Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

[Study on flow field characteristics of dust airflow in vibrating screen and optimization of dust removal system].

In order to solve the problem of dust hazard of vibrating screen machine and difficult treatment in catalyst production process, computational fluid dynamics software Fluent was used to carry out numerical simulation calculation of the local exhaust dust removal system for the main dust dispersing points of the vibrating screen machine, including fine/coarse particles outlet and product outlet blowing and cleaning the dust points. The optimal design scheme and key technical parameters of local ventilation and dust removal system of vibrating screen machine were proposed. The results showed that the dust diffusion could be prevented by setting up an upper suction hood without air blowing, but the exhaust air volume needed to be calculated accurately. On the premise of purge, it is necessary to control the air volume to form a wind speed band of 8 m/s with a height of 15 cm at the feed port, so as to effectively remove the dust on the surface of solid particles of catalyst products and ensure that the catalyst products will not be blown away when falling into the feed barrel. The simulated design was applied to the vibrating sieve powder machine of a catalyst company, and the maximum dust concentration in the workplace was reduced from 45.80 mg/m(3) to 5.46mg/m(3), which effectively improved the working environment in the workplace.

[Establishment and validation of a new predictive equation with multiple risk factors for the development of cardiorenal syndrome type 1 in patients with acute myocardial infarction].

Objective: To investigate the independent risk factors of cardiorenal syndrome type 1 (CRS1) in patients with acute myocardial infarction (AMI) and to build a predictive equation for the development of CRS1 in these patients. Method: Consecutive inpatients with AMI, who hospitalized from January 2017 to December 2018 in the Hunan Provincial People's Hospital, were enrolled in this case-control study. Patients were divided into CRS1 group and non-CRS1 group according to the presence or absence of CRS1.The clinical data were collected through the electronic medical record system of Hunan Provincial People's Hospital. The matching process was conducted with a minimum-distance scoring method and a 1∶1 match between the CRS1 group and the no-CRS1 group, the propensity score was calculated through the logistic regression model. Factors with statistically significant differences in univariate analysis were included in the multivariate logistic regression model to analyze the risk factors of AMI patients with CRS1, then the independent risk factors were used to establish a predicting equation for CRS1 by logistic regression function for model building. Area under the curve (AUC) value and the best cut-off value of the combined predictors was determined according to the ROC curve. Python 3.8 software was used to perform 10-fold cross-validation on modeling samples. Results: A total of 942 patients were included, there were 113 cases in CRS1 group and 829 cases in non-CRS1 group. Ultimately, 99 CRS1 patients were successfully matched to 99 non-CRS1 patient using 1∶1 matching. After propensity score matching, the baseline age and sex along with heart rate, mean arterial pressure, percentage of people with a history of diabetes, hypertension, ST-segment elevation myocardial infarction, myocardial ischemia time, angiotensin converting enzyme inhibitors or angiotensin Ⅱ receptor blockers use, and ß receptor blocker use were similar between the two groups(all P>0.05). The contrast agent dosage was also similar between the two groups (P=0.266). The peak cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide(NT-proBNP), white blood cell count, base estimated glomerular filtration rate (eGFR), albumin and hemoglobin levels were statistically significant between the two groups (all P<0.05). Multivariate logistic regression analysis showed that decreased baseline eGFR, increased NT-proBNP, peak cTnI concentrations and white blood cell count were independent risk factors of CRS1 in AMI patients (all P<0.01).The predicting equation of the combined predictor was established by transforming the logistic model equation, L=0.031×cTnI+0.000 2×NT-proBNP-0.024×eGFR+0.254×white blood cell count, where L represented the combined predictor. ROC curve analysis indicated that the AUC of the peak cTnI, NT-proBNP, baseline eGFR, white blood cell count, and combined predictor were 0.76, 0.85, 0.79, 0.81, and 0.92 respectively (all P<0.05), and the cutoff value of combined predictor was 2.6. The AUC of ROC curve after the model's ten-fold cross validation was 0.89. Conclusions: Decreased baseline eGFR, increased NT-proBNP, peak cTnI concentrations and white blood cell count are the independent risk factors for CRS1 in AMI patients. The combined predictor equation based on the above 4 biomarkers presents a good predictive value for CRS1 in AMI patients.

