Publications by authors named "Eri Tanaka"

49 Publications

Successful Management of Subacute Thyroiditis Following SARS-CoV-2 Infection: A Case Report.

Intern Med 2021 Sep 11. Epub 2021 Sep 11.

Department of Internal Medicine, Hayama heart center, Japan.

Subacute thyroiditis (SAT) is a disorder of the thyroid gland and difficult to diagnose. It is probably triggered by a viral infection. Recently, several articles have reported SAT after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, reports describing SAT after SARS-CoV-2 in Japan are lacking. We herein report the first case of SAT after SARS-CoV-2 infection in Japan. After SARS-CoV-2 infection, some patients can develop not only pneumonia but also SAT. Thus, a careful follow-up is recommended for patients after SARS-CoV-2 infection. Furthermore, the effect of SARS-CoV-2 infection on thyroid dysfunction should not be ignored.
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http://dx.doi.org/10.2169/internalmedicine.7913-21DOI Listing
September 2021

HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA.

J Hepatol 2021 Aug 25. Epub 2021 Aug 25.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Background & Aims: Hepatitis B virus (HBV) causes hepatocellular carcinoma (HCC). While the need for HBV regulatory protein X (HBx) for viral transcription via impairment of the structural maintenance of chromosome 5/6 (Smc5/6) complex was recently demonstrated, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear.

Methods: Degradation of Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx.

Results: Degradation of the Smc5/6 complex triggered by HBx impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the clustered regularly interspaced short palindromic repeats-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells.

Conclusions: Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs.

Lay Summary: HBV regulatory protein X (HBx) degrades the structural maintenance of chromosome 5/6 (Smc5/6) complex, which is required for viral replication. We found that degradation of the Smc5/6 complex also plays a key role in the accumulation of DNA damage, as well as in HBx-mediated tumorigenesis.
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http://dx.doi.org/10.1016/j.jhep.2021.08.010DOI Listing
August 2021

Phase II clinical trial of personalized VCD-VTD sequential therapy using the Vulnerable Elders Survey-13 (VES-13) for transplant-ineligible patients with newly diagnosed multiple myeloma.

Ann Hematol 2021 Jul 31. Epub 2021 Jul 31.

Department of Hematology, Kitasato University School of Medicine, Sagamihara, Japan.

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66-86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235.
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http://dx.doi.org/10.1007/s00277-021-04592-yDOI Listing
July 2021

Clustered and dispersed chromosomal distribution of the two classes of Revolver transposon family in rye (Secale cereale).

J Appl Genet 2021 Sep 10;62(3):365-372. Epub 2021 Mar 10.

Faculty of Agriculture, Tottori University, 4-101 Koyama Minami, Tottori, 680-8550, Japan.

The chromosomal locations of a new class of Revolver transposon-like elements were analyzed by using FISH method on the metaphase chromosome in somatic cell division of the rye cultivar Petkus. First, the Revolver standard element probe λ2 was weakly hybridized throughout the rye chromosome, and comparatively large interstitial signals spotted with a dot shape were detected together with several telomeric regions. The dot shape interstitial signal was stably detected at one site on Chromosome (Chr) 1R (middle part of the interstitial region of the short arm), three sites on Chr 2R (distal part of the interstitial region and adjacent to the centromere on the short arm, middle part of the interstitial region of the long arm), and two sites on Chr 5R (middle part of the interstitial region and adjacent to the centromere on the long arm). The Revolver λ2 probe was effective for identification of 1R, 2R, and 5R chromosomes. On the other hand, Revolver nonautonomous element-specific L626-BARE-100 probe was strongly distributed throughout the rye chromosomes, and considerable numbers and diverse lengths of transcripts were detected by RT-PCR. Although the standard elements were found in localized clusters, the nonautonomous elements tended to be dispersed throughout the genome. Clustered nature of Revolver is a significantly rare case in genomics.
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http://dx.doi.org/10.1007/s13353-021-00617-4DOI Listing
September 2021

Emerging Roles of Exosomal Circular RNAs in Cancer.

