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.

In order to achieve the purpose of rapid detection of duck astrovirus type 1(DAstV-1),specific primers were designed based on the conservative region of ORF1a which belonged to DAstV-1(WF1202 strain).A real-time fluorescent quantitative PCR(qPCR)detective method for DAstV-1 was established.Clinical samples were detected by the qPCR method and the positive samples were used for virus isolation and identification.Results showed that the detection limit of the established method was 4.64×103 copies/μL,which was 10 times higher than the normal RT-PCR method.In addition,no cross-reactions were found with other common infectious disease pathogens in poultry,indicating that the qPCR method had good specificity.What's more,the coef-ficient of variations(Cv)in intra-and inter-assays were 0.85％-2.85％and 0.21％-2.94％,re-spectively,both less than 3％,indicating that the qPCR method had a good repeatability.Using this method,35 tissue samples from different duck farms in 10 provinces from 2020 to 2022 were detected for DAstV-1.Results showed that the positive rate was 25.71％(9/35),and the coinci-dence rate was 94.29％when compared with the normal RT-PCR method.A positive sample ran-domly taken for the virus isolation through duck embryo passage,and the allantoic fluid was col-lected and then was verified by the qPCR method and inoculated with 1-day-old healthy ducklings for the animal regression experiment.The infected ducklings suffered from transient disease but did not die.The liver tissues were all positive with DAstV-1 when detected by qPCR.Meanwhile,autopsy showed that there were slight changes in the livers,and the histopathological observation showed that the liver cells were steatosis.These findings indicated that the isolated DAstV-1 strain had weak pathogenicity and might be a low virulent strain.To sum up,the qPCR detection method of DAstV-1 was successfully established in this work,and could provide technical support for clini-cal diagnosis,isolation and identification,and molecular epidemiology monitoring of DAstV-1.

In order to understand the prevalence of Akabane disease(AKAD)in Guizhou Province and the molecular characteristics of the isolates,the whole-genome sequence of a strain of Akabane virus(AKAV)from a bovine AKAD-positive sample was determined and analyzed.The genotype and genetic variation of the strain were also explored.Based on the conserved S sequence,a fluores-cence quantitative PCR(qPCR)detection method was established and applied for the investigation of AKAV infection status in four large-scale beef cattle farms of Guizhou.Results showed that the S,M and L fragments of the bovine strain were highly homologous to the Tianjin strain(TJ2016/China/2016)and the Australian strain(JaLAB39/Australia/1959),where they were in the same evolutionary branch and belonged to genotype Ⅱ.Sensitivity assay found that the lowest detection limit was 2.5 X 101 copies/μL.Specificity assay showed the established method detected only AKAV with no amplification on bovine bluetongue virus(BLUV),Pasteurella multocida(PM),bovine infectious rhinotracheitis virus(IBRV)and bovine Mycoplasma bovis.The variation coefficients of inter-and intra batches in the repeatability test were both lower than 2.26％.These findings illus-trated that the established qPCR method had high sensitivity,good specificity and repeatability.A total of 298 serum samples from 4 large-scale beef cattle farms in Qianxi City and Huangping County of Guizhou Province were collected and tested for AKAV by the method.Out of 298 sam-ples,25 positive samples(25/298)were detected as positive with a positive rate of 8.39％.In sum-mary,this work provided the reference data for a deep understanding of the molecular prevalence of AKAV in Guizhou Province and laid foundation for the prevention and control of AKAD.

Objective:To compare anatomical locking plate fixation with versus without reconstruction of the coracoclavicular ligament in the treatment of acute and old Neer Ⅱb unstable distal clavicle fractures.Methods:From January 2015 to November 2020, 80 Neer Ⅱb distal clavicle fractures were treated at Department of Orthopaedics, The First Hospital Affiliated to China Pharmaceutical University. There were 49 males and 31 females, aged from 32 to 78 years (average, 47.8 years). Of the 50 fresh fractures, 25 were treated by internal fixation with anatomical locking plate of distal clavicle plus reconstruction of the coracoclavicular ligament with suture anchor (reconstruction group A) while the other 25 by only internal fixation with anatomical locking plate of distal clavicle (non-reconstruction group A). Of the 30 old fractures which had not got united over 3 weeks after injury, 15 were treated by internal fixation with anatomical locking plate of distal clavicle plus reconstruction of the coracoclavicular ligament with suture anchor (reconstruction group B) while the other 15 by only internal fixation with anatomical locking plate of distal clavicle (non-reconstruction group B). At 1, 3 and 6 months postoperatively, Constant-Murley scale and visual analogue scale (VAS) were used to evaluate shoulder function and pain. X-ray follow-ups were conducted to measure the coracoclavicular distance and observe fracture union and complications at the last follow-up.Results:All the 80 patients were followed up for 6 to 24 months (average, 13.8 months). For reconstruction group A and non-reconstruction group A, respectively, the union time for fresh fractures was (11.7±2.8) weeks versus (13.4±1.3) weeks, the rate of coracoclavicular distance increase 12.7%±6.2% versus 14.2%±8.0%, the Constant-Murley score 92.2±4.4 versus 90.9±5.7, showing no statistically significant difference between the 2 groups (all P>0.05). For reconstruction group B and non-reconstruction group B, respectively, the union time for old fractures was (12.8±1.9) weeks versus (19.4±6.7) weeks, the rate of coracoclavicular distance increase 12.3%±6.7% versus 21.5%±13.1%, the Constant-Murley score 93.0±5.9 versus 83.5±8.5, showing statistically significant differences between the 2 groups (all P<0.05). Conclusions:For fresh Neer Ⅱb distal clavicle fractures, simple anatomical locking plate fixation can achieve satisfactory curative efficacy without additional reconstruction of the coracoclavicular ligament. However, for old Neer IIb distal clavicle fractures, additional reconstruction of the coracoclavicular ligament can better maintain the stability of the acromioclavicular joint, reduce the risk of internal fixation failure, and achieve better outcomes.

