Effect of the gut microbiome and inflammation-related proteins on oral leukoplakia: a Mendelian randomization study and mediation analysis.

Background: Oral leukoplakia (OL) is the most common potentially malignant disease of the oral cavity. In recent years, studies have identified a correlation between the gut microbiota (GM) and oral cancer, in addition, inflammation-related proteins have been reported to play an important role in the development of OL. However, the causal relationship between gut microbiota and OL, as well as whether cytokines play a mediating role, remain unclear. Methods: In this Mendelian randomization (MR) study, the genome-wide association studies (GWAS) (n=18340) of the MiBioGen consortium microbiome was used as exposure data. Genetic variation data related to OL were extracted from the Finngen R9 project (513 cases of OL and 411668 controls). The 91 inflammation-related proteins obtained in the literature serve as potential mediators. Two-sample Mendelian randomization analysis was applied to infer causality using Inverse Variance Weighted (IVW), MR Egger, weighted media, simple mode and weighted mode method. Subsequently, sensitivity analysis was conducted to ensure the robustness of the MR results. In addition, we conducted reverse MR analysis to alleviate reverse causality. Finally, we used mediation analysis to determine the pathway mediated by inflammation-related proteins from the gut microbiota to OL. Results: The five bacterial taxa in the gut microbiota indicate a potential causal relationship with the development of OL. Notably, family Clostridiaceae1 was negatively correlated with the risk of OL development, while genus Dorea, genus Ruminococcus1, genus Senegalimasilia and genus Veillonella were positively associated with the risk of OL development. In addition, this study identified a potential causal relationship between interleukin-10 receptor subunit alpha (IL-10RA), interleukin-18 receptor 1(IL18-R1) and the occurrence of OL. In addition, intermediary analysis indicates that IL18-R1 mediated the pathway between the gut microbiota genus Senegalimasilia and OL. Conclusions: In summary, our research emphasize the complex relationship between gut microbiota, inflammation-related proteins and OL. The identified associations and mediating effects provide new insights into potential therapeutic approaches for targeting the gut microbiota in the management of OL, and contribute to its prevention, diagnosis and treatment.

Sonodynamic and sonomechanical effect on cellular stemness and extracellular physicochemical environment to potentiate chemotherapy.

BACKGROUND: Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP. RESULTS: A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness. CONCLUSIONS: This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.

Enzyme-like biomimetic oral-agent enabling modulating gut microbiota and restoring redox homeostasis to treat inflammatory bowel disease.

Reactive oxygen species (ROS), immune dysregulation-induced inflammatory outbreaks and microbial imbalance play critical roles in the development of inflammatory bowel disease (IBD). Herein, a novel enzyme-like biomimetic oral-agent ZnPBA@YCW has been developed, using yeast cell wall (YCW) as the outer shell and zinc-doped Prussian blue analogue (ZnPBA) nanozyme inside. When orally administered, the ZnPBA@YCW is able to adhere to Escherichia coli occupying the ecological niche in IBD and subsequently release the ZnPBA nanozyme for removal of E. coli, meanwhile exhibiting improved intestinal epithelial barrier repair. Moreover, it is found that the ZnPBA nanozyme exhibits remarkable capability in restoring redox homeostasis by scavenging ROS and inhibiting NF-κB signaling pathway. More importantly, the 16S ribosomal RNA gene sequencing results indicate that post-oral of ZnPBA@YCW can effectively regulate gut microbiota by enhancing the bacterial richness and diversity, significantly increasing the abundance of probiotics with anti-inflammatory phenotype while downgrading pathogenic E. coli to the same level as normal mice. Such a novel nanomedicine provides a new idea for efficient treating those ROS-mediated diseases accompanying with flora disorders.

Ca & Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening.

Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment (TME), triple-negative breast cancer (TNBC) has been poorly responsive to immunotherapy so far. Herein, a Ca & Mn dual-ion hybrid nanostimulator (CMS) is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening, which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently. On one hand, glutathione (GSH) depletion and reactive oxygen species (ROS) generation can be achieved due to the mixed valence state of Mn in CMS. On the other hand, as an exotic Ca2+ supplier, CMS causes mitochondrial Ca2+ overload, which further amplifies the oxidative stress. Significantly, tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxidation (LPO). More impressively, CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway, which promotes polarization of tumor-associated macrophages (TAMs) and activation of dendritic cells (DCs) for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes (CTLs) into tumor tissues. Taken together, this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity, offering a new perspective for effective tumor immunotherapy of TNBC.

