Atsushi Watanabe

The Jikei University School of Medicine, Edo, Tōkyō, Japan

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Publications (59)128.13 Total impact

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    ABSTRACT: Abstract: The vascular type of Ehlers–Danlos syndrome (EDS), EDS type IV (Online Mendelian Inheritance in Man [MIM] #130050) is characterized by thin, translucent skin, easy bruising, and arterial, intestinal, and/or uterine fragility during pregnancy, which may lead to sudden death. It is an autosomal dominant inherited disorder caused by type III procollagen gene (COL3A1: MIM #120180) mutations. Approximately 50% of the COL3A1 mutations are inherited from an affected parent, and 50% are de novo mutations. Each child of an affected individual has a 50% chance of inheriting the mutation and developing the disorder. Pregnant women with vascular EDS are at an increased risk of uterine and arterial rupture during the peripartum period, with high maternal morbidity and mortality rates. We report the first case of an asymptomatic 35-year-old woman at a risk of complications of vascular EDS who underwent presymptomatic evaluation during pregnancy. The sequencing results of both her brother and mother had a one-base-pair deletion, resulting in Glutamate at position 730 changing to Lysine and causing a frame shift and premature termination codon at 61 amino acids from the muta- tion position (p. Glu730Lysfs*61) on exon 32 of COL3A1. This deletion caused frameshift, leading to a premature termination codon (TAG) at 181 nucleotides downstream in exon 35, which could not be detected by previous total RNA (ribonucleic acid) method. Thus, she was at risk of complications of vascular EDS, and diagnostic testing was employed at 8 weeks of pregnancy to minimize the risk of developing vascular EDS-related complications. The negative presymptomatic diagnostic result allowed the patient to choose normal delivery at term. Vascular EDS is a serious disorder, with high mortality, especially in high-risk women with vascular EDS during pregnancy. The presymptomatic genetic testing of vascular EDS during pregnancy for a high-risk family can help with the early establishment of preventive measures. Keywords: vascular EDS, type III procollagen gene (COL3A1), testing
    International Medical Case Reports Journal 06/2014; 7:99-102.
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    ABSTRACT: Ehlers-Danlos syndrome, vascular type (vEDS) (MIM #130050) is an autosomal dominant disorder caused by mutation in the type III collagen gene, COL3A1, leading to fragility of blood vessels, bowel and uterus that leads to spontaneous rupture. We report a previously undiagnosed vEDS patient with bowel complications. A 20-year-old female patient was referred to our hospital with abdominal pain. Computed tomography showed notable dilatation of the sigmoid colon with intraperitoneal fluid. Laparotomy revealed dilatation of the sigmoid colon, breakdown of serosa and muscularis propria of the sigmoid colon with impending perforation, and intra-abdominal hemorrhage caused by breakdown of the mesenterium. Resection of the sigmoid colon with Hartmann's pouch and an end colostomy were performed. Physical examination showed joint hypermobility, translucent skin with venous prominence and facial structure abnormalities. Genetic analysis using cDNA extracted from the patient's fibroblasts by reverse transcriptase polymerase chain reaction direct sequencing showed a missense mutation within the triple helix region of COL3A1 (c.2150 G>A; Gly717Asp).
    Case Reports in Gastroenterology 05/2014; 8(2):175-81.
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    ABSTRACT: It has previously been reported that gene profiles in surgically-resected colorectal cancer tissues are altered over time possibly due to the different tissue-acquisition methods and sample extraction timing that were used. However, the changes that occur are still not clearly understood. In the present study, time-dependent changes in gene expression profiling in colorectal surgical specimens were analyzed. Normal and tumor tissues at several time-points (0, 30, 60 and 120 min) were extracted, and RNA quality, microarray experiments, quantitative PCR and bioinformatics clustering were performed. Although RNA integrity was preserved 2 h after resection, inherent increased/decreased gene expression was observed from 30-120 min in approximately 10% of genes. Bioinformatics clustering could not distinguish case-by-case, probably due to gene profiling changes. Irregular changes in gene expression after surgical resection were found, which could be a crucial confounding factor for quantitative analyses.
    Oncology Reports 02/2014; · 2.30 Impact Factor
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    Journal of Investigative Dermatology 02/2014; · 6.19 Impact Factor
