Search

Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coi

Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD.

Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD.

We hypothesized that the disordered tissue architecture in cancer results from the steps that the cells execute the program designed during ontogeny in a spatiotemporally inappropriate manner. HOX genes are known as master regulators of embryonic morphogenesis, and encode transcription factors which regulate the transcription of the downstream genes to realize the program of body plan. In this study, we quantified the expression levels of 39 HOX genes in 41 human non-small cell lung cancer (non-SCLC) and non-cancerous lung tissues by a comprehensive analysis system based on the realtime RT-PCR method. We found that the expression levels of HOXA1, A5, A10 and C6 in squamous cell carcinoma tissues (and HOXA5 and A10 in adenocarcinoma tissues) were significantly higher than those in the non-cancerous tissues. Comparison of HOX gene expressions between adenocarcinoma and squamous cell carcinoma tissues showed higher expressions of HOXA1, D9, D10 and D11 in squamous cell carcinoma tissues than in adenocarcinoma tissues. Immunohistochemical analysis revealed that HOXA5 and A10 proteins were localized in the cytoplasm of tumor cells in both adenocarcinoma and squamous cell carcinoma tissues. These results suggest that the disordered patterns of HOX gene expressions were involved in not only the development of non-SCLC but also histological diversity such as adenocarcinoma and squamous cell carcinoma.

We hypothesized that the disordered tissue architecture in cancer results from the steps that the cells execute the program designed during ontogeny in a spatiotemporally inappropriate manner. HOX genes are known as master regulators of embryonic morphogenesis, and encode transcription factors which regulate the transcription of the downstream genes to realize the program of body plan. In this study, we quantified the expression levels of 39 HOX genes in 41 human non-small cell lung cancer (non-SCLC) and non-cancerous lung tissues by a comprehensive analysis system based on the realtime RT-PCR method. We found that the expression levels of HOXA1, A5, A10 and C6 in squamous cell carcinoma tissues (and HOXA5 and A10 in adenocarcinoma tissues) were significantly higher than those in the non-cancerous tissues. Comparison of HOX gene expressions between adenocarcinoma and squamous cell carcinoma tissues showed higher expressions of HOXA1, D9, D10 and D11 in squamous cell carcinoma tissues than in adenocarcinoma tissues. Immunohistochemical analysis revealed that HOXA5 and A10 proteins were localized in the cytoplasm of tumor cells in both adenocarcinoma and squamous cell carcinoma tissues. These results suggest that the disordered patterns of HOX gene expressions were involved in not only the development of non-SCLC but also histological diversity such as adenocarcinoma and squamous cell carcinoma.

Despite advances in the treatment of esophageal carcinoma, the prognosis for this disease remains poor. Therefore, it is important to obtain a better understanding of the molecular basis of esophageal carcinogenesis. The purpose of this study was to clarify the roles of survivin in esophageal squamous cell carcinoma (ESCC). One hundred 22 ESCC surgical specimens resected from 1989 to 1999 were examined. Survivin expression was assessed by immunohistochemistry. Tumor cells were considered survivin-positive if the immunoreactivity was confined to the nucleus, and a scoring method was applied. Survivin-positive immunostaining was detected in 68 patients (56%). There was a significant association between survivin expression and pN (P = 0.0472). Moreover, the overall survival rate was worse in patients with survivin-positive tumors than in patients with survivin-negative tumors (P = 0.0189). The overexpression of survivin was associated with the overall survival rate and poor prognosis in patients with ESCC. Survivin may be targeted during cancer therapy because of its selective expression in malignant tissue.

Despite advances in the treatment of esophageal carcinoma, the prognosis for this disease remains poor. Therefore, it is important to obtain a better understanding of the molecular basis of esophageal carcinogenesis. The purpose of this study was to clarify the roles of survivin in esophageal squamous cell carcinoma (ESCC). One hundred 22 ESCC surgical specimens resected from 1989 to 1999 were examined. Survivin expression was assessed by immunohistochemistry. Tumor cells were considered survivin-positive if the immunoreactivity was confined to the nucleus, and a scoring method was applied. Survivin-positive immunostaining was detected in 68 patients (56%). There was a significant association between survivin expression and pN (P = 0.0472). Moreover, the overall survival rate was worse in patients with survivin-positive tumors than in patients with survivin-negative tumors (P = 0.0189). The overexpression of survivin was associated with the overall survival rate and poor prognosis in patients with ESCC. Survivin may be targeted during cancer therapy because of its selective expression in malignant tissue.

