Systemic delivery of oncolytic herpes virus using CAR-T cells enhances targeting of antitumor immuno-virotherapy.

Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.

CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.

Expression and clinical significance of VISTA, B7-H3, and PD-L1 in glioma.

Immune checkpoint (IC) therapy has led to a breakthrough in cancer treatment. However, the interaction of ICs is controversial in glioma. We detected features of ICs using transcriptome data and a multicolor immunofluorescence assay. We discovered that B7-H3 increased with grade and age and predicted worse overall survival (OS) at the transcriptional and proteomic levels. VISTA and PD-L1 were associated with OS and grade at the RNA level. At the protein level, VISTA was primarily expressed in tumor cells and TAMs. B7-H3 and VISTA were positively correlated with PD-L1. There was a strong correlation between PD-L1 and CD3 and between VISTA and IBA-1. PD-L1 was coexpressed with T cells. VISTA was coexpressed with TAMs. In T cells, we found a strong correlation in ICs, which worsened in TAMs and tumor cells. In conclusion, B7-H3 is a vital prognostic target for immunotherapy. We provided a potential mechanism for the immunosuppressive microenvironment in glioma.

Diencephalic syndrome in a female child due to intracranial germinoma: a case report.

INTRODUCTION: Diencephalic syndrome (DS) is a rare syndrome with failure to thrive (FTT) as the primary manifestation, which is often associated with astrocytoma or glioma and rarely caused by germinoma. To our knowledge, there are no reports of female patients presenting with DS secondary to germinoma. CASE REPORT: we report a case (an 11-year-old girl) of diencephalic syndrome presenting with FTT. She was diagnosed with severe malnutrition in the local hospital two years before admission and still did not show normal development after long-term nutritional support. Finally, after ruling out increased metabolism, inadequate caloric intake, and nutrient absorption, intracranial MRI showed a space-occupying lesion in the suprasellar cisterna-hypothalamus area. After excluding other causes of FTT, a biopsy was performed for pathological examination and demonstrated a germinoma. An excellent therapeutic effect was achieved during the three-month follow-up after radiotherapy. CONCLUSION: This case reminds us that intracranial tumors should be considered an indispensable etiology for patients with suspicious FTT, and early diagnosis and intervention may achieve a good prognosis.

Effect of antiplatelet treatment on aneurysmal subarachnoid hemorrhage patients after endovascular treatment: a systematic review with meta-analysis.

Antiplatelet treatment (APT) has been reported to be used in some patients with aneurysmal subarachnoid hemorrhage (aSAH) after endovascular treatment, but there is controversy among different studies regarding its clinical effects. This study intends to conduct a meta-analysis to evaluate the impact of APT on aSAH patients after endovascular treatment. The PubMed, EMBASE, and Cochrane Library databases were systematically searched up to January 2022 for eligible English publications. Quality assessment was conducted for the included studies. Publication bias and heterogeneity were assessed by Egger's test and the I2 statistic, respectively. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by meta-analysis. Robustness was checked by subgroup and sensitivity analyses. In total, 597 and 522 patients with and without APT, respectively, in 5 retrospective studies were retained for the meta-analysis. Pooled analyses showed that the APT group had a lower mortality (41/499 [8%] versus 56/402 [14%]; OR = 0.533; 95% CI, 0.347-0.820; P = 0.004) and a higher proportion of favorable clinical outcomes (400/532 [75%] versus 266/421 [63%]; OR = 1.801; 95% CI, 1.359-2.414; P = 0.000) than the control group. There was no significant difference in the incidence of hemorrhagic complications (39/564 [7%] versus 26/503 [5%]; OR = 1.386; 95% CI, 0.825-2.329; P = 0.218) between groups. Although the incidence of delayed cerebral ischemia (DCI) was significantly lower in the APT group (65/512 [13%] versus 105/447 [23%]; OR = 0.325; 95% CI, 0.107-0.988; P = 0.048), it showed substantial heterogeneity (I2 = 64.7%). Subsequent sensitivity analysis suggested that the meta-analysis was robust. Subgroup analyses revealed that long-term (> 2 weeks) APT (60/479 [13%] versus 103/428 [24%]; OR = 0.212; 95% CI, 0.056-0.806; P = 0.023) significantly reduced the DCI rate and that different grouping methods in the included studies may be a source of heterogeneity. In the absence of randomized controlled trials, a meta-analysis of retrospective studies suggested that APT was associated with reduced mortality and better functional outcomes in aSAH patients after endovascular treatment without an increased incidence of hemorrhagic complications. Long-term APT was also associated with a decrease in the incidence of DCI. Well-designed randomized controlled trials are warranted and updated meta-analyses are needed to verify our findings.

