Stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and verteporfin for glioblastoma therapy.

BACKGROUND: The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree. RESULTS: In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects. CONCLUSION: Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.

Repair of buccal mucosa and floor of mouth defects using keystone design perforator island flap.

OBJECTIVE: To assess the feasibility of utilizing the keystone design perforator island flap (KDPIF) for the repair of small to medium-sized defects in the buccal mucosa and floor of mouth (cT1-2 stage tumor). STUDY DESIGN: We conducted a retrospective analysis of eight patients who underwent KDPIF to address oral defects at the Affiliated Hospital of Qingdao University between June 2021 and September 2022. Patient information, including medical history, defect site, flap size, operative time, hospital stay, complications, and postoperative recovery of oral function, was comprehensively evaluated. RESULTS: Eight patients (6 females and 2 males) underwent reconstruction using KDPIF. The mean operation time was 58.5 minutes (55-63 minutes), with an average length of stay of 3.5 days (3-5 days). None of the 8 cases (100%) exhibited flap splitting necrosis or infection. Moreover, no scar contracture was observed, and oral functions, including the degree of opening, type of opening, tongue mobility, speech function, and swallowing function, were successfully restored. One patient (12.5%) experienced bleeding from the incision on the first postoperative day, but following compression, hemostasis was achieved, and the incision healed well. CONCLUSIONS: KDPIF demonstrates technical feasibility and suitability for repairing small to medium-sized buccal mucosa and floor of mouth defects (cT1-2).

Diffuse Large B-cell Lymphoma (Leg Type) Originating in the Skin of the Right Cheek Region: A Case Report and Literature Review.

Primary diffuse cutaneous large B-cell lymphoma, leg type (PCDLBCL-LT), usually affecting one or both lower legs, with a 5-year disease-free survival rate of less than 60%. Solitary facial lesions are extremely rare. Our report is about a 93-year-old woman whose clinical examination revealed a 4 cm × 5 cm × 3 cm mass with a soft texture and smooth margins on the right side of her cheek. Immunohistochemical analyses were consistent with a diagnosis of PCDLBCL-LT. The surgical method for this patient was: extensive resection of the tumor and repair of the defect with an adjacent flap. Neither local recurrence nor systemic invasion was observed during postoperative follow-up (8 months). The clinician must be very careful when making a correct diagnosis based on the clinical and immunohistochemical findings of PCDLBCL-LT. For this type of PCDLBCL-LT isolated in 1 site without invasion of the rest of the body, extensive surgical resection may result in a favorable prognosis.

Cascade-Responsive 2-DG Nanocapsules Encapsulate aV-siCPT1C Conjugates to Inhibit Glioblastoma through Multiple Inhibition of Energy Metabolism.

Aerobic glycolysis is the primary energy supply mode for glioblastoma (GBM) cells to maintain growth and proliferation. However, due to the metabolic reprogramming of tumor cells, GBM can still produce energy through fatty acid oxidation (FAO) and amino acid metabolism after blocking this metabolic pathway. In addition, GBM can provide a steady stream of nutrients through high-density neovascularization, which puts the block energy metabolism therapy for glioma in the situation of "internal and external problems". Herein, based on the abundant reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment and cytoplasm, we successfully designed and developed a cascade-responsive 2-DG nanocapsule delivery system. This nanocapsule contains a conjugate of anti-VEGFR2 monoclonal antibody (aV) and CPT1C siRNA (siCPT1C) linked by a disulfide cross-linker (aV-siCPT1C). The surface of this nanocapsule (2-DG/aV-siCPT1C NC) is loaded with the glycolysis inhibitor 2-DG, and it utilizes GLUT1, which is highly expressed on the blood-brain barrier (BBB) and GBM cells, to effectively penetrate the BBB and target GBM. The nanocapsule realizes multidrug codelivery, jointly blocks glycolysis and FAO of GBM, and reduces angiogenesis. Meanwhile, it also solves the problems of low delivery efficiency of mAb in the central nervous system (CNS) and easy degradation of siRNA. In general, this drug joint delivery strategy could open up a new avenue for the treatment of GBM.

Regulatory roles of cytokines in T and B lymphocytes-mediated immunity in teleost fish.

