Recently, CTNNBl (ß-catenin) has been found to function as an oncoprotein that works in the Wnt s... more Recently, CTNNBl (ß-catenin) has been found to function as an oncoprotein that works in the Wnt signaling pathway, and mutation of this gene has been reported in various human cancers. In this study, we analyzed 44 endometrial cancers and found somatic missense mutations in five (11%) tumors. Interestingly, four (80%) of the five tumors with mutations would cause amino acid alterations at residues next to Ser 33, one of the targets for phosphorylation of glycogen synthase kinase (GSK)-3ß. The tumors with mutations showed accumulation of the CTNNBl protein in cytoplasm and nucleus. This is the first report of frequent somatic mutation of the CTNNBl gene at codons adjacent to those encoding to Ser/Thr residues in endometrial cancer.
Background: Spinal cord ischemic injury is a severe complication of aortic surgery. We hypothesiz... more Background: Spinal cord ischemic injury is a severe complication of aortic surgery. We hypothesized that cerebrospinal fluid (CSF) oxygenation with nanobubbles after reperfusion could ameliorate spinal cord ischemic injury. Methods: Twenty white Japanese rabbits were categorized into 4 groups of 5 rabbits each: sham group, with balloon catheter insertion into the aorta; ischemia group, with spinal cord ischemic injury by abdominal aortic occlusion; nonoxygenated group, with nonoxygenated artificial CSF irrigation after spinal cord ischemic injury; and oxygenated group, with oxygenated artificial CSF irrigation after spinal cord ischemic injury. At 48 hours after spinal cord ischemic injury, the modified Tarlov score to reflect hind limb movement was evaluated. The spinal cord was histopathologically examined by counting anterior horn cells, and microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses were performed. Results: The oxygenated group showed improved neurologic function compared with the ischemia and nonoxygenated groups (P< .01 and P ¼ .019, respectively). Anterior horn neuron prevention in the sham, nonoxygenated, and oxygenated groups was confirmed (mean modified Tarlov score: sham, 9.2 AE 1.9; nonoxygenated, 10.2 AE 2.2; oxygenated, 10.4 AE 2.2; ischemia, 2.7 AE 2.7). Microarray analysis identified 644 genes with twofold or greater increased signals between the ischemia and sham groups. Thirty-three genes related to inflammatory response were enriched among genes differentially expressed between the oxygenated and ischemia groups. Interleukin (IL)-6 and tumor necrosis factor (TNF) expression levels were significantly lower in the oxygenated group compared with the ischemia group, while qRT-PCR showed lower IL-6 and TNF expression levels in the oxygenated group compared with the ischemia group (P < .05). Conclusions: CSF oxygenation with nanobubbles after reperfusion can ameliorate spinal cord ischemic injury and suppress inflammatory responses in the spinal cord. (JTCVS Open 2020;3:1-11) Cerebrospinal fluid oxygenation mitigated ischemia-reperfusion injury to the spinal cord. CENTRAL MESSAGE Cerebrospinal fluid oxygenation with nanobubbles after reperfusion can ameliorate spinal cord ischemia-reperfusion injury in rabbits and suppress inflammatory responses in the spinal cord. PERSPECTIVE Cerebrospinal fluid drainage is a widely used option to prevent and treat spinal cord ischemiareperfusion injury with limited efficacy as a therapeutic modality. Cerebrospinal fluid oxygenation may enable symptom-driven postoperative intervention and serve as a bridging method to supply oxygen to the spinal cord tissues until a collateral network develops. See Commentary on page 12. Video clip is available online. Spinal cord ischemic injury after surgery for thoracic aortic aneurysm is a severe and unpredictable complication. The reported prevalence of paraplegia ranges from 3.8% to 13.2% after thoracoabdominal aortic aneurysm repair 1-3 and from 2.5% to 9.4% after thoracic endovascular aortic repair. 4,5 Several spinal cord protective maneuvers have been documented, including the maintenance of a relatively high mean perfusion pressure during and after reparative surgery, 6 use of systemic 7 and/or local hypothermia around
Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, an... more Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, and for predicting patient survival. Activation of lung metastatic lesions after LN dissection has been described for head and neck cancer and breast cancer. Preclinical studies have reported that dissection of a tumor‐bearing LN is involved in the activation and rapid growth of latent tumor metastases in distant organs, but it is also important to understand how normal (non‐tumor‐bearing) LN resection influences secondary cancer formation. Here, we describe how the resection of tumor‐bearing and non‐tumor‐bearing LN affects distant metastases in MXH10/Mo‐lpr/lpr mice. Tumor cells were administered intravenously and/or intranodally into the right subiliac lymph node (SiLN) to create a mouse model of lung metastasis. Luciferase imaging revealed that tumor cells in the lung were activated after resection of the SiLN, irrespective of whether it contained tumor cells. No luciferase activity wa...