[Advances in Intraoperative Neurophysiological Monitoring Techniques in Transnasal Endoscopic Skull Base Surgery].

Transnasal endoscopic skull base surgery has been increasing in volume in recent years and its indications are constantly expanding. The potential occurrence of intraoperative and postoperative neurovascular complications deserves special attention from neurosurgeons. Multimodal intraoperative neurophysiological monitoring technology allows neurosurgeons to monitor cerebral perfusion and the functional status of the associated cranial nerves in real time, thereby enabling surgeons to make prompt adjustments in surgical procedures and strategies and reduce the risks of postoperative neurological complications in patients. Based on available literature, we reviewed how appropriate monitoring strategies were optimized for different key components of transnasal endoscopic skull base procedures, intending to provide reference for clinicians.

Characterization of novel CTNNB1 mutation in Craniopharyngioma by whole-genome sequencing.

BACKGROUND: Craniopharyngioma (CP) is rare histologically benign but clinically challenging tumor because of its intimate relationship with the critical structure in the central brain. CP can be divided into two major histologic subtypes: adamantinomatous-type CP (ACP) and papillary-type CP (PCP). Although some genetic aberrations for both categories have been revealed in previous studies, the complete spectrum of genetic changes of this tumor remains unknown. METHODS: In this study, we conducted whole genome sequencing (WGS) on twenty-six CPs including 16 ACPs and 10 PCPs together with their matched blood samples. Somatic variants (SNVs, InDels, SVs and CNVs) were identified and mutational signatures were characterized for each patient. We investigated the impact of a novel CTNNB1 mutant on its protein stability, ubiquitination and Wnt pathway activity. Cell proliferation ability of the CTNNB1 mutant in ACP primary cells was additionally analyzed by CCK8 and colony formation assays. RESULTS: We found that CPs had showed less complexity with fewer somatic mutations compared with malignant tumors. Moreover, mutations in CTNNB1 (68.75% of ACP) and BRAF V600E (70.00% of PCP) are mutually exclusive in ACP and PCP, consolidating that the driving roles of these two genes in ACP and PCP, respectively. A novel mutation in the exon 3 of CTNNB1 which compromised both a transversion and in-frame deletion was identified in ACP. This mutation was experimentally validated to confer ß-catenin increased stability by inhibiting its ubiquitination, thus activating Wnt-signaling pathway and promoting cell proliferation. CONCLUSIONS: Whole genome landscape for CP was revealed by WGS analysis, and a novel mutation in the exon 3 of CTNNB1 was identified. This novel mutation activates Wnt-signaling pathway through increasing the stability of ß-catenin. Our findings provided us with more comprehensive insight into the spectrum of genetic alterations in CP.

Interleukin-7-loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma.

