Pharmacokinetics of radioimmunotherapeutic agent of direct labeling mAb ^(188)Re-HAb18

AIM:To labed Anti-hepatoma monoclonal antibody(mAb) fragment HAb18 F(ab')_2 was labeled with 188 Re for the pharmacokinetic model of ^(188)Re-HAb18 F(ab')_2 and to evaluate its pharmacokinetic parameters in hepatoma- bearing nude mice. METHODS:HAb18 F(ab')_2 was directly labeled with ^(188)Re using 2-mercaptoethanol(2-ME)as reducing agents. Labeling efficiency and immunoreactivity of ^(188)Re-HAb18 F (ab')_2 were evaluated by Whatman 3MM paper chromatography and live cell assay,respectively. Biodistribution analysis was also conducted in nude mice bearing human hepatoma in which animals were sacrificed at different time points(1,4,18,24 and 24h)after ^(188)Re-HAb18 F(ab')_2 was injected through tail-vein into hepatoma-bearing nude mice.The blood and radioactivity of organs and mass were measured.The concentrations of ^(188)Re-HAb18 F(ab')_2 were evaluated with a pharrnacokinetic 3P97 software. RESULTS:The optimum labeling efficiency and immunoreactive fraction were 91.7% and 0.78%, respectively.The parameters of ^(188)Re-HAb18 F(ab')_2 were: T_(1/2),2.29h;Vd,1.49×10^(-9)L·Bq^(-1);AUC,20.49×10~9Bq·h· L^(-1);CL,0.45×10^(-3)L·h^(-1).^(188)Re-HAb18 F(ab')_2 could locate specially in hepatoma with high selective reactivity of HAb18 F(ab')_2.^(188)Re-HAbl8 F(ab')_2 was mainly eliminated by kidney.The maximal tumor to blood ratio was at 48h,and maximal tumor to liver ratio was at 18h. CONCLUTION:The pharmacokinetics of ^(188)Re-HAb18 F(ab')_2 fit a I-compartment model.^(188)Re-HAb18 F(ab')_2 can be uptaken selectively at the hepatoma site.

Effects of total glucosides of peony on immunological hepatic fibrosis in rats

AIM: To study the effects of total glucosides of peony (TGP) on immunological hepatic fibrosis induced by human albumin in rats.METHODS: Sixty adult male Sprague-Dawley rats were randomly divided into: Normal group, model group, TGP (60 and 120 mg/kg) treatment groups and colchicines (0.1 mg/kg) treatment group. On the day before the rats were killed, those in TGP or colchicine groups received TGP or colchicine as above from the first day of tail vein injection of human albumin. The rats in normal and model groups were only administered with the same volume of vehicle. At the end of the 16th wk, rats in each group were killed. Blood and tissue specimens were taken. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO), content of malondialdehyde (MDA), activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were measured by biochemical methods. Serum procollagen type Ⅲ (PC Ⅲ) and laminin (LN) were determined by radioimmunoassay. Liver collagen level was determined by measuring hydroxyproline content in fresh liver samples. Hepatic tissue sections were stained with hematoxylin-eosin and examined under a light microscope.RESULTS: Histological results showed that TGP improved the human albumin-induced alterations in the liver structure, alleviated lobular necrosis and significantly lowered collagen content. The antifibrotic effect of TGP was also confirmed by decreased serum content of LN and PCⅢ in TGP-treated group. Moreover, the treatment with TGP effectively reduced the hydroxyproline contentin liver homogenates. However, the level of ALT and AST increased in fibrotic rat but had no significance compared with normal control, whereas the ratio of A/G decreased without significance. TGP had no effect on level of ALT, AST and the ratio of A/G. Furthermore, TGP treatment significantly blocked the increase in MDA and NO, associated with a partial elevation in liver total antioxidant capacity including SOD and GSH-px.CONCLUSION: TGP has beneficial effects on hepaticfibrosis in rats by inhibition of collagen synthesis and decreasing oxidative stress.

Nature products of traditional Chinese medicine provide new ideas in γδT cells for tumor immunotherapy

Due to the unique features of innate immune cells, the role of γδT cells in tumor immunity has gradually attracted more and more attention. Previous studies have found that γδT cells play a dual role in tumor immunology: tumor-promoting and tumor-controlling.The anti-tumor therapy of γδT cells has made remarkable success in clinical application. Especially in recent years, researchers have provided some novel effective ways such as γδT cells exosomes and adoptive chimeric antigen receptor-γδT cells immunotherapy. However, some problems remain to be solved, such as low expansion rate, poor targeting, and tumor microenvironment limiting the effectiveness of γδT immunotherapy. Traditional Chinese medicine is expected to play a positive role in the body immune-enhancing function, promoting the proliferation and activation of γδT cells, and inducing the differentiation ofγδT cells. In this review, we summarize the recent research progress and urgent problems of γδT cells in anti-tumor immunotherapy. Moreover, some new strategies of γδT cells for tumor immunotherapy were proposed.

