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.

Objective To investigate the preliminary clinical effect of closed reduction and cannulated nail internal fixa-tion for femoral neck fracture assisted by robot navigation and positioning system.Methods From July 2019 to January 2020,16 cases of femoral neck fracture(navigation group)were treated with closed reduction and internal fixation guided by robot system,including 7 males and 9 females,aged 25 to 72 years old with an average of(53.61±5.45)years old;Garden classification of fracture:3 cases of type Ⅰ,3 cases of type Ⅱ,8 cases of type Ⅲ,2 cases of type Ⅳ.Non navigation group(control group):20 cases of femoral neck fracture were treated with closed reduction and hollow nail internal fixation,8 males and 12 females,aged 46 to 70 years old with an average of(55.23±4.64)years old;Garden type Ⅰ in 2 cases,type Ⅱ in 4 cases,type Ⅲ in 11 cases,type Ⅳ in 3 cases.The operation time,fluoroscopy times,guide needle drilling times,screw adjustment times,intraoperative bleeding volume and other indicators of two groups were evaluated.Results Both groups were followed up for 12 to 18 months with an average of(15.6±2.8)months.The fractures of both groups were healed without delayed union and nonunion.There was no significant difference in healing time between two groups(P=0.782).There was no significant differ-ence in Harris scores between two groups at the last follow-up(P=0.813).There was no significant difference in operation time between two groups(P＞0.05).There were significant differences between two groups in fluoroscopy times,guide needle drilling times,hollow screw replacement times,and intraoperative bleeding volume(P＜0.05).Conclusion Closed reduction and hollow screw internal fixation assisted by robot navigation system for femoral neck fracture has the advantages of minimally invasive operation,precise screw placement,and reduction of X-ray radiation damage during operation.

OBJECTIVE: To study the protective effect of forsythiaside B (FB) against cerebral oxidative stress injury induced by cerebral ischemia/reperfusion (I/R) in mice and explore the underlying mechanism. METHODS: Ninety C57BL/6 mice were randomized into sham-operated group, middle cerebral artery occlusion (MCAO) model group, and low-, medium and highdose (10, 20, and 40 mg/kg, respectively) FB groups. The expression levels of MDA, ROS, PCO, 8-OHdG, SOD, GSTα4, CAT and GPx in the brain tissue of the mice were detected using commercial kits, and those of AMPK, P-AMPK, DAF-16, FOXO3 and P-FOXO3 were detected with Western blotting. Compound C (CC), an AMPK inhibitor, was used to verify the role of the AMPK pathway in mediating the therapeutic effect of FB. In another 36 C57BL/6 mice randomized into 4 sham-operated group, MCAO model group, FB (40 mg/kg) treatment group, FB+CC (10 mg/kg) treatment group, TTC staining was used to examine the volume of cerebral infarcts, and the levels of ROS and SOD in the brain were detected; the changes in the protein expressions of AMPK, P-AMPK, DAF-16, FOXO3 and P-FOXO3 in the brain tissue were detected using Western blotting. RESULTS: In mice with cerebral IR injury, treatment with FB significantly reduced the levels of ROS, MDA, PCO and 8-OHdG, increased the activities of antioxidant enzymes SOD, GSTα4, CAT and GPx, and enhanced phosphorylation of AMPK and FOXO3 and DAF-16 protein expression in the brain tissue (P < 0.01). Compared with FB treatment alone, the combined treatment with FB and CC significantly reduced phosphorylation of AMPK and FOXO3, lowered expression of DAF-16 and SOD activity, and increased cerebral infarction volume and ROS level in the brain tissue of the mice (P < 0.01). CONCLUSION FB inhibits oxidative stress injury caused by cerebral I/R in mice possibly by enhancing AMPK phosphorylation, promoting the downstream DAF-16 protein expression and FOXO3 phosphorylation, increasing the expression of antioxidant enzymes, and reducing ROS level in the brain tissue.
Mice ; Animals ; AMP-Activated Protein Kinases/metabolism* ; Antioxidants/metabolism* ; Reactive Oxygen Species ; Mice, Inbred C57BL ; Brain Ischemia ; Oxidative Stress ; Infarction, Middle Cerebral Artery ; Reperfusion Injury ; Reperfusion ; Superoxide Dismutase/metabolism*

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.
Humans ; Brain Neoplasms/pathology* ; Neoplasm Recurrence, Local/metabolism* ; Glioma/pathology* ; Neural Stem Cells/pathology* ; Oligodendrocyte Precursor Cells/pathology* ; Tumor Microenvironment

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.
Chemotherapy, Adjuvant ; Female ; Gastrectomy ; Humans ; Male ; Neoadjuvant Therapy ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/surgery*

Background:The purpose of this study was to analyze cases of AO31-A2 intertrochanteric fractures (ITFs) and to identify the relationship between the loss of the posteromedial support and implant failure.Methods:Three hundred ninety-four patients who underwent operative treatment for ITF from January 2003 to December 2017 were enrolled.Focusing on posteromedial support,the A2 ITFs were divided into two groups,namely,those with (Group A,n =153) or without (Group B,n =241) posteromedial support post-operatively,and the failure rates were compared.Based on the final outcomes (failed or not),we allocated all of the patients into two groups:failed (Group C,n =66) and normal (Group D,n =328).We separately analyzed each dataset to identify the factors that exhibited statistically significant differences between the groups,In addition,a logistic regression was conducted to identify whether the loss of posteromedial support of A2 ITFs was an independent risk factor for fixation failure.The basic factors were age,sex,American Society of Anesthesiologists (ASA) score,side of affected limb,fixation method (intramedullary or extramedullary),time from injury to operation,blood loss,operative time and length of stay.Results:The failure rate of group B (58,24.07％) was significantly higher than that of group A (8,5.23％) (x2 =23.814,P ＜ 0.001).Regarding Groups C and D,the comparisons of the fixation method (P =0.005),operative time (P =0.001),blood loss (P =0.002)and length of stay (P =0.033) showed that the differences were significant.The logistic regression revealed that the loss of posteromedial support was an independent risk factor for implant failure (OR =5.986,95％ CI:2.667-13.432) (P ＜ 0.001).Conclusions:For AO31-A2 ITFs,the loss of posteromedial support was an independent risk factor for fixation failure.Therefore,posteromedial wall reconstruction might be necessary for the effective treatment of A2 fractures that lose posteromedial support.

