Detection of DNA methylation of HYAL2 gene for differentiating malignant from benign thyroid tumors / 南方医科大学学报

OBJECTIVE@#To assess the value of DNA methylation level of HYAL2 gene as a molecular marker for differential diagnosis of malignant and benign thyroid tumors.@*METHODS@#DNA methylation of HYAL2 gene in tissue specimens of 190 patients with papillary thyroid cancer (PTC) and 190 age- and gender-matched patients with benign thyroid tumors was examined by mass spectrometry, and the protein expression of HYAL2 was detected immunohistochemically for another 55 pairs of patients. Logistic regression analysis was performed to calculate the odds ratio (OR) and evaluate the correlation of per 10% reduction in DNA methylation with PTC. Receiver operating characteristic (ROC) curve analysis was performed and the area under curve (AUC) was calculated to assess the predictive value of alterations in HYAL2 methylation.@*RESULTS@#Hypomethylation of HYAL2_CpG_3 was significantly correlated with early-stage PTC (OR=1.51, P=0.001), even in stage I cancer (OR=1.42, P=0.007). Age-stratified analysis revealed a significantly stronger correlation between increased HYAL2_CpG_ 3 methylation and early-stage PTC in patients below 50 years than in those older than 50 years (OR: 1.89 vs 1.37, P < 0.05); ROC analysis also showed a larger AUC of 0.787 in younger patients. The results of immunohistochemistry showed that patients with PTC had significantly higher protein expressions of HYAL2 than patients with benign tumors.@*CONCLUSION@#The alterations of DNA methylation level of HYAL2 gene is significantly correlated with early-stage PTC, suggesting the value of DNA methylation level as a potential biomarker for differentiation of malignant from benign thyroid tumors.

Establishment and application of an artificial intelligence diagnosis system for pancreatic cancer with a faster region-based convolutional neural network / 中华医学杂志(英文版)

BACKGROUND@#Early diagnosis and accurate staging are important to improve the cure rate and prognosis for pancreatic cancer. This study was performed to develop an automatic and accurate imaging processing technique system, allowing this system to read computed tomography (CT) images correctly and make diagnosis of pancreatic cancer faster.@*METHODS@#The establishment of the artificial intelligence (AI) system for pancreatic cancer diagnosis based on sequential contrast-enhanced CT images were composed of two processes: training and verification. During training process, our study used all 4385 CT images from 238 pancreatic cancer patients in the database as the training data set. Additionally, we used VGG16, which was pre-trained in ImageNet and contained 13 convolutional layers and three fully connected layers, to initialize the feature extraction network. In the verification experiment, we used sequential clinical CT images from 238 pancreatic cancer patients as our experimental data and input these data into the faster region-based convolution network (Faster R-CNN) model that had completed training. Totally, 1699 images from 100 pancreatic cancer patients were included for clinical verification.@*RESULTS@#A total of 338 patients with pancreatic cancer were included in the study. The clinical characteristics (sex, age, tumor location, differentiation grade, and tumor-node-metastasis stage) between the two training and verification groups were insignificant. The mean average precision was 0.7664, indicating a good training effect of the Faster R-CNN. Sequential contrast-enhanced CT images of 100 pancreatic cancer patients were used for clinical verification. The area under the receiver operating characteristic curve calculated according to the trapezoidal rule was 0.9632. It took approximately 0.2 s for the Faster R-CNN AI to automatically process one CT image, which is much faster than the time required for diagnosis by an imaging specialist.@*CONCLUSIONS@#Faster R-CNN AI is an effective and objective method with high accuracy for the diagnosis of pancreatic cancer.@*TRIAL REGISTRATION@#ChiCTR1800017542; http://www.chictr.org.cn.

Deep neural network-assisted computed tomography diagnosis of metastatic lymph nodes from gastric cancer / 中华医学杂志(英文版)

BACKGROUND@#Artificial intelligence-assisted image recognition technology is currently able to detect the target area of an image and fetch information to make classifications according to target features. This study aimed to use deep neural networks for computed tomography (CT) diagnosis of perigastric metastatic lymph nodes (PGMLNs) to simulate the recognition of lymph nodes by radiologists, and to acquire more accurate identification results.@*METHODS@#A total of 1371 images of suspected lymph node metastasis from enhanced abdominal CT scans were identified and labeled by radiologists and were used with 18,780 original images for faster region-based convolutional neural networks (FR-CNN) deep learning. The identification results of 6000 random CT images from 100 gastric cancer patients by the FR-CNN were compared with results obtained from radiologists in terms of their identification accuracy. Similarly, 1004 CT images with metastatic lymph nodes that had been post-operatively confirmed by pathological examination and 11,340 original images were used in the identification and learning processes described above. The same 6000 gastric cancer CT images were used for the verification, according to which the diagnosis results were analyzed.@*RESULTS@#In the initial group, precision-recall curves were generated based on the precision rates, the recall rates of nodule classes of the training set and the validation set; the mean average precision (mAP) value was 0.5019. To verify the results of the initial learning group, the receiver operating characteristic curves was generated, and the corresponding area under the curve (AUC) value was calculated as 0.8995. After the second phase of precise learning, all the indicators were improved, and the mAP and AUC values were 0.7801 and 0.9541, respectively.@*CONCLUSION@#Through deep learning, FR-CNN achieved high judgment effectiveness and recognition accuracy for CT diagnosis of PGMLNs.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry, No. ChiCTR1800016787; http://www.chictr.org.cn/showproj.aspx?proj=28515.

