Antibody-drug conjugates (ADCs) are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker. Currently, 15 ADCs have been clinically approved worldwide. More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs. ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development. It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells, thereby producing promising antitumor efficacy and favorable adverse effect profiles. However, emergence of drug resistance has severely hindered the clinical efficacy of ADCs. In this review, we introduce the structure and mechanism of ADCs, describe the development of ADCs, summarized the latest research about the mechanisms of ADC resistance, discussed the strategies to overcome ADCs resistance, and predicted biomarkers for treatment response to ADC, aiming to contribute to the development of ADCs in the future.

Humans ; Amyotrophic Lateral Sclerosis/drug therapy* ; Neurons ; Phosphatidylinositol 3-Kinases

Humans ; Carcinoma, Mucoepidermoid/pathology* ; Thyroid Neoplasms/pathology* ; Eosinophilia/pathology*

Humans ; Thyroid Neoplasms/surgery* ; Thyroid Cancer, Papillary

The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
Siderophores/metabolism* ; Iron/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Cryoelectron Microscopy ; Adenosine Triphosphate/metabolism* ; ATP-Binding Cassette Transporters

The purification of parasite-infected erythrocytes from whole blood containing leucocytes is crucial for many downstream genetic and molecular assays in parasitology. Current methodologies to achieve this are often costly and time consuming. Here, we demonstrate the successful application of a cheap and simple Non-Woven Fabric (NWF) filter for the purification of parasitized red blood cells from whole blood. NWF filtration was applied to the malaria-parasitized blood of three strains of mice, and one strain of rat, and to Babesia gibsoni parasitized dog blood. Before and after filtration, the white blood cell (WBC) removal rates and red blood cell (RBC) recovery rates were measured. After NWF filter treatment of rodent malaria-infected blood, the WBC removal rates and RBC recovery rates were, for Kunming mice: 99.51%±0.30% and 86.12%±8.37%; for BALB/C mice: 99.61%±0.15% and 80.74%±7.11%; for C57 mice: 99.71%±0.12% and 84.87%±3.83%; for Sprague-Dawley rats: 99.93%±0.03% and 83.30%±2.96%. Microscopy showed WBCs were efficiently removed from infected dog blood samples, and there was no obvious morphological change of B. gibsoni parasites. NWF filters efficiently remove leukocytes from malaria parasite-infected mouse and rat blood, and are also suitable for filtration of B. gibsoni-infected dog blood.

Anemone flaccida Fr. Schmidt is a perennial medicinal herb that contains pentacyclic triterpenoid saponins as the major bioactive constituents. In China, the rhizomes are used as treatments for a variety of ailments including arthritis. However, yields of the saponins are low, and little is known about the plant's genetic background or phytohormonal responsiveness. Using one-quarter of the 454 pyrosequencing information from the Roche GS FLX Titanium platform, we performed a transcriptomic analysis to identify 157 genes putatively encoding 26 enzymes involved in the synthesis of the bioactive compounds. It was revealed that there are two biosynthetic pathways of triterpene saponins in A. flaccida. One pathway depends on β-amyrin synthase and is similar to that found in other plants. The second, subsidiary ("backburner") pathway is catalyzed by camelliol C synthase and yields β-amyrin as minor byproduct. Both pathways used cytochrome P450-dependent monooxygenases (CYPs) and family 1 uridine diphosphate glycosyltransferases (UGTs) to modify the triterpenoid backbone. The expression of CYPs and UGTs were quite different in roots treated with the phytohormones methyl jasmonate, salicylic acid and indole-3-acetic acid. This study provides the first large-scale transcriptional dataset for the biosynthetic pathways of triterpene saponins and their phytohormonal responsiveness in the genus Anemone.
Anemone ; drug effects ; genetics ; metabolism ; Biosynthetic Pathways ; drug effects ; genetics ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Plant ; drug effects ; Glycosyltransferases ; genetics ; metabolism ; Oleanolic Acid ; analogs & derivatives ; metabolism ; Plant Growth Regulators ; pharmacology ; Plant Proteins ; genetics ; metabolism ; Plants, Medicinal ; Rhizome ; drug effects ; genetics ; metabolism ; Saponins ; metabolism ; Triterpenes ; metabolism

