[Application value of DNA damage repair variants in adjuvant therapy of triple negative breast cancer].

Objective: To investigate the correlation between adjuvant chemotherapy with platinum-containing regimens and DNA damage repair (DDR) defects in early-stage triple negative breast cancer (TNBC), and to provide a basis for precise treatment of TNBC. Methods: Next-generation sequencing (NGS) testing was performed on postoperative breast cancer specimens selected from the Cancer Hospital of Chinese Academy of Medical Sciences from June 2009 to October 2015 to analyze the correlation between DDR gene variants and the efficacy of adjuvant chemotherapy with TNBC platinum-containing regimens, and thus to screen the superior population for adjuvant chemotherapy with TNBC platinum-containing regimens. The study used t-test, χ(2) test, Fisher's exact test, rank sum test and multifactorial logistic analysis to assess the associations between mutated genes and clinicopathological characteristics and prognosis, and Log-rank test and Cox proportional risk model were used for survival and correlation analysis. Results: NGS results were successfully obtained in 149 patients (74 in the platinum-containing group and 75 in the platinum-free group), with a 97.3% (145/149) DDR gene mutation rate and a median number of 4 mutations in all patients. 5-year disease-free survival (DFS) was 85.4% and 75.0% for patients with DDR gene mutations and DDR gene wild-type, respectively, without statistical difference (P=0.825). The 5-year DFS rates of patients with homologous recombination repair (HRR) pathway mutation were 84.6% in platinum-containing (TCb) group and 84.9% in platinum-free (EC-T) group (P=0.554), respectively. The 5-year DFS rates of patients with and without mutations in the platinite-containing HRR pathway were 84.9% and 85.0%, respectively (P=0.751). The number of DDR pathways with mutations and the number of DDR gene mutations were not associated with prognosis (both P>0.05). PIK3CA mutation patients in TCb group had a worse prognosis than wild-type patients (5-year DFS were 71.4% and 88.1%, P=0.037), and KMT2D mutation patients in EC-T group had a worse prognosis than wild-type patients (5-year DFS were 76.9% and 86.8%, P=0.039). Conclusions: DDR gene variation is common in TNBC, more clinical studies are needed to prove whether DDR variation can serve as effective biomarkers for treatment with platinum.

[Evaluation of the predictive effect of PD-L1 expression on survival in early triple-negative breast cancer].

Objectives: To find the prognostic factors related to early triple-negative breast cancer to optimize the therapeutic strategies, and explore the influence of programmed cell death ligand-1(PD-L1)expression in early triple-negative breast cancer on its prognosis, so as to provide support for clinical treatment decisions. Methods: Early triple-negative breast cancer patients treated at the National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences during 1st June, 2009 and 31st Oct, 2015 were enrolled in this study. All the clinicopathological data of patients were collected, and the paraffin sections of the surgical specimens were stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2, secreted protein acidic and rich in cysteine (SPARC), androgen receptor, PD-L1 and other antibodies by the immunohistochemical method. Kaplan-Meier survival and Cox regression curves were used for survival analysis of relevant clinical and pathological results and nomogram survival prediction models were established to explore the influence of relevant factors on the prognosis. Results: A total of 205 patients with triple-negative breast cancer were enrolled. Ninety patients (43.9%) were PD-L1 positive. The median follow-up time was 63 months. Thirty-seven patients were relapsed or recurrent and 16 patients were dead. The 5-year disease-free survival (DFS) rate and overall survival (OS) rate were 86.1% (95% CI: 81.4%-90.8%) and 93.6% (95% CI: 91.0%-97.6%), respectively, in the general population. Univariate Cox regression analysis showed that PD-L1 expression and lymph node metastasis were correlated with DFS and OS (P<0.05). In multivariate analysis, PD-L1 expression was an independent influencing factor of DFS, with PD-L1 positive patients possessing a significant survival benefit in DFS (HR=0.31, 95% CI: 0.13-0.73). Lymph node metastasis was an independent influencing factor of OS, and OS was significantly shortened in patients with positive lymph node metastasis (HR=3.24, 95% CI: 1.15-9.17). PD-L1, lymph node metastasis, menopausal status, Ki-67 index and adjuvant chemotherapy regimen were included to establish the 1- and 3-year DFS and OS nomogram prediction models, resulting in C indices of 0.698 and 0.748, respectively. Conclusions: PD-L1 expression is a predictive biomarker of good prognostic factor in triple-negative breast cancer patients. DFS is significantly prolonged in PD-L1 positive patients and OS also shows a prolongation trend. The nomogram prognosis prediction models have reference values for adjuvant chemotherapy in this patient group.