An Endogenous H2S-Activated Nanoplatform for Triple Synergistic Therapy of Colorectal Cancer.

Overproduced hydrogen sulfide (H2S) is a highly potential target for precise colorectal cancer (CRC) therapy; herein, a novel 5-Fu/Cur-P@HMPB nanomedicine is developed by coencapsulation of the natural anticancer drug curcumin (Cur) and the clinical chemotherapeutic drug 5-fluorouracil (5-Fu) into hollow mesoporous Prussian blue (HMPB). HMPB with low Fenton-catalytic activity can react with endogenous H2S and convert into high Fenton-catalytic Prussian white (PW), which can generate in situ a high level of •OH to activate chemodynamic therapy (CDT) and meanwhile trigger autophagy. Importantly, the autophagy can be amplified by Cur to induce autophagic cell death; moreover, Cur also acted as a specific chemosensitizer of the chemotherapy drug 5-Fu, achieving a good synergistic antitumor effect. Such a triple synergistic therapy based on a novel nanomedicine has been verified both in vitro and in vivo to have high efficacy in CRC treatment, showing promising potential in translational medicine.

[Evaluation of the effectiveness of treatment of 16 patients with tongue microcystic lymphatic malformation using bipolar coagulation forceps combined with 1% lauromacrogol foam sclerotherapy].

PURPOSE: To investigate the clinical efficacy and safety of bipolar coagulation forceps combined with 1% lauromacrogol foam sclerotherapy in the treatment of microcystic lymphatic malformation of tongue. METHODS: The clinical data of 16 patients with microcystic lymphatic malformation of the tongue admitted to the Department of Stomatology of Foshan First People's Hospital from April 2017 to April 2020 were retrospectively analyzed, including 7 males and 9 females, aging from 15 months to 21 years. The average age of patients was 8.32±1.21 years. The efficacy and complications of the patients were evaluated. RESULTS: All 16 patients were followed up for 6 to 12 months. The clinical response was evaluated as eleven patients (68.75%) for grade Ⅳ, three (18.75%) for grade Ⅲ, two (12.5%) for grade Ⅱ, and the effective rate was 87.5%. Necrosis of tongue mucosa and muscle occurred in 1 patient. CONCLUSIONS: Bipolar coagulation forceps combined with 1% lauromacrogol foam sclerotherapy is a minimally invasive, safe and effective treatment for tongue microcystic lymphatic malformation.

[DSA types and treatment strategy of venous malformations of the tongue： an analysis of 132 consecutive patients].

PURPOSE: To explore the DSA classification and treatment strategy of tongue venous malformation. METHODS: From February 2016 to February 2019, the DSA manifestations of 132 cases with venous malformations of the tongue were summarized. They were classified into 4 types according to imaging characteristics: typeⅠ(non-drainage type), typeⅡ(lower- drainage type), type Ⅲ (higher-drainage type), type Ⅳ(extensive type). Different therapeutic schemes were selected according to the types. The non- drainage type was treated with pingyangmycin alone, the lower-drainage type was treated with lauromacrogol foam alone, the higher- drainage type was treated with absolute alcohol combined with lauromacrogol foam, the extensive type was treated as higher-drainage type first and then combined with plastic resection. Among the cases, therapeutic effects and adverse reactions of each group were recorded and compared. RESULTS: One hundred and thirty-two cases in this study were followed up for 12 to 41 months with an average of 15.8 months. After sclerosing therapy, the venous malformations of the tongue of all patients significantly reduced or even disappeared. Type Ⅰincluded 8 cases with an efficiency of 100%, type Ⅱ included 17 cases with an efficiency of 100%, type Ⅲ included 98 cases with an efficiency of 90.8%, typeⅣincluded 9 cases, with an efficiency of 77.8%.The main adverse reactions were tissue necrosis: 0 in typeⅠ, 1(5.88%) in typeⅡ, 16(16.33%) in type Ⅲ, and 7(77.78%) in type Ⅳ. CONCLUSIONS: The classification of venous malformations of the tongue based on DSA is significant and valuable in guiding clinical treatment. The majority of tongue venous malformations are type Ⅲ, and the smallest propotion is type Ⅰ. Transmucosal sclerotherapy with absolute ethanol is of significance for the treatment of venous malformations of the tongue classified in type Ⅲ and type Ⅳ.

Submental Island Flap Combined With Reconstruction Titanium Plate: A New Way to Treat Mandibular Osteoradionecrosis.

