Monoclonal antibody ( mAb ) represents a class of therapeutics experienced dramatic development over the past 30 years. Because of the tremendous differences in physicochemical and biological properties between mAbs and small molecules, the mAb therapeutics significantly differ from the chemical drugs in pharmacokinetic characteristics and underlying mechanisms. Full understanding of those characteristics and mechanisms may efficiently guide the screening and development of mAb medi-cines, and would well support their safety evaluation and clinical dosage regimen designing. This review is to summarize pharma-cokinetics and underlying mechanisms of mAbs from the aspects of absorption, distribution and elimination, as well as the ap-proaches for prediction of mAb pharmacokinetics in humans.

Dysfunction in tyrosine kinase activity disrupts the nor-mal control of cellular phosphorylation signaling pathways,which plays a vital role in genesis and development of various tumors, and makes tyrosine kinases a class of targets of many anti-tumor drugs. Currently most approved tyrosine kinase inhibitors ( TKIs) are based on irreversible binding mechanisms, making them poorly selective, not potent or sustained enough regarding pharmacological effects and prone to triggering resistance. In the past decade, much progress has been made in the development of
a new class of TKIs which irreversibly inhibit their target proteins via the formation of covalent bonds, overcoming the drawbacks of irreversible TKIs. Several irreversible TKIs have entered markets or clinical research phases. This review is to summarize the structural, pharmacological and medicinal chemical properties of investigational and marketed irreversible TKIs as well as their re-cent developments.

Antibody-drug conjugate (ADC) is a new class of therapeutics composed of a monoclonal antibody and small cytotoxin moieties conjugated through a chemical linker. ADC molecules bind to the target antigens expressed on the tumor cell surfaces guided by the monoclonal antibody component. The binding ADC molecules can be internalized and subsequently the toxin moieties can be released within the tumor cells via chemical and/or enzymatic reactions to kill the target cells. The conjugation combines the merits of both components, i.e., the high target specificity of the monoclonal antibody and the highly potent cell killing activity of the cytotoxin moieties. However, such complexities make the pharmacokinetic and metabolic studies of ADCs highly challenging. The major challenges should include characterization of absorption, distribution, metabolism and excretion, investigation of underlying mechanisms, assessment of pharmacokinetic- pharmacodynamic relationship, and analytical method development of ADC drugs. This review will discuss common pharmacokinetic issues and considerations, as well as tools and strategies that can be utilized to characterize the pharmacokinetic and metabolic properties of ADCs.

Objective To investigate the hepatic hemodynamic characteristics of cirrhotic patients with splenectomy using iodine map of dual-source computed tomography(DSCT).Methods Twenty-four cirrhotic patients with splenectomy were selected as a study group,41 cirrhotic patients without splenectomy as a cirrhosis group and other 32 patients with normal liver as a control group.The iodine concentration(IC)in hepatic arterial and venous phases was measured on the iodine map,and the arterial iodine fraction(AIF)and portal venous iodine concentration(PVIC)were calculated.Receiver operating characteristic(ROC)curves were plotted and the area under the curve(AUC)was recorded to evaluate the diagnostic efficacy of each parameter using the DeLong test.Results IC in arterial phase and AIF were significantly higher,and IC in venous phase and PVIC were significantly lower in study group(P<0.05).The AUC values of the four parameters between study group and cirrhosis group were 0.735,0.992,0.943,and 0.994,respectively.Conclusion DSCT iodine map is helpful for clinical quantitative assessment of hepatic hemodynamic characteristics in cirrhotic patients with splenectomy,and the PVIC has optimal independent diagnostic performance.

