Publications by authors named "Hiroko Yano"

40 Publications

Quality of life assessment of cell-free and concentrated ascites reinfusion therapy during initial treatment for advanced ovarian cancer: A prospective cohort study.

J Obstet Gynaecol Res 2021 Jan 20. Epub 2021 Jan 20.

Department of Gynecologic Oncology, Hyogo Cancer Center, Akashi, Japan.

Aim: Cell-free and concentrated ascites reinfusion therapy (CART) is applied to relieve symptoms in patients with malignant ascites. We performed a prospective cohort study to evaluate the efficacy and safety of CART performed on patients with advanced ovarian and peritoneal cancers with massive ascites during the initial treatment.

Methods: From April 2018 to July 2020, CART was performed during the initial treatment of 31 patients with advanced ovarian and peritoneal cancers with cancerous ascites. Patient characteristics and clinical information before and after CART were collected. We performed quality of life assessment using the Japanese version of the M.D. Anderson Symptom Inventory (MDASI-J) 24 h before and after CART.

Results: CART was performed 38 times in 24 patients before or during neoadjuvant chemotherapy and 11 times in 11 patients prior to surgery. Four patients underwent CART before primary surgery and before and/or during chemotherapy. Grade 1-2 fever was observed in 18 of 31 cases (58%), and all were controllable by nonsteroidal anti-inflammatory drugs. CART did not adversely affect the main treatment, chemotherapy, or surgery. CART significantly improved the MDASI-J symptom and interference scores within 24 h after the procedure. The symptom and interference scores decreased from 2.4 to 1.8 and from 4.8 to 3.0, respectively.

Conclusions: CART can be safely performed and is useful for symptom relief and improvement of general condition prior to initial surgery and during initial chemotherapy in ovarian and peritoneal cancers. Performing CART at the time of initial treatment may facilitate initiation of the main treatment.
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http://dx.doi.org/10.1111/jog.14670DOI Listing
January 2021

Infection due to exposed aortic prosthetic graft in perforated duodenal ulcer.

BMJ Case Rep 2020 Oct 27;13(10). Epub 2020 Oct 27.

General Medicine, Kochi Health Sciences Center, Kochi, Japan.

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http://dx.doi.org/10.1136/bcr-2020-239459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592236PMC
October 2020

Therapeutic enhancement of blood-brain and blood-tumor barriers permeability by laser interstitial thermal therapy.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa071. Epub 2020 Jun 30.

Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.

Background: The blood-brain and blood-tumor barriers (BBB and BTB), which restrict the entry of most drugs into the brain and tumor, respectively, are a significant challenge in the treatment of glioblastoma. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique increasingly used clinically for tumor cell ablation. Recent evidence suggests that LITT might locally disrupt BBB integrity, creating a potential therapeutic window of opportunity to deliver otherwise brain-impermeant agents.

Methods: We established a LITT mouse model to test if laser therapy can increase BBB/BTB permeability in vivo. Mice underwent orthotopic glioblastoma tumor implantation followed by LITT in combination with BBB tracers or the anticancer drug doxorubicin. BBB/BTB permeability was measured using fluorimetry, microscopy, and immunofluorescence. An in vitro endothelial cell model was also used to corroborate findings.

Results: LITT substantially disrupted the BBB and BTB locally, with increased permeability up to 30 days after the intervention. Remarkably, molecules as large as human immunoglobulin extravasated through blood vessels and permeated laser-treated brain tissue and tumors. Mechanistically, LITT decreased tight junction integrity and increased brain endothelial cell transcytosis. Treatment of mice bearing glioblastoma tumors with LITT and adjuvant doxorubicin, which is typically brain-impermeant, significantly increased animal survival.

Conclusions: Together, these results suggest that LITT can locally disrupt the BBB and BTB, enabling the targeted delivery of systemic therapies, including, potentially, antibody-based agents.
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http://dx.doi.org/10.1093/noajnl/vdaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344247PMC
June 2020

Suppressive effect upon carboplatin hypersensitivity reaction via pegylated liposomal doxorubicin combination therapy.

Int J Clin Oncol 2020 Sep 23;25(9):1718-1725. Epub 2020 May 23.

Department of Gynecologic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-city, Hyogo, 673-8558, Japan.

Background: Occurrence of hypersensitivity reaction (HSR) in patients having received multiple doses of carboplatin has been reported. Several studies demonstrated reduction of carboplatin-associated HSR with in combination with pegylated liposomal doxorubicin (PLD). The objective of this study was to determine the suppressive effect on carboplatin-induced HSR via combined treatment with PLD within clinical practice.

Methods: We reviewed the medical records of women with primary or recurrent ovarian, fallopian tube, or peritoneal cancer treated with carboplatin containing regimen at our hospital between January 2009 and March 2019. We compared the incidence of carboplatin-induced HSR among patients who received more than one cycle of PLD plus carboplatin (PLD-C) therapy (i.e., PLD-C group) versus patients who never received PLD-C therapy (non-PLD-C group).

