Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Background There are a variety of microorganisms in ambient air, and susceptible people can be infected once contact with pathogenic microorganisms in the environment. In order to avoid the spread of pathogenic bacteria, disinfection is the simplest and most effective way of killing pathogenic bacteria in the environment to block the contact between pathogenic bacteria and humans. Sodium hypochlorite (NaClO) is the most widely used disinfectant, but its safety in ambient air disinfection is not clear yet. Objective To establish a model of bronchial epithelial cell (BEAS-2B) injury induced by NaClO, and to explore the mechanism of the toxic effect of NaClO disinfectants on BEAS-2B. Methods Cells were treated with concentration gradients of 0, 25, 50,100, 200, and 400 μmol·L⁻¹ of the diluted NaClO (100 mmol·L⁻¹) standard solution, respectively, and cell activity was measured by cell counting kit-8 (CCK-8) assay after 15 and 30 min. Cells treated with 0, 25, and 50 μmol·L⁻¹ NaClO were selected to observe the cell morphology under an inverted microscope, apoptosis was determined by flow cytometry Annexin V FITC / PI double staining to determine the final experimental concentration. The morphology of organelles such as mitochondria was observed under a transmission electron microscope. Mitochondrial membrane potential of the cells was detected by JC-1 staining. Intracellular Ca²⁺ concentration was measured with a Fluo-4 AM fluorescent probe. Total cellular reactive oxygen species (ROS) was detected with a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe, cell mitochondrial ROS with a dihydroethidium (DHE) fluorescent probe, and lipid peroxidation intermediate malondialdehyde (MDA) with a commercial kit. Results Compared with 0 μmol·L⁻¹, NaClO treatment group, cell morphology did not change a lot after 25 μmol·L⁻¹ NaClO treatment for 30 min, and the cells began to wrinkle and become round after 30 min treatment with 50 μmol·L⁻¹ NaClO, showing about 70% of normal cell viability (P<0.01). So 30 min 50 μmol·L⁻¹ NaClO treatment was selected for the subsequent experiment. The experimental results found that compared with the 0 μmol·L⁻¹ NaClO treatment group, the number of apoptotic cells increased (P<0.05), the mitochondrial membrane potential decreased (P<0.01), the intracellular Ca²⁺ concentration increased (P<0.05), the cellular ROS level increased (P<0.05), the mitochondrial ROS level increased (P<0.01), and the MDA content increased (P<0.01) in the NaClO treatment group.. Conclusion The study has successfully established a model of BEAS-2B injury induced by NaClO, and found that NaClO can lead to cell damage by inducing apoptosis and oxidative stress in BEAS-2B cells. According to the results, there are two possible reasons. First, NaClO solves in water to form hypochlorous acid (HClO) which is oxidative and increases the intracellular ROS level after entering cells, leading to cellular oxidative stress. Second, HClO enters cells to directly attack the mitochondrial membrane, resulting in the imbalance of potential inside and outside the mitochondrial membrane, and apoptosis caused by Ca²⁺ efflux.

Circuating tumor cells (CTC) are cells that are shed from the primary sites of malignancies and enter the bloodstream through the blood vessel or lymphatic system. The formation of CTC is a key step in the tumor metastasis process. CTC can reflect the heterogeneity of solid tumors in time and space, and can be used as an important supplementary method for pathological diagnosis, prognostic interpretation, disease detection and molecular typing. Some researchers also apply CTC to carry out culture in vitro, functional detection and histochemical analysis. This article reviews the recent research of CTC in diagnosis and assessment of efficacy, prognosis and metastasis of breast cancer.