Front Cell Dev Biol 2020 8;8:568366. Epub 2020 Oct 8.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Circular RNA (circRNA) is a type of non-coding RNA that forms a covalently closed continuous loop. The expression pattern of circRNA varies among cell types and tissues, and many circRNAs are aberrantly expressed in various cancers. Aberrantly expressed circRNAs have been shown to play crucial roles in carcinogenesis, functioning as microRNA sponges or new templates for protein translation. Recent research has shown that circRNAs are enriched in exosomes. Exosomes are secretory vesicles that mediate intercellular communication through the delivery of cargo, including proteins, lipids, DNA, and RNA. Exosome-mediated crosstalk between cancer cells and the tumor microenvironment promotes the epithelial-mesenchymal transition, angiogenesis, and immune escape, and thus may contribute to cancer invasion and metastasis. In this review, we discuss the biological functions of exosomal circRNAs and their significance in cancer progression. Additionally, we discuss the potential clinical applications of exosomal circRNAs as biomarkers and in cancer therapy.
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http://dx.doi.org/10.3389/fcell.2020.568366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578227PMC
October 2020

The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding.

Sci Rep 2020 09 23;10(1):15556. Epub 2020 Sep 23.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

MICA/B proteins are expressed on the surface of various types of stressed cells, including cancer cells. Cytotoxic lymphocytes expressing natural killer group 2D (NKG2D) receptor recognize MICA/B and eliminate the cells. However, cancer cells evade such immune recognition by inducing proteolytic shedding of MICA/B proteins. Therefore, preventing the shedding of MICA/B proteins could enhance antitumor immunity. Here, by screening a protease inhibitor library, we found that the fatty-acid amide hydrolase (FAAH) inhibitor, URB597, suppresses the shedding of MICA/B. URB597 significantly reduced the soluble MICA level in culture medium and increased the MICA level on the surface of cancer cells. The effect was indirect, being mediated by increased expression of tissue inhibitor of metalloproteinases 3 (TIMP3). Knockdown of TIMP3 expression reversed the effect of URB597, confirming that TIMP3 is required for the MICA shedding inhibition by URB597. In contrast, FAAH overexpression reduced TIMP3 expression and the cell-surface MICA level and increased the soluble MICA level. These results suggest that inhibition of FAAH could prevent human cancer cell evasion of immune-mediated clearance.
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http://dx.doi.org/10.1038/s41598-020-72688-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512021PMC
September 2020

Intravascular lymphoma with hypopituitarism: A case report.

World J Clin Oncol 2020 Aug;11(8):673-678

Department of Hematology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan.

Background: Intravascular lymphoma (IVL) is a rare subtype of lymphoma involving the growth of lymphoma cells within the vessel lumina without lymphadenopathy. Because of various modes of presentation and its rarity, IVL is often diagnosed postmortem. Herein, we report a case of intravascular B-cell lymphoma with hypopituitarism, an extremely rare complication, that was successfully treated with chemotherapy.

Case Summary: An 80-year-old Japanese woman presented with a 7-mo history of a tingling sensation in the lower limbs. She also presented with various other symptoms such as pancytopenia, high fever daily, and unconsciousness with hypoglycemia. Although the doctor who previously treated her diagnosed hypoglycemia as being due to hypopituitarism, the cause of the other symptoms remained uncertain despite a 7-mo evaluation period. We performed bone marrow aspiration to evaluate pancytopenia and found that she had hemophagocytic lymphohistiocytosis (HLH). On the basis of a random skin biopsy for assessing the cause of HLH, she was diagnosed with intravascular B-cell lymphoma. HLH and hypopituitarism were considered secondary to IVL. All her clinical findings matched the presentations of IVL. She was immediately treated with chemotherapy and achieved complete response. She was relapse free two years after treatment.

Conclusion: IVL should be included in the differential diagnosis of hypopituitarism, which although life-threatening, is treatable through prompt diagnosis and appropriate chemotherapy.
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http://dx.doi.org/10.5306/wjco.v11.i8.673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443836PMC
August 2020

Aberrant expression of a novel circular RNA in pancreatic cancer.

J Hum Genet 2021 Feb 3;66(2):181-191. Epub 2020 Sep 3.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are produced from pre-mRNAs through a process known as back-splicing. Although circRNAs are expressed under specific conditions, current understanding of their comprehensive expression status is still limited. Here, we performed a large-scale circRNA profiling analysis in human pancreatic ductal adenocarcinoma (PDAC) tissues, using circular RNA-specific RNA sequencing. We identified more than 40,000 previously unknown circRNAs, some of which were upregulated in PDAC tissues, compared with normal pancreatic tissues. We determined the full-length sequence of a circRNA upregulated in PDAC, which was derived from two noncoding RNA loci on chromosome 12. The novel circRNA, named circPDAC RNA, was not expressed in normal human cells, but was expressed in PDAC and other carcinoma cells. While postulated biological functions, such as peptide production from the circPDAC RNA, were not detected, its aberrant expression was confirmed in other PDAC tissues and in serum from a PDAC patient. These results demonstrate that comprehensive studies are necessary to reveal the expression status of circRNAs and that the circPDAC RNA identified here might serve as a novel biomarker for cancers, including PDAC.
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http://dx.doi.org/10.1038/s10038-020-00826-5DOI Listing
February 2021

Angioimmunoblastic T-cell lymphoma accompanied by pure red cell aplasia: A case report.