Results: A total of 414 women were included in this study (48: PLD-C group, 366: non-PLD-C group). Carboplatin-induced HSR occurred in 34 total patients (8.2%) [1/48 (2.1%) in the PLD-C group and 33/366 (9.0%) in the non-PLD-C group], with a median cycle number of carboplatin administration at onset of HSR being 9. Incidences of carboplatin-induced HSR within the PLD-C versus non-PLD-C group at the 8th, 12th, and 16th cycles of carboplatin administration were 2.2% vs 11.2%, 2.2% vs 28.6%, and 2.2% vs 39.1%, respectively [hazard ratio: 19.2 (95% confidence interval: 9.82-39.4), p < 0.0001].

Conclusion: Based on the data analyzed here, a suppressive effect on carboplatin-induced HSR via combination therapy with PLD was confirmed within clinical practice.
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http://dx.doi.org/10.1007/s10147-020-01706-wDOI Listing
September 2020

Dose-dense paclitaxel and carboplatin vs. conventional paclitaxel and carboplatin as neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: a retrospective study.

Int J Clin Oncol 2020 Mar 1;25(3):502-507. Epub 2019 Nov 1.

Department of Gynecologic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-City, 673-8558, Hyogo, Japan.

Background: The purpose of this study was to determine the optimal regimen of neoadjuvant chemotherapy (NAC) for advanced epithelial ovarian, fallopian tube, and peritoneal cancers.

Methods: A clinical information survey involving 171 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer was conducted. These patients underwent NAC followed by interval debulking surgery at the Hyogo Cancer Center (Hyogo, Japan) between January 2006 and December 2015.

Results: The median observation period was 41 (range 4-138) months. Dose-dense paclitaxel and carboplatin (TC) was administered in 101 patients (59%); tri-weekly TC was administered 70 patients (41%). Median progression-free survival was 21 [95% confidence interval (CI) 18-23] months and 15 (95% CI 13-17) months in the dose-dense TC and conventional-TC group [hazard ratio (HR) = 0.69, 95% CI 0.46-0.96; p = 0.02], respectively. The median overall survival was 59 (95% CI 46-72) and 40 (95% CI 32-57) months in the dose-dense TC group and conventional-TC group (HR = 0.72, 95% CI 0.48-1.06; p = 0.09). Multivariate analysis for progression-free survival demonstrated that dose-dense TC represented an independent prognostic factor (HR = 0.70, 95% CI 0.50-0.99; p = 0.04).

Conclusions: Dose-dense TC is a promising regimen of NAC for advanced epithelial ovarian cancer.
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http://dx.doi.org/10.1007/s10147-019-01567-yDOI Listing
March 2020

Leptomeningeal metastases arising from gynecological cancers.

Int J Clin Oncol 2020 Feb 4;25(2):391-395. Epub 2019 Oct 4.

Department of Gynecologic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan.

Background: Most cases of leptomeningeal metastasis (LM) arise from solid tumors, such as breast cancer, lung cancer, or malignant melanoma. LM arising from gynecological cancers are extremely rare. Longer survival owing to recent advances in chemotherapy and other treatments has contributed to the increased frequency of gynecological cancers metastasizing to the central nervous system (CNS). Detailed information regarding LM is scarce; therefore, we conducted a study concerning LM arising from primary gynecological cancers.

Methods: Among 24 patients with CNS metastases from gynecological cancer treated at our hospital between January 2011 and August 2018, those who were eventually diagnosed with LM were included in this retrospective study.

Results: Among 24 patients with CNS metastases, five patients (20.8%) were diagnosed with LM. The primary cancer was endometrial in two, cervical in one, and peritoneal in two patients. Of these five patients, three developed LM as a complication 1-11 months after the treatment of brain metastases; one patient had multiple brain metastases diagnosed at the same time as LM, and one had LM alone, without accompanying brain metastases. The median survival after the diagnosis of LM was 23 (12-69) days, while the median survival of 24 patients after the initial diagnosis of CNS metastases was 106 (13-959) days.

Conclusion: Although LM arising from gynecological cancers is considered rare, identification of LM may be important to predict prognosis and develop new therapeutic strategies.
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http://dx.doi.org/10.1007/s10147-019-01556-1DOI Listing
February 2020

Phase II trial of paclitaxel, carboplatin, and bevacizumab for advanced or recurrent cervical cancer.

Gynecol Oncol 2019 09 5;154(3):554-557. Epub 2019 Jul 5.

Department of Gynecologic Oncology, Hyogo Cancer Center, Hyogo, Japan.

