Publications by authors named "Takashi Kishimoto"

117 Publications

Adenocarcinoma arising in an adrenohepatic fusion-related cyst.

Pathol Int 2022 Jun 13. Epub 2022 Jun 13.

Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/pin.13238DOI Listing
June 2022

Clinicopathological and Genomic Features of Pediatric Intracranial Myxoid Mesenchymal Tumor with both of Gene Fusion and Mutation: A Case Report and Comparison with Adult Cases in the Literature.

NMC Case Rep J 2022 18;9:101-109. Epub 2022 May 18.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan.

Intracranial myxoid mesenchymal tumors (IMMTs) with family gene fusion are rare brain neoplasms characterized by gene fusion between the gene and one of the cyclic AMP response element-binding (CREB) family transcription factor (, , or ) genes. Although half of reported cases are pediatric, the clinical, histologic, and genomic features of IMMTs with rearrangement in pediatric populations are not yet well clarified. Here we describe the case of a 7-year-old girl who presented with seizures due to an extra-axial tumor in the left parietal convexity. Gross total resection was achieved, and the tumor displayed a multilobular structure with solid hypercellular and myxoid hypocellular areas, separated by a variable amount of stroma. The hypercellular areas consisted of round to polygonal cells, whereas the myxoid areas were ovoid to spindled cells. Immunophenotypically, the tumor cells were positive for vimentin, desmin, and EMA. Next-generation sequencing of tumoral DNA revealed gene fusion and a pathogenic mutation of . No recurrence was detected 9 months after resection, without chemotherapy or radiotherapy. In comparison to other pediatric and adult patients with rearrangement, many clinical, radiological, and immunohistochemical features were shared. However, signs of elevated intracranial pressure were more frequently observed, and postoperative radiation was less frequently administered for pediatric patients. Gross total resection (GTR) was the key prognostic factor for better disease control especially among pediatric patients. Further reports of cases with rearrangement with detailed genetic profiles are essential for clarifying the oncogenic pathway and establishing a standard treatment strategy.
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http://dx.doi.org/10.2176/jns-nmc.2021-0385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177164PMC
May 2022

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Lab Invest 2022 May 28. Epub 2022 May 28.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chiba, 260-8677, Japan.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-A mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-A mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.
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http://dx.doi.org/10.1038/s41374-022-00807-6DOI Listing
May 2022

pneumonia in an immunocompetent patient developing a subacute disease course with central consolidation.

Respir Med Case Rep 2022 1;37:101659. Epub 2022 May 1.

Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba, 260-8670, Japan.

pneumonia (PCP) typically occurs in immunocompromised individuals and rarely presents in immunocompetent individuals. A 55-year-old man was referred to our hospital with cough and anorexia that persisted for 2 months. Chest computed tomography revealed bilateral central consolidation. He was diagnosed with PCP via bronchoscopy. His symptoms and imaging findings improved with the administration of only trimethoprim and sulfamethoxazole. Although he had non-alcoholic fatty liver disease, there were no other complications that could potentially cause immunodeficiency. It should be noted that PCP in immunocompetent individuals can have a subacute disease course presenting with bilateral central consolidation.
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http://dx.doi.org/10.1016/j.rmcr.2022.101659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097713PMC
May 2022

Ovarian Malignant Mixed Germ Cell Tumor Composed Mainly of a Polyembryoma Pattern With Vasculogenic Mesenchymal Tumor Components.

Int J Gynecol Pathol 2022 Apr 12. Epub 2022 Apr 12.

Ovarian germ cell tumors composed of numerous well-formed embryonal bodies have been described as exhibiting a "polyembryoma pattern." In addition, some germ cell tumors are occasionally concomitant with neoplastic vascular proliferation. These include angiosarcomas and the recently reported mediastinal vasculogenic mesenchymal tumors. A 9-yr-old Japanese girl underwent surgery for a right ovarian tumor. Histologically, the polyembryoma pattern, nongestational choriocarcinoma, and vasculogenic lesions characterized by a neoplastic repetition of embryonic vasculogenesis have been intermingled. The polyembryoma pattern consisted of numerous complete and incomplete embryonal bodies and glandular structures resembling adult-type and fetal-type intestines. Vasculogenic lesions were composed of variously developed neoplastic vessels within the myxomatous stroma, which extended well beyond one low-power (40×) microscopic field. We concluded that the vasculogenic lesion in our case was the ovarian counterpart of the mediastinal vasculogenic mesenchymal tumor. After the surgery, the patient was administered adjuvant chemotherapy and was alive with no evidence of recurrence or other malignancy at 28 mo postsurgery.
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http://dx.doi.org/10.1097/PGP.0000000000000867DOI Listing
April 2022

Assessment of malignant melanoma lesions using violet-light dermoscopy: A case report.