World J Clin Oncol 2020 Jun;11(6):405-411

Department of Hematology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan.

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma, which is a rare subtype of lymphoma. Patients with AITL often have skin lesions, which are observed in 50% of all cases; the chief complaint of this patient was palpable purpura. AITL often complicates autoimmune or hematological disorders; however, among these, pure red cell aplasia (PRCA) is a very rare complication of AITL. We herein report a case of AITL with PRCA.

Case Summary: A 77-year-old Japanese man presented to our hospital with complaints of loss of appetite for 2 mo and a 10-d history of palpable purpura. On physical examination, the patient was afebrile but had bilateral multiple palpable purpuric lesions over the lower extremities, lower abdomen, and part of the upper extremities. Moreover, lymphadenopathy of the bilateral inguinal, cervical, and supraclavicular nodes was noted. Laboratory and imaging studies and skin biopsy were conducted but were inconclusive. Based on inguinal lymph node excisional biopsy, we diagnosed the patient with AITL. Subsequently, the patient developed progressive normocytic normochromic anemia that necessitated almost daily blood transfusion. The clinical presentations and results of bone marrow assessment were consistent with those of PRCA, which is associated with AITL. Chemotherapy was initiated but was not effective. The patient refused further chemotherapy and opted to continue receiving best supportive care.

Conclusion: PRCA is an extremely rare complication of AITL. As the pathophysiology remains unclear, further research is warranted.
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http://dx.doi.org/10.5306/wjco.v11.i6.405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450812PMC
June 2020

[Implementation and Verification of Tabletop Training Program for Disaster Evacuation Shelter Support for School Pharmacist].

Yakugaku Zasshi 2020 ;140(2):289-300

Faculty of Sciences and Engineering, Setsunan University.

In this paper, as a program targeting school pharmacists engaged in health counseling and health guidance at elementary and junior high schools, which are often evacuation centers, we have rebuilt the disaster evacuation shelter support chart program for community pharmacists. As a result of the questionnaire survey, there were seen 4 groups. There were a group that was conscious of shelter support, a group who felt that they did not have aptitude for disaster relief, a group that was conscious of general support and logistical support, and a group that showed a negative attitude towards disaster relief. From this, it was suggested that this training program worked enlighteningly to support affected area by school pharmacists, and at the same time participants themselves could lead to consideration of aptitude for support at the time of disaster.
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http://dx.doi.org/10.1248/yakushi.19-00139DOI Listing
August 2020

Incorporating Spacer Molecules into the Tetrathiafulvalene--Chloranil Charge-Transfer Framework: Modulating the Neutral-Ionic Phase Transition.

J Phys Chem Lett 2020 Feb 4;11(4):1336-1342. Epub 2020 Feb 4.

Department of Chemistry , Faculty of Science, Hokkaido University , Sapporo 060-0810 , Japan.

The charge-transfer (CT) tetrathiafulvalene--chloranil (TTF-CA) crystal, a representative functional organic electronic material, has been the subject of both basic and applied research. This material shows a neutral-ionic phase transition (NIPT) that induces drastic changes in its physical properties. Here, we use this crystal as a framework and demonstrate a method for modulating physical properties of TTF-CA. A number of multicomponent (ternary) CT crystals were obtained by crystallizing TTF-CA with a third molecular species. These complexes all contain molecular sheets formed with TTF-CA; however, the third molecules were differently inserted between these sheets as spacers to induce a variety of physical properties in the CT crystals. Some showed spacer-modified NIPT, while the transition to the ionic state was suppressed in one complex despite the presence of TTF-CA sheets, which indicates that spacer molecules can modulate the physical properties or functions of CT crystals.
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http://dx.doi.org/10.1021/acs.jpclett.9b03847DOI Listing
February 2020

Amyotrophic lateral sclerosis with appearance of many skein-like inclusions in anterior horn cells.