[Bladder cancer local staging about muscle invasion: 3.0T MRI performance following transurethral resection].

OBJECTIVE: To evaluate the performance of 3.0T magnetic resonance imaging examination (MRI) for the local detecting of muscle invasive bladder cancer following transurethral resection of bladder tumor (TURBT). METHODS: Retrospective study identified 55 patients with pathology-proven bladder cancer who underwent transurethral resection of bladder tumor followed by 3.0T magnetic resonance imaging between September 2012 and April 2019 in our hospital. Two radiologists reviewed pelvic magnetic resonance imaging together and judged muscle invasive bladder cancer. Sensitivity, specificity and accuracy were calculated for the presence of muscle invasion by T2 weighted imaging (T2WI) only, diffusion-weighted imaging (DWI) only and T2WI+DWI compared with the findings at radical cystectomy as the reference standard. RESULTS: Of the 55 patients with pathological results from radical cystectomy, 3.64% (2/55) had no residual disease; 29.09% (16/55) were non-muscle invasive bladder cancer on pathology, including 13 cases in T1 and 3 cases in Ta; 34.55% (19/55) were in stage T2 depending on pathology, 25.45% (14/55) in T3, and 7.27% (4/55) in T4. The average age was 60.76 years, ranging from 42 to 82 years. There were 48 males and 7 females in our study. Before pelvic MRI examination, all the patients received transurethral resection of bladder tumor, including 16 cases taking the operation in our hospital and 39 cases in other hospitals. The interval between the pelvic MRI examination and transurethral resection of bladder tumor was more than 2 weeks in all the patients. They all underwent radical cystectomy within 1 month after the pelvic MRI examination, and no patient underwent radiotherapy or chemotherapy in our study during the interval between the MRI examination and radical cystectomy. T2WI only, DWI only, and T2WI+DWI of 3.0T magnetic resonance imaging for readers were with sensitivity: 94.59%, 83.78%, 91.89%; with specificity: 66.67%, 77.78%, 72.22% and with accuracy: 85.45%, 81.82%, 85.45%, respectively. CONCLUSION: 3.0T MRI may have a role in diagnosing muscle invasive bladder cancer following TURBT. T2WI has the advantage of detecting the location of bladder tumor, and DWI has the advantage of differentiating between the benign and malignant lesion. 3.0T MRI T2WI+DWI has a good utility in the detection of muscle invasive bladder cancer following TURBT with satisfied accuracy.

[Analysis of mortality and leading causes of death in Chinese children under 5-year-old between 2010 and 2016].

We collected death data of children under 5-year-old in China from the national child mortality surveillance system from 2010 to 2016. The change of mortality rate and causes of death were described. The mortality rate of Chinese children under 5-year-old decreased from 16.4‰ to 10.2‰ in all areas between 2010 and 2016, from 20.1‰ to 12.4 ‰ in rural areas and from 7.3‰ to 5.2‰ in urban areas, respectively, with a greater average annual decreasing rate in rural areas than urban area. During these years, in addition to traffic accidents and sepsis, other 8 cause-specific mortality rates showed a downward trend. There were substantial decreases of mortality rates of premature birth or low birth weight, birth asphyxia and neural tube defects. In urban areas, the mortality rate of premature birth or low birth weight, birth asphyxia decreased, and the mortality rate of congenital heart disease and diarrhea substantially decreased. However, there was a substantial increase of mortality rate of septicemia in urban areas. In rural areas, the change of major cause-specific mortality rates were consistent with the national trend.

Expressions and correlation analysis of HIF-1α, survivin and VEGF in patients with hepatocarcinoma.

