Targeting WNT signalling pathways as new therapeutic strategies for osteoarthritis.

Osteoarthritis (OA) is a highly prevalent chronic joint disease and the leading cause of disability. Currently, no drugs are available to control joint damage or ease the associated pain. The wingless-type (WNT) signalling pathway is vital in OA progression. Excessive activation of the WNT signalling pathway is pertinent to OA progression and severity. Therefore, agonists and antagonists of the WNT pathway are considered potential drug candidates for OA treatment. For example, SM04690, a novel small molecule inhibitor of WNT signalling, has demonstrated its potential in a recent phase III clinical trial as a disease-modifying osteoarthritis drug (DMOAD). Therefore, targeting the WNT signalling pathway may be a distinctive approach to developing particular agents helpful in treating OA. This review aims to update the most recent progress in OA drug development by targeting the WNT pathway. In this, we introduce WNT pathways and their crosstalk with other signalling pathways in OA development and highlight the role of the WNT signalling pathway as a key regulator in OA development. Several articles have reviewed the Wnt pathway from different aspects. This candid review provides an introduction to WNT pathways and their crosstalk with other signalling pathways in OA development, highlighting the role of the WNT signalling pathway as a key regulator in OA development with the latest research. Particularly, we emphasise the state-of-the-art in targeting the WNT pathway as a promising therapeutic approach for OA and challenges in their development and the nanocarrier-based delivery of WNT modulators for treating OA.

Analysis of genetic biomarkers, polymorphisms in ADME-related genes and their impact on pharmacotherapy for prostate cancer.

Prostate cancer (PCa) is a non-cutaneous malignancy in males with wide variation in incidence rates across the globe. It is the second most reported cause of cancer death. Its etiology may have been linked to genetic polymorphisms, which are not only dominating cause of malignancy casualties but also exerts significant effects on pharmacotherapy outcomes. Although many therapeutic options are available, but suitable candidates identified by useful biomarkers can exhibit maximum therapeutic efficacy. The single-nucleotide polymorphisms (SNPs) reported in androgen receptor signaling genes influence the effectiveness of androgen receptor pathway inhibitors and androgen deprivation therapy. Furthermore, SNPs located in genes involved in transport, drug metabolism, and efflux pumps also influence the efficacy of pharmacotherapy. Hence, SNPs biomarkers provide the basis for individualized pharmacotherapy. The pharmacotherapeutic options for PCa include hormonal therapy, chemotherapy (Docetaxel, Mitoxantrone, Cabazitaxel, and Estramustine, etc.), and radiotherapy. Here, we overview the impact of SNPs reported in various genes on the pharmacotherapy for PCa and evaluate current genetic biomarkers with an emphasis on early diagnosis and individualized treatment strategy in PCa.

Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer.

OBJECTIVES: Dormancy is a crucial machinery for cancer cells to survive hostile microenvironment. It is considered as the major cause of post-treatment relapse and metastases. However, its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unclear. Here we sought to decipher the impacts of matrix stiffness on OSCC-cell dormancy. MATERIALS AND METHODS: Clinicopathological relevance of matrix stiffness in OSCC was analyzed in a 127 patients' cohort. Impacts of stiffness-related mechanical stress (MS) on OSCC-cell behaviors were investigated in vitro and in vivo. Transcriptomic profiling of MS induced dormant cells were performed, following by mechanistic investigations on MS-induced dormancy. The functional relevance of cGAS in OSCC were analyzed through a bioinformatic approach. RESULTS: Stiffened matrix correlated with poor survival and post-surgical recurrence in OSCC. Stiffness-related MS induces a dormant subpopulation in OSCC cells, which showed increased drug resistance, enhanced tumor repopulating ability, and an unexpected upregulation of epithelial-mesenchymal transition (EMT) and invasiveness. Mechanistically, MS caused DNA damage, resulted in activation of cGAS-STING signaling. Either blocking of cGAS or STING dramatically impeded the MS-induced production of this invasive-dormant subpopulation. Moreover, cGAS was found being central to the cell-cycle regulation and correlated with poor prognosis in OSCC. DISCUSSION: We revealed a previously unsuspected role of cGAS-STING axis in mediating the induction of an invasive-dormant subpopulation in response to mechanical cues. Our findings indicated an adaptive machinery whereby tumor cells survive and escape from harsh microenvironment. Targeting this machinery may be a potential strategy for preventing post-therapeutic recurrence and lymphatic metastasis in OSCC.