J Dermatol 2022 Jul 17;49(7):710-713. Epub 2022 Apr 17.

Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.

Malignant melanomas often present with irregular shapes and in multiple shades of brown under white light. Dermoscopy is used to diagnose malignant melanomas; nevertheless, it is often difficult to differentiate malignant melanoma from healthy pigmented skin. The DZ-D100 dermoscope (Casio Computer) is a digital camera equipped with a white light-emitting diode (LED) and a violet LED, which can capture non-polarized/polarized conventional dermoscopy images (CDS) as well as violet-light dermoscopy (VLD) images. Since the absorption wavelength of melanin approaches that of ultraviolet rays, VLD with a wavelength of 405 nm can be used to visualize it. This camera allows three images with the same composition to be captured simultaneously. In this case, we performed dermoscopy with DZ-D100 to determine the surgical resection margins of a melanoma of the heel in a 76-year-old woman. The pale-colored lesions that were difficult to demarcate by CDS were clearly visible by VLD, presenting as dark areas in the grayscale images. Preoperatively determined lesion boundaries with CDS in combination with VLD were histologically more accurate than those with conventional CDS alone. Therefore, the combination of CDS and VLD may reveal the distribution of subtle pigmentation of fine melanin in the skin, making it easier to distinguish between lesions and healthy skin. As one of the limitations, parts of the heel with thick stratum corneum were also observed to be dark gray in the VLD images. Therefore, the evaluation of pigment lesion should be performed by comparing both CDS and VLD.
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http://dx.doi.org/10.1111/1346-8138.16389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321777PMC
July 2022

Addressing high dose AAV toxicity - 'one and done' or 'slower and lower'?

Expert Opin Biol Ther 2022 Apr 3:1-5. Epub 2022 Apr 3.

Gene Therapy Center and Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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http://dx.doi.org/10.1080/14712598.2022.2060737DOI Listing
April 2022

Lowering the setting value of the esophageal endoscopic submucosal dissection device enabled tissue damage control in vitro porcine model.

Sci Rep 2022 02 23;12(1):3071. Epub 2022 Feb 23.

Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan.

One of the complications of esophageal endoscopic submucosal dissection (ESD) is postoperative stricture formation. Stenosis formation is associated with inflammation and fibrosis in the healing process. We hypothesized that the degree of thermal damage caused by the device is related to stricture formation. We aimed to reveal the relationship between thermal damage and setting value of the device. We energized a resected porcine esophagus using the ESD device (Flush Knife 1.5). We performed 10 energization points for 1 s, 3 s, and 5 s at four setting values of the device. We measured the amount of current flowing to the conducted points and the temperature and evaluated the effects of thermal damage pathologically. As results, the mean highest temperatures for 1 s were I (SWIFT Effect3 Wat20): 61.19 °C, II (SWIFT Effect3 Wat30): 77.28 °C, III (SWIFT Effect4 Wat20): 94.50 °C, and IV (SWIFT Effect4 Wat30): 94.29 °C. The mean heat denaturation areas were I: 0.84 mm, II: 1.00 mm, III: 1.91 mm, and IV: 1.54 mm. The mean highest temperature and mean heat denaturation area were significantly correlated (P < 0.001). In conclusion, Low-current ESD can suppress the actual temperature and thermal damage in the ESD wound.
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http://dx.doi.org/10.1038/s41598-022-06533-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866507PMC
February 2022

Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia.

Nat Commun 2022 01 12;13(1):272. Epub 2022 Jan 12.

Selecta Biosciences, Watertown, MA, USA.

Biologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.
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http://dx.doi.org/10.1038/s41467-021-27945-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755849PMC
January 2022

Solid serous neoplasm of the pancreas with locally aggressive behaviors.

Pathol Int 2021 Nov 9;71(11):795-797. Epub 2021 Sep 9.

Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/pin.13163DOI Listing
November 2021

ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia.

Mol Ther Methods Clin Dev 2021 Sep 16;22:279-292. Epub 2021 Jul 16.

Selecta Biosciences, Watertown, MA, USA.