T and B lymphocytes (T and B cells) are immune effector cells that play critical roles in adaptive immunity and defend against external pathogens in most vertebrates, including teleost fish. In mammals, the development and immune response of T and B cells is associated with cytokines including chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors during pathogenic invasion or immunization. Given that teleost fish have evolved a similar adaptive immune system to mammals with T and B cells bearing unique receptors (B-cell receptors (BCRs) and T-cell receptors (TCRs)) and that cytokines in general have been identified, whether the regulatory roles of cytokines in T and B cell-mediated immunity are evolutionarily conserved between mammalians and teleost fish is a fascinating question. Thus, the purpose of this review is to summarize the current knowledge of teleost cytokines and T and B cells as well as the regulatory roles of cytokines on these two types of lymphocytes. This may provide important information on the parallelisms and dissimilarities of the functions of cytokines in bony fish versus higher vertebrates, which may aid in the evaluation and development of adaptive immunity-based vaccines or immunostimulants.

The nanoprodrug of polytemozolomide combines with MGMT siRNA to enhance the effect of temozolomide in glioma.

Temozolomide (TMZ) is a conventional chemotherapeutic drug for glioma, however, its clinical application and efficacy is severely restricted by its drug resistance properties. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme, which can repair the DNA damage caused by TMZ. A large number of clinical data show that reducing the expression of MGMT can enhance the chemotherapeutic efficacy of TMZ. Therefore, in order to improve the resistance of glioma to TMZ, an angiopep-2 (A2) modified nanoprodrug of polytemozolomide (P(TMZ)n) that combines with MGMT siRNA (siMGMT) targeting MGMT was developed (A2/T/D/siMGMT). It not only increased the amount of TMZ within tumor lesion site, but also reduced MGMT expression in glioma. The in vitro experiments indicated that the A2/T/D/siMGMT effectively enhanced the cellular uptake of TMZ and siMGMT, and resulted in a significant cell apoptosis and cytotoxicity in the glioma cells. The in vivo experiments showed that glioma growth was inhibited and the survival time of animals were prolonged remarkably after A2/T/D/siMGMT was injected via tail vein. The results showed that the therapeutic effect of A2/T/D/siMGMT in the treatment of glioma was significantly improved.

Methionine deprivation inhibits glioma growth through downregulation of CTSL.

The metabolism of tumor cells is characterized by the regulation of demand, nutrient supply and metabolic enzymes, which are different in cancer tissues from those in corresponding healthy tissues. There is growing evidence that dietary composition influences biological processes that contribute to tumor incidence and progression as much as genetic status. One possibility for specific dietary interventions in cancer patients is to limit methionine intake. The role of methionine metabolism in tumors suggests that interference with the methionine metabolism network by either drug or environmental effects may show substantial therapeutic effects, but the molecular mechanism is not completely clear. In this study, methionine deprivation was found to downregulate cathepsin L (CTSL) and induce proliferation inhibition in glioma cells. We also demonstrated that CTSL is a tumor-related gene, and promotes the proliferation and invasion of glioma. Our results showed that the treatment of methionine metabolism and CTSL related genes in glioma cells may be a novel strategy for glioma therapy in the future.

Exosomes Derived from Bone Marrow Mesenchymal Stem Cells Alleviate Ischemia-Reperfusion Injury and Promote Survival of Skin Flaps in Rats.

Free tissue flap transplantation is a classic and important method for the clinical repair of tissue defects. However, ischemia-reperfusion (IR) injury can affect the success rate of skin flap transplantation. We used a free abdomen flap rat model to explore the protective effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs-exosomes) against the IR injury of the skin flap. Exosomes were injected through the tail vein and the flaps were observed and obtained on day 7. We observed that BMSCs-exosomes significantly reduced the necrotic lesions of the skin flap. Furthermore, BMSCs-exosomes relieved oxidative stress and reduced the levels of inflammatory factors. Apoptosis was evaluated via the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and Western blot analysis of Bax, Bcl-2. Simultaneously, BMSCs-exosomes promoted the formation of new blood vessels in the IR flap, as confirmed by the increased expression level of VEGFA and the fluorescence co-staining of CD31 and PCNA. Additionally, BMSCs-exosomes considerably increased proliferation and migration of human umbilical vein endothelial cells and promoted angiogenesis in vitro. BMSCs-exosomes could be a promising cell-free therapeutic candidate to reduce IR injury and promote the survival of skin flaps.

Spindle and kinetochore-associated complex 3 promotes cell growth via the PI3K/AKT/GSK3ß and PI3K/AKT/FOXO1 pathways and is a potential prognostic biomarker for oral squamous cell carcinoma.