Effect of gangliosides pretreatment on expression of caspase-3 in apoptosis of mouse neuroblastoma Neu-ro2a induced by bupivacaine / 临床麻醉学杂志

Objective To discuss the impact of the neurotoxity of bupivacaine and bupivacaine-induced cellular neurotoxicity caused by pretreatment of ganglion (GM-1 )monoglyceride on the ex-pression of caspase-3.Methods The mouse neuroblastoma cells-N2a cells was used as a research object to carry out the following experiments:(1)To observe the damage effects of different concen-trations of bupivacaine on N2a cells and find out the most suitable damage concentration to establish cell damage model.The N2a cells were interacted with bupivacaine with different concentrations [0μmol/L (group C),600 μmol/L (group B1),900 μmol/L (group B2),1 200 μmol/L (group B3), 1 500 μmol/L (group B4),2 000 μmol/L (group B5)]for 6,12,24,36 h and then evaluated by CCK-8 cell survival.Each experiment was repeated three times.The protective function of GM-1 to bupiva-caine-induced N2a cells damage.The N2a cells were treated with different concentrations (0.1μmol/L (group BG1),1.0 μmol/L (group BG2),10 μmol/L (group BG3))of GM-1 pretreatment 24 h,CCK-8 was evaluated in cell viability,Western Blot method was used to detect damaged cells caspase-3 expression levels.Each experiment was repeated three times.Results (1)Bupivacaine could significantly damage N2a cells,the greater the bupivacaine concentration,the longer the action time,the stronger neurotoxicity.(2)GM-1 bupivacaine nerve injury had a significant protective effect in a dose-related manner.The maximum of protective dose of this experiment was 10 μmol/L.Conclusion Bupivacaine can significantly damage N2a cells,correlating with both dose and time double positively,while GM-1 pretreatment significantly reduced the expression of caspase-3 induced by bupivacaine.

[Myeloid-derived suppressor cell expression and significance in peripheral blood and tongue lesions of mouse].

OBJECTIVE: To explore the myeloid-derived suppressor cell (MDSC) expression in the peripheral blood and lesions of 4NQO-induced tongue carcinoma in mouse. METHODS: The established 4NQO mouse model was used to analyze the distribution of MDSC and T cell subsets in the peripheral blood by flow cytometry. The relations of MDSC with T cell subsets and CD4⁺/CD8⁺ changes were evaluated. The distribution of MDSC in the lesions of tongues was analyzed by immu- nohistochemistry, and the expression of arginase 1 (ARG-1) in tongue tissues was detected by real-time polymerase chain reaction. RESULTS: During tumor progression, a significant increase was observed in the frequency of MDSC in the peripheral blood of 4NQO treated mice (P < 0.01). The frequency of MDSC was positively correlated with systemic CD3⁺CD8+T cells but negatively correlated with the CD4⁺/CD8⁺ ratio. Squamous cell carcinomas were extensively infiltrated with MDSC, whereas dysplastic area and normal tongue mucosa had only sparse MDSC infiltration. The majority of MDSCs were located in the stroma, particularly along the tumor invasive front. Moreover, 4NQO-treated mice showed significantly higher ARG-1 mRNA levels in the tumor site (P<0.01). CONCLUSION: MDSC may contribute to oral tumor progression and represents a potential target for immunotherapy of oral cancer.

