Increased levels of serum osteoprotegerin in hypothyroid patients and its normalization with restoration of normal thyroid function

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and an increase in serum osteoprotegerin (OPG) has recently been reported to be associated with the severity of coronary heart disease and cardiovascular mortality. The present study was designed to examine whether hypothyroidism causes an increase in serum OPG, and to determine whether levothyroxine (L-T4) replacement therapy might suppress serum OPG levels in hypothyroid patients. Fifty-three hypothyroid patients with chronic thyroiditis and age- and sex-matched normal control subjects were examined for the levels of serum OPG and plasma von Willebrand factor (vWF), a vascular injury marker. Thirty-seven of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T4 replacement therapy. Baseline OPG was significantly higher in hypothyroid patients than in normal controls (4.51 +/- 0.50 vs 3.72 +/- 0.23 pmol/l (mean +/- S.E.); P = 0.0182). In multivariate analysis, baseline OPG was significantly associated with baseline levels of TSH (r = 0.280, P = 0.0162) and vWF (r = 0.626, P < 0.0001). During one year of L-T4 replacement therapy, hypothyroid patients showed a significant decrease in OPG levels from 4.35 +/- 0.51 to 3.48 +/- 0.26 pmol/l (P = 0.0166), a level comparable to normal controls. The change in serum OPG levels during L-T4 replacement therapy was significantly and independently associated in a negative fashion with baseline vWF (r = -0.503, P = 0.0014). This study suggested that the severity of hypothyroidism and vascular injury might have important independent roles in increasing the serum OPG level in hypothyroid patients. Furthermore, it was demonstrated that a sustained euthyroid state might have the potential to decrease the serum OPG level in hypothyroid patients and that the degree of vascular injury in the hypothyroid state is independently associated with a decrease in serum OPG during a 1-year normalization of thyroid function.     

Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5‐year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor‐β (TGF‐β) signalling by inducing stabilization of TGF‐β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF‐β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF‐β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma

Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL-6, a potent pro-inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL-6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti-human IL-6 receptor antibody, as an anti-lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL-6 protein and VEGF-C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real-time quantitative RT-PCR. In vitro studies showed that IL-6 regulated VEGF-C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3-kinase-Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF-C mRNA expression and OSCC-related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis.     

不分型流感嗜血杆菌上调人类MUC5AC黏液素的基因表达

目的 探索不分型流感嗜血杆菌(NTHi)上调人类MUC5AC黏液素基因表达的细胞分子机制.方法 通过反转录套式-PCR及实时荧光定量PCR分析NTHi所诱导的MUC5AC mRNA的表达,免疫沉淀及Western印迹法检测NTHi对表皮生长因子受体(EGFR)及p38丝裂原活化蛋白激酶(p38MAPK)的激活,采用p38 MAPK或EGFR特异性抑制剂,共转染EGFR显性失活质粒,判断在转录水平对NTHi所诱导的MUC5AC表达的影响,并研究EGFR特异性抑制剂对NTHi所诱导p38MAPK激活的影响.结果 在人结肠上皮细胞株(HM3)细胞中,NTHi在mRNA及转录水平上调人类MUC5AC黏液素基因的表达,NTHi能使EGFR或p38MAPK磷酸化.p38MAPK、EGFR特异性抑制剂或共转染EGFR显性失活质粒,可显著抑制NTHi所诱导的MUC5AC的表达,EGFR特异性抑制剂对NTHi所诱导p38MAPK磷酸化有抑制作用.结论 不分型流感嗜血杆菌可通过EGFR-p38MAPK信号通路,上调人类MUC5AC黏液素基因表达.     

A proposal for smoldering adult T-cell leukemia: a clinicopathologic study of five cases

We have observed five patients with smoldering adult T-cell leukemia (ATL) who had skin lesions as premonitory symptoms. The illness developed slowly, but flared up after several years. Skin lesions appeared in the form of erythema, papules, or nodules. Infiltration of the skin by ATL cells was slight, and the proportion of ATL cells in the peripheral blood was 0%-2%. The serum lactate dehydrogenase (LDH) value was within normal range and was not associated with hypercalcemia; lymphadenopathy, hepatosplenomegaly, and bone marrow infiltration were very slight. In most cases, hypergammaglobulinemia was seen, and in one case, monoclonal hypergammaglobulinemia was observed. All five patients had lived in an area in which ATL was endemic, and their anti-ATLA antibodies were positive; none had ever received a blood transfusion. One patient developed typical ATL after more than 13 yr of illness and died of renal insufficiency. Another patient developed typical ATL after 5 yr of illness and died of cryptococcus meningitis. Based on clinical and pathologic differences, we believe that these cases should be distinguished from typical ATL cases for the purposes of prognosis and treatment.     

Effect of interferon α on calcium and bone metabolism in patients with chronic hepatitis

We investigated the changes of natural type of interferon-α (IFNα) on calcium and bone metabolism in patients with chronic hepatitis C. Natural IFNα was injected intramuscularly at daily doses of 6 million units for 2 weeks to 10 patients with chronic hepatitis caused by hepatitis C virus, and followed by 3-times-a-week administration for another 10 weeks. The markers for bone metabolism including serum bone-Gla protein (BGP) concentration and urinary excretion of pyridinolines (pyridinoline and deoxypyridinoline) were measured before and during the treatment. The twelve-week administration of IFNα reduced pyridinoline excretion from 39.7±13.3 (SD) pmol/μ mol · creatinine to 28.3±8.1 pmol/μ mol · creatinine (p<0.06), and that of deoxypyridinoline from 6.51±3.38 pmol/μ mol · creatinine to 3.91±2.07 pmol/μ mol · creatinine (p<0.01), although serum levels of BGP and parathyroid hormone (PTH) did not show any significant changes. The ratio of BGP/urinary pyridinoline increased from 0.098±0.074 to 0.198±0.093 at the end of 12th week (p<0.03), and that of BGP/deoxypyridinoline increased from 0.630±0.502 to 1.550±0.788 at 12th week (p<0.02). Serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) did not change significantly during the study. IFNα reduces bone resorption in contrast with insignificant effects on bone formation in patients with mild to moderate hepatitis. The effects on calcium and bone metabolism may give beneficial effects for patients with high turnover osteoporosis.     

The association between marital adjustment and compliance with antihypertension regimens

The purpose of this cross-sectional survey was to determine relations between marital adjustment as measured by the Dyadic Adjustment Scale and antihypertension compliance. From seven dependent measures, we found high marital adjustment scores to be significantly correlated with less obesity, lower frequency of forgetting blood pressure medications, and less cessation of blood pressure medicine. These effects were much larger in a younger subsample of respondents who were 28 to 50 years old. The Dyadic Adjustment Scale measures the respondent's perception of the degree of affection and consensus, cohesion, and satisfaction in marriage. We conclude that the perception of positive marital interaction and communication ultimately contributes to controlled blood pressure by helping the patient to maintain healthy weight and to remember and continue taking blood pressure medication.     

Treatment of Adult T Cell Leukaemia by Extracorporeal Photochemotherapy

Four patients with chronic or smouldering type adult T cell leukaemia (ATL) were treated by extracorporeal photochemotherapy (photopheresis). From 4 to 8 months after starting photo-pheresis, skin lesions with ATL cell infiltration began to disappear. Cell surface markers in three patients showed improvement. In one patient, a serial decrease of soluble interleukin-2 receptor levels (950 U/ml to 620) in the serum was observed after 4 months. This pilot study suggests that photopheresis may be successfully applied in ATL. It is still necessary to continue follow-up observations in these patients and to treat a larger number of cases, before definite conclusions can be drawn in the future