Chemotherapy remains one of the major tools, along with surgery, radiotherapy, and more recently targeted therapy, in the war against cancer. There have appeared a plethora of highly potent cytotoxic drugs but the poor discriminability between cancerous and healthy cells of these agents limits their broader application in clinical settings. Therapeutic antibodies have emerged as an important class of biological anticancer agents, thanks to their ability in specific binding to tumor-associated antigens. While this important class of biologics can be used as single agents for the treatment of cancer through antibody-dependent cell cytotoxicity (ADCC), their therapeutical efficacy is often limited. Antitumor antibody drug conjugates (ADCs) combine the target-specificity of monoclonal antibody (mAb) and the highly active cell-killing drugs, taking advantages of the best characteristics out of both components. Thus, insufficiency of most naked mAbs in cancer therapy has been circumvented by arming the immunoglobulin with cytotoxic drugs. Here mAbs are used as vehicles to transport potent payloads to tumor cells. ADCs contain three main components: antibody, linker and cytotoxics (also frequently referred as payload). Antibodies can recognize and specifically bind to the tumor-specific antigens, leading to an antibody-assisted internalization, and payload release. While ADC has demonstrated tremendous success, a number of practical challenges limit the broader applications of this new class of anticancer therapy, including inefficient cellular uptake, low cytotoxicity, and off-target effects. This review article aims to cover recent advances in optimizing linkers with increased stability in circulation while allowing efficient payload release within tumor cells. We also attempt to provide some practical strategies in resolving the current challenges in this attractive research area, particularly to those new to the field.

Objective To comprehensively summarize the recent development of organ transplantation specialty,and raise a suggestion for the future progress of the subject.Methods The info investigation method was employed to retrieve the literature concerning solid organ transplantation published in recent five years domestically and abroad,and the new progresses were analyzed on organ transplantation in both military and civil fields,and also fundamental and clinical researches.Results Researches on organ transplantation had progressed rapidly on foundation and clinical application in recent 5years in armed forces.The major achievements were in immune recognition and adjustment,transplant immune tolerance,the regulating effect of CTLA4Ig on NK cell function,preparation of the preservation fluid,and pathological diagnosis.Conclusions The professional level of organ transplantation in the armed forces had teken the foremost position in advance in the country.During the period of "12th Five-Year Plan" ,researches should be carried out on procurement,preservation and transplantation of the donated organs after cardiac death(DCD)organ.Meanwhile the foundational and clinical researches should be enhanced of immune tolerance,regulatory T lymphocyte,formulation of preservation fluid,and of animal experiment for closely bonding the foundational and clinical researches,and striving for greater research outcome.

The success of organ transplantation depends on the prevetion of acute rejection. T and B lymphocytes, the major components of the cellular and humoral immunization mediating the rejection response, respectively, have been extensively studied. The importance of matural killer(NK) cells in transplantation has become an increasing area of interest as reagents for their study have become available. Basing on this on the killer immunoglobulin-like receptor in the acute rejection response with kidney transplantation.

Objective To investigate the effect of Norvasc combined with Benazepril for treatment elderly hypertensive patients with Non-insulin-dependent diabetes mellitus .Methods 52 cases of elderly hypertensive patients with Non-insulin-dependent diabe-tes mellitus were selected as the study object and were randomly divided into the observation group and the control group ,each with 26 cases of patients .The observation group was given Norvasc combined with Benazepril while the control group was given Nor-vasc .Results After 8 weeks ,the SBP and DBP of the observation group were significantly lower than that of the control group (P<0 .05) .The FBG and 2h PBG were significantly lower than that of the control group as well as the ISI significantly higher (P<0 .05) .Conclusion Norvasc combined with Benazepril can effectively control the blood pressure and plasma glucose of elderly hy-pertensive with Non-insulin-dependent diabetes mellitus ,also improve the ISI of patients .It is deserved to be promoted widely in the clinical work .

Localization and estimation of histamine(HA)content in the wound edge in 81cases of SD rats were carried out by microfluorometric method specific for this aminewhich forms a complex with ophthalaedehyde(OPT).At the same time,thedistribution and the density of the mast calls in the same areas were observed byToluidine blue stain.in all skin specimens with antemortem wounds,both the epidermisand upper dermis exhibited extracellular yellowish fluorescente band of the HA-OPTcomplex.The zone spreaded in wound edge with the lapse of time in antemorteminjuries.The content of HA increased gradually up to 30′,and then yellow hista- mine fluorescence in areas 0-200? extended from wound edge decreased.None of thesefeatures could be observed in normal control skin and postmortemin jured skin.themast cell degranulation could be demonstrated in all antemortem injured skin.Nostatistic relationship between the degranulation of mast cell and the HA-OPTfluorescence existed in either ante-or post-mortem injured groups.This study indi-cated that the skin HA microfluoremetry by OPT method has practical value fordistingushing the ante-from post-mortem wounds and for timing antemortem wounds.

