Functional and esthetic reconstruction of composite lower lip defects with a motor-innervated chimeric facial artery buccinator myomucosal-submental island flap.

OBJECTIVE: This study aimed to assess the functional and esthetic outcomes of a chimeric innervated buccinator myomucosal-submental island flap (BMM-SIF) for large composite lower lip reconstruction. METHODS: This retrospective study included five patients who underwent lower lip tumor resection and BMM-SIF reconstruction at the Hospital of Stomatology, Sun Yat-sen University, between August 2021 and February 2023. Lip function was evaluated using water leakage, cheek puffing tests, and superficial electromyography. Lip appearance was observed using photographs and evaluated through subjective interviews. Donor-site conditions, including facial symmetry and mouth opening, were monitored. RESULTS: All the BMM-SIFs survived. Drooling was the main complication observed shortly after surgery. The water leakage test showed complete oral competence for liquid holding in the 7th month; however, moderate air leakage was present in two patients. Electromyography revealed myoelectric signals from the innervated buccinator at the recipient site. Facial expression and food intake were typically managed. The shape and projection of the vermilion were harmonious and satisfactory for each patient. Neither microstomia nor mouth opening limitation was observed, with an average inter-incisor distance of 37.25±4.4 mm. CONCLUSION: Chimeric motor-innervated BMM-SIF effectively reconstructed large full-thickness lower-lip defects with satisfactory functional and esthetic outcomes.

The competitive mechanism of EZH1 and EZH2 in promoting oral squamous cell carcinoma.

Enhancer of Zeste Homolog 1 (EZH1) and Enhancer of Zeste Homolog 2 (EZH2) are the key components of polycomb repressive complex 2 (PRC2); however, the roles of these proteins in oral squamous cell carcinoma (OSCC) have yet to be elucidated. In this study, we aimed to determine the respective roles of these proteins in OSCC by investigating the expression levels of EZH1 and EZH2 in OSCC tissues (N = 63) by immunohistochemistry. In addition, we used lentiviruses to construct stable OSCC cell lines that overexpressed EZH1 and EZH2. Then, we investigated these cell lines for cell viability, colony formation capacity, stemness, and epithelial-mesenchymal transition (EMT). Binding competition between EZH1 and EZH2 with PRC2 was further evaluated using Co-immunoprecipitation (Co-IP). Compared with normal tissues, the expression levels of EZH2 in OSCC tissues was up-regulated, while the expression of EZH1 was down-regulated. EZH2 enhanced cell viability, colony formation capacity, stemness, and EMT, while EZH1 did not. Furthermore, analysis indicated that EZH1 and EZH2 bound competitively to PRC2 and influenced the methylation status of H3K27. In conclusion, our findings verified that EZH1 and EZH2 play opposing roles in OSCC and that EZH1 and EZH2 compete as the key component of PRC2, thus affecting the characteristics of OSCC via the methylation of H3K27.

P53 Alleviates the Progression of Periodontitis by Reducing M1-type Macrophage Differentiation.

Our objective is to explore the effect of P53 on the progression of periodontitis by regulating macrophages differentiation both in vitro and in vivo. Eighteen normal and periodontitis gingival tissues were collected for detecting P53 expression and macrophages infiltration by immunofluorescence, real-time PCR (qPCR) and western-blot. The differentiation and the inflammatory cytokines (TNF-α and IL-6) expression of THP-1, RAW264.7 and bone marrow derived macrophage (BMDM) cells, treating with Pifithrin-α (P53 inhibitor) or Nutlin-3a (P53 activator) under lipopolysaccharide (LPS) stimulation, were observed by flow cytometry, qPCR and ELISA. The severity of periodontitis, inflammatory cytokines expression and macrophages infiltration were measured in experimental periodontitis wild-type mice and p53 gene conditional knocked-out (p53-CKO) mice, which were established by ligation and LPS injection. A higher number of P53-positive macrophages was found infiltrated in periodontitis tissues. In vitro experiments showed that compared with Nutlin-3a, the proportion of M1-type macrophages and the expression of TNF-α and IL-6 were higher in Pifithrin-α treated cells under LPS stimulation. In vivo experimental periodontitis mice, the Pifithrin-α intraperitoneal injection group showed greater alveolar bone loss, higher levels of TNF-α and IL-6 secretion and more M1-type macrophages infiltration, while the Nutlin-3a intraperitoneal injection group were observed mild symptoms compared with mice in the periodontitis group. P53-CKO mice exhibited more severe periodontitis and more M1-type macrophages infiltrated in local tissues compared with wild-type mice. The activation of p53 gene could alleviate periodontitis by reducing M1-type macrophage polarization. P53 may serve as keeper in the progression of periodontitis, providing new insights into periodontitis treatment.