We conducted a series of surveys to examine the relationships among their experiences and activit... more We conducted a series of surveys to examine the relationships among their experiences and activities on the day of the earthquake, their physical, mental, and economic problems following the disaster, and how their problems changed over time. The initial survey was performed in April 2011, with three follow-up surveys in July 2011, February 2012, and April 2013. The initial survey focused on students' experiences and living conditions during the disaster, which contained questions on their locations and circumstances, family circumstances, lives after the earthquake, voluntary works, physical or mental health problems, and desire for counseling. The follow-up surveys included new items regarding their circumstances, changes in their health problems, and their desire for economic assistance. Students who answered the first survey to the 4th one, with response rates in the following bracket, were as follows: 472 (28.0%), 640 (29.9%), 681 (36.0%), and 678 (39.0%), respectively. Six months after the earthquake, about 20% having experienced physical and/or mental problems. Although there was a trend toward a reduction in suffering and health problems over time, some students' conditions remained unchanged or worsened. It is notable that students who had participated in voluntary activities, despite their own suffering of harm and distress, were identified as the group that required the closest attention. Our present results can be applied to appropriate supports for students in future large-scale disasters.
Japanese Journal of Clinical Oncology, Nov 1, 2003
Background: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of ... more Background: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of the pre-invasive stage of breast cancer and is the precursor to invasive ductal carcinoma (IDC). However, the natural history of the progression from DCIS to IDC remains unknown at the molecular level. Methods: We investigated the loss of heterozygosities (LOHs) in tumors of seven patients with a history of breast biopsy. The seven specimens were diagnosed as DCIS on histopathological re-examination. These patients were diagnosed with ipsilateral breast cancer a few years after biopsy. We used thirteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOHs in breast cancer. DNA isolated from microdissected formalin-fixed, paraffin-embedded tissues was subjected to a PCR-LOH analysis for these chromosome loci, and the pattern of LOHs was compared between the two asynchronous lesions for the seven cases. Results: In all patients except one, the LOHs were concordant at 91% as the informative chromosome loci in cases 1 to 6 were 56, and the concordance in LOH pattern between DCIS and IDC was detected at 50 loci. The LOHs had accumulated in accordance with the tumor progression from DCIS to IDC. The recurrent lesion occurred at or near the site of the primary biopsy and had similar or identical histopathologic features. Conclusions: These recurrences observed were probably residual disease rather than true recurrences. Our results suggest the following: (i) genetic alternations accumulate during cancer progression from DCIS to IDC, (ii) DCIS is a lesion that has a high risk of developing invasive transformation and (iii) after approximately 5 years without treatment, DCIS may develop into IDC.
The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer... more The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer, suggesting the presence of a tumor suppressor gene(s) in this region. We identified a gene termed liEXTlUEXTR1/EXTL3 (liEXTIL hereinafter) that was mapped to chromosome bands 8pl2-p21 where frequent LOHs of this region was reported in breast cancer. The existence of the third breast cancer susceptibility gene was also suggested in this region by linkage analysis. We further performed LOH analysis in 8pl2-p21 in 34 breast cancers and identified a 5-cM region of common allelic loss that overlapped with the locus for positive lod score in familial breast cancer. We further analyzed genomic alterations of liEXTIL in tumors in which frequent LOHs of 8p were reported. A total of 327 cancers (313 primary tumors and 14 cancer cell lines) including 22 primary breast cancers were analyzed, but none of the tumors had somatic mutations: only one thyroid cancer patient without any family history of cancer had a 9-bp insertion in the constitutional DNA. These results suggest that mutations of liEXTIL do not play a major role in the development of sporadic cancers including breast
The number of breast cancer patients is increasing yearly, and it is important to establish effec... more The number of breast cancer patients is increasing yearly, and it is important to establish effective methods for clinical management. We investigated loss of heterozygosity (LOH) in tumors derived from 23 patients that harbored synchronous lesions of atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Fourteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOH in breast cancer. Our results suggested that i) losses of chromosomal regions 8p, 16q, and 17q are early genetic changes, and ii) ADH is a premalignant lesion for the development of breast cancer.
