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博士（医学）, 琉球大学

博士（医学）, 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

博士(工学), 琉球大学

博士(工学), 琉球大学

博士(学術), 琉球大学

博士(工学), 琉球大学

博士(工学), 琉球大学

博士(工学), 琉球大学

博士(工学), 琉球大学

Background: Trichorrhexis invaginata, the main diagnostic feature of Netherton syndrome, is often difficult to detect, especially in adult patients. Objective: We sought to describe a characteristic feature of hairs in Netherton syndrome using a polarized light microscope and the underlying histopathologic changes. Methods: Hairs obtained from 8 patients with Netherton syndrome were observed under polarized light, and we evaluated the correlation between number of band-like patterns and disease severity. Results: Under polarized microscopy, the hair shafts of 8 patients showed a characteristic band-like pattern under polarized light that was not observed in healthy control individuals or patients with atopic dermatitis. This discontinuity of polarized light shows a band-like pattern in which the bands mostly ranged from 0.1 to 1.0 mm in width. The observed ratio of this finding was significantly higher than that of trichorrhexis invaginata observed under light microscopy, and patients with severe dermatitis tended to have a higher ratio than those with less severe dermatitis. Limitations: Comparative examination among other congenital ichthyoses was not performed. Conclusions: A band-like pattern in hairs with polarized light microscopy can be seen in Netherton syndrome and may have potential utility as a diagnostic marker., 博士(医学), 琉球大学

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., 博士(医学), 琉球大学

AdultT-cell leukemia/lymphoma (ATL) is ahuman T-cell leukemia virus type 1 (HTLV-1)–associated T-cell malignancy with generally poor prognosis. Although only ;5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n 5 40; ATL, n 5 40; remission, n 5 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor receptor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch’s t test P , .00001), high discrimination capacity (area under the curve .0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n530; ATL, n568; remission, n54) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL., 博士（保健学）, 琉球大学

Enterobacteriaceae isolates producing CTX-M-type extended-spectrum b-lactamase (ESBL) has been found in hospitalized patients and healthy individuals in communities of the Southeast Asian countries. Medical students might have more risk of ESBL-producing Enterobacteriaceae contagion, because medical students who belong to communities have direct and indirect contacts with workers and patients in healthcare facilities. The aim of this study was to collect information for evaluation of the potential risk of ESBL-producing Enterobacteriaceae contagion in Indonesian undergraduate medical students by characterizing genotypic properties of Escherichia coli isolates-producing CTX-M-type ESBL. A total 141 fecal samples collected from 207 medical students of a university in Surabaya, Indonesia were subjected to PCR, XbaI and S1 nuclease-pulsed-field gel electrophoresis (PFGE), Southern blotting, and sequencing analysis. Eighty-two ESBL-producing Enterobacteriaceae, including 75 E. coli and 7 Klebsiella pneumoniae were isolated from 79 (56.0%) students. Among 75 ESBL-producing E. coli, blaCTX-M-15 was the most prevalent type (44.0%). Although XbaI-PFGE results showed genetic background of the E. coli isolates producing CTX-M-type ESBL were diverse, five clonal spread cases of certain E. coli producing CTX-Mtype ESBL isolates were observed among the medical students. Our results suggested that ESBLproducing Enterobacteriaceae might be circulating among the medical students through contaminated environment such as in a university or communities they belonged., 博士（保健学）, 琉球大学