BACKGROUND: T cell with chimeric antigen receptors (CAR-T) has presented remarkable efficacy for blood cancer as an emerging immunotherapy. However, for solid tumors, the therapeutic efficacy is much impaired due to the lack of infiltration and persistence of CAR-T in tumor tissue. Thus, we constructed an interleukin-7-loaded oncolytic adenovirus and combined the use of oncolytic virus and CAR-T to improve the therapeutic outcome. METHODS: We constructed an interleukin-7-loaded oncolytic adenovirus (oAD-IL7) and a B7H3-targeted CAR-T and explored the efficacy of the single use of oAD-IL7, B7H3-CAR-T, or the combined therapy for glioblastoma in vitro and in vivo. The improved CAR-T anti-tumor efficacy was evaluated according to the proliferation, survival, persistence, exhaustion of T cells, and tumor regression. RESULTS: Constructed oAD-IL7 and B7H3-CAR-T presented moderate cytotoxicity during in vitro study, but failed to induce a thorough and persistent anti-tumor therapeutic efficacy in vivo. The combination of oAD-IL7 and B7H3-CAR-T in vitro resulted in enhanced T cell proliferation and reduced T cell apoptosis. The joint efficacy was further confirmed using tumor-bearing xenograft mice. During in vivo study, the mice treated with both oAD-IL7 and B7H3-CAR-T showed prolonged survival and reduced tumor burden. According to the ex vivo study, oAD-IL7 improved the proliferation and persistence of tumor-infiltrating B7H3-CAR-T, but failed to reverse the exhaustion. CONCLUSIONS: Our results indicated that oAD-IL7 is a promising auxiliary therapy to improve the therapeutic efficacy of B7H3-CAR-T in glioblastoma by providing the activating signals for tumor-infiltrating T cells. Our results also lay the basis for the future clinical trials for the combination of IL7-loaded oncolytic adenovirus and CAR-T therapy for glioblastoma.

Papillary meningioma of the central nervous system: a SEER database analysis.

Papillary meningioma (PM) is a rare central nervous system tumor. We aimed to analyze the characteristics and outcomes of patients with PM (WHO grade III) and identify risk factors that influence survival using the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics, tumor features, and outcomes of 108 PM patients included in the SEER database between 1990 and 2016 were retrieved. Risk factors related to prognosis of PM were assessed by Kaplan-Meier curves and the Cox proportional hazards model. All 108 patients, including 65 males and 43 females (1.5:1), with a median age of 52 years (range, 9 to > 85 years) had undergone surgical resection. Gross total resection (GTR) was achieved in 50%, and 50% underwent subtotal resection (STR). While 55.6% underwent postoperative radiation therapy, 48% did not. The median disease-specific survival (DSS) was 128 months, and the 5-year DSS rate was 77%. In multivariate analysis, age ≤ 52 years and GTR were both independently associated with higher probability of DSS (p = 0.033 and p = 0.029, respectively). Stratification analysis showed that postoperative radiotherapy had no significant impact on the DSS, irrespective of resection extent (p = 0.172). Our SEER analysis showed that age and extent of resection were prognostic factors for PM, but race, tumor size, gender, chemotherapy, and postoperative radiotherapy did not significantly impact DSS of PM patients. There was no significant improvement in survival of patients who underwent radiotherapy and GTR, or radiotherapy and STR, compared with GTR or STR alone.

Screening for genes and subnetworks associated with atypical teratoid/rhabdoid tumors using bioinformatics analysis.

Objectives: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, fast-growing lesions of central nervous system and their prognosis is poor. Nowadays, multimodal managements, including surgery, chemotherapy and radiation therapy are advocated; however, low survival rate and severe neurocognitive toxicity of chemotherapy as well as the irreversible long-term sequelae of irradiation in infants and young children with AT/RTs are alarming. The aim of our study is to provide valid biological information for more tailored advance therapy for these lesions.Methods: Gene expression profile of GSE94349 was downloaded from GEO database and was analyzed using limma R package. Function and enrichment analyses of DEGs were performed based on DAVID database. PPI network construction, hub gene selection and module analysis were conducted in Cytoscape software.Results: In this study, 224 up-regulated genes and 572 down-regulated genes were selected as DEGs. The up-regulated genes were mainly enriched in molecular function and cell component, which mainly included protein binding and nucleus, respectively. The down-regulated DEGs were significantly involved in cell component such as plasma membrane and integral component of membrane. Cell cycle and retrograde endocannabinoid signaling were the main KEGG pathway of up and down DEGs, respectively. CDK1, CCNA2, CDC20, TOP2A were identified as hub genes and two significant network modules were also obtained.Conclusions: Our study may help to further understand the molecular characteristics and provide more tailored targets for future treatment of AT/RTs. Hub genes CDK1, CCNA2, CDC20, TOP2A as well as cell cycle signaling pathway may be new more tailored targets for future treatment of AT/RTs.