Favorable effects of open surgery on patients with extensive skull base osteoradionecrosis through a personalized sequential approach: A case series.

The present study aimed to investigate outcomes following open surgery for extensive skull base ORN. Open surgery through a personalized sequential approach was employed to deal with five cases of extensive skull base ORN. Two patients with mild cases underwent regional debridement and sequestrectomy, and three patients with severe cases underwent extensive resection with reconstruction using free anterolateral thigh (ALT) flap. Biological glues and vascularized flaps were used for obturation of the skull base bony defect to prevent postoperative cerebrospinal fluid (CSF) leakage. The infections were controlled by antibiotic administrations which strictly followed the principles of antimicrobial stewardship (AMS). As results, both regional debridement plus sequestrectomy and extensive resection achieved satisfied outcomes in all patients. No severe complications and delayed hospitalization occurred. During the follow-up period (8-19 months), all patients were alive, pain free, without crusting or purulent discharge, and no sequestration or CSF leakage occurred. In conclusion, a personalized sequential approach including open surgery, pedicled/vascularized free flap reconstruction and AMS was advocated for patients with extensive skull base ORN.

The association of HBV infection and head and neck cancer: a systematic review and meta-analysis.

BACKGROUND: Hepatitis B virus (HBV) infections is an important public health problem worldwide and closely affect extrahepatic cancer. Several recent studies have investigated the relationship between HBV infection and head and neck cancer (HNC), but their findings were inconsistent.In order to address the limitations of small sample sizes, we conducted a meta-analysis to assess the association between HBV and HNC. METHODS: We systematically searched PubMed, Web of Science, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure from inception to August 2023. Original articles published as a case-control or cohort study were included. HBV infection was identified by HBsAg, HBV DNA or ICD codes. Review articles, meeting abstracts, case reports, communications, editorials and letters were excluded, as were studies in a language other than English or Chinese. According to the MOOSE guidelines, frequencies reported for all dichotomous variables were extracted by two reviewers independently. Similarly, the outcomes of OR, RR or HR, and 95% CIs after adjusting for age and gender were collected. RESULTS: Thirteen relevant studies and 58,006 patients with HNC were included. Our analysis revealed a positive correlation between HBV and HNC (OR = 1.50; 95% CI: 1.28-1.77). After adjusting for age and gender, the similar result (OR = 1.30; 95% CI: 1.10-1.54) was obtained. Subgroup analysis further demonstrated a significant association between HBV infection and oral cancer (OR = 1.24; 95% CI: 1.05-1.47), as well as nasopharyngeal carcinoma (OR = 1.41; 95% CI: 1.26-1.58). However, due to the limited number of studies included, the statistical significance was not reached for cancer of the oropharynx (OR = 1.82; 95% CI: 0.66-5.05), hypopharynx (OR = 1.33; 95% CI: 0.88-2.00), and larynx (OR = 1.25; 95% CI: 0.69-2.24) after adjusting for age and gender. When excluding the interference of HIV/HCV, smoking and alcohol use, the final outcome (OR = 1.17; 95% CI: 1.01-1.35) got the same conclusion. CONCLUSIONS: Our study confirmed a positive relationship between HNC, specifically oral cancer and nasopharyngeal carcinoma, and HBV infection. However, further investigation is required at the molecular level to gather additional evidence in HNC.

