Publications by authors named "Shigeshi Ono"

28 Publications

  • Page 1 of 1

Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma.

Mol Oncol 2021 04 8;15(4):1069-1087. Epub 2021 Mar 8.

Department of Translational Molecular Medicine, Division of Molecular Oncology, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.

Resistance to standard cisplatin-based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin-4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways. Initially, immunohistochemistry analysis was conducted in specimens from patients with ESCC (n = 120). In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5-fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively). Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45-18.03; P = 0.02, HR = 3.74, 95% CI, 1.19-11.76, respectively]. Suppression of MRE11A expression was associated with cisplatin resistance in ESCC cell lines. Additionally, MRE11A was found to be ubiquitinated after cisplatin treatment. We observed an amplification of UBQLN4 gene copy numbers and an increase in UBQLN4 protein levels in ESCC tissues. Binding of UBQLN4 to ubiquitinated-MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels following DNA damage and promoting cisplatin resistance. In summary, MRE11A and UBQLN4 protein levels can serve as predictors for NAC response and as prognostic markers in ESCC patients.
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http://dx.doi.org/10.1002/1878-0261.12929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024730PMC
April 2021

Endovascularly Treated Superficial Femoral Artery Aneurysm Rupture Secondary to Campylobacter fetus Bacteremia: A Case Report.

Ann Vasc Surg 2021 Apr 21;72:664.e1-664.e6. Epub 2020 Nov 21.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.

Degenerative aneurysms of the superficial femoral artery (SFA) are relatively rare and often recognized when they become symptomatic such as rupture. Infected SFA aneurysms are much rarer, especially those caused by Campylobacter fetus bacteremia. We report a case of a 67-year-old woman referred to our hospital owing to the presence of a painful reddish swelling on her left thigh. A huge SFA aneurysm rupture was diagnosed, and endovascular treatment with a covered stent was performed. C. fetus was detected in the blood culture thereafter, and antibacterial therapy was successfully performed without any additional surgical interventions. She remained well without any evidence of indolent infection 19 months after the endovascular treatment. The endovascular approach with appropriate prolonged antibacterial therapy would be a feasible alternative for managing selected infected aneurysm cases.
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http://dx.doi.org/10.1016/j.avsg.2020.10.014DOI Listing
April 2021

Endovascular repair of a Clostridium perfringens infected pseudoaneurysm presenting as an intramural air pocket.

IDCases 2020 25;21:e00841. Epub 2020 May 25.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.

An infected aneurysm (IA) is a relatively rare but complex and life-threatening disease. We report a 78-year-old man with an IA in the common iliac artery (CIA) due to . An initial computed tomography (CT) revealed an air pocket in the left CIA, and a pseudoaneurysm was seen on the CT taken the next day, in the area where the air pocket was initially observed. Due to the patient's high surgical risk, emergent endovascular aneurysm repair (EVAR) was performed. No indolent infection was found 1.5 years after the surgery. Because of its high risk of expansion and rupture, accurate diagnosis and immediate treatment is required for managing IAs. The case emphasizes that air density in an arterial wall could be an early radiologic feature of an IA, and EVAR could be a treatment option for IA.
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http://dx.doi.org/10.1016/j.idcr.2020.e00841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260675PMC
May 2020

Aortic sarcoma mimicking a mycotic aneurysm in the thoracoabdominal aorta.

J Vasc Surg Cases Innov Tech 2019 Dec 4;5(4):593-596. Epub 2019 Dec 4.

Department of Surgery, Tokyo Dental College, Ichikawa General Hospital, Chiba, Japan.

Aortic sarcoma is a rare primary tumor with dismal prognosis. Here, we report a case involving a 74-year-old female patient with aortic sarcoma masquerading as a mycotic aneurysm in the thoracoabdominal aorta. She underwent aortic resection with Dacron prosthetic graft replacement because of rapid growth. The postoperative pathological findings of the resected specimen confirmed the diagnosis of aortic mural sarcoma, which was an unexpected result based on repeat computed tomography angiography performed within 2 months preoperatively. The preoperative diagnosis of aortic sarcoma is often difficult because of its rarity, and this case demonstrates some of the diagnostic pitfalls
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http://dx.doi.org/10.1016/j.jvscit.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909102PMC
December 2019

Successful endovascular isolation of a huge true anterior tibial artery aneurysm by the bi-directional approach in a young patient.

Catheter Cardiovasc Interv 2020 05 22;95(6):E175-E178. Epub 2019 Oct 22.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.

Anterior tibial artery aneurysms (ATAAs) are relatively rare entities. Most ATAAs are pseudoaneurysms resulting from trauma, infection, or iatrogenic injury. We observed a 33-year-old woman with a huge true ATAA who did not have any potential cause of pseudoaneurysm or risk factors for atherosclerosis or connective tissue disorder. Endovascular isolation by the bi-directional approach was successfully performed, and the ATAA was totally excluded from the afferent blood flow. Distal flow of the anterior tibial artery was preserved, and pulsation of the dorsal pedis artery was also well preserved. Her postoperative course was uneventful, and follow-up ultrasonography and magnetic resonance imaging revealed the ATAA shrinkage.
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http://dx.doi.org/10.1002/ccd.28562DOI Listing
May 2020

Impact of Stent Graft Design on External Iliac Artery Limb Occlusion Rates After Endovascular Aneurysm Repair: Post-hoc Analysis of a Japanese Multicentre Database.

Eur J Vasc Endovasc Surg 2019 Dec 11;58(6):839-847. Epub 2019 Oct 11.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Objective/background: It was hypothesised that a helical stent with expanded polytetrafluoroethylene (ePTFE) grafts could provide a preventive effect for external iliac artery (EIA) limb occlusion following endovascular aortic aneurysm repair (EVAR). Therefore, a post-hoc analysis of a Japanese multicentre database was conducted to assess the impact of the stent graft design on EIA limb occlusion rates.

Methods: Patients who underwent EVAR with EIA limb deployment between 2008 and 2016 were evaluated. The stent graft limbs were divided into two groups: group A comprised stent graft limbs made of a helical stent with ePTFE grafts (Excluder; n = 255), and group B comprised stent graft limbs made of a Z stent with polyester grafts (Zenith, Flex and Endurant; n = 173). The main outcome was the incidence of limb occlusion and severe limb stenosis (EIA related limb complications). The risk factors for EIA related limb complications were analysed and the midterm results between groups A and B compared. Fine-Gray generalisation of the proportional hazards model was used after propensity score matching to calculate the hazard ratio (HR).

Results: One complication occurred in group A and 10 complications occurred in group B. The risk factors for EIA related limb complications for the entire group were a stent graft limb size ≤10 mm (HR 5.41; p = .01) and inclusion in group B (HR 14.9; p = .009). After propensity matching, group A (n = 159) was matched with group B (n = 159). The cumulative incidence function of EIA related limb complications at five years was 0.66% in group A and 7.8% in group B (HR 8.67; p = .039).

Conclusion: Stent graft design can affect limb patency in EIA limb deployment. When EIA limb deployment is necessary for patients with a small EIA, such as Japanese patients, stent graft limbs made of a helical stent with ePTFE should be used to reduce the risk of limb occlusion.
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http://dx.doi.org/10.1016/j.ejvs.2019.03.025DOI Listing
December 2019

Successful treatment of esophagopleural fistula following pulmonary resection for primary lung cancer: a case report.

Surg Case Rep 2019 May 14;5(1):78. Epub 2019 May 14.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba, 272-8513, Japan.

Background: We report a rare case of esophagopleural fistula (EPF) developing during the postoperative period after pulmonary resection for primary lung cancer.

Case Presentation: A 71-year-old male who underwent video-assisted thoracoscopic right lower lobectomy with lymph node dissection for primary lung cancer developed severe stabbing pain in his right shoulder and high fever 3 days after the operation. The fever persisted, the cough became more productive, and a plain chest X-ray showed slight a few infiltrative opacities in the right lung field. Intravenous antibiotic therapy was initiated. The patient developed a right pneumothorax 5 days after the operation, and contaminated discharge from the right chest tube was noted. A chest computed tomography showed right-sided empyema, while bronchoscopic examination revealed no evidence of a bronchopleural fistula. Open-window thoracostomy (OWT) was performed. Finally, 2 days after the OWT, the patient was diagnosed as having an EPF, because the right chest cavity was found to be contaminated with food materials. Ample purification of the right chest cavity was achieved by repeated dressing changes, and the EPF was finally closed by omentopexy. The post-surgical course was uneventful. Five weeks after the omentopexy, an esophagogram revealed no leakage of the contrast medium from the esophageal wall. The patient was discharged 13 weeks after the omentopexy.

Conclusion: While EPF following pulmonary resection is a rare complication, it can lead to critical situations and the diagnosis is difficult. Prompt OWT and omentopexy were found to be effective treatment procedures for EPF following lung surgery.
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http://dx.doi.org/10.1186/s40792-019-0638-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517458PMC
May 2019

A Hybrid Technique to Manage a Large Perigraft Seroma after an Open Abdominal Aortic Aneurysm Repair: A Case Report.

Ann Vasc Surg 2019 Apr 18;56:352.e1-352.e4. Epub 2018 Oct 18.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Perigraft seroma (PGS) is a relatively rare complication of aortoiliac reconstructive surgery. We, herein, describe a case of a large PGS that was managed by using a hybrid technique of relining the original graft with simultaneous open drainage. An 86-year-old man with a 17.3-cm diameter PGS after prosthetic bifurcated graft replacement for abdominal aortic aneurysm was admitted to our hospital. He presented with abdominal distension and discomfort and had difficulty in taking food. The entire relining of the original covered stent graft with GORE EXCLUDER using aortic extension cuff and iliac extenders and simultaneous open evacuation of PGS were successfully performed. The symptoms of the patient totally improved, and no recurrence was detected at 2 years after the operation. This technique would be a feasible treatment option for this rare complication.
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http://dx.doi.org/10.1016/j.avsg.2018.07.073DOI Listing
April 2019

A Rare Surgical Case of Giant Jejunal Artery Aneurysm in a Young Patient.

Ann Vasc Surg 2018 Jul 5;50:297.e5-297.e8. Epub 2018 Mar 5.

Department of Surgery, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Kanagawa, Japan.

Aneurysms of the abdominal visceral arteries are infrequently encountered. Jejunal artery aneurysm (JAA) is one of the rarest visceral aneurysms, especially in young patients. Endovascular surgery tends to be an effective treatment for visceral artery aneurysms. Here, we report a case of symptomatic JAA with a peripheral dilated vessel in a young patient. However, in consideration of the patient's anatomic suitability and young age, we chose open surgical intervention with intraoperative angiography. Thus, we could resect the aneurysm and the peripheral dilated vessel, preserve the bowel, and leave no devices that could cause further complication. The choice of the most appropriate treatment should depend on aneurysm characteristics and the background of the patient.
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http://dx.doi.org/10.1016/j.avsg.2017.12.023DOI Listing
July 2018

MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma.

J Invest Dermatol 2017 09 16;137(9):1955-1964. Epub 2017 May 16.

Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA; Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA. Electronic address:

The CDK4/6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we show that microRNA-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of microRNA-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, microRNA-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity. Mechanistically, overexpression of miR-200a in metastatic melanoma cells induces cell cycle arrest by targeting CDK6 and decreases the levels of phosphorylated-Rb1 and E2F-downstream targets, diminishing cell proliferation; these effects are recovered by CDK6 overexpression. Conversely, low microRNA-200a expression in metastatic melanoma cells results in higher levels of CDK6 and a more significant response to CDK4/6 inhibitors. We propose that microRNA-200a functions as a "cell cycle brake" that is lost during melanoma progression to metastasis and provides the ability to identify melanomas that are highly proliferative and more prompted to respond to CDK4/6 inhibitors.
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http://dx.doi.org/10.1016/j.jid.2017.03.039DOI Listing
September 2017

Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.