Compared with conventional procedures, an intraoperative navigation system for ventriculoperitoneal shunting via the occipital horn improves outcomes in patients with hydrocephalus.

BACKGROUND: Ventriculoperitoneal shunting (VPS) is a common neurosurgical procedure used to treat hydrocephalus. Although the use of a navigation system in VPS achieves superior results compared with conventional surgery, the relationships among clinical symptoms, ventricular catheter placement, catheter obstruction, and the postoperative Evans index have not been clearly reported. METHODS: We performed a retrospective study of 40 patients with VPS (the navigation surgery group) and 31 patients with VPS (the conventional surgery group). Clinical data, follow-up times, catheterization accuracy, postoperative outcomes, cumulative survival times, and correlations between catheter placement and obstruction, symptom grade and the postoperative Evans index were analyzed. RESULTS: Thirty-seven patients experienced optimal ventricular catheter placement (grade 1), three experienced suboptimal placements (grade 2), and none experienced poor ventricular catheter placement (grade 3) in the navigation surgery group. Greater improvement in postoperative symptoms (p < 0.001), including less catheter readjustment (p < 0.001), was observed in the navigation surgery group. A Kaplan-Meier analysis showed that the cumulative catheter obstruction-free survival time was longer in the navigation surgery group (p = 0.016). Moreover, catheter placement was significantly correlated with catheter obstruction (p < 0.001). Additionally, catheter obstruction was significantly correlated with the symptom grade (p < 0.001) and postoperative Evans index (p = 0.002). CONCLUSION: VPS for hydrocephalus via the occipital horn with a navigation system is superior to the conventional surgical procedure in terms of clinical outcomes, the precision of ventricular catheterization, and the occurrence of complications. Catheter obstruction-free survival times were longer in the navigation surgery group and catheter placement was significantly correlated with catheter obstruction.

Efficacy and safety of bempedoic acid for prevention of cardiovascular events and diabetes: a systematic review and meta-analysis.

BACKGROUND: Bempedoic acid is an oral, once-daily, first-in-class drug being developed for the treatment of hyperlipidemia. However, evidence of bempedoic acid use for the prevention of cardiovascular events and diabetes is lacking. Thus, we aim to evaluate the benefit and safety of bempedoic acid use for the prevention of cardiovascular events and diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials with no language restriction from inception until March 3, 2020. Pairs of reviewers independently identified randomized controlled trials comparing the use of bempedoic acid with placebo or no treatment for primary prevention of cardiovascular events in statin-intolerant patients with hypercholesterolemia. The primary outcomes were major adverse cardiac events, and percent change in LDL-C. RESULTS: We identified 11 trials including a total of 4391 participants. Bempedoic acid use was associated with a reduction in composite cardiovascular outcome (RR 0.75, 95% CI 0.56-0.99; I2 = 0%). Bempedoic acid reduced LDL-C levels (MD - 22.91, 95% CI - 27.35 to - 18.47; I2 = 99%), and similarly reduced CRP levels (MD -24.70, 95% CI - 32.10 to - 17.30; I2 = 53%). Bempedoic acid was associated with a reduction in rates of new-onset or worsening diabetes (RR 0.65, 95% CI 0.44-0.96; I2 = 23%). CONCLUSIONS: Bempedoic acid in patients with hypercholesterolemia was associated with a lower risk of cardiovascular events and diabetes.

Frequent B7-H3 overexpression in craniopharyngioma.

