1.Treatment Strategies and Research Ideas of Acupuncture for Emotional Disorder in Perimenopause
Mei GENG ; Lin-Ling OUYANG ; Xiao-Kang XU ; Gui-Zhen CHEN ; Yun-Xiang XU
Journal of Guangzhou University of Traditional Chinese Medicine 2024;41(11):2912-2917
		                        		
		                        			
		                        			Perimenopause is a vulnerable stage for emotional disorders such as anxiety and depression,which is the result of a combination of bio-psycho-social factors,and it seriously affect the quality of life of perimenopausal women.Therefore,finding safe and effective treatments is one of the urgent problems in modern medicine.This paper summarises the etiology and treatment of emotional disorder in perimenopause in Chinese and western medicine,and on this basis,this paper discusses the clinical diagnostic and treatment strategies and research ideas of acupuncture in treating emotional disorder in perimenopause,thus providing a new idea for the prevention and treatment of emotional disorder in perimenopause.
		                        		
		                        		
		                        		
		                        	
2.Role of Prognostic Marker PRR11 in Immune Infiltration for Facilitating Lung Adenocarcinoma Progression.
Wen Hao WANG ; Chang Geng MA ; Yun Shang CUI ; Bing Yu BAI ; Zhi Mei SHENG ; Jin LIU ; Ao LI ; Bao Gang ZHANG
Biomedical and Environmental Sciences 2023;36(9):862-868
		                        		
		                        			
		                        			The PRR11 gene (Proline Rich 11) has been implicated in lung cancer; however, relationship between PRR11 and immune infiltration is not clearly understood. In this study, we used The Cancer Genome Atlas (TCGA) data to analyze the lung adenocarcinoma patients; PRR11 gene expression, clinicopathological findings, enrichment, and immune infiltration were also studied. PRR11 immune response expression assays in lung adenocarcinoma (LUAD) were performed using TIMER, and statistical analysis and visualization were conducted using R software. All data were verified using Gene Expression Profiling Interactive Analysis (GEPIA), and the Human Protein Atlas (HPA). We found that PRR11 was an important prognostic factor in patients with LUAD. PRR11 expression was correlated with tumor stage and progression. Gene Set Enrichment Analysis (GSEA) showed that PRR11 was enriched in the cell cycle regulatory pathways. Immune infiltration analysis revealed that the number of T helper 2 (Th2) cells increased when PRR11 was overexpressed. These results confirm the role of PRR11 as a prognostic marker of lung adenocarcinoma by controlling the cell cycle and influencing the immune system to facilitate lung cancer progression.
		                        		
		                        		
		                        		
		                        			Humans
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		                        			Prognosis
		                        			;
		                        		
		                        			Adenocarcinoma of Lung/genetics*
		                        			;
		                        		
		                        			Lung Neoplasms/genetics*
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		                        			Biological Assay
		                        			;
		                        		
		                        			Cell Cycle
		                        			
		                        		
		                        	
3.Mortality trend of chronic respiratory diseases in China, 1990-2019.
Zheng LONG ; Wei LIU ; Jin Lei QI ; Yun Ning LIU ; Jiang Mei LIU ; Jin Ling YOU ; Lin LIN ; Li Jun WANG ; Mai Geng ZHOU ; Peng YIN
Chinese Journal of Epidemiology 2022;43(1):14-21
		                        		
