Misa Nakamura

Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal

There is a continuous debate regarding the classification of thyroid follicular lesions and the term “well‐differentiated tumor of uncertain malignant potential (WDT‐UMP)” was recently introduced to cover this problematic spectrum of tumors. The objective of this study was to reappraise WDT‐UMP using morphological, immunochemical, and molecular analysis and to shed more light on encapsulated thyroid follicular‐patterned tumors. A total of 30 cases of WDT‐UMP with equivocal papillary thyroid carcinoma‐type nuclear changes (PTC‐N) or focal unequivocal PTC‐N were examined. As a control, follicular adenoma (n = 29), follicular carcinoma (n = 8), hyalinizing trabecular adenoma (n = 5), and PTC (n = 48) were included. HBME‐1, cytokeratin 19, and galectin‐3 were positive in 12 (40.0%), 10 (33.3%) and 11 (36.7%) cases of WDT‐UMP, respectively. According to the positivity of those markers, significant differences were obtained between WDT‐UMP and PTC encapsulated common type (P = 0.028, 0.010, and 0.004, respectively), infiltrative follicular variant (P = 0.020, 0.026, and 0.008, respectively), and infiltrative common type (P = 0.004, 0.001, and 0.005, respectively), but not between WDT‐UMP and follicular adenoma or follicular carcinoma. BRAFV600E mutation was absent but RET/PTC1 rearrangement was found in only two (6.7%) cases of WDT‐UMP. None of the 20 patients with WDT‐UMP developed recurrence, with an average follow‐up of 80 months. These findings indicate that WDT‐UMP has a favorable outcome and is distinct from PTC in morphological, immunohistochemical, and molecular characteristics. We propose that WDT‐UMP should be classified as “well‐differentiated tumor with uncertain behavior”. (Cancer Sci 2011; 102: 288–294)

A Prunus mume extract stimulated the proliferation and differentiation of osteoblastic MC3T3-E1 cells.

Osteoporosis is a serious disease caused by decreased bone mass. There is constant matrix remodeling in bones, by which bone formation is performed by osteoblastic cells, whereas bone resorption is accomplished by osteoclast cells. We investigated the effect of a Japanese apricot (Prunus mume SIBE. et ZUCC.) extract on the proliferation and osteoblastic differentiation in pre-osteoblastic MC3T3-E1 cells. An alkaline phosphatase (ALP) activity assay, cell proliferation assay, alizarin red staining and expression analysis of osteoblastic genes were carried out to assess the proliferation and osteoblastic differentiation. The water-soluble fraction of Prunus mume (PWF) increased the ALP activity, cell proliferation and mineralization. The gene expression of osteopontin and bone morphogenetic protein-2, which are markers in the early period of osteoblastic differentiation, were significantly enhanced by the PWF treatment. PWF therefore stimulated the proliferation and osteoblastic differentiation of cells and may have potential to prevent osteoporosis.

Novel isoforms of periostin expressed in the human thyroid.

Periostin is an extracellular matrix protein. Five isoforms of human periostin cDNA have been reported, but the expression of periostin isoforms in the human thyroid tissue is by far unknown. A group of primer sets were designed to amplify the full length of cDNA sequence of periostin. Using human thyroid carcinoma and their paired non-neoplastic tissues together with anaplastic thyroid carcinoma cell lines, we examined the presence of periostin cDNA isoforms by RT-PCR and direct DNA sequence analysis. We identified eight coexisting cDNA isoforms in all the tissue samples and cell lines. Three of them were unique to this study. Especially two of them haven’t been previously reported in any species. The eight periostin isoforms differ in the C-terminus from exon XII to exon XXI where alternative splicing usually happens. This is the first report that demonstrates all the eight isoforms of periostin cDNA expressed in the human thyroid gland and identifies three novel isoforms.

