Discovery of novel covalent inhibitors of DJ-1 through hybrid virtual screening.

Background: DJ-1 is a ubiquitously expressed protein with multiple functions. Its overexpression has been associated with the occurrence of several cancers, positioning DJ-1 as a promising therapeutic target for cancer treatment. Methods: To find novel inhibitors of DJ-1, we employed a hybrid virtual screening strategy that combines structure-based and ligand-based virtual screening on a comprehensive compound library. Results: In silico study identified six hit compounds as potential DJ-1 inhibitors that were assessed in vitro at the cellular level. Compound 797780-71-3 exhibited antiproliferation activity in ACHN cells with an IC50 value of 12.18 µM and was able to inhibit the Wnt signaling pathway. This study discovers a novel covalent inhibitor for DJ-1 and paves the way for further optimization.

Multicargo-loaded inverse opal gelatin hydrogel microparticles for promoting bacteria-infected wound healing.

Nowadays, many strategies have been developed to design biomaterials to accelerate bacteria-infected wound healing. Here, we presented a new type of multicargo-loaded inverse opal hydrogel microparticle (IOHM) for regulating oxidative stress, antibiosis, and angiogenesis of the bacteria-infected wound. The methacrylate acylated gelatin (GelMA)-based inverse opal hydrogel microparticles (IOHMs) were obtained by using the colloidal crystal microparticles as templates, and fullerol, silver nanoparticles (Ag NPs), and vascular endothelial growth factor (VEGF) were loaded in IOHMs. The developed multicargo-loaded IOHMs displayed good size distribution and biocompatibility, and when they were applied in cell culture, bacteria culture, and animal experiments, they exhibited excellent anti-oxidative stress properties, antibacterial properties, and angiogenesis. These characteristics of the developed multicargo-loaded IOHMs make them ideal for bacteria-infected wound healing.

An ultra-sensitive platinized nanocavity electrode for analysis of cytosolic catecholamines in one living cell.

The catecholamines, mainly dopamine (DA), are present in the cellular cytosol with low abundance, while, play key roles in various neurodegenerative disorders. Here, platinized nanocavity carbon electrodes are employed to analyze cytosolic catecholamines in a single living PC12 cell, which is not easily quantified using the classic electrodes. The confined structure and excellent conductivity in the platinized nanocavity accelerate the electron transfer of the DA, resulting in a low detection limit down to 50 nM. The sensitivity of DA detection is improved to be 10.73 pA mM-1 nm-1 in the response range of 50 nM-100 µM, which guarantees quantitative analysis of cytosolic catecholamines with low abundance. Eventually, the platinized nanocavity electrode is employed to detect cytosolic catecholamines in a single PC12 cell without an obvious interruption of cellular catecholamine level. The cytosolic catecholamines in a single PC12 cell is measured in situ to be 0.1 µM, which is achieved for the first time at the single cell level using the electrochemical method. The results demonstrate that the nanocavity electrode with a high sensitivity could offer a promising means to dynamically track catecholamines in a single cell.

How does congenital cervicothoracic scoliosis bring about early trunk tilt and coronal imbalance during curve progression: a radiographic analysis to dissect the mechanism of proximal takeoff phenomenon.

