Potential implications of SARS-CoV-2 oral infection in the host microbiota

The oral cavity, as the entry point to the body, may play a critical role in the pathogenesis of SARS-CoV-2 infection that has caused a global outbreak of the coronavirus disease 2019 (COVID-19). Available data indicate that the oral cavity may be an active site of infection and an important reservoir of SARS-CoV-2. Considering that the oral surfaces are colonized by a diverse microbial community, it is likely that viruses have interactions with the host microbiota. Patients infected by SARS-CoV-2 may have alterations in the oral and gut micro-biota, while oral species have been found in the lung of COVID-19 patients. Furthermore, interactions between the oral, lung, and gut microbiomes appear to occur dynamically whereby a dysbiotic oral microbial community could influence respiratory and gastrointest-inal diseases. However, it is unclear whether SARS-CoV-2 infection can alter the local home-ostasis of the resident microbiota, actively cause dysbiosis, or influence cross-body sites interactions. Here, we provide a conceptual framework on the potential impact of SARS- CoV-2 oral infection on the local and distant microbiomes across the respiratory and gastro-intestinal tracts (‘oral-tract axes’), which remains largely unexplored. Studies in this area could further elucidate the pathogenic mechanism of SARS-CoV-2 and the course of infection as well as the clinical symptoms of COVID-19 across different sites in the human host

Crosstalk Between PD-1/PD-L1 Blockade and Its Combinatorial Therapies in Tumor Immune Microenvironment: A Focus on HNSCC

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis and high mortality. More than two-thirds of HNSCC patients still have no effective control of clinical progression, and the five-year survival rate is < 50%. Moreover, patients with platinum-refractory HNSCC have a median survival of < 6 months. The significant toxicity and low survival rates of current treatment strategies highlight the necessity for new treatment modalities. Recently, a large number of studies have demonstrated that programmed cell death protein-1 (PD-1) and its ligand, programmed cell death protein ligand-1 (PD-L1) play an essential role in tumor initiation and progression. PD-1/PD-L1 blockade has shown a desired and long-lasting therapeutic effect in the treatment of HNSCC and other malignancies. However, only a small number of patients with HNSCC can benefit from PD-1/PD-L1 blockade monotherapy, while the majority of patients do not respond. To overcome the unsatisfactory therapeutic effect of PD-1/PD-L1 blockade monotherapy, combining other treatment options for HNSCC (including chemotherapy, radiotherapy, targeted therapy, and immunotherapy) in the treatment scheme has become a commonly used strategy. Herein, the potential mechanisms underlying the crosstalk between PD-1/PD-L1 blockade and its combinatorial therapies for HNSCC were reviewed, and it is hoped that the improved understanding of the crosstalk process would provide further ideas for the design of a combinatorial regimen with a higher efficiency and response rate for the treatment of HNSCC and other malignancies

Involvement of potential pathways in malignant transformation from Oral Leukoplakia to Oral Squamous Cell Carcinoma revealed by proteomic analysis

<p>Abstract</p> <p>Background</p> <p>Oral squamous cell carcinoma (OSCC) is one of the most common forms of cancer associated with the presence of precancerous oral leukoplakia. Given the poor prognosis associated with oral leukoplakia, and the difficulties in distinguishing it from cancer lesions, there is an urgent need to elucidate the molecular determinants and critical signal pathways underlying the malignant transformation of precancerous to cancerous tissue, and thus to identify novel diagnostic and therapeutic target.</p> <p>Results</p> <p>We have utilized two dimensional electrophoresis (2-DE) followed by ESI-Q-TOF-LC-MS/MS to identify proteins differentially expressed in six pairs of oral leukoplakia tissues with dysplasia and oral squamous cancer tissues, each pair was collected from a single patient. Approximately 85 differentially and constantly expressed proteins (> two-fold change, P < 0.05) were identified, including 52 up-regulated and 33 down-regulated. Gene ontological methods were employed to identify the biological processes that were over-represented in this carcinogenic stage. Biological networks were also constructed to reveal the potential links between those protein candidates. Among them, three homologs of proteosome activator PA28 a, b and g were shown to have up-regulated mRNA levels in OSCC cells relative to oral keratinocytes.</p> <p>Conclusion</p> <p>Varying levels of differentially expressed proteins were possibly involved in the malignant transformation of oral leukoplakia. Their expression levels, bioprocess, and interaction networks were analyzed using a bioinformatics approach. This study shows that the three homologs of PA28 may play an important role in malignant transformation and is an example of a systematic biology study, in which functional proteomics were constructed to help to elucidate mechanistic aspects and potential involvement of proteins. Our results provide new insights into the pathogenesis of oral cancer. These differentially expressed proteins may have utility as useful candidate markers of OSCC.</p