[The prospects of DNA damage repair variants guiding platinum compounds in the treatment of triple negative breast cancer].

Triple negative breast cancer (TNBC) is prone to recurrence and metastasis, which is the subtype of poorest prognosis. Chemotherapy is the main treatment, although there is lack of effective adjuvant chemotherapy regimens. The unsatisfactory efficacy of chemotherapy has been a bottleneck in improving the outcome of TNBC. Platinum compounds act directly on DNA to kill tumor cells, and they have a stronger killing effect on tumor cells carrying DNA damage repair (DDR) defects, which is an important entry point to improve the efficacy of TNBC. Biomarkers for predicting the efficacy of platinum drugs in TNBC treatment have always been a hot topic. The DDR pathway contains a large number of related genes, and recent studies have shown that deficiencies in the DDR pathway may be associated with the efficacy of platinum drugs, which is expected to be a biomarker for predicting the efficacy of platinum drugs in breast cancer treatment.

[Research progress of pyruvate kinase type M2 in hepatocellular carcinoma].

Primary hepatocellular carcinoma is one of the most common high-grade malignant tumors in the world. Its incidence ranks fifth among malignant tumors in China, and various therapeutic measures have poor curative effect. Pyruvate kinase type M2 is a key enzyme in the glycolytic pathway, and its abnormal expression in liver cancer is closely related to the proliferation, metastasis, diagnosis, treatment, prognosis, as well as drug and radiation resistance. Therefore, multi-pathway targeted regulation of pyruvate kinase type M2 use is expected to become a new direction for the treatment of primary liver cancer.

[Analysis on the trend of liver cancer morbidity and mortality in certain district, Suzhou City, Jiangsu Province, 2017 to 2019].

Objective: To analyze the trend of liver cancer morbidity and mortality among residents with household registration in certain District, 2017 to 2019. Methods: The crude morbidity and mortality rate of males and females in the whole population were calculated by using the relevant data from the certain District Cancer Registry and Report System and the Cause of Death Surveillance System. The standardized morbidity and mortality rate were calculated according to the age structure of 2000 National Demographic Census and Segi's world population, respectively. Trend in liver cancer morbidity and mortality were evaluated using percent change (PC), annual percentage change, and case-number-weighted annual percent change. Age-specific rates were used to analyze the epidemic trend of liver cancer with age. Results: The crude morbidity rate of liver cancer in the whole population (male and female) of the certain district from 2017 to 2019 were 18.86/100 000, 26.05/100 000 and 11.90/100 000 respectively, and the crude mortality rates were 21.20/100 000, 29.29/100 000 and 13.38/100 000 respectively. The crude morbidity and mortality rate of liver cancer among male showed a downward trend (PC=-16.77% and -20.15% respectively). The crude morbidity and mortality rate of liver cancer among female showed inconsistent changes; however, the crude morbidity rate showed a downward trend, and the crude mortality rate first increased and then decreased (PC=-19.42% and -0.30% respectively). Liver cancer morbidity and mortality rate in male after the age of 30 were increased with age. The two key points of accelerated growth were around the age of 65 and 75, and the peak of morbidity (130.78/100 000) and mortality (201.96/100 000) were after the age of 80. The morbidity and mortality rate were significantly lower in female than those of male aged 60; however, after the age of 65, the morbidity rate was increased rapidly and gradually approached as that of male. After the age of 80 (the peak morbidity and mortality were 104.40/100,000 and 132.87/100,000, respectively), male were about twice as high as those female aged between 75 and 79. Conclusion: Morbidity and mortality rate of liver cancer in the certain District showed an overall downward trend from 2017 to 2019, but it increased with age, and the disease burden was relatively high among the elderly population. Liver cancer mostly occurred in male, so the prevention and control of liver cancer epidemics in middle-aged and elderly should be actively monitored.