Objective. The purpose of this study was to investigate the effect of reconstruction for bone defects in patients with mandibular osteoradionecrosis using submental flap combined with reconstructive titanium plate. Methods. A total of 23 patients with mandibular osteoradionecrosis were included. All patients underwent surgical resection and immediate reconstruction with submental flap combined with reconstructive titanium plate. The postoperative effects and flap success rate were evaluated with a 6- to 18-month follow-up. Results. Twenty-two flaps were successful; 1 flap suffered from partial necrosis in the distal end, but the patient was treated with hyperbaric oxygen therapy and iodoform gauze dressing, and no plate exposure was found after operation in the follow-up period. Conclusion. The use of submental flap combined with reconstructive titanium plate for treating the patients with osteoradionecrosis is a feasible, cost-effective, simple, and safe procedure.

Design strategy of optical probes for tumor hypoxia imaging.

Clinical manifestations of tumors indicate that malignant phenotypes developing in the hypoxic microenvironment lead to resistance to cancer treatment, rendering chemotherapy, radiotherapy, and photodynamic therapy less sensitive and effective in patients with tumor. Visualizing the oxygen level in the tumor environment has garnered much attention due to its implications in precision tumor therapy. Following the rapid development of biomaterials in nanotechnology, various nanomaterials have been designed to visualize the oxygen levels in tumors. Here, we review recent research on detecting oxygen levels in solid tumors for tumor hypoxia imaging. To monitor the hypoxic level of tumors, two main strategies were investigated: directly detecting oxygen levels in tumors and monitoring the hypoxia-assisted reduced microenvironment. We believe that hypoxia as a tumor-specific microenvironment can be a breakthrough in the clinical treatment of tumors.

Hypoxia-Induced Photogenic Radicals by Eosin Y for Efficient Phototherapy of Hypoxic Tumors.

The current reported photosensitizers generally show a decreased reactive oxygen species (ROS) generation property under hypoxia conditions, which is the main reason for the clinical failure of photodynamic therapy (PDT) in treatment of solid tumors. Herein, for the first time, hypoxia-induced photogenic radicals by eosin Y (Eos) were reported for efficient phototherapy of hypoxic tumors. More importantly, Eos shows a higher ROS and radical production efficiency under hypoxia conditions than under normoxia conditions. The photogenic radicals were captured by electron paramagnetic resonance and further verified by ROS and radical probe. Introducing CoCl2 as a hypoxia inducer, the photoinduced therapy of the hypoxia cancer cell model and tumor-bearing mice indicated that bovine serum albumin-Eos in hypoxic tumor sites can produce even higher tumor toxicity, thereby crossing the clinical obstacles of hypoxic tumor therapy. This non-oxygen-dependent PDT may open up an avenue for fighting with hypoxia.

Epidural Tube: A Useful Device in Sialendoscopy Operations.

Salivary endoscopy, which was first described in 1991, is a safe technique with few complications. The sialendoscopy operation has been developed and successfully offered as a minimally invasive and gland-preserving approach for the treatment of chronic obstructive sialadenitis. For many surgeons, entering the duct lumen of the salivary gland is the most difficult and time-consuming step of the sialendoscopy operation. This report introduces a timesaving and straightforward method for entering the duct lumen using an epidural tube, which is a plastic tube with a blunt tip.

Surgical excision of sialoblastoma in the parotid gland in newborn.

OBJECTIVES: To evaluate outcome of surgical excision of sialoblastoma in the parotid gland in newborn. PATIENTS AND METHODS: This was a retrospective review of 3 pediatric patients with sialoblastoma in the parotid gland that underwent surgical resections. All patients are newborn boys. The lesions ranged from 5 cm × 5 cm to 8 cm × 5 cm in size. The tumor was resected en bloc, and the facial nerve was preserved. RESULTS: None surgical complications occurred. The mean follow-up was 34 months; none patients had recurrent lesions. CONCLUSION: Surgical dissection of sialoblastoma in the parotid gland in the newborn is most efficient and safe.

[Expression of transforming growth factor-ß(1) and Ki-67 nuclear antigen in salivary gland mucoepidermoid carcinoma].

