Application of In Situ Mucoadhesive Hydrogel with Anti-Inflammatory and Pro-Repairing Dual Properties for the Treatment of Chemotherapy-Induced Oral Mucositis.

Chemotherapy-induced oral mucositis (CIOM) is a prevalent complication of chemotherapy and significantly affects the treatment process. However, effective treatment for CIOM is lacking due to the unique environment of the oral cavity and the single effect of current drug delivery systems. In this present study, we propose an innovative approach by combining a methacrylate-modified human recombinant collagen III (rhCol3MA) hydrogel system with hyaluronic acid-epigallocatechin gallate (HA-E) and dopamine-modified methacrylate-alginate (AlgDA-MA). HA-E is used as an antioxidant and anti-inflammatory agent and synergizes with AlgDA-MA to improve the wet adhesion of hydrogel. The results of rhCol3MA/HA-E/AlgDA-MA (Col/HA-E/Alg) hydrogel demonstrate suitable physicochemical properties, excellent wet adhesive capacity, and biocompatibility. Notably, the hydrogel could promote macrophage polarization from M1 to M2 and redress human oral keratinocyte (HOK) inflammation by inhibiting NF-κB activation. Wound healing evaluations in vivo demonstrate that the Col/HA-E/Alg hydrogel exhibits a pro-repair effect by mitigating inflammatory imbalances, fostering early angiogenesis, and facilitating collagen repair. In summary, the Col/HA-E/Alg hydrogel could serve as a promising multifunctional dressing for the treatment of CIOM.

Association of gut microbiome and oral cavity cancer: A two sample mendelian randomization and case-control study.

INTRODUCTION: Considering the interconnectedness of the oral cavity and gut tract and the presence of abundant natural microbiota in both. We utilized Mendelian Randomization (MR) in a two-sample study to unveil the genetic causal impact of gut microbiota on the development of oral cavity cancer. MATERIALS & METHODS: The instrumental variables employed in this study consisted of single nucleotide polymorphisms (SNPs) that demonstrated a robust association with 211 distinct gut microbiota taxa, encompassing a sample size of 18,340 individuals. Our investigation sought to explore the potential causal relationship between these genetic variants and the incidence of oral cavity cancer. To accomplish this, we adopted a random effect inverse variance-weighted approach to analyze the causal effect. Additionally, sensitivity analyses were performed utilizing Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests, to assess the robustness and validity of our findings. RESULTS: Five gut microbiota taxa (the family Prevotellaceae, the genus Alloprevotella, the genus Erysipelatoclostridium, the genus Parabacteroides, the genus Ruminococcus gauvreauii group) are predicted to play a causal role in promoting the initiation of the risk of oral cavity cancer. While the genus Christensenellaceae R 7 group, the genus Intestinimonas, the genus Ruminococcaceae, and the order Bacillales causally reduce the risk of oral cavity cancer. Furthermore, no significant evidence suggesting heterogeneity or pleiotropy was observed. DISCUSSION: The novel genetic causal effects of 211 gut microbiota taxa on oral cavity cancer are elucidated in this investigation, thus offering valuable insights for clinical interventions targeting oral cavity cancer.

Detailed characterization of PD-1/PD-L1 and CTLA4 expression and tumor-infiltrating lymphocytes in yolk sac tumors.

BACKGROUND: Immune checkpoint blockade (ICB) is considered as a promising approach for cancer treatment. However, the potency of ICB therapy in yolk sac tumors (YSTs) has not been confirmed, and the comprehensive analysis of tumor immune microenvironment and the expression of PD-1/PD-L1 and CTLA4 were also not thoroughly evaluated. METHODS: Immunohistochemistry was performed in formalin-fixed, paraffin-embedded tumor specimens from 23 YSTs patients to detect the density and distribution of tumor-infiltrating T cells, tertiary lymphoid structures (TLSs), as well as the expression of PD-1/PD-L1 and CTLA4. RESULTS: Overall, more than half (61 %) of all patients exhibited an immune-desert phenotype based on CD3+ T cells. PD-1 expression was identified in five tumor samples (21.7 %), and PD-L1 expression exhibited a different positive rate in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) (39.1 % and 17.4 %). Noteworthily, the rate of positive CTLA4 expression in both TCs and TILs was markedly higher (69.6 % and 56.5 %) than those of PD-1 and PD-L1 expression. Furthermore, TLSs were observed in 21.74 % of all tissues, and samples with TLSs exhibited significantly higher densities of TILs and higher expression of immune checkpoint molecules, particularly PD-1/PD-L1. In addition, tumors located in testes also exhibited a higher density of TILs and higher expression of immune checkpoint molecules. CONCLUSION: Generally a high frequency of CTLA4 expression was found, PD-1/PD-L1 expression, the immune-inflamed phenotype, and TLSs were low frequency in YSTs, however, YSTs in testes showed a higher density of TILs and higher expression of immune checkpoint molecules.

