Publications by authors named "Hironori Abe"

32 Publications

Intracholecystic papillary neoplasm of the gallbladder diagnosed during follow-up of Menetrier's disease: A case report.

Mol Clin Oncol 2021 Nov 17;15(5):233. Epub 2021 Sep 17.

Department of Surgery, Hokkaido Social Work Association Obihiro Hospital, Obihiro, Hokkaido 080-0805, Japan.

Intracholecystic papillary neoplasm of the gallbladder (ICPN) is a type of intraductal papillary neoplasm of the bile duct that occurs in the gallbladder, and is a relatively newer concept. Therefore, there are few reports regarding ICPN. Menetrier's disease is a rare disease characterized by giant hypertrophy of the gastric folds that causes protein-losing gastroenteropathy (PLG). Although Menetrier's disease is a known risk factor for gastric adenocarcinoma, the association between Menetrier's disease and malignancy other than a malignancy of the stomach is unclear. A 69-year-old man presented to the Hokkaido Social Work Association Obihiro Hospital with gallbladder tumours diagnosed by ultrasonography at a previous institution. In addition, he had previously been diagnosed with PLG due to Menetrier's disease. Abdominal contrast-enhanced computed tomography (CT) revealed an irregular mass with a contrast effect at the fundus of the gallbladder on the free abdominal cavity side. Positron emission tomography-CT showed a tumour with a standard uptake value (SUV) of 8.28 at the fundus of the gallbladder. Cholecystectomy and resection of the gallbladder bed were performed. Based on the microscopy findings, the patient was diagnosed with ICPN. Although he had postoperative ileus, he was discharged 14 days postoperatively due to improvement through conservative treatment. Such cases of ICPN complicated with Menetrier's disease are extremely rare. However, patients with Menetrier's disease may need to be screened for malignancies.
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http://dx.doi.org/10.3892/mco.2021.2396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506642PMC
November 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

RNF8 is not required for histone-to-protamine exchange in spermiogenesis†.

Biol Reprod 2021 11;105(5):1154-1159

Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

While an E3 ubiquitin ligase, RNF8, was initially reported to be required for histone-to-protamine exchange in spermiogenesis, we subsequently demonstrated that RNF8 is not involved in this process. Nevertheless, reflecting a lingering misunderstanding in the field, a growing number of studies have continued to postulate a requirement for RNF8 in the histone-to-protamine exchange. For example, a recent study claimed that a mouse PIWI protein, MIWI, controls RNF8-mediated histone-to-protamine exchange. Here, confirming our earlier conclusions, we show that RNF8 is required neither for the establishment of histone H4K16 acetylation, which is an initial step in histone removal during spermiogenesis, nor for the incorporation of two protamine proteins, PRM1 and PRM2. Thus, whereas RNF8 mediates ubiquitination of H2A on the sex chromosomes in meiosis, during the prior stage of spermatogenesis, our genetic evidence underscores that RNF8 is not involved in histone-to-protamine exchange.
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http://dx.doi.org/10.1093/biolre/ioab132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599036PMC
November 2021

A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome with Recurrent Olfactory Neuroblastoma.

Intern Med 2021 Jan 12;60(1):105-109. Epub 2020 Sep 12.

Department of Diabetes, Metabolism, Endocrinology, Rheumatology and Collagen Diseases, Tokyo Medical University, Japan.

A 40-year-old woman who had a history of recurrent olfactory neuroblastoma presented with full moon face, central obesity, buffalo hump, impaired glucose tolerance and bilateral cervical lymph node swelling. Laboratory tests showed morbidly elevated levels of adrenocorticotropic hormone (ACTH) and cortisol, which were not suppressed by high-dose (8 mg) dexamethasone. Biopsies of the enlarged cervical lymph nodes revealed ACTH-positive metastatic olfactory neuroblastoma, and ectopic ACTH syndrome was diagnosed. Metyrapone was used to suppress cortisol production and resulted in decreased levels of ACTH and cortisol. Bilateral cervical tumor resection further reduced the ACTH and cortisol levels, accompanied by a reduction in the metyrapone dosage. Cushing's syndrome was alleviated through ACTH-producing tumor removal.
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http://dx.doi.org/10.2169/internalmedicine.2897-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835471PMC
January 2021

Pioneering meiotic recombination.

Genes Dev 2020 03;34(5-6):395-397

Division of Reproductive Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229, USA.

To induce cell type-specific forms of gene regulation, pioneer factors open tightly packed, inaccessible chromatin sites, enabling the molecular machinery to act on functionally significant information encoded in DNA. While previous studies of pioneer factors have revealed their functions in transcriptional regulation, pioneer factors that open chromatin for other physiological events remain undetermined. In this issue of , Spruce and colleagues (pp. 398-412) report the functional significance of a "pioneer complex" in mouse meiotic recombination. This complex, comprised of the zinc finger DNA-binding protein PRDM9 and the SNF2 family chromatin remodeler HELLS, exposes nucleosomal DNA to designate the sites of DNA double-strand breaks that initiate meiotic recombination. Both HELLS and PRDM9 are required for the determination of these recombination hot spots. Through the identification of a pioneer complex for meiotic recombination, this study broadens the conceptual scope of pioneer factors, indicating their functional significance in biological processes beyond transcriptional regulation.
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http://dx.doi.org/10.1101/gad.336438.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050479PMC
March 2020

The Initiation of Meiotic Sex Chromosome Inactivation Sequesters DNA Damage Signaling from Autosomes in Mouse Spermatogenesis.