Objective To investigate the regulation of naringin on apoptosis of airway inflammatory cells in asthmatic mice and its relationship with Tas2rs.Methods 36 BALB/c mice were randomly divided into 6 groups(n=6):blank control group,ovalbumin model group(OVA),dexamethasone group(10 mg·kg-1,positive control drug),naringin low,medium and high dose groups(10,20,40 mg·kg-1).Airway asthma was induced by OVA in all groups except the blank control group.After continuous administration of solvent,dexamethasone or naringin for 6 days,the respiratory function and the number of cells in alveolar lavage fluid of mice were measured,the lung and airway morphology of mice were observed,respiratory resistance(Rrs),lung elastic resistance(Ers)and respiratory compliance(Crs)were measured,and mRNA expression levels of lung tissue-related pro-apoptotic factors were measured.The mRNA expression levels of Tas2rs and its downstream genes were determined.Results Compared with OVA model group,naringin could dose-dependent decrease Rrs and Ers,increase Crs,and decrease the number of leukocytes,eosinophils,lymphocytes and neutrophils.Compared with OVA model group,the infiltration of inflammatory cells in lung tissue was significantly reduced in high-dose naringin group,and the mRNA expression levels of Tas2r108,Tas2r135,Tas2r143 and their downstream target genes α-gust and Trpm5 in lung and airway tissue were significantly decreased.The mRNA expression levels of proapoptotic factors P53,Bax and Casp3 were increased,while the mRNA expression levels of apoptosis inhibitor Bcl2 were decreased.Conclusion Naringin prophylactic administration can promote the activation of airway Tas2rs signal,decrease the number of airway inflammatory cells and alleviate airway injury in asthmatic mice.Naringin as a Tas2rs agonist can be developed as a potential anti-asthmatic agent.

Objective To investigate the effect of thalidomide combined with infliximab (IFX) in treatment of refractory inflammatory bowel disease (IBD) and its effects on insulin-like growth factor-1 (IGF-1) and transforming growth factor-β1 (TGF-β1). Methods A total of 120 patients with refractory IBD were randomly divided into experimental group and control group, with 60 cases in each group. The two groups were given conventional treatment (mesalazine), the control group was given IFX, and the experimental group was given IFX combined with thalidomide, continuous treatment for two months. The efficacy, intestinal flora disturbance rate, adverse reactions, Crohn's disease activity index (CDAI), Lewis score, serum IGF-1, TGF-β1 levels and nutritional status indexes[albumin (ALB), transferrin (Tf)]before and after treatment for 1 month and 2 months of the two groups were compared. Results The total effective rate of the experimental group was significantly higher than that of the control group (P < 0.05). After one month and two months of treatment, CDAI and Lewis scores of the experimental group were significantly lower than those of the control group (P < 0.05); the serum levels of IGF-1, TGF-β1 as well as ALB and Tf in the experimental group were significantly higher than those in the control group (P < 0.05). The improvement of intestinal flora disturbance rate in the experimental group was significantly better than that in the control group (P < 0.05). There was no significant difference in the incidence of oral and nasal mucosa dryness, throat discomfort, nausea and vomiting between two groups (P>0.05). Conclusion In the treatment of refractory IBD patients, thalidomide combined with IFX can regulate serum IGF-1 and TGF-β1 levels, effectively relieve clinical manifestations, inhibit inflammatory activities, and improve nutritional status and intestinal flora disorders of patients, and it has high safety.

ObjectiveTo understand the current situation and influencing factors of health service demands of new residents in Shanghai. MethodsFrom July to August 2020， a questionnaire survey was conducted in 1 358 new residents from 36 survey points in 7 districts of the city. The questionnaire included the basic medical insurance coverage in the inflow area， the current situation of medical demand and related influencing factors， and the demands for other health services. Results47.1%（562/1 194）of new residents did not choose to seek timely medical treatment when they were not feeling well. The main reason was that the working hours occupied the medical treatment time. Logistic regression analysis showed that the main factors affecting the medical needs in new residents were the average daily working hours， living area and type of residence， health status， physical examination and physical exercise， and the type of basic medical insurance. The demands of new residents for "health consultation of common diseases and frequently occurring diseases"， "health behavior intervention （such as smoking cessation and alcohol restriction）"， "medical guidance and publicity"， "accidental injury prevention （traffic， work， falling， etc.）" and "maintenance of legitimate rights and interests of health" were 57.1%（682/1 194）、41.3%（493/1 194）、34.9%（417/1 194）、32.2%（385/1 194） and 31.9%（381/1 194）， respectively. ConclusionNew residents demands for medical services cannot be met. We should actively improve the working and living conditions of new residents， improve the construction of new residents' health service system， and improve the utilization level of health services.