Clinical application of a three-dimensional-printed model in the treatment of intracranial and extracranial communicating tumors: a pilot study.

BACKGROUND: Surgical management for intracranial and extracranial communicating tumors is difficult due to the complex anatomical structures. Therefore, assisting methods are urgently needed. Accordingly, this study aimed to investigate the utility of a three-dimensional (3D)-printed model in the treatment of intracranial and extracranial communicating tumors as well as its applicability in surgical planning and resident education. METHODS: Individualized 3D-printed models were created for eight patients with intracranial and extracranial communicating tumors. Based on these 3D-printed models, a comprehensive surgical plan was made for each patient, after which the patients underwent surgery. The clinicopathological data of patients were collected and retrospectively analyzed to determine surgical outcomes. To examine the educational capability of the 3D-printed models, specialists and resident doctors were invited to review three of these cases and then rate the clinical utility of the models using a questionnaire. RESULTS: The 3D-printed models accurately replicated anatomical structures, including the tumor, surrounding structures, and the skull. Based on these models, customized surgical approaches, including the orbitozygomatic approach and transcervical approach, were designed for the patients. Although parameters such as operation time and blood loss varied among the patients, satisfactory surgical outcomes were achieved, with only one patient developing a postoperative complication. Regarding the educational applicability of the 3D-printed model, the mean agreement for all eight questionnaire items was above six (seven being complete agreement). Moreover, no significant difference was noted in the agreement scores between specialists and residents. CONCLUSION: The results revealed that 3D-printed models have good structural accuracy and are potentially beneficial in developing surgical approaches and educating residents. Further research is needed to test the true applicability of these models in the treatment of intracranial and extracranial communicating tumors.

SPP1+ TAM subpopulations in tumor microenvironment promote intravasation and metastasis of head and neck squamous cell carcinoma.

Macrophages are heterogeneous cells that play multifaceted roles in cancer progression and metastasis. However, the phenotypic diversity of tumor-associated macrophages (TAMs) in head and neck squamous carcinomas (HNSCC) remains poorly characterized. Here, we comprehensively analyzed the HNSCC single-cell transcriptomic dataset (GSE172577) and identified 5 subsets of myeloid-driven cells as TAMs using Seurat. Deciphering the lineage trajectory of TAMs, we revealed that FCN1+ TAMs could give rise to pro-angiogenesis SPP1+CCL18+ and SPP1+FOLR2+ populations through SPP1-CCL18+ and CXCL9+CXCL10+ TAMs. SPP1+CCL18+ and SPP1+FOLR2+ TAMs harbored pro-angiogenic and metastatic transcriptional programs and were correlated with poor survival of HNSCC patients. Our immunostaining examination revealed that infiltration of SPP1+ TAMs is associated with lymph node metastasis and poor prognosis in patients with HNSCC. Cell-cell communication analysis implied that SPP1+ TAM populations may employ SPP1 signaling to activate metastasis-related ECs. In vitro and in vivo studies, we demonstrated that SPP1hi TAMs enhanced tumor intravasation and metastasis in HNSCC in a manner dependent on the secretion of SPP1, CCL18, and CXCL8. Taken together, our study characterized the cellular heterogeneity of TAM populations and identified two SPP1+ TAM populations that play key roles in HNSCC intravasation and metastasis and serve as predictive markers for patients with HNSCC.

Risk of second primary cancer in patients with head and neck squamous cell carcinoma: a systemic review and meta-analysis.