Curr Biol 2020 02 2;30(3):408-420.e5. Epub 2020 Jan 2.

Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address:

Meiotic sex chromosome inactivation (MSCI) is an essential event in the mammalian male germline. MSCI is directed by a DNA damage response (DDR) pathway centered on the phosphorylation of histone variant H2AX at serine 139 (termed γH2AX). The failure to initiate MSCI is linked to complete meiotic arrest and elimination of germ cells; however, the mechanisms underlying this arrest and elimination remain unknown. To address this question, we established a new separation-of-function mouse model for H2ax that shows specific and complete defects in MSCI. The genetic change is a point mutation in which another H2AX amino acid residue important in the DDR, tyrosine 142 (Y142), is converted to alanine (H2ax-Y142A). In H2ax-Y142A meiosis, the establishment of DDR signals on the chromosome-wide domain of the sex chromosomes is impaired. The initiation of MSCI is required for stage progression, which enables crossover formation, suggesting that the establishment of MSCI permits the timely progression of male meiosis. Our results suggest that normal meiotic progression requires the removal of ATR-mediated DDR signaling from autosomes. We propose a novel biological function for MSCI: the initiation of MSCI sequesters DDR factors from autosomes to the sex chromosomes at the onset of the pachytene stage, and the subsequent formation of an isolated XY nuclear compartment-the XY body-sequesters DDR factors to permit meiotic progression from the mid-pachytene stage onward. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cub.2019.11.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076562PMC
February 2020

[Locally Advanced Gastric Cancer Responding to Neoadjuvant Chemotherapy with Ramucirumab plus Paclitaxel-Case Report].

Gan To Kagaku Ryoho 2019 Oct;46(10):1565-1567

Dept. of Surgery, Hokkaido Social Work Association Obihiro Hospital.

Neoadjuvant chemotherapy(NAC)is a promising approach for the improvement of gastric cancer treatment outcome. S-1 plus cisplatin(SP)or S-1 plus oxaliplatin (SOX)is generallythe first choice of NAC regimen. We experienced that NAC with ramucirumab(RAM)plus paclitaxel(PTX)was effective in locallyadvanced gastric cancer, but that with SOX was ineffective. A 68-year-old man developed locallyadvanced gastric cancer and received NAC with SOX, which was stopped because of tumor enlargement. The patient was then given NAC with RAM plus PTX, which was effective and enabled radical excision. Anti-angiogenic agents maycause wound healing complications, which mayincrease the risk of leakage. However, he was discharged without postoperative complications. Therefore, RAM plus PTX can be a promising NAC regimen for locallyadvanced gastric cancer.
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October 2019

Assessing hypoglycemia frequency using flash glucose monitoring in older Japanese patients with type 2 diabetes receiving oral hypoglycemic agents.

Geriatr Gerontol Int 2019 Oct 4;19(10):1030-1035. Epub 2019 Sep 4.

Department of Diabetes, Metabolism, Endocrinology, Rheumatology and Collagen Diseases, Tokyo Medical University, Tokyo, Japan.

Aim: It is important to consider hypoglycemia for glycemic control in elderly patients with type 2 diabetes. Continuous blood glucose monitoring system is an effective method to investigate blood glucose fluctuation. This study examined hypoglycemia frequency using continuous blood glucose monitoring system in older patients with type 2 diabetes.

Methods: A total of 70 patients with type 2 diabetes aged >65 years, receiving oral treatment only and having a glycated hemoglobin (HbA1c) level of <8% were enrolled. Flash glucose monitoring system was used for the device. Patients were classified into three groups according to the type of medicine administered, in addition to other oral hypoglycemics, and were compared: (i) those taking sulfonylureas (SU); (ii) those taking glinides; and (iii) those who did not take either SU or glinides.

Results: There was a significant positive correlation between the coefficient of variation and hypoglycemic frequency in all the patients, and a significant negative correlation between HbA1c and hypoglycemia in those receiving SU. When hypoglycemia was defined as glucose levels <54 mg/dL and <70 mg/dL, the cut-off HbA1c values for developing hypoglycemia were 6.3% and 6.7%, sensitivity was 75.0% and 76.2%, and specificity was 90.9% and 77.6%, respectively.

Conclusions: In older patients with type 2 diabetes receiving SU, hypoglycemic frequency increases with decreases in HbA1c level. In particular, in patients with HbA1c levels of <6.3% receiving SU, it is necessary to consider medication modification. Geriatr Gerontol Int 2019; 19: 1030-1035.
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http://dx.doi.org/10.1111/ggi.13765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852429PMC
October 2019

Rare case of idiopathic sclerosing cholangitis, which was difficult to distinguish from cholangiocarcinoma: A case report.

Exp Ther Med 2018 Dec 5;16(6):5224-5226. Epub 2018 Oct 5.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.

It is often difficult to correctly diagnose patients who present with dilation of the bile duct. Cholangiocarcinoma, primary sclerosing cholangitis (PSC) and immunoglobulin (Ig)G4-related sclerosing cholangitis must be considered as potential diagnoses for these cases. The current study presents a 73-year-old female patient who presented with a high fever and abdominal pain. Contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography revealed stenosis and dilation of the intrahepatic bile duct without solid components. It was suspected that the patient had intrahepatic cholangiocarcinoma. A left liver lobectomy, cholecystectomy and distal gastrectomy combined with a D2 lymph node dissection were performed. A pathological examination of the liver revealed increased fibrosis in the stroma, irregular bile duct dilation and clusters of inflamed lymph cells. No carcinoma or IgG4-positive plasma cells were observed and the typical findings of PSC were not detected. Based on these clinical and pathological results, the diagnosis was idiopathic sclerosing cholangitis, which is particularly rare. It is often difficult to preoperatively differentiate between cholangiocarcinoma and benign bile duct stenosis.
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http://dx.doi.org/10.3892/etm.2018.6832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256851PMC
December 2018

Chromosome Spread Analyses of Meiotic Sex Chromosome Inactivation.

Methods Mol Biol 2018 ;1861:113-129

Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

A distinct form of X chromosome inactivation takes place during male meiosis, when the male sex chromosomes undergo a phenomenon known as meiotic sex chromosome inactivation (MSCI). MSCI is directed by DNA damage response signaling independent of Xist RNA to silence the transcriptional activity of the sex chromosomes, an essential event in male germ cell development. Here, we present protocols for the preparation and analyses of chromosome spread slides of mouse meiotic spermatocytes, thereby enabling a quick, inexpensive, and powerful cytological method to complement gene expression studies.
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http://dx.doi.org/10.1007/978-1-4939-8766-5_10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243718PMC
June 2019

RNF8 and SCML2 cooperate to regulate ubiquitination and H3K27 acetylation for escape gene activation on the sex chromosomes.

PLoS Genet 2018 02 20;14(2):e1007233. Epub 2018 Feb 20.

Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.

The sex chromosomes are enriched with germline genes that are activated during the late stages of spermatogenesis. Due to meiotic sex chromosome inactivation (MSCI), these sex chromosome-linked genes must escape silencing for activation in spermatids, thereby ensuring their functions for male reproduction. RNF8, a DNA damage response protein, and SCML2, a germline-specific Polycomb protein, are two major, known regulators of this process. Here, we show that RNF8 and SCML2 cooperate to regulate ubiquitination during meiosis, an early step to establish active histone modifications for subsequent gene activation. Double mutants of Rnf8 and Scml2 revealed that RNF8-dependent monoubiquitination of histone H2A at Lysine 119 (H2AK119ub) is deubiquitinated by SCML2, demonstrating interplay between RNF8 and SCML2 in ubiquitin regulation. Additionally, we identify distinct functions of RNF8 and SCML2 in the regulation of ubiquitination: SCML2 deubiquitinates RNF8-independent H2AK119ub but does not deubiquitinate RNF8-dependent polyubiquitination. RNF8-dependent polyubiquitination is required for the establishment of H3K27 acetylation, a marker of active enhancers, while persistent H2AK119ub inhibits establishment of H3K27 acetylation. Following the deposition of H3K27 acetylation, H3K4 dimethylation is established as an active mark on poised promoters. Together, we propose a model whereby regulation of ubiquitin leads to the organization of poised enhancers and promoters during meiosis, which induce subsequent gene activation from the otherwise silent sex chromosomes in postmeiotic spermatids.
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http://dx.doi.org/10.1371/journal.pgen.1007233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834201PMC
February 2018

L-Carnitine supplementation reduces the general fatigue of cancer patients during chemotherapy.

Mol Clin Oncol 2018 Mar 16;8(3):413-416. Epub 2018 Jan 16.

Department of Surgery, Hokkaido Social Work Association Obihiro Hospital, Obihiro, Hokkaido 080-0805, Japan.

L-Carnitine (LC) plays an important role in the metabolism of fatty acids, and LC deficiency is associated with a feeling of weakness or general fatigue. Cancer patients receiving chemotherapy often develop LC deficiency, which is considered to be a factor contributing to general fatigue. The aim of the present study was to evaluate the efficacy of LC supplementation as a treatment for general fatigue in cancer patients during chemotherapy. A total of 11 cancer patients who were suffering from general fatigue during chemotherapy in our hospital between September 2014 and December 2015 were examined (6 cases involved adjuvant chemotherapy and 5 cases involved chemotherapy for unresectable or recurrent disease). The patients were administered 1,500 mg/day of levocarnitine , and the change in mean daily fatigue from the baseline to 8 weeks was assessed using the Brief Fatigue Inventory. The change in the plasma levels of albumin and the lymphocyte counts from the baseline to 8 weeks were also assessed. LC supplementation reduced general fatigue in all cases. Moreover, LC supplementation maintained the plasma levels of albumin and lymphocyte counts during chemotherapy, and enabled patients to continue chemotherapy sequentially without dose reduction. Therefore, LC supplementation improved general fatigue in all the examined cancer patients during chemotherapy. This treatment may make improve the tolerability of chemotherapy in cancer patients by reducing general fatigue and improving the nutritional status.
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http://dx.doi.org/10.3892/mco.2018.1557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795559PMC
March 2018

CHEK1 coordinates DNA damage signaling and meiotic progression in the male germline of mice.