Hyalinizing clear cell carcinoma of salivary gland: a clinicopathological study of 8 cases

Background and purpose: Hyalinizing clear cell carcinoma (HCCC) of salivary gland is a rare tumor with low-grade malignancy, which usually occurs in minor salivary glands. Due to its rarity, the tumor type is not well known to pathologists and misdiagnosis frequently occurred. The aim of this study was to investigate the histologic, immunophenotypic and molecular features of HCCC. Methods: Eight cases of salivary gland HCCC diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center from January 2015 to October 2019 were collected. Clinicopathologic characteristics were analyzed, and fluorescence in situ hybridization (FISH) assay was used to detect EWSR1 translocation in tumor tissue. Diagnostic criteria and differential diagnosis were summarized, with a review of the literature. Results: All patients were female, aged 26 to 68 years, and the tumor locations included the oral cavity, nasopharynx, parotid gland and other sites of head and neck. Microscopically, the tumors consisted mainly of clear cells and eosinophilic cells with variable proportions, arranged in nests, sheets and trabeculae. In 1 case, the tumor was composed almost entirely of eosinophilic cells; in 6 cases, obvious nuclear pseudo-inclusion bodies were seen; in 1 case, neoplastic cells were connected to the surface squamous epithelium; in 1 case, the glandular structure was seen in some areas of the tumor; in 3 cases, a sheath of lymphocyte was formed around the tumor nests; in 7 cases, there was a sclerosing or hyalinizing stromal reaction, showing desmoplastic changes; and 1 case featured stoma with myxoid changes. There was no definite keratinization or necrosis in all tumors, and mitotic figures were generally rare. Immunohistochemical staining showed that tumor cells of 8 cases were diffusely positive for AE1/AE3 protein, 7 cases expressed P63, and 7 cases focally expressed low molecular weight keratin CK7 or CAM5.2, however, S-100, calponin, PAX-8 and CD10 were all negative. All tumors showed low proliferative activity, with the Ki-67 proliferation index less than 5%. FISH test revealed EWSR1 translocation in all 8 cases. All patients demonstrated no recurrence or metastasis during the follow up ranging 4-50 months. Conclusions: HCCC of salivary gland is a low-grade malignancy occurring mainly in minor salivary glands, with characteristic histological and molecular features. This cancer type needs to be distinguished with many morphologic mimics of salivary gland. Most cases with salivary HCCC feature a good prognosis

Correlation Between Oral Lichen Planus and Thyroid Disease in China: A Case–Control Study

BackgroundA possible relationship between oral lichen planus (OLP) and thyroid disease has received attention in recent years.ObjectiveThis study aimed to evaluate the correlation between OLP and thyroid diseases in Chinese ethnic patients.Methods192 OLP patients, 123 patients with oral lichenoid lesions (OLLs), and 162 controls were recruited in this case–control study. All participants received screening for thyroid function and underwent ultrasound. Sex and age of the patients in the three groups were matched. The prevalence of thyroid diseases in the subjects was analyzed. Using logistic regression, the odds ratio (OR) with 95% confidence intervals was appraised for associations between OLP, OLL, and different types of thyroid diseases [Hashimoto’s thyroiditis (HT), hypothyroidism, and thyroid nodule].ResultsThe prevalence of thyroid diseases in the OLP group (72.4%) and OLL group (68.3%) was higher than the control group (49.4%) with statistical significance. The OR of HT was 3.16 (1.87–5.33) for OLP, 2.09 (1.18–3.70) for OLL, while the OR of thyroid nodule was 2.31 (1.30–4.09) for OLP.ConclusionOur study suggested a close relationship between OLP/OLL and HT and thyroid nodule in a Chinese population. The possible mechanism behind this association warrants further investigation

Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers

Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance