Publications by authors named "Takashi Miwa"

116 Publications

A case of diabetic ketoacidosis in a patient with COVID-19 and newly diagnosed type 1 diabetes.

Clin Case Rep 2021 Sep 24;9(9):e04881. Epub 2021 Sep 24.

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

To improve severe ketoacidosis with COVID-19, insulin treatment, invasive mechanical ventilation therapy, and continuous hemodiafiltration with sodium bicarbonate infusion were effective.
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http://dx.doi.org/10.1002/ccr3.4881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462362PMC
September 2021

Parallel Wiring Using a Single Intravascular Ultrasound Catheter with Double Rapid Exchange Lumens Technique for Chronic Total Occlusions in Peripheral Artery Disease.

J Endovasc Ther 2021 Aug 6:15266028211036483. Epub 2021 Aug 6.

Cardiovascular Center, Tokeidai Memorial Hospital, Sapporo, Japan.

Purpose: To describe a parallel wiring using a single intravascular ultrasound catheter with double rapid exchange lumens (PASSABLE) technique for peripheral CTOs.

Technique: The technique is demonstrated in a 73-year-old patient with CTOs of the superficial femoral and popliteal artery. Intravascular ultrasound (IVUS) examination revealed the first guidewire was advanced to the intramedial space of the popliteal artery. Following insertion of the first guidewire into only the distal rapid exchange lumen of the IVUS catheter and a second guidewire into the proximal rapid exchange lumen, a guidewire torquer was passed over it and tightened close to an exit port of the proximal rapid exchange lumen to prevent it from exiting an entry port while advancing the IVUS catheter. The IVUS catheter was advanced to the intraplaque region using only the distal rapid exchange lumen and the second guidewire was then advanced to the intraplaque region under IVUS guidance. The IVUS-guided wiring using the second guidewire on both the distal and proximal rapid exchange lumen was continued and resulted in a successful guidewire crossing into the distal true lumen.

Conclusion: This novel technique may prove beneficial in enabling operators to perform IVUS-guided parallel wiring more easily and efficiently.
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http://dx.doi.org/10.1177/15266028211036483DOI Listing
August 2021

Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells.

Oncogene 2021 Sep 30;40(36):5495-5504. Epub 2021 Jul 30.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Here, we evaluated the therapeutic potential of antibodies (Abs) targeting cholinergic receptor nicotinic beta 2 subunit (CHRNB2) in gastric cancer. To investigate the effects of these Abs on malignant phenotypes in vitro and in mouse xenograft models, we generated gene knockouts through genome editing, performed RNA interference-mediated knockdown of gene expression, and ectopically expressed CHRNB2 in gastric cancer cells. The effects of anti-CHRNB2 Abs on the proliferation of cancer cells were evaluated both in vitro and in vivo. We determined the effects of Chrnb2 deficiency on mice and the clinical significance of CHRNB2 expression in gastric cancer clinical specimens. Knockdown of CHRNB2 attenuated gastric cancer cell proliferation, whereas forced overexpression of CHRNB2 increased cell proliferation. Knockout of CHRNB2 significantly influenced cell survival and functions associated with metastasis. The effects of polyclonal Abs targeting the C- and N-termini of CHRNB2 guided the development of anti-CHRNB2 monoclonal Abs that inhibited the growth of gastric cancer cells in vitro and in vivo. Pathway analysis revealed that CHRNB2 interfered with signaling through the PI3K-AKT and JAK-STAT pathways. Chrnb2-deficient mice exhibited normal reproduction, organ functions, and motor functions. CHRNB2 regulates multiple oncological phenotypes associated with metastasis, and blockade of CHRNB2 expression using specific Abs shows promise for controlling metastasis in gastric cancer.
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http://dx.doi.org/10.1038/s41388-021-01945-9DOI Listing
September 2021

Falsely diagnosed thyrotoxicosis caused by anti-streptavidin antibodies and pre-wash procedures.

Thyroid Res 2021 Jul 10;14(1):17. Epub 2021 Jul 10.

Department of Diabetes, Metabolism and Endocrinology, Tokyo Medical University, 6-7-1 Nishishinjuku Shinjuku-ku, Tokyo, 160-0023, Japan.

