Background/Aims: Biliary tract cancer (BTC) frequently harbors KRAS mutations, which are associated with resistance to traditional treatment and a poor prognosis. Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL. Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against KRAS-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using KRAS-mutant and KRAS-wild type BTC cell lines, patient-derived xenografts (PDX), and KRAS oncogene-driven tumor models, as well as other KRAS-mutant cancer cell lines. Results: Initially, we discovered that the loss of GATA2 reduced the viability of KRAS-mutant but not KRAS-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in KRAS-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in KRAS-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced KRAS-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a KRAS oncogene-driven tumor model, as well as in other KRAS-mutant cancer cell lines. Conclusions In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in KRAS-mutant BTC and potentially other cancers.

Cachexia is a common complication in patients with lung cancer. It aggravates the toxic and side effects of chemotherapy, hinders the treatment plan, weakens the responsiveness of chemotherapy, reduces the quality of life, increases complications and mortality, and seriously endangers the physical and mental health of patients with lung cancer. The causes and pathogenesis of tumor cachexia are extremely complex, which makes its treatment difficult and complex. Controlling cachexia in lung cancer patients requires many means such as anti-tumor therapy, inhibition of inflammatory response, nutritional support, physical exercise, and relief of symptoms to exert the synergistic effect of multimodal therapy against multiple mechanisms of tumor cachexia. To date, there has been a consensus within the discipline that no single therapy can control the development of cachexia. Some therapies have made some progress, but they need to be implemented in combination with multimodal therapy after fully assessing the individual characteristics of lung cancer patients. This article reviews the application of drug therapy and nutritional support in lung cancer patients, and looks forward to the research direction of cachexia control in lung cancer patients.
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Cachexia/therapy* ; Combined Modality Therapy ; Humans ; Lung Neoplasms/drug therapy* ; Neoplasms/complications* ; Nutritional Support/adverse effects* ; Quality of Life

Objective To establish a comprehensive method combining physical model experiment and numerical simulation for studying airflow state of upper respiratory tract. Methods Based on CT medical images published online, a three-dimensional (3D) model of human upper respiratory tract was reconstructed. Based on 3D printing technology, an experimental model of the upper respiratory tract was established and the flow process of respiration was measured. A numerical simulation model was created based on the meshing of upper respiratory tract model and the turbulent Realizable k-ε model. Results Firstly, the result of numerical simulation was compared with the experimental conditions, and good agreement was achieved. The numerical simulation results showed that the airflow in respiratory process was in a parabolic shape; the distribution of flow field, pressure on wall and vortex structure were different between inspiratory and expiratory phases; there were air residues in the upper and lower nasal passages during the respiratory exchange process. In addition, the effects of airflow on physiological environment of the upper respiratory tract were preliminarily analyzed through the steak line, pressure field and vortex structure distribution. Conclusions The method proposed in this paper has the characteristics of pertinence, rapidity and accuracy, which gives full play to the advantages of reliable physical experiments and fine numerical simulation, and is applicable for studying different problems of the upper respiratory tract in different cases, with a high value for personalized diagnosis and treatment in clinic.

PURPOSE: The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA/AKT1 mutations in Chinese breast cancer patients and explored their roles in tumor phenotypes and disease prognosis. MATERIALS AND METHODS: Tumors from 507 breast cancer patients were prospectively collected from the West China Hospital between 2008 and 2013. Whole exons of AKT1 and PIK3CA were detected in fresh-frozen tumors using next-generation sequencing, and correlations between PIK3CA/AKT1 mutations and clinicopathological features were analyzed. RESULTS: The AKT1 mutation was found in 3.6% (18/507) of patients. Tumors from patients that carried the AKT1 mutation were estrogen receptor (ER)+/progesterone receptor (PR)+/human epidermal growth factor receptor 2 (HER2)‒ and were more likely to have high expression levels of Ki67. The prevalence of the PIK3CA mutation was 46.5% (236/507), and 35 patients carried two or three variants of the PIK3CA gene. PIK3CA mutations were associated with ER+/PR+/HER2‒ status. The prognosis of patients with one mutation in PIK3CA (or PIK3CA/AKT1) was not significantly different than that of patients with wild-type PIK3CA (or PIK3CA/AKT1), while patients with two or three variants in PIK3CA (or PIK3CA/AKT1) exhibited poorer outcomes in the entire group and in all three subgroups (ER+, HER2‒, Ki67 high), particularly with respect to overall survival. CONCLUSION: A high frequency of somatic PIK3CA mutations was detected in Chinese breast cancer patients. In addition to the mutation frequency, the tumor mutational burden of the PIK3CA and AKT1 genes should also be of concern, as they may be associated with poor prognosis.
Asian Continental Ancestry Group* ; Breast Neoplasms* ; Breast* ; China ; Estrogens ; Exons ; Humans ; Mutation Rate ; Phenotype ; Prevalence* ; Prognosis ; Prospective Studies ; Receptor, Epidermal Growth Factor