PURPOSE: To dissect the mechanism of how congenital cervicothoracic scoliosis (CTS) drive the occurrence of early trunk tilt, namely proximal takeoff phenomenon (PTO) during curve progression. METHODS: CTS patients were stratified into case and control groups according to the presence of PTO. The radiographic deformity parameters of head-neck-shoulder complex were measured and compared between the two groups. The main risk factors for PTO were identified through multiple linear regression analysis. RESULTS: 16 CTS patients with PTO were recruited, and the non-PTO group consisted of 19 CTS patients without PTO. The average Cobb angle was 64.9 ± 19.8° in PTO group and 57.7 ± 21.9° in control group (p > 0.05). Significant difference could be observed for head shift, neck tilt, trunk inclination, apex-C7 deformity angular ratio (DAR), apex translation ratio, C6 tilt, clavicle angle (CA), radiographic shoulder height (RSH), head-neck translation and coronal balance distance (CBD) (All p < 0.05) but not head tilt (p > 0.05). Multiple linear regression analysis revealed that head shift, but not neck tilt correlated significantly with the severity of trunk inclination (ß = 0.106, p = 0.003), while apex-C7 DAR and apex translation ratio were the two factors contributing significantly to the severity of head shift (ß = 0.620, p = 0.020; ß = - 0.371, p = 0.004). CONCLUSIONS: Development and progression of head shift rather than neck tilt is a significant causative factor initiating the occurrence of trunk tilt and proximal takeoff in CTS. A higher apex-C7 DAR representing a short angular upper hemi curve and a lower apex translation ratio representing poor proximal coronal compensation are key risk factors predisposing to head shift.

Differential Gene Expression Profiles and Pathways Highlight the Role of Osteoimmunology in Neurofibromatosis Type 1-Related Dystrophic Scoliosis With Osteopenia.

STUDY DESIGN: Microarray approach and integrated gene network analysis. OBJECTIVE: To explore the differential genetic expression profile, Gene Ontology terms, and Kyoto Encyclopedia of Genes and Genomes pathways in human trabecular bone (HTB)-derived cells of dystrophic scoliosis secondary to neurofibromatosis type 1 (DS-NF1) and compare these to normal controls. SUMMARY OF BACKGROUND DATA: The pathogenesis of DS-NF1 and the accompanying generalized osteopenia remain unclear. We hypothesized that HTBs may play a significant role in the etiology and pathogenesis of DS-NF1. MATERIALS AND METHODS: Microarray analysis was used to identify differentially expressed genes of HTBs from patients with DS-NF1 compared with those from healthy individuals. Functional and pathway enrichment analysis were implemented through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway database. Then, the "search tool for the retrieval of interacting genes/proteins" database, Cytoscape, and "Molecular Complex Detection" were applied to construct the protein-protein interaction (PPI) network and screen hub genes. Pathway enrichment analysis was further performed for hub genes and gene clusters identified through module analysis. Six potential crucial genes were selected for validation by reverse transcription polymerase chain reaction. RESULTS: Bioinformatic analysis revealed that there are 401 previously unrecognized differentially expressed genes (238 up and 163 downregulated genes) in HTBs from patients with DS-NF1, and they were mainly enriched in terms of immune response, type-I interferon (IFN) signaling, TNF signaling pathway and etinoic acid inducible gene I-like receptor signaling pathway. Five hub genes, including signal transducer and activator of transcription 1, 2'-5'-oligoadenylate synthetase-like, IFN induced with helicase C domain 1, IFN regulatory factor 7, and MX dynamin-like GTPase 1 were identified through PPI network, which were mainly enriched in terms of Jak-STAT and etinoic acid inducible gene I-like receptor signaling pathway. An independently dysregulated protein cluster containing CCL2, CXCL1, CXCL3, CX3CL1, TLR1 , and CXCL12 was also identified through the PPI network. This indicated that the upper abnormally expressed genes may play essential roles in DS-NF1 pathogenesis and accompanied osteopenia. CONCLUSION: Six key genes were identified in the progression of DS-NF1-related osteopenia. Immune response might play a key role in the progression of osteopenia, whereas a CXCL12 -mediated osteogenic effect might play a protective role.

Higher Baseline Serum Myokine of FSTL1 May Serve as a Potential Predictive Biomarker for Successful Brace Treatment in Girls With Adolescent Idiopathic Scoliosis.