Objective: We evaluated the efficacy and safety of the combination of paclitaxel, carboplatin, and bevacizumab in patients with advanced or recurrent cervical cancer.

Methods: Subjects included patients with advanced or recurrent cervical cancer not amenable to curative treatment with surgery or radiation therapy. Treatment consisted of paclitaxel 175 mg/m, carboplatin area under the curve 6 mg/mL/min, and bevacizumab 15 mg/kg every 21 days until disease progression, complete remission, or limiting toxicity. The primary endpoint was the objective response.

Results: In total, 34 patients received a median of 6 treatment cycles (range 2-25). The median follow-up period was 18.5 months (range 2-29). The objective response was 88% (95% confidence interval: 72.5%-96.7%). Seventeen patients (50%) experienced complete response, whereas 13 patients experienced (38%) partial response with a median duration of 6 months. Grades 3 and 4 hematologic toxicities manifested as neutropenia in 14 (41.2%), leukopenia in 14 (41.2%), anemia in 11 (32.4%), and thrombocytopenia in 9 (26.5%) patients. One patient who underwent prior pelvic irradiation developed grade 2 rectovaginal fistula.

Conclusion: The combination of paclitaxel, carboplatin, and bevacizumab is effective and safe in patients with advanced or recurrent cervical cancer.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.018DOI Listing
September 2019

Correlation between pre-operative and final histological diagnosis on endometrial cancer.

Int J Gynecol Cancer 2019 06 4;29(5):886-889. Epub 2019 Jan 4.

Department of Gynecologic Oncology, Hyogo Cancer Center, Hyogo, Japan.

Objective: We conducted a retrospective study to evaluate the correlation between pre-operative and post-operative histological diagnoses on endometrial cancer, and to describe the treatments and outcomes when post-operative diagnoses are downgraded from pre-operative histology.

Methods: Patients who underwent surgery for endometrial cancer in our facility between 2010 and 2013 were enrolled in the study. The definition of downgrade discordance is in accordance with the following criteria: 1) the pre-operative and post-operative histological diagnoses were both endometrioid and the final pathology was a lower grade than the pre-operative pathology and 2) the pre-operative diagnosis was not endometrioid, whereas the post-operative diagnosis was endometrioid grade 2 or less.

Results: A total of 250 patients were enrolled, and the concordance rates were 56% for endometrioid adenocarcinoma grade 1 (EMG1), 67% for EMG2, 67% for EMG3, 82% for carcinosarcoma, 71% for serous carcinoma, and 67% for clear cell carcinoma. Eighteen cases (6.6%) were identified as downgrade discordancy. Of the 18 patients, the triage for adjuvant therapy remained the same for 15 cases (83%), all of whom had no evidence of disease at their last visit. Three cases had discordances with respect to triage for adjuvant therapy; the therapies were triaged based on post-operative diagnosis. Of these patients one had a recurrence.

Conclusions: Good correlation was observed between pre-operative and final histological diagnoses of endometrioid carcinoma (56%-67%) and type 2 carcinoma (67%-82%). Approximately 7% (18/250) of patients had downgrade discordancy; however, triage for adjuvant therapy did not change for approximately 80% (15/18) of the patients with downgrade discordancy. Further studies are needed to evaluate the effectiveness of triages that are based on post-operative diagnoses.
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http://dx.doi.org/10.1136/ijgc-2018-000041DOI Listing
June 2019

The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity.

J Biol Chem 2018 07 11;293(30):11850-11866. Epub 2018 Jun 11.

From the Department of Neurological Surgery,

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt-expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt-expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt-induced DNA hypermethylation at the regulatory region and reactivate expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt-induced neuronal death and may in part operate through epigenetic mechanisms.
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http://dx.doi.org/10.1074/jbc.RA117.001211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066321PMC
July 2018

Mesenteric vein thrombosis following impregnation fertilization-embryo transfer.

World J Gastrointest Surg 2017 Oct;9(10):209-213

Department of Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo 660-0892, Japan.

Pregnancy is an acquired hypercoagulable state. Most patients with thrombosis that develops during pregnancy present with deep vein leg thrombosis and/or pulmonary embolism, whereas the development of mesenteric vein thrombosis (MVT) in pregnant patients is rare. We report a case of MVT in a 34-year-old woman who had achieved pregnancy fertilization-embryo transfer (IVF-ET). At 7 wk of gestation, the patient was referred to us due to abdominal pain accompanied by vomiting and hematochezia, and she was diagnosed with superior MVT. Following resection of the gangrenous portion of the small intestine, anticoagulation therapy with unfractionated heparin and thrombolysis therapy via a catheter placed in the superior mesenteric artery were performed, and the patient underwent an artificial abortion. Oral estrogen had been administered for hormone replacement as part of the IVF-ET procedure, and additional precipitating factors related to thrombosis were not found. Pregnancy itself, in addition to the administered estrogen, may have caused MVT in this case. We believe that MVT should be included in the differential diagnosis of a pregnant patient who presents with an acute abdomen.
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http://dx.doi.org/10.4240/wjgs.v9.i10.209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661126PMC
October 2017

Pelvic fractures after definitive and postoperative radiotherapy for cervical cancer: A retrospective analysis of risk factors.

