Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG^@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.

Male ; Humans ; Spermatic Cord ; Mesothelioma ; Mesothelioma, Malignant

Animals ; Mice ; Colon ; Histological Techniques

Objective: To investigate the clinicopathological features, immunophenotype, molecular features and differential diagnosis of primary synovial sarcoma of the lung (PSSL). Methods: Twelve cases of PSSL were collected at Henan Provincial People's Hospital, during May 2010 and April 2021, and their clinicopathological parameters were summarized. SS18-SSX, H3K27Me3, and SOX2 were added to the original immunomarkers to evaluate their diagnostic value for PSSL. Results: The age of 12 patients when diagnosed ranged from 32 to 75 years (mean of 50 years). There were 7 males and 5 females, 2 left lung cases and 10 right lung cases. Of the 6 patients who underwent surgical resection, five cases were confined to lung tissue (T1), one case had mediastinal invasion (T3), two cases had regional lymph node metastasis (N1), and none had distal metastasis. Microscopically, 11 cases showed monophasic spindle cell type and one case showed biphasic type composed of mainly epithelial cells consisting of cuboidal to columnar cells with glandular and cribriform structures. It was difficult to make the diagnosis by using the biopsy specimens. Immunohistochemistry (IHC) showed CKpan expression in 8 of 12 cases; EMA expression in 11 of 12 case; TLE1 expression in 8 of 12 cases; S-100 protein expression in two of 12 cases; various expression of bcl-2 and vimentin in 12 cases, but no expression of SOX10 and CD34 in all the cases. The Ki-67 index was 15%-30%. The expression of SS18-SSX fusion antibody was diffusely and strongly positive in all 12 cases. SOX2 was partially or diffusely expressed in 8 of 12 cases, with strong expression in the epithelial component. H3K27Me3 was absent in 3 of 12 cases. SS18 gene translocation was confirmed by fluorescence in situ hybridization (FISH) test in all 12 samples. Six cases underwent surgery and postoperative chemotherapy, while the other six cases had chemotherapy alone. Ten patients were followed up after 9-114 months, with an average of 41 months and a median of 26 months. Five patients survived and five died of the disease within two years. Conclusions: PSSL is rare and has a broad morphological spectrum. IHC and molecular tests are needed for definitive diagnosis. Compared with current commonly used IHC markers, SS18-SSX fusion antibody has better sensitivity to PSSL, which could be used as an alternative for FISH, reverse transcription-polymerase chain reaction or next generation sequencing in the diagnosis of PSSL.
Male ; Female ; Humans ; Adult ; Middle Aged ; Aged ; Biomarkers, Tumor/analysis* ; Sarcoma, Synovial/diagnosis* ; In Situ Hybridization, Fluorescence ; Histones/genetics* ; Proto-Oncogene Proteins/metabolism* ; Oncogene Proteins, Fusion/genetics* ; Repressor Proteins/metabolism* ; Lung/pathology* ; Lung Neoplasms

Humans ; Mesenchymoma/surgery* ; Soft Tissue Neoplasms ; Osteomalacia

Adult ; Brain ; Brain Diseases ; Heat Stroke ; Humans ; Magnetic Resonance Imaging ; Male ; Retrospective Studies

Objective:To explore the effect of a Chinese medicinal composition ( Xiadanqi) on the prevention of radon exposure induced injuries of lung in vitro and in vivo. Methods:Mice were randomly divided into three groups of blank control group, radon-exposed group alone and radon-exposed group intervened with Chinese medicinal composition. The pathological changes of lung tissues in each group after 120 WLM were observed by HE and Masson staining, and the expressions of α-SMA protein and Vimentin protein in lung tissues were detected by immunohistochemistry staining. The levels of oxidative stress in lung tissue of each group were detected with SOD and MDA kits. At the same time, a radon exposed cell model and a radon exposure + Xiadanqi intervention cell model were constructed using an ecological radon chamber. The cell adhesion abilities of different groups were detected by an adhesion kit. The cell migration ability of each group was determined by the transwell migration experiment. The expression of E-cadherin and Vimentin protein was detected by Western blot. Results:Compared with the radon exposure group, the concentration of MDA was decreased ( t=4.43, P<0.05), the activity of SOD was increased ( t=3.22, P<0.05), and α-SMA and Vimentin protein expressions were decreased ( t=3.08, 7.57, P<0.05) in lung tissue of mice intervened with 2 mg/g Xiadanqi. In vitro, compared with radon exposure group, the migration ability was reduced ( t=4.78, 13.01, P<0.05), the cell adhesion property was enhanced ( t=3.41, 12.55, P<0.05), the expression of E-cadherin protein was increased ( t=2.96, 19.57, P<0.05), and the expression of Vimentin protein was obviously reduced ( t=21.00, 33.32, P<0.05) in radon-exposed cells with the treatment of Chinese medicine (150 μg/ml and 200 μg/ml). Conclusions:The Chinese medicinal composition ( Xiadanqi) has a certain radioprotective effect on radon exposure induced injury by reducing oxidative stress, attenuating EMT and fibrosis, and thus it may be applied as a protective agent for radon induced injury.

Objective: To understand the disease progression and human leukocyte antigen (HLA) gene polymorphism of HIV-infected persons without disease progress for long term, also known as long-term non-progressors (LTNPs), in Henan province. Methods: A retrospective study was conducted in 48 LTNPs with complete detection and follow-up information during 2011-2016 in Henan. Changes of CD(4)(+)T cells counts (CD(4)) and viral load (VL) during follow-up period were discussed. Polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) was used for the analyses of HLA-A, HLA-B and HLA-DRB1 alleles between LTNPs and healthy controls. Results: From 2011 to 2016, forty-eight LTNPs showed a decrease of the quartile (P(25)-P(75)) of CD(4) from 601.00 (488.50-708.72)/μl to 494.00 (367.00-672.00)/μl, and the difference was significant (P<0.05). The increase of the quartile (P(25)-P(75)) of log(10)VL from 3.40 (2.87-3.97) to 3.48 (2.60-4.37), but the difference was not significant (P>0.05). HLA polymorphism analysis revealed that HLA-B*13:02 and HLA-B*40:06 were more common in LTNPs (P<0.05), while HLA-B*46:01 and HLA-DRB1*09:01 were more common in healthy controls (P<0.05). Conclusions: The CD(4) of LTNPs in Henan showed a downward trend year by year. HLA-B*13:02 and B*40:06 might be associated with delayed disease progression for HIV infected persons in Henan.
Adult ; Alleles ; Asian People/genetics* ; China ; Disease Progression ; Female ; HIV ; HIV Infections/virology* ; HIV-1/immunology* ; HLA-B Antigens/genetics* ; Humans ; Middle Aged ; Polymorphism, Genetic ; Retrospective Studies ; Viral Load