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K1 gene transformation activities in AIDS-related and classic type Kaposi’s sarcoma : Correlation with clinical presentation
Get PDF琉球大学博士(医学)Kaposi’s sarcoma-associated herpesvirus (KSHV) causes both AIDS-related Kaposi’s sarcoma (KS) and classic KS, but their clinical presentations are different, and respective mechanisms remain to be elucidated. The KSHV K1 gene is reportedly involved in tumorigenesis through the immunoreceptor tyrosine-based activation motif (ITAM). Since we found the sequence variations in the K1 gene of KSHV isolated from AIDS-related KS and classic KS, we hypothesized that the transformation activity of the K1 gene contributes to the different clinical presentations. To evaluate our hypothesis, we compared the transformation activities of the K1 gene between AIDS-related KS and classic KS. We also analyzed ITAM activities and the downstream AKT and NF-κB. We found that the transformation activity of AIDS-related K1 was greater than that of classic K1, and that AIDS-related K1 induced higher ITAM activity than classic K1, causing more potent Akt and NF-κB activities. K1 downregulation by siRNA in AIDS-related K1 expressing cells induced a loss of transformation properties and decreased both Akt and NF-κB activities, suggesting a correlation between the transformation activity of K1 and ITAM signaling. Our study indicates that the increased transformation activity of AIDS-related K1 is associated with its clinical aggressiveness, whereas the weak transformation activity of classic type K1 is associated with a mild clinical presentation and spontaneous regression. The mechanism of spontaneous regression of classic KS may provide new therapeutic strategy to cancer.学位論
Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T‐cell leukemia/lymphoma
Get PDF琉球大学博士(医学)Adult T‐cell leukemia/lymphoma (ATLL) is a mature T‐cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK‐STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression‐free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.学位論
Development of the 12-item questionnaire for quantitative assessment of depressive mixed state (DMX-12)
Get PDF琉球大学博士(医学)Background: Conventional categorical criteria have limitations in assessing the prevalence and severity of depressive mixed state (DMX). Thus, we have developed a new scale for screening and quantification of DMX and examined the symptomatological structure and severity of DMX in individuals with major depressive episode (MDE). Methods: Subjects were 154 patients with MDE (57 males and 97 females; age 13–83 years). Our original Japanese version of the self-administered 12-item questionnaire to assess DMX (DMX-12), together with the Quick Inventory of Depressive Symptomatology Self- Report Japanese version (QIDS-SR-J) and global assessment of functioning, were administered to each participant. The symptomatological structure of the DMX-12 was examined by exploratory factor analysis. Multiple regression analyses were used to analyze factors contributing to the DMX-12 scale. The relationships of this scale with categorical diagnoses (mixed depression by Benazzi and mixed features by DSM-5) were also investigated. Results: A three-factor model of the DMX-12 was extracted from exploratory factor analysis, namely, “spontaneous instability”, “vulnerable responsiveness”, and “disruptive emotion/behavior”. Multiple regression analyses revealed that age was negatively correlated with total DMX-12 score, while bipolarity and the QIDS-SR-J score were positively correlated. A higher score on the disruptive emotion/behavior subscale was observed in patients with mixed depression and mixed features. Conclusion: The DMX-12 seems to be useful for screening DMX in conjunction with conventional categorical diagnoses. Severely depressed younger subjects with potential bipolarity are more likely to develop DMX. The disruptive emotion/behavior subscale of the DMX-12 may be the most helpful in distinguishing patients with DMX from non-mixed patients.学位論
