Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Objective To compare the value of Child-Pugh score, Model for End-Stage Liver Disease (MELD) score, MELD combined with serum sodium concentration (MELD-Na) score, CLIF Consortium Acute Decompensation (CLIF-C AD) score, and Freiburg index of post-transjugular intrahepatic portosystemic shunt (TIPS) survival (FIPS) score in predicting the survival of patients undergoing TIPS. Methods A retrospective analysis was performed for the clinical data of 447 patients with liver cirrhosis who underwent TIPS in several hospitals in southwest China, among whom there were 306 patients in the survival group and 62 in the death group. The scores of the above five models were calculated, and a survival analysis was performed based on these models. The independent samples t -test was used for comparison of normally distributed continuous data between groups, and the non-parametric Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the Pearson chi-square test was used for comparison of categorical data between groups; a multivariate Cox regression analysis was used for correction analysis of known influencing factors with statistical significance which were not included in the scoring models; the Kaplan-Meier method was used to evaluate the discriminatory ability of each model in identifying risks in the surgical population, and the log-rank test was used for analysis. The area under the receiver operating characteristic curve (AUC), C-index at different time points, and calibration curve were used to evaluate the predictive ability of each scoring model. Results Compared with the death group, the survival group had significantly lower age ( Z =2.884, P < 0.05), higher albumin ( t =3.577, P < 0.05), and Na + ( Z =-3.756, P < 0.05) and significantly lower proportion of patients with alcoholic cirrhosis ( χ 2 =22.674, P < 0.05), aspartate aminotransferase ( Z =2.141, P < 0.05), prothrombin time ( Z =2.486, P < 0.05), international normalized ratio ( Z =2.429, P < 0.05), total bilirubin ( Z =3.754, P < 0.05), severity of ascites ( χ 2 =14.186, P < 0.05), and scores of the five models (all P < 0.05). Survival analysis showed that all scoring models effectively stratified the prognostic risk of the patients undergoing TIPS. Comparison of the C-index of each scoring model at different time points showed that Child-Pugh score had the strongest ability in predicting postoperative survival, followed by MELD-Na score, MELD score, and CLIF-C AD score, and FIPS score had a relatively poor predictive ability; in addition, the prediction efficiency of each score gradually decreased over time. Child-Pugh score had the largest AUC of 0.832 in predicting 1-year survival rate after surgery, and MELD-Na score had the largest AUC of 0.726 in predicting 3-year survival rate after surgery, but FIPS score had a poor ability in predicting 1- and 3-year survival rates. Conclusion All five scoring models can predict the survival of patients with liver cirrhosis after TIPS and can provide effective stratification of prognostic risk for such patients. Child-Pugh score has a better ability in predicting short-term survival, while MELD-Na score has a better ability in predicting long-term survival, but FIPS score has a relatively poor predictive ability in predicting both short-term and long-term survival.

OBJECTIVE Cognitive deficit is a com-mon comorbidity in temporal lobe epilepsy(TLE)and that is not well controlled by current therapeutics.Currently,how epileptic seizure affects cognitive performance remains largely unclear.The subiculum is the major out-put of the hippocampus,which projects to entorhinal cor-tex and other more distinct brain regions.Physiologically,the subiculum codes spatial working memory and naviga-tion information including place,speed,and trajectory.Importantly,prior studies have noted the importance of the subiculum in the beginning,spreading,and generaliz-ing process of hippocampal seizure.How seizure-activated neurons in subiculum participate in cognitive impairment remains largely elusive.METHODS In this study,we sought to label the subicular seizure-activated c-fos+ neu-rons with a special promoter with enhanced synaptic activity-responsive element E-SARE in the subiculum,combined with chemogenetics and designer receptors exclusively activated by designer drugs(DREADDs),Ca2+ fiber photometry approaches,and behavioral tasks,to reveal the role of these neurons in cognitive impairment in epilepsy.RESULTS We found that chemogenetic inhibi-tion of subicular seizure-tagged c-fos+ neurons(mainly CaMK Ⅱ α+ glutamatergic neurons)alleviates seizure generalization and improves cognitive performance in the hippocampal CA3 kindling TLE model.While inhibition of seizure-labeled c-fos+ GABAergic interneuron shows no effect on seizure and cognition.As a comparison,che-mogenetic inhibition of the whole subicular CaMK Ⅱ α+ neuron impairs cognitive function in na?ve mice in basal condition.Notably,inhibition of subicular seizure-tagged c-fos+ neurons enhances the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks.CONCLUSION Our results dem-onstrate that subicular seizure-activated c-fos+ neurons contribute to cognitive impairment in TLE,suggesting sei-zure-tagged c-fos+ neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