Gynecol Oncol 2017 12 18;147(3):585-588. Epub 2017 Oct 18.

Department of Gynecologic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-city, Hyogo 673-8558, Japan.

Objectives: This study clarified the incidence of and identified the risk factors for post-radiation pelvic insufficiency fractures (PIFs) in women who received postoperative definitive or adjuvant radiotherapy (RT) for cervical cancer.

Patients And Methods: The medical records and data of imaging studies, including computed tomography scan and magnetic resonance imaging, of women with cervical cancer who received external-beam RT for the entire pelvic area between January 2003 and December 2012 at our institution were reviewed.

Results: A total of 533 patients with histologically diagnosed cervical cancer who received RT (298: definitive RT, 235: adjuvant RT) were included in this study. Eighty-four patients (15.8%) developed PIF in the irradiated field. Median age at onset of PIF was 72.5years (range: 54-95years), and 82 of them (98%) were postmenopausal women. Sixty-nine patients (80%) developed PIF within 3years from the completion of RT. The median time for the development of PIF was 14months (range: 1-81months). The most commonly involved fracture site was the sacral bone. Postmenopausal state, coexistence of rheumatoid arthritis, and high-dose-rate intracavitary brachytherapy (HDR-ICBT) use were significant predisposing factors for the development of PIF, according to multivariate analysis.

Conclusions: The incidence rate of PIF among patients who received RT for locally advanced cervical cancer was 15.8%. The principal predisposing factors for post-radiation PIF were postmenopausal state, rheumatoid arthritis, and HDR-ICBT use. Active interventions, including bone density screening followed by medication, should be considered during the early stage of RT for women with high-risk factors of PIF.
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http://dx.doi.org/10.1016/j.ygyno.2017.09.035DOI Listing
December 2017

Steroid Pulse Therapy for De Novo Minimal Change Disease During Pregnancy.

Am J Case Rep 2017 Apr 18;18:418-421. Epub 2017 Apr 18.

Department of Obstetrics and Gynecology, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan.

BACKGROUND Nephrotic syndrome occurs very rarely, in only about 0.01%-0.02% of all pregnancies, and de novo minimal change disease during pregnancy is especially rare. Nephrotic syndrome and, especially, minimal change disease are highly responsive to steroids, and preterm labor may be avoidable if the maternal condition is improved with steroid therapy. Therefore, prompt diagnosis and proper management are critical to maternal and fetal outcome when severe proteinuria occurs during pregnancy. CASE REPORT A 30-year-old pregnant Japanese woman presented with systemic edema, oliguria, and severe proteinuria and hypoalbuminemia at 25 weeks of gestation, although she was normotensive. The patient had high urinary protein selectivity. Her illness was diagnosed as de novo nephrotic syndrome with high steroid responsiveness rather than pre-eclampsia. She began steroid pulse therapy the day after admission. Complete remission was confirmed after 3 weeks. The patient did not relapse during pregnancy and delivered a healthy male baby at 37 weeks of gestation. A renal biopsy at a relapse after delivery confirmed minimal change disease. CONCLUSIONS In pregnant women with de novo minimal change disease, serious maternal and/or fetal complications may occur if severe proteinuria and hypoalbuminemia are unabated for an extended time. Evaluation of urinary protein selectivity is noninvasive and useful for prediction of steroid responsiveness. Results of urinary protein selectivity can be obtained earlier than results of renal biopsy. Renal biopsy during pregnancy is not always necessary for initiation of steroid therapy. Rapid initiation of steroid pulse therapy may enable quicker achievement of remission and prevent serious perinatal complications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404478PMC
http://dx.doi.org/10.12659/ajcr.902910DOI Listing
April 2017

Sulfated glycosaminoglycans and non-classically secreted proteins, basic FGF and epimorphin, coordinately regulate TGF-β-induced cell behaviors of human scar dermal fibroblasts.

J Dermatol Sci 2017 May 3;86(2):132-141. Epub 2017 Feb 3.

Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan. Electronic address:

Background: Upon skin injuries, dermal fibroblasts actively produce transforming growth factor-β (TGF-β), which leads to the formation of α-smooth muscle actin (αSMA)-positive granulation tissues. The hyperplasia or incomplete regression of these tissues subsequently causes scar formation in the skin, where sulfated glycosaminoglycans (GAGs), side chains of unique proteoglycans, are supposed to play important roles.