OBJECTIVE: To investigate the expressions of HIF-1α, surviving, and VEGF in patients with hepatocarcinoma as well as the correlation analysis among them. PATIENTS AND METHODS: 65 patients, who were admitted to our hospital and diagnosed as hepatocarcinoma from January 2014 to October 2015, were selected as hepatocarcinoma group, while 50 healthy cases that do not have hepatocarcinoma were selected as normal control group. The expression levels of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of hepatocarcinoma group and normal liver tissues of control group were detected by immunohistochemical (SP) staining method; then, the correlation among them was explored. The expression levels of HIF-1α, surviving, and VEGF protein in hepatocarcinoma tissues and corresponding normal tissues were detected by Western blot. RESULTS: The positive expression rate of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of hepatocarcinoma group was respectively 46.2%, 55.4%, and 61.5%, significantly higher than that in cancer adjacent normal liver tissues of control group which was 2%, 2%, and 2%, and the differences were statistically significant (p<0.05). The expressions of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of patients with hepatocarcinoma were correlated with clinical stage, tumor differentiation degree and extrahepatic metastasis (p<0.05), but were not related to gender and tumor size (p>0.05). By Spearman rank correlation analysis, it could be seen that HIF-1α expression was positively correlated with VEGF protein expression in hepatocarcinoma tissues (r=0.683, p<0.05). Survivin expression was positively correlated with VEGF protein expression (r=0.717, p<0.05). There was no significant correlation between HIF-1α expression and survivin expression (p>0.05). The relative quantitative value of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of hepatocarcinoma group was respectively 3.04±0.23, 2.26±0.31, and 2.57±0.36, significantly higher than that in cancer adjacent liver tissues of control group which was 1.07±0.17, 1.31±0.27, and 1.42±0.43, and the differences were statistically significant (p<0.05). From Western blot electrophoresis scanning, it could be seen that the expressions of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues were higher than those in cancer adjacent normal liver tissues. CONCLUSIONS: The expressions of HIF-1α, surviving, and VEGF played important roles in the occurrence, invasion, and metastasis of hepatocarcinoma. In hepatocarcinoma tissues, HIF-1α, and survivin protein expression was positively correlated with VEGF expression, but survivin protein was not related to HIF-1α expression, which indicated that HIF-1α and survivin may inhibit the apoptosis of hepatocarcinoma cells and promote tumor angiogenesis by up-regulating the expression of VEGF protein, thus accelerating the occurrence and development of hepatocarcinoma.

[Efficacy and safety of oseltamivir in children with suspected influenza: a multicenter randomized open-label trial].

Objective: To evaluate the efficacy and safety of oseltamivir in the treatment of suspected influenza in children. Method: A multicenter, randomized and open-label trial was conducted among 229 individuals with suspected influenza which were collected from the clinic of 5 hospitals in Guangdong province (Guangzhou Women and Children's Medical Center, Shenzhen Baoan District Maternity and Child Care Service Center, the Second Affiliated Hospital of Shantou University Medical College, Dongguan Maternity and Child Care Service Centre, Yuexiu District Children's Hospital of Guangzhou) from April to July 2015. They were randomized either to oseltamivir group (oseltamivir 30-75 mg, twice daily for 5 days) or control group who were given symptom relief medicines for 5 days. Result: No significant difference was found between two groups in influenza symptoms of the patients before the treatment(P>0.05). Altogether 229 individuals (114 in oseltamivir group, 115 in control group) were analyzed for efficacy, in which 73 individuals (42 oseltamivir, 31 control), 31.9%, were identified as influenza-infected through laboratory test. No significant difference was found between the two groups in the duration of fever although shortened. In the 229 individuals , the cumulative alleviation proportion between oseltamivir and control group was not significantly different (P>0.05): the median duration of illness was 69.9 hours (95% CI 65.3-91.5) in oseltamivir group and 75.4 hours (95%CI 63.9-91. 7) in control group; the median duration of fever was 40.4 hours (95%CI 31.5-53.4) in oseltamivir group and 44.0 hours (95%CI 33.2-50.0) in control group. In the 73 individuals, the cumulative alleviation proportion between oseltamivir and control group was significantly different (P<0.05). The median duration of illness was 61.2 hours (95%CI 48.0-121. 0) in oseltamivir group, being significantly shorter than that of 116.0 hours (95%CI 91.5-175.0) in control group. But it was not significantly different that the median duration of fever was 32.8 hours (95%CI 24.0-47.0 ) in oseltamivir group and 55.8 hours (95%CI 43.6-78.3 ) in control group (P>0.05). And the median duration of fever in 60 individuals (38 oseltamivir, 22 control) was significantly different between two groups(P<0.05), who had finished a course of taking oseltamivir in the 73 individuals, 34.8 hours (95%CI 24.0-48.5 ) in oseltamivir group being significantly shorter than that of 53.3 hours (95%CI 43.6-104.0 ) in control group. There was certain difference in side effects rate between the two groups (oseltamivir 10%, control 2%, P<0.05). The main side-effects were gastrointestinal symptoms (stomachache, diarrhea, poor appetite, vomiting). Conclusion: The duration of illness and fever in suspected influenza patients treated with oseltamivir was shorter than those in the patients treated with no oseltamivir, the difference was not statistically significant, when 31.9% was confirmed with positive result of virus test in suspected influenza in children. But in these patients with positive result of virus test, the duration of illness was significantly shortened with treatment with oseltamivir as compared with no treatment with oseltamivir, and it would be better if full oseltamivir course was completed for reducing the duration of fever. Oseltamivir treatment was safe with mild side effects.