One-Abutment at One-Time in Posterior Edentulism: A Systematic Review and Meta-Analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to investigate the clinical significance of one-abutment at one-time protocol in healed posterior edentulism. METHODS: An online search was undertaken in November 2022, which included PubMed, Cochrane Library, Wiley Online Library, and Google Scholar in addition to manual searching. The Cochrane Collaboration tool was performed to assess the quality of selected articles. Marginal bone loss (MBL) was estimated by the performance of meta-analysis. Moreover, all the pooled analyses were based on random-effect models. Subgroup analysis was applied to evaluate the effects of different variables. RESULTS: In line with the inclusion criteria, 6 trials with 446 dental implants were identified. The meta-analysis showed a total of 0.22 mm less MBL within 6 months and decreased by 0.30 mm at 1-year follow-up in favor of one-abutment at one-time protocol. A significant loss MBL was found in implants placed equicrestally using one-abutment at one-time protocol [6 months: mean difference (MD): -0.22 mm; 95% CI, -0.34 to 0.10 mm, P =0.0004; 12 months: MD: -0.32 mm; 95% CI, -0.40 to -0.24 mm, P <0.00001), whereas no difference was found between 2 groups in an implant placed subscrestally (6 months: MD: 0.14 mm; 95% CI, -0.03 to 0.22 mm; P =0.11; 12 months: MD: -0.12 mm; 95% CI, -0.32 to 0.08 mm; P =0.23). CONCLUSIONS: Implant platform position might greatly affect the marginal bone level. Moreover, one-abutment at one-time protocol demonstrated better bone preservation in implants placed equicrestally in healed posterior edentulism. CLINICAL RELEVANCE: This study highlights the significant clinical application of one-abutment at one-time protocol in healed posterior edentulism.

A TMVP1-modified near-infrared nanoprobe: molecular imaging for tumor metastasis in sentinel lymph node and targeted enhanced photothermal therapy.

BACKGROUND: TMVP1 is a novel tumor targeting polypeptide screened by our laboratory with a core sequence of five amino acids LARGR. It specially binds to vascular endothelial growth factor receptor-3 (VEGFR-3), which is mainly expressed on neo-lymphatic vessels in sentinel lymph node (SLN) with tumor metastasis in adults. Here, we prepared a targeted nanoprobe using TMVP1-modified nanomaterials for tumor metastasis SLN imaging. RESULTS: In this study, TMVP1-modified polymer nanomaterials were loaded with the near-infrared (NIR) fluorescent dye, indocyanine green (ICG), to prepare a molecular imaging TMVP1-ICG nanoparticles (NPs) to identify tumor metastasis in SLN at molecular level. TMVP1-ICG-NPs were successfully prepared using the nano-precipitation method. The particle diameter, morphology, drug encapsulation efficiency, UV absorption spectrum, cytotoxicity, safety, and pharmacokinetic properties were determined. The TMVP1-ICG-NPs had a diameter of approximately 130 nm and an ICG loading rate of 70%. In vitro cell experiments and in vivo mouse experiments confirmed that TMVP1-ICG-NPs have good targeting ability to tumors in situ and to SLN with tumor metastasis by binding to VEGFR-3. Effective photothermal therapy (PTT) with TMVP1-ICG-NPs was confirmed in vitro and in vivo. As expected, TMVP1-ICG-NPs improved ICG blood stability, targeted tumor metastasis to SLN, and enhanced PTT/photodynamic (PDT) therapy, without obvious cytotoxicity, making it a promising theranostic nanomedicine. CONCLUSION: TMVP1-ICG-NPs identified SLN with tumor metastasis and were used to perform imaging-guided PTT, which makes it a promising strategy for providing real-time NIR fluorescence imaging and intraoperative PTT for patients with SLN metastasis.

Gambogic Acid Induces Pyroptosis of Colorectal Cancer Cells through the GSDME-Dependent Pathway and Elicits an Antitumor Immune Response.

Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that affect cell cycle arrest, apoptosis, and autophagy. Here, we found that GA decreased the viability of the CRC cell lines, HCT116 and CT26, in a dose- and time-dependent manner, and multiple pores and large bubbles in the membranes, which are morphological characteristics of pyroptosis, were observed by light microscopy and transmission electron microscopy (TEM). Furthermore, the cleavage of gasdermin E (GSDME) was observed after exposure to GA, along with concomitant activation of caspase-3. Additionally, GSDME-dependent pyroptosis triggered by GA could be attenuated by siRNA-mediated knockdown of GSDME and treatment with the caspase-3 inhibitor. Moreover, we found that GA induced pyroptosis and significantly inhibited tumor growth in CT26 tumor-bearing mice. Strikingly, significantly increased proportions of CD3+ T cells, cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) were observed in the tumor microenvironment in the GA-treated groups. Moreover, significantly increased proportions of CTLs and effector memory T cells (TEM) (CD8+ CD44+ CD62L-) were also detected in the spleens of the GA-treated groups, suggesting that the pyroptosis-induced immune response generated a robust memory response that mediated protective immunity. In this study, we revealed a previously unrecognized mechanism by which GA induces GSDME-dependent pyroptosis and enhances the anticancer immune response. Based on this mechanism, GA is a promising antitumor drug for CRC treatment that induces caspase-3-GSDME-dependent pyroptosis. This study provides novel insight into cancer chemoimmunotherapy.