Our previous study indicated that DUSP6/ MKP-3/PYST1 could act as a tumor suppressor in human pan... more Our previous study indicated that DUSP6/ MKP-3/PYST1 could act as a tumor suppressor in human pancreatic cancer. DUSP6 was frequently underexpressed in primary pancreatic cancer tissues by an unknown mechanism. In this study, we demonstrated that hypermethylation of the expressional control region of DUSP6 could account for its abrogation in cultured human pancreatic cancer cells and in primary pancreatic cancer tissues. First, we checked intrinsic transcriptional expression levels of DUSP6 by a quantitative real time PCR assay in 16 cultured pancreatic cancer cell lines and found that the cells could be classified into four groups: very-low-level expression, low-level expression, high-level expression, and veryhigh-level expression. We observed restored expression of DUSP6 after treatment with 5-azacytidine and trichostatin A, a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, respectively, in cells with intrinsically very-low-level and low-level expression of DUSP6. Using a sodium-bisulfite-modification assay, we found that CpG sequences in intron 1 of DUSP6 were heavily methylated in MIA PaCa-2 and PAN07JCK, both showing the very low level of intrinsic expression of the gene. On the other hand, no methylation in this region was detected in 14 other cell lines. We checked the methylation state of this region by a methylation-specific PCR method in 12 primary pancreatic cancer tissues and compared it with the expression state of DUSP6 investigated by immuno-histochemistry. Methylation was detected in five of eight cases with abolished expressions of DUSP6, four of which were poorly differentiated adenocarcinoma. On the other hand, none of the four cases with preserved expression of DUSP6 showed methylation. The methylation state significantly correlated with both the abolishment of protein expression (p = 0.038) and the histological subtype of adenocarcinoma (p = 0.023) by chi-square test. These results indicate that hypermethylation of the CpG islands in intron 1 may account for the strong suppression of DUSP6 expression. Other mechanism(s) and/or other CpG sites outside of our investigation may have some influence upon expressional suppression. Our combined results suggest that hypermethylation with modification of histone deacetylation play an important role in transcriptional suppression of DUSP6 in human pancreatic cancer.
Recent advances in the development of chemotherapies have helped improve the prognosis of pancrea... more Recent advances in the development of chemotherapies have helped improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). However, predicting factors for the outcomes of chemotherapies (either gemcitabine or S-1) have not yet been established. We analyzed the expression of 4 major epithelial-to-mesenchymal transition-inducing transcription factors in 38 PDAC patients who received adjuvant chemotherapy after radical resection to examine the association with patients’ prognoses. The TWIST1-positive group showed a significantly poorer prognosis than the TWIST1-negative group for both the relapse‐free survival (median survival time [MST] of 8.9 vs. 18.5 months, P = 0.016) and the overall survival (MST of 15.2 vs. 33.4 months, P = 0.023). A multivariate analysis revealed that TWIST1 positivity was an independent prognostic factor for a poor response to adjuvant chemotherapies (hazard ratio 2.61; 95% confidence interval 1.10–6.79; P = 0.029). These results suggest that TWIST1 can...
To understand the molecular pathogenesis of human esophageal cancer, we performed a comparative g... more To understand the molecular pathogenesis of human esophageal cancer, we performed a comparative genomic hybridization (CGH) analysis using 10 esophageal squamous cell carcinomas. Frequent gains of lq, 3q, 7p, 7q, 8q, llq, and 20q and losses of 3p, 4p, 4q, 5q, 9p, lip, llq, 13q, 18q, 21q, and Y were observed. Among these regions, 21q has not yet been investigated in detail. We performed an allelotype study using 55 squamous cell carcinomas of the esophagus and 20 microsatellite markers on 21q and found LOH in 36 cases (65%): 22 (61%) of 36 cases with LOH indicated allelic loss in all informative loci, suggesting loss of the whole chromosome arm 21q, and five smallest regions of overlap were found. Our present results suggest the existence of a tumor suppressor gene(s) that plays a role in the genesis of squamous cell carcinoma of the esophagus.
The endoscopic net forceps with the support of a laryngeal mask airway are a dependable choice fo... more The endoscopic net forceps with the support of a laryngeal mask airway are a dependable choice for retrieving a round metallic object from an airway.
Gemcitabine (GEM) has shown clinical activity in several solid tumors such as pancreatic and bili... more Gemcitabine (GEM) has shown clinical activity in several solid tumors such as pancreatic and biliary tract cancers, urinary cancer, and non-small cell lung cancers, but a substantial number of patients acquire GEM chemoresistance. GEM functions after phosphorylation by deoxycytidine kinase (DCK) and its inactivation is one of the important mechanisms for acquisition of gemcitabine resistance. We established eight GEM resistant cell lines including four pancreatic, two biliary tract, and two gastrointestinal cancers and investigated mechanisms for acquisition of GEM resistances; six GEM resistant cell lines harbored complete inactivating mutations of DCK by protein-truncating mutation or complete or partial loss of the gene, and one gastric cancer cell line harbored a missense mutation that inactivate DCK activity. One pancreatic cancer cell line lost GEM sensitivity by unknown mechanism. Our present results strongly suggest that genetic alteration of DCK can be the major cause of ac...