A major barrier to adeno-associated virus (AAV) gene therapy is the inability to re-dose patients due to formation of vector-induced neutralizing antibodies (Nabs). Tolerogenic nanoparticles encapsulating rapamycin (ImmTOR) provide long-term and specific suppression of adaptive immune responses, allowing for vector re-dosing. Moreover, co-administration of hepatotropic AAV vectors and ImmTOR leads to an increase of transgene expression even after the first dose. ImmTOR and AAV Anc80 encoding the methylmalonyl-coenzyme A (CoA) mutase (MMUT) combination was tested in a mouse model of methylmalonic acidemia, a disease caused by mutations in the gene. Repeated co-administration of Anc80 and ImmTOR was well tolerated and led to nearly complete inhibition of immunoglobulin (Ig)G antibodies to the Anc80 capsid. A more profound decrease of plasma levels of the key toxic metabolite, plasma methylmalonic acid (pMMA), and disease biomarker, fibroblast growth factor 21 (FGF21), was observed after treatment with the ImmTOR and Anc80-MMUT combination. In addition, there were higher numbers of viral genomes per cell (vg/cell) and increased transgene expression when ImmTOR was co-administered with Anc80-MMUT. These effects were dose-dependent, with the higher doses of ImmTOR providing higher vg/cell and mRNA levels, and an improved biomarker response. Combining of ImmTOR and AAV can not only block the IgG response against capsid, but it also appears to potentiate transduction and enhance therapeutic transgene expression in the mouse model.
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http://dx.doi.org/10.1016/j.omtm.2021.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399083PMC
September 2021

Diagnostic value of IMP3 and p53 immunohistochemical staining in EUS-guided fine-needle aspiration for solid pancreatic tumors.

Sci Rep 2021 08 26;11(1):17257. Epub 2021 Aug 26.

Department of Gastroenterology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

We previously identified insulin-like growth factor-II messenger ribonucleic acid-binding protein 3 (IMP3) as a valuable marker to distinguish malignant from benign lesions in pancreatic solid masses. The aim of this prospective study was to evaluate the usefulness of IMP3 and p53 immunohistochemical staining in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples for pancreatic solid masses. The study recruited 90 consecutive patients with pancreatic masses, including 62 pancreatic ductal adenocarcinomas (PDACs), 11 benign tumors, and 17 other tumors, who underwent EUS-FNA, and conducted IMP3 and p53 immunohistochemical staining. The main outcome measurement was improved diagnostic utility using IMP3 and p53 immunohistochemical staining. IMP3 and p53 expressions were detected in 60.8% and 49.4% of malignant lesions, 69.4% and 58.1% of PDACs, and 0% of benign lesions, respectively. In PDAC and benign tumors, the use of IMP3 and/or p53 immunostaining increased the sensitivity of cytohistological analysis from 88.7 to 93.5%, although the difference was not statistically significant. The sensitivity of histological analysis combined with that of IMP3 staining was 91.9%, which was significantly greater than that of histology alone (80.6%). The use of IMP3 and p53 immunohistochemical staining did not significantly improve the sensitivity of cytohistological analysis; however, IMP3 staining may be helpful for the histological analysis of malignant pancreatic tumors.
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http://dx.doi.org/10.1038/s41598-021-96492-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390649PMC
August 2021

ImmTORTM to amplify the efficacy and reduce immunogenicity of biologics.

Emerg Top Life Sci 2021 11;5(5):597-600

Selecta Biosciences, Inc., Watertown, MA, U.S.A.

In recent months as vaccines against the SARS-CoV-2 virus continue to rollout across the globe, there has been a renewed interest in ways to activate or ignite the immune system. For a vaccine to be effective, it must be immunogenic and specific to provoke the body's defenses to mount an effective response that protects the host from disease. However, there are other situations wherein the immune system mounts an unwanted immune response that can be detrimental to health, either directly, by causing an autoimmune disease, or indirectly, by compromising the safety and/or efficacy of biologic drugs. In these scenarios, it would be desirable to have a 'tolerogenic vaccine' that could selectively and effectively mitigate these unwanted immune responses. ImmTORTM, a nanoparticle technology, is being developed to address the issue of immunogenicity for gene therapy vectors and other biologic drugs. By targeting antigen-presenting cells, ImmTORTM has the potential to amplify the efficacy of biologic therapies and unlock the full potential of such treatments to improve the lives of those who suffer from serious and debilitating diseases.
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http://dx.doi.org/10.1042/ETLS20210127DOI Listing
November 2021

Cerebral large artery stenosis and occlusion in POEMS syndrome.

BMC Neurol 2021 Jun 24;21(1):239. Epub 2021 Jun 24.

Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8677, Chiba, Japan.

Background: This study aimed to investigate the frequency and risk factors for cerebral artery stenosis and occlusion in patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome.