Objective:To compare the detection performance of serum free light chain (sFLC) in two platforms and evaluate the comparability of serum free light chain results in patients with multiple myeloma (MM).Methods:To evaluate the detection performance (repeatability, accuracy, linear range, reference range, interfering substances, etc.) of sFLC kit based on polyclonal antibodies. Spearman correlation analysis and Bland-Altman were used to analyze 214 sFLC results obtained on two detection platforms at the same time to evaluate the correlation between the results of the two methods and analyze the causes of methodological bias. 119 cases with aMM and 23 cases of disease control group (AL, WM, POEMS syndrome, MGUS, diffuse large B-cell lymphoma) initially diagnosed in the hematology department of Zhongshan Hospital of Fudan University from March 2020 to March 2021 were all included. A retrospective analysis was conducted to calculate the area under the curve of receiver operating characteristic (AUC-ROC) and obtain the optimal sensitivity and specificity cut-off points for the diagnosis of MM patients on monoclonal antibody platform.Results:Repeatability, accuracy, linear range, reference interval and anti-interfering capacity of the detection platform based on polyclonal antibodies were verified to meet clinical needs. The overall consistency of FLC/κ, FLC/λ and κ/λ ratios in two methods was 89.3%, 84.1% and 77.1% respectively; but the correlation results were highly heterogeneous. The correlation coefficient of FLC/κ R 2 was 0.922( P<0.001), while the correlation coefficients R 2of the FLC/λ and κ/λ ratios were only 0.349 and 0.441( P<0.001). After segment analysis, it was found that the correlation of FLC/λ was improved within the linear range and R 2 could rise to 0.78( P<0.001). Compared with monoclonal antibody platform, the vast majority points of FLC/κ fell within the 95% limit by Bland Altman analysis. While the results of FLC/λ on polyclonal antibody platform showed significant positive bias. The AUC of MM diagnosis on monoclonal antibody platform was 0.751 ( P=0.001), and the optimal cutoff value was 24.67. Conclusion:The overall consistency between the two platforms was good, but there were significant differences between the results, so they were not comparable and could not be interchanged. For monitoring the prognosis of patients with multiple myeloma, the same platform should be selected for testing.

N ⁶-methyladenosine (m⁶A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m⁶A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m⁶A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Objective:To summarize the prognosis of medullary thyroid carcinoma (MTC) patients with biochemical recurrence (the increase of postoperative calcitonin and no abnormal imaging) and to investigate the optimal cut-off value of calcitonin for postoperative structural recurrence (with imaging abnormality).Methods:Literature retrieval was conducted for PubMed, CNKI, EMbase, Web of Science, Cochrane and other databases, and literatures related to the increase of calcitonin after MTC surgery were included. Review Manager 5.4 software was used for Meta-analysis of the recurrence and death. SPSS 23.0 software was used and receiving operating characteristic (ROC) curve was used to analyze the rising folds of postoperative calcitonin level in comparison with the maximum value of experiment detection, and to predict the outcome of biochemical recurrence transforming to structural recurrence, and then the optimal cut-off value could be worked out.Results:A total of 7 studies including 1 005 MTC patients (276 cases of biochemical recurrence and 542 cases of biochemical cure). Meta-analysis showed that structural recurrence rate in postoperative biochemical recurrence group [40.6% (112/276) vs. 2.2% (12/542); OR = 27.99, 95% CI 14.57-53.78, P < 0.001] and mortality [10.0% (19/190) vs. 0.96% (3/312); OR = 7.26, 95% CI 2.42-21.84, P < 0.001] were higher than those in the biochemical cure group (normal postoperative calcitonin level and no disease state). The data of 89 MTC patients with biochemical recurrence were collected in another 4 studies. ROC curve analysis showed that area under the curve of the rising folds of postoperative calcitonin level in predicting structural recurrence was 0.825; according to the cut-off value at all sections, the optimal cut-off value of the increased postoperative calcitonin was 50 times, the sensitivity was 66. 7%, the specificity was 88.6%. Conclusions:MTC patients with postoperative biochemical recurrence have higher structural recurrence rate and mortality compared with patients with normal postoperative calcitonin. The postoperative elevation of calcitonin more than 50 times the maximum value of the laboratory detection can be taken as the critical diagnostic value, when more than 50 times is prone to structural recurrence.

