Although the artificial intelligence diagnosis technology of traditional Chinese medicine(TCM)is constantly developing,the existing intelligent syndrome differentiation models can only output the diagnosis results and cannot display the reasoning process of TCM diagnosis.They do not have the interpretability of TCM diagnostic knowledge and are difficult to truly reflect the process of TCM's syndrome differentiation.This can be a long-standing problem that has puzzled the academic community.This article elaborates on the development process and technical characteristics of intelligent diagnosis in traditional Chinese medicine,explores multiple key technologies and bottlenecks in current research in reasoning of TCM's Syndrome Differentiation,and factors affecting diagnosis.A novel intelligent diagnosis model architecture that can infer and explain the process of TCM'ssyndrome differentiation was proposed,and the implementation process of the model and algorithm was explained,and detailed data instance analysis was conducted.This article will provide new methods for the development of intelligent syndrome differentiation of TCM and open up new research ideas for clinical decision-making assistance of TCM.

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.
Humans ; Neoplasms/pathology* ; Biomarkers ; Prognosis ; Oceans and Seas ; China/epidemiology*

Objective:To investigate the epidemiological characteristics, diagnosis, treat-ment and prognosis of gallbladder cancer in China from 2010 to 2017.Methods:The single disease retrospective registration cohort study was conducted. Based on the concept of the real world study, the clinicopathological data, from multicenter retrospective clinical data database of gallbladder cancer of Chinese Research Group of Gallbladder Cancer (CRGGC), of 6 159 patients with gallbladder cancer who were admitted to 42 hospitals from January 2010 to December 2017 were collected. Observation indicators: (1) case resources; (2) age and sex distribution; (3) diagnosis; (4) surgical treatment and prognosis; (5) multimodality therapy and prognosis. The follow-up data of the 42 hospitals were collected and analyzed by the CRGGC. The main outcome indicator was the overall survival time from date of operation for surgical patients or date of diagnosis for non-surgical patients to the end of outcome event or the last follow-up. Measurement data with normal distribu-tion were represented as Mean±SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and com-parison between groups was conducted using the U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Univariate analysis was performed using the Logistic forced regression model, and variables with P<0.1 in the univariate analysis were included for multivariate analysis. Multivariate analysis was performed using the Logistic stepwise regression model. The life table method was used to calculate survival rates and the Kaplan-Meier method was used to draw survival curves. Log-rank test was used for survival analysis. Results:(1) Case resources: of the 42 hospitals, there were 35 class A of tertiary hospitals and 7 class B of tertiary hospitals, 16 hospitals with high admission of gallbladder cancer and 26 hospitals with low admission of gallbladder cancer, respectively. Geographical distribution of the 42 hospitals: there were 9 hospitals in central China, 5 hospitals in northeast China, 22 hospitals in eastern China and 6 hospitals in western China. Geographical distribution of the 6 159 patients: there were 2 154 cases(34.973%) from central China, 705 cases(11.447%) from northeast China, 1 969 cases(31.969%) from eastern China and 1 331 cases(21.611%) from western China. The total average number of cases undergoing diagnosis and treatment in hospitals of the 6 159 patients was 18.3±4.5 per year, in which the average number of cases undergoing diagnosis and treatment in hospitals of 4 974 patients(80.760%) from hospitals with high admission of gallbladder cancer was 38.8±8.9 per year and the average number of cases undergoing diagnosis and treatment in hospitals of 1 185 patients(19.240%) from hospitals with low admission of gallbladder cancer was 5.7±1.9 per year. (2) Age and sex distribution: the age of 6 159 patients diagnosed as gallbladder cancer was 64(56,71) years, in which the age of 2 247 male patients(36.483%) diagnosed as gallbladder cancer was 64(58,71)years and the age of 3 912 female patients(63.517%) diagnosed as gallbladder cancer was 63(55,71)years. The sex ratio of female to male was 1.74:1. Of 6 159 patients, 3 886 cases(63.095%) were diagnosed as gallbladder cancer at 56 to 75 years old. There was a significant difference on age at diagnosis between male and female patients ( Z=-3.99, P<0.001). (3) Diagnosis: of 6 159 patients, 2 503 cases(40.640%) were initially diagnosed as gallbladder cancer and 3 656 cases(59.360%) were initially diagnosed as non-gallbladder cancer. There were 2 110 patients(34.259%) not undergoing surgical treatment, of which 200 cases(9.479%) were initially diagnosed as gallbladder cancer and 1 910 cases(90.521%) were initially diagnosed as non-gallbladder cancer. There were 4 049 patients(65.741%) undergoing surgical treatment, of which 2 303 cases(56.878%) were initially diagnosed as gallbladder cancer and 1 746 cases(43.122%) were initial diagnosed as non-gallbladder cancer. Of the 1 746 patients who were initially diagnosed