Artificial intelligence system of faster region-based convolutional neural network surpassing senior radiologists in evaluation of metastatic lymph nodes of rectal cancer / 中华医学杂志(英文版)

BACKGROUND@#An artificial intelligence system of Faster Region-based Convolutional Neural Network (Faster R-CNN) is newly developed for the diagnosis of metastatic lymph node (LN) in rectal cancer patients. The primary objective of this study was to comprehensively verify its accuracy in clinical use.@*METHODS@#Four hundred fourteen patients with rectal cancer discharged between January 2013 and March 2015 were collected from 6 clinical centers, and the magnetic resonance imaging data for pelvic metastatic LNs of each patient was identified by Faster R-CNN. Faster R-CNN based diagnoses were compared with radiologist based diagnoses and pathologist based diagnoses for methodological verification, using correlation analyses and consistency check. For clinical verification, the patients were retrospectively followed up by telephone for 36 months, with post-operative recurrence of rectal cancer as a clinical outcome; recurrence-free survivals of the patients were compared among different diagnostic groups, by methods of Kaplan-Meier and Cox hazards regression model.@*RESULTS@#Significant correlations were observed between any 2 factors among the numbers of metastatic LNs separately diagnosed by radiologists, Faster R-CNN and pathologists, as evidenced by rradiologist-Faster R-CNN of 0.912, rPathologist-radiologist of 0.134, and rPathologist-Faster R-CNN of 0.448 respectively. The value of kappa coefficient in N staging between Faster R-CNN and pathologists was 0.573, and this value between radiologists and pathologists was 0.473. The 3 groups of Faster R-CNN, radiologists and pathologists showed no significant differences in the recurrence-free survival time for stage N0 and N1 patients, but significant differences were found for stage N2 patients.@*CONCLUSION@#Faster R-CNN surpasses radiologists in the evaluation of pelvic metastatic LNs of rectal cancer, but is not on par with pathologists.@*TRIAL REGISTRATION@#www.chictr.org.cn (No. ChiCTR-DDD-17013842).

Single-incision versus conventional laparoscopic cholecystectomy: a meta-analysis / 中华外科杂志

<p><b>OBJECTIVE</b>To study feasibility and security of single-incision laparoscopic cholecystectomy (SILC).</p><p><b>METHODS</b>Clinical trials comparing SILC with conventional laparoscopic cholecystectomy (LC) for benign gallbladder disease published from 2010 to 2012 were retrieved. A meta-analysis was conducted to evaluate operative time, blood loss, conversion rate, post-operative pain, wound satisfaction score, post-operative hospital stay and post-operative complications between SILC group and LC group. A fixed effect model or random effect model was established to collect the data.</p><p><b>RESULTS</b>Eleven random clinical trials on 859 patients qualified for the meta-analysis, 449 patients being allocated to SILC and 410 patients to LC. There was no significant difference between SILC group and LC group for blood loss, conversion rate, post-operative pain, post-operative hospital stay and post-operative complications. However, operative time was significantly longer in SILC group than LC group (IV = 16.66, 95%CI: 9.60 - 23.72, Z = 4.62, P = 0.00). Furthermore, wound satisfaction score was significantly higher in SILC group than in LC group (IV = 0.95, 95%CI: 0.56 - 1.34, Z = 4.76, P = 0.00).</p><p><b>CONCLUSIONS</b>SILC may be superior to LC in terms of cosmetic outcome, but not in operative time. Currently, SILC is a safe procedure for proper patients in experienced surgeons.</p>

Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Dihydropyrimidine dehydrogenase (DPD), a key enzyme involved in the catabolism of 5-fluorouracil (5-FU), is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene (DPYD) and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.</p><p><b>METHODS</b>Three hundred and sixty-two patients with gastric cancer in the Chinese population were treated with fluorouracil-based adjuvant chemotherapy. The single nucleotide polymorphic genotypes of DPYD were determined by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) using DNA samples isolated from peripheral blood collected before treatment.</p><p><b>RESULTS</b>The average response rate for chemotherapy was 46.7%. A significantly different distribution of the rs1801159 (c2=8.76, P=0.012) genotypes was observed. Homozygous genotype rs1801159A/A was over-represented in responsive patients. Conversely, carriers of the rs1801159A/G genotype were prevalent in non-responsive patients. In the haplotype association analysis, there was significant difference in global haplotype distribution between the groups (c2=3.96, P=0.0465).</p><p><b>CONCLUSIONS</b>These results suggest that polymorphisms of rs1801159 in DPYD may be used as valuable predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in the Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of DPYD as predictive markers for gastric cancer in response to fluorouracil-based therapies are warranted.</p>

Association of TGFB1 gene polymorphism -509C/T with disease severity in childhood allergic rhinitis / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the association between the promoter polymorphism -509C/T of the transforming growth factor-β1 gene (TGFB1) and the disease severity of allergic rhinitis (AR) in childhood.</p><p><b>METHODS</b>A total of 96 Chinese patients with persistent AR aged 3 - 17 (9.4 ± 3.8) years old were enrolled in the study. Among these patients 53.1% were mild cases (n = 51) and 46.9% were moderate-to-severe cases (n = 45). Genotyping was performed on peripheral blood genomic DNA by using PCR-RFLP. Serum levels of TGF-β1 was measured by ELISA, and serum total IgE, specific IgE and eosinophil cationic protein (ECP) levels were determined using an ImmunoCAP100E system. Statistical analysis was conducted with SPSS11.0 software.</p><p><b>RESULTS</b>Significant differences were found in genotype frequencies for the TGFB1-509C/T polymorphism between mild and moderate-to-severe AR patients (χ(2) = 8.361, P = 0.015). Children with persistent AR bearing the TT genotype of the -509C/T polymorphism had significantly increased risk for moderate-to-severe AR (Fisher's exact test, P = 0.007) compared to children with the CC/CT genotypes. There was no significant association between the -509C/T polymorphism and serum TGF-β1 levels (F = 0.389, P = 0.679); however, serum total IgE (F = 4.210, P = 0.018) and ECP (H = 6.297, P = 0.043) levels were found to be significantly associated with the polymorphism.</p><p><b>CONCLUSION</b>The results suggest that the TGFB1 gene polymorphism -509C/T may play a potential role in the severity of persistent AR in childhood.</p>

Study on the dose-response relationships between the drinking water fluoride and bone mineral density, and serum osteocalcin / 中国地方病学杂志

Objective To analyze the relationships between the drinking water fluoride and bone mineral density (BMD), and serum osteocalcin (BGP) and to explore the BMD and serum BGP as significant early screening biomarkers for fluorosis especially for early bone damage in endemic fluorosis areas. Methods Wamiao (severe endemic fluorosis area, as fluoride exposed group) and Xinhuai (non endemic fluorosis area, as control group) Village were selected in 2006. One hundred and fouty-six objects were chosen from 2 villages (103 in Wamiao, 43 in Xinhuai). The sex, age, body height, body weight, drinking water fluoride in each object's household well, BMD, and serum BGP were investigated, and the dose-response relationships were analyzed between the drinking water fluoride and BMD, and serum BGP. CurveExpert 1.3 Software was used to fit the dose-response relationships between the rate of abnormal BMD, the rate of abnormal serum BGP, and the drinking water fluoride. Results The levels of drinking water fluoride in males' and females' families in fluoride exposed group were [(2.38±0.68), (2.62±0.91 )mg/L] significant higher than that in control group [(0.35±0.08), (0.36±0.07)mg/L], the difference being statistically significant(t values were 14.27 and 11.08,and P<0.01, respectively). BMD in males in fluoride exposed group [(0.78±0.07)g/cm2] was significant lower than that in control group[(0.83±0.08)g/cm2], the difference being statistically significant (t=2.37,P<0.05). Serum BGP in males and females in fluoride exposed group [(4.17±0.67), (4.11±0.57) μg/L] were significant higher than that in control group [(1.48±0.40), (1.44±0.39)μg/L], the difference being statistically significant (t values were 17.64 and 19.40, and P<0.01, respectively]. BMD in the group with drinking water fluoride≥2.92 mg/L[(0.66±0.15 )g/cm2] was significant lower than that in the group with drinking water fluoride<0.42 mg/L [(0.76±0.12)g/cm2], the difference being statistically significant (P<0.01). The levels of serum BGP in the groups with the drinking water 0.42-,2.05-, ≥.92 mg/L[(3.83±1.07), (4.22±0.72), (3.99±0.63) μg/L] were significant higher than that in the group with the drinking water<0.42 mg/L [(1.44±0.37) μg/L], the difference being statistically significant (P<0.01). The equation for the dose-response relationship between the drinking water fluoride and the rate of abnormal BMD was y=(0.284-0.058x)-1.260, r=0.999 94; and y=100.05/(1+78.62e-4.5x), r=0.999 99 for the drinking water fluoride and the rate of abnormal serum BGP. Conclusions There were significant dose-response relationships between drinking water fluoride and BMD and serum BGP. It indicated that BMD and BGP might be considered as early screening biomarkers for endemic fluorosis, especially for the bone damage.