Pancreatic cancer has a well-known reputation as one of the leading causes of cancer deaths world... more Pancreatic cancer has a well-known reputation as one of the leading causes of cancer deaths worldwide. Thus, acquisition of efficient approaches and markers for accurate detection at the earlier stages of the disease should be prioritized. We have been focusing on tumor suppressor genes (TSGs) activity in pancreatic cancer to find effective methods for its genetic diagnosis and/or treatment. In this study, we utilized the technique of micro-cell-mediated chromosome transfer (MMCT) to introduce a normal copy of human chromosome 18 individually into some pancreatic cancer cells. Subsequently, the tumorigenic ability of the resulting hybrids was assessed in vitro and in vivo. In vitro growth of the hybrid clones was significantly delayed as compared to the parental cells. This was paralleled by the hybrid cells promotion of invasive carcinomas in nude mice at a significantly lower rate and with a longer latency than the parental tumor cells. This study provides evidence that MMCT is an...
ABSTRACT A novel type of alpha-amylase was detected in a lung carcinoid tissue after surveying th... more ABSTRACT A novel type of alpha-amylase was detected in a lung carcinoid tissue after surveying the cDNA library constructed from this tumor mRNA. Nucleotide sequence analysis showed that the amylase expressed in this carcinoid tumor has 13 and 6 amino acid substitutions when compared with salivary amylase (Amy1) and pancreatic amylase (Amy2), respectively. The nucleotide sequence homologies of cDNAs between this carcinoid amylase and amy1, amy2 are 97.5% and 98.2%, respectively. The nucleotide sequence comparison strongly suggests that this new amylase is the product of the amy3 gene that has been detected in human genome [Emi et al., Gene 62 (1988) 229-235]
Biochemical and Biophysical Research Communications, 1989
Two types of cDNA, which code for the two types of rat pancreatic secretory trypsin inhibitors (P... more Two types of cDNA, which code for the two types of rat pancreatic secretory trypsin inhibitors (PSTIs), were cloned and sequenced. Both predicted amino acid sequences consisting of 79 amino acids, with the secretion signal peptide consisting of 18 and 23 amino acids for PSTI-I and PSTI-II, respectively. The nucleotide sequences were 91% homologous between the two cDNAs, but 68% and 65% homologous, respectively, when compared with human PSTI cDNA. Northern blot analyses showed that PSTI-I is expressed in the pancreas, whereas PSTI-II is expressed in the pancreas and the liver using the same promoter. Southern blot analyses suggested that both PSTI-I and PSTI-II genes are single copy genes per haploid genome. Duplication of rat PSTI gene seems to have occurred recently, after the divergence of humans and rats.
Adhesion tests are complex, time-consuming and expensive, while the most important criterion for ... more Adhesion tests are complex, time-consuming and expensive, while the most important criterion for a probiotic lactobacilli is the ability to adhere to the human intestine. Thirty lactobacilli isolates from human intestinal tissues were measured for cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity using a microtiter plate screening method. GAPDH activities were detected in 21 out of 30 samples from 12 h cultures and in all samples from 18 h cultures. This suggests GAPDH is universally expressed on the bacterial cell surfaces from many lactobacilli. A statistically significant positive correlation was shown between GAPDH activity and adhesion using the BIACORE adhesion assay (P < 0.01). The new screening method using GAPDH enzymatic activity without an adhesion test may be possible due to the significant positive correlation of GAPDH activity with adhesion of lactobacilli derived from the human intestine.
Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, ... more Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine resistance is regulated by various factors, including aberrant genetic and epigenetic controls, metabolism of gemcitabine, the microenvironment, epithelial-tomesenchymal transition, and acquisition of cancer stem cell properties. In many situations, results using cell lines offer valuable lessons leading to the first steps of important findings. In this review, we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance, including nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ATP-binding cassette transporters, and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance.
Background: Key molecules regulating the immune checkpoint have shed light on the efforts to cont... more Background: Key molecules regulating the immune checkpoint have shed light on the efforts to control several cancers. Recently, immune checkpoint inhibitors for cancer therapy such as antibodies against programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA4) have been developed. In head and neck squamous cell carcinomas (HNSCCs), such immune checkpoint inhibitors have come into clinical use and are expected to improve patients’ prognoses. Recently, miR-34a has been shown to be a downstream micro RNA of TP53 that regulates PD-L1 in several types of cancer. To reveal the correlations between miR-34a and PD-L1 in HNSCCs in terms of clinical significance, we analyzed 19 HNSCC cell lines.Methods: We measured the expression levels of miR-34a and PD-L1 in 10 HNSCC cell lines as well as in 9 of their derived acquired cisplatin (CDDP) resistant cell lines by qRT-PCR and Western blotting. Results were further analyzed b...