Clinical evaluation of sublingual administration of dust mite drops in the treatment of allergic asthma and allergic rhinitis of children.

OBJECTIVE: This study focuses on evaluating the clinical effects of sublingual dust mite drops for the treatment of allergic asthma in children. PATIENTS AND METHODS: 156 pediatric patients with allergic rhinitis and asthma were randomly divided into control and observation groups (78 cases each). For the control group the standard global initiative for asthma (GINA) asthma control scheme was adopted; meanwhile, the observation group patients received the standard GINA combined with sublingual administration of dust mite drops, once per day, gradually increasing the dose to reach a high maintenance level. After six months the sublingual drops were stopped and then the effects of the treatments on both groups of patients were compared. RESULTS: The symptoms of asthma and rhinitis in the daytime and nighttime for both groups decreased gradually with time. However, the observation group's outcome at the 6th, 12th and 24th month were significantly better than those of the control group (p < 0.05). Moreover, the FVC, FEV1 and PEF values of the two groups increased gradually, but those of the observation group improved more obviously (p < 0.05). The total effective rate of the observation group at the 6th and 24th months was significantly higher than that of the control group (p < 0.05). The contrast of complete and good control at 6 months had no statistical significance (p > 0.05). But at the 24th month, the observation group had significantly higher rates of complete and good control (p < 0.05). During the median time of sublingual administration of 20.3 months (ranging from 6 to 36 months), there were no evident adverse reactions. Finally, after the intervention, there were no significant differences between the IgE levels of the two groups (p > 0.05); however, the levels of IL-2 increased gradually and improved more in the observation group (p < 0.05). CONCLUSIONS: The results of our study support the notion that sublingual administration of dust mite drops to treat allergic rhinitis and asthma can improve clinical symptoms, increase the efficiency rate and increase the serum IL-2 level, and does not cause an increase in adverse reactions or IgE levels in treated children.

[Current status of hearing loss and related influencing factors in workers with noise exposure in refining and chemical industry].

Objective: To investigate the current status of hearing loss and related influencing factors in workers with noise exposure in refining and chemical industry. Methods: From August 2015 to March 2016, the investigation method of collecting the data of past occupational health examinations and measuring noise in working environment was used to enroll 8 672 male workers. Results: Of all workers, 11.6% were diagnosed with hearing loss. There were significant differences in the distribution of hearing impairment among workers exposed to noise at different ages, device types and types of work (χ(2)=17.80, 77.80 and 30.53, all P<0.05) . The level of noise exposure≥85 dB (A) (OR=5.79, 95%CI 3.70-8.81) , working years with noise exposure (OR=1.57, 95%CI 1.05-2.43) , and 25 years (OR=3.29, 95%CI 2.08-5.71) were risk factors for hearing loss in workers with noise exposure in refining and chemical industry. Conclusion: The level of noise exposure and working years with noise exposure are main influencing factors for hearing loss in workers with noise exposure in refining and chemical industry.