Craniopharyngiomas (CPs) are uncommon intracranial benign neoplasms that located in sellar/parasellar region with clinically challenging. B7-H3 is an immune checkpoint molecule highly expressed in many malignant tumors. In this study, we analyzed whether B7-H3 is expressed in 44 CPs samples (adamantinomatous CPs: n = 30 and papillary CPs: n = 14), and whether it could serve as an immunotherapy target in CPs. Immunohistochemical analysis showed that B7-H3 was highly expressed in adamantinomatous CPs (184.3 ±â€¯13.58) and papillary CPs (223.2 ±â€¯11.89), while almost undetectable in normal brain tissue (24 ±â€¯4.9). Besides, B7-H3 expression level was correlated with poor prognosis of patients with CPs. Immunofluorescence and Western blot analysis further suggested that ß-catenin co-localized with B7-H3 and could promote its expression in adaCPs. B7-H3 expression level was positively correlated with staining intensity of IBA1+ cells, but negatively with T cell infiltration in CPs, suggesting that B7-H3 might play a role in the regulation of tumor microenvironment in CPs. Moreover, B7-H3/CD3 bi-specific T cell engager (BiTE) efficiently inhibited the growth of human primary craniopharyngioma cells in a time- and dose-dependent manner. Our results revealed B7-H3 was highly expressed in CPs and targeting B7-H3 might therefore be an effective therapeutic strategy against craniopharyngioma.

SAE1 promotes human glioma progression through activating AKT SUMOylation-mediated signaling pathways.

BACKGROUND: The SUMO-activating enzyme SAE1 is indispensable for protein SUMOylation. A dysregulation of SAE1 expression involves in progression of several human cancers. However, its biological roles of SAE1 in glioma are unclear by now. METHODS: The differential proteome between human glioma tissues and para-cancerous brain tissues were identified by LC-MS/MS. SAE1 expression was further assessed by immunohistochemistry. The patient overall survival versus SAE1 expression level was evaluated by Kaplan-Meier method. The glioma cell growth and migration were evaluated under SAE1 overexpression or inhibition by the CCK8, transwell assay and wound healing analysis. The SUMO1 modified target proteins were enriched from total cellular or tissue proteins by incubation with the anti-SUMO1 antibody on protein-A beads overnight, then the SUMOylated proteins were detected by Western blot. Cell apoptosis and cell cycle were analyzed by flow cytometry. The nude mouse xenograft was determined glioma growth and tumorigenicity in vivo. RESULTS: SAE1 is identified to increase in glioma tissues by a quantitative proteomic dissection, and SAE1 upregulation indicates a high level of tumor malignancy grade and a poor overall survival for glioma patients. SAE1 overexpression induces an increase of the SUMOylation and Ser473 phosphorylation of AKT, which promotes glioma cell growth in vitro and in nude mouse tumor model. On the contrary, SAE1 silence induces an obvious suppression of the SUMOylation and Ser473 phosphorylation of Akt, which inhibits glioma cell proliferation and the tumor xenograft growth through inducing cell cycle arrest at G2 phase and cell apoptosis driven by serial biochemical molecular events. CONCLUSION: SAE1 promotes glioma cancer progression via enhancing Akt SUMOylation-mediated signaling pathway, which indicates targeting SUMOylation is a promising therapeutic strategy for human glioma.

Automatic detection on intracranial aneurysm from digital subtraction angiography with cascade convolutional neural networks.