Recently, CTNNBl (ß-catenin) has been found to function as an oncoprotein that works in the Wnt s... more Recently, CTNNBl (ß-catenin) has been found to function as an oncoprotein that works in the Wnt signaling pathway, and mutation of this gene has been reported in various human cancers. In this study, we analyzed 44 endometrial cancers and found somatic missense mutations in five (11%) tumors. Interestingly, four (80%) of the five tumors with mutations would cause amino acid alterations at residues next to Ser 33, one of the targets for phosphorylation of glycogen synthase kinase (GSK)-3ß. The tumors with mutations showed accumulation of the CTNNBl protein in cytoplasm and nucleus. This is the first report of frequent somatic mutation of the CTNNBl gene at codons adjacent to those encoding to Ser/Thr residues in endometrial cancer.
Background: Spinal cord ischemic injury is a severe complication of aortic surgery. We hypothesiz... more Background: Spinal cord ischemic injury is a severe complication of aortic surgery. We hypothesized that cerebrospinal fluid (CSF) oxygenation with nanobubbles after reperfusion could ameliorate spinal cord ischemic injury. Methods: Twenty white Japanese rabbits were categorized into 4 groups of 5 rabbits each: sham group, with balloon catheter insertion into the aorta; ischemia group, with spinal cord ischemic injury by abdominal aortic occlusion; nonoxygenated group, with nonoxygenated artificial CSF irrigation after spinal cord ischemic injury; and oxygenated group, with oxygenated artificial CSF irrigation after spinal cord ischemic injury. At 48 hours after spinal cord ischemic injury, the modified Tarlov score to reflect hind limb movement was evaluated. The spinal cord was histopathologically examined by counting anterior horn cells, and microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses were performed. Results: The oxygenated group showed improved neurologic function compared with the ischemia and nonoxygenated groups (P< .01 and P ¼ .019, respectively). Anterior horn neuron prevention in the sham, nonoxygenated, and oxygenated groups was confirmed (mean modified Tarlov score: sham, 9.2 AE 1.9; nonoxygenated, 10.2 AE 2.2; oxygenated, 10.4 AE 2.2; ischemia, 2.7 AE 2.7). Microarray analysis identified 644 genes with twofold or greater increased signals between the ischemia and sham groups. Thirty-three genes related to inflammatory response were enriched among genes differentially expressed between the oxygenated and ischemia groups. Interleukin (IL)-6 and tumor necrosis factor (TNF) expression levels were significantly lower in the oxygenated group compared with the ischemia group, while qRT-PCR showed lower IL-6 and TNF expression levels in the oxygenated group compared with the ischemia group (P < .05). Conclusions: CSF oxygenation with nanobubbles after reperfusion can ameliorate spinal cord ischemic injury and suppress inflammatory responses in the spinal cord. (JTCVS Open 2020;3:1-11) Cerebrospinal fluid oxygenation mitigated ischemia-reperfusion injury to the spinal cord. CENTRAL MESSAGE Cerebrospinal fluid oxygenation with nanobubbles after reperfusion can ameliorate spinal cord ischemia-reperfusion injury in rabbits and suppress inflammatory responses in the spinal cord. PERSPECTIVE Cerebrospinal fluid drainage is a widely used option to prevent and treat spinal cord ischemiareperfusion injury with limited efficacy as a therapeutic modality. Cerebrospinal fluid oxygenation may enable symptom-driven postoperative intervention and serve as a bridging method to supply oxygen to the spinal cord tissues until a collateral network develops. See Commentary on page 12. Video clip is available online. Spinal cord ischemic injury after surgery for thoracic aortic aneurysm is a severe and unpredictable complication. The reported prevalence of paraplegia ranges from 3.8% to 13.2% after thoracoabdominal aortic aneurysm repair 1-3 and from 2.5% to 9.4% after thoracic endovascular aortic repair. 4,5 Several spinal cord protective maneuvers have been documented, including the maintenance of a relatively high mean perfusion pressure during and after reparative surgery, 6 use of systemic 7 and/or local hypothermia around
Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, an... more Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, and for predicting patient survival. Activation of lung metastatic lesions after LN dissection has been described for head and neck cancer and breast cancer. Preclinical studies have reported that dissection of a tumor‐bearing LN is involved in the activation and rapid growth of latent tumor metastases in distant organs, but it is also important to understand how normal (non‐tumor‐bearing) LN resection influences secondary cancer formation. Here, we describe how the resection of tumor‐bearing and non‐tumor‐bearing LN affects distant metastases in MXH10/Mo‐lpr/lpr mice. Tumor cells were administered intravenously and/or intranodally into the right subiliac lymph node (SiLN) to create a mouse model of lung metastasis. Luciferase imaging revealed that tumor cells in the lung were activated after resection of the SiLN, irrespective of whether it contained tumor cells. No luciferase activity wa...