Background: Anti-streptavidin antibodies are causal determinants of analytical interference during Thyroid function tests, and numerous reports have detailed such interference, with anti-streptavidin antibodies attracting attention.

Case Presentation: We conducted a straightforward investigation of interference due to anti-streptavidin antibodies, with a case of a 60-year-old Japanese man who consulted our department for inconsistencies between his clinical course and Thyroid function tests. Experiments were conducted using Cobas8000 e602, which employs assay procedures with pre-wash to evaluate FT4 and FT3 levels.

Conclusions: To our knowledge, this is the first published report to clearly investigate such interferences using a combination of polyethylene glycol precipitation, heterophilic blocking tube precipitation, streptavidin-coated magnetic particle precipitation, and different instruments with or without pre-wash. Clinicians should consider that interferences caused by anti-streptavidin antibodies could lead to a misdiagnosis of thyrotoxicosis. Moreover, discussions between laboratory specialists, clinicians, and manufacturers are required to identify interferences and avoid unnecessary examinations and inappropriate treatment.
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http://dx.doi.org/10.1186/s13044-021-00108-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272342PMC
July 2021

Non-Destructive and Quantitative Evaluation of Rebar Corrosion by a Vibro-Doppler Radar Method.

Authors:
Takashi Miwa

Sensors (Basel) 2021 Apr 5;21(7). Epub 2021 Apr 5.

Division of Electronics and Informatics, Faculty of Science and Technology, Gunma University, Tenjin-cho 1-5-1, Kiryu, Gunma 376-8515, Japan.

It is well known that evaluation of rebar corrosion is important for the maintenance of reinforced concrete structures, but, it is difficult to simply, quickly and quantitatively evaluate the amount of corrosion of rebars embedded in concrete by conventional non-destructive evaluation (NDE) methods such as electrical, electromagnetic and mechanical method. This paper proposes a vibro-Doppler radar (VDR) measurement method to quantitatively evaluate rebar corrosion by measuring the vibration ability of the rebar forcibly vibrated in concrete by an excitation coil. It is experimentally demonstrated in RC test pieces that the rebar vibration displacement obtained by developed VDR method is valid and is less affected by the moisture in the concrete. In addition, simultaneous monitoring of the rebar vibration displacement of the test pieces is performed through an electrolytic corrosion test and the measured vibration displacement is compared to the rebar corrosion loss evaluated. As the results, it is cleared that the rebar vibration displacement starts to increase from slightly before the occurrences of corrosion crack on the concrete surface as the corrosion loss increases. It is also shown that the rebar vibration displacement becomes 4 times higher than that in initial condition at the rebar corrosion loss of 250 mg/cm. This implies that the VDR has potential to nondestructively and quantitatively evaluate rebar corrosion in concrete.
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http://dx.doi.org/10.3390/s21072546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038566PMC
April 2021

G-protein subunit gamma-4 expression has potential for detection, prediction and therapeutic targeting in liver metastasis of gastric cancer.

Br J Cancer 2021 Jul 14;125(2):220-228. Epub 2021 Apr 14.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: The liver is the most common site for haematogenous metastasis of gastric cancer, and liver metastasis is fatal.

Methods: We conducted a transcriptomic analysis between metastatic foci in the liver, primary tumour and adjacent tissues from gastric cancer patients with metastasis limited to the liver. We determined mRNA expression levels in tumour tissues of 300 patients with gastric cancer via quantitative RT-PCR. The oncogenic phenotypes of GNG4 were determined with knockdown, knockout and forced expression experiments. We established and compared subcutaneous and liver metastatic mouse xenograft models of gastric cancer to reveal the roles of GNG4 in tumorigenesis in the liver.

Results: GNG4 was upregulated substantially in primary gastric cancer tissues as well as liver metastatic lesions. High levels of GNG4 in primary cancer tissues were associated with short overall survival and the likelihood of liver recurrence. Functional assays revealed that GNG4 promoted cancer cell proliferation, the cell cycle and adhesiveness. Tumour formation by GNG4-knockout cells was moderately reduced in the subcutaneous mouse model and strikingly attenuated in the liver metastasis mouse model.

Conclusions: GNG4 expression may provide better disease monitoring for liver metastasis, and GNG4 may be a novel candidate therapeutic target for liver metastasis.
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http://dx.doi.org/10.1038/s41416-021-01366-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292368PMC
July 2021

Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53-Bcl-2 intrinsic apoptosis pathway.