		                        			
		                        			Objective: To analyze mortality and its trend of chronic respiratory diseases (CRD) in China from 1990 to 2019. Methods: Based on the provincial results of China from the 2019 Global Burden of Disease (GBD) study, the average annual percent change (AAPC) of standardized mortality rates of different CRDs were analyzed by using Joinpoint 4.8.0.1, and the age-standardized mortality rate of CRD was calculated by using the GBD 2019 world standard population. Based on the comparative risk assessment theory of GBD, the attributable deaths due to 12 CRD risk factors were estimated, including smoking, indoor air pollution, occupational gas exposure, particulates and smog exposure, environmental particulate pollution, low temperature, passive smoking, ozone pollution, occupational exposure to silica, occupational asthma, high body mass index, high temperature and occupational exposure to asbestos. Results: From 1990 to 2019, the number of deaths and standardized mortality of chronic obstructive pulmonary disease (COPD) showed a downward trend (P<0.001). The number of COPD deaths decreased from 1 244 000 (912 000 - 1 395 000) in 1990 to 1 037 000 (889 000 - 1 266 000) in 2019. AAPC=-0.9% (95%CI: -1.5% - -0.3%), P<0.001; The standardized mortality rate decreased from 217.9/100 000 (163.3/100 000 - 242.0/100 000) in 1990 to 65.2/100 000 (55.5/100 000 - 80.1/100 000) in 2019. AAPC= -4.2% (95%CI:-5.2% - -3.2%), P<0.001. The number of deaths from asthma decreased from 40 000 (30 000 - 58 000) in 1990 to 25 000 (20 000 - 31 000) in 2019. AAPC=-2.0% (95%CI: -2.6% - -1.4%), P<0.001; The standardized mortality rate of asthma decreased from 6.4/100 000 (4.7/100 000 - 9.5/100 000) in 1990 to 1.5/100 000 (1.2/100 000 - 1.9/100 000) in 2019. AAPC=-5.1% (95%CI: -5.8% - -4.4%), P<0.001. The number of pneumoconiosis deaths decreased from 11 000 (8 000 - 14 000) in 1990 to 10 000 (8 000 - 14 000) in 2019, AAPC=-0.2%(95%CI:-0.4% - 0.1%), P=0.200; The standardized mortality rate of pneumoconiosis decreased from 1.4/100 000 (1.0/100 000 - 1.7/100 000) in 1990 to 0.5/100 000 (0.4/100 000 - 0.7/100 000) in 2019. AAPC=-3.1% (95%CI: -3.4% - -2.8%), P<0.001. The number of deaths from pulmonary interstitial diseases and pulmonary sarcoidosis increased from 3 000 (3 000 - 6 000) in 1990 to 8 000 (6 000 - 10 000) in 2019, AAPC=3.5% (95%CI: 2.7% - 4.2%), P<0.001; The corresponding standardized mortality rate changed little from 1990 to 2019, and AAPC was not statistically significant.The age-standardized mortality rates of different CRDs were higher in men than those in women. In 1990 and 2019, the mortality rates of COPD, asthma, pneumoconiosis and interstitial pulmonary disease and pulmonary sarcoidosis increased with age. In 2019, the population attributable fractions (PAFs) for smoking, environmental particulate pollution, occupational gas exposure, particulate and smog exposure, low temperature exposure and passive smoking were 71.1% (68.0% - 74.3%), 24.7% (20.1% - 30.0%), 19.3% (13.0% - 25.4%), 15.7% (13.6% - 18.3%) and 8.8% (4.5% - 13.1%) respectively in men, and the PAFs for environmental particulate pollution, smoking, low temperature exposure, occupational gas exposure, particulate and smog exposure, and passive smoking were 24.1% (19.6% - 29.3%), 21.9% (18.7% - 25.2%), 16.4% (14.0% - 19.2%), 15.6% (10.2% - 21.1%) and 14.7% (7.9% - 21.3%) respectively in women. Conclusions: During 1990-2019, the overall death level of CRD decreased significantly in China, but it is still at high level in the world. Active prevention and control measures should be taken to reduce the death level caused by CRD.
		                        		
