cm, and decreased to 0.87±0.38 cm after the initial operation, 0.81±0.38 cm at 1 year, and 0.77±0.37 cm at the last follow-up; preoperative sagittal balance was 1.94±0.78 cm, and 1.42±0.56 cm after operation, 1.28±0.55 cm at 1 year, and 1.26±0.57 cm at the last follow-up; The preoperative apical vertebra offset was 4.33±1.85 cm, and 2.16±1.47 cm after the initial operation, 1.63±1.17 cm at 1 year, and 1.61±1.23 cm at the last follow-up; SAL increased from preoperative 0.88±0.05 to 0.94±0.03 postoperatively, and 0.96±0.01 at 1-year follow-up, and 0.97±0.01 at the last follow-up. The differences between the above indicators before and after surgery were statistically significant ( P<0.05); there was a statistically significant difference in SAL between the 1-year follow-up and the last follow-up ( t=3.80, P=0.001), and other indicators were not statistically significant. Among the 20 cases, there were 5 cases of postoperative complications, including 2 cases of pedicle screw loosening and displacement, 2 cases of transverse process hook decoupling, and 1 case of proximal junctional kyphosis (PJK). The complication rate was 25% (5/20), all of them underwent revision treatment, and the prognosis was good after timely treatment. Conclusion:The dual growth bar technique can effectively control the progression of EOS deformity, preserve the longitudinal growth potential of the spine, and buy time for the development of the thorax in children, which has high safety.