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    ABSTRACT: We show here that microRNA (miR)-150 is significantly downregulated in advanced cutaneous T-cell lymphoma (CTCL), and that this downregulation is strongly associated with tumor invasion/metastasis. Inoculation of CTCL cell lines into NOD/Shi-scid IL-2γnul mice led to CTCL cell migration to multiple organs; however, prior transfection of the cells with miR-150 substantially reduced the invasion/metastasis by directly downregulating CCR6, a specific receptor for the chemokine CCL20. We also found that IL-22 and its specific receptor subunit, IL22RA1, were aberrantly overexpressed in advanced CTCL, and that production of IL-22 and CCL20 was increased in cultured CTCL cells. IL22RA1 knockdown specifically reduced CCL20 production in CTCL cells, suggesting IL-22 upregulation may activate production of CCL20 and its binding to CCR6, thereby enhancing the multidirectional migration potential of CTCL cells. CTCL cells also exhibited nutrition- and CCL20-dependent chemotaxis, which were inhibited by miR-150 transfection or CCR6 knockdown. From these findings we conclude that, in the presence of continuous CCR6 upregulation accompanied by miR-150 downregulation, IL-22 activation leads to continuous CCL20-CCR6 interaction in CTCL cells and, in turn, autocrine metastasis to distal organs. This suggests miR-150, CCL20, and CCR6 could be key targets for the treatment of advanced CTCL.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: Suprapancreatic lymph node dissection is critical for gastric cancer surgery. Beginning in 2010, a medial approach was adopted for suprapancreatic lymph node dissection during laparoscopic gastrectomy for distal gastric cancer in our institution. The aim of this study was to compare surgical outcomes of the medial approach and conventional approach in laparoscopic gastric surgery. Between January 2007 and December 2012, a total of 100 patients with clinical T1 or T2 tumors underwent laparoscopic distal gastrectomy involving suprapancreatic lymph node dissection by the medial approach (n = 44) and conventional approach (n = 56) with curative intent. The comparison was based on clinicopathological characteristics and surgical outcome. The laparoscopic procedure was not converted to laparotomy in any patient. The patients' demographics and tumor characteristics did not show any statistically significant difference, except for tumor location. In the conventional approach group, the tumors were at a higher position (p = 0.037) and more frequently received Roux-en-Y reconstruction (p < 0.001). Intracorporeal anastomosis was significantly more common in the medial approach group (p < 0.001). Compared with the conventional approach, the medial approach was associated with significantly less operative blood loss (p < 0.001), more retrieved suprapancreatic lymph nodes (p = 0.019), and a shorter hospital stay (p = 0.018). The rates of complications were comparable between the two groups. This study suggests that the medial approach to suprapancreatic lymph node dissection seems to be convenient and useful in laparoscopic gastric cancer surgery.
    Surgical Endoscopy 01/2014; · 3.43 Impact Factor
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    ABSTRACT: The vascular type of Ehlers-Danlos syndrome (EDS), EDS type IV (Online Mendelian Inheritance in Man [MIM] #130050) is characterized by thin, translucent skin, easy bruising, and arterial, intestinal, and/or uterine fragility during pregnancy, which may lead to sudden death. It is an autosomal dominant inherited disorder caused by type III procollagen gene (COL3A1: MIM #120180) mutations. Approximately 50% of the COL3A1 mutations are inherited from an affected parent, and 50% are de novo mutations. Each child of an affected individual has a 50% chance of inheriting the mutation and developing the disorder. Pregnant women with vascular EDS are at an increased risk of uterine and arterial rupture during the peripartum period, with high maternal morbidity and mortality rates. We report the first case of an asymptomatic 35-year-old woman at a risk of complications of vascular EDS who underwent presymptomatic evaluation during pregnancy. The sequencing results of both her brother and mother had a one-base-pair deletion, resulting in Glutamate at position 730 changing to Lysine and causing a frame shift and premature termination codon at 61 amino acids from the mutation position (p. Glu730Lysfs*61) on exon 32 of COL3A1. This deletion caused frameshift, leading to a premature termination codon (TAG) at 181 nucleotides downstream in exon 35, which could not be detected by previous total RNA (ribonucleic acid) method. Thus, she was at risk of complications of vascular EDS, and diagnostic testing was employed at 8 weeks of pregnancy to minimize the risk of developing vascular EDS-related complications. The negative presymptomatic diagnostic result allowed the patient to choose normal delivery at term. Vascular EDS is a serious disorder, with high mortality, especially in high-risk women with vascular EDS during pregnancy. The presymptomatic genetic testing of vascular EDS during pregnancy for a high-risk family can help with the early establishment of preventive measures.
    International Medical Case Reports Journal 01/2014; 7:99-102.
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    ABSTRACT: Hypophosphatasia (HPP) is an inherited disorder characterized by defective bone mineralization caused by mutations in the alkaline phosphatase gene (ALPL). Clinically, the disease spans a great continuum of disease severity and six forms can be distinguished according to the age of onset. The most severe is the autosomal recessive perinatal form, a major prenatal skeletal dysplasia in Japan. The ALPL mutation c.1559delT causes perinatal HPP and occurs frequently in the Japanese. Most patients with perinatal HPP in Japan are homozygous for c.1559delT, and their parents are usually heterozygous with no evidence of consanguinity. Here we identified a fetus with perinatal HPP resulting from an unusual mechanism known as paternal uniparental isodisomy (UPD) of chromosome 1. Sequence analysis of ALPL in the patient revealed the presence of the homozygous mutation c.1559delT. We suspected UPD because the father and mother were heterozygous and wild type, respectively. Analysis of polymorphic microsatellite markers spanning chromosome 1 and whole-genome arrays revealed a uniparental inheritance from the father and excluded deletions or de novo mutations. This is the first description of perinatal HPP caused by UPD. This report also emphasizes the low recurrence risk of a non-mendelian inheritance pattern in UPD and the value of determining parental genotypes with homozygous mutations in a patient to confirm whether the condition is caused by UPD or not, even when the mutation is detected as a hot spot, as described in the literature.