[Association between CDH23 gene polymorphisms and susceptibility to noise-induced hearing loss in the Chinese population: a meta-analysis].

Objective: To investigate the association between cadherin-23 (CDH23) gene polymorphisms and susceptibility to noise-induced hearing loss (NIHL) in the Chinese population through a meta-analysis. Methods: In June 2016, CNKI, VIP, Wanfang Data, and PubMed were searched for studies on the association between CDH23 gene polymorphisms and susceptibility to NIHL in the Chinese population. The articles were screened according to inclusion and exclusion criteria and related data were extracted. RevMan 5.3 was used for the meta-analysis. Results: A total of three Chinese articles were included. For CDH23-rs1227049, the risk of NIHL in people with C allele was 0.82 times (95%CI 0.39-1.73) that in people with G allele, the risk of NIHL in people with CG+CC genotype in the dominant model was 0.70 times (95%CI 0.34-1.43) that in people with GG genotype, the risk of NIHL in people with CC genotype in the recessive model was 1.23 times (95%CI 0.28-5.43) that in people with CG+GG genotype, and the risk of NIHL in people with CC genotype in the additive model was 1.05 times (95%CI 0.20-5.44) that in people with GG genotype (all P>0.05) . For CDH23-rs1227051, the risk of NIHL in people with T allele was 0.98 times (95%CI 0.71-1.37) that in people with C allele, and the risk of NIHL in people with CT+CC genotype in the dominant model was 1.09 times (95%CI 0.75-1.57) that in patients with TT genotype (both P>0.05) . Conclusion: There is still no enough evidence for the determination of CDH23-rs1227049 and CDH23-rs1227051 to be the susceptibility gene loci of NIHL.

Generating orthogonally circular polarized states embedded in nonplanar geometric beams.

We experimentally demonstrated the generation of orthogonally circular polarized states embedded in nonplanar geometric beams. Experimental results revealed that the production of circularly polarized beams, induced by crystal birefringence, is quantized. Numerical analyses of the polarization and the spatial morphology are consistent with the experimental results.

Optimal waist-to-height ratio cutoff values for predicting cardio-metabolic risk in Han and Uygur adults in northwest part of China.

BACKGROUND/OBJECTIVES: Optimal obesity indices in predicting cardio-metabolic risk are less studied in Asian. We evaluated optimal waist-to-height ratio (WHtR) for predicting hypertension, dyslipidemia and diabetes in Han and Uygur populations in Xinjiang, a northwest part of China. SUBJECTS/METHODS: This study involved 5603 Han and 4657 Uyghur participants. Anthropometric data, blood pressure, serum total cholesterol (TC), triglyceride, low-density lipoprotein, high-density lipoprotein and fasting glucose were determined. The cutoff values of WHtR were calculated; the relation between WHtR and prevalence of cardio-metabolic risks was evaluated. RESULTS: There was a positive correlation between WHtR and blood pressure, TC, triglycerides and fasting glucose in both Han and Uygur participants (all P<0.001). The prevalence of hypertension, dyslipidemia and diabetes was higher with increased WHtR for both ethnic groups after adjusted by age. Calculated cutoff values of WHtR for predicting hypertension, dyslipidemia, diabetes or ⩾ 2 of these risk factors were 0.54 for both men and women in Han and 0.55 in male and 0.57 in female Uygur participants. A significant difference in blood pressure, triglycerides and fasting glucose between subgroups with WHtR either above or below the cutoff values was observed in both men and women of the two ethnicities. CONCLUSIONS: The optimal cutoff value of WHtR is a useful screen tool for predicting cardio-metabolic risks in Han and Uygur population in Xinjiang, northwest part of China.

Analysis of differentially expressed proteins involved in hand, foot and mouth disease and normal sera.