OBJECTIVE: This study elucidated the clinical significance, functions, and mechanism of action of spindle and kinetochore-associated complex 3 (SKA3) in oral squamous cell carcinoma (OSCC). STUDY DESIGN: The SKA3 levels within the patients with OSCC were determined using the The cancer genome atlas (TCGA) database and clinical samples. The functions of SKA3 in OSCC cells were evaluated by cell counting Kit-8 (Beyotime Biotechnology, Haimen, China), 5-ethynyl-2'-deoxyuridine, wound healing, transwell invasion, flow cytometry, and xenograft nude mice model assays. A quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot were performed to assess mRNA and protein expression levels in specimens and cells, respectively. RESULTS: The SKA3 was highly expressed in OSCC tissues, and its knockdown suppressed OSCC cell proliferation, migration, and invasion, and promoted their apoptosis. Mechanistically, SKA3 was shown to modulate OSCC cell proliferation and apoptosis via the PI3K/AKT/GSK3ß and PI3K/AKT/FOXO1 pathways. CONCLUSIONS: Biologically, SKA3 has a potential carcinogenic role in OSCC progression and is a promising prognostic biomarker and therapeutic target.

IGF2BP2 maybe a novel prognostic biomarker in oral squamous cell carcinoma.

AIM: The main of the present study was to investigate the role of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in oral squamous cell carcinoma (OSCC) with the overarching of providing new biomarkers or potential therapeutic targets for OSCC. METHODS: We combined datasets downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and samples collected from the clinic to evaluate the expression of IGF2BP2 in OSCC. IGF2BP2 survival analysis was respectively performed based on TCGA, GEO, and clinical samples. Correlations between IGF2BP2 expression and clinicopathological parameters were then analyzed, and signaling pathways associated with IGF2BP2 expression were identified using gene set enrichment analysis (GSEA 4.1.0). Moreover, an IGF2BP2 co-expressed gene network was constructed, followed by gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on IGF2BP2 co-expressed genes. Finally, TIMER and CIBERSORT were used to analyze the correlations among IGF2BP2, IGF2BP2-coexpressed genes, and tumor-infiltrating immune cells (TICs). RESULTS: IGF2BP2 was highly expressed in OSCC and significantly correlated with overall survival of OSCC patients (P<0.01). High IGF2BP2 expression correlated with poor overall survival. The GSEA results showed that cell apoptosis-, tumor-, and immune-related pathways were significantly enriched in samples with high IGF2BP2 expression. Furthermore, GO and KEGG enrichment analyses results of IGF2BP2 co-expressed genes indicated that these genes are mainly associated with immunity/inflammation and tumorigenesis. In addition, IGF2BP2 and its co-expressed genes are associated with TICs (P<0.01). CONCLUSION: IGF2BP2 may be a potential prognostic biomarker in OSCC and correlates with immune infiltrates.

Efficacy and Safety of Pembrolizumab Monotherapy for Recurrent/Unresectable/Metastatic Oral Squamous Cell Carcinoma: A Single-Center Study in China.

Background: Although pembrolizumab is recommended as a first-line treatment for advanced recurrent/unresectable/metastatic (R/U/M) head and neck squamous carcinoma, the differences in its efficacy among different populations need to be investigated. Methods: We reviewed 15 consecutive patients with R/U/M oral squamous cell carcinoma (OSCC) treated with pembrolizumab monotherapy at the Affiliated Hospital of Qingdao University between February 2021 and May 2022. All the 15 patients had known programmed death-ligand 1 expression and received multiple cycles of pembrolizumab monotherapy as first-line treatment. We evaluated and analyzed patients' basic characteristics, time to first remission, the clinical efficacy of pembrolizumab monotherapy, and treatment-related adverse reactions. Results: The objective response rate of the 15 patients was 60%. Six patients (40.0%) achieved partial response, while three patients (20.0%) achieved complete response. In our study, the objective response status of the patients was observed in two to five cycles (mean, 3.6 cycles). For patients who responded well to immunotherapy, the mean Karnofsky Performance Status (KPS) score after treatment was significantly higher than that before treatment (P < 0.001). The progression-free survival rates were 66.9% and 50.1% at 6 months and 1 year, respectively. Eight adverse events were observed, comprising four cases of rash and one case each of hypothyroidism, interstitial pneumonia, cheilitis, and cerebral thrombosis. Conclusion: Our study suggests that pembrolizumab is beneficial to the most responsive patients with R/U/M OSCC in our single-center study and may shed light on the management of OSCC.

Assessment of Potential Prognostic Value of Peroxiredoxin 1 in Oral Squamous Cell Carcinoma.