    Bone 12/2013; · 4.46 Impact Factor
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    ABSTRACT: Pathological scars are fibroproliferative skin disorders that are characterised by the accumulation of fibroblasts and collagens. It is increasingly understood that their development and progression may be related to local skin mechanics, such as stretching. The present study evaluated the morphological and functional effects of cellular stretch on normal human dermal fibroblasts and explored the mechanotransduction mechanisms that may be involved. When fibroblasts were subjected to 24 h of cyclic axial stretching (10 cycles min(-1)), they migrated faster and for a longer distance than unstretched cells. The increased migration resulted in the cells reorienting themselves perpendicular to the direction of stretching. This was associated with reduced cellular apoptosis and unchanged proliferation. Stretching did not increase collagen synthesis but did elevate collagen degradation. These biological effects appeared to be mediated by the integrin and Wnt mechanotransduction pathways, which transmitted the mechanical stimulus via cell-substrate interactions, cell-cell junctions and indirect cell-cell communications. A better understanding of such fibroblast mechanoresponses in vitro will help the development of novel interventions that can prevent, reduce or even reverse pathological scar formation and/or progression in vivo.
    Journal of Plastic Reconstructive & Aesthetic Surgery 08/2013; · 1.44 Impact Factor
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    Atsushi Watanabe, Banyar Than, Takashi Shimada
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    ABSTRACT: Pharmacogenomics (PGx) involves investiga-tion into the genetic basis of interindividual differences in drug responses, such as efficacy, dose requirements, and adverse events. PGx can be used as a tool for personalizing health care on the basis of individual genetic variations. It may decrease the amount of time needed to identify the most beneficial drug and dosage for a patient, minimize exposure to ineffective treatments, reduce the rates of adverse drug reactions, and improve the economic effi-ciency of the health care system. However, there are a number of obstacles blocking the achievement of person-alized therapy through the full implementation of PGx. In this review, we focus on the barriers to the implementation of a system for PGx in the pretest, the PGx test, and posttest phases, and the solution for these barriers.
    07/2013;
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    Atsushi Watanabe, Banyar Than Naing, Takashi Shimada
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacogenomics (PGx) involves investiga-tion into the genetic basis of interindividual differences in drug responses, such as efficacy, dose requirements, and adverse events. PGx can be used as a tool for personalizing health care on the basis of individual genetic variations. It may decrease the amount of time needed to identify the most beneficial drug and dosage for a patient, minimize exposure to ineffective treatments, reduce the rates of adverse drug reactions, and improve the economic effi-ciency of the health care system. However, there are a number of obstacles blocking the achievement of person-alized therapy through the full implementation of PGx. In this review, we focus on the barriers to the implementation of a system for PGx in the pretest, the PGx test, and posttest phases, and the solution for these barriers.
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  • Nippon Geka Gakkai zasshi 01/2013; 114(1):62-5.
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    ABSTRACT: Side population (SP) cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11) express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3) express genes involved in the cell cycle and mitosis (e.g., , , , ), polycomb (e.g., ) and ubiquitin-proteasome (e.g., ) more strongly than do non-SP cells. Moreover, , and were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680) and a proteasome inhibitor (bortezomib) with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3) and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.
    PLoS ONE 01/2013; 8(3):e56954. · 3.53 Impact Factor
