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 significance and mechanism of ten-eleven translocation (Tet1) against Mycobacterium marinum ( Mm) infection in mice. Methods:SPF wild-type C57BL/6 and Tet1-knockout (Tet1KO) mice were injected intravenously with Mm. All mice were monitored and the abscesses formed in tail were observed and quantified. Pathological changes in mouse tail tissues were observed using hematoxylin and eosin (HE) staining and transmission electron microscopy and the differences between the two groups were analyzed. Immunohistochemistry staining was used to detect the expression and distribution of TNF-α and TGF-β in mouse tail tissues. Moreover, mouse tail tissues were cultured on 7H10 plates for bacterial counting. The expression of NF-κBp65 and TGF-β was detected by Western blot. Results:Obvious lesions including abscesses and ulcers were formed in the Mm-infected C57BL/6, but only scattered small abscesses were observed in Mm-infected Tet1KO mice. During Mm infection, the bacterial load was gradually increased in C57BL/6 mice, but decreased in Tet1KO mice. Histopathological examination showed that obvious inflammatory cell infiltration and typical granulomatous lesions were found in Mm-infected C57BL/6 mice, while no significant inflammatory cell infiltration was detected in Mm-infected Tet1KO mice. Immunohistochemistry staining demonstrated that the expression of TNF-α and TGF-β was lower in Mm-infected Tet1KO mice than in Mm-infected C57BL/6 mice. Moreover, the expression of phosphorylated NF-κBp65 and TGF-β was significantly reduced in Mm-infected Tet1KO mice as compared with that in Mm-infected C57BL/6 mice. Conclusions:Deletion of Tet1 could alleviate the inflammatory damage mediated by Mm and enhance the host immune response to bacteria.

Objective To observe the effect of aspirin on the proliferation inhibition and apoptosis of human adrenal cortical cancer cells, and to explore preliminarily the related mechanisms. Methods The human adrenal cortical cancer cells were cultured in vitro. The experimental group was DEME/F-12 complete medium which contained different concentrations of aspirin (final concentration of 0.125, 0.25, 0.5, 1 mg/ml). The control group was DEME/F-12 complete medium which had no aspirin but 1%anhydrous ethanol instead. After treatment by aspirin at different concentrations for different durations (24, 48, 72 hours), we detected the proliferation inhibition of SW-13 cells and H295R cells by methyl thiazolyl tetrazolium (MTT) method, observed the changes of cell morphology with the inverted microscope; Observed and counted apoptotic cells through Hoechst33258 fluorescent staining, tested the cell apoptosis by flow cytometry, and detected the expression of Bcl-2 and Bax by western blotting. Results The date of MTT showed that after treated by different concentrations of aspirin,the growth inhibition ratio of SW-13 cells and H295R cells were higher than the control group (P＜0.05), and at the same time, the inhibition ratio would increase when the drug concentration increased ( P＜0. 05 ), with a dose-dependent tendency. When the drug concentration was constant, the inhibition ratio increased with the duration of the drug (P＜0.05), which showed a time-dependent tendency. The number of apoptosis cells and the cell apoptosis rate of both SW-13 and H295R which were treated by different concentrations of aspirin for 48 hours were higher than the control group ( P＜0. 01). According to the analysis of grayscale value of western blotting, Aspirin can increase the expression of Bax ( P＜0.05). On the contrary, the expression of bcl-2 in the experimental group was lower than that in the control group (P＜0.05). Conclusion Aspirin may inhibit the growth of human adrenal cortical cancer cell in vitro and induce its apoptosis, and the possible mechanism may be correlated with the up-regulation of the expression of Bax, and down regulation of Bcl-2 expression.

In June 2016,a disease among the cultured rock carp (Procypris rabaudi) in Yongchuan of Chongqing Municipality occurred.The aim of this study was to investigate biological characteristics and provide reference for Aeromonas veronii identification diagnosis and treatment.Pathogenic bacteria strain YY01 from the dying fishes were examined and isolated.Strain YY01's taxonomic status was identified by observing the morphology,studying the physiological and biochemical characters and sequencing the 16S rRNA and housekeeping gene gyrB.Its pathogenicity was checked by artificial infection experiment and virulence genes.Furthermore,effective medicine was detected by drug sensitivity.The 16S rRNA and gyrB gene sequence of the strain YY01 was more than 99％ homology with that of Aeromonas veronii,suggesting that the pathogen was Aeromonas veronii,which was also identified by the results of biochemical analysis.The LD50 of strain YY01 to rcok carp was 5.06 × 104 CFU/g.Four virulence genes were detected from YY01,including aerolysin (aer),hemolysin (Hly),Outer Membrane Protein Gene A (OmpA) and adhesion (Aha) genes.Antibiotic sensitivity assays showed that among 40 antibiotics tested,22 were sensitive and 11 were resistant.In conclusion,the strain YY01 is identified as Aeromonas veronii and it is proved to have strong pathogenicity.