Methods: We reviewed results of magnetic resonance angiography (MRA) or computed tomography angiography (CTA) in 61 patients with POEMS syndrome seen between 2010 and 2017. Stenosis or occlusion was assessed in the initial MRA/CTA. Multivariate analysis was used to identify risk factors for artery stenosis/occlusion. In an autopsy case, pathologic examination was conducted of the occluded middle cerebral arteries.

Results: Stenosis (> 50 %) or occlusion of the major cerebral arteries was found in 29 (47.5 %) patients on the initial MRA/CTA. The internal carotid artery was involved most frequently (32.8 %), followed by the anterior (21.3 %) and middle (16.4 %) cerebral arteries. The basilar (1.3 %) and vertebral (3.6 %) arteries were rarely affected. Cerebral infarction developed in eight (13.1 %) patients. The serum vascular endothelial growth factor (VEGF) level was an independent predictor for stenosis/occlusion (odds ratio, 1.228; 95 % confidence interval, 1.042-1.447; P = 0.014). An autopsy study showed occluded middle cerebral arteries by fibrous and myxomatous thickening of intima with splitting of the internal elastic lamina. Follow-up MRA in 23 patients showed improved, worsened, and unchanged stenosis in 20.7 %, 8.7 %, and 69.6 %, respectively.

Conclusions: Cerebral large-vessel stenosis or occlusion is frequently seen in approximately half of patients with POEMS syndrome. Vasculopathy was related to serum VEGF levels and thereby disease activity. Assessment of cerebral vessels is recommended in these patients to improve management.
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http://dx.doi.org/10.1186/s12883-021-02260-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223276PMC
June 2021

Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles.

Front Immunol 2021 25;12:637469. Epub 2021 May 25.

Selecta Biosciences, Watertown, MA, United States.

ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4 and CD8 T cells, and the emergence of a large population of CD4CD8 (double negative) T cells. ImmTOR treatment protected mice in a concanavalin A-induced model of acute hepatitis, as evidenced by reduced production of inflammatory cytokines, infiltrate of activated leukocytes, and tissue necrosis. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR treatment.
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http://dx.doi.org/10.3389/fimmu.2021.637469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186318PMC
September 2021

Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke.

BMC Med 2021 06 9;19(1):131. Epub 2021 Jun 9.

Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.

Background: Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS.

Methods: Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay.

Results: The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297-311 of DIDO1, 426-440 of FOXJ2, and 607-621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case-control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS.

Conclusions: Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.
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http://dx.doi.org/10.1186/s12916-021-02001-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188684PMC
June 2021

Tolerogenic Nanoparticles Impacting B and T Lymphocyte Responses Delay Autoimmune Arthritis in K/BxN Mice.

ACS Chem Biol 2021 10 26;16(10):1985-1993. Epub 2021 May 26.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States.

Current treatments for unwanted antibody responses largely rely on immunosuppressive drugs compromising overall immunity. New approaches to achieve antigen-specific tolerance are desirable to avoid unwanted side effects. Several nanoparticle-based approaches that utilize different mechanisms to tolerize the B or T cell arms of the humoral immune response have shown promise for induction of antigen-specific tolerance, raising the possibility that they could work synergistically if combined. Earlier we showed that Siglec-engaging tolerance-inducing antigenic liposomes (STALs) that display both an antigen (Ag) and glycan ligands of the inhibitory co-receptor CD22 (CD22L) lead to robust antigen-specific B cell tolerance to protein antigens in naive mice. In another approach, administration of free Ag with poly(lactic--glycolic acid)-rapamycin nanoparticles (PLGA-R) induced robust antigen-specific tolerance through production of regulatory T cells. Here we illustrate that coadministration of STALs together with PLGA-R to naive mice induced more robust tolerance to multiple antigen challenges than either nanoparticle alone. Moreover, in K/BxN mice that develop spontaneous autoimmune arthritis to the self-antigen glucose-6-phosphate-isomerase (GPI), co-delivery of GPI-LP-CD22L and PLGA-R delayed onset of disease and in some mice prevented the disease indefinitely. The results show synergy between B cell-tolerizing STALs and T cell-tolerizing PLGA-R and the potential to induce tolerance in early stage autoimmune disease.
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http://dx.doi.org/10.1021/acschembio.1c00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526371PMC
October 2021

Enhancement of liver-directed transgene expression at initial and repeat doses of AAV vectors admixed with ImmTOR nanoparticles.

Sci Adv 2021 02 24;7(9). Epub 2021 Feb 24.