Objective:To investigate the prognostic value and related factors of heart-type fatty acid binding protein (H-FABP) in patients with heart failure.Methods:A total of 877 consecutive patients who were admitted to heart failure care unit of Fuwai hospital and diagnosed as heart failure from July 2015 to July 2017 were enrolled in this study. Baseline serum H-FABP concentration was measured by fluorescence lateral flow immunoassay. According to serum H-FABP levels, patients were divided into three groups: low H-FABP group (H-FABP≤4.04 ng/ml, n=292), middle H-FABP group (H-FABP 4.04-7.02 ng/ml, n=292) and high H-FABP group (H-FABP≥7.02 ng/ml, n=293). The general clinical characteristics were collected and compared among the three groups. According to whether heart failure was caused by coronary artery disease or not, patients with heart failure were divided into ischemic heart failure and non-ischemic heart failure. Multivariate linear regression analysis was performed to explore the independent risk factors of H-FABP. The primary endpoint events were the composite of all-cause death or heart transplantation. Multivariate Cox regression analyses, receiver operating characteristic (ROC) curves, risk prediction tests with multivariate Cox regression model and Kaplan-Meier analyses were conducted to investigate the relationship between H-FABP and the prognosis of heart failure. Results:Multivariate linear regression analysis showed that age, coronary artery disease, alanine aminotransferase, uric acid and N-terminal pro-B type natriuretic peptide (NT-proBNP) were positively associated with H-FABP (β=0.012, 0.238, 0.001, 0.345 and 0.063 respectively,all P<0.05), while female, hemoglobin, albumin, sodium, and estimated glomerular filtration rate (eGFR) were negatively associated with H-FABP (β=-0.184, -0.006, -0.016, -0.034 and -0.006 respectively, all P<0.05). One hundred and nineteen patients (13.6%) lost to follow-up, and 246 patients (32.5%) suffered from all-cause death or heart transplantation during the median follow-up duration of 931 (412-1 185) days. Multivariate Cox regression analysis showed that baseline H-FABP (log 2H-FABP) level was the independent predictor of all-cause death or heart transplantation in patients with heart failure ( HR=1.39, P<0.001). ROC curves showed that baseline H-FABP was a predictor of all-cause death or heart transplantation in patients with heart failure within 3 months, 1 year and 2 years (areas under the curves were 0.69, 0.69 and 0.71 respectively), and the best cut-off values were 5.85 ng/ml, 6.54 ng/ml and 6.54 ng/ml respectively. Risk prediction test with multivariate Cox regression model showed that baseline H-FABP could provide additional prognostic value in predicting all-cause death or heart transplantation for patients with heart failure on top of basic model and baseline NT-proBNP ( P<0.001). Taking 6.54 ng/ml and trisected levels of H-FABP as cut-off values respectively, Kaplan-Meier analyses showed that the survival rates were significantly different among the two or three groups ( P<0.001). Subgroup analyses showed that baseline H-FABP (log 2H-FABP) level was an independent predictor of all-cause death or heart transplantation in patients with ischemic heart failure ( HR=1.74, P<0.001), as well as in patients with non-ischemic heart failure ( HR=1.28, P=0.027). Conclusions:Age, sex, coronary artery disease, hemoglobin, albumin, alanine aminotransferase, sodium, eGFR, uric acid and NT-proBNP are associated with H-FABP level. Baseline H-FABP level is an independent predictor of all-cause death or heart transplantation in patients with heart failure. On top of basic model and baseline NT-proBNP, baseline H-FABP could provide additional prognostic value in predicting adverse events for patients with heart failure.