		                        		
		                        		
		                        			Asthma
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		                        			China/epidemiology*
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		                        			Female
		                        			;
		                        		
		                        			Global Burden of Disease
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Male
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		                        			Mortality
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		                        			Pulmonary Disease, Chronic Obstructive
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		                        			Quality-Adjusted Life Years
		                        			
		                        		
		                        	
4.Mechanism of Shengmai Injection on Anti-Sepsis and Protective Activities of Intestinal Mucosal Barrier in Mice.
Juan LU ; Yue YU ; Xiao-Jing WANG ; Rui-Ping CHAI ; Xin-Kai LYU ; Ming-Hui DENG ; Mei-Geng HU ; Yun QI ; Xi CHEN
Chinese journal of integrative medicine 2022;28(9):817-822
		                        		
		                        			OBJECTIVE:
		                        			To study the mechanism of Shengmai Injection (SMI, ) on anti-sepsis and protective activities of intestinal mucosal barrier.
		                        		
		                        			METHODS:
		                        			The contents of 11 active components of SMI including ginsenoside Rb1, Rb2, Rb3, Rd, Re, Rf, Rg1, Rg2, ophioposide D, schisandrol A and schisantherin A were determined using ultra-performance liquid chromatography. Fifty mice were randomly divided into the blank, the model, the low-, medium- and high-dose SMI groups (0.375, 0.75, 1.5 mL/kg, respectively) by random number table, 10 mice in each group. In SMI group, SMI was administrated to mice daily via tail vein injection for 3 consecutive days, while the mice in the blank and model groups were given 0.1 mL of normal saline. One hour after the last SMI administration, except the blank group, the mice in other groups were intraperitoneally injected with lipopolysaccharide (LPS) saline solution (2 mL/kg) at a dosage of 5 mL/kg for development of endotoxemia mice model. The mice in the blank group were given the same volume of normal saline. Inflammatory factors including interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), interleukin (IL)-2 and IL-10 were measured by flow cytometry. Myosin light-chain kinase (MLCK), nuclear factor κB (NF-κB) levels, and change of Occludin proteins in jejunum samples were analyzed by Western blot.
		                        		
		                        			RESULTS:
		                        			The decreasing trends of INF-γ, TNF-α and IL-2 were found in serum of SMI treatment groups. In SMI-treated mice, the content of Occludin increased and MLCK protein decreased compared with the model group (P<0.05 or P<0.01). The content of cellular and nuclear NF-κB did not change significantly (P>0.05).
		                        		
		                        			CONCLUSION
		                        			SMI may exert its anti-sepsis activity mainly through NF-κB-pro-inflammatory factor-MLCK-TJ cascade.
		                        		
		                        		
		                        		
		                        			Animals
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		                        			Drug Combinations
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		                        			Drugs, Chinese Herbal
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		                        			Mice
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		                        			NF-kappa B/metabolism*
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		                        			Occludin
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		                        			Saline Solution
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		                        			Sepsis/drug therapy*
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		                        			Tumor Necrosis Factor-alpha/metabolism*
		                        			
		                        		
		                        	
5.Hypertension Prevalence, Awareness, Treatment, and Control and Their Associated Socioeconomic Factors in China: A Spatial Analysis of A National Representative Survey.
Wei WANG ; Mei ZHANG ; Cheng Dong XU ; Peng Peng YE ; Yun Ning LIU ; Zheng Jing HUANG ; Cai Hong HU ; Xiao ZHANG ; Zhen Ping ZHAO ; Chun LI ; Xiao Rong CHEN ; Li Min WANG ; Mai Geng ZHOU
Biomedical and Environmental Sciences 2021;34(12):937-951
		                        		
		                        			Objective:
		                        			We aimed to investigate and interpret the associations between socioeconomic factors and the prevalence, awareness, treatment, and control of hypertension at the provincial level in China.
		                        		
		                        			Methods:
		                        			A nationally and provincially representative sample of 179,059 adults from the China Chronic Disease and Nutrition Surveillance study in 2015-2016 was used to estimate hypertension burden. The spatial Durbin error model was fitted to investigate socioeconomic factors associated with hypertension indicators.
		                        		