OBJECTIVE: To investigate the expression and significance of transforming growth factor-ß(1) (TGF-ß(1)) and Ki-67 nuclear antigen in salivary gland mucoepidermoid carcinoma. METHODS: The expression of TGF-ß(1) and Ki-67 nuclear antigen in 20 cases of salivary gland pleomorphic adenoma and 45 cases of mucoepidermoid carcinoma were detected by the streptavidin-peroxidase immunohistochemical method. RESULTS: Expression of TGF-ß(1) (39/45) and Ki-67 nuclear antigen (43/45) in mucoepidermoid carcinoma was significantly higher than in pleomorphic adenoma (P < 0.05). TGF-ß(1) expression was significantly higher in moderately/poorly differentiated mucoepidermoid carcinoma (16/16) than that in well differentiated mucoepidermoid carcinoma (23/29) and pleomorphic adenoma (12/20) (P < 0.05), but not different between well differentiated mucoepidermoid carcinoma (6/23) and pleomorphic adenoma (8/12) (P > 0.05). The expression of Ki-67 was increased with the increment of TGF-ß(1) expression in mucoepidermoid carcinoma (P < 0.05). CONCLUSIONS: The high expression of TGF-ß(1) may play an important role in cell differentiation and malignant proliferation of mucoepidermoid carcinoma.

Digital subtraction angiography-guided percutaneous sclerotherapy of venous malformations with pingyangmycin and/or absolute ethanol in the maxillofacial region.

PURPOSE: The present study evaluated the safety and efficacy of digital subtraction angiography-guided percutaneous sclerotherapy of venous malformations (VMs) with pingyangmycin and/or absolute ethanol in the maxillofacial region. We present our safe and novel method for treating venous malformations. PATIENTS AND METHODS: A total of 20 patients (21 locations) diagnosed with VMs were enrolled in the present trial. Evaluated by preoperative digital subtraction angiography, the lesions were categorized into 4 types according to the venous drainage features. Of the 20 patients, 5 had type I VMs, 5 had type II, 6 had type III and 3 had type IV VMs. One patient had type I and type III VMs in different locations of the maxillofacial region. For types I and II lesions, pingyangmycin sclerotherapy was performed. Multistage sclerotherapy with absolute ethanol and pingyangmycin was performed on types III and IV lesions. RESULTS: After evaluation and guided by preoperative digital subtraction angiography, all the patients were treated successfully and safely. Of the 20 patients, the clinical outcome was excellent in 13, good in 6, and fair in 1. No disease recurrence was noted during the follow-up evaluations (range 6 to 25 months, median 13.55). The complications were fever in 5 patients after the first session of sclerotherapy, incomplete facial paralysis in 1, swelling in 1, and ulceration in 3. No major complications were observed. CONCLUSIONS: Digital subtraction angiography-guided phlebography of VMs in the maxillofacial region is one of the approaches to classify VMs using anatomic and hemodynamic features. A strong association was seen between the type of VM and the approach of sclerotherapy. Percutaneous sclerotherapy using pingyangmycin and/or absolute ethanol is a safe and effective method of treating symptomatic VMs.

[Use of lower trapezius musculocutaneous pedicle flap in repairing of maxillofacial region penetrating defect].

OBJECTIVE: To investigate an safe and effective new technology (treatment) to repair maxillofacial region penetrating defect. METHODS: The lower trapezius musculocutaneous flap is parallel just like as two leaves which is connected to each other, and was folded to provide the liner of oral cavity and external cover. RESULTS: Totally twelve folding lower trapezius musculocutaneous pedicle flap survived. Postoperative follow-up for 1 approximately 3 years, the patients restored the function as well as the shape of maxillofacial region. CONCLUSIONS: The lower trapezius musculocutaneous pedicle flap is a suitable material for maxillofacial region reconstruction, further more, the successful rate is perfect.

[Paralytic shellfish toxins in shellfish from the coast of high frequent harmful algae blooms occurrence areas in East China Sea and South China Sea].

The paralytic shellfish poisoning (PSP) toxicity levels of shellfish collected from shellfish growing zones in Zhoushan areas of East China Sea and Shenzhen areas of South China Sea during January-November 2002 were determined with AOAC bioassay method. The results showed that the toxicity levels of shellfish from Zhoushan were very low, and few shellfish samples could be detected the PSP toxicities. The same levels appeared in the shellfish from Shenzhen, but the percentage of shellfish samples contaminated PSP was up to 30%, and the scallop Chalmys nobilis was dominated in the contaminated shellfish species. Analyses on the toxic profiles of digest gland and edible tissue extraction of scallop from Shenzhen showed that a similar suite of toxins presented in the gland and edible tissues. The high potency neoSTX and low potency GTX5 had a high proportions, up to 60.8% and 11.4%, respectively in the tissue, and the high potency GTX1 + 2 and GTX5 were the dominant toxins, up to 38.9% and 20%, respectively in the gland. Most of the toxin were accumulated in ingested gland of scallop, and the toxic content in gland was about 8 folds more than that in the edible tissues.