Side Effects during Treatment of Advanced Gastric Carcinoma by Chemotherapy Combined with CIK-cell Transfusion in Elderly People

OBJECTIVE To study the side effects and therapeutic results of autologous cytokine-induced killer （CIK） cell treatment in elderly patients with advanced gastric cancer. METHODS CIK cells were induced and cultured using biotechnics in vitro, and then the cells were infused back into the patients. Sixty elderly gastric cancer patients treated by chemotherapy （FOLFOX4 protocol） were followed-up. Among them, 29 patients were treated with CIK cells during application of chemotherapy. Short-term curative effects and adverse events from the CIK transfusion and chemotherapy were observed. RESULTS Eight cases developed partial remission （PR）, 9 cases moderate remission （MR）, 7 cases stable disease （SD） and 5 cases progressive disease （PD）. Out of a total of 29 patients who received chemotherapy combined with autologous CIK therapy, the total remission rate （PR ＋ MR） was 58.6%. The total remission rate following chemotherapy alone was 45.2%, including 5 PR cases, 9 MR cases, 7 SD cases, and 10 PD cases. There was a relatively lower rate of severe chemotherapic toxicities in the CIK-cell transfusion group. Side effects of autologous CIK transfusion included chills （13 cases）, fever （9 cases）, nausea and vomiting （1 case） and general malaise （3 cases）. Side effects were treated with conventional therapy resulting in their amelioration. No patients developed shock, blood capillary leakage syndrome, or abnormalities in routine blood, urine, liver and renal function tests.CONCLUSION Adoptive immunotherapy with autologous CIK cells may decrease the clinical signs and symptoms of elderly patients who suffer from advanced gastric cancer. Adverse reactions of patients can be alleviated by conventional therapy. Autologous CIK-cell transfusion may improve endurance to chemotherapy.

Novel approaches towards conquering hepatitis B virus infection

Currently approved treatments for hepatitis B virus （HBV） infection include the immunomodulatory agent, IFN-α, and nucleos（t）ide analogues. Their efficacy is limited by their side effects, as well as the induction of viral mutations that render them less potent. It is thus necessary to develop drugs that target additional viral antigens. Chemicals and biomaterials by unique methods of preventing HBV replication are currently being developed, including novel nucleosides and newly synthesized compounds such as capsid assembling and mRNA transcription inhibitors. Molecular therapies that target different stages of the HBV life cycle will aid current methods to manage chronic hepatitis B （CriB） infection. The use of immunomodulators and gene therapy are also under consideration. This report summarizes the most recent treatment possibilities for CHB infection. Emerging therapies and their potential mechanisms, efficacy, and pitfalls are discussed.

Biomarkers in kidney transplantation: From bench to bedside

Immunosuppressive drug level monitoring and serum creatinine are widely used for kidney transplantation （KT） monitoring. Monitoring of drug level is not the direct measurement of the immune response while the rising of creatinine is too late for detection of allograft injury. Kidney biopsy, the gold standard for KT monitoring, is invasive and may lead to complications. Many biomarkers have been discovered for direct monitoring of the immune system in KT and the beneft of some biomarkers has reached clinical level. In order to use biomarkers for KT monitoring, physicians have to understand the biology including kinetics of each marker. This can guide biomarker selection for specific condition. Herein, we summarize the recent fndings of donor specifc anti-human leukocyte antigen antibody, B lymphocyte stimulator, interferon-gamma induced protein of 10 kDa, and intracellular adenosine triphosphate monitoring, all of which have very strong evidence support for the clinical use in KT.

Safety and Efficacy of Digoxin TherapymWhere Are We Now？

The aim of our study was to determine the criteria and key factors for the effectiveness of digoxin therapy. A prospective opened-type study was carried out in conditions of everyday clinical practice. The concentrations of digoxin were quantified from blood samples taken following the achievement of drug steady-state （using AxSYM microparticle enzyme immunoassay-MEIA）. The risk/benefit ratio was evaluated based upon the correlation between measured blood concentrations of the drug and clinical response. Study results （100 decompensated patients） revealed that therapy indication field was correctly covered, showing a higher prevalence in elderly. On average, each examinee had 2 or 3 comorbidities. Applied daily dose of digoxin ranged from 0.053 mg to 0.25 mg. Renal function was assessed by creatinine clearance which is one of the key factors for the accomplishment of optimal digoxin serum concentrations （p 〈 0.05）. Co-administration of seven drugs was complicating factor for the management of rational therapy. 76/100 patients were within referent range （0.8-2.0 ng/mL）, while 13/100 were above the upper limit. Four side effects in total were recorded （nausea, vomiting, confusion）, whereas in only two patients digoxin was excluded from the therapy. Digoxin confirmed the justifiability of its use in contemporary clinical practice.

Integrated combination delivery of IDO inhibitor and paclitaxel for cancer treatment

In order to realize the combination of chemotherapy and immunotherapy,a reduction-responsive paclitaxel(PTX)prodrug PEG-SS-PTX was synthesized and used as a carrier to encapsulate IDO inhibitor CY-1-4 for preparing PEG-SS-PTX/CY-1-4 NPs.PEG-SS-PTX/CY-1-4 NPs were evaluated by cytotoxicity,immunogenic cell death(ICD)induction ability and anti-tumor efficacy.Dynamic light scattering(DLS)results showed that the size of PEG-SS-PTX/CY-1-4 NPs was about 149 nm.In vitro experiments indicated that its cytotoxicity was in a concentration-dependent manner,and it induced the ICD of B16-F10 cells.In vivo studies in melanoma mouse model indicated that PEG-SS-PTX/CY-1-4 NPs significantly inhibited the tumor growth and reduced the expression of IDO in tumor tissues.Moreover,it increased the rate of CD8+T cells in the spleen.In summary,PEG-SS-PTX/CY-1-4 NPs achieved good anti-tumor effects and reduced the dose of chemotherapy drugs,which was a safe and effective combined delivery system.