as non-gallbladder cancer, there were 774 cases(19.116%) diagnosed as gallbladder cancer during operation and 972 cases(24.006%) diagnosed as gallbladder cancer after operation. Of 6 159 patients, there were 2 521 cases(40.932%), 2 335 cases(37.912%) and 1 114 cases(18.087%) undergoing ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) examination before initial diagnosis, respec-tively, and there were 3 259 cases(52.914%), 3 172 cases(51.502%) and 4 016 cases(65.205%) undergoing serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis, respectively. One patient may underwent multiple examinations. Results of univariate analysis showed that geographical distribution of hospitals (eastern China or western China), age ≥72 years, gallbladder cancer annual admission of hospitals, whether undergoing ultrasound, CT, MRI, serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis were related factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.45, 1.98, 0.69, 0.68, 2.43, 0.41, 1.63, 0.41, 0.39, 0.42, 95% confidence interval as 1.21-1.74, 1.64-2.40, 0.59-0.80, 0.60-0.78, 2.19-2.70, 0.37-0.45, 1.43-1.86, 0.37-0.45, 0.35-0.43, 0.38-0.47, P<0.05). Results of multivariate analysis showed that geographical distribution of hospitals (eastern China or western China), sex, age ≥72 years, gallbladder cancer annual admission of hospitals and cases undergoing ultrasound, CT, serum CA19-9 examination before initially diagnosis were indepen-dent influencing factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.36, 1.42, 0.89, 0.67, 1.85, 1.56, 1.57, 0.39, 95% confidence interval as 1.13-1.64, 1.16-1.73, 0.79-0.99, 0.57-0.78, 1.60-2.14, 1.38-1.77, 1.38-1.79, 0.35-0.43, P<0.05). (4) Surgical treatment and prognosis. Of the 4 049 patients undergoing surgical treatment, there were 2 447 cases(60.435%) with complete pathological staging data and follow-up data. Cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb were 85(3.474%), 201(8.214%), 71(2.902%), 890(36.371%), 382(15.611%), 33(1.348%) and 785(32.080%), respectively. The median follow-up time and median postoperative overall survival time of the 2 447 cases were 55.75 months (95% confidence interval as 52.78-58.35) and 23.46 months (95% confidence interval as 21.23-25.71), respectively. There was a significant difference in the overall survival between cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb ( χ2=512.47, P<0.001). Of the 4 049 patients undergoing surgical treatment, there were 2 988 cases(73.796%) with resectable tumor, 177 cases(4.371%) with unresectable tumor and 884 cases(21.833%) with tumor unassessable for resectabi-lity. Of the 2 988 cases with resectable tumor, there were 2 036 cases(68.139%) undergoing radical resection, 504 cases(16.867%) undergoing non-radical resection and 448 cases(14.994%) with operation unassessable for curative effect. Of the 2 447 cases with complete pathological staging data and follow-up data who underwent surgical treatment, there were 53 cases(2.166%) with unresectable tumor, 300 cases(12.260%) with resectable tumor and receiving non-radical resection, 1 441 cases(58.888%) with resectable tumor and receiving radical resection, 653 cases(26.686%) with resectable tumor and receiving operation unassessable for curative effect. There were 733 cases not undergoing surgical treatment with complete pathological staging data and follow-up data. There was a significant difference in the overall survival between cases not undergoing surgical treatment, cases undergoing surgical treatment for unresectable tumor, cases undergoing non-radical resection for resectable tumor and cases undergoing radical resection for resectable tumor ( χ2=121.04, P<0.001). (5) Multimodality therapy and prognosis: of 6 159 patients, there were 541 cases(8.784%) under-going postoperative adjuvant chemotherapy and advanced chemotherapy, 76 cases(1.234%) under-going radiotherapy. There were 1 170 advanced gallbladder cancer (pathological staging ≥stage Ⅲa) patients undergoing radical resection, including 126 cases(10.769%) with post-operative adjuvant chemotherapy and 1 044 cases(89.231%) without postoperative adjuvant chemo-therapy. There was no significant difference in the overall survival between cases with post-operative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.23, P=0.629). There were 658 patients with pathological staging as stage Ⅲa who underwent radical resection, including 66 cases(10.030%) with postoperative adjuvant chemotherapy and 592 cases(89.970%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.05, P=0.817). There were 512 patients with pathological staging ≥stage Ⅲb who underwent radical resection, including 60 cases(11.719%) with postoperative adjuvant chemotherapy and 452 cases(88.281%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemo-therapy and cases without post-operative adjuvant chemo-therapy ( χ2=1.50, P=0.220). Conclusions:There are more women than men with gallbladder cancer in China and more than half of patients are diagnosed at the age of 56 to 75 years. Cases undergoing ultrasound, CT, serum CA19-9 examination before initial diagnosis are independent influencing factors influencing initial diagnosis of gallbladder cancer patients. Preoperative resectability evaluation can improve the therapy strategy and patient prognosis. Adjuvant chemotherapy for gallbladder cancer is not standardized and in low proportion in China.