Objective To investigate the efficacy and side effects of acarbose and metformin in the treatment of type 2 diabetes mellitus. Methods 100 patients with type 2 diabetes mellitus's choice of the January 2015 to March 2017 in our hospital, the patients were randomly divided into two groups: the control group was treated with metformin, acarbose treatment in observation group; the two groups before and after treatment of blood glucose control, the adverse reaction condition of comprehensive observation, will be granted the relevant data recorded and analyzed. Results Patients with fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin improvement than the control group, the difference was statistically significant (P<0.05); two groups of patients with adverse reaction rate comparison, the difference was not statistically significant. Conclusion Patients with type 2 diabetes choose acarbose treatment effect significantly, can effectively improve the patients fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin, clinical symptoms of patients can be improved, low incidence of adverse reactions.

Objective To construct the mouse CD40 RNA interfering(RNAi) lentiviral vector and prepare dendritic cells (DCs) with low expression of CD40. And to explore the mechanism of inducing T lymphocyte incompetence by blocking CD40/CD40L costimulatory pathway. Methods Mouse myeloid DCs were cultured in selective medium containing necessary cytokines for DC growth in vitro. CD40 RNAi gene was transfected into DCs with lentiviral vector. The expression levels of CD40 mRNA and protein were assayed by real-time quantitative PCR and flow cytometry respectively. The influences on DCs stimulating the proliferation ability of T lymphocyte were observed through mixed lymphocyte culture(MLC). Results Myeloid DCs have been harvested from mouse through cell culture in vitro. A mouse CD40 RNAi ientiviral vector was built successfully. The lentiviral titer was 8×10~9 TU/ml. The CD40 mRNA inhibition rate after infection was significantly higher(P<0.05). The CD40 protein expression of DCs was significandy lower(P<0.05). The result of MLC demonstrated that the index of stimulation to T lymphocyte of CD40 RNAi transfected DC significantly decreased compared with non-transfected DC and empty plasmid transfected DC(P< 0.01). Conclusion Large quantity of myeloid DCs with typical histological configuration are obtained through in vitro culture in selective medium which may activate naive T lymphocyte to generate immune response. While DCs were infected by CD40 RNAi lentiviral vector, CD40 protein expression was inhibited significantly. The DCs could hamper the activation of allogeneic T lymphocyte by blocking CD40/CD40L cestimulatory pathway and induce T cell allergy. This will make the good foundation for studying the immune tolerance of CD40 RNAi.

Objective To investigate the effect of blocking CD40/CD40L costimulatory pathway by the lentiviral vector-mediated RNA interference on the survival of mouse cardiac allograft. Methods Mouse bone marrow-derived dendritic cells (DCs) were infected by CD40-RNAi lentiviral vector in vitro, and tolerogenic DCs (Tol-DCs) with decreased CD40 expression were prepared. Fluorescence real-time quantitative PCR and flow cytometry were used to analyze the expression of CD40 mRNA and DC surface antigens CD40, CD11c, MHC Ⅱ before and after infection. Mouse model of heterotropic abdominal heart transplantation was established. Seven days prior to heart transplantation, Tol-DCs with decreased CD40 expression were transfused into recipient mice intravenously (lentivirus infected DC group). Control group and non-infected DC group were assigned simultaneously. The survival of cardiac allograft was monitored and pathological grade of acute rejection 7 days after heterotropic abdominal heart transplantation was determined. Results The transcription of CD40 mRNA of DCs was down-regulated significantly at 48 h after CD40-RNAi lentiviral vector infection, and the inhibition rate was 80. 9%. The expression of CD40 protein was also significantly decreased as compared with control group (40. 07% ± 4. 03% ) ( P ＜ 0. 05 ).Compared to control group (8 ± 2 days) and non-infected DC group (9 ± 1 days), the survival time of cardiac allograft in CD40-RNAi lentivirus infected DC group (14 ± 4 days) was significantly prolonged (P＜ 0. 05 ), and the pathological grade of acute rejection decreased significantly ( P ＜ 0. 05 ).Conclusion Blocking CD40/CD40L costimulatory pathway could hamper the activation of allogeneic T lymphocyte, inhibit the acute rejection and prolong the survival of mouse cardiac allograft.