Br J Cancer 2021 04 3;124(8):1449-1460. Epub 2021 Feb 3.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies.

Methods: We performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients.

Results: Ethanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis.

Conclusions: Upregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53-Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.
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http://dx.doi.org/10.1038/s41416-021-01271-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039033PMC
April 2021

A Local Oscillator Phase Compensation Technique for Ultra-Wideband Stepped-Frequency Continuous Wave Radar Based on a Low-Cost Software-Defined Radio.

Sensors (Basel) 2021 Jan 24;21(3). Epub 2021 Jan 24.

Faculty of Science and Technology, Gunma University, Tenjin-cho 1-5-1, Kiryu, Gunma 376-8515, Japan.

The paper discusses a way to configure a stepped-frequency continuous wave (SFCW) radar using a low-cost software-defined radio (SDR). The most of high-end SDRs offer multiple transmitter (TX) and receiver (RX) channels, one of which can be used as the reference channel for compensating the initial phases of TX and RX local oscillator (LO) signals. It is same as how commercial vector network analyzers (VNAs) compensate for the LO initial phase. These SDRs can thus acquire phase-coherent in-phase and quadrature (I/Q) data without additional components and an SFCW radar can be easily configured. On the other hand, low-cost SDRs typically have only one transmitter and receiver. Therefore, the LO initial phase has to be compensated and the phases of the received I/Q signals have to be retrieved, preferably without employing an additional receiver and components to retain the system low-cost and simple. The present paper illustrates that the difference between the phases of TX and RX LO signals varies when the LO frequency is changed because of the timing of the commencement of the mixing. The paper then proposes a technique to compensate for the LO initial phases using the internal RF loopback of the transceiver chip and to reconstruct a pulse, which requires two streaming: one for the device under test (DUT) channel and the other for the internal RF loopback channel. The effect of the LO initial phase and the proposed method for the compensation are demonstrated by experiments at a single frequency and sweeping frequency, respectively. The results show that the proposed method can compensate for the LO initial phases and ultra-wideband (UWB) pulses can be reconstructed correctly from the data sampled by a low-cost SDR.
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http://dx.doi.org/10.3390/s21030780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865734PMC
January 2021

Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting to Treat Peritoneal Metastasis of Gastric Cancer.

Mol Ther Nucleic Acids 2020 Dec 6;22:791-802. Epub 2020 Oct 6.

Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII () and to identify the function of in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to -knockdown efficacy, activity, and off-target effects. We evaluated the effects of knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.
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http://dx.doi.org/10.1016/j.omtn.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644579PMC
December 2020

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

A Novel Homozygous Mutation of Thyroid Peroxidase Gene Abolishes a Disulfide Bond Leading to Congenital Hypothyroidism.

Int J Endocrinol 2020 30;2020:9132372. Epub 2020 Aug 30.

Tokyo Medical University, Department of Diabetes, Metabolism and Endocrinology, Tokyo 160-0023, Japan.

Congenital hypothyroidism (CH) is the most prevalent congenital endocrine disorder and causes mental retardation. A male Japanese patient with first cousin marriage parents was diagnosed as CH at 10 months. He was born before introduction of mass screening for CH. With continuous thyroid hormone replacement therapy, normal thyroid hormone status was maintained until adulthood. Genetic screening of next-generation sequencing was performed at the age of 52 years, and we identified a new homozygous thyroid peroxidase (TPO) gene mutation (GRCh38.p13, chromosome 2 at position 1493997, c.1964 G>T, p.Cys655Phe). TPO is an important enzyme to produce thyroid hormone. As demonstrated by a homology analysis of TPO proteins among different species, cysteine 655 residue is highly conserved, suggesting an important role in maintaining TPO function and structure. An study with three-dimensional structure of the novel mutation was performed and suggested that the mutation abolished disulfide bond between cysteines at positions 598 and 655. An functional analysis using HEK293 cells revealed that TPO activity of the mutant was significantly impaired compared with that of the wild type. Furthermore, study of immunohistochemistry showed that localization of TPO in cells did not differ between the wild type and the mutant. In conclusion, this single disulfide bond loss mutation of a new TPO homozygous mutation, p.Cys655Phe, reduced TPO activity and caused congenital hypothyroidism without affecting subcellular localization of TPO proteins.
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http://dx.doi.org/10.1155/2020/9132372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477596PMC
August 2020

Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer.

