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Background: Tumor necrosis factor‐related apoptosis‐inducing ligand activates apoptotic pathways and could potentially be used in anticancer treatments. However, oral squamous cell carcinoma cells are known to be resistant to tumor necrosis factor‐related apoptosis‐inducing ligand‐induced cell death. It has been previously reported that hyperthermia upregulates tumor necrosis factor‐related apoptosis‐inducing ligand‐induced apoptosis in other cancers. As such, we evaluated whether hyperthermia upregulates tumor necrosis factor‐related apoptosis‐inducing ligand‐mediated apoptosis in a tumor necrosis factor‐related apoptosis‐inducing ligand‐resistant oral squamous cell carcinoma cell line. Methods: The oral squamous cell carcinoma cell line HSC3 was cultured and divided into hyperthermia and control groups. We investigated the antitumor effects of recombinant human tumor necrosis factor‐related apoptosis‐inducing ligand using cell proliferation and apoptosis assays. Additionally, we measured death receptor 4 and 5 levels, and determined death receptor ubiquitination status, as well as E3 ubiquitin ligase targeting of death receptor in both hyperthermia and control groups before recombinant human tumor necrosis factor‐related apoptosis‐inducing ligand administration. Results: Treatment with recombinant human tumor necrosis factor‐related apoptosis‐inducing ligand produced greater inhibitory effects in the hyperthermia group than in the control group. Moreover, death receptor protein expression in the hyperthermia group was upregulated on the cell surface (and overall), although death receptor mRNA was downregulated. The half‐life of death receptor was several hours longer in the hyperthermia group; concomitantly, E3 ubiquitin ligase expression and death receptor ubiquitination were downregulated in this group. Conclusion: Our findings suggested that hyperthermia enhances apoptotic signaling by tumor necrosis factor‐related apoptosis‐inducing ligand via the suppression of death receptor ubiquitination, which upregulates death receptor expression. These data suggest that the combination of hyperthermia and tumor necrosis factor‐related apoptosis‐inducing ligand has implications in developing a novel treatment strategy for oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, on acute ischemia‐induced bladder dysfunction in rats. Methods: Eight‐week‐old female Wistar‐ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon‐like peptide‐1 [GLP‐1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE‐2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP‐4) activity, GLP‐1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. Results: No differences in blood glucose levels among the groups were observed. DPP‐4 activity decreased in the Lig + Ana group (P <.01). GLP‐1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P <.01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P <.05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P <.01); however, this measure improved in the Lig + Ana group (P <.01). Conclusions: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP‐1 receptor‐independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia‐induced bladder dysfunctions. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) has a low five-year survival rate because of its high rate of recurrence and metastasis. After surgical resection or radiation, the main treatments for HNSCC, patients sometimes experience functional or aesthetic disorders. Therefore, there is a great demand for the development of non-surgical treatment strategies to improve clinical outcomes and patients' quality of life. One such non-surgical treatment is mild hyperthermia (mHT). Many studies have investigated combination treatments with mHT and immune checkpoint inhibitors in preclinical settings. However, there have been no detailed reports on the effects of mHT on immune checkpoint molecules. Here, we investigated the effects of mHT on the tumor microenvironment (TME), particularly on programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1), in SCCVII cells and a squamous cell carcinoma mouse model. First, we found that PD-L1 mRNA levels and surface PD-L1 expression significantly increased after mHT. Second, a single tumor model was used to determine the effect of HT on the TME. mHT enhanced the accumulation of CD4 + and CD8 + T cells, elevated PD-L1 expression in the TME, and decreased the PD-1 positive rate of CD4 + T cells. Finally, using a bilateral tumor model, we found that anti-PD-L1 monotherapy and combination therapy resulted in longer survival than the isotype control or mHT monotherapy. Moreover, the combination therapy resulted in a significantly higher survival rate than anti-PD-L1 monotherapy. In conclusion, our findings elucidate changes in PD-L1 expression in the TME and strengthen the rationale for mHT and PD-L1 blockade combination therapy., Competing Interests: S. N. and K. Y. are employees of Asuka Medical Inc. The authors declare no conflict of interest regarding the publication of this paper.