Objective To explore the change in 25 hydroxyvitamin D[25 -(OH)D]level in school - aged children with orthostatic hypertension (OHT). Methods Nineteen cases of school - aged children with OHT confirmed diagnosis by head - up tilt table test at the Department of Pediatric Cardiovasology,Children′s Medical Center,the Second Xiangya Hospital,Central South University,from October 2014 to February 2017,were selected as OHT group, including 17 males and 2 females,and their ages were from 7 to 14(11. 21 ± 2. 70)years old. Nineteen healthy children including 17 males and 2 females and aged 8 to 14(11. 05 ± 2. 35)years old who had a healthy examination of child care at the hospital in the same period were selected as healthy control group. In two groups of children all possible basic diseases were eliminated,such as severe liver and kidney disease,abnormal thyroid function and metabolic bone disease and/ or the long - term use of 25 -(OH)D metabolism drugs,accepted the serum 25 -(OH)D detection. Results (1)There was no significant difference in age and gender between the OHT group and the healthy control group(t = 0. 559,P > 0. 05;χ2 = 0. 000,P > 0. 05). The 25 -(OH)D levels were significantly lower in the OHT group than those in the healthy control group [(39. 62 ± 10. 65)nmol/ L vs. (64. 83 ± 10. 28)nmol/ L,t = - 7. 422,P <0. 01]. (2)25 -(OH)D levels had no correlation with age,gender,height,body mass,systolic pressure,or diastolic blood pressure (r = 0. 254,0. 047,0. 195,0. 019,- 0. 191,- 0. 184,all P > 0. 05). Taking 25 -(OH)D level as dependent variable,age,gender,height,body mass,systolic pressure,diastolic blood pressure as independent variables, multiple stepwise regression equation to predict 25 -(OH)D level was not fit. Conclusion Lower level of 25 -(OH)D may be one of the mechanisms for the onset of the school - aged children with OHT.

Objective To investigate the Huatan Huoxue Jiangqi prescription in treating AECOPD clinical curative effect. Methods 123 patients with AECOPD were randomly divided into the treatment group and the control group. The two groups were treated with western medicine, and the treatment group added with Chinese herbal medicine treatment with Huatan Huoxue Jiangqi prescription. The syndrome effect, clinical symptom score, CAT score, mMRC classification, lung function, the serum FIB and CRP levels were obtained to evaluate the efficacy of the two groups before and after treatment. Results The syndrome effect of the treatment group was significantly better than that of the control group. Compared with the control group, there was significant difference between traditional Chinese medicine syndrome score, CAT score (P < 0.05); Lung function (including FEV1, FEV1%, FEV1/FVC) was significantly improved in the treatment group after treatment (P < 0.05). The serum FIB and CRP levels decreased significantly in the treatment group compared with the control group (P < 0.05). Conclusion Huatan Huoxue Jiangqi prescription has reliable effets on treating AECOPD.

Objective To observe the therapeutic effect of traditional Chinese medicine(TCM)granules made by the formula of Shegan Mahuang decoction for treatment of patients with asthma. Methods A prospective study was conducted,51 cases of light to moderate asthma(cold type)patients were randomly divided into treatment group (25 cases)and control group(26 cases). Conventional symptomatic treatments were of the same in two groups. The patients in control group were given salbutamol aerosol inhalation,100μg each time,4 times per day;based on the treatment of the control group,additionally the above mentioned TCM granules dissolved in water was administered orally 1 dose/day taken twice once in the morning and another once in the evening in treatment group. The therapeutic course was 12 weeks in both groups. Before and after treatment,the asthma control test(ACT)score,forced expiratory volume in 1 second(FEV1)and peak expiratory flow(PEF)were observed. The therapeutic effect,adverse reaction and compliance were evaluated. Results The number of patients with asthma completely controlled in the treatment group was significantly higher than that in the control group(16 cases vs. 9 cases,χ2=4.82,P=0.028). In the patients of two groups,FEV1,PEF and ACT scores were significantly improved after treatment,and in the treatment group,they were obviously higher than those in control group〔FEV1(L):2.67±0.46 vs. 2.32±0.47,PEF(L/min):327.6±49.4 vs. 273.1±42.8,ACT score:22.8±2.0 vs. 21.1±2.6,all P<0.05〕. After treatment,FEV1%predicted value was increased in the treatment group but decreased in control group,there was significantly statistical difference〔(0.68±0.07)% vs.(0.80±0.11)%,P<0.05〕,no significant adverse reaction was found,compliance was good. Conclusion TCM granules made by formula of Shegan Mahuang decoction can improve the clinical symptoms, pulmonary function and control level in patients with asthma,so it is an effective medicine for the control of asthma.