Hum Mol Genet 2018 04;27(7):1136-1149

Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

The continuity of life depends on mechanisms in the germline that ensure the integrity of the genome. The DNA damage response/checkpoint kinases ATM and ATR are essential signaling factors in the germline. However, it remains unknown how a downstream transducer, Checkpoint Kinase 1 (CHEK1 or CHK1), mediates signaling in the male germline. Here, we show that CHEK1 has distinct functions in both the mitotic and meiotic phases of the male germline in mice. In the mitotic phase, CHEK1 is required for the resumption of prospermatogonia proliferation after birth and the maintenance of spermatogonia. In the meiotic phase, we uncovered two functions for CHEK1: one is the stage-specific attenuation of DNA damage signaling on autosomes, and the other is coordination of meiotic stage progression. On autosomes, the loss of CHEK1 delays the removal of DNA damage signaling that manifests as phosphorylation of histone variant H2AX at serine 139 (γH2AX). Importantly, CHEK1 does not have a direct function in meiotic sex chromosome inactivation (MSCI), an essential event in male meiosis, in which ATR is a key regulator. Thus, the functions of ATR and CHEK1 are uncoupled in MSCI, in contrast to their roles in DNA damage signaling in somatic cells. Our study reveals stage-specific functions for CHEK1 that ensure the integrity of the male germline.
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http://dx.doi.org/10.1093/hmg/ddy022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185175PMC
April 2018

[A Case of Biopsy Confirmed Unresectable Retroperitoneal Seminoma Successfully Treated with Chemotherapy].

Gan To Kagaku Ryoho 2017 Nov;44(11):1037-1040

Dept. of General Surgery, Hokkaido Social Work Association Obihiro Hospital.

We herein report a case of a retroperitoneal tumor of unknown origin that was diagnosed as a seminoma after tumor biopsy and was successfully treated with chemotherapy containing bleomycin, etoposide, and cisplatin(BEP). A 47-year old man visited our hospital with left abdominal pain. An endoscopic examination revealed an ulcer lesion on the third part of the duodenum. Abdominal CT scan revealed a retroperitoneal tumor invading the abdominal aorta with the tumor thrombus in the inferior vena cava(IVC). An endoscopic biopsy could not identify the tumor's origin because of the negative staining of various surface markers on immunohistochemistry. Surgical biopsy of the unresectable retroperitoneal tumor that was finally diagnosed as a seminoma was performed. The patient was treated with BEP according to the International Germ Cell Consensus Classification(IGCCC)for risks, and orchiectomy was performed. He has been alive for 7 months with progressive shrinkage of the retroperitoneal tumor, in which 18F-fluorodeoxyglucose(FDG)positron emission tomography(PET)has shown a dramatic reduction of the maximum standardized uptake value(SUV)during chemotherapy.
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November 2017

Long-term survival and prognosis associated with conversion surgery in patients with metastatic gastric cancer.

Mol Clin Oncol 2017 Feb 10;6(2):163-166. Epub 2017 Jan 10.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.

In gastric cancer, primary systemic chemotherapy is the standard approach for the management of patients with initially unresectable metastasis, and it occasionally leads to a reduction in the size of the lesion, which facilitates surgical resection. The aim of this study was to examine the prognosis of patients who were able to undergo complete resection following chemotherapy. A total of 10 patients who underwent radical surgery for stage IV primary gastric cancer after chemotherapy between 2009 and 2015 at the Department of Surgery of Hokkaido Social Work Association Obihiro Hospital (Obihiro, Japan) were retrospectively investigated. Three regimens were used (S-1, n=1; S-1 + cisplatin, n=8; and S-1 + docetaxel, n=1). The mean time from chemotherapy to surgery was 210 days. One total gastrectomy + splenectomy + colectomy, one total gastrectomy + splenectomy, four total gastrectomies and three distal gastrectomies were performed. There were two cases of pancreatic fistula formation postoperatively. All the patients survived for >1 year. Of the 10 patients, 5 survived without recurrence. The median survival time was 871.1 days after diagnosis. Therefore, curative resection after chemotherapy is associated with a better prognosis in stage IV gastric cancer patients.
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http://dx.doi.org/10.3892/mco.2017.1128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351747PMC
February 2017

Sonazoid Can Help Visualize the Intraductal Spread of Breast Cancer.

Am Surg 2016 Dec;82(12):e352-354

Department of Surgery, Hokkaido Social Work Association Obihiro Hospital, Hokkaido, Japan.

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December 2016

Accurate evaluation of axillary sentinel lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid in breast cancer: a preliminary clinical trial.

Springerplus 2015 17;4:509. Epub 2015 Sep 17.

Department of Surgery, Hokkaido Social Work Association Obihiro Hospital, 2 East 5 South 9, Obihiro, Hokkaido 080-0805 Japan.