Int J Clin Exp Pathol 2019 1;12(11):4156-4161. Epub 2019 Nov 1.

Department of Clinical Laboratory Medicine and Diagnostic Pathology, Shiga University of Medical Science Ohtsu, Shiga, Japan.

We report an autopsy case of amyotrophic lateral sclerosis (ALS), in which an abnormally large number of skein-like inclusions (SLIs) was found in anterior horn cells. The patient was a 73-year-old man, who presented with dysarthria. His motor neuron symptoms were predominantly of the upper-neuron type, and cognitive impairment was also noted. He died of septic shock 13 months after onset of the first neurological symptoms. Autopsy revealed marked loss of upper motor neurons, severe degeneration of the pyramidal tract, mild to moderate loss of anterior horn cells, and the appearance of many SLIs, which were immunoreactive for both pTDP-43 (phosphorylated transactivation responsive DNA-binding protein of 43 kDa) and ubiquitin, in anterior horn cells. Intra-axonal pTDP-43-positive granules arranged in a bead-like fashion were also found. The appearance of pTDP-43-positive intracytoplasmic inclusions in the brain was mostly restricted to the motor cortex. An Alzheimer type tau-pathology was found mainly in the hippocampus (Braak stage III), and many argyrophilic grains were distributed in the limbic area. Atypical ALS showing a rapid clinical course associated with cognitive impairment and predominant involvement of the upper motor neurons has recently been reported. The present case shares some clinical and pathologic findings with this type of atypical ALS. The appearance of a large number of SLIs is an unusual finding. Although its pathologic significance remains unknown, it cannot simply be ascribed to the relative preservation of anterior horn cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949794PMC
November 2019

Detection of circulating colorectal cancer cells by a custom microfluid system before and after endoscopic metallic stent placement.

Oncol Lett 2019 Dec 4;18(6):6397-6404. Epub 2019 Nov 4.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Although the detection of circulating tumor cells (CTCs) should be crucial for future personalized medicine, no efficient and flexible methods have been established. The current study established a polymeric custom-made chip for capturing CTCs with a high efficiency and flexibility. As an example of clinical application, the effects of self-expandable metallic stent (SEMS) placement on the release of cancer cells into the blood of patients with colorectal cancer and bowel obstruction were analyzed. This was assessed as the placement of SEMS may cause mechanical damage and physical force to malignant tissue, increasing the risk of cancer cell release into the bloodstream. The present study examined the number of CTCs using a custom-made chip, before, at 24 h after and at 4 days after SEMS placement in patients with colorectal cancer. The results revealed that, among the 13 patients examined, the number of CTCs was increased in three cases at 24 h after SEMS placement. However, this increase was temporary. The number of CTCs also decreased at 4 days after stent placement in most cases. The CTC chip of the current study detected the number of CD133-positive cancer stem-like cells, which did not change, even in the patient whose total number of CTCs temporarily increased. The results indicated that this custom-made microfluid system can efficiently and flexibly detect CTCs, demonstrating its potential for obtaining information during the management of patients with cancer.
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http://dx.doi.org/10.3892/ol.2019.11047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876337PMC
December 2019

Sclerosing Mesenteritis Mimicking IgG4-related Disease.

Intern Med 2020 Feb 8;59(4):513-518. Epub 2019 Nov 8.

Division of Diagnostic Pathology, Department of Clinical Laboratory Medicine, Shiga University of Medical Science Hospital, Japan.

A 72-year-old man was followed as an outpatient at our hospital for 6 years after surgery for small cell carcinoma of left adrenal gland origin. Follow-up abdominal computed tomography showed a 6-cm mass in the left lower mesentery. The patient underwent open laparotomy. The histological diagnosis was sclerosing mesenteritis. The previous specimens of the left adrenal mass were then re-examined with a microscope, and panniculitis was found around the small cell carcinoma. Both lesions were histologically similar to IgG4-related disease (RD), but they did not completely meet the diagnostic criteria of IgG4-RD clinically or histologically.
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http://dx.doi.org/10.2169/internalmedicine.3221-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056383PMC
February 2020

[Successful lung transplantation after long-term ventilator and extracorporeal membrane oxygenation support in a patient with severe bronchiolitis obliterans following allogeneic bone marrow transplantation].

Rinsho Ketsueki 2019 ;60(8):920-923

Division of Hematology, Shonan Kamakura General Hospital.