We hypothesized that the disordered tissue architecture in cancer results from the steps that the cells execute the program designed during ontogeny in a spatiotemporally inappropriate manner. HOX genes are known as master regulators of embryonic morphogenesis, and encode transcription factors which regulate the transcription of the downstream genes to realize the program of body plan. In this study, we quantified the expression levels of 39 HOX genes in 41 human non-small cell lung cancer (non-SCLC) and non-cancerous lung tissues by a comprehensive analysis system based on the realtime RT-PCR method. We found that the expression levels of HOXA1, A5, A10 and C6 in squamous cell carcinoma tissues (and HOXA5 and A10 in adenocarcinoma tissues) were significantly higher than those in the non-cancerous tissues. Comparison of HOX gene expressions between adenocarcinoma and squamous cell carcinoma tissues showed higher expressions of HOXA1, D9, D10 and D11 in squamous cell carcinoma tissues than in adenocarcinoma tissues. Immunohistochemical analysis revealed that HOXA5 and A10 proteins were localized in the cytoplasm of tumor cells in both adenocarcinoma and squamous cell carcinoma tissues. These results suggest that the disordered patterns of HOX gene expressions were involved in not only the development of non-SCLC but also histological diversity such as adenocarcinoma and squamous cell carcinoma.

Background The extent of paraaortic lymph node (PAN) metastasis parellels that of distant metastases in patients with biliary carcinoma. Accurate preoperative assessment of PAN metastasis has a crucial impact on surgical indications. In this retrospective study, we evaluated whether computed tomography (CT) scans were useful for diagnosing PAN metastases and excluding patients with PAN metastases from an indication for surgery. Methods Between March 1999 and November 2003, 57 patients with biliary carcinoma underwent radical lymphadenectomy or surgical biopsy of PANs. Nine of these patients were diagnosed as having PAN metastasis microscopically. All patients had undergone abdominal CT scans before surgery. To diagnose PAN metastases, we used the following diagnostic criteria. (1) Size; when lymph nodes were greater than 12mm, 10mm, 8mm, or 6mm in longo or short-axis diameter, the nodes were considered metastatic. (2) Shape and size; when the axial ratio of a lymph node was greater than 0.5, 0.7, 1.0, and the maximum diameter of the long or short axis was greater than 12mm, 10mm, 8mm, or 6mm, the node was considered metastatic. (3) Internal structure; if the internal structure of a PAN was heterogeneous, the node was considered metastatic. A positive predictive value was calculated for each included criterion when patients numbered ten or more. Results Positive predictive values using the above criteria ranged from 13% to 36%. Only one patient had PANs with heterogeneous internal structures. Conclusions We were unable to determine surgical indications based on the morphological criteria revealed by a CT scan.

Background The extent of paraaortic lymph node (PAN) metastasis parellels that of distant metastases in patients with biliary carcinoma. Accurate preoperative assessment of PAN metastasis has a crucial impact on surgical indications. In this retrospective study, we evaluated whether computed tomography (CT) scans were useful for diagnosing PAN metastases and excluding patients with PAN metastases from an indication for surgery. Methods Between March 1999 and November 2003, 57 patients with biliary carcinoma underwent radical lymphadenectomy or surgical biopsy of PANs. Nine of these patients were diagnosed as having PAN metastasis microscopically. All patients had undergone abdominal CT scans before surgery. To diagnose PAN metastases, we used the following diagnostic criteria. (1) Size; when lymph nodes were greater than 12mm, 10mm, 8mm, or 6mm in longo or short-axis diameter, the nodes were considered metastatic. (2) Shape and size; when the axial ratio of a lymph node was greater than 0.5, 0.7, 1.0, and the maximum diameter of the long or short axis was greater than 12mm, 10mm, 8mm, or 6mm, the node was considered metastatic. (3) Internal structure; if the internal structure of a PAN was heterogeneous, the node was considered metastatic. A positive predictive value was calculated for each included criterion when patients numbered ten or more. Results Positive predictive values using the above criteria ranged from 13% to 36%. Only one patient had PANs with heterogeneous internal structures. Conclusions We were unable to determine surgical indications based on the morphological criteria revealed by a CT scan.