Clin Cancer Res 2017 Aug 7;23(16):4831-4842. Epub 2017 Apr 7.

Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.

Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma. The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; = 137, JWCI cohort; = 40) and The Cancer Genome Atlas database (TCGA cohort, = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression. We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II = 0.013, stage III = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma ( = 137; HR 1.810; = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's -0.455; < 0.001), is significantly associated with KPC1 downregulation (JWCI; = 0.028, TCGA; = 0.003). This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559338PMC
August 2017

Secondary Aortoenteric Erosion Followed by Recurrent Lower Extremity Abscesses.

Ann Vasc Surg 2017 Jul 22;42:302.e1-302.e5. Epub 2017 Mar 22.

Department of Vascular Surgery, Kawasaki Municipal Hospital, Kanagawa, Japan.

A secondary aortoenteric fistula (SAEF) is a relatively rare complication of aortoiliac reconstructive surgery, often involving relatively fixed duodenal third portion and a vascular anastomosis. We observed a 52-year-old man with a recurrent right lower leg abscess following the erosion between ipsilateral bifurcated prosthetic graft limb and nonfixed jejunum. In situ graft-sparing surgical treatment with aggressive debridement was successfully performed. A SAEF may occur even at a nonvascular anastomosis site, or in nonfixed small bowel, and may become a source of a septic embolus. A high index of suspicion for SAEF is required for early diagnosis and treatment of this life-threatening complication.
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http://dx.doi.org/10.1016/j.avsg.2016.11.020DOI Listing
July 2017

Correction: Ono, S.; Lam, S.; Nagahara, M.; Hoon, D.S.B. Circulating microRNA Biomarkers as Liquid Biopsy for Cancer Patients: Pros and Cons of Current Assays. J. Clin. Med. 2015, 4, 1890-1907.

J Clin Med 2016 Sep 12;5(9). Epub 2016 Sep 12.

Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA.

The authors wish to make the following corrections to this paper [1]:[...].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039484PMC
http://dx.doi.org/10.3390/jcm5090081DOI Listing
September 2016

[Local Control of Advanced Breast Cancer with Mohs Paste and Systemic Therapy].

Gan To Kagaku Ryoho 2016 Apr;43(4):443-5

Dept. of Surgery, Saiseikai Yokohama-shi Tobu Hospital.

Unresectable locally advanced breast cancer results in a decline in patient quality of life because of the presence of bleeding, exudates, and strong odor. The clinical application of supportive care using Mohs paste for improving quality of life has become widespread. We report 2 cases of locally advanced breast cancer treated with systemic therapy and chemosurgery. Case 1 was a Japanese woman in her fifties who had a locally advanced left breast cancer. She had continuous bleeding and exudates, and received Mohs chemosurgery and endocrine therapy. One month later, the surface healed and dried up. The bleeding, exudates, and strong odor disappeared almost completely. Case 2 was a Japanese woman in her forties who had a locally advanced left breast cancer with massive exudates and oozing blood. She underwent Mohs chemosurgery 20 times, but the exudates and bleeding were not controlled. According to pathological findings, we confirmed her breast cancer to be of the triple negative subtype. After 2 courses of therapy with 5-fluorouracil, epirubicin, and cyclophosphamide, the tumor immediately decreased in diameter by 65%. The bleeding, exudates, and strong odor disappeared. Although Mohs chemosurgery is useful for local control of locally advanced breast cancer, this alone is insufficient to treat the disease. Early introduction of systemic therapy is considered essential in breast cancer treatment.
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April 2016

Circulating microRNA Biomarkers as Liquid Biopsy for Cancer Patients: Pros and Cons of Current Assays.