Objective:To investigate the effects of sorafenib on hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) levels and recurrence in patients with intrahepatic cholangiocarcinoma with microvascular invasion.Methods:Ninety-two patients with intrahepatic cholangiocarcinoma who received treatment in Yiwu Central Hospital between November 2013 and November 2019 were included in this study. They were randomly assigned to undergo either conventional basic treatment (control group, n = 46) or conventional basic treatment and sorafenib treatment (study group, n = 46). Clinical efficacy, the incidence of adverse reactions and recurrence rate were compared between the two groups. Before and after treatment, HIF-1, alpha fetoprotein (AFP) and VEGF levels were also compared between the two groups. Results:After treatment, total effective rate in the study group was significantly higher than that in the control group [63.04% (29 /46) vs. 28.26% (13/46), χ2 = 11.215, P < 0.05]. After treatment, HIF-1, AFP and VEGF levels in each group were significantly lower than those before treatment (all P > 0.05). After treatment, HIF-1 [(165.23 ± 39.67) pg/mL], AFP [(109.16 ± 67.31) ng/mL] and VEGF [(297.28 ± 42.41) pg/mL] levels in the study group were significantly lower than those in the control group [(205.56 ± 40.23) pg/mL, (235.17 ± 106.41) ng/mL, (365.16 ± 40.91) pg/mL, t = 4.841, 6.788, 7.813, all P < 0.05]. There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Six-month follow-up revealed that the incidence of recurrence in the study group was significantly lower than that in the control group ( χ2 = 4.792, P < 0.05). Conclusion:Sorafenib can reduce the HIF-1, AFP and VEGF levels in patients with intrahepatic cholangiocarcinoma with microvascular invasion, improve the clinical efficacy, decrease the incidence of recurrence, but cannot increase the incidence of adverse reactions.

Objective To investigate the trend in incidence, causative drugs, clinical types and treatment of drug eruption. Methods Clinical data were collected from 922 inpatients with drug eruption in Huashan Hospital, Fudan University from January 2009 to December 2013, and analyzed retrospectively. Results From 2009 to 2013, the percentage of inpatients with drug eruption among all inpatients in the Department of Dermatology in a given year varied from 9.45% to 10.01%, and the percentage of inpatients with severe drug eruption among inpatients with drug eruption from 17.45% to 28.24%. Of the 922 cases, 371 (40.2%)were caused by single drugs, and 551 (59.8%)by multiple drugs. Among the 371 cases of drug eruption caused by single drugs, the top five causative drugs were traditional Chinese medicine(72 cases), cephalosporins(38 cases), amoxicillin(27 cases), antipyretic analgesics(26 cases)and tetanus antitoxin (24 cases)in 278 cases of non-severe drug eruption, antiepileptic agents (33 cases), allopurinol (28 cases), antipyretic analgesics (7 cases), cephalosporins (6 cases)and traditional Chinese medicine (6 cases)in 93 cases of severe drug eruption. Of the 922 patients, 422 (45.8%)presented with maculopapular eruption, 259 (28.1%)with urticaria, 135(14.6%)with Stevens-Johnson syndrome, 49(5.3%)with toxic epidermal necrolysis, 33(3.6%)with drug reaction with eosinophilia and systemic symptoms (DRESS), and 7 (0.8%)with acute generalized exanthematous pustulosis (AGEP). A total of 791 (85.8%)patients with drug eruption received glucocorticoid treatment. The dose of glucocorticoids was(47.61 ± 12.07)mg prednisone equivalent per day in 550 patients with non-severe drug eruption, and (73.10 ± 18.23)mg prednisone equivalent per day in 221 patients with severe drug eruption. Totally, 110 (11.0%) patients with drug eruption were treated with combined intravenous immunoglobulin (IVIG)because of poor response to glucocorticoids alone. Of 224 patients with severe drug eruption, only 2 (0.9%)died. Conclusions Carbamazepine and allopurinol are the main causative drugs for severe drug eruption, while traditional Chinese medicine is the first causative drug for non-severe drug eruption. From 2009 to 2013, the annual mortality of severe drug eruption decreased considerably.