Objective:To explore the molecular pathogenesis of hereditary protein C (PC) deficiency due to a p. Gly86Asp variant of the PROC gene through in vitro expression experiment.Methods:Wild type and Gly86Asp mutant expression plasmids of PC were constructed and respectively transfected into HEK 293FT cells. Total RNA was extracted from the transfected cells, and the expression of PROC gene was determined by quantitative real-time PCR (qRT-PCR). PC antigen (PC: Ag) in the supernatant of cell culture and cell lysate was determined by enzyme-linked immunosorbent assay (ELISA), and the level of PC protein was detected by Western blotting. Results:qRT-PCR has detected no significant difference in the transcription level of wild-type and mutant-type PC. Compared with the wild type, the level of mutant PC: Ag in the supernatant and cell lysate were 81.3%±2.6% and 110.0%±2.8%, respectively. No difference was detected in the molecular weight between the wild-type and mutant-type PC by Western blotting. The PC content of mutant type was higher than wild-type in cell lysate, while the opposite was found with the cell culture supernatant.Conclusion:The impaired secretion by mutant PC may be the molecular mechanism of PC deficiency caused by the p.

Objective:To evaluate the testing capacity of HIV-1 viral load testing laboratories, and to provide data references for further improving the accuracy of laboratory test result in China.Methods:The test result of 155 positive samples distributed by the National AIDS Reference Laboratory to each laboratory from 2005 to 2019 were summarized and grouped according to the test assay and sample number. The independent sample t-test was used to evaluate the economic status and the proficiency testing (PT) assessment period on the stability of the test results. And, one-way analysis of variance was used to evaluate the influence of the types of laboratories and reagents on the stability of test results.Results:The number of HIV-1 viral load testing laboratories increased from 13 in 2005 to 267 in 2019. The participating institutions were mainly centers for disease control and prevention(CDC)and hospitals. Since 2015, the excellent rate of laboratories has remained above 85%, and the unqualified rate has remained below 3%. The associated factor analysis showed that the laboratory testing stability of HIV-1 viral load associated with the PT assessment period and the types of testing reagents, and the laboratories participating in the PT assessment for more than 5 years showed better stability.Conclusions:Participating in the annual proficiency testing program helped improve the laboratory capability of HIV-1 viral load testing in China.

Objective:The purpose of this study is to use the next-generation sequencing (NGS) technology platform to detect the methylation rate of phosphatase and tensin homolog deleted on chromosome ten ( PTEN) promoter region in hepatocellular carcinoma (HCC) tissue samples, and to analyze the clinical significance of its correlation with the prognosis of patients receiving sorafenib treatment. Methods:The 52 pairs of tumor tissue and para-cancerous tissue samples from HCC patients treated with sorafenib alone, which were collected and preserved in the Liver Tumor Diagnosis and Research Center of the former 302 Hospital of the People′s Liberation Army by the National Natural Science Foundation of China Youth Project with the project batch number 81702986 in 2018, were extracted total DNA from the samples. Then the DNA samples were treated with bisulfite and specific primers were designed to amplify the PTEN promoter region. Finally, the amplified products were analyzed by second-generation sequencing. In the analysis of clinical significance of PTEN methylation, log-rank statistical analysis was used to calculate whether there was a statistical difference in survival between the patient groups. Results:The methylation rate of PTEN promoter region in tumor tissues (29.17%±9.58%) was significantly higher than that in paracancer tissues (4.17%±2.86%)( t=19.970, P<0.05). At the same time, in HCC tissues, the methylation rate of the PTEN promoter region is negatively correlated with its expression ( F=47.270, P<0.000 1; Y=-1 800× X+38.03), and the PTEN methylation rate is negatively correlated with the prognosis of patients receiving the molecularly targeted drug Sorafenib (χ2=4.313, P<0.05). Conclusion:This study successfully established a new method for detecting methylation in the promoter region of PTEN, and the methylation rate of PTEN can be used as one of the targets of HCC diagnosis and targeted therapy.