STUDY DESIGN: A retrospective case-control study. OBJECTIVE: This study aimed to investigate whether myokine, which is related to exercise and muscle mass, could serve as a biomarker for predicting bracing outcomes. SUMMARY OF BACKGROUND DATA: Several risk factors have been documented to be associated with bracing failure in patients with adolescent idiopathic scoliosis (AIS). However, serum biomarkers have not been extensively explored. PATIENTS AND METHODS: Skeletally immature females with AIS, without previous histories of bracing or surgery, were included. Peripheral blood was collected at the time of the bracing prescription. Baseline serum concentrations of 8 myokines [apelin, fractalkine, brain-derived neurotrophic factor, erythropoietin, osteonectin, fatty-acid-binding protein 3, follistatin-like 1 (FSTL1), and musclin] were measured by multiplex assays. Patients were followed up until weaned from bracing and then designated as a "failure" (defined as Cobb angle progression >5°) or "success." A logistic regression analysis was performed that accounted for serum myokines and skeletal maturity. RESULTS: We included 117 patients, with 27 in the failure group. Patients in the failure group had lower initial Risser sign and lower baseline serum levels of myokines, including FSTL1 (2217.3 ± 617.0 vs . 1369.3 ± 704.9, P = 0.002), apelin [116.5 (12.0, 335.9) vs . 83.5 (10.5, 221.1), P = 0.016], fractalkine (979.6 ± 457.8 vs . 743.8 ± 456.1, P = 0.020), and musclin [211.3 (16.3, 370.3) vs . 67.8 (15.5, 325.6), P = 0.049]. Following adjusted analysis, serum FSTL1 [odds ratio = 10.460; (2.213-49.453)] was determined to be predictive of bracing effectiveness. CONCLUSION: Patients who failed AIS bracing had significantly lower mean baseline levels of FSTL1 than those who achieved success. FSTL1 may serve as a biomarker that can inform outcomes after bracing.

Intratumoral Microbiota-Host Interactions Shape the Variability of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma in Recurrence and Metastasis.

Differences in tissue microbiota-host interaction between lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) about recurrence and metastasis have not been well studied. In this study, we performed bioinformatics analyses to identify the genes and tissue microbes significantly associated with recurrence or metastasis. All lung cancer patients were divided into the recurrence or metastasis (RM) group and the nonrecurrence and nonmetastasis (non-RM) group according to whether or not they had recurred or metastasized within 3 years after the initial surgery. Results showed that there were significant differences between LUAD and LUSC in gene expression and microbial abundance associated with recurrence and metastasis. Compared with non-RM, the bacterial community of RM had a lower richness in LUSC. In LUSC, host genes significantly correlated with tissue microbe, whereas host-tissue microbe interaction in LUAD was rare. Then, we established a novel multimodal machine learning model based on genes and microbes to predict the recurrence and metastasis risk of a LUSC patient, which achieves an area under the curve (AUC) of 0.81. In addition, the predicted risk score was significantly associated with the patient's survival. IMPORTANCE Our study elucidates significant differences in RM-associated host-microbe interactions between LUAD and LUSC. Besides, the microbes in tumor tissue could be used to predict the RM risk of LUSC, and the predicted risk score is associated with patients' survival.

How to rectify the convex coronal imbalance in patients with unstable dystrophic scoliosis secondary to type I neurofibromatosis: experience from a case series.

BACKGROUND: There was a paucity of valid information on how to rectify the convex coronal imbalance effectively in dystrophic scoliosis secondary to Type I neurofibromatosis (DS-NF1), while postoperative inadvertent aggravation of CCI occurred regularly resulting in poor patient satisfaction. We aimed to identify the risk factors for persistent postoperative CCI in DS-NF1, and to optimize the coronal rebalancing strategies based on the lessons learned from this rare case series. METHODS: NF1-related scoliosis database was reviewed and those with significant CCI (> 3 cm) were identified, sorted and the outcomes of surgical coronal rebalance were analyzed to identify the factors being responsible for failure of CCI correction. RESULTS: CCI with dystrophic thoracolumbar/lumbar apex was prone to remain uncorrected (7 failure cases in 11) when compared to those with thoracic apex (0 failure cases in 4) (63.6% vs. 0.0%, p = 0.077). Further comparison between those with and without post-op CCI showed a higher correction of main curve Cobb angle (65.9 ± 9.1% vs. 51.5 ± 37.3%, p = 0.040), more tilted instrumentation (10.3 ± 3.6° vs. 3.2 ± 3.1°, p = 0.001) and reverse tilt and translation of upper instrumented vertebra (UIV) to convex side (8.0 ± 2.3° vs. -3.4 ± 5.9°, p < 0.001; 35.4 ± 6.9 mm vs. 12.3 ± 13.1 mm, p = 0.001) in the uncorrected imbalanced group. Multiple linear regression analysis revealed that △UIV translation (pre- to post-operation) (ß = 0.832; p = 0.030) was significantly correlated with the correction of CBD. CONCLUSION: Thoracolumbar/lumbar CCI in dystrophic scoliosis was prone to suffer high risk of persistent post-op CCI. Satisfying coronal rebalance should avoid UIV tilt and translation to the convex side, tilted morphology of instrumentation and over correction maneuvers for main curve, the upper hemi-curve region in particular.