We implemented 2-D DIGE technology on proteins prepared from serum obtained from children with hand, foot and mouth disease (HFMD) and controls, to study the differentially expressed proteins in control and HFMD serum samples. Proteins found to be differentially expressed were identified with matrix-assisted laser desorption/ionization time-of-flight/ time-of-flight mass spectrometry (MALDI-TOF/TOF MS) analysis. We identified 30 proteins from mild HFMD samples and 39 proteins from severe HFMD samples, compared with the normal controls. 25 proteins among them (14 up-regulated and 11 down-regulated proteins) are found in both HFMD groups. Classification analysis and protein-protein interaction map showed that they associate with multiple functional groups, including transporter activity and atalytic activity. These findings build up a comprehensive profile of the HFMD proteome and provide a useful basis for further analysis of the pathogenic mechanism and the regulatory network of HFMD.

Mortality rate for children under 5 years of age in China from 1996 to 2006.

OBJECTIVES: To study the change in mortality rate for children under 5 years of age in China over the past decade, and to evaluate China's progress in achieving Millennium Development Goal 4. STUDY DESIGN: Population-based descriptive study. METHODS: A population-based survey was conducted through a nationwide multi-level surveillance network. The mortality rate and the leading causes of death for children under 5 years of age were analysed. RESULTS: The mortality rate for children under 5 years of age in China dropped by 54.2% between 1996 and 2006 (from 45.0 per 1000 livebirths to 20.6). During this period, deaths due to pneumonia and diarrhoea dropped by 69.4% and 69.7%, respectively. The proportion of deaths due to pneumonia dropped from 23.4% in 1996 to 15.6% in 2006, and the proportion of deaths due to diarrhoea dropped from 5.6% in 1996 to 3.7% in 2006. CONCLUSION: The mortality rate for children under 5 years of age in China dropped remarkably from 1996 to 2006. This reduction was mainly due to a significant decrease in deaths due to pneumonia and diarrhoea. Based on the survey results, China should be able to achieve Millennium Development Goal 4.

Expression of Mina53 and its significance in gastric carcinoma.

AIM: To study the expression of Mina53 and its relationships with clinicopathological characteristics, antioncogene inactivation and tumor proliferation in human gastric carcinoma, and to explore the role of Mina53 in carcinogenesis and tumor progression. METHODS: Expression of Mina53 and proliferating cell nuclear antigen (PCNA) was determined in gastric carcinoma (n=79), gastric dysplasia (n=21) and normal gastric tissues (n=20), while p53 was measured in gastric carcinoma tissues by immunohistochemistry. RESULTS: Mina53 was negatively expressed in all normal mucosa tissues. Dysplasia specimens showed weakly positive staining for Mina53 in 3 of 21 cases. Elevated expression of Mina53 was observed in 72 (91.1%) of the gastric carcinomas. No significant associations were found between Mina53 and clinicopathological characteristics such as sex, age, histological differentiation, distant metastasis and lymph node metastasis (p>0.05). There was a significant association with depth of invasion (X2=5.385, p<0.05) and TMN stage (X2=6.255, p<0.05). In gastric carcinoma, positive staining for p53 was detected in 53 of 79 cases (67.1%), showing a significant association with Mina53 (X2=5.161, p<0.05). The mean (+/- SD) PCNA labeling index for gastric carcinoma was 39.47+/-16.92%. Mina53 expression was positively associated with PCNA level (r=0.756, p<0.01). CONCLUSION: Mina53 was overexpressed in gastric carcinoma and associated with tumor proliferation and antioncogene inactivation. Mina53 could therefore play an important role in the carcinogenesis and progression of gastric carcinoma.

Disruption of the Saccharomyces cerevisiae cell-wall pathway gene SLG1 causes hypersensitivity to the antitumor drug bleomycin.