BACKGROUND: An intracranial aneurysm is a cerebrovascular disorder that can result in various diseases. Clinically, diagnosis of an intracranial aneurysm utilizes digital subtraction angiography (DSA) modality as gold standard. The existing automatic computer-aided diagnosis (CAD) research studies with DSA modality were based on classical digital image processing (DIP) methods. However, the classical feature extraction methods were badly hampered by complex vascular distribution, and the sliding window methods were time-consuming during searching and feature extraction. Therefore, developing an accurate and efficient CAD method to detect intracranial aneurysms on DSA images is a meaningful task. METHODS: In this study, we proposed a two-stage convolutional neural network (CNN) architecture to automatically detect intracranial aneurysms on 2D-DSA images. In region localization stage (RLS), our detection system can locate a specific region to reduce the interference of the other regions. Then, in aneurysm detection stage (ADS), the detector could combine the information of frontal and lateral angiographic view to identify intracranial aneurysms, with a false-positive suppression algorithm. RESULTS: Our study was experimented on posterior communicating artery (PCoA) region of internal carotid artery (ICA). The data set contained 241 subjects for model training, and 40 prospectively collected subjects for testing. Compared with the classical DIP method which had an accuracy of 62.5% and an area under curve (AUC) of 0.69, the proposed architecture could achieve accuracy of 93.5% and the AUC of 0.942. In addition, the detection time cost of our method was about 0.569 s, which was one hundred times faster than the classical DIP method of 62.546 s. CONCLUSION: The results illustrated that our proposed two-stage CNN-based architecture was more accurate and faster compared with the existing research studies of classical DIP methods. Overall, our study is a demonstration that it is feasible to assist physicians to detect intracranial aneurysm on DSA images using CNN.

Recent Perspectives in Hot Melt Extrusion-Based Polymeric Formulations for Drug Delivery: Applications and Innovations.

Hot melt extrusion (HME), a technology which mixing the advantages of solid dispersion technology and mechanical preparation, is accepted in varied applications in pharmaceutical formulations. When combined with other techniques, such as nanotechnique, three-dimensional printing, and co-extrusion, HME becomes much more multifunctional in the application of drug delivery. While in most cases, polymers employed in HME are responsible for the final property of products. The process of HME together with the selection of materials employed in HME were described briefly. In addition, the applications of HME in drug delivery and its currently status in the pharmaceutical field were also included. Some commercial products produced by HME have met the approval of FDA, indicating the commercial viability of this technique. Although showing great potential in pharmaceutical manufacturing, HME is still challenged by high temperature, shear force, and high input energy. Development of equipment, modifying the parameters, and optimization of polymeric formulations are needed for a safe, effective, and multifunctional hot melt extrusion drug delivery system. Also, wider range of combinations between HME and other techniques may provide guideline for developing multiple applications in drug delivery.

Small-Molecule Inhibitors Targeting Protein SUMOylation as Novel Anticancer Compounds.

SUMOylation, one of post-translational modifications, is covalently modified on lysine residues of a target protein through an enzymatic cascade reaction similar to protein ubiquitination. Along with identification of many SUMOylated proteins, protein SUMOylation has been proven to regulate multiple biologic activities including transcription, cell cycle, DNA repair, and innate immunity. The dysregulation of protein SUMOylation and deSUMOylation modification is linked with carcinogenesis and tumor progression. The SUMOylation-associated enzymes are usually elevated in various cancers, which function as cancer biomarkers to relate to poor outcomes for patients. Considering the significance of protein SUMOylation in regulating diverse biologic functions in cancer progression, numerous small-molecule inhibitors targeting protein SUMOylation pathway are developed as potentially clinical anticancer therapeutics. Here, we systematically summarize the latest progresses of associations of small ubiquitin-like modifier (SUMO) enzymes with cancers and small-molecular inhibitors against human cancers by targeting SUMOylation enzymes. We also compared the pros and cons of several special anticancer inhibitors targeting SUMO pathway. As more efforts are invested in this field, small-molecule inhibitors targeting the SUMOylation modification pathway are promising for development into novel anticancer drugs.

Clinical and prognostic role of annexin A2 in adamantinomatous craniopharyngioma.