Scoliosis: an unusual clinical presentation of paraspinal ganglioneuroma.

PURPOSE: To comprehensively present the clinical characteristics and treatment strategies in patients with scoliosis secondary to ganglioneuroma (S-GN). METHODS: Six patients with S-GN treated surgically at a median age of 12 years were retrospectively reviewed and the median follow-up period was 6 years (4-14 years). The radiological features of GN and the associated scoliosis were evaluated. The surgical strategies and the corresponding outcomes were investigated. RESULTS: All patients had a delayed diagnosis age of GN than scoliosis (12 vs. 9 years). GN was located at the posterior mediastinum in four patients (66.7%) and at retroperitoneum in two, respectively. Tumor occupancies were frequently detected on the X-ray films for four patients (66.7%), being uniformly on the convexity of the main curve. All patients complained of rapid progressive deformities during the growth period. Five patients (83.3%) received total tumor resections, one accepted partial resection. Deformity correction was implemented for all patients with an average rate of 66.4% on the main curve. No recurrence of the GN was detected for all totally tumor-resected patients at the latest follow-up. CONCLUSION: S-GN is often misdiagnosed clinically. Paravertebral mass neighboring the apex of scoliosis can be meticulously detected from the X-ray films. Total tumor resection should be aggressively performed if possible. The deformity correction could be satisfactorily obtained and the risk of recurrence of the GN was relatively low.

Could screw/hook insertion at the apical vertebrae with rib head dislocation effectively retract the corresponding rib head from spinal canal in dystrophic scoliosis secondary to type 1 neurofibromatosis?

BACKGROUND: Rib head dislocation (RHD) in dystrophic scoliosis of type 1 neurofibromatosis (DS-NF1) is a unique disorder caused by skeletal dystrophy and scoliotic instability. No particular surgical manipulation is mentioned in the literature to instruct the spine surgeons to effectively obtain more migration of the dislocated rib head without resection. The present study aimed to investigate the effectiveness of screw/hook insertion at vertebrae with RHDs on the retraction of penetrated rib head from spinal canal. METHODS: 37 neurologically intact patients with DS-NF1 and concomitant 53 RHDs undergoing scoliosis surgery without rib head excision were retrospectively reviewed. We used pre and postoperative whole-spine radiographs to determine the Cobb angle and the vertebral translation (VT), and the CT scans to evaluate the intraspinal rib length (IRL) and rib-vertebral angle (RVA). The dislocated ribs were assigned into two groups according to the presence of screw/hook insertion at vertebrae with RHD: screw/hook group and non-screw/hook group. RESULTS: 37 dislocated ribs with screws/hooks insertion at corresponding vertebrae were assigned into the screw/hook group and the remaining 16 dislocated ribs consisted of the non-screw/hook group. In the screw/hook group, the correction rates of Cobb angle and VT were significantly higher than the non-screw/hook group after surgery (58.7 ± 16.0% vs. 30.9 ± 12.4%, p = 0.003; 61.8 ± 18.8% vs. 35.1 ± 16.6%, p = 0.001; respectively). Similarly, more correction rates of IRL and RVA were found in the screw/hook group than the non-screw/hook group (63.1 ± 31.3% vs. 30.1 ± 20.7%, p = 0.008; 17.6 ± 9.7% vs. 7.2 ± 3.6%, p = 0.006; respectively). Multiple linear regression analysis revealed that the correction rates of Cobb angle, VT and RVA contributed significantly to correction of IRL (ß = 0.389, 0.939 and 1.869, respectively; p = 0.019, 0.001 and 0.002, respectively). CONCLUSION: Screw/hook insertion at dystrophic vertebrae with RHDs contributed significantly to the degree of retraction of penetrated rib head from spinal canal. This effectiveness is mediated by more corrections of VT and RVA.