A 29-year-old man was diagnosed with acute myeloid leukemia at 20 years of age; he achieved a second complete remission at 22 years of age after an allogeneic unrelated bone marrow transplantation. After 14 months, he developed bronchiolitis obliterans (BO) due to chronic graft-versus-host disease. Home ventilator management was continuously performed for 3 years, but the patient required extracorporeal membrane oxygenation (ECMO) after progression to type 2 respiratory failure. A matched brain-dead lung donor was found after 5 months of intensive care management on ECMO, and bilateral lung transplantation was successfully performed. BO is a progressive refractory respiratory disease with poor prognosis. Careful management of infection, monitoring organ function, and lung transplantation at the appropriate time of initiation of mechanical ventilation or ECMO may save a patient's life. However, it is crucial to collaborate with higher education institutions or medical professionals in other departments.
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http://dx.doi.org/10.11406/rinketsu.60.920DOI Listing
September 2019

Expression of circular RNA CDR1‑AS in colon cancer cells increases cell surface PD‑L1 protein levels.

Oncol Rep 2019 Oct 19;42(4):1459-1466. Epub 2019 Jul 19.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113‑8655, Japan.

The expression of CDR1‑AS, a representative circular RNA, is closely linked with poor prognosis in gastrointestinal cancers, such as colon, liver, and pancreatic cancers. Although it is well known that CDR1‑AS antagonizes microRNA‑7 function through its sequence similarities in the brain, its biological function and link with the malignant potential of cancer cells remain unclear, partly due to the difficulties of ectopic expression of circular RNAs. In the present study, SW620, a colon cancer cell line that stably expresses CDR1‑AS RNA circularized, was established using the laccase 2 gene cassette, and its biological function associated with malignant behavior was determined. In contrast to previous studies, cell growth or invasion ability was not altered by CDR1‑AS expression. However, the expression levels of CMTM4 and CMTM6, which were recently recognized as critical regulators of PD‑L1 protein expression at the cell surface, were significantly increased. Accordingly, the cell surface PD‑L1 protein levels were increased in CDR1‑AS‑expressing cells. Notably, the effects were not canceled out by overexpressing microRNA‑7, indicating that the increase in cell surface PD‑L1 in CDR1‑AS‑expressing cells was not dependent on microRNA‑7 function. These results indicated that expression of this circular RNA in cancer cells may lead to poor prognosis by increasing cell surface PD‑L1 levels through microRNA‑7‑independent mechanisms.
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http://dx.doi.org/10.3892/or.2019.7244DOI Listing
October 2019

Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx-DDB1 Interaction.

Cell Mol Gastroenterol Hepatol 2019 24;7(2):297-312. Epub 2018 Oct 24.

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Background & Aims: Hepatitis B virus (HBV) infection is a major health concern worldwide. Although currently used nucleos(t)ide analogs efficiently inhibit viral replication, viral proteins transcribed from the episomal viral covalently closed circular DNA (cccDNA) minichromosome continue to be expressed long-term. Because high viral RNA or antigen loads may play a biological role during this chronicity, the elimination of viral products is an ultimate goal of HBV treatment. HBV regulatory protein X (HBx) was recently found to promote transcription of cccDNA with degradation of Smc5/6 through the interaction of HBx with the host protein DDB1. Here, this protein-protein interaction was considered as a new molecular target of HBV treatment.

Methods: To identify candidate compounds that target the HBx-DDB1 interaction, a newly constructed split luciferase assay system was applied to comprehensive compound screening. The effects of the identified compounds on HBV transcription and cccDNA maintenance were determined using HBV minicircle DNA, which mimics HBV cccDNA, and the natural HBV infection model of human primary hepatocytes.

Results: We show that nitazoxanide (NTZ), a thiazolide anti-infective agent that has been approved by the FDA for protozoan enteritis, efficiently inhibits the HBx-DDB1 protein interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system and in human primary hepatocytes naturally infected with HBV.

Conclusions: These results indicate that NTZ, which targets an HBV-related viral-host protein interaction, may be a promising new therapeutic agent and a step toward a functional HBV cure.
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http://dx.doi.org/10.1016/j.jcmgh.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357790PMC
May 2019

Blastic plasmacytoid dendritic cell neoplasm with response to pralatrexate.

Ann Hematol 2019 Mar 16;98(3):801-803. Epub 2019 Jan 16.

Division of Hematology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.

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http://dx.doi.org/10.1007/s00277-019-03611-3DOI Listing
March 2019

Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus.