[Evaluation of the efficacy and safety of combination of gemcitabine and nedaplatin for patients with HER-2 negative metastatic breast cancer].

Objective: To assess the therapeutic efficacy and safety of the gemcitabine combined with nedaplatin (GN) chemotherapy for metastatic human epidermal growth factor receptor-2 (HER-2) negative breast cancer patients. Methods: Forty-five patients with HER-2 negative recurrent metastatic breast cancer who had received prior adjuvant or neoadjuvant therapy with anthracycline and/or taxanes were enrolled. All the patients received GN regime from January 2014 to February 2019. The therapeutic efficacy was evaluated according to response evaluation criteria in solid tumors (RECIST) 1.1. The adverse response was evaluated and monitored according to common terminology criteria for adverse events (CTCAE). The progression-free survival (PFS) and overall survival (OS) and prognostic factors were also analyzed. Results: All of the 45 patients received 4 course GN, 1 of them achieved complete response, 21 achieved partial response. The objective response rate was 48.9 (95% CI: 33.7%-64.1%). Grade 3-4 hematological toxicities include leukopenia occurred in 10 (22.2%) of patients, neutropenia in 13 (28.9%) patients, and thrombocytopenia in 8 (17.6%) patients. The grade 3-4 hematological toxicities mainly manifested as nausea and vomiting, and the incidence was 4.4% (2/45). Among the 45 patients, 34 died, the median PFS was 5.1 (95% CI: 3.9-6.1) months and the median OS was 17.6 (95% CI: 13.1-20.9) months. Conclusion: The combination of gemcitabine and nedaplatin is an effective and tolerable treatment for metastatic breast cancer patients previously treated with anthracyclines and/or taxanes.

[Effects and related mechanism of 5-aza-2'-deoxycytidine on endothelial function in rats with hyperhomocysteinemia].