J Clin Med 2015 Oct 23;4(10):1890-907. Epub 2015 Oct 23.

Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA.

An increasing number of studies have focused on circulating microRNAs (cmiRNA) in cancer patients' blood for their potential as minimally-invasive biomarkers. Studies have reported the utility of assessing specific miRNAs in blood as diagnostic/prognostic biomarkers; however, the methodologies are not validated or standardized across laboratories. Unfortunately, there is often minimum limited overlap in techniques between results reported even in similar type studies on the same cancer. This hampers interpretation and reliability of cmiRNA as potential cancer biomarkers. Blood collection and processing, cmiRNA extractions, quality and quantity control of assays, defined patient population assessment, reproducibility, and reference standards all affect the cmiRNA assay results. To date, there is no reported definitive method to assess cmiRNAs. Therefore, appropriate and reliable methodologies are highly necessary in order for cmiRNAs to be used in regulated clinical diagnostic laboratories. In this review, we summarize the developments made over the past decade towards cmiRNA detection and discuss the pros and cons of the assays.
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http://dx.doi.org/10.3390/jcm4101890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626661PMC
October 2015

Idiopathic splenic arteriovenous fistula without splenic artery aneurysm.

BMJ Case Rep 2015 Apr 22;2015. Epub 2015 Apr 22.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Splenic arteriovenous fistula (SAVF) without a splenic arterial aneurysm is a rare entity and may either be congenital or acquired. Acquired SAVFs are commonly due to adjacent splenic arterial aneurysm rupture, trauma or infection. We report a large idiopathic SAVF in a 50-year-old woman who had no symptoms. CT showed that the fistula was around the splenic hilum and no other specific findings. SAVF has a risk of sudden onset of portal hypertension and it should be treated as soon as diagnosed. Endovascular treatment for SAVF is now being performed successfully with increasing frequency, however, there is still no definitive evidence of treatment for SAVF. Treatment options should be determined appropriately depending on individual case characteristics and vascular anatomical variations. Our case was treated successfully with splenectomy, and long-term results are good without need of reintervention.
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http://dx.doi.org/10.1136/bcr-2015-209688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420807PMC
April 2015

A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients.

Oncotarget 2015 Mar;6(9):7053-64

Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.

Circulating cell-free(cf) microRNAs (miRNAs) have been reported to exist in plasma. MicroRNA-210(miR-210) is known to play important roles in the tumor hypoxic state. We hypothesized that the expression levels of cf-miR-210 in plasma would predict early clinical recurrence in melanoma patients. A direct miRNA assay on plasma (RT-qPCR-DP) was developed to improve cf-miRNA assay logistics, eliminate RNA extraction, and reduce specimen amount required. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) melanoma tissues (n = 108) and assessed by RT-qPCR. Plasma (10 μl; n = 264) was procured from AJCC Stage III/IV patients in phase III clinical trials. A RT-qPCR-DP was performed to detect cf-miR-210. MiR-210 was significantly higher in metastatic tumors compared to primary tumors. Cf-miR-210 was significantly higher in melanoma patients versus healthy donor controls. In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012). ROC curve analysis demonstrated that patients with elevated cf-miR-210 were more likely to have disease recurrence. Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001). Lactate dehydrogenase (LDH) level was also assessed within patients, and the AIC values for proportional hazards regression models of cf-miR-210(120.01) and LDH (122.91) demonstrated that cf-miR-210 is a better recurrence indicator. We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466669PMC
http://dx.doi.org/10.18632/oncotarget.3142DOI Listing
March 2015

MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A.

Oncotarget 2015 Feb;6(5):3211-24

Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.

To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3' untranslated regions of the tumor-suppressor genes PTEN and CDKN1A, respectively,and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413648PMC
http://dx.doi.org/10.18632/oncotarget.3085DOI Listing
February 2015

Genome-wide hypomethylation and specific tumor-related gene hypermethylation are associated with esophageal squamous cell carcinoma outcome.