Selecta Biosciences, Watertown, MA 02472, USA.

Systemic AAV (adeno-associated virus) gene therapy is a promising approach for the treatment of inborn errors of metabolism, but questions remain regarding its potency and durability. Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been shown to block the formation of neutralizing anti-capsid antibodies, thereby enabling vector re-administration. Here, we further demonstrate that ImmTOR admixed with AAV vectors also enhances hepatic transgene expression at the initial dose of AAV vector, independent of its effects on adaptive immunity. ImmTOR enhances AAV trafficking to the liver, resulting in increased hepatic vector copy numbers and transgene mRNA expression. Enhanced transgene expression occurs through a mechanism independent of the AAV receptor and cannot be replicated in vivo with free rapamycin or empty nanoparticles. The multipronged mechanism of ImmTOR action makes it an attractive candidate to enable more efficient transgene expression at first dose while simultaneously inhibiting adaptive responses against AAV to enable repeat dosing.
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http://dx.doi.org/10.1126/sciadv.abd0321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904260PMC
February 2021

Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector.

Mol Ther Methods Clin Dev 2021 Mar 17;20:169-180. Epub 2020 Nov 17.

International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked liver disorder caused by partial or total loss of OTC enzyme activity. It is characterized by elevated plasma ammonia, leading to neurological impairments, coma, and death in the most severe cases. OTCD is managed by combining dietary restrictions, essential amino acids, and ammonia scavengers. However, to date, liver transplantation provides the best therapeutic outcome. AAV-mediated gene-replacement therapy represents a promising curative strategy. Here, we generated an AAV2/8 vector expressing a codon-optimized human cDNA by the α1-AAT liver-specific promoter. Unlike standard codon-optimization approaches, we performed multiple codon-optimization rounds via common algorithms and ortholog sequence analysis that significantly improved mRNA translatability and therapeutic efficacy. AAV8-hOTC-CO (codon optimized) vector injection into adult OTC mice (5.0E11 vg/kg) mediated long-term complete correction of the phenotype. Adeno-Associated viral (AAV) vector treatment restored the physiological ammonia detoxification liver function, as indicated by urinary orotic acid normalization and by conferring full protection against an ammonia challenge. Removal of liver-specific transcription factor binding sites from the AAV backbone did not affect gene expression levels, with a potential improvement in safety. These results demonstrate that AAV8-hOTC-CO gene transfer is safe and results in sustained correction of OTCD in mice, supporting the translation of this approach to the clinic.
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http://dx.doi.org/10.1016/j.omtm.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786024PMC
March 2021

Postmortem magnetic resonance imaging revealed bilateral globi pallidi lesions in a death associated with prolonged carbon monoxide poisoning: a case report.

Int J Legal Med 2021 May 14;135(3):921-928. Epub 2021 Jan 14.

Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

A man and a woman were found dead in the same car with a burned coal briquette. The cause of death of the woman was assigned to acute carbon monoxide (CO) poisoning without difficulty based on typical findings associated with this condition, including elevation of carboxyhaemoglobin (COHb). However, the man had an unremarkable elevation of COHb and a higher rectal temperature compared to that of the woman. Postmortem computed tomography (PMCT) revealed ambiguous low-density areas in the bilateral globi pallidi. Further analysis by postmortem magnetic resonance (PMMR) imaging showed these lesions more clearly; the lesions appeared as marked high signal intensity areas on both the T2-weighted images and the fluid-attenuated inversion recovery sequences. A subsequent autopsy revealed signs of pneumonia, dehydration, starvation, and hypothermia, suggesting that the man died from prolonged CO poisoning. Both globi pallidi contained grossly ambiguous lesions, and a detailed neuropathologic investigation revealed these lesions to be coagulative necrotic areas; this finding was compatible with a diagnosis of prolonged CO poisoning. This case report shows that postmortem imaging, especially PMMR, is useful for detecting necrotic lesions associated with prolonged CO poisoning. This report further exemplifies the utility of PMMR for detecting brain lesions, which may be difficult to detect by macroscopic analysis.
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http://dx.doi.org/10.1007/s00414-021-02506-1DOI Listing
May 2021

Simultaneous brain and lung metastases of pancreatic ductal adenocarcinoma after curative pancreatectomy: a case report and literature review.

BMC Gastroenterol 2021 Jan 6;21(1). Epub 2021 Jan 6.

Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Background: Pancreatic ductal adenocarcinoma (PDAC) rarely metastasizes to the brain; therefore, the features of brain metastasis of PDAC are still unknown. We encountered simultaneous metastases to the brain and lung in a PDAC patient after curative surgery. Case presentation A 68-year-old man with PDAC in the tail of the pancreas underwent distal pancreato-splenectomy. He received gemcitabine as adjuvant chemotherapy for 6 months. Two months later, brain and lung metastases occurred simultaneously. Considering the systemic condition, the patient received gamma knife treatment and an Ommaya reservoir was inserted for drainage. The patient's condition gradually worsened and he received the best supportive care. To the best of our knowledge, only 28 cases in which brain metastases of PDAC were identified at the time of ante-mortem have been reported to date, including the present case. Notably, the percentage of simultaneous brain and lung metastases was higher (32%) in a series of reviewed cohorts. Thus, lung metastasis might be one of the risk factors for the development of brain metastasis in patients with PDAC. As a systemic disease, it can be inferred that neoplastic cells will develop brain metastasis via hematogenous dissemination beyond the blood-brain barrier, even if local recurrence is controlled. In our case, immunohistochemical staining showed that the neoplastic cells were positive for carbonic anhydrase 9 (CAIX), mucin core protein 1 (MUC1), and MUC5AC in the resected primary PDAC.

Conclusion: We describe a case of simultaneous brain and lung metastases of PDAC after curative pancreatectomy, review previous literature, and discuss the clinical features of brain metastasis of PDAC.
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http://dx.doi.org/10.1186/s12876-020-01587-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789346PMC
January 2021

Serum anti-LRPAP1 is a common biomarker for digestive organ cancers and atherosclerotic diseases.

Cancer Sci 2020 Dec 4;111(12):4453-4464. Epub 2020 Oct 4.

Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti-human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S-transferase-fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis-related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well-known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking.
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http://dx.doi.org/10.1111/cas.14652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734161PMC
December 2020

Comprehensive Analysis of Barrett's Esophagus: Focused on Carcinogenic Potential for Barrett's Cancer in Japanese Patients.

Dig Dis Sci 2021 08 25;66(8):2674-2681. Epub 2020 Aug 25.

Department of Gastroenterology, Graduate School of Medicine, Chiba University Hospital, Inohana 1-8-1, Chiba-City, 260-8670, Japan.

Background/aim: Barrett's esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). Therefore, an accurate diagnosis of BE is important for the subsequent follow-up and early detection of EAC. However, the definitions of BE have not been standardized worldwide; columnar-lined epithelium (CLE) without intestinal metaplasia (IM) and/or < 1 cm is not diagnosed as BE in most countries. This study aimed to clarify the malignant potential of CLE without IM and/or < 1 cm genetically.

Method: A total of 96 consecutive patients (including nine patients with EAC) who had CLE were examined. Biopsies for CLE were conducted, and patients were divided into those with IM and > 1 cm (Group A) and those without IM and/or < 1 cm (Group B). Malignant potential was assessed using immunochemical staining for p53. Moreover, causative genes were examined using next-generation sequencing (NGS) on ten patients without Helicobacter pylori infection and without atrophic gastritis.

Result: Of the 96 patients, 66 were in Group B. The proportion of carcinoma/dysplasia in Group A was significantly higher than that in Group B (26.7% in Group A and 1.5% in Group B; p < 0.01). However, one EAC patient was found in Group B. In the immunostaining study for non-EAC patients, an abnormal expression of p53 was not observed in Group A, whereas p53 loss was observed in three patients (4.6%) in Group B. In the NGS study, a TP53 mutation was found in Group B.

Conclusion: CLE without IM and/or < 1 cm has malignant potential. This result suggests that patients with CLE as well as BE need follow-up.
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http://dx.doi.org/10.1007/s10620-020-06563-1DOI Listing
August 2021

Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies.

Front Immunol 2020 20;11:969. Epub 2020 May 20.

Selecta Biosciences, Watertown, MA, United States.