The exon 12-containing LHX6 isoforms promote cervical cancer cell proliferation by regulating the MAPK signaling pathway.

LIM homeobox 6 (LHX6) has been reported to be downregulated and inhibits cell proliferation in various cancers. Alternative splicing of LHX6 leads to six annotated isoforms, which can be found in the NCBI database. However, the expression patterns and potential roles of these isoforms remain poorly characterized in cervical cancer. Here, we demonstrated that the LHX6 isoforms containing exon 12 (LHX6EX(+12) group) and isoforms lacking exon 12 (LHX6EX(-12) group) were differentially expressed in cervical tissue by qRT-PCR. The mRNA expression level of LHX6EX(+12) group was higher than that of LHX6EX(-12) group in cervical cancer tissue. Knockdown of LHX6EX(+12) group and all LHX6 isoforms (LHX6All group) inhibited cell growth, increased cell apoptosis, and induced cell cycle arrest from G0/G1 phase to S phase in vitro. Consistently, overexpression of the LHX6EX(+12) group promoted cervical cancer cell proliferation in vitro. In contrast, no significant differences in cell proliferation were found between LHX6EX(-12) isoform knockdown group and its control. RNA-sequencing suggested that the LHX6EX(+12) isoform group might exert its cancer-promoting effects in cervical cancer via regulating MAPK signaling pathway. Downregulation of the LHX6EX(+12) group significantly suppressed the phosphorylation of MRK, ERK, JNK, and P38 at the protein level. We also identified some unique biological processes and signaling pathways in which each isoform group might be involved. In summary, our results indicated that LHX6EX(+12) isoform group was the dominant oncogenic type of LHX6 in cervical cancer, which may be a new biomarker and a potential precise therapeutic target for cervical cancer in the future.

A novel ICG-labeled cyclic TMTP1 peptide dimer for sensitive tumor imaging and enhanced photothermal therapy in vivo.

TMTP1 is a polypeptide independently screened in our laboratory, which can target tumors in situ and metastases. In previous work, we have successfully developed a near-infrared (NIR) probe TMTP1-PEG4-ICG for tumor imaging. However, the limited ability to target tumor micrometastases hinders its further clinical application. Multimerization of peptides has been extensively demonstrated as an effective strategy to increase receptor binding affinity due to "multivalent effect" or "apparent cooperative affinity". In this study, a novel TMTP1 homodimer-directed NIR probe (TMTP1-PEG4)2-ICG was successfully constructed and synthesized. The cyclic TMTP1 peptides were bridged by two PEG4 linkers and then labeled with ICG-NHS for tumor imaging and photothermal therapy. In vivo biodistribution were assessed in normal BALB/c mice, and tumor targeting abilities of (TMTP1-PEG4)2-ICG and its monomer were evaluated and compared in 4T1-bearing subcutaneous tumor and lymph node metastasis model mice. Biodistribution analysis in vivo revealed that (TMTP1-PEG4)2-ICG was cleared mainly in both liver and kidney dependent way. Comparing with free ICG dye or TMTP1-PEG4-ICG probe, this improved (TMTP1-PEG4)2-ICG dimer showed more sensitive tumor imaging and could clearly identify tumors at a minimum volume of 10 mm3. Additionally, when compared to its monomer, lymph node (LN) metastases could also be apparently visualized and easily distinguished from normal LN by the novel dimer at 24 h post-injection. The blocking study revealed that the tumor accumulation of this probe was specifically medicated by receptor-ligand interaction. Furthermore, with the increase in stability and tumor targeting ability of ICG in vivo, the probe could also be an attractive photothermal agent to significantly inhibit tumor growth under 808 nm NIR laser irradiation. In conclusion, our work revealed that the novel (TMTP1-PEG4)2-ICG dimer could be a promising theranostic agent for sensitive tumor imaging and imaging-guided photothermal therapy, indicating its broad prospects for further clinical transformation.

TMTP1-Modified, Tumor Microenvironment Responsive Nanoparticles Co-Deliver Cisplatin and Paclitaxel Prodrugs for Effective Cervical Cancer Therapy.

BACKGROUND AND PURPOSE: Cisplatin-paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release. METHODS: TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo. RESULTS: The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects. CONCLUSION: Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.