Annexin A2 (AnxA2) is a highly conserved Ca2+-regulated membrane binding protein, which affects cell mobility and tumor progression. Adamantinomatous craniopharyngioma (AdaCP) are a kind of epithelial tumors of the sellar region with high tendency to recur. Robust biomarkers are required to predict tumor behavior and to establish follow-up individualized treatment approaches. In this study, we firstly compared four surgical AdaCP samples with normal brain by two-dimensional gel electrophoresis (2DE) proteomic analysis. Potential prognostic biomarkers were further validated in a large cohort of 65 AdaCPs by immunohistochemistry. The effects of AnxA2 on AdaCP cells proliferation and migration were analyzed in vitro with isolated primary AdaCP cells as well as SV40T-immortalized cells. Finally, the gefitinib sensitivity of AdaCPs with differentially expressed AnxA2 and the potential molecular mechanisms were examined by flow cytometric analysis, Real-time PCR and immunoblot assays. Proteomic analysis indicated that AnxA2 was the protein spot with the most elevated expression in AdaCP samples. Immunohistochemistry assays indicated the expression level of AnxA2 was significantly higher in recurrent AdaCPs compared with primary ones. Moreover, AnxA2+ AdaCP cells exhibited enhanced proliferation and migration ability compared with AnxA2- AdaCP cells in vitro. Further, we show that AnxA2+ AdaCP cells exhibited elevated expression of EGFR and downstream p-AKT (S308) and p-AKT (S473), and were more sensitive to tyrosine kinase inhibitor gefitinib. Our data suggest that AnxA2 may serve as a promising biomarker for AdaCP progression, recurrence and drug susceptibility. Our data support potential clinical implications for the follow-up treatment of AdaCP patients with high AnxA2 expression.

Downregulation of ARHGDIA contributes to human glioma progression through activation of Rho GTPase signaling pathway.

The protein ARHGDIA has been found to play distinct roles in cancer progression for several tumors. However, it remains elusive whether and how ARHGDIA plays functions in human glioma. In this study, we discovered that ARHGDIA is much downregulated in human glioma; meanwhile, its expression negatively correlates with glioma malignancy and positively relates to prognosis of glioma patients. It has independent predictive value of ARHGDIA expression level for overall survival of human glioma patients. Glioma patients with ARHGDIA-positive expression have a longer overall survival time than ARHGDIA-negative patients. Knockdown of ARHGDIA promotes cell proliferation, cell cycle progression, and cell migration due to the activation of Rho GTPases (Rac1, Cdc42, and RhoA) and Akt phosphorylation, whereas overexpression of ARHGDIA suppresses cell growth, cell cycle progression, and cell migration. ARHGDIA is a potential prognostic marker and therapeutic target for human glioma.

AP-57/C10orf99 is a new type of multifunctional antimicrobial peptide.

Antimicrobial peptides (AMPs) are an evolutionarily conserved component of the innate immune response that provides host defence at skin and mucosal surfaces. Here, we report the identification and characterization of a new type human AMPs, termed AP-57 (Antimicrobial Peptide with 57 amino acid residues), which is also known as C10orf99 (chromosome 10 open reading frame 99). AP-57 is a short basic amphiphilic peptide with four cysteines and a net charge +14 (MW = 6.52, PI = 11.28). The highest expression of AP-57 were detected in the mucosa of stomach and colon through immunohistochemical assay. Epithelium of skin and esophagus show obvious positive staining and strong positive staining were also observed in some tumor and/or their adjacent tissues, such as esophagus cancer, hepatocellular carcinoma, squamous cell carcinoma and invasive ductal carcinoma. AP-57 exhibited broad-spectrum antimicrobial activities against Gram-positive Staphylococcus aureus, Actinomyce, and Fungi Aspergillus niger as well as mycoplasma and lentivirus. AP-57 also exhibited DNA binding capacity and specific cytotoxic effects against human B-cell lymphoma Raji. Compared with other human AMPs, AP-57 has its distinct characteristics, including longer sequence length, four cysteines, highly cationic character, cell-specific toxicity, DNA binding and tissue-specific expressing patterns. Together, AP-57 is a new type of multifunctional AMPs worthy further investigation.