Hepatology 2019 05 13;69(5):1903-1915. Epub 2019 Mar 13.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Hepatitis B virus (HBV) infection is a major health concern worldwide. To prevent HBV-related mortality, elimination of viral proteins is considered the ultimate goal of HBV treatment; however, currently available nucleos(t)ide analogs rarely achieve this goal, as viral transcription from episomal viral covalently closed circular DNA (cccDNA) is not prevented. HBV regulatory protein X was recently found to target the protein structural maintenance of chromosomes 5/6 (Smc5/6) for ubiquitination and degradation by DDB1-CUL4-ROC1 E3 ligase, resulting in enhanced viral transcription from cccDNA. This ubiquitin-dependent proteasomal pathway requires an additional ubiquitin-like protein for activation, neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8). Here, we show that pevonedistat, a NEDD8-activating enzyme inhibitor, works efficiently as an antiviral agent. Pevonedistat significantly restored Smc5/6 protein levels and suppressed viral transcription and protein production in the HBV minicircle system in in vitro HBV replication models and in human primary hepatocytes infected naturally with HBV. Conclusion: These results indicate that pevonedistat is a promising compound to treat chronic HBV infection.
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http://dx.doi.org/10.1002/hep.30491DOI Listing
May 2019

Inflammation and de-differentiation in pancreatic carcinogenesis.

World J Clin Cases 2018 Dec;6(15):882-891

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Pancreatic cancer is a malignancy with an extremely poor prognosis. Chronic pancreatitis is a well-known risk factor for pancreatic cancer. Inflammation is thought to influence carcinogenesis through DNA damage and activation of intracellular signaling pathways. Many transcription factors and signaling pathways co-operate to determine and maintain cell identity at each phase of pancreatic organogenesis and cell differentiation. Recent studies have shown that carcinogenesis is promoted through the suppression of transcription factors related to differentiation. Pancreatitis also demonstrates transcriptional changes, suggesting that multifactorial epigenetic changes lead to impaired differentiation. Taken together, these factors may constitute an important framework for pancreatic carcinogenesis. In this review, we discuss the role of inflammation and de-differentiation in the development of pancreatic cancer, as well as the future of novel therapeutic applications.
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http://dx.doi.org/10.12998/wjcc.v6.i15.882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288496PMC
December 2018

No transformation of a fundic gland polyp with dysplasia into invasive carcinoma after 14 years of follow-up in a proton pump inhibitor-treated patient: A case report.

Pathol Int 2018 Dec 4;68(12):706-711. Epub 2018 Dec 4.

Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan.

A fundic gland polyp (FGP) is a common gastric polyp. Intraepithelial neoplasia in FGPs, referred to as FGP with dysplasia, is often seen in patients with familial adenomatous polyposis (FAP). In sporadic FGPs, low-grade dysplasia (LGD) is rare, and high-grade dysplasia (HGD) or carcinoma arising from sporadic FGPs is extremely rare. Because of this rarity, the prognosis and appropriate management of these lesions have not been clarified. In the present case, a sporadic FGP with LGD did not develop into invasive carcinoma, but contained foci of HGD 14 years after diagnosis. The biopsy specimen of the polyp taken at the first esophagogastroduodenoscopy 15 years earlier was diagnosed as FGP without dysplasia. At the second histological examination, LGD was found. Because the polyp increased in size during proton pump inhibitor therapy for 14 years, endoscopic mucosal resection was performed. The pathological diagnosis of the resected specimen was FGP with HGD mixed in LGD, with no invasive carcinoma. Dysplasia in FGPs might have less malignant potential regardless of dysplasia or size.
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http://dx.doi.org/10.1111/pin.12739DOI Listing
December 2018

ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells.

NPJ Aging Mech Dis 2018 15;4:11. Epub 2018 Nov 15.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655 Japan.

During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2. However, in this study, the constitutive expression of ISGs in human-derived senescent fibroblasts and in fibroblasts from a patient with Werner syndrome, which leads to premature aging, was mediated mainly by the unphosphorylated forms of STATs in the absence of INF production. Under homeostatic conditions, STAT1, STAT2, and IRF9 were localized to the nucleus of aged cells. Although knockdown of JAK1, a key kinase of STAT1 and STAT2, did not affect ISG expression or IFN-stimulated response element (ISRE)-mediated promoter activities in these senescent cells, knockdown of STAT1 or STAT2 decreased ISG expression and ISRE activities. These results suggest that the ISGF3 complex without clear phosphorylation is required for IFN-independent constitutive ISG transcription in senescent cells.
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http://dx.doi.org/10.1038/s41514-018-0030-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237867PMC
November 2018

Submucosal fat accumulation in human colorectal tissue and its association with abdominal obesity and insulin resistance.