Objective: To understand the epidemiological characteristics of scrub typhus and influencing factors in Yunnan province, and provide further information for the prevention and control of scrub typhus. Methods: Based on the incidence data of scrub typhus reported in Yunnan from 2006 to 2013, the epidemiological characteristics of scrub typhus were analyzed and related environmental factors were identified with panel negative binomial regression model. Results: A total of 8 980 scrub typhus cases were reported during 2006-2013 in Yunnan. The average annual incidence was 2.46/100 000, with an uptrend observed. Natural focus expansion was found, affecting 71.3% of the counties in 2013. The epidemic mainly occurred in summer and autumn with the incidence peak during July-October. The annual incidence was higher in females than in males. More cases occurred in children and farmers, the proportions of cases in farmers and pre-school aged children showed an obvious increase. Panel negative binomial regression model indicated that the transmission risk of scrub typhus was positive associated with monthly temperature and monthly relative humidity. Furthermore, an "U" pattern between the risk and the increased coverage of cropland and grassland as well as an "inverted-U" pattern between the risk and increased coverage of shrub were observed. Conclusion: It is necessary to strengthen the scrub typhus surveillance in warm and moist areas as well as the areas with high coverage of cropland and grassland in Yunnan, and the health education in children and farmers who are at high risk.
Child ; China/epidemiology* ; Environment ; Epidemics ; Farmers ; Female ; Humans ; Incidence ; Male ; Models, Statistical ; Orientia tsutsugamushi ; Risk Factors ; Scrub Typhus/transmission* ; Temperature

Objective: To estimate the cervical and breast cancer screening coverage and related factors among women aged 35-69 years who were in the National Cervical and Breast Screening Program, to provide evidence for improving cervical and breast cancer control and prevention strategy. Methods: Data used in this study were abstracted from the 2013 Chinese Chronic Diseases and Risk Factors Surveillance Program. A total of 66 130 women aged 35-64 years and 72 511 women aged 35-69 years were included for this study. Weighted prevalence, (with 95% confidence interval, CI) was calculated for complex sampling design. Rao-Scott χ(2) method was used to compare the screening coverage among subgroups. A random intercept equation which involved the logit-link function, was fitted under the following five levels: provincial, county, township, village and individual. Fix effects of all explanatory variables were converted into OR with 95%CI. Results: In 2013, 26.7% (95%CI: 24.6%-28.9%) of the 35-64 year-old women reported that they ever had been screened for cervical cancer and 22.5% (95% CI: 20.4%-24.6%) of the 35-69 year-olds had ever undergone breast cancer screening. Lower coverage was observed among women residing in rural and central or western China than those in urban or eastern China (P<0.000 1). The coverage among women aged 50 years or older was substantially lower than those aged 35-49 years. Those who were with low education level, unemployed, low household income and not covered by insurance, appeared fewer number on this cervical or breast cancer screening program (P<0.000 1). Women living in rural and western China were having less chance of receiving the breast cancer screening (P<0.05), but the difference was not statistically significant. Conclusion: It is essential to strengthen the community-based cervical and breast cancer screening programs, in order to increase the coverage. More attention should be paid to women aged 50 years or older, especially those socioeconomically disadvantaged ones.
Adult ; Aged ; Breast Neoplasms/prevention & control* ; China/epidemiology* ; Early Detection of Cancer/statistics & numerical data* ; Female ; Healthcare Disparities ; Humans ; Mammography/statistics & numerical data* ; Mass Screening/statistics & numerical data* ; Middle Aged ; Papanicolaou Test/statistics & numerical data* ; Prevalence ; Risk Factors ; Rural Population ; Socioeconomic Factors ; Uterine Cervical Neoplasms/prevention & control*

Objective: To understand the prevalence of alcohol drinking in 20-79 years old males with different educational backgrounds and smoking behaviors in different areas of China. Methods: A multi-stage cluster random sampling survey was conducted in 150 surveillance sites in 2010-2012 Chinese nutrition and health surveillance in China. At least 1 000 subjects were selected in each surveillance site. Alcohol drinking prevalence and pattern information were collected by using personal health and food frequency questionnaire in face to face interviews. Results: A total of 60 791 males aged 20-79 years were surveyed. The prevalence of alcohol drinking was 57.8% (58.3% in rural area, 57.3% in urban area). The mean daily alcohol intake level was 32.7 g (33.3 g in rural area, 32.1 g in urban area). The rate of almost drinking every day and daily alcohol intake level were highest among males aged 50-59 years. Mean daily alcohol intake level, rate of almost drinking every day and excessive drinking decreased with the increase of education level. Non-smokers had higher rate of never drinking and lower prevalence of drinking and excessive drinking, lower mean daily alcohol intake level, and lower rate of almost drinking every day compared with current and past smokers. Conclusions: Alcohol drinking was common in males aged 20-79 years in China, and, the difference was not obvious between rural residents and urban residents. The differences in daily intake level of different alcohol drinks among males with different characteristics had certain significance. Significant difference in excessive drinking was found among different age groups, those with different education levels and those with different smoking history.
Adult ; Aged ; Alcohol Drinking/epidemiology* ; Asian People ; China/epidemiology* ; Cross-Sectional Studies ; Humans ; Male ; Middle Aged ; Prevalence ; Rural Population ; Smoking/epidemiology* ; Socioeconomic Factors ; Surveys and Questionnaires