Mol Cancer 2020 08 26;19(1):131. Epub 2020 Aug 26.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs).

Methods: Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr mice, and assessed the clinical significance of NPTXR expression in GC specimens.

Results: NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr mice showed no abnormalities in reproduction, development, metabolism, or motor function.

Conclusions: NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.
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http://dx.doi.org/10.1186/s12943-020-01251-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448342PMC
August 2020

Sarcoid neuropathy with conduction block showing nerve fascicle compression by perineurial granuloma formation.

Clin Neurol Neurosurg 2020 09 28;196:105962. Epub 2020 May 28.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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http://dx.doi.org/10.1016/j.clineuro.2020.105962DOI Listing
September 2020

[A case of systemic AL amyloidosis diagnosed on muscle biopsy].

Rinsho Shinkeigaku 2020 Jan 17;60(1):60-63. Epub 2019 Dec 17.

Department of Neurology, Toyonaka Municipal Hospital.

A 69-year-old man was admitted to our hospital with a 1-year history of progressive easy fatigability while walking. He presented with proximal muscle weakness dominant in the lower extremities, hoarseness, and mild dysphagia. Muscle pseudo-hypertrophy was observed in the gastrocnemius. A biopsy specimen from the left deltoid muscle revealed amyloid deposition in the blood vessels and ring-like fibers. These findings suggested amyloid myopathy. The serum and urine immunofixation electrophoresis detected κ type Bence-Jones proteins, and bone marrow examination showed an increase in atypical plasma cells; thus, we established a diagnosis of multiple myeloma. Thereafter, he experienced frequent diarrhea, and the gastrointestinal endoscopy revealed extensive amyloid deposition in the upper and lower digestive tract. We started treatment with lenalidomide and dexamethasone; however, his condition worsened, and he died of aspiration pneumonia. Amyloid myopathy indicated systemic AL amyloidosis; therefore, muscle biopsy was necessary in this case.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001339DOI Listing
January 2020

Level of Melanotransferrin in Tissue and Sera Serves as a Prognostic Marker of Gastric Cancer.

Anticancer Res 2019 Nov;39(11):6125-6133

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aim: The aim of the study was to identify novel biomarkers that are vital for improving management of patients with gastric cancer (GC).

Materials And Methods: An RNA-sequencing analysis was conducted using gastric tissue from patients with metastatic GC. In vitro cell functions were evaluated by siRNA-mediated knockdown assays. A total of 230 pairs of gastric tissue were subjected to expression analysis of mRNA and protein in situ. The serum levels of the candidate biomarker were determined by ELISA.

Results: MELTF was identified as a candidate biomarker. Inhibition of MELTF expression suppressed the invasion ability of GC cells. Increased tissue MELTF mRNA expression was associated with shorter survival. Furthermore, staining intensity of tissue MELTF protein was linked to recurrence rates. Serum MELTF levels gradually were increased from healthy controls to advanced GC. Patients with high serum MELTF levels had poor prognosis.

Conclusion: Both tissue and serum MELTF levels may serve as biomarkers of GC progression.
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http://dx.doi.org/10.21873/anticanres.13820DOI Listing
November 2019

Establishment of Peritoneal and Hepatic Metastasis Mouse Xenograft Models Using Gastric Cancer Cell Lines.

In Vivo 2019 Nov-Dec;33(6):1785-1792

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background/aim: Establishment of mouse xenograft models is necessary for oncological research and depends on the characteristics of the cell lines and the immune system of the host. In this study, we describe the development of mouse xenograft models using human gastric cancer (GC) cell lines.

Materials And Methods: MKN1 stably-expressing luciferase (MKN1-Luc), N87, KATO III, MKN45 stably-expressing luciferase (MKN45-Luc), NUGC4, and OCUM-1 human GC cell lines were injected intraperitoneally into mice to establish peritoneal metastasis models. MKN45-Luc were injected into subcutaneously implanted spleen, and MKN1-Luc and MKN45-Luc were injected directly into the portal veins of mice for the establishment of hepatic metastasis models.

