Discovery of Novel PD-L1 Small-Molecular Inhibitors with Potent In Vivo Anti-tumor Immune Activity.

Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8+ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.

Syntheses, Biological Evaluations, and Mechanistic Studies of Benzo[c][1,2,5]oxadiazole Derivatives as Potent PD-L1 Inhibitors with In Vivo Antitumor Activity.

A series of novel benzo[c][1,2,5]oxadiazole derivatives were designed, synthesized, and biologically evaluated as inhibitors of PD-L1. Among them, compound L7 exhibited 1.8 nM IC50 value in a homogeneous time-resolved fluorescence (HTRF) assay, which was 20-fold more potent than the lead compound BMS-1016. In the surface plasmon resonance (SPR) assay, L7 bound to human PD-L1 (hPD-L1) with a KD value of 3.34 nM, without showing any binding to hPD-1. In the cell-based coculture assay, L7 blocked PD-1/PD-L1 interaction with an EC50 value of 375 nM, while BMS-1016 had an EC50 value of 2075 nM. Moreover, compound L24, an ester prodrug of L7, was orally bioavailable and displayed significant antitumor effects in tumor models of syngeneic and PD-L1 humanized mice. Mechanistically, L24 exhibited significant in vivo antitumor effects probably through promoting antitumor immunity. Together, this series of benzoxadiazole PD-L1 inhibitors holds promise for tumor immunotherapy. Preclinical trials with selected compounds are ongoing in our laboratory.

Application of a simple skin stretching system and negative pressure wound therapy in repair of complex diabetic foot wounds.

The management of complex diabetic foot wounds with large skin defects poses a challenge for surgeons. We presented a simple skin stretching system and negative pressure wound therapy for the repair of complex diabetic foot wounds to examine the effectiveness and safety.A total of 16 patients with diabetic foot ulcers were retrospectively reviewed between January 2015 and October 2020. All patients underwent the treatment by 3 stages. In stage 2, these difficult-to-close wounds of diabetes foot were residual. This method was applied to the wounds with a median defect size of 20.42 cm2 (range, 4.71-66.76 cm2).The median time for closure of complex diabetic foot wounds was 14 days ranging from 8 to 19 days. With respect to the absolute rates of reduction, it was observed with a median of 1.86 cm2/day, ranging from 0.29 cm2/day to 8.35 cm2/day. In accordance with the localization of the defect, the patients were divided into 3 groups: side of the foot (37.5%), dorsum of the foot (50.0%), and others (12.5%). There was no statistical difference between side of the foot and dorsum of the foot in terms of the median defect size with P = 0.069 (Kruskal-Wallis test). Otherwise, there were statistically significant differences regarding the median time and the median absolute rates (P < 0.05; Kruskal-Wallis test). No severe complications were encountered in this study.In summary, our results show that application of the simple skin stretching system and NPWT is an effective and safe approach to complex diabetic foot wounds. Nevertheless, more attention should be paid to the appropriate patient selection and intraoperative judgment to ensure wound closure and avoid undue complications.

LINC00324 accelerates the proliferation and migration of osteosarcoma through regulating WDR66.

Osteosarcoma (OS) is a type of malignancy featured with high morbidity and easy metastasis. Although past years have witnessed the great improvement in the treatments of OS, there remains a long way to go. Therefore, further research on the underlying molecular mechanism of OS progression is in imminent need. Long noncoding RNAs (lncRNA) are recognized as a cluster of transcripts over 200 bases. Increasing studies have unveiled their significant regulatory roles in cancers, including in osteosarcoma. Long intergenic non-protein coding RNA 324 (LINC00324) is a newly identified lncRNA exerting oncogenic functions in several cancers, but its role in OS is yet to be uncovered. Therefore, the present study planned to explore the role of LINC00324 in osteosarcoma. We first validated the upregulation of LINC00324 in OS tissues and cell lines and established its correlation with OS tumor progression and metastasis. Importantly, the prognostic significance of LINC00324 was identified in patients with OS. Gain- and loss-of-function assays revealed that LINC00324 accelerated cell proliferation and migration in OS. Mechanistically, we revealed that LINC00324 stabilized WD repeat-containing protein 66 (WDR66) messenger RNA through interacting with Hu antigen R. Rescue assays verified that WDR66 was required for the regulation of LINC00324 in promoting proliferation and migration of OS cells. In conclusion, the present study proved that LINC00324 accelerated the proliferation and migration of osteosarcoma cells through regulating WDR66, providing a new prognostic target for osteosarcoma.

rhPDGF-BB combined with ADSCs in the treatment of Achilles tendinitis via miR-363/PI3 K/Akt pathway.