Objective: The aim of this study is to clarify the effects of sulfated GAGs on dermal cell behaviors triggered by the TGF-β signaling, along with its possible regulators basic fibroblast growth factor (bFGF) and cell surface epimorphin. bFGF and epimorphin might regulate the TGF-β-induced αSMA expression, they could exert such effects only in specific cellular contexts, given that they lack conventional signal sequences for extracellular localization.

Methods: Human scar-derived dermal fibroblasts (HSFs) were treated with TGF-β alone, TGF-β plus bFGF, and TGF-β plus cell surface expression of epimorphin. The effects of GAGs on the expression of αSMA and the cellular morphology were then investigated.

Results: A highly sulfated chondroitin sulfate (CS-E) or its substitute (heparinoid) had marked inhibitory effects on TGF-β-mediated changes in HSF behaviors. We found that heparinoid can directly associate with TGF-β, bFGF and epimorphin. We also found that bFGF downregulated αSMA, which was attenuated by heparinoid, whereas epimorphin augmented αSMA expression, which was further amplified by heparinoid.

Conclusions: TGF-β, bFGF and epimorphin in the extracellular microenvironment cooperatively affect HSF behaviors under the control of a highly sulfated chondroitin sulfate. These results provide important evidence towards understanding the regulation of TGF-β-induced HSF behaviors.
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http://dx.doi.org/10.1016/j.jdermsci.2017.01.014DOI Listing
May 2017

An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma.

Proc Natl Acad Sci U S A 2016 12 7;113(51):E8247-E8256. Epub 2016 Dec 7.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110;

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD-dependent network. Accordingly, we demonstrate E2F2 is required for GSC self-renewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.
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http://dx.doi.org/10.1073/pnas.1610921114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187672PMC
December 2016

Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity.

Sci Rep 2016 08 12;6:31022. Epub 2016 Aug 12.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.

Although epigenetic abnormalities have been described in Huntington's disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression. Inhibition of DNMTs in HD model primary cortical or striatal neurons restored the expression of several key genes, including Bdnf, an important neurotrophic factor implicated in HD. Accordingly, the Bdnf promoter exhibited aberrant cytosine methylation in mutant Htt-expressing cortical neurons. In vivo, pharmacological inhibition of DNMTs in HD mouse brains restored the mRNA levels of key striatal genes known to be downregulated in HD. Thus, disturbances in DNA methylation play a critical role in mutant Htt-induced neuronal dysfunction and death, raising the possibility that epigenetic strategies targeting abnormal DNA methylation may have therapeutic utility in HD.
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http://dx.doi.org/10.1038/srep31022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981892PMC
August 2016

The CDC20-APC/SOX2 signaling axis: An achilles' heel for glioblastoma.

Mol Cell Oncol 2016 May 20;3(3):e1075644. Epub 2015 Aug 20.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.

Glioblastoma stem-like cells (GSCs) play a critical role in glioblastoma progression and recurrence. We discuss recent results on the role of the mitotic ubiquitin ligase cell division cycle 20-anaphase-promoting complex (CDC20-APC) in the governance of cardinal GSC functions through a mechanism involving the transcription factor sex-determining region Y-box 2 (SOX2). These findings expand the non-mitotic roles of CDC20-APC with implications for stem cell biology.
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http://dx.doi.org/10.1080/23723556.2015.1075644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909416PMC
May 2016

Correlation between acute conjunctivitis and Asian dust on ocular surfaces.

J Toxicol Environ Health A 2016 4;79(8):367-75. Epub 2016 May 4.

a Department of Ophthalmology , Fukuoka University , Fukuoka , Japan.

The aim of this study was to determine the presence of Asian dust particles (ADP) in patients suffering from conjunctivitis and its correlation with clinical scores for conjunctivitis. Forty-five patients from the Fukuoka area who were newly diagnosed acute conjunctivitis were selected. The degrees of inflammatory reaction, itchy sensation, hyperemia, eye discharge, and foreign body sensation were clinically recorded and scored. Eyes were washed with physiological solution. Solid particles collected from the washing solution were observed using a scanning electron microscope. Of the 45 samples, 44 were positive for the elements silicon (Si) and aluminum (Al), which are components of ambient Asian dust. Higher conjunctivitis scores were found in the subgroup in which the Asian dust/whole particle ratio was greater than average. This is the first apparent report on the correlation between amount of ADP exposure at the ocular surface and severity of ocular symptoms.
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http://dx.doi.org/10.1080/15287394.2016.1162248DOI Listing
May 2017

A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells.

Cell Rep 2015 Jun 11;11(11):1809-21. Epub 2015 Jun 11.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.
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http://dx.doi.org/10.1016/j.celrep.2015.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481182PMC
June 2015

Incidence of spontaneous twin anemia-polycythemia sequence in monochorionic-diamniotic twin pregnancies: Single-center prospective study.

