The N-linked glycosylations of TIGIT Asn32 and Asn101 facilitate PVR/TIGIT interaction.

Although the PVR/TIGIT immune checkpoint axis has been suggested as a promising target for cancer immunotherapy and multiple TIGIT-targeting therapies are undergoing clinical trials, the underlying regulatory mechanisms of PVR/TIGIT interaction remain inconclusive. Here we show that TIGIT N-glycosylations are critical for maintaining the interaction between TIGIT and PVR. TIGIT has two N-glycosylation residues, N32 and N101. N-glycosylation on N101 of TIGIT and, to less extent, on N32, play potent roles in PVR binding. Taken together, these findings suggest that the N-glycosylation sites on TIGIT, especially residue N101, may be potential targets for PVR/TIGIT immune checkpoint blockade.

Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.

The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.

Development of high-efficiency superparamagnetic drug delivery system with MPI imaging capability.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.

Assessment of conbercept therapy for high myopia macular neovascularization by optical coherence tomography angiography.

This study aimed to evaluate the efficacy and safety of the intravitreal injection of conbercept in the treatment of macular neovascularization (MNV) secondary to high myopia and to observe the application of optical coherence tomography angiography (OCTA) in the treatment follow-up. We reviewed the medical records of 20 patients (21 eyes) with MNV secondary to high myopia who were enrolled in the Department of Ophthalmology of the First Hospital of China Medical University between May 2018 and January 2020. Each patient received one or more intravitreal injections of conbercept (0.5 mg/0.05 mL). The treatment was conducted according to a 1 + PRN (pro re nata) regimen. The changes of best corrected visual acuity (BCVA), central macular thickness (CMT), and selected MNV and flow areas measured by OCTA were observed over a 6-month follow-up period. The mean logarithm of the minimum angle of resolution (logMAR) BCVA was 1.03 ± 0.61 before treatment and improved to 0.83 ± 0.59 (P = 0.007), 0.78 ± 0.62 (P = 0.001), 0.81 ± 0.73 (P = 0.027), and 0.79 ± 0.72 (P = 0.023) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. The mean CMT was 358.16 ± 206.11 µm before treatment and decreased to 295.38 ± 178.70 µm (P = 0.003), 288.34 ± 165.60 µm (P = 0.004), 284.36 ± 163.07 µm (P = 0.005), and 283.00 ± 160.32 µm (P = 0.004) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. Nineteen eyes (90.5%) had stable or improved vision at 6 months of follow-up. One month after conbercept injection, in OCTA images, the small-diameter blood vessels of the MNV decreased, the intertwined small blood vessels decreased or even disappeared, and the main or larger-diameter blood vessels were still present. The mean selected MNV and blood flow areas were 0.62 ± 0.81 and 0.22 ± 0.27 mm2, respectively, before treatment and decreased to 0.23 ± 0.33 and 0.07 ± 0.08 mm2 (P = 0.04 for both), respectively, 1 month after treatment. No drug-related systemic or ocular adverse effects were observed. Our results suggest that conbercept can effectively and safely improve BCVA and reduce CMT in patients with myopic MVN (mMNV). OCTA can be used to observe MNV area, blood flow area, and MNV morphological changes after treatment with conbercept, thus providing a reference for treatment follow-up.

Conbercept and Ranibizumab Pretreatments in Vitrectomy with Silicone Oil Infusion for Severe Diabetic Retinopathy.

PURPOSE: We compared the efficacies of intravitreal ranibizumab (IVR) and intravitreal conbercept (IVC) as the adjuvant pretreatments for vitrectomy with silicone oil infusion for tractional retinal detachment (TRD) secondary to proliferative diabetic retinopathy. METHODS: This retrospective study comprised 74 patients (79 eyes) who underwent vitrectomy with silicone oil tamponade for diabetic TRD. They received IVC (37 eyes) or IVR (42 eyes) at standard doses 3-5 days preoperatively and were followed up for ∼6 months. Anatomic success rate, intra- and postoperative complications, and visual outcomes were compared between both groups. RESULTS: Initial (IVC vs. IVR: 97% vs. 98%) and final anatomic success rates (100% in each group) and mean visual acuity changes were not significantly different (P = 0.46). Intraoperative complications [iatrogenic retinal breaks (P = 0.58) and intraoperative bleeding (P = 0.66)], postoperative complications [fibrin formation (P = 0.51), postoperative preretinal bleeding (P = 0.88), progressing or persistent neovascular glaucoma (P = 0.63), progressive fibrovascular proliferation (P = 0.93), and recurrent retinal detachment (P = 0.93)], and surgical variables [surgical time (P = 0.53)] were similar between both groups. CONCLUSIONS: Conbercept and ranibizumab are equally effective surgical adjuvants for vitrectomy with silicone oil infusion in patients with diabetic TRD.

Novel microvascular invasion-based prognostic nomograms to predict survival outcomes in patients after R0 resection for hepatocellular carcinoma.

PURPOSE: To propose a novel histopathological classification system for microvascular invasion (MVI) and to establish nomograms to predict postoperative survival and early tumor recurrence in patients with hepatocellular carcinoma (HCC) after R0 liver resection. METHODS: The clinicopathological and follow-up data of 686 consecutive patients with HCC who underwent R0 liver resection in our hospital between December 2009 and April 2010 were retrospectively reviewed. A classification system was established based on histological characteristics of MVI. Nomograms were then formulated using a multivariate Cox proportional hazards model to analyze. The results were validated using bootstrap resampling and a new 225-patient validation cohort operated in May and June 2010 at the same institution. RESULTS: A 4-stratification classification system of MVI was established, which satisfactorily determined the risk of survival and early tumor recurrence. Then, an eight-factor nomogram for survival prediction and a seven-factor nomogram for prediction of early tumor recurrence were established. The concordance indices were 0.78 for the survival-prediction nomogram and 0.72 for the recurrence-prediction nomogram. These indices were both significantly higher than the following three commonly used staging systems: tumor-node-metastasis staging system (seventh edition, 0.67/0.65), Japan Integrated Staging System (0.58/0.58) and Chinese University Prognostic Index (0.52/0.51). The calibration curves showed good agreement between predictions by the nomograms and actual survival outcomes. These results were confirmed in the validation cohort. CONCLUSIONS: The novel classification system of MVI and the nomograms enabled more accurate predictions of risk of tumor recurrence and overall survival in patients with HCC after R0 liver resection.