Results: Peritoneal metastasis was formed after implantation of MKN1-Luc, N87, KATO III, MKN45-Luc, and NUGC4 in nude mice, but not formed in OCUM-1 even in NOD/SCID mice. After intrasplenic injection of MKN45-Luc, we found no hepatic metastasis formation. We identified hepatic metastasis formation after direct injection of MKN45-Luc and MKN1-Luc into the portal veins of NOD/SCID mice.

Conclusion: Peritoneal and hepatic metastasis mouse xenograft models were successfully established using several human GC cell lines.
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http://dx.doi.org/10.21873/invivo.11669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899157PMC
March 2020

PRAME as a Potential Biomarker for Liver Metastasis of Gastric Cancer.

Ann Surg Oncol 2020 Jun 28;27(6):2071-2080. Epub 2019 Oct 28.

Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Background: Liver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome.

Objective: In this study, we aimed to identify novel genes associated with liver metastasis of GC.

Methods: Global expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis.

Results: Among 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R.

Conclusions: PRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis.
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http://dx.doi.org/10.1245/s10434-019-07985-6DOI Listing
June 2020

Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer.

Int J Cancer 2020 05 23;146(10):2865-2876. Epub 2019 Oct 23.

Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Liver metastasis is often fatal in patients with gastric cancer, therefore, we aimed to identify genes associated with the mechanisms of liver metastasis of gastric cancer (GC) and to investigate their potential to predict recurrence and to serve as targets of therapy. Recurrence pattern-specific transcriptome analysis was performed to identify liver metastasis-associated genes. A stable knockout cell line was generated to investigate metabolic pathways that contribute to the malignant phenotype in vitro and vivo. Three hundred GC patients were analyzed to demonstrate an association between gene expression levels and clinicopathological parameters. As a results extracellular matrix complex subunit 1 (FRAS1) was identified as a liver metastasis-associated gene. Pathway analysis revealed that FRAS1 expression was significantly correlated with the expression of genes encoding TGFB1, MAP1B, AHNAK, BMP2, MUC1, BIRC5, MET, CDH1, RB1 and MKI67. FRAS1 expression was associated with the activation of the EGFR and PI3K signaling pathways. The proliferation ability of FRAS1 knockout cell line (FRAS1-KO) was inhibited compared to that of the parent cell line through caspase activity increment and cell cycle alteration. FRAS1-KO cells exhibited increased responsiveness to oxygen stress and diminished stemness, invasiveness, and migration. Mouse models of GC revealed decreases in tumor formation and generation of metastasis by FRAS1-KO cells. Moreover, the cumulative liver recurrence rate was significantly increased in patients with GC with high FRAS1 expression levels. We concluded that FRAS1 contributes to the malignant phenotype of GC, especially liver metastasis, and may therefore serve as a predictive marker or a target for treating liver metastasis.
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http://dx.doi.org/10.1002/ijc.32705DOI Listing
May 2020

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

Characterization of Anti-Goat Podoplanin Monoclonal Antibody PMab-235 Using Immunohistochemistry Against Goat Tissues.

Monoclon Antib Immunodiagn Immunother 2019 Oct 12;38(5):213-219. Epub 2019 Aug 12.

Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.

Podoplanin (PDPN)/T1alpha is expressed on lymphatic endothelial cells, type I alveolar cells of the lungs, and podocytes of the kidney. PDPN possesses three platelet aggregation-stimulating (PLAG) domains (PLAG1, PLAG2, and PLAG3) of the N-terminus and the PLAG-like domains (PLDs). We previously reported an anti-goat PDPN (gPDPN) monoclonal antibody (mAb), PMab-235, which was developed using the Cell-Based Immunization and Screening (CBIS) method. PMab-235 is very useful in flow cytometry, Western blotting, and immunohistochemical analyses; however, the binding epitope of PMab-235 remains to be elucidated. In this study, we investigated the epitopes of PMab-235 using enzyme-linked immunosorbent assay and immunohistochemistry. The results revealed that the critical epitope of PMab-235 produced by CBIS method is Arg75, Leu78, and Pro79 of gPDPN, which is included in PLD. The findings of our study can be applied to the production of more functional anti-gPDPN mAbs.
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http://dx.doi.org/10.1089/mab.2019.0022DOI Listing
October 2019

Classification of Clinically Diagnosed Alzheimer's Disease Associated with Diabetes Based on Amyloid and Tau PET Results.