博士（保健学）, 琉球大学

博士（医学）, 琉球大学

博士（医学）, 琉球大学

博士（医学）, 琉球大学

博士（医学）, 琉球大学

博士（医学）, 琉球大学

博士(医学), 琉球大学

博士（医学）, 琉球大学

博士（医学）, 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

博士(学術), 琉球大学

博士(学術), 琉球大学

博士(理学), 琉球大学

博士(学術), 琉球大学

博士(理学), 琉球大学

博士(学術), 琉球大学

博士(理学), 琉球大学

博士(理学), 琉球大学

博士（理学）, 琉球大学

博士(保健学), 琉球大学

博士(工学), 琉球大学

博士(医学), 琉球大学

博士(医学), 琉球大学

As visual quantification of the density of tumor-infiltrating lymphocytes (TILs) lacks in precision, digital image analysis (DIA) approach has been applied in order to improve. In several studies, TIL density has been examined on hematoxylin and eosin (HE)-stained sections using DIA. The aim of the present study was to quantify TIL density on HE sections of core needle biopsies using DIA and investigate its association with clinicopathological parameters and pathological response to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The study cohort comprised of patients with HER2-positive breast cancer, all treated with neoadjuvant anti-HER2 therapy. DIA software applying machine learning-based classification of epithelial and stromal elements was used to count TILs. TIL density was determined as the number of TILs per square millimeter of stromal tissue. Median TIL density was 1287/mm^2 (range, 123–8101/mm^2). A high TIL density was associated with higher histological grade (P = 0.02), estrogen receptor negativity (P = 0.036), and pathological complete response (pCR) (P < 0.0001). In analyses using receiver operating characteristic curves, a threshold TIL density of 2420/mm^2 best discriminated pCR from non-pCR. In multivariate analysis, high TIL density (> 2420/mm^2) was significantly associated with pCR (P < 0.0001). Our results indicate that DIA can assess TIL density quantitatively, machine learning-based classification algorithm allowing determination of TIL density as the number of TILs per unit area, and TIL density established by this method appears to be an independent predictor of pCR in HER2-positive breast cancer., 博士(医学), 琉球大学

Graft-versus-host disease (GVHD) constitutes the most frequent complications after the allogeneic hematopoietic stem cell transplantation for a variety of hematological malignancies. In the present study, we explored the prophylactic potential of adipose tissue-derived mesenchymal stem cells (AD-MSCs) in controlling GVHD in murine models with a special focus on bone marrow aplasia related with acute GVHD. The CB6F1 mice were induced GVHD by the injection intravenously of C57BL/6 (B6-Ly-5.1) splenocytes without conditioning irradiation or chemotherapy. AD-MSCs from C3H mice were injected intravenously via tail veins. GVHD was assessed using flowcytometry analysis of peripheral blood cells and histopathologic analysis of target organs. Histopathological analyses revealed that AD-MSCs markedly suppressed the infiltration of lymphocytes into liver as well as the aplasia in bone marrow. This study is the first to clarify the effectiveness of AD-MSCs against bone marrow aplasia in GVHD, supporting a rationale of AD-MSCs for ameliorating bone marrow suppression and infectivity after allo-HSCT in human clinics., 博士(医学), 琉球大学

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., 博士(医学), 琉球大学

Purpose: To evaluate the advantages of ultra-high-resolution computed tomography (U-HRCT) scans for the quantitative measurement of emphysematous lesions over conventional HRCTscans. Materials and methods: This study included 32 smokers under routine clinical care who underwent chest CT performed by a U-HRCT scanner. Chronic obstructive pulmonary disease (COPD) was diagnosed in 13 of the 32 participants. Scan data were reconstructed by 2 different protocols: i) U-HRCT mode with a 1024×1024 matrix and 0.25-mm slice thickness and ii) conventional HRCT mode with a 512×512 matrix and 0.5-mm slice thickness. On both types of scans, lesions of emphysema were quantitatively assessed as percentage of low attenuation volume (LAV%, <−950 Hounsfield units). LAV% values determined for scan data from the U-HRCT and conventional HRCT modes were compared by the Wilcoxon matched-pairs signed rank test. The association between LAV% and forced expiratory volume in 1 s per forced vital capacity (FEV_1/FVC) was assessed by the Spearman rank correlation test. Results: Mean values for LAV% determined for the U-HRCT and conventional HRCT modes were 8.9 ± 8.8% and 7.3 ± 8.4%, respectively (P<0.0001). The correlation coefficients for LAV% and FEV_1/FVC on the U-HRCT and conventional HRCT modes were 0.50 and 0.49, respectively (both P<0.01). Conclusion: Compared with conventional HRCT scans, U-HRCT scans reveal emphysematous lesions in greater detail, and provide slightly increased correlation with airflow limitation., 博士(医学), 琉球大学