J Thorac Oncol 2015 Mar;10(3):509-17

*Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, 2200 Santa Monica Blvd, Santa Monica, CA 90404; †Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 160-8582; and ‡Biostatistics Division, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, 2200 Santa Monica Blvd, Santa Monica, CA 90404.

Introduction: Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.

Methods: We explored genome-wide DNA methylation data from The Cancer Genome Atlas project and identified a panel of tumor-related genes hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n = 140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n = 28) using a quantitative methylation-specific polymerase chain reaction.

Results: Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p = 0.02) and American Joint Committee on Cancer stage (p = 0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (p < 0.0001), and lower in greater than or equal to T2 (n = 69) than T1 tumors (n = 45; p = 0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p = 0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; p = 0.006 and p = 0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (greater than two genes) presented worse OS (p = 0.003).

Conclusions: This study demonstrates that epigenetic alterations of a panel of tumor-related genes and the noncoding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients.
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http://dx.doi.org/10.1097/JTO.0000000000000441DOI Listing
March 2015

Transposed brachiobasilic arteriovenous fistula.

Ann Vasc Dis 2013 30;6(2):164-8. Epub 2013 May 30.

Department of Vascular Surgery, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, Japan.

We performed transposed brachiobasilic arteriovenous fistula (TBBAVF) in 24 patients from January 2006 to August 2010. The operative time was 90-210 minutes (mean: 136 minutes). All patients had edema of an upper extremity and 2 patients had wound complications. Major complications were not seen. The primary patency rates at one and two years were 89.7% and 69.0%, respectively. The secondary patency rates at one and two years were 95.7% and 73.6%, respectively. TBBAVF has good primary and secondary patency rates with few severe complications. (English Translation of Jpn J Phlebology 2011; 22: 33-38.).
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http://dx.doi.org/10.3400/avd.oa.13-00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692985PMC
July 2013

Intravenous Lobular Capillary Hemangioma Occurring after Needle Insertion during Routine Health Checkup.

Ann Vasc Dis 2013 28;6(1):102-5. Epub 2013 Feb 28.

Department of Cardiovascular Surgery, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, Japan.

Surgery was performed on a 53-year-old male patient with a painful mass in front of the elbow. The mass originally occurred after needle insertion during a routine health checkup and grew in size during a 1-year period. Intravenous tumor with arterio-venous fistula was diagnosed, and it was resected. Histopathological diagnosis of intravenous lobular capillary hemangioma was made. Occurrence of this tumor after a routine health checkup is rare. The etiology of this tumor occurring simultaneously with arteriovenous fistula is discussed.
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http://dx.doi.org/10.3400/avd.cr.12.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635011PMC
May 2013

Rapid development of aneurysmal formation after successful endovascular treatment of chronic total occlusion of a persistent sciatic artery.

Ann Vasc Surg 2013 May 30;27(4):499.e5-8. Epub 2013 Mar 30.

Department of Vascular Surgery, Kawasaki Municipal Hospital, Kanagawa, Japan.

Persistent sciatic artery (PSA) is a rare congenital anomaly that is frequently complicated by atherosclerotic changes, such as occlusion and aneurysmal formation. This report describes a case of a chronic total occlusion (CTO) of a unilateral, complete-type PSA in the right thigh of a 74-year-old woman that was treated successfully with endovascular angioplasty and stent placement. Within 3 months, however, a PSA aneurysm developed in the gluteal region. This aneurysm was repaired endovascularly through placement of a stent graft. To the authors' knowledge, rapid formation of a PSA aneurysm and successful endovascular treatment of both CTO of a PSA and of a PSA aneurysm have not been reported previously.
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http://dx.doi.org/10.1016/j.avsg.2012.05.031DOI Listing
May 2013

Neutrophil elastase inhibitor improves survival rate after ischemia reperfusion injury caused by supravisceral aortic clamping in rats.