The inflammatory chemokines interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1, are reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although bronchiolar epithelial cells and macrophages are known to be the cellular sources, the relative contribution of each cell type remains to be elucidated. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never-smokers or smokers without either airflow limitation or emphysema. No difference was observed in macrophages. Complementary DNA (cDNA) array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory chemokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase–polymerase chain reaction and cDNA microarrays, to investigate functional profiles of individual structural and inflammatory cells in human lungs.

The inflammatory chemokines interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1, are reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although bronchiolar epithelial cells and macrophages are known to be the cellular sources, the relative contribution of each cell type remains to be elucidated. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never-smokers or smokers without either airflow limitation or emphysema. No difference was observed in macrophages. Complementary DNA (cDNA) array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory chemokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase–polymerase chain reaction and cDNA microarrays, to investigate functional profiles of individual structural and inflammatory cells in human lungs.

Figure 1-4 are missed., Purpose: Stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries is a radical operation performed for locally advanced cancer of the pancreatic body. However, it is not known whether the collateral pathways that develop immediately from the superior mesenteric artery to the gastroduodenal and hepatic arteries provide sufficient blood flow to support the hepatobiliary system and the stomach. This article examines the ischemic gastropathy that can occur after this procedure and identifies the predisposing conditions. Methods: Between 1997 and 2001, nine patients underwent stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries. Concomitant resection of the right gastric artery or gastroduodenal artery was performed due to cancer infiltration in three patients. Results: Irregular, shallow, and wide ulcerations thought to be ischemic in origin developed in these three patients, but all the ulcerations healed in 1–2 weeks with antiulcer medication. None of the other six patients had evidence of gastric ischemia. Conclusions Ischemic gastropathy is rare after distal pancreatectomy with celiac axis resection alone; however, division of additional arteries supplying the stomach may predispose to ischemic gastropathy.

The inflammatory chemokines interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1, are reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although bronchiolar epithelial cells and macrophages are known to be the cellular sources, the relative contribution of each cell type remains to be elucidated. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never-smokers or smokers without either airflow limitation or emphysema. No difference was observed in macrophages. Complementary DNA (cDNA) array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory chemokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase–polymerase chain reaction and cDNA microarrays, to investigate functional profiles of individual structural and inflammatory cells in human lungs.

Purpose: Stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries is a radical operation performed for locally advanced cancer of the pancreatic body. However, it is not known whether the collateral pathways that develop immediately from the superior mesenteric artery to the gastroduodenal and hepatic arteries provide sufficient blood flow to support the hepatobiliary system and the stomach. This article examines the ischemic gastropathy that can occur after this procedure and identifies the predisposing conditions. Methods: Between 1997 and 2001, nine patients underwent stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries. Concomitant resection of the right gastric artery or gastroduodenal artery was performed due to cancer infiltration in three patients. Results: Irregular, shallow, and wide ulcerations thought to be ischemic in origin developed in these three patients, but all the ulcerations healed in 1–2 weeks with antiulcer medication. None of the other six patients had evidence of gastric ischemia. Conclusions Ischemic gastropathy is rare after distal pancreatectomy with celiac axis resection alone; however, division of additional arteries supplying the stomach may predispose to ischemic gastropathy., Figure 1-4 are missed.

The inflammatory chemokines interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1, are reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although bronchiolar epithelial cells and macrophages are known to be the cellular sources, the relative contribution of each cell type remains to be elucidated. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were interleukin-8, macrophage inflammatory protein-1, and monocyte chemoattractant protein-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never-smokers or smokers without either airflow limitation or emphysema. No difference was observed in macrophages. Complementary DNA (cDNA) array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory chemokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase–polymerase chain reaction and cDNA microarrays, to investigate functional profiles of individual structural and inflammatory cells in human lungs.