J Alzheimers Dis 2019 ;71(1):261-271

Department of Geriatric Medicine, Tokyo Medical University, Tokyo, Japan.

Background/objective: Although type 2 diabetes mellitus (DM) is a risk factor for the development of dementia, the underlying brain pathologies and mechanisms vary among patients. In this study, we classified patients with clinically diagnosed Alzheimer's disease (AD) associated with DM into subgroups based on their amyloid and tau accumulation patterns on positron emission tomography (PET), and analyzed the differences in clinical features and brain imaging findings between the subgroups.

Methods: Sixty-four patients with probable or possible AD associated with DM were classified using PiB (detects amyloid, A) and PBB3 (detects tau, T) PET studies. Patients were classified into the A+/T+ group (n = 35, AD pathology), the A- /T+ group (n = 19, tauopathy), and the A- /T- group (n = 10, non-amyloid/non-tau neuronal damage).

Results: Compared with the A+/T+ group, the A- /T+ group showed less-well controlled glycemia, longer duration of diabetes, more glucose variability, higher frequency of insulin therapy and biochemical hypoglycemia, and greater impairment of frontal lobe function, slower progression of cognitive decline, fewer APOE4 carriers, less severe medial temporal lobe atrophy, and lower frequency of posterior cerebral hypoperfusion. This subgroup showed different clinical and radiological features from AD.

Conclusion: Among patients with clinically diagnosed AD with DM, there are subgroups with neuronal damage independent of AD pathology. A subgroup of dementia patients suspected of having tauopathy is strongly associated with DM-related metabolic abnormalities. This study highlights the identification of a novel dementia subgroup (diabetes-related dementia), which is important for considering appropriate therapies and care in clinical practice.
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http://dx.doi.org/10.3233/JAD-190620DOI Listing
October 2020

Albumin-Bilirubin Score Predicts Tolerability to Adjuvant S-1 Monotherapy after Curative Gastrectomy.

J Gastric Cancer 2019 Jun 22;19(2):183-192. Epub 2019 Apr 22.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: Due to adverse events, dose reduction or withdrawal of adjuvant chemotherapy is required for some patients. To identify the predictive factors for tolerability to postoperative adjuvant S-1 monotherapy in gastric cancer (GC) patients, we evaluated the predictive values of blood indicators.

Materials And Methods: We analyzed 98 patients with pStage II/III GC who underwent postoperative adjuvant S-1 monotherapy. We retrospectively analyzed correlations between 14 parameters obtained from perioperative routine blood tests to assess their influence on the withdrawal of postoperative adjuvant S-1 monotherapy, within 6 months after discontinuation.

Results: Postoperative adjuvant chemotherapy was discontinued in 21 patients (21.4%) within 6 months. Univariable analysis revealed that high preoperative albumin-bilirubin (ALBI) scores had the highest odds ratio (OR) for predicting the failure of adjuvant S-1 chemotherapy (OR, 6.47; 95% confidence interval [CI], 2.08-20.1; cutoff value, -2.696). The high ALBI group had a significantly shorter time to failure of postoperative adjuvant S-1monotherapy (hazard ratio, 3.48; 95% CI, 1.69-7.25; P=0.001). Multivariable analysis identified high preoperative ALBI score as an independent prognostic factor for tolerability (OR, 10.3; 95% CI, 2.33-45.8; P=0.002).

Conclusions: Preoperative ALBI shows promise as an indicator associated with the tolerability of adjuvant S-1 monotherapy in patients with pStage II/III GC.
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http://dx.doi.org/10.5230/jgc.2019.19.e15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589428PMC
June 2019

ASO Author Reflections: Homeobox C10 Influences on the Malignant Phenotype of Gastric Cancer Cell Lines and its Elevated Expression Positively Correlates with Recurrence and Poor Survival.

Ann Surg Oncol 2019 12 25;26(Suppl 3):596-597. Epub 2019 Apr 25.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

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http://dx.doi.org/10.1245/s10434-019-07405-9DOI Listing
December 2019

MRG-1 is required for both chromatin-based transcriptional silencing and genomic integrity of primordial germ cells in Caenorhabditis elegans.