Posterior 3-Column Osteotomy for Treatment of Congenital Kyphosis with Multiple Thoracolumbar/Lumbar Anterior Unsegmented Vertebrae: A Comparison Between Patients with Increasing Number of Anterior Unsegmented Vertebrae.

BACKGROUND: A 3-column osteotomy is sometimes challenging in congenital kyphosis (CK) with many anterior unsegmented vertebrae (AUVs). This study compared surgical outcomes of single-level 3-column osteotomy and associated complications in CK with increasing number of AUVs. METHODS: We retrospectively reviewed 25 consecutive patients with AUVs in CK who underwent surgery at a mean age of 16.2 ± 10.3 years. Patients were stratified into 2 groups according to the number of AUVs: 3 AUVs and ≥4 AUVs. Osteotomy types, surgical outcomes, and related complications were analyzed and compared between groups. RESULTS: The 3 AUVs group comprised 13 patients, and the ≥4 AUVs group comprised 12 patients. Pedicle subtraction osteotomy, grade 4 osteotomy, vertebral column resection, and vertebral column decancellation accounted for 15.4%, 38.5%, 46.1%, and 0% of procedures in the 3 AUVs group and 8.3%, 0%, 83.3%, and 8.3% of procedures in the ≥4 AUVs group. Preoperative focal kyphosis, which was significantly higher in the ≥4 AUVs group (82.9° ± 28° vs. 59.7° ± 9.4°, P = 0.010), was corrected in both groups postoperatively. The ≥4 AUVs group had significantly higher remaining kyphosis (33.6° ± 13.4° vs. 15.1° ± 9.1°, P < 0.001) with a significantly lower correction rate (61.2% ± 13.6% vs. 75.0% ± 15.6%, P = 0.001). The complication rate, mainly involving vertebral subluxation and proximal junctional kyphosis, was significantly higher in the ≥4 AUVs group than the 3 AUVs group (8/12 vs. 1/13, P = 0.004). CONCLUSIONS: Posterior single-level 3-column osteotomy can achieve satisfactory kyphosis correction in CK with 3 AUVs. Decreasing kyphosis correction and increasing surgery-related complications are prone to develop when treating CK with ≥4 AUVs.

Levels and ecological risk of heavy metals in the surface sediments of tidal flats along the North Jiangsu coast, China.

We investigated the contamination levels of nine heavy metals (Mn, Pb, V, Cr, Co, Ni, Cu, Zn, and As) in 153 surface sediment samples collected along five tidal flats on the North Jiangsu coast, China. The spatial distributions of most heavy metals gradually decreased from the northern Sheyang region to the southern Jianggang region, while slightly increasing in the Rudong region. Principal component analysis indicated that Co, Ni, Cu, Zn, and As were mainly derived from the natural environment, V and Cr were mainly derived from human activities. Additionally, Mn and Pb influenced by both natural and human sources. The geo-accumulation index and the contamination factor indicated that heavy metal contamination in the sediments exhibited little to no pollution levels. The potential ecological risk index exhibiting low ecological risks. Meanwhile, the mean probable effect level quotient values indicating slight toxicity. Cr and Ni were the major contributors to toxicity.