Breast cancer is the most common type of cancer in women. The 5-year survival rate in patients with breast cancer ranges from 74 to 82 %. Sentinel lymph node biopsy has become an alternative to axillary lymph node dissection for nodal staging. We evaluated the detection of the sentinel lymph node and metastasis of the lymph node using contrast enhanced ultrasonography with Sonazoid. Between December 2013 and May 2014, 32 patients with operable breast cancer were enrolled in this study. We evaluated the detection of axillary sentinel lymph nodes and the evaluation of axillary lymph nodes metastasis using contrast enhanced computed tomography, color Doppler ultrasonography and contrast enhanced ultrasonography with Sonazoid. All the sentinel lymph nodes were identified, and the sentinel lymph nodes detected by contrast enhanced ultrasonography with Sonazoid corresponded with those detected by computed tomography lymphography and indigo carmine method. The detection of metastasis based on contrast enhanced computed tomography were sensitivity 20.0 %, specificity 88.2 %, PPV 60.0 %, NPV 55.6 %, accuracy 56.3 %. Based on color Doppler ultrasonography, the results were sensitivity 36.4 %, specificity 95.2 %, PPV 80.0 %, NPV 74.1 %, accuracy 75.0 %. Based on contrast enhanced ultrasonography with Sonazoid, the results were sensitivity 81.8 %, specificity 95.2 %, PPV 90.0 %, NPV 90.9 %, accuracy 90.6 %. The results suggested that contrast enhanced ultrasonography with Sonazoid was the most accurate among the evaluations of these modalities. In the future, we believe that our method would take the place of conventional sentinel lymph node biopsy for an axillary staging method.
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http://dx.doi.org/10.1186/s40064-015-1291-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573976PMC
September 2015

Expression of matrix metalloproteinases in bovine luteal cells induced by prostaglandin F2α, interferon γ and tumor necrosis factor α.

J Reprod Dev 2015 30;61(4):277-86. Epub 2015 Apr 30.

Laboratory of Reproductive Physiology, Graduate School of Environmental and Life Science, Okayama University, Okayama 700-8530, Japan.

We recently demonstrated that luteal cells flow out from the ovary via lymphatic vessels during luteolysis. However, the regulatory mechanisms of the outflow of luteal cells are not known. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basal membrane, and tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs. To test the hypothesis that MMP expression in luteal cells is regulated by luteolytic factors, we investigated the effects of prostaglandin F2α (PGF), interferon γ (IFNG) and tumor necrosis factor α (TNF) on the mRNA expression of MMPs and TIMPs in cultured luteal cells. Luteal cells obtained from the CL at the mid-luteal stage (days 8-12 after ovulation) were cultured with PGF (0.01, 0.1, 1 μM), IFNG (0.05, 0.5, 5 nM) and TNF (0.05, 0.5, 0.5 nM) alone or in combination for 24 h. PGF and IFNG significantly increased the expression of MMP-1 mRNA. In addition, 1 μM PGF in combination with 5 nM IFNG stimulated MMP-1 and MMP-9 mRNA expression significantly more than either treatment alone. In contrast, IFNG significantly decreased the level of MMP-14 mRNA. The mRNA expression of TIMP-1, which preferentially inhibits MMP-1, was suppressed by 5 nM INFG. One μM PGF and 5 nM IFNG suppressed TIMP-2 mRNA expression. These results suggest a new role of MMPs: luteal MMPs stimulated by PGF and IFNG break down the extracellular matrix surrounding luteal cells, which accelerates detachment from the CL during luteolysis, providing an essential prerequisite for outflow of luteal cells from the CL to lymphatic vessels.
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http://dx.doi.org/10.1262/jrd.2014-150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547985PMC
June 2016

Accurate diagnosis of axillary lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid.

Mol Clin Oncol 2015 Mar 31;3(2):299-302. Epub 2014 Dec 31.

Departments of Surgery, Obihiro Hospital, Obihiro, Hokkaido 080-0805.

Axillary lymph node enlargement following sentinel lymph node biopsy (SLNB) is often difficult to accurately diagnose. In keeping with the characteristically tortuous and aberrant pattern of tumor neovasculature, metastatic lymph nodes exhibit peripheral and mixed vascularity, resulting in a microvasculature that is often difficult to visualize. Contrast-enhanced ultrasonography (CEUS) with Sonazoid, a new generation contrast agent for ultrasonography, allows for the visualization of lymph node microvessels and may enable a more accurate evaluation of lymph node metastasis. This is a case report of axillary lymph node enlargement following SLNB, in which CEUS with Sonazoid resulted in an accurate diagnosis. On the basis of our experience with this case, we have initiated a clinical trial to evaluate the detection of lymph node metastasis through the use of CEUS in breast cancer patients.
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http://dx.doi.org/10.3892/mco.2014.483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360813PMC
March 2015

Lymphatic involvement in the disappearance of steroidogenic cells from the corpus luteum during luteolysis.

PLoS One 2014 20;9(2):e88953. Epub 2014 Feb 20.

Laboratory of Reproductive Physiology, Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.