Genes Cells 2019 May 26;24(5):377-389. Epub 2019 Apr 26.

Department of Biology, Graduate School of Science, Kobe University, Kobe, Japan.

In Caenorhabditis elegans, germline cells remain transcriptionally silenced during embryogenesis. The transcriptional silencing is achieved by two different mechanisms: One is the inhibition of RNA polymerase II in P2-P4 cells at the establishment stage, and another is chromatin-based silencing in two primordial germ cells (PGCs) at the maintenance stage; however, the molecular mechanism underlying chromatin-based silencing is less understood. We investigated the role of the chromodomain protein MRG-1, which is an essential maternal factor for germline development, in transcriptional silencing in PGCs. PGCs lacking maternal MRG-1 showed increased levels of two histone modifications (H3K4me2 and H4K16ac), which are epigenetic markers for active transcription, and precocious activation of germline promoters. Loss of MES-4, a H3K36 methyltransferase, also caused similar derepression of the germline genes in PGCs, suggesting that both MRG-1 and MES-4 function in chromatin-based silencing in PGCs. In addition, the mrg-1 null mutant showed abnormal chromosome structures and a decrease in homologous recombinase RAD-51 foci in PGCs, but the mes-4 null mutant did not show such phenotypes. Taken together, we propose that MRG-1 has two distinct functions: chromatin-based transcriptional silencing and preserving genomic integrity at the maintenance stage of PGCs.
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http://dx.doi.org/10.1111/gtc.12683DOI Listing
May 2019

Differential contribution of C5aR and C5b-9 pathways to renal thrombic microangiopathy and macrovascular thrombosis in mice carrying an atypical hemolytic syndrome-related factor H mutation.

Kidney Int 2019 07 27;96(1):67-79. Epub 2019 Feb 27.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulated complement activation. Clinically, aHUS is effectively treated by an anti-C5 monoclonal antibody (mAb) but whether the disease is mediated by the C5a receptor (C5aR) or C5b-9 pathway, or both, is unknown. Here we address this in a factor H mutant mouse (FH) which developed complement-mediated TMA as well as macrovascular thrombosis caused by an aHUS-related factor H point mutation (mouse W1206R, corresponding to human W1183R). C5 deficiency and anti-C5 mAb treatment blocked all disease manifestations in FH mice. C5aR1 gene deficiency prevented macrovascular thrombosis in various organs but did not improve survival or reduce renal TMA. Conversely, C6 or C9 deficiency significantly improved survival and markedly diminished renal TMA but did not prevent macrovascular thrombosis. Interestingly, as they aged both FH C6 and FH C9 mice developed glomerular disease reminiscent of C3 glomerulonephritis. Thus, C5aR and C5b-9 pathways drove different aspects of disease in FH mice with the C5aR pathway being responsible for macrovascular thrombosis and chronic inflammatory injury while the C5b-9 pathway caused renal TMA. Our data provide new understanding of the pathogenesis of complement-mediated TMA and macrovascular thrombosis in FH mice and suggest that C5 blockade is more effective for the treatment of aHUS than selectively targeting the C5aR or C5b-9 pathway alone.
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http://dx.doi.org/10.1016/j.kint.2019.01.009DOI Listing
July 2019

Complement Factor H Mutation W1206R Causes Retinal Thrombosis and Ischemic Retinopathy in Mice.

Am J Pathol 2019 04 1;189(4):826-838. Epub 2019 Feb 1.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Single-nucleotide polymorphisms and rare mutations in factor H (FH; official name, CFH) are associated with age-related macular degeneration and atypical hemolytic uremic syndrome, a form of thrombotic microangiopathy. Mice with the FH W1206R mutation (FH) share features with human atypical hemolytic uremic syndrome. Herein, we report that FH mice exhibited retinal vascular occlusion and ischemia. Retinal fluorescein angiography demonstrated delayed perfusion and vascular leakage in FH mice. Optical coherence tomography imaging of FH mice showed retinal degeneration, edema, and detachment. Histologic analysis of FH mice revealed retinal thinning, vessel occlusion, as well as degeneration of photoreceptors and retinal pigment epithelium. Immunofluorescence showed albumin leakage from blood vessels into the neural retina, and electron microscopy demonstrated vascular endothelial cell irregularity with narrowing of retinal and choroidal vessels. Knockout of C6, a component of the membrane attack complex, prevented the aforementioned retinal phenotype in FH mice, consistent with membrane attack complex-mediated pathogenesis. Pharmacologic blockade of C5 also rescued retinas of FH mice. This FH mouse strain represents a model for retinal vascular occlusive disorders and ischemic retinopathy. The results suggest complement dysregulation can contribute to retinal vascular occlusion and that an anti-C5 antibody might be helpful for C5-mediated thrombotic retinal diseases.
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http://dx.doi.org/10.1016/j.ajpath.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458521PMC
April 2019