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Methanol, ethyl acetate, and water were used to extract the continuous cropping soils of Panax notoginseng, with the solution/soil ratios of 3:1, 6:1, and 9:1. We investigated the effects of those soil extracts on the growth and population of root-rot pathogens of P. notoginseng. Results showed that the methanol, ethyl acetate and water extracts all promoted mycelial growth of Fusarium oxysporum and Fusarium solani after 72 h of plate culture. The response indices of methanol and ethyl acetate extracts on the growth of F. oxysporum were 14.0%-19.8% and 16.2%-20.2%, being higher than that of water extract (8.9%-14.2%), but without significant difference between diffe-rent extraction ratios. However, methanol extract inhibited the mycelial growth of Alternaria spp. The inhibitory effect was highest at the extraction ratio of 3:1, reaching -33.2% to -38.5%. Ethyl acetate and water extracts did not affect the mycelial growth of Alternaria spp. After four weeks of soil culture, methanol, ethyl acetate and water extracts all increased the F. oxysporum populations. The positive effect of water extract was higher than that of methanol (1.68×104-6.73×104 copies·g-1 dry soil) and ethyl acetate (1.77×104-3.72×104 copies·g-1 dry soil) extracts, being 3.49×106-9.56×106 copies·g-1 dry soil. This increment was weakened along with the increase of extraction ratio. Both water extract and methanol extract with low extraction ratio could increase the F. solani populations, while there were no significant effects of methanol, ethyl acetate and water extracts on the population of Alternaria spp. Therefore, the extracts from continuous P. notoginseng cropping soil showed allopathically promoting effects on the growth and population of root-rot pathogens, F. oxysporum and F. solani, which may be one of the reasons for the occurrence of root rot and other soil-borne diseases in replanted P. notoginseng gardens.

Autotoxic Ginsenoside Disrupts Soil Fungal Microbiomes by Stimulating Potentially Pathogenic Microbes.

Autotoxic ginsenosides have been implicated as one of the major causes for replant failure of Sanqi ginseng (Panax notoginseng); however, the impact of autotoxic ginsenosides on the fungal microbiome, especially on soilborne fungal pathogens, remains poorly understood. In this study, we aimed to investigate the influence of the ginsenoside monomers Rg1, Rb1, and Rh1, and that of their mixture (Mix), on the composition and diversity of the soil fungal community, as well as on the abundance and growth of the soilborne pathogen Fusarium oxysporum in pure culture. The addition of autotoxic ginsenosides altered the composition of the total fungal microbiome, as well as the taxa within the shared and unique treatment-based components, but did not alter alpha diversity (α-diversity). In particular, autotoxic ginsenosides enriched potentially pathogenic taxa, such as Alternaria, Cylindrocarpon, Gibberella, Phoma, and Fusarium, and decreased the abundances of beneficial taxa such as Acremonium, Mucor, and Ochroconis Relative abundances of pathogenic taxa were significantly and negatively correlated with those of beneficial taxa. Among the pathogenic fungi, the genus Fusarium was most responsive to ginsenoside addition, with the abundance of Fusarium oxysporum consistently enhanced in the ginsenoside-treated soils. Validation tests confirmed that autotoxic ginsenosides promoted mycelial growth and conidial germination of the root rot pathogen F. oxysporum In addition, the autotoxic ginsenoside mixture exhibited synergistic effects on pathogen proliferation. Collectively, these results highlight that autotoxic ginsenosides are capable of disrupting the equilibrium of fungal microbiomes through the stimulation of potential soilborne pathogens, which presents a significant hurdle in remediating replant failure of Sanqi ginseng.IMPORTANCE Sanqi ginseng [Panax notoginseng (Burk.) F. H. Chen] is geoauthentically produced in a restricted area of southwest China, and successful replanting requires a rotation cycle of more than 15 to 30 years. The increasing demand for Sanqi ginseng and diminishing arable land resources drive farmers to employ consecutive monoculture systems. Replant failure has severely threatened the sustainable production of Sanqi ginseng and causes great economic losses annually. Worse still, the acreage and severity of replant failure are increased yearly, which may destroy the Sanqi ginseng industry in the near future. The significance of this work is to decipher the mechanism of how autotoxic ginsenosides promote the accumulation of soilborne pathogens and disrupt the equilibrium of soil fungal microbiomes. This result may help us to develop effective approaches to successfully conquer the replant failure of Sanqi ginseng.