Objective:To investigate the correlation between circulating tumor cell (CTC) detection, RAS/RAF gene mutation and clinicopathological characteristics in patients with colorectal cancer (CRC).Methods:The Amplification Refractory Mutation System (ARMS)-polymerase chain reaction (PCR) were used to detect the gene mutation in the tumor tissues of 138 CRC patients in the Third Affiliated Hospital of Sun Yat-sen University from May 2017 to May 2020. At the same time, the venous blood of 138 patients was collected and enriched for CTC genotyping by mRNA in situ hybridization. The correlation between CTC, RAS/RAF gene mutation and clinicopathological features of CRC patients was analyzed.Results:The mutation rates of KRAS, NRAS and BRAF genes were 48.6%(67/138), 5.1%(7/138) and 1.4%(2/138), respectively; The overall positive rate of CTC was 84.1%(116/138). The positive rates of different CTC types were: 23.1%(32/138) in epithelial type, 71.7%(99/138) in mixed type and 12.3%(17/138) in interstitial type respectively. The positive rate of CTC in CRC patients with clinical stage Ⅲ-Ⅳ, lymph node metastasis (N1-N3) and distant metastasis (M1) was significantly higher than that in CRC patients with stage Ⅰ-Ⅱ, no lymph node metastasis (N0) and no distant metastasis (M0) (all P<0.05). The total number of CTC, mixed CTC and interstitial CTC were positively correlated with clinical stage, lymph node metastasis and distant metastasis (all P<0.05). RAS/RAF gene mutation, gender, age, tumor location and tumor differentiation did not affect the positive rate of CTC (all P>0.05). Conclusions:The results of CTC typing are of great research significance for comprehensive treatment, prognosis assessment and stratified management of CRC, among which the interstitial type of CTC may be a high risk factor for the recurrence and metastasis of CRC.

Objective:To explore the effect of electromyography biofeedback therapy combined with oxiracetam on peripheral blood heme oxidase-1 (HO-1), soluble apoptotic molecules and cognitive function in patients with senile vascular dementia (VaD).Methods:One hundred and fourteen elderly patients with VaD from May 2018 to May 2020 in Xingtai Third Hospital were selected and divided into two groups according to the random number table method, with 57 cases in each group. Both groups were given conventional treatment. On this basis, the control group was given oxiracetam, and the observation group was given electromyography biofeedback therapy combined with oxiracetam. The treatment effects after treated for 1 month was compared between the two groups. The levels of serum HO-1, soluble apoptotic molecules sFas, sFasL before and after treatment were compared between the two groups. Cognitive function evaluated by Wechsler Memory Scale (WMS), Mini Mental State Examination (MMSE). The scores of Chinese Stroke Scale (CSS), Ability of Daily Living (ADL) before and after treatment and adverse reactions were compared between the two groups.Results:After treated for 1 month, the total effective rate in the observation group was higher than that in the control group: 93.0%(53/57) vs. 77.2%(44/57), the difference was statistically significant ( P<0.05). After treated for 1 month, the level of serum HO-1 in the two groups was higher than that before treatment, and the level of serum HO-1 in the observation group was higher than that in the control group: (30.21 ± 4.05) μg/L vs. (24.19 ± 3.47) μg/L, the difference was statistically significant ( P<0.05). The levels of serum sFas and sFasL in two groups after treatment were lower than those before treatment, and the levels of serum sFas and sFasL in the observation group were lower than those the control group after treatment: (81.57 ± 16.23) ng/L vs. (118.49 ± 25.09) ng/L, (135.47 ± 24.41) ng/L vs. (200.71 ± 30.29) ng/L, the differences were statistically significant ( P<0.05). After treated for 1 month, the CSS scores in the observation group was lower than the control group: (13.48 ± 2.15) scores vs. (17.22 ± 3.02) scores; the WMS, MMSE, and ADL scores in the observation group were higher than those in the control group: (97.75 ± 10.27) scores vs. (88.43 ± 9.16) scores, (23.82 ± 2.50) scores vs. (21.38 ± 2.19) scores, (60.16 ± 6.24) scores vs. (51.29 ± 5.52) scores, the differences were statistically significant ( P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups ( P>0.05). Conclusions:Electromyography biofeedback therapy combined with oxiracetam has a significant effect in the treatment of elderly patients with VaD. It can significantly improve vascular endothelial function, regulate apoptosis factors, strengthen cognitive function, promote recovery of nerve function and daily living ability without increasing adverse reactions.