J Obstet Gynaecol Res 2015 Jun 16;41(6):857-60. Epub 2014 Dec 16.

Division of Obstetrics and Perinatology, Maternal and Perinatal Care Center, Seirei Hamamatsu General Hospital, Shizuoka, Japan.

Aim: The purpose of this study was to prospectively estimate the incidence of spontaneous twin anemia-polycythemia sequence (TAPS) in monochorionic-diamniotic twin pregnancies.

Methods: We prospectively examined umbilical cord hemoglobin (Hb) and reticulocyte count of consecutive monochorionic-diamniotic twin pregnancies delivered at Seirei Hamamatsu General Hospital from December 2006 to September 2013. We excluded cases of twin-twin transfusion syndrome, intrauterine fetal demise, and missing data (Hb and reticulocyte count missing from the medical record). TAPS was diagnosed using the postnatal criteria of intertwin Hb difference >8.0 g/dL and reticulocyte count ratio >1.7. Acute feto-fetal hemorrhage was defined as Hb difference >7 g/dL and reticulocyte count ratio <1.7.

Results: A total of 185 monochorionic-diamniotic twin pregnancies were included in this study. Three fulfilled the diagnostic criteria for postnatal TAPS, and one fulfilled the diagnostic criteria for acute feto-fetal hemorrhage.

Conclusion: The incidence of spontaneous TAPS in monochorionic-diamniotic twin pregnancies was 1.6% (3/185) at Seirei Hamamatsu General Hospital.
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http://dx.doi.org/10.1111/jog.12641DOI Listing
June 2015

Inhibition of mitochondrial protein import by mutant huntingtin.

Nat Neurosci 2014 Jun 18;17(6):822-31. Epub 2014 May 18.

1] Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [2] University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Mitochondrial dysfunction is associated with neuronal loss in Huntington's disease (HD), a neurodegenerative disease caused by an abnormal polyglutamine expansion in huntingtin (Htt). However, the mechanisms linking mutant Htt and mitochondrial dysfunction in HD remain unknown. We identify an interaction between mutant Htt and the TIM23 mitochondrial protein import complex. Remarkably, recombinant mutant Htt directly inhibited mitochondrial protein import in vitro. Furthermore, mitochondria from brain synaptosomes of presymptomatic HD model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import is an early event in HD. The mutant Htt-induced mitochondrial import defect and subsequent neuronal death were attenuated by overexpression of TIM23 complex subunits, demonstrating that deficient mitochondrial protein import causes mutant Htt-induced neuronal death. Collectively, these findings provide evidence for a direct link between mutant Htt, mitochondrial dysfunction and neuronal pathology, with implications for mitochondrial protein import-based therapies in HD.
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http://dx.doi.org/10.1038/nn.3721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174557PMC
June 2014

Large simple hepatic cysts leading to gastric fundal varices in a noncirrhotic patient.

Fukuoka Igaku Zasshi 2013 Nov;104(11):449-55

A 74-year-old noncirrhotic woman presented with abdominal distension and pain in the right hypochondrium. Contrast-enhanced computed tomography (CT) demonstrated multiple large simple liver cysts occupying the right lobe of the liver, the largest of which was 19 cm in diameter. Gastric varices were enhanced in the fundus of the stomach. The patient underwent surgery to deroof the hepatic cysts with ablation using argon beam coagulation. Esophagogastroduodenoscopy (EGD) showed that the portal hypertensive gastropathy was ameliorated after the operation; however, the fundal varices were only slightly decreased. After the operation, we observed that the hepatic vein waveform gradually changed from a gently curved pattern to a normal triphasic pattern. We treated the fundal varices with balloon-occluded retrograde transvenous obliteration 3 months after the initial operation. We describe our successful treatment of this rare case and discuss the utility of hepatic vein waveform analysis in the study of portal hypertension.
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November 2013

[Total laparoscopic splenectomy for a patient with multiple surgeries including living donor liver transplantation].

Fukuoka Igaku Zasshi 2013 Mar;104(3):64-7

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University.

The case was a 50 years old female, with history of multiple previous surgeries including living donor liver transplantation for primary biliary cirrhosis, pancreatoduodenectomy for carcinoma in the duodenal papilla Vater, revision of Roux-en-Y anastomosis for intractable cholangitis due to short Roux limb. She was hospitalized this time for decompensated liver cirrhosis due to recurrent cholangitis, with apparent hypersplenism and risky esophageal varices. After a few session of endoscopic treatment for esophageal varices, we applied total laparoscopic splenectomy for hypersplenism in a patient with multiple surgical histories, for seeking better surgical field for safety. The surgery was completed as planned preoperatively under good surgical field.
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March 2013

Phosphagen kinase in Schistosoma japonicum: characterization of its enzymatic properties and determination of its gene structure.