		                        			Results:
		                        			Overall, it was estimated that 29.20% of the participants were hypertensive nationwide, among whom, 34.32% were aware of their condition, 27.69% had received antihypertensive treatment, and 7.81% had controlled their condition. Per capita gross domestic product (GDP) was associated with hypertension prevalence (coefficient: -2.95, 95% 
		                        		
		                        			Conclusion
		                        			Hypertension indicators were not only directly influenced by socioeconomic factors of local area but also indirectly affected by characteristics of geographical neighbors. Population-level strategies should involve optimizing supportive socioeconomic environment by integrating clinical care and public health services to decrease hypertension burden.
		                        		
		                        		
		                        		
		                        			Adult
		                        			;
		                        		
		                        			Aged
		                        			;
		                        		
		                        			Aged, 80 and over
		                        			;
		                        		
		                        			China/epidemiology*
		                        			;
		                        		
		                        			Cross-Sectional Studies
		                        			;
		                        		
		                        			Female
		                        			;
		                        		
		                        			Health Knowledge, Attitudes, Practice
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Hypertension/psychology*
		                        			;
		                        		
		                        			Male
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		                        			Middle Aged
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		                        			Prevalence
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		                        			Socioeconomic Factors
		                        			;
		                        		
		                        			Spatial Analysis
		                        			;
		                        		
		                        			Young Adult
		                        			
		                        		
		                        	
6.Mortality and years of life lost of colorectal cancer in China, 2005-2020: findings from the national mortality surveillance system.
Wei WANG ; Peng YIN ; Yun-Ning LIU ; Jiang-Mei LIU ; Li-Jun WANG ; Jin-Lei QI ; Jin-Ling YOU ; Lin LIN ; Shi-Di MENG ; Fei-Xue WANG ; Mai-Geng ZHOU
Chinese Medical Journal 2021;134(16):1933-1940
		                        		
		                        			BACKGROUND:
		                        			Colorectal cancer (CRC) is the fourth cause of cancer death in China. We aimed to provide national and subnational estimates and changes of CRC premature mortality burden during 2005-2020.
		                        		
		                        			METHODS:
		                        			Data from multi-source on the basis of the national surveillance mortality system were used to estimate mortality and years of life lost (YLL) of CRC in the Chinese population during 2005-2020. Estimates were generated and compared for 31 provincial-level administrative divisions in China.
		                        		
		                        			RESULTS:
		                        			Estimated CRC deaths increased from 111.41 thousand in 2005 to 178.02 thousand in 2020; age-standardized mortality rate decreased from 10.01 per 100,000 in 2005 to 9.68 per 100,000 in 2020. Substantial reduction in CRC premature mortality burden, as measured by age-standardized YLL rate, was observed with a reduction of 10.20% nationwide. Marked differences were observed in the geographical patterns of provincial units, and they appeared to be obvious in areas with higher economic development. Population aging was the dominant driver which contributed to the increase in CRC deaths, followed by population growth and age-specific mortality change.
		                        		
		                        			CONCLUSIONS
		                        			Substantial discrepancies were observed in the premature mortality burden of CRC across China. Targeted considerations were needed to promote a healthy lifestyle, expand cost-effective CRC early screening and diagnosis, and improve medical treatment to reduce CRC mortality among high-risk populations and regions with inadequate healthcare resources.
		                        		
		                        		
		                        		
		                        			China/epidemiology*
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		                        			Colorectal Neoplasms
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		                        			Humans
		                        			
		                        		
		                        	
7.Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial.
Jie WU ; Shu-Wei DUAN ; Hong-Tao YANG ; Yue-Yi DENG ; Wei LI ; Ya-Ni HE ; Zhao-Hui NI ; Yong-Li ZHAN ; Shan LIN ; Zhi-Yong GUO ; Jun ZHU ; Jing-Ai FANG ; Xu-Sheng LIU ; Li-Hua WANG ; Rong WANG ; Nian-Song WANG ; Xiao-Hong CHENG ; Li-Qun HE ; Ping LUO ; Shi-Ren SUN ; Ji-Feng SUN ; Ai-Ping YIN ; Geng-Ru JIANG ; Hong-Yu CHEN ; Wen-Hu LIU ; Hong-Li LIN ; Meng LIANG ; Lu MA ; Ming CHEN ; Li-Qun SONG ; Jian CHEN ; Qing ZHU ; Chang-Ying XING ; Yun LI ; Ji-Ning GAO ; Rong-Shan LI ; Ying LI ; Hao ZHANG ; Ying LU ; Qiao-Ling ZHOU ; Jun-Zhou FU ; Qiang HE ; Guang-Yan CAI ; Xiang-Mei CHEN
Journal of Integrative Medicine 2021;19(2):111-119
		                        		