OBJECTIVES: Second primary cancer is a common event in patients with head and neck squamous cell carcinoma. However, the incidence and relevant factors vary by studies. We conducted a systematic review and meta-analysis of observational studies to estimate the incidence and relevant risk factors. MATERIALS AND METHODS: PubMed and Web of Science were searched for studies published between January 2000 and December 2020 that reported the incidence of SPC in HNSCC patients. Per 1000-person-year incidence and odds ratios were used to estimate the incidence and potential risk factors. Due to the high heterogeneity, random-effects models were used to estimate the incidence and 95% confidence interval. RESULTS: Seven thousand seven hundred thirteen articles were identified from the databases, in which 60 studies were included in this meta-analysis. The pooled incidence of the total, synchronous, and metachronous SPC in patients with HNSCC were 29.116 per 1000-person-year, 6.960 per 1000-person-year, and 26.025 per 1000-person-year, respectively. The head and neck region was the most common area where SPC occurred, followed by the lung (7.472 per 1000-person-year) and upper digestive tract (2.696 per 1000-person-year). Smoking, alcohol consumption, betel quid chewing, primary cancer of T1-2, and N0 were risk factors, while HPV infection (OR 0.47, 95% CI 0.30-0.72) was the protective factor. CONCLUSIONS: SPC is frequently observed in HNSCC patients and had great impact on the prognosis. The findings could promote a more individualized follow-up strategy for SPC in HNSCC patients. CLINICAL RELEVANCE: This systemic review and meta-analysis provide sufficient evidence for the establishment of the follow-up strategy for head and neck squamous cancer patients.

Injectable decellularized extracellular matrix hydrogel promotes salivary gland regeneration via endogenous stem cell recruitment and suppression of fibrogenesis.

Saliva is key to the maintenance of oral homeostasis. However, several forms of salivary gland (SG) disorders, followed by hyposalivation, often result in dental caries, oral infection, and decreased taste, which dramatically affect the quality of patient's life. Functional biomaterials hold great potential for tissue regeneration in damaged or dysfunctional SGs and maintaining the good health of oral cavity. Herein, we prepared an injectable hydrogel derived from decellularized porcine submandibular glands (pDSG-gel), the material and biological properties of the hydrogel were systematically investigated. First, good biocompatibility and bioactivities of the pDSG-gel were validated in 2D and 3D cultures of primary submandibular gland mesenchymal stem cells (SGMSCs). Especially, the pDSG-gel effectively facilitated SGMSCs migration and recruitment through the activation of PI3K/AKT signaling pathway, suggested by transcriptomic analysis and immunoblotting. Furthermore, proteomic analysis of the pDSG revealed that many extracellular matrix components and secreted factors were preserved, which may contribute to stem cell homing. The recruitment of endogenous SG cells was confirmed in vivo, upon in situ injection of the pDSG-gel into the defective SGs in rats. Acinar and ductal-like structures were evident in the injury sites after pDSG-gel treatment, suggesting the reconstruction of functional SG units. Meanwhile, histological characterizations showed that the administration of the pDSG-gel also significantly suppressed fibrogenesis within the injured SG tissues. Taken together, this tissue-specific hydrogel provides a pro-regenerative microenvironment for endogenous SG regeneration and holds great promise as a powerful and bioactive material for future treatments of SG diseases. STATEMENT OF SIGNIFICANCE: Decellularized extracellular matrix (dECM) has been acknowledged as one of the most promising biomaterials that recapitalizes the microenvironment in native tissues. Hydrogel derived from the dECM allows in situ administration for tissue repair. Herein, a tissue-specific dECM hydrogel derived from porcine salivary glands (pDSG-gel) was successfully prepared and developed for functional reconstruction of defective salivary gland (SG) tissues. The pDSG-gel effectively accelerated endogenous SG stem cells migration and their recruitment for acinar- and ductal-like regeneration, which was attributed to the activation of PI3K/AKT signaling pathway. Additionally, the introduction of the pDSG-gel resulted in highly suppressed fibrogenesis in the defective tissues. These outcomes indicated that the pDSG-gel holds great potential in clinical translation toward SG regeneration through cell-free treatments.

Repurposing Dihydroartemisinin to Combat Oral Squamous Cell Carcinoma, Associated with Mitochondrial Dysfunction and Oxidative Stress.