In mammals, the corpus luteum (CL) is an essential endocrine gland for the establishment and maintenance of pregnancy. If pregnancy is not established, the CL regresses and disappears rapidly from the ovary. A possible explanation for the rapid disappearance of the CL is that luteal cells are transported from the ovary via lymphatic vessels. Here, we report the presence of cells positive for 3β-hydroxysteroid dehydrogenase (3β-HSD), an enzyme involved in progesterone synthesis, in the lumen of lymphatic vessels at the regressing luteal stage and in the lymphatic fluid collected from the ovarian pedicle ipsilateral to the regressing CL. The 3β-HSD positive cells were alive and contained lipid droplets. The 3β-HSD positive cells in the lymphatic fluid were most abundant at days 22-24 after ovulation. These findings show that live steroidogenic cells are in the lymphatic vessels drained from the CL. The outflow of steroidogenic cells starts at the regressing luteal stage and continues after next ovulation. The overall findings suggest that the complete disappearance of the CL during luteolysis is involved in the outflow of luteal cells from the CL via ovarian lymphatic vessels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088953PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930584PMC
January 2015

Proliferation of luteal steroidogenic cells in cattle.

PLoS One 2013 27;8(12):e84186. Epub 2013 Dec 27.

Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan ; Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.

The rapid growth of the corpus luteum (CL) after ovulation is believed to be mainly due to an increase in the size of luteal cells (hypertrophy) rather than an increase in their number. However, the relationship between luteal growth and the proliferation of luteal steroidogenic cells (LSCs) is not fully understood. One goal of the present study was to determine whether LSCs proliferate during CL growth. A second goal was to determine whether luteinizing hormone (LH), which is known have roles in the proliferation and differentiation of follicular cells, also affects the proliferation of LSCs. Ki-67 (a cell proliferation marker) was expressed during the early, developing and mid luteal stages and some Ki-67-positive cells co-expressed HSD3B (a steroidogenic marker). DNA content in LSCs isolated from the developing CL increased much more rapidly (indicating rapid growth) than did DNA content in LSCs isolated from the mid CL. The cell cycle-progressive genes CCND2 (cyclin D2) and CCNE1 (cyclin E1) mRNA were expressed more strongly in the small luteal cells than in the large luteal cells. LH decreased the rate of increase of DNA in LSCs isolated from the mid luteal stage but not in LSCs from the developing stage. LH suppressed CCND2 expression in LSCs from the mid luteal stage but not from the developing luteal stage. Furthermore, LH receptor (LHCGR) mRNA expression was higher at the mid luteal stage than at the developing luteal stage. The overall results suggest that the growth of the bovine CL is due to not only hypertrophy of LSCs but also an increase in their number, and that the proliferative ability of luteal steroidogenic cells decreases between the developing and mid luteal stages.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873966PMC
August 2014

Roles of prostaglandin F2alpha and hydrogen peroxide in the regulation of Copper/Zinc superoxide dismutase in bovine corpus luteum and luteal endothelial cells.

Reprod Biol Endocrinol 2012 Oct 26;10:87. Epub 2012 Oct 26.

Laboratory of Reproductive Physiology, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan.

Background: Prostaglandin F2alpha (PGF) induces luteolysis in cow by inducing a rapid reduction in progesterone production (functional luteolysis) followed by tissue degeneration (structural luteolysis). However the mechanisms of action of PGF remain unclear. Reactive oxygen species (ROS) play important roles in regulating the luteolytic action of PGF. The local concentration of ROS is controlled by superoxide dismutase (SOD), the main enzyme involved in the control of intraluteal ROS. Thus SOD seems to be involved in luteolysis process induced by PGF in cow.

Methods: To determine the dynamic relationship between PGF and ROS in bovine corpus luteum (CL) during luteolysis, we determined the time-dependent change of Copper/Zinc SOD (SOD1) in CL tissues after PGF treatment in vivo. We also investigated whether PGF and hydrogen peroxide (H2O2) modulates SOD1 expression and SOD activity in cultured bovine luteal endothelial cells (LECs) in vitro.

Results: Following administration of a luteolytic dose of PGF analogue (0 h) to cows at the mid-luteal stage, the expression of SOD1 mRNA and protein, and total SOD activity in CL tissues increased between 0.5 and 2 h, but fell below the initial (0 h) level at 24 h post-treatment. In cultured LECs, the expression of SOD1 mRNA was stimulated by PGF (1-10 microM) and H2O2 (10-100 microM) at 2 h (P<0.05). PGF and H2O2 increased SOD1 protein expression and total SOD activity at 2 h (P<0.05), whereas PGF and H2O2 inhibited SOD1 protein expressions and total SOD activity at 24 h (P<0.05). In addition, H2O2 stimulated PGF biosynthesis at 2 and 24 h in bovine LECs. Overall results indicate that, SOD is regulated by PGF and ROS in bovine LECs. SOD may play a role in controlling intraluteal PGF and ROS action during functional and structural luteolysis in cows.
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http://dx.doi.org/10.1186/1477-7827-10-87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545964PMC
October 2012

Sonodynamic therapy of cancer using novel sonosensitizers.

Anticancer Res 2007 Nov-Dec;27(6A):3673-7

Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Sonodynamic therapy (SDT) of cancer is based on preferential uptake and/or retention of a sonosensitizing drug (sonosensitizer) in tumor tissues and subsequent activation of the drug by ultrasound irradiation. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer. This is a unique advantage in the non-invasive treatment of nonsuperficial tumors when compared to laser light used for photodynamic therapy. Recently, it has been found that photochemically active porphyrins also show significant antitumor effects when activated with ultrasound. The mechanism of sonodynamic action has been suggested to involve photoexcitation of the sensitizer by sonoluminescent light, with subsequent formation of singlet oxygen. This mini-review provides a brief overview of the following four sonosensitizers useful in SDT: i) a homogeneous complex of oligomers of hematoporphyrin, Photofrin II; ii) a gallium porphyrin complex, ATX-70; iii) a hydrophilic chlorin derivative, A7X-S10, and iv) a novel porphyrin derivative devoid of photosensitivity, DCPH-P-Na (I).
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December 2007

Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen.