OBJECTIVE: To investigate the effects and related mechanism of 5-aza-2'-deoxycytidine(Aza) on endothelial function in Hyperhomocysteinemia rats. METHODS: Adult male SD rats were divided into 3 groups (n=7 each): control group, hyperhomocysteinemia (HHcy) group and Aza group according to the random number table. Control group rats were fed with normal diet. HHcy group rats were fed with diet adding 3% L-methionine. Aza group rats were fed with diet adding 3% L-methionine and Aza (0.5 mg/kg) injection for consecutive three days per week for 8 weeks. After 8 weeks, content of rat plasma homocysteine (Hcy) was detected by enzyme linked immunosorbent assay (ELISA). The rat mesenteric artery endothelium-dependent diastolic function was detected. The nitric oxide synthase (eNOS) activity and asymmetric dimethyl fine ammonia acid (ADMA) content were detected by ELISA, and the content of nitric oxide was detected by nitrate reductase method in the mesenteric arteries. The mRNA expression of DNA methyl transferase 1 (DNMT1) and dimethyl arginine acid dimethylamine hydrolase 2 (DDAH2) in the mesenteric arteries were detected by real-time fluorescence quantitative PCR, and the protein expressions of DNMT1 and DDAH2 in the mesenteric arteries were detected by Western blot. The DDAH2 promoter methylation level in the mesenteric arteries was detected by nested methylation specific PCR. RESULTS: (1) The content of plasma Hcy was significantly higher in the HHcy group and Aza group compared to the control group ((29.00±0.94) µmol/L and (26.43±0.47) µmol/L vs.(10.34±0.63) µmol/L, both P<0.01), which was significantly reduced in the Aza group compared with the HHcy group (P<0.05). (2) Acetylcholine-mediated relaxation at various concentrations was significantly lower in the HHcy group and the Aza group compared with the control group (both P<0.05), which was significantly increased in Aza group compared with HHcy group (P<0.05). SNP-mediated relaxation at various concentrations was similar among the three groups(all P>0.05). (3) Compared with the control group, the content of nitric oxide in the HHcy group was significantly decreased ((0.52±0.01) µmol/g vs.(0.42±0.00) µmol/g, P<0.01), which could be increased by Aza((0.49±0.01) µmol/g, P<0.05); the eNOS activity in the HHcy group was significantly decreased ((0.74±0.01) U/mg vs. (0.57±0.00) U/mg, P<0.01), which could be significantly increased by Aza ((0.65±0.01) U/mg, P<0.01); the content of ADMA in the HHcy group was significantly increased ((0.34±0.01) µmol/g vs. (0.37±0.00) µmol/g, P<0.05), which could be significantly decreased by Aza ((0.32±0.01) µmol/g, P<0.05). (4) Compared with the control group, the relative expression of DDHA2 mRNA in the HHcy group was significantly decreased (0.15±0.01 vs.0.12±0.01, P<0.01), which could be significantly increased by Aza (0.13±0.01, P<0.05); the relative expression of DDHA2 protein in the HHcy group was significantly decreased (0.31±0.02 vs. 0.24±0.01, P<0.01), which could be significantly increased by Aza (0.28±0.01, P<0.01). Compared with the control group, the relative expression of DNMT1 mRNA in the HHcy group was significantly increased (0.23±0.01 vs.0.43±0.01, P<0.01), which could be significantly decreased by Aza (0.39±0.01, P<0.05); the relative expression of DNMT1 protein in the HHcy group was significantly increased (0.35±0.01 vs. 0.50±0.01, P<0.01), which could be significantly decreased by Aza (0.47±0.01, P<0.05). (5) Compared with the control group, the methylated/non methylated ratio of DDHA2 promoter in the HHcy group was significantly increased (1.04±0.03 vs. 1.26±0.03, P<0.01), which could be significantly decreased by Aza (0.80±0.03, P<0.01). CONCLUSION: Aza can inhibit the activity of DNMT1, reduce DDAH2 promoter methylation level, increase the expression of DDAH2, decrease the content of ADMA, increase eNOS activity and content of nitric oxide, thus lead to the improvement of endothelial dysfunction in mesenteric artery of Hyperhomocysteinemia rats.

Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy.

UNLABELLED: The genesis and development of hepatocellular carcinoma (HCC) is related to the abnormity of signaling pathway, telomerase, cell cycle, apoptosis, angiogenesis, and others, in which STAT3 signaling pathway plays a key role. The HCC cell line HepG2 was transfected with small interfering RNA (siRNA) directed against STAT3. After 72 h, cell growth and cycle were analysed by MTT and Flow cytometry. Then, the protein was extracted and the protein expression of STAT3, Smad3, p44/42, TERT, caspase-3, XIAP, Grp-78, HSP-27, MMP-2, MMP-9, VEGF-A, cyclin A, and cyclin E was detected by Western blot. After the transfection, HCC cell growth was inhibited during the 24-72 h time period and the cell cycle was arrested in G0/G1. STAT3 protein expression was inhibited at 72 h after the transfection. Interestingly, Smad3, p-caspase-3, p-p44/42, Grp78, cyclin A, and cyclin E protein expression was increased at 72 h, while TERT, caspase-3, XIAP, MMP-2, MMP-9, and VEGF-A protein expression decreased at 72 h. However, P44/42, and HSP27 protein expression showed no change following transfection. The results demonstrated that STAT3 signaling pathway may participate in HCC genesis and development through regulating the protein expression of other signaling pathway, telomerase, apoptosis, cell cycle and angiogenesis; thereby, blockade of the Stat3 pathway represents a potential strategy for future treatment. KEYWORDS: STAT3, signaling pathway, telomerase, cell cycle, apoptosis, angiogenesis.

Age-stratified analysis of SARS-CoV-2 infection and case fatality rate in China, Italy, and South Korea.