United European Gastroenterol J 2018 Aug 20;6(7):1065-1073. Epub 2018 Mar 20.

Division of Gastroenterology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan.

Background: In addition to visceral fat, peripheral ectopic fat accumulation is suggested to play a role in the pathophysiology of metabolic syndrome, which is known to be associated with not only cardiovascular diseases and type 2 diabetes mellitus but also colorectal cancer.

Objective: This study aims to clarify whether there is ectopic fat accumulation in human colorectal tissue in association with metabolic syndrome or its components such as abdominal obesity and insulin resistance.

Methods: Lipid contents of colorectal tissue were measured in 27 patients with colorectal polyp excised endoscopically. In addition, lipid droplets were immunohistochemically estimated using anti-perilipin antibody in 32 patients with colorectal cancer resected surgically.

Results: Increasing tissue triglyceride/phospholipid ratio was associated with increasing body mass index, fasting plasma insulin level and homeostasis model assessment as an index of insulin resistance (HOMA-IR), and also decreasing serum adiponectin level. Lipid droplets were observed in the submucosal region of colorectal tissue. The amount of lipid droplets was associated with increasing body mass index, waist circumference and visceral fat area.

Conclusion: This study showed the presence of submucosal fat accumulation in human colorectal tissue and its association with abdominal obesity and insulin resistance.
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http://dx.doi.org/10.1177/2050640618766926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137583PMC
August 2018

Carotid artery stenting with proximal embolic protection via the transbrachial approach: sheathless navigation of a 9-F balloon-guiding catheter.

Neuroradiology 2018 Oct 22;60(10):1097-1101. Epub 2018 Aug 22.

Department of Neurology, Saiseikai Fukuoka General Hospital, 1-3-46, Tenjin, Chuo-ku, Fukuoka City, Fukuoka, 810-0001, Japan.

Purpose: Transbrachial carotid artery stenting (TB-CAS) is performed as an alternative procedure for patients with hostile vascular anatomy of the aortic arch and aortic or peripheral artery disease. Proximal protection during TB-CAS is not generally feasible because a small size of the brachial artery may preclude using a large-diameter sheath introducer. We, herein present a novel method that enables proximal protection during TB-CAS by sheathless navigation of a 9-F balloon-guiding catheter equivalent to a 7-F sheath.

Methods: We analyzed eight consecutive patients who underwent TB-CAS with proximal protection using the sheathless method from April 2016 to June 2017. Relevant demographic, radiographic, and procedural features were retrospectively reviewed.

Results: We performed TB-CAS using our method for five patients with a bovine or type 3 aortic arch, for one patient with combined peripheral artery disease, and for two patients with a type 1 or 2 aortic arch. We successfully navigated the balloon-guiding catheter via the brachial artery and performed CAS under proximal flow control in all patients. However, we experienced kinking and exchange of the balloon-guiding catheter in one patient and a periprocedural thromboembolic event occurred. A pseudoaneurysm at the access site developed in one patient.

Conclusion: TB-CAS with proximal embolic protection using the sheathless method is feasible and may provide an alternative approach in carefully selected patients who have difficult anatomy in the transfemoral approach and plaques with a high risk of distal embolization.
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http://dx.doi.org/10.1007/s00234-018-2085-2DOI Listing
October 2018

Cholangitis complicated by infection of a simple hepatic cyst.

Clin J Gastroenterol 2018 Dec 8;11(6):493-496. Epub 2018 Jun 8.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

An 87-year-old man was admitted to our hospital due to fever and elevated liver enzymes. Computed tomography (CT) scan revealed bile duct stones with a dilated biliary system, which confirmed the diagnosis of cholangitis. A 12-cm simple hepatic cyst was also seen in the right liver, which had been detected on CT scan 5 years before, and did not change in size. Fever did not subside even after endoscopic biliary drainage and a repeated CT scan showed an enlarged cyst up to 14 cm, suggesting cyst infection. An enlarged hepatic cyst collapsed after percutaneous transhepatic drainage, along with resolution of fever. Simple hepatic cysts are common and most of them are asymptomatic. Infection of simple hepatic cysts is a rare condition and the major entry route is considered as the biliary tract as communication between the biliary tract and cysts is reportedly observed in those cases. However, in our case, no communication was seen on cholangiogram or cystogram on fluoroscopy and bilirubin level of the cyst aspirate was low. Given the fact that patients with cholangitis are rarely complicated by hepatic cyst infection, other routes of bacterial entry to simple hepatic cysts should also be considered.
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http://dx.doi.org/10.1007/s12328-018-0874-0DOI Listing
December 2018

Hepatitis B virus pathogenesis: Fresh insights into hepatitis B virus RNA.

