Glioma is difficult to treat due to the unique tumor microenvironment and blood-brain barrier. (13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine (PF403), a phenanthroindolizidine alkaloid, has been identified as a promising therapeutic agent for the treatment of glioma. However, the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated. Hence, a strategy without chemical modification was applied to identify the target of PF403. In this study, we identified nicotinamide phosphoribosyl transferase (NAMPT) as the target of PF403 by using thermal proteome profiling (TPP). Moreover, microscale thermophoresis (MST), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments confirmed that NAMPT exhibits good affinity for PF403. Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT, leading to a decrease in the concentration of nicotinamide adenine dinucleotide (NAD⁺) in U87 cells. X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of pi-pi interactions with residue Tyr188 to maintain binding with NAMPT (PDB code 8Y55). After NAMPT was knocked down with lentivirus, PF403 lost or partially lost its antitumor activity at the cellular and animal levels. These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.

Objective:To improve the perception of computed tomography(CT)images in detecting fine fracture through multi-task network of global attention,and to realize the detection of the target of fine fracture at case level through multi-task,and to quickly and accurately identify and locate fracture from a large number of CT images,so as to assist doctors to timely conduct treatment.Methods:A grouped Non-local network method was introduced to calculate the remote dependency relationship between each position of CT image continuous sections and channel.A single-stage detector of multi-objective detection model three dimension(3D)RetinaNet was integrated with the medical image semantic segmentation architecture(3D U-Net).A end-to-end multi-task 3D convolutional network was realized,which realized the detection of case level for fine fracture through multi-task collaboration.Select 600 CT scan images from the Rib Frac Dataset of rib fractures provided by the MICCAI 2020 Challenge,and they were divided into training set(500 cases)and test set(100 cases)as the ratio of 5:1 to test the precise performance of multi-task 3D convolutional network.Results:The precise performance of multi-task 3D convolutional network method was better than that of single-task FracNet,3D RetinaNet and 3D Retina U-Net in detection,which average precision was respectively higher 7.8%and 11.4%than 3D RetinaNet and 3D Retina U-Net.It was better than two kinds of single-task network detection method included 3D Faster R-CNN and 3D Mask R-CNN,and the average precision of that was respectively higher 6.7%and 3.1%than them.Conclusion:The integrated different modules of global attention multi-task network can improve the detection performance of fine fracture.The introduction of grouped Non-local network method can further improve the precise performance for the targets of fine fractures in detection.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

[This corrects the article DOI: 10.1016/j.apsb.2022.02.031.].

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors. Brain metastasis, such as breast cancer and lung cancer, also leads to high mortality. The available medicines are limited due to blood-brain barrier. Abnormal activation of phosphatidylinositol 3-kinases (PI3K) signaling pathway is prevalent in glioblastoma and metastatic tumors. Here, we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3K inhibitor with excellent anti-tumor activity against human glioblastoma. XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3K signaling pathway, induced cell cycle arrest in G1 phase as well. Additionally, XH30 inhibited the migration of glioma cells and blocked the activation of PI3K pathway by interleukin-17A (IL-17A), which increased the migration of U87MG. Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models. XH30 also repressed tumor growth in brain metastasis models of lung cancers. Moreover, XH30 reduced IL-17A and its receptor IL-17RA in vivo. These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3 T lymphocytes re-distribution by inducing lymphocytes' homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment.

Objective:To retrospectively analyze the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) accompanied with diarrhea.Methods:From January 11 to February 6 in 2020, the clinical data of 663 patients diagnosed with COVID-19 admitted to Renmin Hospital of Wuhan University were collected and divided into diarrhea group and non-diarrhea group according to whether they had diarrhea or not. The differences in baseline characteristics, basic disease history, clinical manifestations, chest computed tomography (CT), laboratory findings, disease severity and mortality between the two groups were compared. Chi-square test and Fisher exact test were used for statistical analysis.Results:Among 663 COVID-19 patients, 70 (10.6%) patients accompanied with diarrhea. The proportion of fatigue and increased lactate dehydrogenase (LDH) levels of diarrhea group were higher than those of non-diarrhea group (58.6%, 41/70 vs. 28.2%, 167/593; and 64.2%, 43/67 vs. 50.4%, 277/550), and the differences were statistically significant ( χ2=26.891 and 4.566, both P<0.05). There was no statistically significant difference in the proportion of pneumonia in chest CT between diarrhea group and non-diarrhea group (100.0%, 62/62 vs. 99.4%, 529/532) ( P>0.05). There were no statistically significant differences in the proportions of mild and normal type, severe type and critical type between diarrhea group and non-diarrhea group (35.7%, 25/70 vs. 38.6%, 229/593; 50.0%, 35/70 vs. 47.2%, 280/593; and 14.3%, 10/70 vs. 14.2%, 84/593, respectively) (all P>0.05). There were no statistically significant differences in the mortality of mild and normal type, severe type and critical type between diarrhea group and non-diarrhea group (0 vs. 0.5%, 3/593; 0 vs. 0 and 1.4%, 1/70 vs. 3.5%, 21/593) (all P>0.05). Conclusions:Patients with COVID-19 accompanied with diarrhea are more likely to have fatigue and increased LDH level. Diarrhea is not significantly correlated with the disease severity of patients with COVID-19.

Objective To investigate the morphological changes of the brainstem in patients with Alzheimer's disease (AD) and their relationship with hippocampal morphological changes.Methods Sixty AD patients (AD group) and sixty age-and gender-matched normal elderly (normal control group) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.The hippocampus and the brainstem of each subject were segmented and their normalized volumes were calculated.According to the hippocampal volume standard value (Z-score),AD patients were divided into two subgroups (hippocampal atrophy group (n=51) and hippocampal spared group (n=9)).A voxel-based morphology (VBM) study was also performed to investigate the morphological differences of the brainstem between the normal control group and the AD group,as well as between the AD subgroups.Results Compared with the normal control group,the brainstem volume in the AD group decreased significantly (16 741.31±1 739.11 vs 15 609.67±1 451.60,t=3.870,P=0.001).In AD subgroups,the volume of the brainstem in the hippocampal atrophy group was significantly smaller than that in the hippocampal spared group (16 556.30 ± 1 514.86 vs 15 442.62 ± 1 389.05,t=2.189,P=0.033).Pearson correlation analysis showed that Mini-Mental State Examination scores were positively correlated with the hippocampal and the brainstem volumes (r=0.590,P＜0.01;r=0.234,P＜0.05),and there was a positive correlation between the hippocampal and the brainstem volume changes in patients with AD (r=0.315,P=0.014).VBM results showed that both the bilateral midbrain and the bilateral pons in the AD group had significant atrophy compared with the normal control group (P＜0.05).In the AD subgroups,the bilateral midbrain and the left pons in the hippocampal atrophy group were significantly atrophied compared with the hippocampal spared group (P＜0.05).Conclusion The brainstem showed morphological changes in patients with AD,and the morphological changes of the brainstem in AD patients with different degrees of hippocampal atrophy were different,indicating the morphological changes of the hippocampus and the brainstem may have an interrelated relationship.