To investigate the mechanism of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and human adipose-derived stem cells (hADSCs) in the treatment of Achilles tendinitis. Biomechanical indices of stiffness, stress, and maximum load-to-failure were detected by biomechanical test. mRNA and protein levels of miR-363, p-PI3K/AKT, tendon-related genes Collagen I, Scleraxis (Scx), and Tenascin C (TNC) were measured by qRT-PCR and western blot. The proliferation of hADSCs was accessed by MTT assay. Biomechanical indices of stiffness, stress, and maximum load-to-failure, and mRNA and protein levels of tendon-related genes could be improved by rhPDGF-BB or hADSCs alone, and could be further improved by rhPDGF-BB + hADSCs. rhPDGF-BB and hADSCs downregulated the expression of miR-363 and upregulated the levels of p-PI3K/Akt, and rhPDGF-BB + hADSCs further strengthened these effects. In addition, rhPDGF-BB promoted the proliferation of hADSCs in vitro and upregulated the expression of tendon-related genes. miR-363 mimic downregulated the levels of p-PI3K/Akt, miR-363 inhibitor upregulated the levels of p-PI3K/Akt, and miR-363 mimic and PI3K/Akt pathway inhibitor LY294002 reversed the positive effect of rhPDGF-BB on the proliferation of hADSCs, which suggested that rhPDGF-BB promoted the proliferation of hADSCs via miR-363/PI3K/Akt pathway. Biomechanical indices and tendon-related genes could be improved by rhPDGF-BB and hADSCs. Moreover, rhPDGF-BB promoted the proliferation of hADSCs via miR-363/PI3K/Akt pathway, indicating that rhPDGF-BB combined with ADSCs could treat Achilles tendinitis via miR-363/PI3K/Akt pathway.

[Iincidence of postoperative delirium after hip surgery in elderly patients: a meta-analysis].

OBJECTIVE: To evaluate incidence of postoperative delirium after hip surgery in elderly patients by meta-analysis. METHODS: From January 1, 2014 to December 31, 2013, clinical literatures about postoperative delirium after hip surgery in elderly patients,were searched from the Pubmed. Literature extract table were formed according to inclusion and exclusion criteria. Stata-12.0 was applied for Meta-analysis. P was used to test heterogeneity of study, random-effect model was performed when I2 > 50%. Subgroup analysis was used according to stage of age, assessment scale of delirium and statistical area of literature. Begg test was used to test publication bias. RESULTS: Twenty-one literatures were included. Incidence of postoperative delirium after hip surgery in elderly patients by weighted and combination was 17% [95% CI (16%, 18%)]. Incidence of postoperative delirium after optional hip surgery was decreased more than emergency operation in included 5 literatures [OR = 0.32, 95% CI (0.22, 0.45)]. Incidence of postoperative delirium in patients less than 80 years old was 21% [95% CI (19%, 23%)], while 21% [95% CI (19%, 24%)] in patients more than 80 years old. Incidence of postoperative delirium in CAM evaluation scale was 23% [95% CI (21%, 26%)], while 19% [95% CI (17%, 21%)] in other evaluation scales. Incidence of postoperative delirium in Asian area was 17% [95% CI (15%, 20%)], while 23% [95% CI (21%, 25%)] in European and American area. There was no publication bias tested by Begg test (P < 0.05). CONCLUSION: Incidence of postoperative delirium after hip surgery in elderly patients increases higher, especially in emergency operation. A standardizing research method is benefit for evaluate incidence of postoperative delirium after hip surgery in elderly patients, decreasing heterogeneity and publication bias.

Two new Aprostocetus species (Hymenoptera: Eulophidae: Tetrastichinae), fortuitous parasitoids of invasive eulophid gall inducers (Tetrastichinae) on Eucalyptus and Erythrina.

Two closely related new species of Aprostocetus Westwood (Hymenoptera: Eulophidae: Tetrastichinae) are described as fortuitous parasitoids of invasive gall inducers in two other genera of Tetrastichinae, Leptocybe Fisher & LaSalle and Quadrastichus Girault. Aprostocetus causalis La Salle & Wu is a parasitoid of Leptocybe invasa Fisher & La Salle on Eucalyptus spp. (Myrtaceae) in China and Thailand, and A. felix La Salle, Yang & Lin is a parasitoid of Quadrastichus erythrinae Kim on Erythrina spp. (Fabaceae) in Taiwan. Epitetrastichus nigriventris Girault, 1913 is removed from synonymy from Aprostocetus gala (Walker), and treated as the valid species A. nigriventris (Girault). 

First report of Endoclita signifer (Lepidoptera: Hepialidae) as a new pest on Eucalyptus.

Endoclita signifier Walker (Lepidoptera: Hepialidae) has become a new wood borer pest in Eucalyptus plantations in southern China. This article documents survey results of its geographic distribution and host plant range in Guangxi and its morphological measurements, life cycle and behavior. In total, 83 Eucalyptus growing counties were surveyed. E. signifier was found in 59 counties. Host plants included 31 species in 16 families and 24 genera. Four Eucalyptus hybrid species were recorded as its host plant with E. grandis x E. urophylla and E. urophylla x E. grandis infested the heaviest. The infestation of Eucalyptus trees 1-2 yr old was heavier than that of older trees. Most individuals of E. signifier took 1 yr to complete a generation, overwintering as larvae in tunnels in wooden stems, and pupating in February of the following year. Adults emerge, mate, and lay eggs in April, and the eggs hatch in late April or early May. Adult emergence peaks between 17:00-18:59 hours. Mating flights last under 30 min at dusk and the copulation duration was 24 h. Moths were large, weighting and average of 3.4 g. Eggs and newly hatched larvae were very small, weighing only 0.127 +/- 0.001 mg and 0.093 +/- 0.017 mg, respectively. The larvae have two distinct development stages. One stage spends 1-2 mo living in the forest litter, the second stage then moves to woody stems where it feeds for approximately 10 mo. Larvae start boring into hosts between June and November, mainly in July and August. This study indicated that E. signifier, a highly polyphagous native species, has shifted host to exotic Eucalyptus and can cause significant damage to plantations.