PURPOSE: The role of the peroxiredoxin (PRDX) family in oral squamous cell carcinoma (OSCC) remains unclear. This study aimed to investigate the expression of PRDXs and their effects on the prognosis in OSCC. METHODS: The expression of PRDXs and their effects on prognosis were analysed in 216 OSCC samples from The Cancer Genome Atlas (TCGA) database. OSCC tissues and adjacent noncancerous tissues (ANTs) were obtained from 68 clinical patients. Quantitative real-time (qRT)-PCR, Western blot, and immunohistochemical (IHC) staining were used to verify the relationship between the expression level of PRDX1 and different clinical features. Gene set enrichment analysis (GSEA) was used to examine the molecular mechanism of PRDX1 in OSCC. RESULTS: PRDX1 was found to be the only gene in PRDX family that highly expressed in OSCC samples and affected the prognosis of patients with OSCC. PRDX1 expression was significantly related to tumor stage, lymphatic metastasis, and pathological grade. A nomogram consisting of tumor stage, N stage, and PRDX1 level was constructed. GSEA showed that high expression of PRDX1 involved many cancer-related molecular functions and signaling pathways. CONCLUSION: PRDX1 may play an important role in the occurrence and development of OSCC, and may be a potential new target for OSCC treatment.

The R168G heterozygous mutation of tropomyosin 3 (TPM3) was identified in three family members and has manifestations ranging from asymptotic to serve scoliosis and respiratory complications.

According to existing reports, mutations in the slow tropomyosin gene (TPM3) may lead to congenital fiber-type disproportion (CFTD), nemaline myopathy (NM) and cap myopathy (CD). They are all congenital myopathies and are associated with clinical, pathological and genetic heterogeneity. A ten-year-old girl with scoliosis was unable to wean from mechanical ventilation after total intravenous anesthesia. The girl has scoliosis, respiratory insufficiency, motion delay and muscle weakness; her younger brother has a similar physiology but does not have scoliosis or respiratory insufficiency, and her parents are healthy. We conducted genetic testing and found a c.502C > G (p.R168G) heterozygous mutation in the family. This mutation originated from the father and was autosomal dominant. Muscle biopsy results indicated that no special structures were present, and the type I fiber ratio was not notably high compared to previous reports. Although the family members have the same mutations, their clinical manifestations are quite different.

Knowledge of Chinese dentists on HPV, their willingness and barriers to recommend HPV vaccination to patients.

Objective: This study aimed to assess the knowledge of Chinese dentists on human papilloma virus (HPV), their willingness and factors prevention them from recommending patients for HPV vaccination, and to identify ways through which dentists can acquire HPV-related knowledge.Methods: This was a cross-sectional study based on Chinese dentists. The anonymous self-filled questionnaire method was used to collect demographic information of participants, their knowledge of HPV, willingness and barriers to recommending HPV vaccines to patients, and the strategies they can adopt to obtain HPV-related knowledge.Results: A total of 517 dentists completed the questionnaire, and 89.94% of dentists were willing to recommend HPV vaccination to patients. Participants aged 30-39 years, male dentists and dentist-in-charge had relatively lower knowledge scores than other groups. Besides, participants aged 30-39 years, working in private hospitals, and practicing in Southern China had a lower willingness to recommend HPV vaccination to patients. Recommending HPV vaccination to patients is not within the scope of practicing dentists, and concerns about the safety of the HPV vaccine were found to be the main barriers preventing its recommendation. Notably, 97.87% of dentists were eager to acquire HPV-related knowledge, and agreed for the first time to enroll in relevant educational courses.Conclusion: Chinese dentists had expressed a strong desire to recommend HPV vaccines to patients, even though their knowledge of HPV was scanty. Therefore, measures to improve their understanding of HPV vaccines and eliminate barriers suppressing their willingness to recommend HPV vaccines are urgently needed.

Correction: Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.

Correction for 'Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation' by Zongren Zhao et al., Biomater. Sci., 2020, 8, 5306-5316, DOI: 10.1039/D0BM00338G.

Hypoxia-Responsive Lipid-Polymer Nanoparticle-Combined Imaging-Guided Surgery and Multitherapy Strategies for Glioma.

