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Objectives: Although inflammatory markers, such as the neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio and local immune markers have been shown to have prognostic utility, limited information is available regarding inflammatory and pre‐existing tumour‐infiltrating lymphocyte density and their association with prognosis in patients with hypopharyngeal squamous cell carcinoma. We investigated the prognostic ability of inflammatory markers and tumour‐infiltrating lymphocyte density in stage III and stage IV hypopharyngeal squamous cell carcinoma patients receiving definitive treatment. Design: Retrospective cohort study. Setting: Kurume University Hospital. Participants: Ninety‐six stage III or stage IV hypopharyngeal squamous cell carcinoma patients treated at the Kurume University Hospital between 2000 and 2014. Main outcome measures: Inflammatory markers and pre‐treatment tumour‐infiltrating lymphocyte density were examined from recorded haematologic data and immunohistochemical analysis. Results: Multivariate analyses showed that the CD8+ tumour‐infiltrating lymphocyte density was an independent predictive factor for distant metastasis and overall survival, whereas inflammatory markers, including the neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio, were not correlated with distant metastasis or overall survival. Conclusions: Higher pre‐treatment CD8+ tumour‐infiltrating lymphocyte density is a useful predictive biomarker for reduced distant metastasis and better prognosis. [ABSTRACT FROM AUTHOR]

We have previously shown that an acute osmotic stimulation induces the expression of a c- fos and monomeric red fluorescent protein 1 ( mRFP1) fusion transgene in osmosensitive rat brain areas, including the supraoptic ( SON) and paraventricular nuclei ( PVN). However, the effects of chronic stimuli, such as dehydration, have not been investigated. In the present study, the expression patterns of the c- fos- mRFP1 fusion gene in the forebrain and the brainstem of male and female transgenic rats were studied in seven experimental groups: ad lib. water (euhydration), water deprivation for 12, 24 or 48 h (dehydration) and water deprivation for 46 h + ad lib. water for 2, 6 or 12 h (rehydration). The number of cells that express nuclear mRFP1 fluorescence was quantified in the hypothalamus, the circumventricular organs and the brainstem. Compared to the euhydrated state, the number of transgene expressing cells significantly increased in all forebrain areas and in the rostral ventrolateral medulla after dehydration and 2 h of rehydration. In the nucleus of the solitary tract and area postrema, the number of mRFP1 fluorescent cells was markedly increased after 2 h of rehydration. Although the number of mRFP1 fluorescent cells in the organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ remained significantly increased after 6 h of rehydration, reaching control levels after 12 h of rehydration, the number of mRFP1 fluorescent cells in the SON and the PVN reached control levels after 6 h of rehydration. There were no significant differences between male and female rats. These results show that the expression of the c- fos- mRFP1 fusion gene changes in the forebrain and the brainstem not only after acute osmotic stimulation, but also after chronic osmotic stimulation. Interestingly, these studies reveal the differential activation of different neuronal groups over the time course of dehydration and rehydration. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanism of the regulation of glucagon secretion is critical for treating the dysfunction of α cells observed in diabetes. Glucagon-like peptide (GLP)-1 analogues reduce plasma glucagon and are assumed to contribute to their action to lower blood glucose. It has previously been demonstrated that the central administration of brain-derived neurotrophic factor ( BDNF) improves glucose metabolism by a mechanism independent of feeding behaviour in obese subjects. Using male rats, we examined whether BDNF influences glucagon secretion from α cells via the the central nervous system. We investigate whether: (i) the central infusion of BDNF stimulates glucagon and/or insulin secretion via the pancreatic efferent nerve from the hypothalamus; (ii) the intraportal infusion of GLP-1 regulates glucose metabolism via the central and peripheral nervous system; and (iii) BDNF receptor and/or BDNF-positive fibres are localised near α cells of islets. The portal glucagon level decreased with the central administration of BDNF (n = 6, in each; P < 0.05); in contrast, there was no significant change in portal insulin, peripheral glucagon and insulin levels with the same treatment. This reduction