J Surg Res 2013 Mar 8;180(1):e31-6. Epub 2012 May 8.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: Sivelestat sodium hydrate is a specific neutrophil elastase inhibitor effective in acute lung injury (ALI) associated with systemic inflammatory response syndrome. Bowel ischemia reperfusion injury (IRI) induced by supravisceral aortic clamping is associated with an excessive systemic inflammatory response, resulting in remote organ damage, including ALI. In this study, we investigated whether sivelestat can attenuate neutrophil sequestration in the lung, alleviate ALI, and improve survival in a rat bowel IRI model.

Methods: Adult male Sprague-Dawley rats underwent bowel IRI induced by supravisceral aortic clamping and were randomly assigned to receive sivelestat or saline (control) and monitored for survival. We randomly assigned other rats to undergo laparotomy alone (sham operation), IRI alone, or IRI and sivelestat treatment. We evaluated blood samples for organ function, cytokine levels, and neutrophil elastase activity after reperfusion. Organs were analyzed histologically. We also determined lung injury in another set of rats.

Results: Bowel IRI induced a significant increase in serum variables indicative of organ function, cytokine concentrations, neutrophil elastase activity, and lung permeability and edema, which reflected the presence of both systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome. Treatment with sivelestat significantly improved survival rate, lung permeability and edema, and significantly decreased levels of creatinine, interleukin 6, interleukin 10, and neutrophil elastase activity. Histological studies showed that sivelestat-treated rats had less bowel IRI-induced damage to lung and liver tissue than controls.

Conclusion: In a rat model, administration of sivelestat attenuated the effects of bowel IRI induced by supravisceral aortic clamping, and improved the survival rate.
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http://dx.doi.org/10.1016/j.jss.2012.04.037DOI Listing
March 2013

Suppressive effects of interleukin-18 on liver function in rat liver allografts.

J Surg Res 2012 Jul 27;176(1):293-300. Epub 2011 Aug 27.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: Interleukin-18 (IL-18) is a potent proinflammatory cytokine that augments both innate and acquired immune responses. It is also a crucial regulator of lymphocyte production of interferon-γ (IFN-γ), which can promote acute cellular rejection of transplanted solid organs.

Methods: To evaluate the role of IL-18 in liver transplantation, we constructed an adenoviral vector encoding IL-18 binding protein (Adex-IL18bp), which specifically suppressed the biologic activity of IL-18, and examined the effect of this suppression on liver allografts by using a high-responder rat model (ACI to Lewis) of orthotopic liver transplantation (OLTx). Donor rats were given one intravenous injection of Adex-IL18bp or Adex-LacZ (control vector) 2 d before OLTx.

Results: Seven days after OLTx, overexpression of IL-18bp resulting from the adenovirus gene transfer was associated with significantly decreased serum alanine aminotransferase levels and less histologic hepatic injury in recipient rats with Adex-IL18bp-pretreated donors compared with Adex-LacZ controls. Adex-IL18bp pretreatment also significantly prolonged rat/allograft survival, inhibited expression of IFN-γ, and reduced levels (versus control values) of both CXCL10 and CX3CL1, which can be induced by IFN-γ.

Conclusion: These results suggest that IL-18 has an important role in liver allograft rejection through IFN-γ and chemokines and that specific suppression of IL-18 may improve liver function early after transplantation.
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http://dx.doi.org/10.1016/j.jss.2011.07.053DOI Listing
July 2012

Complete removal of infected abdominal aortic stent-graft with suprarenal fixation.

Ann Vasc Surg 2011 Oct 31;25(7):980.e7-10. Epub 2011 May 31.

Department of Vascular Surgery, Kawasaki Municipal Hospital, Kanagawa, Japan.