Myeloid-derived suppressor cell expression and significance in peripheral blood and tongue lesions of mouse / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To explore the myeloid-derived suppressor cell (MDSC) expression in the peripheral blood and lesions of 4NQO-induced tongue carcinoma in mouse.</p><p><b>METHODS</b>The established 4NQO mouse model was used to analyze the distribution of MDSC and T cell subsets in the peripheral blood by flow cytometry. The relations of MDSC with T cell subsets and CD4⁺/CD8⁺ changes were evaluated. The distribution of MDSC in the lesions of tongues was analyzed by immu- nohistochemistry, and the expression of arginase 1 (ARG-1) in tongue tissues was detected by real-time polymerase chain reaction.</p><p><b>RESULTS</b>During tumor progression, a significant increase was observed in the frequency of MDSC in the peripheral blood of 4NQO treated mice (P < 0.01). The frequency of MDSC was positively correlated with systemic CD3⁺CD8+T cells but negatively correlated with the CD4⁺/CD8⁺ ratio. Squamous cell carcinomas were extensively infiltrated with MDSC, whereas dysplastic area and normal tongue mucosa had only sparse MDSC infiltration. The majority of MDSCs were located in the stroma, particularly along the tumor invasive front. Moreover, 4NQO-treated mice showed significantly higher ARG-1 mRNA levels in the tumor site (P<0.01).</p><p><b>CONCLUSION</b>MDSC may contribute to oral tumor progression and represents a potential target for immunotherapy of oral cancer.</p>

Management of donor and recipient veins in the vascularied autogeneous submandibular gland transfer / 中华显微外科杂志

Objective To discuss the management and selection of donor and recipient veins in the transfer of vascularied autogeneous submandibular gland (SMG).Methods The SMGs of 48 patients with severe keratoconjunctivitis were transfered to the temporal region by microsurgery from June,2002 to June,2013.The secreted saliva was used as the substitute of tear.Donor and accepting-site vessels,vessels crisis and managements,survival of grafts were retrospectively analysed.Results Transplantation succeeded in 45 patients and failed in 3.For donor veins,39 were facial veins,12 were venae comitantes of facial artery,1 was vein near the duct.For revipient veins,41 were superficial temporary veins,6 were deep temporary veins and 5 were veins in the upper neck.For revipient artery,except superficial temporary artery,deep temporary artery was also a good selection.After surgery,2/5 venous crisis cases were rescued by reanastomosising veins.TC99m examination suggested that the 49 TSMGs were survived,and the ducts were unobstructed.Follow up lasted for 6 months to 10 years,the symptoms of photophobia and anemophobia were alleviated,the symptoms of corneal xerosis disappeared.Good clinical efficacy was obtained after transplantion.Conclusion During SMGs transplantion,facial veins,venae comitantes of facial artery or vein near the duct can be used for donor vein.For recipient veins,except the superficial temporary veins as major,deep temporary veins or veins in the upper neck is also a secection.Correct selection and microsurgical management of donor and revipient veins are keys to successful SMGs transplantion.

The expression and significance of the Notch signaling pathway molecules in tongue squamous cell carcinoma / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To explore the expression of Notch signaling receptors Notchl, Notch3 and its ligand Jaggedl, Jagged2 in tongue squamous cell carcinoma (TSCC).</p><p><b>METHODS</b>mRNA and protein expression levels of tissue samples from 74 cases of tongue cancer patients and human tongue cell line Cal-27 were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot. Its relationship with cell proliferation and clinical pathology was analyzed.</p><p><b>RESULTS</b>mRNA and protein expression were detected in tongue cancer tissues, adjacent tissues and cell lines. Notchl and Notch3 protein expression in tongue cancer was higher than the adjacent tissues. Jaggedl and Jagged2 protein expression in tongue cancer and adjacent tissues had no difference. Notchl and Notch3 protein had correlation with tongue cancer clinical staging. Pathway protein expression had no correlation with pathological grade, age, gender. Notchl protein expression in lymph node metastasis-positive cases was higher than in lymph node metastasis-negative cases. The expression of Notch3 and Jagged2 had correlation. Jaggedl expression grade in metastasis-positive cases was higher than in negative cases.</p><p><b>CONCLUSION</b>Notch signaling molecules have active expression in TSCC and may play important roles in tongue cancer development.</p>