of glucagon secretion was abolished by pancreatic efferent denervation (n = 6, in each; P < 0.05). In an immunohistochemical study, pancreatic α cells were stained specifically with BDNF and tyrosine-related kinase B, a specific receptor for BDNF, and α cells were also co-localised with BDNF. Moreover, intraportal administration of GLP-1 decreased glucagon secretion, as well as blood glucose, whereas it increased the BDNF content in the pancreas; these effects were inhibited with the central infusion of BDNF antibody (n = 6, in each; P < 0.05). BDNF and GLP-1 affect glucose metabolism and modulate glucagon secretion from pancreatic α cells via the central and peripheral nervous systems. [ABSTRACT FROM AUTHOR]

Background Smoking and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. This study tested the hypothesis that smoking is associated with insulin resistance/hyperinsulinaemia and cardiovascular autonomic dysfunction in type 2 diabetic patients who are not treated with insulin. Materials and methods The study patients were 22 current smokers with type 2 diabetes mellitus (age: 57 ± 5 years, mean ± SD) and 30 age-matched never-smoked patients with type 2 diabetes mellitus (control group, 57 ± 8 years). The quality of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin (F-IRI), homeostasis model assessment (HOMA) index and haemoglobin A1c (HbA1c). The severity of smoking status was expressed by the Brinkman index, which is calculated as number of cigarettes per day multiplied by years of smoking. Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart-rate variability, plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. Results Baroreflex sensitivity was lower in the current smokers group than in the never-smoked group ( P < 0·05). Early and delayed 123I-MIBG myocardial uptake values were lower ( P < 0·05, and P < 0·01, respectively) and the percentage washout-rate of 123I-MIBG was higher ( P < 0·0001) in the current smokers group than in the never-smoked group. Fasting immunoreactive insulin (F-IRI) concentration ( P < 0·0001) and the homeostasis model assessment (HOMA) index ( P < 0·0001) were higher in the current smokers group than the never-smoked group. Multiple logistic regression analysis revealed that smoking was independently predicted by F-IRI and the percentage washout-rate of 123I-MIBG. Conclusions The results of the study suggested that smoking was associated with cardiovascular autonomic dysfunction and hyperinsulinaemia and that F-IRI and the percentage washout-rate of 123I-MIBG were independent predictors of smoking in these Japanese patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Laminin receptor is a non-integrin cell-surface receptor that binds laminin present on the basement membrane. It has been reported to be associated with infiltration and metastasis of various malignant tumors. However, no studies regarding tongue cancer have been reported. This study aimed to clarify the role of laminin receptor in squamous cell carcinoma of the tongue., Methods: We performed immunohistochemical staining of specimens from 66 patients with squamous cell carcinoma of the tongue and assessed laminin receptor expression and clinicopathological factors. As epithelial-mesenchymal transition has been shown to be associated with infiltration and metastasis of malignant tumors, staining for E-cadherin, vimentin, and N-cadherin were also performed., Results: Of 20 patients with postoperative recurrence, 14 exhibited high laminin receptor expression (p = 0.0025). Kaplan-Meier analysis revealed a significantly shorter time to postoperative recurrence for the high laminin receptor expression group than that for the low laminin receptor expression group (p = 0.0008). Based on multivariate analyses for postoperative recurrence, high laminin receptor expression was associated with poor prognosis (high expression vs. low expression; HR =3.19, 95% CI =0.92-11.08; p = 0.0682). There was a correlation between laminin receptor and N-cadherin (p = 0.0089) but not between laminin receptor and E-cadherin (p = 0.369) or vimentin (p = 0.4221)., Conclusion: These results suggest that high laminin receptor expression is a useful prognostic factor for postoperative recurrence and may be a target for molecular therapy to treat squamous cell carcinoma of the tongue., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Limited information is available regarding the role of programmed death ligand 1 (PD-L1) expression and CD8 + tumor-infiltrating lymphocyte (TIL) density in the tumor immune microenvironment (TIM) of patients with salivary gland carcinoma (SGC). This study aimed to assess the association between the prognosis of SGC patients and the probability of PD-L1 expression in