Oral squamous cell carcinoma (OSCC), with aggressive locoregional invasion, has a high rate of early recurrences and poor prognosis. Dihydroartemisinin (DHA), as a derivative of artemisinin, has been found to exert potent antitumor activity. Recent studies reported that DHA suppresses OSCC cell growth and viability through the regulation of reactive oxygen species (ROS) production and mitochondrial calcium uniporter. However, the mechanism underlying the action of DHA on OSCCs remains elusive. In the study, we observed that 159 genes were remarkably misregulated in primary OSCC tumors associated with DHA-inhibited pathways, supporting that OSCCs are susceptible to DHA treatment. Herein, our study showed that DHA exhibited promising effects to suppress OSCC cell growth and survival, and single-cell colony formation. Interestingly, the combination of DHA and cisplatin (CDDP) significantly reduced the toxicity of CDDP treatment alone on human normal oral cells (NOK). Moreover, DHA remarkably impaired mitochondrial structure and function, and triggered DNA damage and ROS generation, and activation of mitophagy. In addition, DHA induced leakage of cytochrome C and apoptosis-inducing factor (AIF) from mitochondria, elevated Bax/cleaved-caspase 3 expression levels and compromised Bcl2 protein expression. In the OSCC tumor-xenograft mice model, DHA remarkably suppressed tumor growth and induced apoptosis of OSCCs in vivo. Intriguingly, a selective mitophagy inhibitor Mdivi-1 could significantly reinforce the anticancer activity of DHA treatment. DHA and Mdivi-1 can synergistically suppress OSCC cell proliferation and survival. These data uncover a previously unappreciated contribution of the mitochondria-associated pathway to the antitumor activity of DHA on OSCCs. Our study shed light on a new aspect of a DHA-based therapeutic strategy to combat OSCC tumors.

Activation of NLRP3 signaling contributes to cadmium-induced bone defects, associated with autophagic flux obstruction.

Cadmium (Cd) is a widespread environmental and industrial pollutant to cause various bone metabolic diseases. Our former study reported that Cd promoted adipogenesis and inhibited osteogenic differentiation of primary bone marrow-derived mesenchymal stem cells (BMSCs) by NF-κB inflammation signaling and oxidative stress, and Cd-induced osteoporosis of long bone and compromised repair of cranial bone defect in vivo. However, the underlying mechanisms of Cd-induced bone damage remain elusive. In this study, we used Sprague Dawley (SD) rat and NLRP3-knockout mouse models to elucidate the exact effects and molecular mechanisms of Cd-induced bone damage and aging. Herein we found that the exposure of Cd preferentially targeted a few specific tissues such as bone and kidney. Cd triggered NLRP3 inflammasome pathways and the accumulation of autophagosomes of primary BMSCs, and also Cd stimulated the differentiation and bone resorption function of primary osteoclasts. Moreover, Cd not only activated ROS/NLRP3/caspase-1/p20/IL-1ß pathways, but also influenced Keap1/Nrf2/ARE signaling. The data revealed that autophagy dysfunction and NLRP3 pathways synergistically mediated the impairments of Cd in bone tissues. Loss of NLRP3 function partially alleviated Cd-induced osteoporosis and craniofacial bone defect in the NLRP3-knockout mouse model. Furthermore, we characterized the protective effects and potential therapeutic targets of the combined treatment of anti-aging agents (rapamycin+melatonin+NLRP3 selective inhibitor MCC950) on Cd-induced bone damage and inflammatory aging. These results illuminate that ROS/NLRP3 pathways and autophagic flux obstruction are involved in the Cd-induced toxic actions of bone tissues. Collectively, our study unveils some therapeutic targets and the regulatory mechanism to prevent Cd-caused bone rarefaction. The findings improve the mechanistic understanding of environmental Cd exposure-caused bone metabolism disorders and tissue damage.

The contralateral-based submental artery island flap: feasibility and oncological safety in oral cancer-related defect reconstruction.

OBJECTIVES: Oncologic risk is a serious concern of submental artery island flaps. Here, we introduce the contralateral-based submental artery island flap (C-SAIF) and demonstrate its feasibility and long-term oncological safety in reconstructing oral cancer-related defects. METHODS: An anatomical study was performed concentrating on the pedicle length in seven cadavers. Then, a retrospective study was carried out on C-SAIF patients operated on by a single team. The standard surgical technique of C-SAIF was conducted. Outcomes including operative time, length of hospital stay, volume of intraoperative blood loss, and scores of the Multidisciplinary Salivary Gland Society (MSGS) questionnaire were compared with a similar cohort reconstructed with anterolateral thigh free flap (ALTF). In addition, oncological outcomes were evaluated by the 5-year cumulative survival rate between C-SAIF and ALTF patients. RESULTS: The pedicle length of C-SAIF was sufficient for the flap to be extended to the contralateral oral cavity. Fifty-two patients were included in the retrospective study, and nineteen of them underwent reconstruction with C-SAIF. The operative time of C-SAIF was shorter (p = 0.003), and the intraoperative blood loss was less (p = 0.004) than that of ALTF. There was no difference in MSGS scores. The results of survival analysis revealed comparable survival curves for the two groups in terms of overall survival, disease-specific survival, and disease-free survival. CONCLUSION: C-SAIF is a feasible and reliable flap for reconstructing oral cancer-related defects. Moreover, it is an effective island flap to preserve the perforator and pedicle without compromising oncological safety.

Speech disorders in patients with Tongue squamous cell carcinoma: A longitudinal observational study based on a questionnaire and acoustic analysis.

BACKGROUND: Speech disorders are common dysfunctions in patients with tongue squamous cell carcinoma (TSCC) that can diminish their quality of life. There are few studies with multidimensional and longitudinal assessments of speech function in TSCC patients. METHODS: This longitudinal observational study was conducted at the Hospital of Stomatology, Sun Yat-sen University, China, from January 2018 to March 2021. A cohort of 92 patients (53 males, age range: 24-77 years) diagnosed with TSCC participated in this study. Speech function was assessed from preoperatively to one year postoperatively using the Speech Handicap Index questionnaire and acoustic parameters. The risk factors for postoperative speech disorder were analyzed by a linear mixed-effects model. A t test or Mann‒Whitney U test was applied to analyze the differences in acoustic parameters under the influence of risk factors to determine the pathophysiological mechanisms of speech disorders in patients with TSCC. RESULTS: The incidence of preoperative speech disorders was 58.7%, which increased up to 91.4% after surgery. Higher T stage (P＜0.001) and larger range of tongue resection (P = 0.002) were risk factors for postoperative speech disorders. Among the acoustic parameters, F2/i/decreased remarkably with higher T stage (P = 0.021) and larger range of tongue resection (P = 0.009), indicating restricted tongue movement in the anterior-posterior direction. The acoustic parameters analysis during the follow-up period showed that F1 and F2 were not significantly different of the patients with subtotal or total glossectomy over time. CONCLUSIONS: Speech disorders in TSCC patients is common and persistent. Less residual tongue volume led to worse speech-related QoL, indicating that surgically restoring the length of the tongue and strengthening tongue extension postoperatively may be important.

CCR7 Mediated Mimetic Dendritic Cell Vaccine Homing in Lymph Node for Head and Neck Squamous Cell Carcinoma Therapy.

Immunotherapy has been recognized as one of the most promising treatment strategies for head and neck squamous cell carcinoma (HNSCC). As a pioneering trend of immunotherapy, dendritic cell (DC) vaccines have displayed the ability to prime an immune response, while the insufficient immunogenicity and low lymph node (LN) targeting efficiency, resulted in an unsubstantiated therapeutic efficacy in clinical trials. Herein, a hybrid nanovaccine (Hy-M-Exo) is developed via fusing tumor-derived exosome (TEX) and dendritic cell membrane vesicle (DCMV). The hybrid nanovaccine inherited the key protein for lymphatic homing, CCR7, from DCMV and demonstrated an enhanced efficiency of LN targeting. Meanwhile, the reserved tumor antigens and endogenous danger signals in the hybrid nanovaccine activated antigen presenting cells (APCs) elicited a robust T-cell response. Moreover, the nanovaccine Hy-M-Exo displayed good therapeutic efficacy in a mouse model of HNSCC. These results indicated that Hy-M-Exo is of high clinical value to serve as a feasible strategy for antitumor immunotherapy.