Int J Cancer 2004 Feb;108(4):564-70

Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka, Japan.

We generated fully human mAbs (HmAbs) to carcinoembryonic antigen (CEA) using the KM mouse, which carries a human chromosome 14 fragment containing the entire Ig H chain loci and human kappa L chain segments in the mouse genome. Forty-six hybridoma clones producing HmAbs to CEA were thus obtained by fusing the P3-U1 mouse myeloma cells with splenocytes of the KM mice immunized with CEA. Among them, 22 clones produced HmAbs that reacted with CEA but not with 3 other CEA-related cell adhesion molecule (CEACAM) family members, CEACAM1, CEACAM6 and CEACAM8. In 12 HmAbs examined, 8 were IgG4, 2 were IgG3, 1 was IgG2, and the other was IgG1. The affinity constants for CEA of these HmAbs were comparable to those of the previously prepared mouse anti-CEA mAbs (MmAbs). BIAcore analyses revealed that 1 and 2 of the 22 HmAbs react with 2 epitopes defined by MmAbs on the domain N and the domain A1 or B1 of CEA, respectively. In the presence of human complement in vitro, 2 HmAbs tested showed substantial cytotoxicity, namely, 50-65%, against CEA-expressing tumor cells. With human lymphokine-activated killer cells in vitro, 3 HmAbs tested exhibited 40-65% Ab-dependent cell-mediated cytotoxicity against the tumor cells. Moreover, one of the HmAbs induced a significant inhibition of tumor growth when administered to mice xenografted with the CEA-expressing cells. Considering their lack of immunogenicity to humans, these CEA-specific HmAbs may be useful for immunotherapeutic approaches as well as for immunodiagnosis.
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http://dx.doi.org/10.1002/ijc.11608DOI Listing
February 2004

Significance of tumor-associated antigens in the diagnosis and therapy of cancer: an overview.

Anticancer Res 2002 Nov-Dec;22(6C):4255-64

Department of Biochemistry, Fukuoka University School of Medicine, 7-45-1 Jonan-ku, Fukuoka, 814-0180, Japan.

An enormous effort using a wide variety of approaches has been undertaken over the last three decades to transform both basic and clinical research into improved diagnoses and therapies of cancer. This brief overview summarizes the significance of tumor-associated antigens (TAAs) in the diagnosis and therapy of cancer. Current data suggest that immunotherapy and gene therapy using antibody-recognized TAAs as their targets are promising, whereas those using T cell-recognized peptide epitopes of TAAs as their targets remain controversial regarding their efficacy, mainly due to general losses of HLA molecules in tumor cells.
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March 2003

Preparation of recombinant MK-1/Ep-CAM and establishment of an ELISA system for determining soluble MK-1/Ep-CAM levels in sera of cancer patients.

J Immunol Methods 2002 Dec;270(2):227-33

Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan.

The MK-1 antigen, also termed as Ep-CAM, is a membrane glycoprotein that is overexpressed on the majority of tumor cells of epithelial origin and thereby can be used as a target of immunodetection and immunotherapy of cancer. It has previously been shown that several type-I transmembrane proteins, including E-cadherin, ErbB-2 and intercellular adhesion molecule-1 (ICAM-1), may be useful as tumor markers because they are released into the circulation of many cancer patients. To address the question of whether MK-1, the same type-I membrane protein, is also released into the sera, we developed a sandwich-type enzyme-linked immunosorbent assay (ELISA) system by preparing a recombinant MK-1 protein and two anti-MK-1 monoclonal antibodies with different epitope specificities. Using this ELISA, we found that the MK-1 levels in serum samples from healthy volunteers were all less than 2 ng/ml, whereas the Mk-1 levels in sera of about 10% of patients with malignant tumors of various tissue origins were increased to 2-78 ng/ml, indicating that MK-1 is released from tumor cells into the circulation under certain conditions. These findings should be borne in mind when trying to perform passive antibody therapy for cancer using anti-MK-1 antibody.
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http://dx.doi.org/10.1016/s0022-1759(02)00332-0DOI Listing
December 2002

Opposite effects of thrombospondin-1 via CD36 and CD47 on homotypic aggregation of monocytic cells.