OBJECTIVE: We aimed to compare the characteristics of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China, Italy, and South Korea. MATERIALS AND METHODS: Detailed national epidemiological information of COVID-19 was retracted from the latest statistics reports from China, Italy, and South Korea. Population-based analysis of the age distribution among confirmed cases was conducted and their crude case fatality ratio in each c RESULTS: The age distributions among COVID-19 cases were relatively similar between China and Italy with primarily elderly populations infected, which were considerably different from that in South Korea with primarily younger individuals infected. Most deaths occurred among elderly individuals who were older than 60 years in both Italy (98.0%) and South Korea (87.9%), consistent with the previous data from China (81.0%). CONCLUSIONS: Most deaths occurred among elderly individuals who were over 60 in China, Italy, and South Korea. South Korea's data suggest that younger individuals might be more susceptible to SARS-CoV-2 infection, which might be fully under detected in China and Italy.

ZEB2-AS1 regulates the expression of TAB3 and promotes the development of colon cancer by adsorbing microRNA-188.

OBJECTIVE: This study aimed to explore the possible role and mechanism of lncRNA ZEB2-AS1 in the pathogenesis of colon cancer (CCa). PATIENTS AND METHODS: The expression level of ZEB2-AS1 in 41 colon cancer tissue samples and 25 normal tissues was detected by qRT-PCR, and appropriate colon cancer cell lines were screened for in vitro experiments. Subcellular localization of ZEB2-AS1 was examined. After ZEB2-AS1 was transfected into colon cancer cells by liposome method, the cell proliferation, migration ability, and cell apoptosis percentage were evaluated by CCK-8 test, transwell assay, and flow cytometry, respectively. In addition, bioinformatics was applied to detect the target genes of microRNA-188. The Luciferase gene reporter assay was then performed to analyze the relative activity of Luciferase between microRNA-188 and TAB3 or ZEB2-AS1. At the same time, the control sequence, microRNA-188 mimics, microRNA-188 mimics+ ZEB2-AS1, si-TAB3, and microRNA-188 inhibitor+ si-TAB3 were respectively transfected into cells to further verify the interaction between TAB3 and microRNA-188 or ZEB2-AS1. Besides, the glucose and lactate levels were measured to explore their roles in glycolysis. RESULTS: The expression of ZEB2-AS1 in colon cancer tissues and cells was significantly higher than that in normal ones, and ZEB2-AS1 was confirmed to be mostly located in the cytoplasm. In addition, ZEB2-AS1 overexpression could enhance the cell proliferation rate and migration ability as well as reduce the cell apoptosis, which could be reversed by microRNA-188 overexpression. In addition, bioinformatics prediction and Dual-Luciferase reporter assays revealed that ZEB2-AS1 could bind to microRNA-188, which could directly target TAB3. At the same time, it was found that the overexpression of ZEB2-AS1 and low expression of microRNA-188 promoted glycolysis, while the opposite result was observed after overexpression of microRNA-188 and low expression of TAB3. CONCLUSIONS: The expression of ZEB2-AS1 is significantly increased in colon cancer tissues and cells, which can promote the proliferation, migration, and promote apoptosis of colon cancer cells. It may be involved in the development of this cancer through the process of glycolysis regulated by microRNA-188/TAB3.

Should postoperative haemoglobin and potassium levels be checked routinely following blood-conserving primary total joint arthroplasty?

AIMS: Despite declining frequency of blood transfusion and electrolyte supplementation following total joint arthroplasty, postoperative blood analyses are still routinely ordered for these patients. This study aimed to determine the rate of blood transfusion and electrolyte restoration in arthroplasty patients treated with a perioperative blood conservation protocol and to identify risk factors that would predict the need for transfusion and electrolyte supplementation. PATIENTS AND METHODS: Patients undergoing primary total joint arthroplasty of the hip or knee between July 2016 and February 2017 at a single institution were included in the study. Standard preoperative and postoperative laboratory data were collected and reviewed retrospectively. A uniform blood conservation programme was implemented for all patients. Need for blood transfusion or potassium supplementation was determined through a coordinated decision by the care team. Rates of transfusion and supplementation were observed, and patient risk factors were noted. RESULTS: The overall rate of blood transfusion was 1.06% in the study population of 1132 total joint arthroplasties performed in 1023 patients. Of the 12 patients requiring transfusion, 11 were female, ten occurred in patients undergoing total hip arthroplasty, and all 12 patients had a preoperative haemoglobin level less than 130 g/l. Operative duration and surgical blood loss were significantly greater in those patients requiring blood transfusion. Nearly all patients requiring transfusion had a history of, or risk factors for, cardiovascular disease. Potassium supplementation was required in 15.5% of the study cohort; 72% of these patients receiving potassium presented with a potassium level less than 4 mmol/l during preoperative testing, while the remaining 28% had a past medical history of either significant anaemia, cardiopulmonary, cardiovascular, or renal diseases that had required substantial medical management. CONCLUSION: A consistent blood-conserving perioperative strategy effectively minimized need for blood transfusion in total joint arthroplasty patients below previously reported rates in the literature. We suggest that postoperative full blood counts and basic metabolic panels should not routinely be ordered in these patients unless their preoperative haemoglobin and potassium is below 130 g/dl or 4 mmol/l respectively, and they have medical comorbidities.