We conducted a series of surveys to examine the relationships among their experiences and activit... more We conducted a series of surveys to examine the relationships among their experiences and activities on the day of the earthquake, their physical, mental, and economic problems following the disaster, and how their problems changed over time. The initial survey was performed in April 2011, with three follow-up surveys in July 2011, February 2012, and April 2013. The initial survey focused on students' experiences and living conditions during the disaster, which contained questions on their locations and circumstances, family circumstances, lives after the earthquake, voluntary works, physical or mental health problems, and desire for counseling. The follow-up surveys included new items regarding their circumstances, changes in their health problems, and their desire for economic assistance. Students who answered the first survey to the 4th one, with response rates in the following bracket, were as follows: 472 (28.0%), 640 (29.9%), 681 (36.0%), and 678 (39.0%), respectively. Six months after the earthquake, about 20% having experienced physical and/or mental problems. Although there was a trend toward a reduction in suffering and health problems over time, some students' conditions remained unchanged or worsened. It is notable that students who had participated in voluntary activities, despite their own suffering of harm and distress, were identified as the group that required the closest attention. Our present results can be applied to appropriate supports for students in future large-scale disasters.
Japanese Journal of Clinical Oncology, Nov 1, 2003
Background: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of ... more Background: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of the pre-invasive stage of breast cancer and is the precursor to invasive ductal carcinoma (IDC). However, the natural history of the progression from DCIS to IDC remains unknown at the molecular level. Methods: We investigated the loss of heterozygosities (LOHs) in tumors of seven patients with a history of breast biopsy. The seven specimens were diagnosed as DCIS on histopathological re-examination. These patients were diagnosed with ipsilateral breast cancer a few years after biopsy. We used thirteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOHs in breast cancer. DNA isolated from microdissected formalin-fixed, paraffin-embedded tissues was subjected to a PCR-LOH analysis for these chromosome loci, and the pattern of LOHs was compared between the two asynchronous lesions for the seven cases. Results: In all patients except one, the LOHs were concordant at 91% as the informative chromosome loci in cases 1 to 6 were 56, and the concordance in LOH pattern between DCIS and IDC was detected at 50 loci. The LOHs had accumulated in accordance with the tumor progression from DCIS to IDC. The recurrent lesion occurred at or near the site of the primary biopsy and had similar or identical histopathologic features. Conclusions: These recurrences observed were probably residual disease rather than true recurrences. Our results suggest the following: (i) genetic alternations accumulate during cancer progression from DCIS to IDC, (ii) DCIS is a lesion that has a high risk of developing invasive transformation and (iii) after approximately 5 years without treatment, DCIS may develop into IDC.
The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer... more The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer, suggesting the presence of a tumor suppressor gene(s) in this region. We identified a gene termed liEXTlUEXTR1/EXTL3 (liEXTIL hereinafter) that was mapped to chromosome bands 8pl2-p21 where frequent LOHs of this region was reported in breast cancer. The existence of the third breast cancer susceptibility gene was also suggested in this region by linkage analysis. We further performed LOH analysis in 8pl2-p21 in 34 breast cancers and identified a 5-cM region of common allelic loss that overlapped with the locus for positive lod score in familial breast cancer. We further analyzed genomic alterations of liEXTIL in tumors in which frequent LOHs of 8p were reported. A total of 327 cancers (313 primary tumors and 14 cancer cell lines) including 22 primary breast cancers were analyzed, but none of the tumors had somatic mutations: only one thyroid cancer patient without any family history of cancer had a 9-bp insertion in the constitutional DNA. These results suggest that mutations of liEXTIL do not play a major role in the development of sporadic cancers including breast
The number of breast cancer patients is increasing yearly, and it is important to establish effec... more The number of breast cancer patients is increasing yearly, and it is important to establish effective methods for clinical management. We investigated loss of heterozygosity (LOH) in tumors derived from 23 patients that harbored synchronous lesions of atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Fourteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOH in breast cancer. Our results suggested that i) losses of chromosomal regions 8p, 16q, and 17q are early genetic changes, and ii) ADH is a premalignant lesion for the development of breast cancer.