Objective:To investigate the inhibitory effect of RMT1-10-induced tolerogenic dendritic cells (Tol-DCs) in vitro on high-risk corneal allograft rejection in mice and its mechanism. Methods:One hundred SPF male BALB/c mice and fifty SPF male C57BL/6 mice were selected.Bone marrow-derived immature dendritic cells (imDCs) obtained from C57BL/6 mice were divided into imDCs group, mature dentritic cells (mDCs) group, RMT1-10 group, and IgG isotype control group.The imDCs in the four groups were cultured with no intervention, lipopolysaccharide, RMT1-10 and lipopolysaccharide, or IgG isotype antibody and lipopolysaccharide for 7 days according to grouping.The expression levels of different phenotypes of DCs including CD11c, CD80, CD86, major histocompatibility complex (MHC)-Ⅱ, T cell immunoglobulin and mucin domain containing molecule (Tim)-4 and CD103 in the four groups were detected by flow cytometry.The concentrations of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in the DCs supernatants were determined by enzyme-linked immunosorbent assay.A mixed lymphocyte culture system was established, and the stimulation index (SI) of CD4 + T cell proliferation stimulated with DCs was detected by cell counting kit 8 method.Corneal neovascularization was induced by corneal stromal suture in BALB/c mice, and the 80 mice with neovascularization in 4 quadrants growing into the middle and peripheral cornea were used as recipients.The recipient mice were randomized into imDCs group, mDCs group, RMT1-10 group, and IgG isotype control group using the random number table method, with 20 mice in each group.An injection of corresponding DCs (1×10 6 cells/100 μl) was administered to the recipient mice via the tail vein according to grouping.At 7 days following the injection, C57BL/6 mice were used as donors and penetrating keratoplasty was performed.Within one month after the operation, signs of corneal grafts rejection, including opacity, edema and neovascularization, were observed by slit lamp biomicroscopy and scored every day.At 21 days after the operation, 5 recipients selected from each group were subcutaneously injected with naive C57BL/6 splenocytes (1×10 6 cells/100 μl) behind the ear.The delayed type hypersensitivity (DTH) was evaluated by ear swelling at 24 hours after the subcutaneous injection.The use and care of experimental animals complied with the Regulations on the Management of Experimental Animals promulgated by the State Science and Technology Commission.This study protocol was approved by an Ethics Committee of the Affiliated Hospital of Chengde Medical University (No.CYFYLL2020055). Results:Compared with mDCs group, the expressions of CD80, CD86 and MHC-Ⅱ, and the percentage of Tim-4-positive cells in CD11c-positive cells were significantly decreased in RMT1-10 group, showing statistically significant differences (all at P<0.001). The percentage of Tim-4-positive cells were significantly decreased in RMT1-10 group than imDCs group, and the percentage of CD103-positive cells in RMT1-10 group was significantly higher than imDCs group, mDCs group and IgG isotype control group (all at P<0.001). The concentrations of IL-10 and TGF-β in the cell culture supernatant of RMT1-10 group were significantly higher than those of the other three groups, with statistically significant differences (all at P<0.001). There were statistically significant differences in the SI of CD4 + T cell proliferation simulated by DCs ( Fgroup=1 833.00, P<0.001; Fratio=230.40, P<0.001; Finteraction=3.06, P=0.01). The SI of DCs/CD4 + T cells ratio at 1∶5, 1∶10, 1∶20 and 1∶40 were all significantly lower in imDCs group than mDCs group, and were all significantly lower in RMT1-10 group than imDCs group (all at P<0.05). There was a statistically significant difference in corneal graft survival curve among various groups ( χ2=77.69, P<0.001). The survival rate of RMT1-10 group was significantly higher than that of imDCs group ( χ2=9.74, P=0.002), and the survival rate of imDCs group was significantly higher than that of mDCs group ( χ2=31.02, P<0.001). The ear swelling of recipient mice of positive control group, mDCs group, IgG isotype control group, imDCs group and RMT1-10 group was (503.6±17.2), (475.7±17.6), (456.2±18.8), (225.2±39.4), (118.1±12.6), and (106.4±7.4) μm, with a statistically significant difference among them ( F=377.10, P<0.001). The mice ear swelling was more serious in positive control group than mDCs group, more serious in IgG isotype control group than imDCs group, and more serious in imDCs group than RMT1-10 group (all at P<0.05). Conclusions:RMT1-10 can inhibit the rejection of high-risk corneal transplantation in mice, the mechanism of which may be attributed to inducing imDCs to transform into Tol-DCs in vitro and up-regulating the expression of TGF-β and IL-10, which promotes antigen-specific immune tolerance after adoptive transfer, thereby indirectly prolongs the survival of corneal grafts.