		                        			BACKGROUND:
		                        			Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease.
		                        		
		                        			OBJECTIVE:
		                        			This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium.
		                        		
		                        			DESIGN, SETTING, PARTICIPANTS AND INTERVENTION:
		                        			This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m
		                        		
		                        			MAIN OUTCOME MEASURES:
		                        			The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment.
		                        		
		                        			RESULTS:
		                        			A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group.
		                        		
		                        			CONCLUSION:
		                        			SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone.
		                        		
		                        			TRIAL REGISTRATION NUMBER
		                        			NCT02063100 on ClinicalTrials.gov.
		                        		
		                        		
		                        		
		                        	
8.Study on the relationship between health literacy and health status among residents in Qingdao
Rui WANG ; Xiao-rong JIA ; Shan-peng LI ; Ping HU ; Peng LIN ; Mei-yun GENG ; Ya-ni WANG ; Zhen-shi XU ; Fei QI
Chinese Journal of Disease Control & Prevention 2019;23(1):70-74
		                        		
		                        			
		                        			 Objective To analyze the status of health literacy and its relationship with chronic diseases and self-reported health among residents in Qingdao, discuss the influence of health literacy on health status and provide the scientific basis for the development of health education strategies and measures. Methods The stratified multistage and probability proportionate to population size sampling(PPS sampling) method was adopted in this investigation. In 2017, a questionnaire survey was conducted among 16 700 permanent residents aged 15-69 from 10 districts in Qingdao. Results  The overall level of health literacy status was 15.92%, the prevalence rate of chronic diseases was 19.31%, the self-reported health proportion of good, fair and poor were 81.68%, 12.12% and 1.71% among residents in Qingdao. Logistic regression analysis showed that, after adjusting for urban and rural areas, gender, age, education, income and occupation, health literacy was a protective factor for people with chronic diseases and self-evaluated health(OR=1.232,P=0.003;OR=1.159,P=0.033). Three aspects of health literacy were correlated with chronic diseases and self-reported health among people (all P<0.05). Conclusions  Health literacy is positively correlated with the health status of residents. The improvement of health literacy is an important way to enhance the health status of residents. 
		                        		
		                        		
		                        		