Intratumoral platelet microthrombi in oral squamous cell carcinoma: A marker of lymph node metastasis.

OBJECTIVE: A hypercoagulable state exists in patients with oral squamous cell carcinoma (OSCC), but the role of platelets in the tumour microenvironment has not been explored. This study revealed the status of intratumoral plateletmicrothrombi (PLT-MT) and their clinicopathological relevance and predictive value in OSCC. STUDY DESIGN: This study retrospectively evaluated 106 OSCC patients. Tumour and tumour-adjacent tissue specimens were used to stain PLT-MT. Clinicopathological information, patient follow-ups and outcomes and preoperative coagulation and inflammatory hematologic indicators were collected, and their correlation with PLT-MT was analysed. RESULTS: Intratumoral PLT-MT was present in 35 of 106 patients with OSCC who had higher preoperative D-dimer, CRP, FIB and PT levels and lower TT levels. PLT-MT was an independent correlative factor of lymph node metastasis and suggested worse OS in N0 patients. CONCLUSIONS: Intratumoral PLT-MT was found in OSCC and was correlated with a hypercoagulable inflammatory state. PLT-MT was an independent marker of lymph node metastasis and showed potential in prognosis prediction.

Nanoparticulate Cationic Poly(amino acid)s Block Cancer Metastases by Destructing Neutrophil Extracellular Traps.

Cancer metastasis that is resistant to conventional therapies has become a major cause of patient death. Recent reports indicate that the neutrophil extracellular trap (NET) is closely associated with cancer distant metastases, and the cell-free DNA of NETs has been identified as the ligand of the transmembrane protein CCDC25 of cancer cells, acting as a chemokine to induce cancer cell migration to distant organs. In this work, we present the poly(aspartic acid) based-cationic materials to interfere with the interaction between NET-DNA and CCDC25, and furthermore to inhibit NET-DNA-mediated cancer cell chemotaxis and migration. Because of a stronger binding affinity to DNA and favorable retention in the liver, nanoparticulate poly(aspartic acid) derivatives (cANP) efficiently reduce the level of hepatic NET-DNA infiltration, leading to a significant suppression of cancer metastases in mice and several human metastatic models. Moreover, the cANP exhibits no toxicity to organs of animals during the entire treatment. Thus, this work suggests a strategy for controlling cancer metastases, which will benefit patients in clinics.

Preliminary study on the molecular features of mutation in multiple primary oral cancer by whole exome sequencing.

Multiple primary cancers (MPCs) refer to cancers that occur simultaneously or metachronously in the same individual. The incidence of MPC has increased recently, as the survival time of malignant tumor patients has been greatly prolonged. It is difficult to differentiate MPC from primary cancers (PCs) in the same anatomical region from the clinical manifestation alone. However, their biological behaviors appear to be distinct. In this study, we show that the prognosis of multiple primary oral cancers (MP-OCs) is worse than primary oral cancers (P-OCs). To better understand the molecular mechanisms of MP-OC, we used whole exome sequencing (WES) to analyze samples from 9 patients with MP-OC and 21 patients with P-OC. We found more somatic mutations in MP-OC than in P-OC. MP-OC had more complicated mutation signatures, which were associated with age-related and Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) activity-related signatures. Tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH) of MP-OC trended higher compared to P-OC. KEGG and GO analysis showed the differential pathways of MP-OC versus P-OC. In addition, MP-OC took amplification, not loss, as the main pattern of copy number variation (CNV), while P-OC took both. Lastly, we did not find significantly different mutant germline genes, but MSH-6 mutation may be a potential MP-OC driver. In short, our preliminary results show that MP-OC and P-OC have different molecular characteristics.