Adrenomedullin, Bcl-2 and microvessel density in normal, hyperplastic and neoplastic endometrium

Adrenomedullin (ADM) is a multifunctional 52‐amino acid peptide involved in numerous physiological and pathological processes, including angiogenesis, growth regulation, differentiation, and vasodilation. ADM is thought to act through the G protein‐coupled receptor calcitonin receptor‐like receptor, with specificity being conferred by receptor‐associated modifying protein 2. The aim of the present study was to clarify the roles of ADM status, and tumor vessels in endometrium. Specimens were examined for ADM, microvessel density (MVD), area of venules (AV) and Bcl‐2 oncoprotein using an immunoperoxidase method. The difference of ADM between normal proliferative phase and hyperplasia without atypia was significant (P < 0.05). The level of Bcl‐2 was significantly different between hyperplasia without atypia and hyperplasia with atypia (P < 0.05). ADM, MVD and AV in the endometrium increased in a stepwise manner from normal, simple or complex hyperplasia with or without atypia to grade 1 adenocarcinoma. In contrast, expression of Bcl‐2 oncoprotein was decreased. These parameters identify the role of ADM expression and Bcl‐2 protein in relation to cell growth and vasodilating in the neoplastic changes.

Peach (Prunus persica) extract inhibits angiotensin II-induced signal transduction in vascular smooth muscle cells

Angiotensin II (Ang II) is a vasoactive hormone that has been implicated in cardiovascular diseases. Here, the effect of peach, Prunus persica L. Batsch, pulp extract on Ang II-induced intracellular Ca(2+) mobilization, reactive oxygen species (ROS) production and signal transduction events in cultured vascular smooth muscle cells (VSMCs) was investigated. Pretreatment of peach ethyl acetate extract inhibited Ang II-induced intracellular Ca(2+) elevation in VSMCs. Furthermore, Ang II-induced ROS generation, essential for signal transduction events, was diminished by the peach ethyl acetate extract. The peach ethyl acetate extract also attenuated the Ang II-induced phosphorylation of epidermal growth factor receptor and myosin phosphatase target subunit 1, both of which are associated with atherosclerosis and hypertension. These results suggest that peach ethyl acetate extract may have clinical potential for preventing cardiovascular diseases by interfering with Ang II-induced intracellular Ca(2+) elevation, the generation of ROS, and then blocking signal transduction events.

Locomotive syndrome is associated with body composition and cardiometabolic disorders in elderly Japanese women

BackgroundA concept referred to as locomotive syndrome (LS) was proposed by the Japanese Orthopaedic Association in order to help identify middle-aged and older adults who may be at high risk of requiring healthcare services because of problems associated with locomotion. Cardiometabolic disorders, including obesity, hypertension, diabetes, and dyslipidemia, have a high prevalence worldwide. The purpose of this study was to determine the associations between LS and both body composition and cardiometabolic disorders.MethodsThe study participants were 165 healthy adult Japanese women volunteers living in rural areas. LS was defined as a score ≥16 on the 25-question Geriatric Locomotive Function Scale (GLFS-25). Height, body weight, body fat percentage, body mass index (BMI), and bone status were measured. Bone status was evaluated by quantitative ultrasound (i.e., the speed of sound [SOS] of the calcaneus) and was expressed as the percent of Young Adult Mean of the SOS (%YAM). Comorbid conditions of hypertension, hyperlipidemia, and diabetes were assessed using self-report questionnaires.ResultsTwenty-nine participants (17.6 %) were classed as having LS. The LS group was older, shorter, and had a higher body fat percentage, a higher BMI, and lower bone status than the non-LS group. Multiple logistic regression analysis showed that participants with a BMI ≥23.5 kg/m2 had a significantly higher risk for LS than those with a BMI <23.5 kg/m2 (odds ratio [OR] = 3.78, p < 0.01). Furthermore, GLFS-25 scores were higher in participants with than those without hypertension, diabetes, or obesity, and significantly increased with the number of present disorders.ConclusionsThese findings suggest that BMI may be a useful screening tool for LS. Furthermore, because hypertension and diabetes were associated with LS, the prevention of these disorders accompanied by weight management may help protect against LS.

3,4-Dihydroxybenzaldehyde Derived from Prunus mume Seed Inhibits Oxidative Stress and Enhances Estradiol Secretion in Human Ovarian Granulosa Tumor Cells

Granulosa cells form ovarian follicles and play important roles in the growth and maturation of oocytes. The protection of granulosa cells from cellular injury caused by oxidative stress is an effective therapy for female infertility. We here investigated an effective bioactive compound derived from Prunus mume seed extract that protects granulosa cells from hydrogen peroxide (H2O2)-induced apoptosis. We detected the bioactive compound, 3,4-dihydroxybenzaldehyde (3,4-DHBA), via bioactivity-guided isolation and found that it inhibited the H2O2-induced apoptosis of granulosa cells. We also showed that 3,4-DHBA promoted estradiol secretion in granulosa cells and enhanced the mRNA expression levels of steroidogenic factor 1, a promoter of key steroidogenic enzymes. These results suggest that P. mume seed extract may have clinical potential for the prevention and treatment of female infertility.