World J Gastroenterol 2018 Jun;24(21):2261-2268

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Hepatitis B virus (HBV) is still a worldwide health concern. While divergent factors are involved in its pathogenesis, it is now clear that HBV RNAs, principally templates for viral proteins and viral DNAs, have diverse biological functions involved in HBV pathogenesis. These functions include viral replication, hepatic fibrosis and hepatocarcinogenesis. Depending on the sequence similarities, HBV RNAs may act as sponges for host miRNAs and may deregulate miRNA functions, possibly leading to pathological consequences. Some parts of the HBV RNA molecule may function as viral-derived miRNA, which regulates viral replication. HBV DNA can integrate into the host genomic DNA and produce novel viral-host fusion RNA, which may have pathological functions. To date, elimination of HBV-derived covalently closed circular DNA has not been achieved. However, RNA transcription silencing may be an alternative practical approach to treat HBV-induced pathogenesis. A full understanding of HBV RNA transcription and the biological functions of HBV RNA may open a new avenue for the development of novel HBV therapeutics.
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http://dx.doi.org/10.3748/wjg.v24.i21.2261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989240PMC
June 2018

Invasive Pulmonary Aspergillosis in the Epidural Space in a Patient with Acute Myelogenous Leukemia with Myelodysplasia-related Changes: A Case Study and Literature Review of Vertebral Aspergillosis in Japan.

Intern Med 2018 Nov 6;57(21):3205-3212. Epub 2018 Jun 6.

Division of Hematology, Shonan Kamakura General Hospital, Japan.

Vertebral aspergillosis is a rare infectious disease with a high mortality rate. We herein report a 70-year-old woman with acute myelogenous leukemia with myelodysplasia-related changes, nontuberculous mycobacteriosis, and bronchiectasis who presented with a fever and cough. Her clinical symptoms and laboratory test results suggested febrile neutropenia and pneumonia. However, her clinical course was further complicated by lower extremity weakness. Magnetic resonance imaging of the spine showed consolidation contiguously spreading toward the epidural space between the T4 and T5. Cytological testing of the pleural effusion revealed Aspergillus fumigatus. We also review and summarize previously reported cases of vertebral aspergillosis in Japan.
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http://dx.doi.org/10.2169/internalmedicine.1135-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262695PMC
November 2018

DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels.

Oncotarget 2018 Apr 20;9(30):20953-20964. Epub 2018 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Hepatitis B virus (HBV) infection, which is a major health concern worldwide, can lead to liver cirrhosis and hepatocellular carcinoma. Although current nucleos(t)ide analogs efficiently inhibit viral reverse transcription and viral DNA load clinically, episomal viral covalently closed circular DNA (cccDNA) minichromosomes and transcripts from cccDNA continue to be expressed over the long term. We hypothesized that, under these conditions, viral transcripts may have biological functions involved in pathogenesis. Here, we show that the host protein DExH-box helicase 9 (DXH9) is associated with viral RNAs. We also show that viral-derived circular RNA is produced during HBV replication, and the amount is increased by knockdown of the DHX9 protein, which, in turn, results in decreased viral protein levels but does not affect the levels of HBV DNA. These phenomena were observed in the HBV-producing cell culture model and HBV mini-circle model mimicking HBV cccDNA, as well as in human primary hepatocytes infected with HBV. Based on these results, we conclude that, in HBV infection, the RNA binding factor DHX9 is a novel regulator of viral circular RNA and viral protein levels.
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http://dx.doi.org/10.18632/oncotarget.25104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940377PMC
April 2018

Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer.

Mol Cancer Res 2018 08 10;16(8):1255-1262. Epub 2018 May 10.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To determine the biological role of satellite RNAs in carcinogenesis , we constructed mouse major satellite (MajSAT) RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT RNA expression accelerates oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase. Aberrant expression of satellite RNAs accelerates oncogenesis through a mechanism involving increased DNA damage. .
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0139DOI Listing
August 2018
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