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    ABSTRACT: A 63-year-old woman was admitted to our hospital with high-grade fever, liver dysfunction, and pancytopenia. Computed tomography of the whole body revealed hepatosplenomegaly but no lymphoadenopaties. Bone marrow aspiration showed infiltrations of CD20-positive large atypical B-lymphocytes with severe hemophagocytosis. Although she was a human T-cell leukemia virus type 1 carrier, the atypical lymphocyte in bone marrow had IgH rearrangement but not TCR rearrangement. From these clinical and laboratory data, the patient was diagnosed as having B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) and treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). After 4 cycles of R-CHOP, she had achieved complete remission. However, increased numbers of CD4+CD25+ flower cells were observed in peripheral blood and HTLV-1 provirus DNA was detected after 5 cycle of R-CHOP. The patient was diagnosed as adult T-cell leukemia-lymphoma (ATL) complicated by B-LAHS. Our observations suggest that continuous immunosuppressive statement for B-cell lymphoma or the chemotherapy against B-LAHS may induce the development of ATL in an HTLV-1 carrier.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 12/2012; 53(12):2008-12.
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    ABSTRACT: We report a 34-year-old Japanese female with the vascular type of Ehlers-Danlos syndrome. She had thin translucent skin, extensive bruising, toe joint hypermobility, left lower extremity varicose veins, and chronic wrist, knee and ankle joint pain. She also had dizziness caused by autonomic dysfunction. Magnetic resonance angiography showed tortuous vertebral and basilar arteries, mild left carotid canal bulging, and right anterior tibial artery hypoplasia. Electron microscopic examinations of a skin biopsy revealed extremely dilated rough endoplasmic reticulum in dermal fibroblasts and wide variability of individual collagen fibril diameters. A molecular analysis using a conventional total RNA method and a high-resolution melting curve analysis using genomic DNA revealed a novel missense mutation within exon 48 of the COL3A1 gene, c.3428G>A, leading to p.Gly1143Glu.
    Congenital Anomalies 12/2012; 52(4):207-210.
  • Atsushi Watanabe, Takashi Shimada
    Nippon rinsho. Japanese journal of clinical medicine 09/2012; 70 Suppl 7:475-9.
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    ABSTRACT: BACKGROUND: In patients having carcinoma in the remnant stomach, total resection of the remnant stomach with lymph node dissection is a prerequisite. MATERIALS AND METHODS: We present the first series of successful totally laparoscopic complete gastrectomy (TLCG) for gastric remnant cancer. RESULTS: TLCG was successfully performed without adverse events during surgery in five patients with gastric remnant cancer. The median age of the patients was 72 years (range, 56-84 years), and there were three men and two women. Three of them had a Billroth I reconstruction and two had a Billroth II reconstruction, and in four cases following partial gastrectomy for gastric cancer and one for gastroduodenal ulcer. The median operative time was 360 min; blood loss was 20 ml. The median number of retrieved lymph nodes was 19. No complications occurred postoperatively, and all of the patients were discharged within the ninth postoperative day. CONCLUSIONS: Although TLCG for gastric remnant cancer is a technically difficult and challenging operation that requires careful lysis of adhesion and dissection along the major vessels, as well as intracorporeal anastomosis, this procedure is technically feasible. Long-term follow-up is mandatory to validate oncological outcome.
    Langenbeck s Archives of Surgery 07/2012; · 1.89 Impact Factor
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    ABSTRACT: Although proximal gastrectomy has become a procedure of choice for patients' early cancer in the upper third of stomach, no clinical guide for optimal gastric resection in order to avoid postoperative jejunal ulcer is available. The aim of this study was to investigate whether determining the distribution of parietal and chief cells of the stomach using Congo red test is clinically relevant. The F-line was defined as a boundary line between fundic and intermediate area of the stomach according to the pathological findings in 29 patients who underwent total gastrectomy for early gastric cancer, whereas the f-line was regarded as a boundary line between intermediate and pyloric area. In the additional 6 patients undergoing vagus-preserving proximal gastrectomy with jejunal pouch interposition, endoscopic Congo red test was preoperatively performed to determine the F-f-line. The distances from the pyloric ring to f-line on the lesser and greater curvatures were variable. Long-term outcomes of proximal gastrectomy guided by preoperative endoscopic Congo red test were favorable. It is suggested that preoperative endoscopic Congo red test is useful to determine the appropriate cutting line in order to avoid postoperative jejunal ulcer after proximal gastrectomy.
    Hepato-gastroenterology 07/2012; 59(117):1478-9. · 0.77 Impact Factor
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    ABSTRACT: Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects. For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls. Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation. This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies.
    Clinical Endocrinology 04/2012; 77(5):707-14. · 3.40 Impact Factor

Publication Stats

469 Citations
128.13 Total Impact Points

Institutions

  • 2009–2014
    • The Jikei University School of Medicine
      • Department of Surgery
      Edo, Tōkyō, Japan
  • 2001–2014
    • Nippon Medical School
      • • Department of Biochemistry and Molecular Biology
      • • Department of Molecular and Medical Genetics
      • • Nippon Medical School Hospital
      • • Department of Plastic and Reconstructive Surgery
      Edo, Tōkyō, Japan
  • 2003
    • Akita University Hospital
      Akita, Akita, Japan