		                        	
9.Interferon-Gamma Release Assay is Not Appropriate for the Diagnosis of Active Tuberculosis in High-Burden Tuberculosis Settings: A Retrospective Multicenter Investigation.
Wan-Li KANG ; Gui-Rong WANG ; Mei-Ying WU ; Kun-Yun YANG ; A ER-TAI ; Shu-Cai WU ; Shu-Jun GENG ; Zhi-Hui LI ; Ming-Wu LI ; Liang LI ; Shen-Jie TANG
Chinese Medical Journal 2018;131(3):268-275
BACKGROUNDInterferon-gamma release assay (IGRA) has been used in latent tuberculosis (TB) infection and TB diagnosis, but the results from different high TB-endemic countries are different. The aim of this study was to investigate the value of IGRA in the diagnosis of active pulmonary TB (PTB) in China.
METHODSWe conducted a large-scale retrospective multicenter investigation to further evaluate the role of IGRA in the diagnosis of active PTB in high TB-epidemic populations and the factors affecting the performance of the assay. All patients who underwent valid T-SPOT.TB assays from December 2012 to November 2015 in six large-scale specialized TB hospitals in China and met the study criteria were retrospectively evaluated. Patients were divided into three groups: Group 1, sputum culture-positive PTB patients, confirmed by positive Mycobacterium tuberculosis sputum culture; Group 2, sputum culture-negative PTB patients; and Group 3, non-TB respiratory diseases. The medical records of all patients were collected. Chi-square tests and Fisher's exact test were used to compare categorical data. Multivariable logistic analyses were performed to evaluate the relationship between the results of T-SPOT in TB patients and other factors.
RESULTSA total of 3082 patients for whom complete information was available were included in the investigation, including 905 sputum culture-positive PTB cases, 914 sputum culture-negative PTB cases, and 1263 non-TB respiratory disease cases. The positive rate of T-SPOT.TB was 93.3% in the culture-positive PTB group and 86.1% in the culture-negative PTB group. In the non-PTB group, the positive rate of T-SPOT.TB was 43.6%. The positive rate of T-SPOT.TB in the culture-positive PTB group was significantly higher than that in the culture-negative PTB group (χ2 = 25.118, P < 0.01), which in turn was significantly higher than that in the non-TB group (χ2 = 566.116, P < 0.01). The overall results were as follows: sensitivity, 89.7%; specificity, 56.37%; positive predictive value, 74.75%; negative predictive value, 79.11%; and accuracy, 76.02%.
CONCLUSIONSHigh false-positive rates of T-SPOT.TB assays in the non-TB group limit the usefulness as a single test to diagnose active TB in China. We highly recommend that IGRAs not be used for the diagnosis of active TB in high-burden TB settings.
10. Comparative study on genotype distribution of HPV infection in the tissues of cervical squamous cell carcinoma and cervical adenocarcinoma
Cai-ge SHI ; Yun GU ; Jian-xiang GENG ; Xin GU ; Xue-mei FAN ; Xiao-lan XU ; Yu WANG ; Jing MEI ; Xue ZHAO
Journal of Medical Postgraduates 2018;31(8):840-843
		                        		
		                        			
		                        			 Objective There are few  large sample data reports of comparative study on genotype distribution of human papillomavirus (HPV) infection in the tissues of cervical squamous cell carcinoma and cervical adenocarcinoma in China. This study aimed to investigate the clinical value of genotype distribution of HPV infection in the tissues of cervical squamous cell carcinoma and cervical adenocarcinoma in regional (mainly in Jiangsu Province) patients.Methods We collected 1044 paraffin tissue specimens of female cervical squamous cell carcinoma (826 cases) and cervical adenocarcinoma (218 cases) in 29 hospitals from November 1978 to December 2017. HPV DNA was extracted from the tissues and through the combination of gene-chip and polymerase chain reaction technology, 23 genotypes of HPV were detected in all the tissues of cervical squamous cell carcinoma and cervical adenocarcinoma, and comparative study was conducted on the  genotype distribution of HPV infection.Results Among 1044 cases of cervical squamous cell carcinoma and cervical adenocarcinoma, 901 were found with HPV and the detection rate was 86.30%. The detection rate of cervical squamous cell carcinoma was 91.53% (756/826), among which 16,18,58,33,52,31 types were the most common and the detection rate of 16 type was significantly higher than that of 18 types (56.84% vs 9.93%, P<0.05). The detection rate of cervical adenocarcinoma was 66.51% (145/218), among which 16,18,31,33,52,58 types were the most common, and the detection rates of 16 type and 18 type was of no significant (35.29% vs 32.35%, P>0.05).Conclusion The HPV detection rates are different in the regional female cervical squamous cell carcinoma and cervical adenocarcinoma tissues. 16,18,31,33,52 and 58 types are the most common genotypes in cervical squamous cell carcinoma and cervical adenocarcinoma. The detection rate of 16 type is overly higher than that of 18 type in cervical squamous cell carcinoma, while the detection rates of 16 type and 18 type in cervical adenocarcinoma are very close. 
		                        		
		                        		
		                        		
		                        	
            
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