Objective:To assess the risk of COVID-19 foreign imports cases to China.Methods:We collected epidemic data (cumulative daily confirmed cases in each country, cumulative confirmed imported cases), demographic data (population density, population) and information on potential source groups of tourists (the daily estimated number of overseas Chinese, overseas Chinese students, overseas workers, foreign students coming to China and flight passengers) and the global health security index (GHS) to assess and predict risk of imported cases for recent (February 1 st to April 25 th) and future (after April 26 th). Results:Strong positive correlation was found among variables including the number of imported cases, cumulative confirmed cases, attack rate, number of overseas Chinese, number of overseas Chinese students, number of foreign students coming to China, number of flight passengers and GHS. In the recent risk analysis, imported cases of Russian were the highest, followed by United Kingdom, United States, France and Spain. In the future risk prediction, 44 countries including United States and Singapore are evaluated as potential high-risk countries in the future through the attack rate index of each country and the estimated average number of daily passengers.Conclusion:The risk assessment of COVID-19 imported cases can be used to identify high-risk areas in recent and future, and might be helpful to strengthen the prevention and control of the epidemic and ultimately overcome the epidemic.

Objective:To infer the start time of the resurgent COVID-19 epidemic in Xinfadi wholesale market in Beijing in June 2020 and evaluate the effect of comprehensive prevention and control measures in this epidemic.Methods:SEIR dynamics model was used to fit daily onset infections to search the start date of this resurgent COVID-19 epidemic in Beijing. The number of cumulative infections from June 12 to July 1 in Beijing were fitted considering different levels of control strength.Results:The current reemerged COVID-19 epidemic in Beijing probably started between May 22 and May 28 (cumulative probability: 95 %), with the highest probability on May 25 (23 %). The R0 of the current reemerged COVID-19 epidemic was 4.22 (95 %CI: 2.88-7.02). Dynamic model fitting suggested that by June 11, the cumulative number of COVID-19 cases would reached 99 (95 %CI: 77-121), which was in line with the actual situation, and without control, by July 1, the cumulative number of COVID-19 cases would reach 65 090 (95 %CI: 39 068-105 037). Since June 12, comprehensive prevention and control measures have been implemented in Beijing, as of July 1, compared with uncontrolled situation, the number of infections had been reduced by 99 %, similar to the fitting result of a 95 % reduction of the transmission rate. The sensitivity analysis showed consistent results. Conclusions:For the emergent outbreak of COVID-19, the dynamics model can be used to infer the start time of the transmission and help tracing the source of epidemic. The comprehensive prevention and control measures taken in Beijing have quickly blocked over 95 % of the transmission routes and reduced 99 % of the infections, containing the sudden epidemic timely and effectively, which have value in guiding the prevention and control of the epidemic in the future.

Extremely unbalanced data here refers to datasets where the values of independent or dependent variables exhibit severe unbalance in proportions, such as extremely unbalanced case-control ratio, very low incidence rate of disease, heavily censored time-to-event data, and low-frequency or rare variants. In such scenarios, the statistic derived from hypothesis test using the classical statistical method, e.g., logistic regression model and Cox proportional hazard regression model, might deviate from theoretical asymptotic distribution, resulting in inflation or deflation of type I error. With the increased availability and exploration of resources from large-scale population cohorts in genome-wide association study (GWAS), there is a growing demand for effective and accurate statistical approaches to handle extremely unbalanced data in independent and non-independent samples. Our study introduces classical statistical methods in genetic statistics firstly, then, summarizes the failure of classical statistical methods in dealing with extremely unbalanced data through simulation experiments to draw researchers' attention to the extremely unbalanced data in GWAS.

Confounders are difficult to avoid in studies on observational comparative effectiveness. It is often unclear whether the confounders have been completely eliminated after controlling the measured or unmeasured potential confounding effects or if sensitivity analysis is needed when using the specific statistical methods, under given circumstances. This manuscript summarizes and evaluates the confounding sensitivity analysis methods. Based on different studies, sensitivity analyses need to use different approaches. The traditional sensitivity analysis can be applied for the measured confounders. Currently, the relatively systematic sensitivity analyses for unmeasured confounders would include confounding function, bounding factor and propensity score calibration. Additionally, more investigations are associated with Monte Carlo and Bayesian sensitivity analysis. Reliability of the research conclusion thus may largely be improved when the sensitivity analysis results are consistent with the main analysis.

During the epidemics of COVID-19 in domestic China and recently continuing rapid spread worldwide, a bunch of studies fitted the epidemics by transmission dynamics model to nowcast and forecast the trend of epidemics of COVID-19. However, due to little known of the new virus in early stage and much uncertainty in the comprehensive strategies of prevention and control for epidemics, majority of models, not surprisingly, predict in less accuracy, although the dynamics model has its great value in better understanding of transmission. This comment discusses the principle assumptions and limitations of the dynamics model in forecasting the epidemic trend, as well as its great potential role in evaluation the efforts of prevention and control strategies.