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., 博士(医学), 琉球大学

Background: Our previous report described how postoperative progression of sarcopenia predicted longterm prognosis after complete resection of non-small cell lung cancer (NSCLC) in heavy smokers. However, there are currently no effective means to treat progressive sarcopenia. In this study, we aimed to confirm our previous findings in a larger population and to identify factors associated with postoperative progression of sarcopenia to propose possible preventative measures.Methods: This retrospective study analyzed the data of 1,095 patients who underwent curative lobar resection for NSCLC at Kanagawa Cancer Center. We divided patients into four groups according to sex and Brinkman index (BI) above or below 600. Six-month postoperative changes in the skeletal muscle index (SMI) were calculated and associations between clinicopathological factors including changes in SMI and mortality from postoperative 6 months were examined. Only in groups in which postoperative depletion of SMI was shown to be associated with the prognosis, we identified clinicopathological factors associated with depletive SMI.Results: The overall survival rates of 1,095 patients were 89.8% and 82.5% at 3 and 5 years, respectively. The median 6-month change in SMI was –3.4% (range, −22.3% to +17.9%). Multivariate analysis revealed that poor prognosis was independently predicted by a large reduction in the SMI (cut-off value: −10%) in males with a BI ≥600. In 391 heavy-smoking males, factors associated with a postoperative change in SMI ≤−10% were history of other cancers (including gastric cancer) low forced expiratory volume in one second (FEV 1.0, cut-off value: 1,870 mL), and prolonged operation time (cut-off value: 200 minutes).Conclusions: Perioperative measures to prevent postoperative sarcopenia are appropriate for heavy smokers. We obtained some clues regarding countermeasures, one of which may be avoiding long-time operation. Further studies including clinical trials to assess periopera, 博士(医学), 琉球大学

Background Left ventricular (LV) wall thickening relative to the LV radius, known as a concentric LV structure, is a mechanism that compensates for pressure overload and is related to the risk of cardiovascular events and heart failure. The prognostic value of a concentric LV structure, however, has not been examined in acute decompensated heart failure (ADHF). Methods This single-center, observational, retrospective, cohort study analyzed 385 consecutive patients hospitalized due to ADHF. On hospital admission, relative wall thickness (RWT) and the ratio of LV mass to LV end-diastolic volume (LVM/LVEDV) were measured by transthoracic echocardiography as markers of a concentric LV structure. The association of either RWT or LVM/LVEDV with all-cause death as the primary outcome was analyzed. Results During the follow-up period (median, 235 days), 95 (25%) patients died. The high-RWT group had a poorer prognosis than the low-RWT group (log-rank test, P = 0.009). High RWT was a significant risk (HR: 1.95, 95% CI: 1.28–2.97, P = 0.002) in the Cox proportional hazard model analysis adjusted by the Get With The Guideline score, which is an established risk score. In contrast, there was no significant difference in survival between the low and high-LVM/LVEDV groups (P = 0.42). In the non-severe valvular disease subgroup, patients with high RWT consistently showed worse survival than the low- RWT group (P = 0.028 by log-rank test, HR: 1.96, 95% CI: 1.24–3.11, P = 0.004). There was no significant difference in survival between the low and high-LVM/LVEDV groups (P = 0.42). Conclusions A concentric LV structure represented by a high RWT was associated with a poor prognosis in ADHF. The lack of association between LVM/LVEDV and mortality may result from methodological issues., 博士(医学), 琉球大学