Objective To explore the effect of rapamycin on pulmonary fibrosis in rats and its mechanism.Methods Pulmonary fibrosis model was induced by intratracheal instillation of bleomycin (5mg/kg).Control group was treated by intratracheal instillation of saline (1.25 ml/kg) to obtain the negative control.The rats of the rapamycin-treated group were given rapamycin (1 mg/kg per day) by gastric perfusion for consecutive 10 days beginning on the third day after intratracheal instillation of bleomycin.On the 28th day,all rats were sacrificed and the peripheral blood and the lung tissues were harvested.Lung tissues were performed hematoxylin-eosin (HE) staining.The severity of pulmonary fibrosis in rats was assessed by Ashcroft score.Lung tissues were performed immunohistochemical staining to detect the expression of transforming growth factor beta (TGF-beta).The expression level was judged by integrated optical density.Results The severity of pulmonary fibrosis was improved in rats of rapamycin-treated group compared with the rats of bleomycin-treated group.A significant difference in Ashcroft score was found between rapamycin-treated group and bleomycin-treated group(2.92 ± 0.64 vs 5.76 ± 1.76,P ＜ 0.01).The expression level of TGF-β was increased in rapamycin-treated group compared with the normal control group (5520.00 ± 1614.20 vs 3370.00 ± 1478.14,P ＜0.01).The expression level of TGF-β was decreased in rapamycin-treated group compared with the bleomycin-treated group (5520.00 ± 1614.20 vs 7772.00 ±1526.46 P ＜0.01).Conclusions Rapamycin can prevent bleomycin-induced pulmonary fibrosis.

This study compared the efficacy and safety of tiotropium bromide inhalation powder (spiriva) and doxofylline oral tablet (doxofylline) in the treatment of chronic obstructive pulmonary disease (COPD). A multi-center, randomized, double-blind, double-dummy, parallel-controlled study involved 127 eligible stable moderate to severe COPD patients treated with inhaled tiotropium dry powder (18 μg/day) or oral doxofylline tablets (0.2 g/time, 2 times a day) for 12 and 24 weeks. Before and after treatment for 12 weeks and 24 weeks, respectively, pulmonary function, 6-min walking distance and dyspnea index were recorded. The results showed that in both tiotropium group and doxofylline groups, after 12-week treatment, FEV(1), FEV(1)/FVC% and 6-min walk distance were significantly higher than those before the medication, while dyspnea index decreased as compared with that before treatment. After 24-week treatment, a slight improvement in the measures was observed as compared with that of 12-weeks treatment, but the difference was not statistically significant. With both 12-week and 24-week treatment, the effect of tiotropium was slightly better than that of doxofylline tablets, with the difference being statistically insignificant. The major adverse events in the tiotropium group and doxofylline group were observed in 9 cases (9.9%) and 12 cases (12.9%), respectively, and no statistically significant difference was found between them. We are led to conclude that both tiotropium at 18 μg a day and doxofylline tablets at 0.2 g/day (two times a day) are effective and safe for the treatment of COPD.

This study compared the efficacy and safety of tiotropium bromide inhalation powder (spiriva) and doxofylline oral tablet (doxofylline) in the treatment of chronic obstructive pulmonary disease (COPD).A multi-center,randomized,double-blind,double-dummy,parallel-controlled study involved 127 eligible stable moderate to severe COPD patients treated with inhaled tiotropium dry powder (18 μg/day) or oral doxofylline tablets (0.2 g/time,2 times a day) for 12 and 24 weeks.Before and after treatment for 12 weeks and 24 weeks,respectively,pulmonary function,6-min walking distance and dyspnea index were recorded.The results showed that in both tiotropium group and doxofylline groups,after 12-week treatment,FEV1,FEV1/FVC％ and 6-min walk distance were significantly higher than those before the medication,while dyspnea index decreased as compared with that before treatment.After 24-week treatment,a slight improvement in the measures was observed as compared with that of 12-weeks treatment,but the difference was not statistically significant.With both 12-week and 24-week treatment,the effect of tiotropium was slightly better than that of doxofylline tablets,with the difference being statistically insignificant.The major adverse events in the tiotropium group and doxofylline group were observed in 9 cases (9.9％) and 12 cases (12.9％),respectively,and no statistically significant difference was found between them.We are led to conclude that both tiotropium at 18 μg a day and doxofylline tablets at 0.2 g/day (two times a day) are effective and safe for the treatment of COPD.