Stent-graft infections after endovascular aneurysm repair are rare but can have devastating consequences. Open surgery to treat such infections is associated with considerable morbidity and mortality. Removal of the stent-graft is technically challenging, especially when it has a suprarenal fixation. Several in situ reconstructions have been described, with varying results. We report a case in which a Zenith stent-graft became infected after endovascular aneurysm repair to treat an abdominal aortic aneurysm and blue toe syndrome. The endoprosthesis was removed completely, and in situ reconstruction was performed successfully and without complications by using a rifampin-soaked Dacron graft.
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http://dx.doi.org/10.1016/j.avsg.2011.01.011DOI Listing
October 2011

Dieulafoy lesion in the ileum of a child: a case report.

J Pediatr Surg 2011 May;46(5):e17-9

Department of Surgery, Kawasaki Municipal Hospital, Kawasaki-ku, Kawasaki, Kanagawa 210-0013, Japan.

A 14-year-old girl had massive bleeding from a Dieulafoy lesion of the ileum. A preoperative dynamic computed tomography scan detected the point of bleeding. Selective arteriography with embolization using microcoils could not stop the bleeding, but the microcoils were useful as markers of the location of the bleeding point. The position of the microcoils was confirmed by intraoperative fluoroscopy. A partial resection of the ileum that included the lesion was performed. The pathologic finding was Dieulafoy lesion of the ileum. Dieulafoy lesion is a rare condition that usually presents in the stomach. Dieulafoy lesion of the ileum is extraordinarily rare, and to our knowledge, this is only the second case report of an ileal lesion in a child.
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http://dx.doi.org/10.1016/j.jpedsurg.2011.01.028DOI Listing
May 2011

Protective effect of high-mobility group box 1 blockade on acute liver failure in rats.

Shock 2010 Dec;34(6):573-9

Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

High-mobility group box 1 (HMGB1) is a monocyte-derived inflammatory mediator that is released in some conditions including shock, tissue injury, and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in a drug-induced rat acute liver failure (ALF) model and investigated the effect of HMGB1 blockade on ALF. Adult male Sprague-Dawley rats, weighing 250 to 300 g, were used for this study. d-galactosamine was injected into the penile vein to induce ALF. To determine HMGB1 levels, plasma and hepatic tissue samples were serially collected after the d-galactosamine injection. To test the effect of HMGB1 blockade, anti-HMGB1 polyclonal antibodies or control antibodies were injected into the penile vein right after injection of d-galactosamine. Levels of HMGB1 were increased in plasma and decreased in hepatic tissue after induction of ALF. Immunohistochemical examination for HMGB1 showed that liver from animals with ALF had little staining, whereas normal liver had strong staining in the nuclei. Injection of anti-HMGB1 antibodies resulted in significant suppression of plasma HMGB1 and hepatic enzymes, marked suppression of plasma inflammatory cytokines, marked improvement of histological findings, and significant improvement of survival. The decrease of hepatic HMGB1 was also significantly suppressed in the group injected with anti-HMGB1 antibodies. The present study suggests that in ALF, the liver may release HMGB1 into the plasma, and that neutralizing the released HMGB1 has a protective effect against injury.
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http://dx.doi.org/10.1097/SHK.0b013e3181df0433DOI Listing
December 2010

Reconstructive surgery for a fusiform common celiomesenteric trunk aneurysm and coexistent abdominal aortic aneurysm: report of a case.

Surg Today 2009 8;39(1):55-8. Epub 2009 Jan 8.

Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

A celiomesenteric trunk (CMT) accounts for fewer than 1% of all visceral artery anomalies. Aneurysms involving a CMT are exceptionally rare: our search of the literature found only eight cases reported. We treated a 73-year-old man with both a fusiform CMT aneurysm and an abdominal aortic aneurysm (AAA). The celiac artery and superior mesenteric artery were reconstructed by performing a retrograde prosthetic-graft bypass originating from the right limb of the bifurcated aortic graft used to repair the AAA. To our knowledge, this is the first report of successful surgical treatment of a CMT aneurysm and coexistent AAA.
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http://dx.doi.org/10.1007/s00595-008-3784-9DOI Listing
April 2009
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