Our previous study indicated that DUSP6/ MKP-3/PYST1 could act as a tumor suppressor in human pan... more Our previous study indicated that DUSP6/ MKP-3/PYST1 could act as a tumor suppressor in human pancreatic cancer. DUSP6 was frequently underexpressed in primary pancreatic cancer tissues by an unknown mechanism. In this study, we demonstrated that hypermethylation of the expressional control region of DUSP6 could account for its abrogation in cultured human pancreatic cancer cells and in primary pancreatic cancer tissues. First, we checked intrinsic transcriptional expression levels of DUSP6 by a quantitative real time PCR assay in 16 cultured pancreatic cancer cell lines and found that the cells could be classified into four groups: very-low-level expression, low-level expression, high-level expression, and veryhigh-level expression. We observed restored expression of DUSP6 after treatment with 5-azacytidine and trichostatin A, a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, respectively, in cells with intrinsically very-low-level and low-level expression of DUSP6. Using a sodium-bisulfite-modification assay, we found that CpG sequences in intron 1 of DUSP6 were heavily methylated in MIA PaCa-2 and PAN07JCK, both showing the very low level of intrinsic expression of the gene. On the other hand, no methylation in this region was detected in 14 other cell lines. We checked the methylation state of this region by a methylation-specific PCR method in 12 primary pancreatic cancer tissues and compared it with the expression state of DUSP6 investigated by immuno-histochemistry. Methylation was detected in five of eight cases with abolished expressions of DUSP6, four of which were poorly differentiated adenocarcinoma. On the other hand, none of the four cases with preserved expression of DUSP6 showed methylation. The methylation state significantly correlated with both the abolishment of protein expression (p = 0.038) and the histological subtype of adenocarcinoma (p = 0.023) by chi-square test. These results indicate that hypermethylation of the CpG islands in intron 1 may account for the strong suppression of DUSP6 expression. Other mechanism(s) and/or other CpG sites outside of our investigation may have some influence upon expressional suppression. Our combined results suggest that hypermethylation with modification of histone deacetylation play an important role in transcriptional suppression of DUSP6 in human pancreatic cancer.
Recent advances in the development of chemotherapies have helped improve the prognosis of pancrea... more Recent advances in the development of chemotherapies have helped improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). However, predicting factors for the outcomes of chemotherapies (either gemcitabine or S-1) have not yet been established. We analyzed the expression of 4 major epithelial-to-mesenchymal transition-inducing transcription factors in 38 PDAC patients who received adjuvant chemotherapy after radical resection to examine the association with patients’ prognoses. The TWIST1-positive group showed a significantly poorer prognosis than the TWIST1-negative group for both the relapse‐free survival (median survival time [MST] of 8.9 vs. 18.5 months, P = 0.016) and the overall survival (MST of 15.2 vs. 33.4 months, P = 0.023). A multivariate analysis revealed that TWIST1 positivity was an independent prognostic factor for a poor response to adjuvant chemotherapies (hazard ratio 2.61; 95% confidence interval 1.10–6.79; P = 0.029). These results suggest that TWIST1 can...
To understand the molecular pathogenesis of human esophageal cancer, we performed a comparative g... more To understand the molecular pathogenesis of human esophageal cancer, we performed a comparative genomic hybridization (CGH) analysis using 10 esophageal squamous cell carcinomas. Frequent gains of lq, 3q, 7p, 7q, 8q, llq, and 20q and losses of 3p, 4p, 4q, 5q, 9p, lip, llq, 13q, 18q, 21q, and Y were observed. Among these regions, 21q has not yet been investigated in detail. We performed an allelotype study using 55 squamous cell carcinomas of the esophagus and 20 microsatellite markers on 21q and found LOH in 36 cases (65%): 22 (61%) of 36 cases with LOH indicated allelic loss in all informative loci, suggesting loss of the whole chromosome arm 21q, and five smallest regions of overlap were found. Our present results suggest the existence of a tumor suppressor gene(s) that plays a role in the genesis of squamous cell carcinoma of the esophagus.
The endoscopic net forceps with the support of a laryngeal mask airway are a dependable choice fo... more The endoscopic net forceps with the support of a laryngeal mask airway are a dependable choice for retrieving a round metallic object from an airway.
Gemcitabine (GEM) has shown clinical activity in several solid tumors such as pancreatic and bili... more Gemcitabine (GEM) has shown clinical activity in several solid tumors such as pancreatic and biliary tract cancers, urinary cancer, and non-small cell lung cancers, but a substantial number of patients acquire GEM chemoresistance. GEM functions after phosphorylation by deoxycytidine kinase (DCK) and its inactivation is one of the important mechanisms for acquisition of gemcitabine resistance. We established eight GEM resistant cell lines including four pancreatic, two biliary tract, and two gastrointestinal cancers and investigated mechanisms for acquisition of GEM resistances; six GEM resistant cell lines harbored complete inactivating mutations of DCK by protein-truncating mutation or complete or partial loss of the gene, and one gastric cancer cell line harbored a missense mutation that inactivate DCK activity. One pancreatic cancer cell line lost GEM sensitivity by unknown mechanism. Our present results strongly suggest that genetic alteration of DCK can be the major cause of ac...