Mol Biochem Parasitol 2013 Apr 16;188(2):91-8. Epub 2013 Apr 16.

Department of Environmental Health Sciences, Kochi Medical School, Oko, Nankoku City, Kochi 783-8505, Japan.

Phosphagen kinases (PKs) play a major role in the regulation of energy metabolism in animals. Creatine kinase (CK) is the sole PK in vertebrates, whereas several PKs are present in invertebrates. Here, we report the enzymatic properties and gene structure of PK in the trematode Schistosoma japonicum (Sj). SjPK has a unique contiguous dimeric structure comprising domain 1 (D1) and domain 2 (D2). The three states of the recombinant SjPK (D1, D2, and D1D2) show a specific activity for the substrate taurocyamine. The comparison of the two domains of SjPK revealed that D1 had a high turnover rate (kcat=52.91) and D2 exhibited a high affinity for taurocyamine (Km(Tauro) =0.53±0.06). The full-length protein exhibited higher affinity for taurocyamine (Km(Tauro) =0.47±0.03) than the truncated domains (D1=1.30±0.10, D2=0.53±0.06). D1D2 also exhibited higher catalytic efficiency (kcat/Km(Tauro) =82.98) than D1 (40.70) and D2 (29.04). These results demonstrated that both domains of SjTKD1D2 interacted efficiently and remained functional. The three-dimensional structure of SjPKD1 was constructed by the homology modeling based on the transition state analog complex state of Limulus AK. This protein model of SjPKD1 suggests that the overall structure is almost conserve between SjPKD1 and Limulus AK except for the flexible loops, that is, particularly guanidino-specificity (GS) region, which is associated with the recognition of the corresponding guanidino substrate. The constructed NJ tree and the comparison of exon/intron organization suggest that SjTK has evolved from an arginine kinase (AK) gene. SjTK has potential as a novel antihelminthic drug target as it is absent in mammals and its strong activity may imply a significant role for this protein in the energy metabolism of the parasite.
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http://dx.doi.org/10.1016/j.molbiopara.2013.04.001DOI Listing
April 2013

[A case of successful multi-venous reconstruction using recipient's jugular vein in right lobe-living donor liver transplantation].

Fukuoka Igaku Zasshi 2012 Sep;103(9):186-90

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

In right lobe-living donor liver transplantation (RT-LDLT), hepatic venous reconstruction of the graft is essential to prevent posttansplant graft congestion and have a good outcome. The patient was a 56-year-old man who had decompensated liver cirrhosis secondary hepatitis C with massive ascites, jaundice and hepatic encephalopathy. He underwent LDLT using his son's right lobe graft. Preoperative simulation by 3D-CT volumetry revealed that the right lobe graft needed multi-venous reconstruction for right inferior hepatic vein (RIHV) and middle hepatic venous tributaries. Preoperative CT scan revealed that the recipient had portal venous thrombus and stenosis, which meant that the recipient's explanted portal vein (EPV) was not suitable for the venous reconstruction of the right lobe graft. Therefore, the recipient's internal and external jugular veins (IJV and EJV) were procured for venous reconstruction. The multiple veins of the right lobe graft were reconstructed to have single co-orifice at the backtable, and the co-orifice was anastomosed to inferior vena cava in short time. The recipient discharged on postoperative day 22 with good venous patency. In RT-LDLT unavailable for recipient's EPV, recipient's IJV and EJV grafts are very useful for multi-venous reconstruction.
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September 2012

The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity.

J Neurosci 2011 Oct;31(41):14496-507

Neuroapoptosis Laboratory and Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Melatonin mediates neuroprotection in several experimental models of neurodegeneration. It is not yet known, however, whether melatonin provides neuroprotection in genetic models of Huntington's disease (HD). We report that melatonin delays disease onset and mortality in a transgenic mouse model of HD. Moreover, mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MT1). We observe high levels of MT1 receptor in mitochondria from the brains of wild-type mice but much less in brains from HD mice. Moreover, we demonstrate that melatonin inhibits mutant htt-induced caspase activation and preserves MT1 receptor expression. This observation is critical, because melatonin-mediated protection is dependent on the presence and activation of the MT1 receptor. In summary, we delineate a pathologic process whereby mutant htt-induced loss of the mitochondrial MT1 receptor enhances neuronal vulnerability and potentially accelerates the neurodegenerative process.
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http://dx.doi.org/10.1523/JNEUROSCI.3059-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213696PMC
October 2011

[A case of capecitabine-resistant recurrent breast cancer found to be responsive to S-1].

Gan To Kagaku Ryoho 2010 Dec;37(13):2909-11

Dept. of Surgery, Matsuyama Red Cross Hospital.