Matrix Biol 2002 Aug;21(5):441-8

Department of Biochemistry, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

Thrombospondin-1 (TSP-1), an extracellular matrix protein, has a multimodular structure and each domain specifies a distinct biological function through interaction with a specific ligand. In this study we found that exogenously added TSP-1 inhibits phorbol myristate acetate (PMA)/LPS-induced homotypic aggregation of human monocytic U937 cells, whereas the 70-kDa fragment of TSP-1 generated by the proteolytic cleavage of the intact molecule promotes the homotypic aggregation. The aggregation was also inhibited by anti-CD47 mAb or the 4N1K peptide, of which sequence is derived from the CD47-binding site of TSP-1 and absent in the 70-kDa fragment. In contrast, the augmented cell aggregation by the 70-kDa fragment was hampered by anti-CD36 mAb or antibody against the CD36-binding site of TSP-1. The cell aggregation of U937 cells was completely blocked, even in the presence of the 70-kDa fragment, by mAb against leukocyte function associated antigen-1 (LFA-1) or intercellular adhesion molecule-1 (ICAM-1). We therefore propose that TSP-1 may regulate LFA-1/ICAM-1-mediated cell adhesion of monocytes/macrophages by either the inhibitory effect through CD47 or the promoting effect through CD36 depending on which domain/fragment is functional in a given biological setting.
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http://dx.doi.org/10.1016/s0945-053x(02)00036-7DOI Listing
August 2002

Targeting of interleukin-2 to human MK-1-expressing carcinoma by fusion with a single-chain Fv of anti-MK-1 antibody.

Anticancer Res 2002 Jul-Aug;22(4):2001-7

First Department of Biochemistry, Fukuoka University School of Medicine, Japan.

Background: Targeting of cytokines into the tumor sites using antibody-cytokine fission proteins represents a novel approach in cancer immunotherapy. We previously reported a novel monoclonal antibody, FU-MK-1, which recognizes a glycoprotein antigen (termed MK-1 antigen) that is overexpressed on the surface of a majority of carcinomas.

Materials And Methods: To target IL-2 and cytotoxicity of effector cells to MK-1-expressing tumor cells, we genetically fused recombinant human interleukin-2 (rhIL-2) to a single chain variable fragment (scFv) antibody derived from FU-MK-1. The resulting fission protein, designated FUscFv/IL-2 was expressed in Pichia pastoris, purified by Ni-affinity chromatography, and characterized for the MK-1-binding specificity and the IL-2 biological activity.

Results: The FUscFv/IL-2 fusion protein effectively introduced a specific cytotoxicity of lymphokine-activated killer cells to the tumor cells and consequently suppressed the tumor growth in a SCID mouse xenograft model.

Conclusion: This approach may be used for in vivo administration to localize IL-2 to tumor tissues, enhancing the immune response to human MK-1-expressing tumors while reducing systemic side-effects.
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September 2002

Targeted sonodynamic therapy of cancer using a photosensitizer conjugated with antibody against carcinoembryonic antigen.

Anticancer Res 2002 May-Jun;22(3):1575-80

Department of Biochemistry, Fukuoka University School of Medicine, Japan.

The goal of this study was to develop a strategy for the selective destruction of cancer cells by ultrasonic irradiation in the presence of an antibody-conjugated photosensitizer. To this end, a photoimmunoconjugate (PIC) was prepared between ATX-70, a photosensitizer of a gallium-porphyrin analogue, and F11-39, a high affinity monoclonal antibody (MAb) against carcinoembryonic antigen (CEA), which is often overexpressed in various carcinoma cells. This conjugate, designated F39/ATX-70, retained immunoreactivity against purified CEA and CEA-expressing cells as determined by enzyme-linked immunosorbent assay, flow cytometry and immunofluorescence microscopic analysis. The cytotoxicity of F39/ATX-70 against CEA-expressing human gastric carcinoma cells in vitro was found to be greater than that of ATX-70 when applied in combination with ultrasound irradiation. When in vivo anti-tumor effects in a mouse xenograft model were assessed, intravenous administration of F39/ATX-70 followed by ultrasonic irradiation produced a marked growth inhibition of tumor compared with irradiation alone or irradiation after administration of ATX-70. These results suggest that the PIC between anti-CEA MAb and ATX-70 may have applications in sonodynamic therapy where destruction of CEA-expressing tumor is required.
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September 2002

T-cell immunotherapy for human MK-1-expressing tumors using a fusion protein of the superantigen SEA and anti-MK-1 scFv antibody.

Anticancer Res 2002 Mar-Apr;22(2A):769-76

Department of Biochemistry, Fukuoka University School of Medicine, Japan.

Background: The bacterial superantigen staphylococcal enterotoxin A (SEA) is an extremely potent activator of T lymphocytes when presented on major histocompatibility complex (MHC) class II molecules. To develop a tumor-specific superantigen for cancer therapy, we constructed a recombinant fusion protein of SEA and the single-chain variable fragment (scFv) of the FU-MK-1 antibody, which recognizes a glycoprotein antigen (termed MK-1 antigen) present on most carcinomas.

Materials And Methods: We employed recombinant DNA techniques to fuse recombinant mutant SEA to an scFv antibody derived from FU-MK-1 and the resulting fusion protein (SEA/FUscFv) was produced by a bacterial expression system, purified with a metal-affinity column, and characterized for its MK-1-binding specificity and its antitumor activity.

Results: The SEA/FUscFv fusion protein retained the reactivity with MK-1-expressing tumor cells, introduced a specific cytotoxicity of lymphokine-activated killer T-cells to the tumor cells, and consequently suppressed the tumor growth in a SCID mouse xenograft model.

Conclusion: This genetically engineered SEA/FUscFv fusion protein may serve as a potentially useful immunotherapeutic reagent for human MK-1-expressing tumors.
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June 2002
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