Recombinant Adenovirus Expressing a Soluble Fusion Protein PD-1/CD137L Subverts the Suppression of CD8+ T Cells in HCC.

Oncolytic viruses are an excellent platform for developing effective strategies in cancer immunotherapy. Several challenges remain in the use of viro-immunotherapy for cancer, such as the lack of costimulatory signals and negative regulation of immune checkpoints. In this study, we designed a novel adenovirus expressing a soluble fusion protein, programmed cell death protein 1 (PD-1)/CD137L, which contains the extracellular domains of PD-1 and CD137L at each terminus (Ad5-PC). Ad5-PC preserved the costimulatory activity of CD137L and facilitated the persistence of activated CD8+ T cells. Ad5-PC induced strikingly increased antitumor activity in both ascitic and subcutaneous hepatocellular carcinoma (HCC) tumor models, with 70% and 60% long-term cure rates, respectively. The improved antitumor effect of Ad5-PC was attributed to the sustained high-level lymphocyte activation and interferon (IFN)-γ production in the tumor microenvironment, and was essentially dependent on CD8+ T cells rather than natural killer (NK) cells. Moreover, Ad5-huPC-expressing human soluble PD-1/CD137L fusion protein was effective in suppressing tumor growth and improving survival in a humanized mouse model. We confirmed that Ad5-PC induced tumor-specific and systematic protection against tumor rechallenges at both in situ and distant sites. Thus, Ad5-PC harnesses several distinct functions to efficiently overcome several major hurdles of viro-immunotherapy.

Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints.

In recent years, the role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments, including surgery, chemotherapy and radiotherapy. Of note, the clinical successes of immune checkpoint blockade, such as PD-1 and CTLA-4, represent a landmark event in cancer immunotherapy development. Therefore, further exploration of how immune checkpoints are regulated in the tumor microenvironment will provide key insights into checkpoint blockade therapy. In this review, we discuss in details about the regulation of immune checkpoints mediated by immune cells, oncolytic viruses, epigenetics, and gut microbiota and mutual regulation by co-expressed checkpoints. Finally, predictions are made for future personalized cancer immunotherapy based on different checkpoint modulations.

Effects of functional groups on the structure, physicochemical and biological properties of mesoporous bioactive glass scaffolds.

Functionalization of biomaterials with specific functional groups is one of the most straightforward strategies to induce specific cell responses to biomaterials. In this study, thiol (SH) and amino (NH2) functional groups have been successfully modified on the surfaces of mesoporous bioactive glass (MBG) scaffolds to form thiol-functionalized MBG (SH-MBG) and amino-functionalized MBG (NH2-MBG) scaffolds by a post-grafting technique. The effects of the functional groups on the structure, physicochemical and biological properties of MBG scaffolds were systematically investigated. The results showed that the functionalization of MBG scaffolds did not change their structures, and the SH-MBG and NH2-MBG scaffolds still had hierarchical pore architecture (macropores of 300-500 µm and mesopores of 3.5-4 nm) and high porosity (84-86%), similar to the MBG scaffolds. Furthermore, the SH-MBG and NH2-MBG scaffolds possessed similar apatite mineralization ability and biocompatibility compared to the MBG scaffolds. Importantly, the SH-MBG and NH2-MBG scaffolds significantly stimulated adhesion, proliferation and differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Therefore, functionalization of MBG scaffolds with SH and NH2 functional groups would be a viable way to tailor the surface characteristics for stimulating biological responses of hBMSCs, and the functionalized MBG scaffolds would be a promising bioactive material for bone tissue engineering applications.