tumor and/or immune cells using the tumor proportion score (TPS), mononuclear immune cell density score (MIDS), combined positive score (CPS), and CD8 + TIL density in the TIM., Study Design: Retrospective cohort study., Methods: We retrospectively reviewed 73 SGC patients treated with definitive surgery between 2000 and 2015. Immunohistochemical analysis was used to assess TPS, MIDS, CPS, and CD8 + TIL density, followed by prognostic evaluation of these immune-related parameters., Results: Histological grade was associated with TPS, MIDS, and CPS based on PD-L1 expression, and these scores exhibited a significant association with CD8 + TIL density. Patients with positive TPS had an unfavorable disease-free survival and overall survival. Multivariate analyses indicated that the TPS was a significant and independent prognostic factor., Conclusion: Our results suggest that TPS might be a useful prognostic biomarker in SGC patients receiving definitive surgery. Laryngoscope, 131:E1481-E1488, 2021., (@ 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: Limited information exists regarding the associations between pre-existing immune parameters in the tumor immune microenvironment (TIM) and either chemoradiosensitivity or prognosis for patients with squamous cell carcinoma of the nasopharynx or oropharynx involving virus-related or nonvirus-related tumors., Study Design: Retrospective cohort study., Methods: We retrospectively reviewed 141 patients with EBV+, p16+, or EBV- and p16- statuses who are receiving chemoradiotherapy. We performed immunohistochemistry using pretreatment biopsy specimens to analyze the programed death ligand 1 (PD-L1) levels in tumor and immune cells and CD8+ tumor-infiltrating lymphocyte (TIL) density. We evaluated chemoradiosensitivity and prognosis with respect to these immune-related parameters., Results: Virus-related tumors showed associations with both PD-L1 expression and high CD8+ TIL density. Patients with higher CD8+ TIL density or greater numbers of PD-L1+ tumor and immune cells showed significant rates of favorable local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Multivariate analyses demonstrated that higher CD8+ TIL density is an independent, significant, and favorable predictive factor for LRFS (P = .005) and OS (P = .003), although it is not a significant predictor of PFS (P = .077)., Conclusions: Higher CD8+ TIL density represents a useful and favorable biomarker of chemoradiosensitivity in patients receiving chemoradiotherapy for nasopharyngeal or oropharyngeal cancer., Level of Evidence: 3 Laryngoscope, 131:E1179-E1189, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Background Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs-RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. Methods and Results A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age-matched and sex-matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls ( P =0.004) and was significantly associated with a decreased ankle-brachial pressure index ( P =0.007) and an increased intima-media thickness ( P =0.026). RAGE and α-smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls ( P =0.013 and P <0.001, respectively). Soluble RAGE (inversely) and use of aspirin were independently correlated with changes in left ventricular systolic function after aortic valve replacement ( P =0.012 and P =0.002, respectively). Conclusions Our present study suggests that RAGE may play a role in the pathogenesis of calcified AS, which is a prognostic marker in patients with AS after aortic valve replacement.

BACKGROUND Interleukin (IL)-22, a member of the IL-10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL-22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription-3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS We evaluated the STAT3 activation after IL-22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL-22 injection. Coimmunostaining of phosphorylated STAT3 and α-actinin revealed that STAT3 activation occurred in cardiomyocytes after IL-22 administration. In heart tissue from intact mice, real-time PCR demonstrated significant expression of IL-22 receptor subunit 1, and coimmunostaining of IL-22 receptor subunit 1 and α-actinin showed IL-22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL-22 activated STAT3, and we detected IL-22 receptor subunit 1 expression. Overall, these results indicated that IL-22 directly activated the myocardial IL-22-receptor subunit 1-STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS-treated mice, IL-22-treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL-22-treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS Our present findings suggest that IL-22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.