OBJECTIVETo observe the changes in electrocardiographic parameters in children with complete left bundle branch block (CLBBB) after the transcatheter closure of simple ventricular septal defect (VSD).

METHODSA total of 21 children with CLBBB early after transcatheter closure of perimembranous VSD were recruited. Another 21 children without any type of arrhythmia after transcatheter closure of perimembranous VSD were enrolled as the control group. The sex, age, and the size of occluder were matched between the two groups. The changes in the following indices were compared between the two groups: left ventricular voltage, QT interval, corrected QT interval (QTc), QT dispersion (QTd), corrected QT dispersion (QTcd), JT dispersion (JTd), and corrected JT dispersion (JTcd) on the electrocardiogram before transcatheter closure and at 1, 3, 5, 30 days after transcatheter closure.

RESULTSLeft ventricular voltage and JTcd changed with operation time in the CLBBB and control groups (P<0.05). There were interaction effects between time and grouping in the changes in left ventricular voltage and QTd (P<0.05). There was a significant difference in JTcd between the CLBBB and control groups (P<0.05). There was also a significant difference in left ventricular voltage between the CLBBB and control groups at 3 and 5 days after the transcatheter closure (P<0.05).

CONCLUSIONSThere are significant differences in electrocardiographic left ventricular voltage and JTcd between VSD children with and without CLBBB early after transcatheter closure. JTcd might be useful in predicting the development of CLBBB early after transcatheter closure of VSD.

Adolescent ; Bundle-Branch Block ; physiopathology ; Cardiac Catheterization ; Child ; Child, Preschool ; Electrocardiography ; Female ; Heart Septal Defects, Ventricular ; surgery ; Humans ; Male ; Postoperative Complications ; physiopathology

AIM:To study the changes of tear film and ocular surface after the coaxial incision 2.5mm and 3.0mm in the phacoemulsification.METHODS: Seventy patients (92 eyes) from February 2015 to February 2016 in our hospital were enrolled.The patients were randomly divided into two groups.Thirty-four patients (46 eyes) in Group A: coaxial 2.5mm incision phacoemulsification cataract extraction and intraocular lens(IOL) implantation.Thirty-six patients (46 eyes) in Group B: the conventional coaxial 3.0mm small incision phacoemulsification cataract extraction and IOL implantation.The break up time (BUT),Schirmer`s Ⅰ test (SⅠt) and lid-parallel conjunctival folds (LIPCOF) were assessed preoperatively and postoperatively.RESULTS: At 1wk,1 and 3mo postoperatively,the BUT in two groups decreased after operations,and the BUT of Group B was significantly lower than those of Group A,the differences were statistically significant (t=3.089,4.497,4.322;all P<0.05).The SⅠt in two groups increased after operations,the SⅠt of Group B was significantly higher than those of Group A and the differences were statistically significant (t=-6.286,-3.992,-3.278;all P<0.05).The LIPCOF score in two groups increased after operations,the LIPCOF score of Group B was significantly higher than those of Group A and the differences were statistically significant (t=-6.552,-5.131,-3.652;all P<0.05).At 6mo postoperatively,compared with the preoperative data,the BUT,SⅠt and LIPCOF score in Group A showed no statistically significant differences (t=0.646,0.551,0.165;P>0.05).The BUT,SⅠt and LIPCOF score in Group B showed statistically significant differences (t=-4.059,3.629,4.211;all P<0.05).CONCLUSION: Ocular surface has less damage and tear film has little influence at early stage after the coaxial 2.5mm incision phacoemulsmcation,compared with the conventional coaxial 3.0mm incision phacoemulsification surgery.

BACKGROUND:The development of minimaly invasive technology significantly reduces the occurrence of surgical complications due to spinal metastases. Currently, the minimaly invasive treatment basicaly has three broad categories: vertebral cement augmentation, radiofrequency ablation combined with vertebroplasty, intraoperative radiotherapy combined with vertebroplasty. OBJECTIVE:To summarize the research progress of three kinds of minimaly invasive treatments for spinal metastases. METHODS:PubMed and Wanfang databases were searched using the keywords of spinal metastases, vertebroplasty, radiofrequency ablation, radiotherapy in English and Chinese, respectively. RESULTS AND CONCLUSION:Vertebral cement augmentation with good analgesic effect has been used widely, and the efficiency is up to 80%-90%. But its effect to kil tumors is very limited that is unable to control tumor growth. Radiofrequency ablation and radiation can kil the tumor, but cannot rebuild the vertebral stability. Therefore, the combination of different technologies can improve the therapeutic effect on spinal tumors. In recent years, intraoperative radiation and implantation of radioactive particles or radioactive bone cement have been developed as new technologies. However, there is no conclusion that these new technologies have better outcomes than the vertebral cement augmentation because of less reports and lack of long-term folow-up. Especialy in the metastatic patients with damaged vertebral posterior wal and tumors invaded into vertebral canal, the risk of nerve function damage caused by bone cement leakage is stil very high, even after many attempts. Above al, there is no a perfect minimaly invasive treatment for spinal metastases.