Objective:To evaluate the value of phase analysis of gated myocardial perfusion imaging (GMPI) in predicting major adverse cardiac events (MACE) in patients with coronary atherosclerotic heart disease.Methods:Patients who underwent two-day rest-stress GMPI in the Department of Nuclear Medicine of Beijing Hospital from September 2012 to January 2014 were selected as observed subjects and analyzed retrospectively. The general clinical information, GMPI images and related parameters including phase standard deviation (PSD), phase histogram bandwidth (PBW), entropy, left ventricular ejection fraction (LVEF), summed stress score (SSS), peak ejection rate (PER), peak filling rate (PFR) were noted. Patients were followed up until the onset of MACE (cardiac death, nonfatal myocardial infarction, and late revascularization within 60 d after GMPI). χ2 test, independent-sample t test or Wilcoxon rank sum test were used to compare data between different groups. The independent risk factors of MACE were obtained by Cox proportional risk regression model. Kaplan-Meier survival curve analysis was used to analyze the cumulative survival rate without MACE. Results:A total of 505 patients (235 males, 270 females, median age: 73 years) were followed up successfully, with a median follow-up period of 55.6(52.0, 60.5) months. There were 54 cases (10.7%) with MACE: 6 patients with cardiac death, 27 patients with non-fatal myocardial infarction, and 21 patients with late revascularization. The incidence of hypertension and hyperlipidemia in patients with MACE was significantly higher than that in patients without MACE ( χ2 values: 4.126, 6.021, both P<0.05); LVEF, PFR and absolute value of PER of patients with MACE were significantly lower ( t/ z values: 6.261, 5.683, -4.246, all P<0.05), while SSS, PSD, PBW and entropy were significantly higher ( t/ z values: 5.024, 5.874, 7.119, -6.405, all P<0.05). Cox proportional risk regression model showed that abnormal PBW(>80°), abnormal entropy(>58 J·mol -1·K -1) and SSS≥12 were independent risk factors for MACE (odds ratio( OR) values: 2.795(95% CI: 1.259-6.201), 3.213(95% CI: 1.468-7.029), 3.640 (95% CI: 1.999-6.628), all P<0.05). The 5-year cumulative MACE-free survival rates of abnormal PSD group(>26.7°), abnormal PBW group and abnormal entropy group were 51.2%, 63.2% and 46.7%, which were significantly lower than those of normal PSD group (92.3%; χ2=77.768, P<0.05), normal PBW group (94.2%; χ2=77.741, P<0.05) and normal entropy group (92.8%; χ2=117.437, P<0.05). The 5-year cumulative MACE-free survival rate (31.7%) of patients with abnormal PBW and SSS≥12 was significantly lower than that of patients with normal PBW or patients with abnormal PBW and SSS<12 (80.1%-94.4%; χ2=185.4, P<0.01). The combination analysis of entropy and SSS showed similar results. Conclusions:PBW and entropy obtained by GMPI phase analysis are independent risk factors for predicting MACE in coronary artery disease. GMPI phase analysis is useful for coronary artery disease risk stratification.

Objective:To investigate the role of preoperative 18F-fluorodeoxyglucose (FDG) PET/CT imaging in mid-long-term prognosis of patients with resectable non-small cell lung cancer (NSCLC). Methods:Seventy resectable NSCLC patients (35 males, 35 females, median age 64 years) in Beijing Hospital between April 2010 and August 2016 were enrolled into this retrospectively study. All patients underwent 18F-FDG PET/CT imaging followed by pulmonary resection with mediastinal or hilar lymph nodes dissection within 1 month. The findings of PET/CT imaging including characteristics of primary lesions and mediastinal or hilar lymph nodes (size and maximum standardized uptake value (SUV max) of primary lesion, SUV max and distribution of high metabolic lymph nodes (HML)) were analyzed, and patients were followed up. Survival outcome indicators were defined as overall survival (OS) and progression-free survival (PFS). Survival analysis was conducted by Kaplan-Meier method, log-rank method and Cox proportional hazard models to assess the predictive factors. Results:Patients were followed up for 0.9-8.2 years. Among 70 patients, 31.4% (22/70) had disease progression and 24.3% (17/70) died. As for OS, there were significantly differences between patients with SUV max of primary lesion≥10 and <10 (4.6 vs 7.6 years), with size of primary lesion >3 cm and ≤3 cm (4.8 vs 7.4 years), with unilateral mediastinal or hilar HML and bilateral sides or without HML (4.4 vs 7.4 years), with SUV max of mediastinal or hilar lymph nodes ≥5.0 and <5.0 (3.8 vs 7.3 years) ( χ2 values: 10.135-15.238, all P<0.01), as well as PFS (3.9 vs 6.7, 3.8 vs 6.6, 3.8 vs 6.4, 3.3 vs 6.3 years; χ2 values: 8.410-14.600, all P<0.01). Cox multivariate analysis demonstrated that the size and SUV max of primary lesion were independent predictive factors of OS and PFS (all P<0.01). Moreover, the distribution of mediastinal or hilar HML had marginal significance in predicting OS ( P=0.051). Conclusions:Size and SUV max of primary lesion in preoperative 18F-FDG PET/CT imaging are predictive factors for the survival of postoperative NSCLC. The distribution of the mediastinal or hilar HML may have significance for the survival prediction of postoperative NSCLC.

