ABSTRACT
Currently there is being conducted an extensive search to find new prognostic factors in oral squamous cell carcinoma which would assist in better patient management. One of the most promising prognostic markers is the density of tumour infiltrating lymphocytes. 100 cases of patients with oral squamous cell carcinoma that underwent surgical resection between 2006 and June 2016 at our institution were included in this study. From each case the most representative HE stained slide was identified and the density of tumour infiltrating lymphocytes were classified as non-brisk or brisk, which was included in the survival analysis. Upon analysis there was a strong correlation between non-brisk (n = 28) and brisk (n = 72) tumour infiltrating lymphocytes and the primary clinical outcomes: overall survival (p = 0.0472) and local recurrence-free survival (p = 0.00037). Univariate and multivariate Cox regression model confirmed the high prognostic value of tumour infiltrating lymphocytes as the independent prognostic indicator of better survival, being even superior, in our study, to the traditional pTNM system. This study provides robust evidence that the density of tumour infiltrating lymphocytes demonstrates a high prognostic significance in oral squamous cell carcinoma.
Subject(s)
Carcinoma, Squamous Cell/diagnosis , Lymphocytes, Tumor-Infiltrating/cytology , Mouth Neoplasms/diagnosis , Carcinoma, Squamous Cell/immunology , Humans , Mouth Neoplasms/immunology , PrognosisABSTRACT
We examined the role of epidermal growth factor (EGF) receptor in the pathogenesis of leptin-induced hypertension in the rat. Leptin, administered in increasing doses (0.1-0.5 mg/kg/day) for 10 days, increased phosphorylation levels of non-receptor tyrosine kinase, c-Src, EGF receptor and extracellular signal-regulated kinases (ERK) in aorta and kidney, which was accompanied by the increase in plasma concentration and urinary excretion of isoprostanes and H2O2. Blood pressure and renal Na+,K+-ATPase activity were higher, whereas urinary sodium excretion was lower in animals receiving leptin. The effects of leptin on renal Na+,K+-ATPase, natriuresis and blood pressure were abolished by NADPH oxidase inhibitor, apocynin, Src kinase inhibitor, PP2, EGF receptor inhibitor, AG1478, protein farnesyltransferase inhibitor, manumycin A, and ERK inhibitor, PD98059. In contrast, inhibitors of insulin-like growth factor-1 and platelet-derived growth factor receptors, AG1024 and AG1295, respectively, only slightly reduced ERK phosphorylation and had no effect on blood pressure in rats receiving leptin. These data indicate that: (1) experimental hyperleptinemia is associated with oxidative stress and c-Src-dependent transactivation of the EGF receptor, which stimulates ERK in vascular wall and the kidney, (2) overactivity of EGF receptor-ERK pathway contributes to leptin-induced hypertension by stimulating renal Na+,K+-ATPase and reducing sodium excretion, (3) inhibitors of c-Src, EGF receptor and ERK may be considered as a novel therapy for hypertension associated with hyperleptinemia, e.g. in patients with obesity and metabolic syndrome.
Subject(s)
Aorta, Abdominal/metabolism , Aorta, Thoracic/metabolism , ErbB Receptors/metabolism , Hypertension/chemically induced , Hypertension/metabolism , Kidney/metabolism , Leptin/pharmacology , Animals , Aorta, Abdominal/drug effects , Aorta, Thoracic/drug effects , CSK Tyrosine-Protein Kinase , Extracellular Signal-Regulated MAP Kinases/metabolism , Glomerular Filtration Rate , Hypertension/physiopathology , Isoprostanes/blood , Isoprostanes/urine , Kidney/drug effects , Leptin/blood , Male , Oxidative Stress , Protein-Tyrosine Kinases/metabolism , Rats , Rats, Wistar , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , src-Family KinasesABSTRACT
We investigated if extracellular signal-regulated kinases (ERK) and oxidative stress are involved in the pathogenesis of arterial hypertension induced by chronic leptin administration in the rat. Leptin was administered at a dose of 0.25 mg/kg twice daily s.c. for 4 or 8 days. Blood pressure (BP) was higher in leptin-treated than in control animals from the third day of the experiment. The superoxide dismutase (SOD) mimetic, tempol, normalized BP in leptin-treated rats on days 6, 7 and 8, whereas the ERK inhibitor, PD98059, exerted a hypotensive effect on days 3 through 6. Leptin increased ERK phosphorylation level in renal and aortic tissues more markedly after 4 than after 8 days of treatment. In addition, leptin reduced urinary Na(+) excretion and increased renal Na(+),K(+)-ATPase activity, and these effects were abolished on days 4 and 8 by PD98059 and tempol, respectively. The levels of NO metabolites and cGMP were reduced in animals receiving leptin for 8 days. Markers of oxidative stress (H(2)O(2) and lipid peroxidation products) were elevated to a greater extent after 4 than after 8 days of leptin treatment. In contrast, nitrotyrosine, a marker of protein nitration by peroxynitrite, was higher in animals receiving leptin for 8 days. NADPH oxidase inhibitor, apocynin, prevented leptin's effect on BP, ERK, Na(+),K(+)-ATPase/Na(+) excretion and NO formation at all time points. SOD activity was reduced, whereas glutathione peroxidase (GPx) activity was increased in the group treated with leptin for 8 days. These data indicate that: (1) ERK, activated by oxidative stress, is involved only in the early phase of leptin-induced BP elevation, (2) the later phase of leptin-induced hypertension is characterized by excessive NO inactivation by superoxide, (3) the time-dependent shift from ERK to O(2)(-)-NO dependent mechanism may be associated with reduced SOD/GPx ratio, which favors formation of O(2)(-) instead of H(2)O(2).