Retinoid X receptor γ up‐regulation is correlated with dedifferentiation of tumor cells and lymph node metastasis in papillary thyroid carcinoma

The expression of retinoid X receptor γ (RXRγ) and the clinicopathological parameters of total 69 patients with papillary thyroid carcinoma (PTC) larger than 1 cm were examined. The PTCs were classified into two groups according to the presence of loss of cellular polarity/cohesiveness (LOP/C). The expression of RXRγ mRNA was examined by reverse transcriptase polymerase chain reaction and quantitative real‐time PCR. The RXRγ mRNA up‐regulation was found to be positively correlated with extrathyroid invasion (r = 0.293, P = 0.019), advanced tumor stage (r = 0.318, P = 0.016) and lymph node metastasis (LNM) (r = 0.338, P = 0.005), as well as LOP/C (r = 0.345, P = 0.004), which was proposed as a histological characteristic of poor cellular differentiation. The RXRγ mRNA expression, as well as extrathyroid invasion, LOP/C and advanced tumor stage, was further confirmed to be one of the independent predictive factors (Odds ratio: 6.545; 95% confidence interval: 1.575–27.208) of LNM using multivariate analysis. These results suggest that RXRγ may play a role in the dedifferentiation and metastasis of PTC.

Up-regulation of urinary-type plasminogen activator correlates with high-risk papillary thyroid carcinoma with BRAFV600E mutation and its possible molecular mechanism

The aim of the present study is to investigate the relationship between urinary-type plasminogen activator (uPA) expression and clinicopathological features in papillary thyroid carcinoma (PTC) and to determine the signal transduction of PTC cells in vitro. PTC tissues from 42 patients were analyzed for the expression of uPA and the BRAF(V600E) mutation. BCPAP, a PTC cell line harboring the BRAF(V600E) mutation, was used to study MAPK signaling. PCR and direct sequencing were applied to analyze BRAF(V600E) mutation status. uPA mRNA expression was measured using a quantitative RT-PCR method, and uPA protein was localized using an immunohistochemical method. The ERK protein status was detected by Western blot analysis. uPA gene expression was significantly increased in PTC tissues as compared to the corresponding non-tumor tissues. Furthermore, the up-regulation of uPA mRNAs was correlated with high-risk clinicopathological features, including extrathyroid invasion, loss of cellular polarity/cohesiveness, and the BRAF(V600E) mutation. Marked dephosphorylation of ERK1/2 and down-regulation of uPA expression were detected when BCPAP was treated with a MEK inhibitor, U0126. MEK inhibitors might be a potential treatment strategy for aggressive PTC with BRAF(V600E) through inhibition of uPA expression.

Bone and cartilage forming malignant tumor of breast-Osteosarcoma of breast.

今回われわれは, 骨軟骨形成を伴う乳腺の悪性腫瘍のうち, 骨肉腫の1例を経験したので, 細胞所見とともに報告する. 症例は57歳女性, 平成8年12月右乳房腫瘤に気付き受診. 穿刺吸引細胞診が実施された. 細胞像は散在性, またはゆるやかな結合性を示す細胞集塊が認められた. 核クロマチンは中等度に増量していたが, 比較的均一であり, N/C比の増加も著明ではなかった. しかし核分裂像が多数認められたため悪性の疑いと診断した. 背景には多核巨細胞が散見され, 炎症も考えられた. 手術標本では腫瘤は単一の病変で組織学的には乳管上皮の悪性像を示す部分はなく, 腫瘍は, 骨, 軟骨を形成する紡錘形問質細胞と多核巨細胞の2種の細胞より構成されていた. 葉状腫瘍や癌との移行が認められないことから骨肉腫と診断した. 免疫組織化学的には紡錘形細胞は, ケラチン陰性, ビメンチンが陽性であった. また背景にみられた多核巨細胞は酒石酸耐性酸フォスファターゼ陽性で破骨細胞への分化を示していた.