[Measurement and analysis of cochlea in children with congenital sensorineural hearing loss with normal inner ear structure].

Objective:The cochlea of children with congenital sensorineural hearing loss with normal inner ear structure was measured and analyzed by high-resolution temporal bone CT(HRCT) imaging technique,its application value before cochlear implantation was evaluated and the appropriate electrode was selected.Method:We collected temporal bone HRCT images of 120 patients with congenital sensorineural hearing loss,according to gender divided into two groups,including 60 males and 60 females.We used the PACS software to measure the distance A(the largest distance from the round window to the lateral wall) and the distance H(height of the cochlea) and calculate the cochlear duct length. Reproducibility of these data were evaluated and the results between the different groups were compared.Result:Measurement of parameter values between the intraobserver and interobserver showed great reproducibility. In the male children group,the measured values are shown as distance Aï¼»(8.55±0.31)mmï¼½,distance Hï¼»(4.57±0.28)mmï¼½and the cochlear duct length(CDL)ï¼»(27.59±1.23)mmï¼½; and in the female children group, the measured values are shown as distance Aï¼»(8.45±0.32)mmï¼½,distance Hï¼»(4.42±0.34)mmï¼½and the cochlear duct length(CDL)ï¼»(27.20±1.17)mm.The A,H,and CDL of the male cochlea were greater than those of the female, the difference was statistically significant(P<0.05).Conclusion:Measuring the distance A and distance H of the cochlea and calculating the cochlear duct length CDL can be used to select a suitable length of electrode or to customize a personalized electrode. This is a simple and effective assessment method before cochlear implantation..

Relationship between the characteristics of immunopathological expression of hepatitis C virus antigen and hepatocytic injury.

Biopsied liver tissues from 352 cases were tested for hepatitis C virus (HCVAg) with improved PAP immunohistologic chemical method. Furthermore, corresponding seroantibody to hepatitis C virus was also tested. The total HCVAg positive rate was 9.1%. The HCVAg positive rate in chronic persistent hepatitis (CPH) was 5%. The HCVAg positive rate in chronic active hepatitis (CAH) was 11.2%. The HCVAg positive rate raised gradually along with the severity of hepatocytic injury. HCVAg may be seen in necrotic liver cells exfoliating into the liver sinus, indicating a close relationship between HCVAg and hepatocytic injury. Expression of HCVAg was mostly of the nucleus type in CPH cases and was mostly of the plasma type in CAH cases. The periphery of nucleus type-expressed positive cells generally had no marked inflammatory cell infiltration. The periphery of plasma type-expressed positive cells had a certain amount of inflammatory cell infiltration. Along with the severity of hepatocytic injury, HCVAg expressed itself in a positive correlation according to the nucleus and plasma types. The HCVAg positive cells were located mostly in the lobular peripheral band and rarely located in the venoperipheral band. It was possible that this had some relation with the lobular microcirculation of blood and blood supply. In this study, there was no obvious correlation between the HCVAg positive rate in hepatic tissues and the anti-HCV positive rate in sera. Neither the patients with HCVAg positive liver tissues nor the patients with seropositive anti-HCV had any history of blood transfusion and the use of blood products.(ABSTRACT TRUNCATED AT 250 WORDS)