The development of anti-drug antibodies (ADAs) is a common cause for treatment failure and hypersensitivity reactions for many biologics. The focus of this review is the development of ImmTOR, a platform technology designed to prevent the formation of ADAs that can be applied broadly across a wide variety of biologics by inducing immunological tolerance with ImmTOR nanoparticles encapsulating rapamycin. The induction of tolerance is antigen-specific and dependent on the incorporation of rapamycin in nanoparticles and the presence of the antigen at the time of administration of ImmTOR. Evidence for the induction of specific immune tolerance vs. general immune suppression is supported by the findings that: (1) ImmTOR induces regulatory T cells specific to the co-administered antigen; (2) tolerance can be transferred by adoptive transfer of splenocytes from treated animals to naïve recipients; (3) the tolerance is durable to subsequent challenge with antigen alone; and (4) animals tolerized to a specific antigen are capable of responding to an unrelated antigen. ImmTOR nanoparticles can be added to new or existing biologics without the need to modify or reformulate the biologic drug. The ability of ImmTOR to mitigate the formation of ADAs has been demonstrated for coagulation factor VIII in a mouse model of hemophilia A, an anti-TNFα monoclonal antibody in a mouse model of inflammatory arthritis, pegylated uricase in hyperuricemic mice and in non-human primates, acid alpha-glucosidase in a mouse model of Pompe disease, recombinant immunotoxin in a mouse model of mesothelioma, and adeno-associated vectors in a model of repeat dosing of gene therapy vectors in mice and in non-human primates. Human proof-of concept for the mitigation of ADAs has been demonstrated with SEL-212, a combination product consisting of ImmTOR + pegadricase, a highly immunogenic enzyme therapy for the treatment of gout. ImmTOR represents a promising approach to preventing the formation of ADAs to a broad range of biologic drugs.
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http://dx.doi.org/10.3389/fimmu.2020.00969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251066PMC
March 2021

Endoscopic Ultrasound Criteria for Arterial Invasion in Pancreatic Cancer of the Body and Tail.

Pancreas 2020 04;49(4):561-567

From the Departments of Gastroenterology.

Objectives: We aimed to determine the difference in endoscopic ultrasonography (EUS) images between portal vein (PV) and arterial invasion of pancreatic cancer and to develop criteria for arterial involvement.

Methods: We reviewed EUS data of consecutive patients who underwent distal pancreatectomy from December 2010 to May 2017. We categorized the tumor-vessel relationship into 4 and 5 types, respectively, for the PV and arteries: (a) clear separation between tumor and vessel; (b) tumor border at vessel, echo-rich vessel wall uninterrupted; (c) echo-rich vessel wall interrupted; (d) vessel contour irregularity; and (e) arterial wall thickening or echogenic band surrounding the artery. We compared EUS outcomes with surgical and pathological results.

Results: Overall, 56 patients underwent distal pancreatectomy, of whom 22 received en bloc celiac axis resection. The pathological invasion rates of PVs and arteries were 46.2% and 0% in (c), and 72.5% and 42.4% in (d) (P = 0.046, P = 0.016), respectively. The overall sensitivity and specificity were 92.1% and 83.2%, respectively, for diagnosing venous invasion and 70.0% and 84.4%, respectively, for arterial invasion.

Conclusions: Different EUS criteria may be necessary for diagnosing arterial and portal venous invasions. Criterion (d) might be appropriate for diagnosing arterial invasion.
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http://dx.doi.org/10.1097/MPA.0000000000001523DOI Listing
April 2020

Diffusion-Weighted Magnetic Resonance Imaging and 18-Fluorodeoxglucose Positron Emission Tomography With Computed Tomography for Evaluating Malignancy of Branch Duct and Mixed Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Pancreas 2019 May/Jun;48(5):e43-e45

Department of Gastroenterology, Graduate School of Medicine, Chiba UniversityChiba, Japan. Department of Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan Diagnostic Imaging Center, Sannou Hospital Medical Center, Chiba, Japan Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1097/MPA.0000000000001316DOI Listing
February 2020

Underwater cold snare polypectomy for colorectal adenomas.

Dig Endosc 2019 Nov 27;31(6):662-671. Epub 2019 May 27.

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

Background And Aim: Cold snare polypectomy (CSP) is a safe treatment for colorectal adenomas. However, the R0 resection rate is not sufficiently high because of inadequate resection of muscularis mucosa. We hypothesized that CSP in an underwater environment could improve this procedure by helping to safely achieve resection containing the muscularis mucosa. We have named this procedure underwater cold snare polypectomy (UCSP). We aimed to investigate the efficacy and safety of UCSP for colorectal adenomas.

Methods: Between May 2017 and April 2018, patients diagnosed with colorectal adenomas <9 mm underwent UCSP. After follow-up colonoscopy 3 weeks later, the patients post-UCSP scars were biopsied. Outcomes were compared with those of a historical control group who underwent conventional CSP in our previous study using propensity score-matching methods.

Results: Overall, 224 lesions in 65 patients were prospectively resected by UCSP. Pathologically, 209 lesions were adenomas (4.5 ± 1.5 mm) including one intramucosal carcinoma. Only one pathological residual adenoma was identified, but there was no significant difference in the residual rate between the UCSP and CSP groups (both 1.0%). No complications were observed. R0 resection rate and rate of area containing the muscularis mucosa in the UCSP group were significantly higher than those in the CSP group (80.2% vs 32.7%, P < 0.001; 50.0% vs 35.3%, P = 0.015).