Objective:To investigate the diagnostic value of 18F-fluorodeoxyglucose (FDG) PET/CT in detecting N 1 or N 2 metastasis of lymph node (LN) with different densities in patients with non-small cell lung cancer (NSCLC). Methods:A total of 118 patients (68 males, 50 females, age range: 27-87 (65.4±10.8) years) with N 0-N 2 M 0 NSCLC in Beijing Hospital between October 2007 and December 2017 were included in this study. All patients underwent 18F-FDG PET/CT, followed by surgery within 1 month. The pathological findings of the resected hilar mediastinal LN were taken as the gold standard, and ratios of LN metastasis were calculated for different density groups (calcification, partial calcification, hyper density, hypodensity/isodensity). The cut-off values of LN size (short diameter) and the maximum standardized uptake value (SUV max) in the detection of N 1 and N 2 metastases was determined by the receiver operating characteristic (ROC) curve, and the diagnostic efficiencies were calculated. Independent-sample t test, Mann-Whitney U test and χ2 test (partition of χ2) were used for data analysis. Results:A total of 433 LN has the histopathologic results: 365 LN was in stage N 0, 68 LN was in stage N 1-N 2. There were no metastases in calcification group (0/8). The metastatic LN proportions in partial calcification group (28.6%, 8/28), hypodensity/isodensity group (20.3%, 44/217) were significantly higher than that in the hyper density group (8.9%, 16/180; χ2 values: 7.369, 9.945, both P<0.017 (threshold for partition of χ2)). There was no significant difference between the partial group and hypodensity/isodensity group ( χ2=1.021, P>0.017). The SUV max of N 1+ N 2 group was significantly higher than that in N 0 group (6.94 (4.51, 11.36) vs 2.45 (1.93, 3.42); z=-10.388, P<0.01). According to the ROC curve, the cut-off value of SUV max in detecting hilar and mediastinal LN was 3.66. The diagnostic sensitivity, specificity and accuracy for N 1+ N 2 metastasis was 85.3%, 78.9%, 80.0% respectively. The cut-off values of SUV max for hypodensity/isodensity group and hyper density group were 3.66 and 2.79 respectively, and the corresponding sensitivities, specificities, accuracies and positive predictive values (PPV) were 93.2%, 86.7%, 88.0%, 64.1% vs 93.8%, 57.9% ( χ2=10.724), 61.1% ( χ2=7.326, P<0.01), 17.9%( χ2=32.971, P<0.01). The specificity of LN size (1.0 cm)+ SUV max was significantly higher that of LN size or SUV max alone (94.2% vs 80.9%, 86.7%; χ2 values: 14.048, 5.661, both P<0.05) in hypodensity/isodensity group. The specificity and accuracy of LN size (1.0 cm)+ SUV max were significantly higher those of SUV max alone ( χ2 values: 58.043, 37.037, both P<0.01) in hyper density group. Conclusions:18F-FDG PET/CT is useful in diagnosing the N 1+ N 2 metastases in hypodensity/isodensity LN, but has limitation in diagnosing the partial calcification LN. Combination of lymph node short diameter and SUV max cut-off value can improve the diagnostic specificity or accuracy of 18F-FDG PET/CT for hypodensity/isodensity and high density LN.