Pancreatic cancer has a well-known reputation as one of the leading causes of cancer deaths world... more Pancreatic cancer has a well-known reputation as one of the leading causes of cancer deaths worldwide. Thus, acquisition of efficient approaches and markers for accurate detection at the earlier stages of the disease should be prioritized. We have been focusing on tumor suppressor genes (TSGs) activity in pancreatic cancer to find effective methods for its genetic diagnosis and/or treatment. In this study, we utilized the technique of micro-cell-mediated chromosome transfer (MMCT) to introduce a normal copy of human chromosome 18 individually into some pancreatic cancer cells. Subsequently, the tumorigenic ability of the resulting hybrids was assessed in vitro and in vivo. In vitro growth of the hybrid clones was significantly delayed as compared to the parental cells. This was paralleled by the hybrid cells promotion of invasive carcinomas in nude mice at a significantly lower rate and with a longer latency than the parental tumor cells. This study provides evidence that MMCT is an...
ABSTRACT A novel type of alpha-amylase was detected in a lung carcinoid tissue after surveying th... more ABSTRACT A novel type of alpha-amylase was detected in a lung carcinoid tissue after surveying the cDNA library constructed from this tumor mRNA. Nucleotide sequence analysis showed that the amylase expressed in this carcinoid tumor has 13 and 6 amino acid substitutions when compared with salivary amylase (Amy1) and pancreatic amylase (Amy2), respectively. The nucleotide sequence homologies of cDNAs between this carcinoid amylase and amy1, amy2 are 97.5% and 98.2%, respectively. The nucleotide sequence comparison strongly suggests that this new amylase is the product of the amy3 gene that has been detected in human genome [Emi et al., Gene 62 (1988) 229-235]
Biochemical and Biophysical Research Communications, 1989
Two types of cDNA, which code for the two types of rat pancreatic secretory trypsin inhibitors (P... more Two types of cDNA, which code for the two types of rat pancreatic secretory trypsin inhibitors (PSTIs), were cloned and sequenced. Both predicted amino acid sequences consisting of 79 amino acids, with the secretion signal peptide consisting of 18 and 23 amino acids for PSTI-I and PSTI-II, respectively. The nucleotide sequences were 91% homologous between the two cDNAs, but 68% and 65% homologous, respectively, when compared with human PSTI cDNA. Northern blot analyses showed that PSTI-I is expressed in the pancreas, whereas PSTI-II is expressed in the pancreas and the liver using the same promoter. Southern blot analyses suggested that both PSTI-I and PSTI-II genes are single copy genes per haploid genome. Duplication of rat PSTI gene seems to have occurred recently, after the divergence of humans and rats.
Adhesion tests are complex, time-consuming and expensive, while the most important criterion for ... more Adhesion tests are complex, time-consuming and expensive, while the most important criterion for a probiotic lactobacilli is the ability to adhere to the human intestine. Thirty lactobacilli isolates from human intestinal tissues were measured for cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity using a microtiter plate screening method. GAPDH activities were detected in 21 out of 30 samples from 12 h cultures and in all samples from 18 h cultures. This suggests GAPDH is universally expressed on the bacterial cell surfaces from many lactobacilli. A statistically significant positive correlation was shown between GAPDH activity and adhesion using the BIACORE adhesion assay (P < 0.01). The new screening method using GAPDH enzymatic activity without an adhesion test may be possible due to the significant positive correlation of GAPDH activity with adhesion of lactobacilli derived from the human intestine.
Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, ... more Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine resistance is regulated by various factors, including aberrant genetic and epigenetic controls, metabolism of gemcitabine, the microenvironment, epithelial-tomesenchymal transition, and acquisition of cancer stem cell properties. In many situations, results using cell lines offer valuable lessons leading to the first steps of important findings. In this review, we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance, including nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ATP-binding cassette transporters, and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance.
Background: Key molecules regulating the immune checkpoint have shed light on the efforts to cont... more Background: Key molecules regulating the immune checkpoint have shed light on the efforts to control several cancers. Recently, immune checkpoint inhibitors for cancer therapy such as antibodies against programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA4) have been developed. In head and neck squamous cell carcinomas (HNSCCs), such immune checkpoint inhibitors have come into clinical use and are expected to improve patients’ prognoses. Recently, miR-34a has been shown to be a downstream micro RNA of TP53 that regulates PD-L1 in several types of cancer. To reveal the correlations between miR-34a and PD-L1 in HNSCCs in terms of clinical significance, we analyzed 19 HNSCC cell lines.Methods: We measured the expression levels of miR-34a and PD-L1 in 10 HNSCC cell lines as well as in 9 of their derived acquired cisplatin (CDDP) resistant cell lines by qRT-PCR and Western blotting. Results were further analyzed b...
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Papers by Akira Horii