Objective To investigate the expression and significance of the endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and vascular endothelial growth factor(VEGF) in adrenocortical lesions of primary aldosteronism. Methods The expressions of EG-VEGF, and VEGF were detected by immunohistochemistry and real-time fluorescence quantitative PCR in samples of 18 cases of adrenocortical adenoma, 6 adrenocortical hyperplasia, and 8 normal adrenal cortex. The correlation between the expressions of EG-VEGF, VEGF, and clinicopathological parameters was analyzed. Results The expression of EG-VEGF or VEGF in adrenocortical adenomas was higher than that in adrenocortical hyperplasia or normal adrenal cortex ( all P＜0. 05 ), and the expression of EG-VEGF or VEGF between adrenocortical hyperplasia samples and normal adrenal cortex samples was indistinctive. There was no statistically significant correlation between EG-VEGF or VEGF expression and sex, age, blood pressure, serum potassium, plasma renin activity, except in case of serum aldosterone( P＜0.05 ). A positive correlation between EG-VEGF and VEGF ( P＜0. 01 ) was found. Conclusions EG-VEGF and VEGF may play a significant role in the formation and development of adrenocortical tumors in primary aldosteronism.

The expressions of Ki67 and FHIT were detected by immunohistochemical staining in 15 cases of adrenocortical carcinoma, 42 cases with adrenocortical adenoma,6 cases of adrenocortical hyperplasia, and 10 cases of normal adrenocortical tissue. The results showed that the highest expression of Ki67 and the lowest expression of FHIT were found in adrenocortical carcinoma. There were significant differences in the Ki67 and FHIT between adrenocortical adenoma and adrenocortical carcinoma ( both P < 0. 05 ). There existed negative correlation between the expressions of Ki67 and FHIT( r=-0. 712, P<0.05 ). Ki67 over-expression and loss of FHIT expression may be involved in the occurrence and development of adrenocortical carcinoma. It is suggested that combined detections of Ki67 and FHIT may have reference significance in the differentiation of adrenocortical adenoma from adrenocortical carcinoma.

Objective To study relationship between Ki67 ,fragile histindine tried (FHIT) and adrenocortical tumors. Methods Ki67 and FHIT was detected by immunohistochemical staining in edrenecortical carcinoma(n=14) ,edrenocortical adenoma(n = 61) and normal adrenocortical tissue adjacent to tumor(n = 10). Results Ki67 was not expressed in normal adrenecortical tissue but highest expressed in adrenocortical carcinoma as well as in adrenocortical adenoma,and however,the expression of FHIT was expressed in a different way to Ki67. Negative correlation was observed between Ki67 and FHIT (r = -0.721 ,P <0.005). Conclusion The correlation of Ki67, FHIT with adrenocortical tumor, suggest that the detection of both Ki67 and FHIT can provide objective and simple diagnosis method to identify adrencortical adenomas from adrencortical carcinomas.

Objective To investigate the effect of different pharmacotherapy after lacrimal passage plastic laser operation. Methods Divided 90 patients (103 eyes) with nasolacrimal duct obstruction into group A (33 eyes), group B (36 eyes) and group C (34 eyes) randomly, each group consisted of 30 cases. Tetracycline cortisone ophthalmic ointment (TCO) was used to perfuse lacrimal duct in the end of the operation in group A, while TDO was used in group B and group C. In the first three postoperative irrigation, TDO was used only in group C, there are no no ointment during the course of irrigation in the other two groups. Followed-up survey for 3 months, evaluated the efficacy of the treatment in 3 groups. Results The therapeutic efficacy was significant better in group B than in group A (P

Dogs were bled and maintained at the mean arterial pressure(MAP)of 6.67 kPa(moderate shock)or of 5.33 kPa(severe shock)for 2 hours.Then the blood shed was transfused back to the animals and observation on the dogs was carried on for 2 more hours.26 mongrel dogs,weighing 10~16 kg,were randomized into Group I of normoxia and moderate shock(NMS,n=7),Group I of normoxia and severe shock(NSS,n=7).Group I of hypoxia at a simulated alti- tude of 4 000 m and moderate shock(HMS,n=6),and Group IV of hypoxia and severe shock(HSS,n=6).The changes of the cardiovascular function and the oxygen transport were observed in these animals after anesthetization.It was found that the cardiovascular function was similar in HMS and NMS groups.The decrease of VO2 of HMS animals was similar to that of NSS dogs.Decompensation occurred earlier in HSS animals and resulted in high mortality.

Measurement of the cardiac output and local blood flow was accomplished in acute hypoxic rat with ~(99m)Tc-labeled toad red blood cells (~(99m)Tc-RBC) as biologic microspheres and the reference sample method (RSM). Hypoxia was produced by switching from room air to an 10% O_2-90%N_2 gas mixture. 40000-60000 of ~(99m)Tc-RBC were injected into the left ventricle of anaesthetized, artificially aerated rat and the reference sample was withdrawn from femoral arterial cannula in order to measure the cardiac output and local blood flow after 20 minutes inhaling hypoxic gas mixture. Results indicate that under a condition of artificial ventilation, acute hypoxia results in decrease of cardiac output and heart rate, and redistribute blood flow away from splanchmic organs to the heart and brain.