Homeobox C10 Influences on the Malignant Phenotype of Gastric Cancer Cell Lines and its Elevated Expression Positively Correlates with Recurrence and Poor Survival.

Ann Surg Oncol 2019 May 23;26(5):1535-1543. Epub 2019 Jan 23.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa.

Methods: Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer.

Results: PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis.

Conclusions: Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.
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http://dx.doi.org/10.1245/s10434-019-07166-5DOI Listing
May 2019

Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer.

Ann Surg Oncol 2019 Mar 7;26(3):836-844. Epub 2019 Jan 7.

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer.

Methods: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA.

Results: DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells.

Conclusions: Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer.
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http://dx.doi.org/10.1245/s10434-018-07149-yDOI Listing
March 2019

Anterior tibial artery rupture treated using covered stent in a patient with vascular Ehlers-Danlos syndrome.

J Cardiol Cases 2018 Dec 24;18(6):197-200. Epub 2018 Aug 24.

Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare degenerative connective tissue disease caused by a mutation of the gene that results in systemic vascular fragility. Arterial rupture is a potentially fatal serious complication that is the most commonly reported cause of death among patients with this disease, as ruptured vessels remain fragile even after surgical or endovascular reconstruction. Therefore, treatment for vascular complications in patients with vEDS remains controversial. Rupture or pseudoaneurysm of the infrapopliteal artery is extremely rare. We describe a 38-year-old woman with vEDS who presented with sudden widespread rupture of the anterior tibial artery. She was treated by endovascular reconstruction using covered stents. She has remained free of vascular events for two years after surgery, and the course has been uneventful. Endovascular reconstruction using covered stents might offer an alternative for relatively small ruptured arteries and avoid disturbing blood flow in the lower extremities of patients with vEDS. < Vascular Ehlers-Danlos syndrome (vEDS) causes systemic vascular fragility that results in arterial rupture. However, rupture of the arteries in the lower extremities is rare, and definitive treatment has not been established. Endovascular reconstruction with covered stents might offer an alternative treatment for ruptured arteries in the lower extremities of patients with vEDS.>.
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http://dx.doi.org/10.1016/j.jccase.2018.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306516PMC
December 2018

expression correlates with hormone receptor status in breast cancer.

Oncol Lett 2018 Dec 3;16(6):7223-7230. Epub 2018 Oct 3.

Department of Breast and Endocrine Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.

Breast cancer (BC) is the most frequently diagnosed malignant tumor in women worldwide, and the development of new molecules associated with BC is essential for the management of this disease. RAS and EF-hand domain-containing () encodes the GTPase enzyme that belongs to the Rab family. Although the effects of this gene have been reported in several malignant tumor types, the role of in BC has not been completely elucidated. The aim of the present study was to investigate the importance of expression in BC. mRNA expression levels were evaluated in BC and non-cancerous mammary cell lines. The association between mRNA expression levels and clinicopathological factors in 167 patients with BC were then determined. Among the 13 examined BC cell lines, ER-negative/HER2-negative cell lines expressed lower mRNA levels, when compared with the other examined cell lines (P=0.014). Of the 167 patients examined, patients with negative hormone receptor status exhibited significantly lower mRNA expression levels (P<0.001). In addition low expression in BC tissues was associated with negative estrogen receptor status (P<0.001), negative progesterone receptor status (P<0.001), and triple-negative status (P<0.001). Additionally, although the differences were not statistically significant, patients with low expression levels exhibited poorer disease-free survival (P=0.123) and overall survival (P=0.086) than other patients. The results of the present study indicate that mRNA expression levels are associated with hormone receptor status in BC.
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http://dx.doi.org/10.3892/ol.2018.9542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256290PMC
December 2018
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