Bleomycin is an antitumor drug that damages DNA via a free radical-dependent mechanism, and yeast mutants defective in DNA repair are hypersensitive to the drug. To identify possible pathways that may contribute to bleomycin resistance in yeast, we characterized a panel of bleomycin-sensitive mutants that were previously isolated by insertion mutagenesis using the transposon miniTn3::Leu2::LacZ::AMP( R). One of these mutants harbored a single insertion in the SLG1 gene, which encodes a cell membrane protein that senses cell wall stress, and functions to maintain cell wall function by activating the protein kinase C signaling pathway. Deletion of the SLG1 gene in parental strains caused hypersensitivity to bleomycin, and this correlated with an accumulation of damaged DNA. A plasmid that expresses the native SLG1 gene or that increases PKC1 gene dosage restored bleomycin resistance to the slg1Delta mutant. Two-dimensional gel electrophoresis revealed that exposure to bleomycin triggered the expression of certain proteins, presumably to maintain cell wall function, in a Slg1-dependent manner. In addition, mutants lacking cell wall function were found to be hypersensitive to bleomycin. We conclude that mutants deficient in proteins that maintain cell wall function are severely compromised in their ability to limit bleomycin entry into the cell. Therefore, these mutants are burdened with increased genotoxicity upon exposure to bleomycin in the medium. Our results show that major mechanisms other than DNA repair are operating in yeast to mediate bleomycin resistance.

Crystal structure of human epidermal growth factor and its dimerization.

Epidermal growth factor (EGF) is a typical growth-stimulating peptide and functions by binding to specific cell-surface receptors and inducing dimerization of the receptors. Little is known about the molecular mechanism of EGF-induced dimerization of EGF receptors. The crystal structure of human EGF has been determined at pH 8.1. There are two human EGF molecules A and B in the asymmetric unit of the crystals, which form a potential dimer. Importantly, a number of residues known to be indispensable for EGF binding to its receptor are involved in the interface between the two EGF molecules, suggesting a crucial role of EGF dimerization in the EGF-induced dimerization of receptors. In addition, the crystal structure of EGF shares the main features of the NMR structure of mouse EGF determined at pH 2.0, but structural comparisons between different models have revealed new detailed features and properties of the EGF structure.

Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation.

Nrf2 regulates expression of genes encoding enzymes with antioxidant (e.g. heme oxygenase-1 (HO-1)) or xenobiotic detoxification (e.g. NAD(P)H:quinone oxidoreductase, glutathione S-transferase) functions via the stress- or antioxidant-response elements (StRE/ARE). Nrf2 heterodimerizes with small Maf proteins, but the role of such dimers in gene induction is controversial, and other partners may exist. By using the yeast two-hybrid assay, we identified activating transcription factor (ATF) 4 as a potential Nrf2-interacting protein. Association between Nrf2 and ATF4 in mammalian cells was confirmed by co-immunoprecipitation and mammalian two-hybrid assays. Furthermore, Nrf2.ATF4 dimers bound to an StRE sequence from the ho-1 gene. CdCl(2), a potent inducer of HO-1, increased expression of ATF4 in mouse hepatoma cells, and detectable induction of ATF4 protein preceded that of HO-1 (30 min versus 2 h). A dominant-negative mutant of ATF4 inhibited basal and CdCl(2)-stimulated expression of a StRE-dependent/luciferase fusion construct (pE1-luc) in hepatoma cells but only basal expression in mammary epithelial MCF-7 cells. A dominant mutant of Nrf2 was equally inhibitory in both cell types in the presence or absence of CdCl(2). These results indicate that ATF4 regulates basal and CdCl(2)-induced expression of the ho-1 gene in a cell-specific manner and possibly in a complex with Nrf2.

Crystallization and preliminary X-ray diffraction studies of human epidermal growth factor.

Human epidermal growth factor (hEGF), a 6.2 kDa protein of 53 amino acids with three internal disulfide bridges, has been crystallized by the hanging-drop method. hEGF crystallizes in space group P3(1)21 (or P3(2)21) using MgCl(2) as precipitant, with unit-cell parameters a = b = 61.4, c = 87.0 A. Another type of crystal, obtained using NaCl as precipitant, belongs to a tetragonal point group and has unit-cell dimensions a = b = 102.5, c = 166.6 A. The trigonal crystals with the smaller unit cell diffract X-rays better and a native data set from a single crystal has been collected to 3.0 A resolution.