Background Locally advanced cancer of the pancreatic body involving the celiac and/or common hepatic arteries is often considered unresectable. Radical distal pancreatectomy with en bloc resection of these arteries without reconstruction was recently introduced to treat these tumors. However, experience is still limited. This study reviewed the safety and utility of the operation. Patients and methods We retrospectively studied the charts of 13 patients who underwent radical distal pancreatectomy. Results Unplanned arterial reconstruction was required in three patients due to accidental injury. The postoperative mortality rate was 0% despite a morbidity rate of 62%. Patient's intractable abdominal and/or back pain was completely relieved immediately after surgery. Contrary to expectations, postoperative diarrhea was mild. The surgical margins, including the retroperitoneum, were clear histologically (R0 resection) in all patients. The 1- and 2-year survival rates were 51% and 14%, respectively, and median survival was 12.2 months. The site of recurrence was the liver in six patients and retroperitoneum in one. Conclusions Distal pancreatectomy with en bloc resection of the celiac artery is feasible and safe, offers a high resectability rate, and has dramatic analgesic effect. Local control of disease is excellent despite frequent hepatic recurrence.

Figure 1 is missed, Background The caudate lobe of the liver is divided into three subsegments based on the portal blood supply: the Spiegel lobe, the paracaval portion (S1r), and the caudate process. An isolated paracaval (S1r) subsegmentectomy is indicated for a small hepatocellular carcinoma localized within S1r. Because this challenging procedure has not been described, we report the details of successful surgical technique. Methods The portal pedicle isolation technique provides easy access to the S1r portal pedicle. A tape is passed along the midline of the anterior surface of the vena cava and its lower end is passed through the caudate parenchyma dorsoventrally to establish a landmark for the left border of S1r. A liver-splitting anterior approach is used to open the interlobar plane widely to the precaval tape. As exposing the vena cava and the root of the right hepatic vein, parenchymal dissection is advanced to the right and then, upward. Results The procedure was performed successfully in a 51-year-old man with hepatitis B who had a 2-cm hepatocellular carcinoma in S1r. Blood loss was 645 ml. Conclusions An isolated paracaval subsegmentectomy of the caudate lobe can be performed successfully, although it is likely to remain an uncommonly used procedure.

Background Locally advanced cancer of the pancreatic body involving the celiac and/or common hepatic arteries is often considered unresectable. Radical distal pancreatectomy with en bloc resection of these arteries without reconstruction was recently introduced to treat these tumors. However, experience is still limited. This study reviewed the safety and utility of the operation. Patients and methods We retrospectively studied the charts of 13 patients who underwent radical distal pancreatectomy. Results Unplanned arterial reconstruction was required in three patients due to accidental injury. The postoperative mortality rate was 0% despite a morbidity rate of 62%. Patient's intractable abdominal and/or back pain was completely relieved immediately after surgery. Contrary to expectations, postoperative diarrhea was mild. The surgical margins, including the retroperitoneum, were clear histologically (R0 resection) in all patients. The 1- and 2-year survival rates were 51% and 14%, respectively, and median survival was 12.2 months. The site of recurrence was the liver in six patients and retroperitoneum in one. Conclusions Distal pancreatectomy with en bloc resection of the celiac artery is feasible and safe, offers a high resectability rate, and has dramatic analgesic effect. Local control of disease is excellent despite frequent hepatic recurrence.

Background The caudate lobe of the liver is divided into three subsegments based on the portal blood supply: the Spiegel lobe, the paracaval portion (S1r), and the caudate process. An isolated paracaval (S1r) subsegmentectomy is indicated for a small hepatocellular carcinoma localized within S1r. Because this challenging procedure has not been described, we report the details of successful surgical technique. Methods The portal pedicle isolation technique provides easy access to the S1r portal pedicle. A tape is passed along the midline of the anterior surface of the vena cava and its lower end is passed through the caudate parenchyma dorsoventrally to establish a landmark for the left border of S1r. A liver-splitting anterior approach is used to open the interlobar plane widely to the precaval tape. As exposing the vena cava and the root of the right hepatic vein, parenchymal dissection is advanced to the right and then, upward. Results The procedure was performed successfully in a 51-year-old man with hepatitis B who had a 2-cm hepatocellular carcinoma in S1r. Blood loss was 645 ml. Conclusions An isolated paracaval subsegmentectomy of the caudate lobe can be performed successfully, although it is likely to remain an uncommonly used procedure., Figure 1 is missed