Glioma is the most prevalent type of malignant brain tumor and is usually very aggressive. Because of the high invasiveness and aggressive proliferative growth of glioma, it is difficult to resect completely or cure with surgery. Residual glioma cells are a primary cause of postoperative recurrence. Herein, we describe a hypoxia-responsive lipid polymer nanoparticle (LN) for fluorescence-guided surgery, chemotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT) combination multitherapy strategies targeting glioma. The hypoxia-responsive LN [LN (DOX + ICG)] contains a hypoxia-responsive component poly(nitroimidazole)25 [P-(Nis)25], the glioma-targeting peptide angiopep-2 (A2), indocyanine green (ICG), and doxorubicin (DOX). LN (DOX + ICG) comprises four distinct functional components: (1) A2: A2 modified nanoparticles effectively target gliomas, enhancing drug concentration in gliomas; (2) P-(Nis)25: (i) the hydrophobic component of LN (DOX + ICG) with hypoxia responsive ability to encapsulate DOX and ICG; (ii) allows rapid release of DOX from LN (DOX + ICG) after 808 nm laser irradiation; (3) ICG: (i) ICG allows imaging-guided surgery, combining PDT and PTT therapies; (ii) upon irradiation with an 808 nm laser, ICG creates a hypoxic environment; (4) DOX inhibits glioma growth. This work demonstrates that LN (DOX + ICG) might provide a novel clinical approach to preventing post-surgical recurrence of glioma.

Correction: Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.

Correction for 'Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation' by Zongren Zhao et al., Biomater. Sci., 2020, DOI: .

Combined Delivery of Temozolomide and siPLK1 Using Targeted Nanoparticles to Enhance Temozolomide Sensitivity in Glioma.

INTRODUCTION: Temozolomide (TMZ) is the first-line chemotherapeutic option to treat glioma; however, its efficacy and clinical application are limited by its drug resistance properties. Polo-like kinase 1 (PLK1)-targeted therapy causes G2/M arrest and increases the sensitivity of glioma to TMZ. Therefore, to limit TMZ resistance in glioma, an angiopep-2 (A2)-modified polymeric micelle (A2PEC) embedded with TMZ and a small interfering RNA (siRNA) targeting PLK1 (siPLK1) was developed (TMZ-A2PEC/siPLK). MATERIALS AND METHODS: TMZ was encapsulated by A2-PEG-PEI-PCL (A2PEC) through the hydrophobic interaction, and siPLK1 was complexed with the TMZ-A2PEC through electrostatic interaction. Then, an angiopep-2 (A2) modified polymeric micelle (A2PEC) embedding TMZ and siRNA targeting polo-like kinase 1 (siPLK1) was developed (TMZ-A2PEC/siPLK). RESULTS: In vitro experiments indicated that TMZ-A2PEC/siPLK effectively enhanced the cellular uptake of TMZ and siPLK1 and resulted in significant cell apoptosis and cytotoxicity of glioma cells. In vivo experiments showed that glioma growth was inhibited, and the survival time of the animals was prolonged remarkably after TMZ-A2PEC/siPLK1 was injected via their tail vein. DISCUSSION: The results demonstrate that the combination of TMZ and siPLK1 in A2PEC could enhance the efficacy of TMZ in treating glioma.

Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.

Glioma is the most aggressive primary malignant brain tumor. The eradication of the gliomas by performing neurosurgery has not been successful due to the diffuse nature of malignant gliomas. Temozolomide (TMZ) is the first-line agent in treating gliomas after surgery, and its therapeutic efficacy is limited mainly due to the high activity levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. Herein, we used an injectable matrix metalloproteinase (MMP) enzyme responsive hydrogel that loaded TMZ and O6-benzylamine (BG) (MGMT inhibitor) for eradicating residual TMZ-resistant gliomas after surgery. The hydrogels exhibited three features: (1) TMZ and BG could be encapsulated within the hydrophobic lamellae of the hydrogel to form Tm (TMZ + BG) hydrogels; (2) The hydrogels could release TMZ and BG in response to the high concentration of MMP enzymes after glioma surgery; (3) The hydrogels could increase local TMZ concentration and reduce side effects of BG. In vivo, the Tm (TMZ + BG) hydrogels inhibited the MGMT expression and sensitized TMZ-resistant glioma cells to TMZ. Moreover, the Tm (TMZ + BG) hydrogels effectively reduced the recurrence of TMZ-resistant glioma after surgery and significantly enhanced the efficiency of TMZ to inhibit glioma growth. Together, these data suggest that an MMP-responsive hydrogel is a promising localized drug delivery method to inhibit TMZ-resistant glioma recurrence after surgery.

Correction to: Co-delivery of GOLPH3 siRNA and gefitinib by cationic lipid-PLGA nanoparticles improves EGFR-targeted therapy for glioma.

The correct affiliation no 2 is presented in this paper.