Relationship between FAS/FASL gene polymorphisms and susceptibility of coal worker's pneumoconiosis / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the effects of FAS and FASL gene polymorphisms on genetic susceptibility of coal worker's pneumoconiosis and their relationship to the pulmonary fibrosis.</p><p><b>METHODS</b>340 with coal worker's pneumoconiosis (CWP) and 312 coal mine workers (controls) exposed to the coal dusts were selected. FAS-1377G > A, FAS-670A > G and FASL-844T > C gene polymorphisms were analyzed by PCR-RFLP techniques.</p><p><b>RESULTS</b>The distribution frequencies of genotypes of FAS-1377, FAS-670, FASL-844 genotypes in CWP had no significant differences compared to the control. Compared to CWP patients with exposure year > or = 25, the risk of pneumoconiosis with FAS-1377 GA/AA genotype was significantly higher than those with FAS-1377GG in the patients working age < 25 years (P = 0.098, 95% CI: 0.932 approximately 2.298); the risk of CWP in those with FAS-670AG genotype was higher than those with FAS-670GG genotype (P = 0.098, 95% CI: 0.928 approximately 2.404) the risks of CWP in those with FASL-844TT genotype and FASL-844TC genotype were respectively higher than those with FASL-844CC genotype (P = 0.039, 95% CI: 1.088 approximately 27.358, P = 0.089, 95% CI: 0.852 approximately 2.101). The frequencies of genotypes of FASL-844T > C were significantly different between CWP patients with exposure year > or = 25 and < 25. The risk of CWP with FASL-844TT genotype was significantly higher than that of FASL-844TT + TC (P = 0.054, 95% CI: 0.971 approximately 23.833). The risk of CWP patients with FASL-844TT/CT + FAS-1377GA genotype was 1.810-fold than the patients with FASL-844CC + FAS-1377GG genotype. The risk of CWP patients with FASL-844TT/CT + FAS-670AG genotype was 2.117-fold than the patients with FASL-844CC + FAS-670AA genotype. The risk of CWP patients with FASL-844TT/TC + FAS-1377GA/AA + FAS-670AG/GG genotype was 2.043-fold than the patients with FASL-844CC + FAS-1377GG+FAS-670AA genotype.</p><p><b>CONCLUSION</b>FAS-1377G > A, FAS-670A > G and FASL-844T > C gene polymorphisms may not be associated with the susceptibility of CWP in Han nationality, but these three gene polymorphisms and their joint actions may influence on the progression of CWP.</p>

The role of reactive oxygen species in N-4-hydroxyphenyl retinamide induced apoptosis in bladder cancer cell lineT24 / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To study the mechanism of the apoptosis induced by N-[4-hydroxyphenyl] retinamide (4-HPR) in bladder cancer cell line T24, and the involvement of DNA damage and repair.</p><p><b>METHODS</b>T24 cells were treated with 4-HPR at the concentration of 2.5, 5.0 and 10.0 micromol/L, and the cell grow inhibition was measured by cell counting assay. The fluorescent intensity of reactive oxygen species (ROS) was determined by spectrofluorometer. The apoptosis was measured by flow cytometry and DNA fragment assay. The expression of XRCC1 protein and activation of caspase-3 were detected by Western blot.</p><p><b>RESULTS</b>4-HPR induced apoptosis in T24 cell. A dose-dependent increase in the percentage of apoptosis cells was observed (1.8%, 4.0% and 10.5% respectively at 2.5, 5.0, 10.0 micromol/L 4HPR). In the meantime, ROS level in the cell was increased (peaked at 3 fold). It also caused down-regulation of the expression of XRCC1, and activation of caspase-3. Vitamin C effectively inhibited ROS rise induced by 4-HPR, and also partially inhibited cell growth, apoptosis, and down-regulation of the expression of XRCC1.</p><p><b>CONCLUSION</b>The generation of ROS and DNA damage may be the major mechanism of the apoptosis of bladder cancer cell line T24 induced by 4-HPR.</p>