ERK pathway regulated the programmed death ligand-1 (PD-L1) expression which was linked to the response of programmed death-1 (PD-1)/PD-L1 blockade therapy. So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy. In this study, PD0325901, an oral potent ERK inhibitor, strongly enhanced the efficacy of PD-1 antibody

Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.
Adenosine Triphosphatases ; Carcinoma, Non-Small-Cell Lung ; Doxorubicin ; Drug Resistance, Multiple* ; Drug Therapy ; Humans ; In Vitro Techniques* ; Leukemia ; Lymphoma ; Parents ; Phosphorylation ; Phosphotransferases ; Rhodamine 123 ; United States Food and Drug Administration

Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

Objective To explore the atypical ultrasonic appearances of breast fibroadenoma and analyze the cause of mis diagnosis.Methods A total of 493 lesions in 485 patients of breast fibroadenoma detected by ultrasound examination andconfirmed by pathology were retrospectively analyzed.Atypical appearances were analyzed and misdiagnosis rate were cal-culated.Statistical methods were taken to compare the misdiagnosis rates in lesions with various atypical appearances andthose with none or single atypical appearance.Misdiagnosis rates in lesions with different sizes and pathological types wereanalyzed statically.Then misdiagnosing causes were analyzed.Results A total of 404 lesions were diagnosed correctly,in-cluding 99 lesions with atypical appearances,and the other 89 lesions were misdiagnosed,which showed atypical appear-ances.The misdiagnosis rate of lesions with ≥2 atypical features was higher than that with none or single atypical feature(x2 =256.40,P＜ 0.05).Large lesions (maximum diameter＞ 3 am) showed higher misdiagnosis rates than small ones(maximum diameter ≤3 cm,x2=6.73,P＜0.05),and complex fibroadenoma lesions also showed higher misdiagnosisrate than simple ones (x2 =188.01,P＜0.05).Conclusion The lesions with various atypical appearances,large size andcomplex fibroadenoma in pathology are easy to be misdiagnosed.

Objective To evaluate the one-year clinical outcomes in patients with the vulnerable plaque sealing with drug-eluting stents for the treatment of intermediate coronary stenosis. Methods 327 patients with an-giographically intermediate lesions(diameter stenosis 50%~70%)with the vulnerable plaque which were detected by 64 slice coronary CT were prospectively enrolled. Patients were divided into medical therapy group (n = 160) and sirolimus-eluting stent group group(n=160). The incidences of one-year major adverse cardiovascular events (MACE)was evaluated(cardiac death,myocardial infarction ,revascularization). Results The MACE tended to be lower in the sirolimus-eluting stent group than medical therapy group(3.13%vs. 10%,log-rankχ2=6.62,P=0.01). The incident of cardiac death and myocardial infarction were lower in the sirolimus-eluting stent group than medical therapy group(1.25%vs. 5.63%,log-rankχ2=4.61,P=0.03). Conclusion The treatment of the siroli-mus-eluting stent can reduce MACE for the paitents with the vulnerable plaque of intermediate coronary stenosis than medical therapy only.

BACKGROUND: A number of studies have shown that long non-coding RNA DANCR can play an important role in various pathophysiological processes through Wnt/β-catenin signaling pathway.OBJECTIVE: To explore the effect of long non-coding RNA DANCR on the proliferation and chondrogenesis of synovium-derived mesenchymal stem cells.METHODS: Passage 3 synovium-derived mesenchymal stem cells were obtained and transfected with pcDNA3.1-GP (control) and pcDNA3.1-GP(DANCR Homo) (experimental). Cell viability was estimated at 1, 2, 3, 4, 5, 6 and 7 days after DANCR transfection. The passage 3 cells were cultured in the chondriogenic medium for 14 days. And the chondrogenesis potential of cells was examined by toluidine blue staining. The chondrogenic-specific marker genes Aggrecan, Type II collagen (Col2) and Sox9 were determined by Real-time PCR.RESULTS AND CONCLUSION: The synovium-derived mesenchymal stem cells exhibited S-shaped curves in the two groups, with cell arrest at 1-2 days and rapid proliferation beginning at 3 days. Cell counting kit-8 assay and toluidine blue staining showed overexpressing DANCR significantly promoted proliferation in synovium-derived mesenchymal stem cells. The aggregates from synovium-derived mesenchymal stem cells in the experimental group had a greater amount of toluidine blue staining than the control group. In addition, we detected the higher expression of chondrogenic specific marker genes, such as Col2, Sox9 and Aggrecan, in the experimental group than the control group at 14 days after chondrogenic induction (P < 0.05). These results demonstrate that long non-coding RNA DANCR could enhance chondrogenic differentiation and proliferation of human synovium-derived mesenchymal stem cells and increase the expression of chondrogenic specific marker genes.