Thirteen months following surgery, local recurrence and multiple lung metastases occurred. Hormone therapy was continued following the recurrence but was found to be ineffective, so the patient was referred to our hospital 9 months after the recurrence. Capecitabine-based chemotherapy was administered but found to be ineffective; 3 months later, the anti-cancer drug was changed to S-1. After 3 months of S-1 administration, a CT scan showed a marked reduction in sites of recurrence and metastasis, making it possible to control progression of the disease over a longer period. No critical adverse reactions were observed, suggesting that S-1 can be useful and safe for the treatment of capecitabine-resistant recurrent breast cancer.
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December 2010

Relation between cooling sheet effect and tear histamine concenration in allergic conjunctivitis.

Yakugaku Zasshi 2010 Jul;130(7):971-5

Kobayashi Pharmaceutical Co., Ltd, Chome, Ebara, Shinagawa-ku, Tokyo, Japan.

Six allergic conjunctivitis patients (12 eyes) and 4 healthy volunteers (8 eyes) were investigated in terms of the effect of cooling sheets on eye itching and tear histamine concentration, before and 5 min after cooling the eyelids with cooling sheets. The severity of itching was evaluated with a five-level itching score. The combination treatment of levocabastine with cooling sheets significantly reduced eye itching, while no significant change in tear histamine concentration was observed before and after cooling sheet use. The cooling sheets are useful for reducing eye itching in the therapy of allergic conjunctivitis. The tear histamine concentration did not correlate with the antiitching effect of cooling sheets in this study.
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http://dx.doi.org/10.1248/yakushi.130.971DOI Listing
July 2010

The ARMS/Kidins220 scaffold protein modulates synaptic transmission.

Mol Cell Neurosci 2010 Oct 12;45(2):92-100. Epub 2010 Jun 12.

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.

Activity-dependent changes of synaptic connections are facilitated by a variety of scaffold proteins, including PSD-95, Shank, SAP97 and GRIP, which serve to organize ion channels, receptors and enzymatic activities and to coordinate the actin cytoskeleton. The abundance of these scaffold proteins raises questions about the functional specificity of action of each protein. Here we report that basal synaptic transmission is regulated in an unexpected manner by the ankyrin repeat-rich membrane-spanning (ARMS/Kidins220) scaffold protein. In particular, decreases in the levels of ARMS/Kidins220 in vivo led to an increase in basal synaptic transmission in the hippocampus, without affecting paired pulse facilitation. One explanation to account for the effects of ARMS/Kidins220 is an interaction with the AMPA receptor subunit, GluA1, which could be observed after immunoprecipitation. Importantly, shRNA and cell surface biotinylation experiments indicate that ARMS/Kidins220 levels have an impact on GluA1 phosphorylation and localization. Moreover, ARMS/Kidins220 is a negative regulator of AMPAR function, which was confirmed by inward rectification assays. These results provide evidence that modulation of ARMS/Kidins220 levels can regulate basal synaptic strength in a specific manner in hippocampal neurons.
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http://dx.doi.org/10.1016/j.mcn.2010.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923264PMC
October 2010

Superovulatory response, oocyte spontaneous activation, and embryo development in WMN/Nrs inbred rats.

Exp Anim 2010 ;59(1):35-45

Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.

WMN/Nrs inbred rats have been widely used in radiation biology for years. However, their reproductive profile has never been examined. We examined various reproductive characteristics of WMN/Nrs inbred rats such as superovulatory response, oocytes spontaneous activation (OSA), and embryo development in vitro and in vivo. Superovulation was induced in 3- to 9-week-old females by injection of 150 IU/kg PMSG and 150 IU/Kg hCG by 48 h apart. Only 8- and 9-week-old animals superovulated averaging 31.4 and 43.9 oocytes, respectively, and superovulation did not depend on estrous cycle. Animals 3-7 weeks of age did not superovulate. Because Wistar strains have been known to show a high incidence of OSA, factors expected to affect OSA in WMN/Nrs, including the time interval of various steps from euthanasia to oocyte recovery, incubation media, estrous cycle, and anesthetic treatments, were examined. The time from animal euthanasia to oviduct excision was the only factor shown to affect OSA. We also compared in vitro and in vivo embryo developmental competence between embryos obtained by natural ovulation and superovulation. Although percent in vitro development of 2-cell embryos to blastocysts was similar for embryos obtained by natural ovulation (63.7%) and superovulation (69.7%), fetus development after oviductal transfer of 2-cell embryos was significantly lower in embryos obtained by superovulation than in those obtained by natural ovulation (60.2% vs. 87.5%, P=0.02). Our results provide important normative data regarding future applications of rat assisted reproductive technologies (ARTs) such as in vitro fertilization and cryopreservation in WMN/Nrs strain and may be applicable to other strains of laboratory rats.
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http://dx.doi.org/10.1538/expanim.59.35DOI Listing
June 2010