Objective:The purpose of this study is to use the next-generation sequencing (NGS) technology platform to detect the methylation rate of phosphatase and tensin homolog deleted on chromosome ten ( PTEN) promoter region in hepatocellular carcinoma (HCC) tissue samples, and to analyze the clinical significance of its correlation with the prognosis of patients receiving sorafenib treatment. Methods:The 52 pairs of tumor tissue and para-cancerous tissue samples from HCC patients treated with sorafenib alone, which were collected and preserved in the Liver Tumor Diagnosis and Research Center of the former 302 Hospital of the People′s Liberation Army by the National Natural Science Foundation of China Youth Project with the project batch number 81702986 in 2018, were extracted total DNA from the samples. Then the DNA samples were treated with bisulfite and specific primers were designed to amplify the PTEN promoter region. Finally, the amplified products were analyzed by second-generation sequencing. In the analysis of clinical significance of PTEN methylation, log-rank statistical analysis was used to calculate whether there was a statistical difference in survival between the patient groups. Results:The methylation rate of PTEN promoter region in tumor tissues (29.17%±9.58%) was significantly higher than that in paracancer tissues (4.17%±2.86%)( t=19.970, P<0.05). At the same time, in HCC tissues, the methylation rate of the PTEN promoter region is negatively correlated with its expression ( F=47.270, P<0.000 1; Y=-1 800× X+38.03), and the PTEN methylation rate is negatively correlated with the prognosis of patients receiving the molecularly targeted drug Sorafenib (χ2=4.313, P<0.05). Conclusion:This study successfully established a new method for detecting methylation in the promoter region of PTEN, and the methylation rate of PTEN can be used as one of the targets of HCC diagnosis and targeted therapy.

JS001 (toripalimab) is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1 (PD1). In this study, we used a different iodine isotype (I) to label JS001 probes to target the human PD1 (hPD1) antigen. , the half maximal effective concentration (EC) value of I-JS001 did not significantly differ from that of JS001. The uptake of I-JS001 by activated T cells was 5.63 times higher than that by nonactivated T cells after 2 h of incubation. The binding affinity of I-JS001 to T cells of different lineages after phytohemagglutinin (PHA) stimulation reached 4.26 nmol/L. Humanized C57BL/6 mice bearing mouse sarcoma S180 cell tumors were validated for immuno-positron emission tomography (immuno-PET) imaging. Pathological staining was used to assess the expression of PD1 in tumor tissues. The homologous Ihuman IgG (IhIgG) group or blocking group was used as a control group. Immuno-PET imaging showed that the uptake in the tumor area of the I-JS001 group at different time points was significantly higher than that of the blocking group or the I-hIgG group in the humanized mouse model. Taken together, these results suggest that this radiotracer has potential for noninvasive monitoring and directing tumor-specific personalized immunotherapy in PD1-positive tumors.

Objective To study the effects of simple portal hypertension on the endotoxin levels in serum and intestinal mucosa of rats. Methods A total of 16 rats were divided into the blank control group (4 rats) and the model groups (3-day group, 7-day group and 10-day group, 4 rats in each group). The rat model of partial portal vein ligation was established in the model groups, and samples of blood and jejunum, ileum and colon of the rats were taken on the 3rd, 7th and 10th days, respectively. Changes in the serum endotoxin levels were detected by ELISA. Histopathological changes of the intestinal tissues were examined by HE staining. Results The rat model of partial portal vein ligation was successfully established in all the model groups. The serum levels of endotoxin on the 3rd, 7th and 10th days in the model groups were not significantly different from that in the normal control group. Damages of different intestinal segments were not serious on the 3rd day after modeling. However, on the 7th day after modeling, there were some sowllen and damaged intestinal villi in the intestinal mucosa of each intestinal segment, and the connection between the epithelial cells and the lamina propria was broken, compared with that at 3 days after modeling. In addition, there were obvious damages in the intestinal mucosa and lamina propria on the 10th day, compared with that at 3 d and 7 d after modeling. Conclusions In the case of normal liver function, portal hypertension can cause intestinal mucosal damages within a short period of time, but the amount of endotoxin produced by intestine does not exceed the processing capacity of the liver and thus does not cause an increase in the serum endotoxin level.

Objective BALB/c mutant curly mice and normal BALB/c mice were genetically detected by microsatellite DNA marker analysis to detect the differential microsatellite loci between BALB/c mutant curly mice and normal mice.Methods 38 microsatellite DNA loci were selected and their variation in the BALB/c mutant curly mice, BALB/c mutant hairless mice and normal BALB/c mice were detected by multiplex fluorescence PCR and STR scanning genotyping.Results There were 27 the same microsatellite loci between the 38 microsatellite loci in BALB/c mutant curly mice and normal mice,and there were 11 differential loci, with a mutation rate of 28.9%(11/38). There were 30 the same sites between BABL/c mutant hairless mice and normal mice,and there were 8 different loci,with a mutation rate of 21.1%(8/38). There were also 12 differential loci between BABL/c mutant curly mice and hairless mice. Conclusions BALB/c mutant curly mice have a higher mutation rate and are significantly higher than those of hairless mice,demonstrating that the mutations in curly mice and hairless mice are two completely different mutations. These results provide reliable theoretical data for the future study and development of BALB/c mutant curly mice.