Conclusion: Underwater cold snare polypectomy for diminutive and small colorectal adenomas was safe and effective from the perspective of pathological complete resection, which is likely facilitated by achieving an adequate depth of resection.
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http://dx.doi.org/10.1111/den.13427DOI Listing
November 2019

Fatal atlantoaxial dislocation due to an odontoid synchondrosis fracture in a child with chromosome 9 abnormality: A case report.

J Forensic Leg Med 2019 Feb 29;61:92-96. Epub 2018 Nov 29.

Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba city, Chiba Prefecture, 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

A 5-year-old boy with a chromosome-9 abnormality and multiple external and visceral malformations was found in cardiopulmonary arrest during a regular visit to the hospital; he did not respond to cardiopulmonary resuscitation and died. An odontoid process fracture and calcification and fibrosis of the muscles around the superior cervical vertebra were observed during the autopsy. Postmortem computed tomography revealed an anterior dislocation of the atlas; odontoid synchondrosis fracture; and delayed, incomplete bony fusion of the odontoid process relative to his age. The cause of his death was a superior spinal cord injury. The tissue surrounding the upper cervical spine presented with myositis ossificans, suggesting a prior injury. He experienced a minor traffic accident 3 months before his death. It was concluded that the odontoid synchondrosis fracture occurred during the accident based on the incomplete bony fusion and atlantoaxial instability, which were consistent with the findings of myositis ossificans. Delayed fatal dislocation may then have occurred under the influence of a minor external force. Odontoid process abnormalities and atlantoaxial instability are common in patients with trisomy 21 and other congenital diseases; however, the condition's association with chromosome-9 abnormalities has not been reported. In children with various chromosomal abnormalities, periodic assessment of instability and morphology of the cervical spine, and a lowered examination threshold for the children at risk, could prove useful in the prevention injuries leading to fatality, and provide additional information to rule out abuse.
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http://dx.doi.org/10.1016/j.jflm.2018.11.011DOI Listing
February 2019

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration.

Nat Commun 2018 10 5;9(1):4098. Epub 2018 Oct 5.

Sorbonne Université and INSERM U974, 105 boulevard de l'Hôpital, 75651, Paris, France.

Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates. SVP[Rapa] dosed with AAV vectors reduces B and T cell activation in an antigen-selective manner, inhibits CD8 T cell infiltration in the liver, and efficiently blocks memory T cell responses. SVP[Rapa] immunomodulatory effects can be transferred from treated to naive mice by adoptive transfer of splenocytes, and is inhibited by depletion of CD25 T cells, suggesting a role for regulatory T cells. Co-administration of SVP[Rapa] with AAV vector represents a powerful strategy to modulate vector immunogenicity and enable effective vector re-administration.
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http://dx.doi.org/10.1038/s41467-018-06621-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173722PMC
October 2018

Ectopic overexpression of Kir6.1 in the mouse heart impacts on the life expectancy.

Sci Rep 2018 08 6;8(1):11723. Epub 2018 Aug 6.

Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.

We recently reported the reduced ATP-sensitive potassium (K) channel activities in the transgenic mouse heart overexpressing the vascular type K channel pore-forming subunit (Kir6.1). Although dysfunction of cardiac K channel has been nominated as a cause of cardiomyopathy in human, these transgenic mice looked normal as wild-type (WT) during the experiment period (~20 weeks). Extended observation period revealed unexpected deaths beginning from 30 weeks and about 50% of the transgenic mice died by 55 weeks. Surface ECG recordings from the transgenic mice at rest demonstrated the normal sinus rhythm and the regular ECG complex as well as the control WT mice except for prolonged QT interval. However, the stress ECG test with noradrenaline revealed abnormal intraventricular conduction delay and arrhythmogeneity in the transgenic mouse. Fibrotic changes in the heart tissue were remarkable in aged transgenic mice, and the cardiac fibrosis developed progressively at least from the age of 30 weeks. Gene expression analyses revealed the differentiation of cardiac fibroblasts to myofibroblasts with elevated cytokine expressions was initiated way in advance before the fibrotic changes and the upregulation of BNP in the ventricle. In sum, Kir6.1TG mice provide an electro-pathological disease concept originated from K channel dysfunction.
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http://dx.doi.org/10.1038/s41598-018-30175-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078942PMC
August 2018
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