FADDのリン酸化の状態と根治的前立腺全摘除術後の生化学的再発は関連する

OBJECTIVE: To assess whether the phosphorylated Fas-associated death domain protein (FADD) at 194 serine (p-FADD) is valuable as a marker of biochemical recurrence in hormone-naive patients who had undergone radical prostatectomy. MATERIALS AND METHODS: We used radical prostatectomy specimens from 106 patients. None of the patients had received neoadjuvant or adjuvant therapy. The percentage of positive p-FADD cells (nuclear staining) was immunohistochemically evaluated. The correlation between FADD phosphorylation and the clinicopathologic parameters was assessed. The correlation between the biochemical recurrence-free rate and the p-FADD expression level was analyzed using the Kaplan-Meier method. RESULTS: Overall, 39 patients developed biochemical recurrence. We investigated the expression of p-FADD in 106 patients with prostate cancer using immunohistochemistry. We compared our findings with the clinicopathologic parameters, including the follow-up data. Patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (P < .001). A significant inverse correlation was found between the positive p-FADD rate and the Gleason score. CONCLUSION: A low expression of p-FADD could be a predictor of biochemical recurrence in hormone-naive patients who have undergone radical prostatectomy.博士（医学）・乙第1313号・平成25年5月29

Preventive Effect of Lactacystin, a Selective Proteasome Inhibitor, on Ischemic Acute Renal Failure in Rats

ABSTRACT To elucidate the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF), we examined the effect of a selective proteasome inhibitor, lactacystin, on ARF induced by ischemia/reperfusion. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. Intraperitoneal injection of lactacystin at a dose of 0.1 mg/kg before the occlusion tended to attenuate the deterioration of renal function. The higher dose of lactacystin (1 mg/kg) markedly attenuated the ischemia/ reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion, all of which were markedly suppressed by the higher dose of lactacystin. In addition, endothelin (ET)-1 content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after the reperfusion, and this elevation was abolished by the higher dose of lactacystin. These results indicate that lactacystin prevents the development of ischemia/reperfusion-induced ARF, and the effect is accompanied by suppression of the enhanced ET-1 production in the kidney, thereby suggesting that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ischemic ARF, possibly through the enhancement of ET-1 production in postischemic kidneys

Soluble Mesothelin-related Peptides (SMRP) as a Biomarker for Malignant Pleural Mesothelioma

悪性胸膜中皮腫はアスベスト曝露に起因する難治性悪性腫瘍であり,我が国においては2030年まで増加し続けることが予測されている.これまで,悪性胸膜中皮腫のバイオマーカーについての検討は少なく,補助診断あるいは治療効果や予後予測に際して有用かつ信頼できるバイオマーカーはなかった.今回,我々は,悪性胸膜中皮腫診断における可溶型メソテリン関連蛋白(SMRP: soluble mesothelin-related peptides)のバイオマーカーとしての意義を前向きの多施設共同研究で検討した.本稿では,悪性胸膜中皮腫に関する知見,治療法,および診断のためのバイオマーカーについて特に重要な論文を中心にレビューし,さらに,我々が行った前向きの多施設共同研究の結果の一部を報告する.Malignant pleural mesothelioma (MPM) is a highly aggressive, incurable neoplasm associated with asbestos exposure. It is estimated that the incidence of this disease will continue to increase until at least the year 2030 in Japan. There is some evidence that patients with MPM respond better to treatment if it is delivered early in the disease. A few MPM biomarkers have been reported, but until recently, no reliable serum marker to help the diagnosis of MPM or to predict response to treatment or prognosis, had been identified. Therefore, we performed a prospective, multicenter study to evaluate the significance of soluble mesothelin-related peptides (SMRP) as a biomarker for diagnosis of MPM. In this paper, we review the key advances in the understanding, treatment, and a biomarker for the diagnosis of MPM. Furthermore, we report some results of a prospective, multicenter study

Surgical Management of Recurrent Thymic Epithelial Tumors: A Retrospective Analysis Based on the Japanese Nationwide Database

BackgroundThere is no standard treatment for recurrent thymic epithelial tumors. Although the efficacy has not been validated based on the large series studies, surgical resection is sometimes employed for patients with recurrent thymic tumors. The aim of this study is to evaluate the surgical outcomes for recurrent thymic epithelial tumors based on the Japanese nationwide database.MethodsFrom the database of patients whose thymic epithelial tumors were treated surgically from 1991 through 2010, the cohort who developed recurrence after the initial resection was extracted. Clinicopathological factors were reviewed, and the prognostic factors of re-resected cases were examined.ResultsTwenty-eight hundred thirty-five patients who underwent surgical resection of thymic epithelial tumors were registered to the database. Among these patients, 420 (14.8%) experienced recurrence. One hundred sixty-two patients were treated surgically and 243 were treated nonsurgically for recurrent disease. The 5- and 10-year postrecurrence survival rates were 82.7% and 68.2%, respectively, in the surgery group and 43.5% and 25.4%, respectively, in the nonsurgery group (p < 0.001). According to univariate analyses, female sex and the pathological Masaoka I-II stage, nonthymic carcinoma, absence of preoperative treatment and longer recurrent-free interval (RFI) were significantly favorable factors for survival in the surgery group. According to the multivariate analysis, nonthymic carcinoma histology and longer RFI were identified to be independent prognostic factors.ConclusionsThe surgical outcomes of recurrent thymic epithelial tumors are favorable in selected patients. The role of re-resection may be limited in the setting of thymic carcinoma and/or a short RFI

Earliest histopathological changes in COVID-19 pneumonia with comprehensive gene expression analyses: A case series study

Aims. In COVID-19 pneumonia, early detection and appropriate treatment are essential to prevent severe exacerbation. Therefore, it is important to understand the initiating events of COVID-19 pneumonia. However, at present, the literature about early stage disease has been very limited. Here, we investigated the earliest histopathological changes and gene expression profiles associated with COVID-19 pneumonia. Methods and Results. We carefully examined 25 autopsied cases with different clinical courses. Dilation of capillaries and edematous thickening of the alveolar septa were found even in areas that macroscopically looked almost normal. Pneumocytes, histocytes/ macrophages, and vascular endothelial cells were immunohistochemically positive for tissue factor, which is an important early responder to tissue injuries. Comprehensive gene expression analyses revealed that those lesions presented differential profiles compared to those of control lungs and were associated with a significant upregulation of the lysosomal pathway. Conclusions. Alveolar capillary dilation and edematous thickening may be the earliest histopathological change detected in COVID-19 pneumonia. Intensive investigations of such lesions may lead to an understanding of the initiating event of not only COVID-19 pneumonia but also of general diffuse alveolar damage