Hereditary breast cancer refers to malignant tumors caused by pathogenic germline mutations of breast cancer susceptibility genes (BRCA). At present, it is believed that BRCA1/2 genes are most closely related to the development of hereditary breast cancer. Mutation will lead to loss of normal function, instability of genome, and then lead to tumorigenesis. Especially for those with germline mutations, not only the risk of breast cancer will be greatly increased, but also the probability of ovarian cancer and other cancers will be increased. With the emergence and clinical application of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, BRCA1/2 genes have been regarded as new targets for the treatment of breast cancer. This article reviews the latest research of breast cancer with BRCA1/2 gene mutations.

Objective To investigate HBV RNA level in patients with HBV-related hepatocellular carcinoma after long-term antiviral therapy and its clinical significance. Methods A total of 60 patients with HBV-related hepatocellular carcinoma who were admitted to Tianjin Second People's Hospital from June 2019 to August 2020 were enrolled in this study. These patients received antiviral therapy with nucleos(t)ide analogues (NAs) for at least two years, and high-sensitivity HBV DNA detection showed a HBV RNA level of < 20 IU/mL at least twice at an interval of 3 months. Liver function, HBV serum markers, and HBV RNA level were measured for all patients. The Kruskal-Wallis H test was used for comparison between multiple groups, and the Wilcoxon rank-sum test was used for comparison between two groups; a Pearson correlation analysis was used to investigate the influencing factors for HBV RNA. Results Among the 60 patients with HBV-related hepatocellualr carcinoma who received long-term antiviral treatment, 9 (15%) tested positive for HBV RNA. According to the level of alpha-fetoprotein (AFP), the patients were divided into AFP positive group and AFP negative group, and there was no significant difference in HBV RNA level between the two groups [0(0-3.57) vs 0(0-2.00), Z =-1.474, P =0.141). According to Barcelona Clinic Liver Cancer (BCLC) stage, they were divided into BCLC stage A group and BCLC stage B+C+D group, and there was no significant difference in HBV RNA level between the two groups [0(0-2.0) vs 0(0-2.0), Z =-0.607, P =0.544]. According to HBeAg level, the patients were divided into HBeAg positive group and HBeAg negative group, and there was a significant difference in HBV RNA level between the two groups [2.99(0-4.80) vs 0(0-0.50), Z =-3.400, P =0.001]. According to the titer of HBsAg, they were divided into HBsAg≤100 IU/mL group, 100 IU/mL < HBsAg < 1500 IU/mL group, and HBsAg ≥1500 IU/mL group, and there was a significant difference in HBV RNA level between the three groups [0(0-0.0) vs 0(0-0.20) vs 2.00(0.0-4.54), H =-7.899, P =0.019]. A Pearson correlation analysis was performed for age, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, alpha-fetoprotein, HBsAg, and HBeAg, and the results showed that HBsAg level was correlated with HBV RNA quantification ( r =0.292, P < 0.05). Conclusion In patients with HBV-related hepatocellualr carcinoma receiving long-term antiviral therapy with NAs, HBV RNA can still be detected after HBV DNA is lower than the lower limit of detection. HBsAg titer may be correlated with serum HBV RNA level.