Controlled and Sequential Delivery of Stromal Derived Factor-1 α (SDF-1α) and Magnesium Ions from Bifunctional Hydrogel for Bone Regeneration.

Bone healing is a complex process that requires the participation of cells and bioactive factors. Stromal derived factor-1 α (SDF-1α) and magnesium ions (Mg2+) both are significant bioactive factors for cell recruitment and osteogenesis during bone regeneration. Thus, a bifunctional hydrogel containing a sequential delivery system is fabricated to improve osteogenesis. During sequential delivery of the hydrogel, SDF-1α is predominantly released at the early stage of bone mesenchymal stem cells (BMSCs) recruitment, while Mg2+ are constantly delivered at a later stage to improve osteogenic differentiation of recruited cells. In addition, due to the early release of SDF-1α, the hydrogel showed strong BMSCs recruitment and proliferation activity. Mg2+ can not only induce up-regulation of osteogenic gene expression in vitro, but also promote bone tissue and angiogenesis in vivo. Taken together, the injection of xanthan gum-polydopamine crosslinked hydrogel co-loading SDF-1α and Mg2+ (XPMS hydrogel) provides a novel strategy to repair bone defects.

An Appearance Data-Driven Model Visualizes Cell State and Predicts Mesenchymal Stem Cell Regenerative Capacity.

Mesenchymal stem cells (MSCs) are widely used in treating various diseases. However, lack of a reliable evaluation approach to characterize the potency of MSCs has dampened their clinical applications. Here, a function-oriented mathematical model is established to evaluate and predict the regenerative capacity (RC) of MSCs. Processed by exhaustive testing, the model excavates four optimal fitted indices, including nucleus roundness, nucleus/cytoplasm ratio, side-scatter height, and ERK1/2 from the given index combinations. Notably, three of them except ERK1/2 are cell appearance-associated features. The predictive power of the model is validated via screening experiments of these indices by predicting the RC of newly enrolled and chemical inhibitor-treated MSCs. Further RNA-sequencing analysis reveals that cell appearance-based indices may serve as major indicators to visualize the results of integration-weighted signals in and out of cells and reflect MSC stemness. In general, this study proposes an appearance data-driven predictive model for the RC and stemness of MSCs.

Recovery pattern analysis of swallowing function in patients undergoing total glossectomy and hemiglossectomy.

OBJECTIVES: To investigate the recovery process of swallowing function and ascertain swallowing pattern in patients undergoing total glossectomy (TG). MATERIALS AND METHODS: A cohort study was conducted in consecutive patients with tongue squamous cell carcinoma who received TG/hemiglossectomy (HG) from May 2017 to December 2019. Exposure factors included tongue resection range (HG and TG) and postoperative radiotherapy (PRT and non-PRT). The swallowing functions were evaluated by M.D. Anderson dysphagia inventory (MDADI), water swallow test (WST), and tongue pressure (TP) at pretreatment, 1, 4, 7, 12, 18 and 24 months postoperatively. Videofluoroscopy swallowing study (VFSS) was applied to analyze swallowing pattern of TG patients. RESULTS: A total of 67 patients were enrolled, of which 17 underwent TG and 50 underwent HG. Both MDADI and TP of the TG and PRT group were lower than those of the HG and non-PRT group. TG patients had no evident improvement in MDADI and TP after surgery. There was a higher risk of swallowing unsafety with abnormal WST outcome in TG (P < 0.001, OR = 106.52) than that in HG. VFSS analysis identified prolonged oral and pharyngeal transit time, disorganized swallowing sequence, abnormal hyoid bone movement, and frequent invalid swallows in patients with TG. A shortened OTT (<5066.50 ms) and a larger pharyngeal constriction ratio (PCR > 0.31) were associated with increased risks of penetration and aspiration. CONCLUSION: Postoperative swallowing pattern is a characteristic of severely impaired safety and efficacy in patients with TG. Impaired OTT and PCR are variables that should be examined when determining the need for rehabilitation treatment.