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Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl 4 ) for 4 weeks to induce liver fibrosis, followed by combined CCl 4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl 4 for 2 weeks, followed by CCl 4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-β-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-β/Smad pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Schizophrenia (SCZ) is one of the major psychiatric disorders. The genetic factor is certainly influential in the onset of the disease but is not decisive. There is no identified molecular/cellular marker of the disease, and the pathomechanism is still unknown. In this study, we generated human induced pluripotent stem cells (iPSCs) derived from SCZ-discordant fraternal twins, and they could contribute to elucidation of the pathomechanism of SCZ., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disease, characterized by abnormal calcium deposits in basal ganglia of the brain. The affected individuals exhibit movement disorders, and progressive deterioration of cognitive and psychiatric ability. The genetic cause of the disease is mutation in one of several different genes, SLC20A2, PDGFB, PDGFRB, XPR1 or MYORG, which inheritably or sporadically occurs. Here we generated an induced pluripotent stem cell (iPSC) line from an IBGC patient, which is likely be a powerful tool for revealing the pathomechanisms and exploring potential therapeutic candidates of IBGC., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to clarify the role of Methicillin-resistant Staphylococcus aureus (MRSA) carriers in the development of surgical site infection (SSI) after colorectal surgery., Summary Background Data: MRSA is commonly implicated in hospital-acquired infections. Active surveillance culture (ASC) using the nasal swab test is useful to detect MRSA in surgical patients. We hypothesized that MRSA carriers would be more susceptible to SSI after colorectal surgery METHODS: Patients who underwent ASC between 2010 and 2013 were included in this study. The incidence of SSI was compared between MRSA carriers and non-carriers using the chi-square test. The odds ratio for SSI was computed using logistic regression analyses., Results: Among 355 patients, 12 (3.4%) were identified as MRSA carriers and 343 as non-carriers. Of all the patients, 65 patients (18.3%) developed an SSI. Of these, 6 cases were in MRSA carriers and 59 cases were in non-carriers (p < 0.01). This meant that half of the 12 MRSA carriers developed an SSI, compared with only 17.2% of non-carriers (59 cases out of 343 patients). Therefore, MRSA carriers had a significantly higher risk of SSI (adjusted odds ratio = 4.77 [1.37 to 16.6], p = 0.01)., Conclusions: Detection of MRSA via ASC is significantly associated with the development of SSI after colorectal surgery. These findings indicate that ASC for MRSA is useful to predict an SSI., Competing Interests: Declaration of Competing Interest Koji Okabayashi reports grants from Taiho Oncology Inc, CHUGAI PHARMACEUTICAL CO., LTD., and Toray Industries, Inc. Kitagawa has received grants and personal fees from AsahiKASEI Co., Ltd., grants and personal fees from TAIHO PHARMACEUTICAL CO., LTD, grants and personal fees from CHUGAI PHARMACEUTICAL CO., LTD., grants from DAIICHI SANKYO COMPANY, LIMITED, grants from Merck Serono Co., Ltd., grants and personal fees from EA Pharma Co., Ltd., grants and personal fees from Yakult Honsha Co. Ltd., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Otsuka Pharmaceutical Factory Inc., grants and personal fees from SHIONOGI & CO., LTD. , grants from KAKEN PHARMACEUTICAL CO.,LTD., grants from Kowa Pharmaceutical Co., Ltd., grants and personal fees from Astellas Pharma Inc., grants from MEDICON INC., grants and personal fees from DAINIPPON SUMITOMO PHARMA Co., Ltd., grants and personal fees from Taisho Toyama Pharmaceutical Co., Ltd., grants from Kyouwa Hakkou Kirin Co., Ltd., grants from Pfizer Japan Inc., grants and personal fees from ONO PHARMACEUTICAL CO., LTD., grants and personal fees from NIHON PHARMACEUTICAL CO., LTD., grants from Japan Blood Products Organization, grants from Medtronic Japan Co., Ltd., grants and personal fees from Sanofi K.K., grants from Eisai Co., Ltd. , grants from TSUMURA & CO., grants from KCI Licensing, Inc., grants from ABBOTT JAPAN CO., LTD., grants from FUJIFILM Toyama Chemical Co., Ltd., outside the submitted work., (Copyright © 2020. Published by Elsevier Ltd.)

Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder caused by mutations of the glucose-6-phosphatase (G6PC) gene. Mutations of the G6PC gene lead to excessive accumulation of glycogen in the liver, kidney, and intestinal mucosa due to the deficiency of microsomal glucose-6-phosphatase. Human induced pluripotent stem cells (iPSCs) enable the production of patient-derived hepatocytes in culture and are therefore a promising tool for modeling GSD1a. Here, we report the establishment of human iPSCs from a GSD1a patient carrying a G6PC mutation (c.648G > T; p.Leu216 = )., (Copyright © 2020. Published by Elsevier B.V.)

Background & Aims: Toll-like receptor 4 (TLR4) plays an essential role in mediating organ injury in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Herein, we assess whether inhibiting TLR4 signaling can ameliorate liver failure and serve as a potential treatment., Methods: Circulating TLR4 ligands and hepatic TLR4 expression were measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo (10 mg/kg intraperitoneally) in rodent models of ACLF (bile duct ligation + lipopolysaccharide [LPS]; carbon tetrachloride + LPS) and ALF (galactosamine + LPS) and in vitro on immortalized human monocytes (THP-1) and hepatocytes (HHL5). The in vivo therapeutic effect was assessed by coma-free survival, organ injury and cytokine release and in vitro by measuring IL-6, IL-1β or cell injury (TUNEL), respectively., Results: In patients with cirrhosis, hepatic TLR4 expression was upregulated and circulating TLR4 ligands were increased (p <0.001). ACLF in rodents was associated with a switch from apoptotic cell death in ALF to non-apoptotic forms of cell death. TAK-242 reduced LPS-induced cytokine secretion and cell death (p = 0.002) in hepatocytes and monocytes in vitro. In rodent models of ACLF, TAK-242 administration improved coma-free survival, reduced the degree of hepatocyte cell death in the liver (p <0.001) and kidneys (p = 0.048) and reduced circulating cytokine levels (IL-1β, p <0.001). In a rodent model of ALF, TAK-242 prevented organ injury (p <0.001) and systemic inflammation (IL-1β, p <0.001)., Conclusion: This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF; its inhibition reduces the severity of organ injury and improves outcome. TAK-242 may be of therapeutic relevance in patients with liver failure., Lay Summary: Toll-like receptor 4 (or TLR4) mediates endotoxin-induced tissue injury in liver failure and cirrhosis. This receptor sensitizes cells to endotoxins, which are produced by gram-negative bacteria. Thus, inhibiting TLR4 signaling with an inhibitor (TAK-242) ameliorates organ injury and systemic inflammation in rodent models of acute and acute-on-chronic liver failure., Competing Interests: Conflict of interest Rajiv Jalan has research collaborations with Takeda, and Yaqrit, and consults for Yaqrit. Rajiv Jalan is the founder of Yaqrit Limited, which is developing UCL inventions for treatment of patients with cirrhosis. Rajiv Jalan is an inventor of ornithine phenylacetate, which was licensed by UCL to Mallinckrodt. He is also the inventor of Yaq-001, DIALIVE and Yaq-005, the patents for which have been licensed by his University into a UCL spinout company, Yaqrit Ltd. Cornelius Engelmann has on-going research collaboration with Sequana Medical, Merz Pharmaceutical and Novartis. He has received speaker fees from Novartis, Gilead and Merz Pharmaceuticals. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Age-related macular degeneration (AMD) is a late-onset progressive blinding disease. We established human induced pluripotent stem cells (iPSCs) from an AMD patient. The generated iPSC line showed pluripotency markers and three-germ layer differentiation ability in vitro. This iPSC line will be useful for elucidating the pathomechanisms of and drug discovery for AMD., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a devastating movement disorder with an unknown etiology. Multiplications of the SNCA gene cause the autosomal dominant form of familial PD as well as missense mutations of the gene. We established and characterized a human induced pluripotent stem cell (iPSC) line from a PD patient carrying SNCA duplication. The iPSC line displayed a capacity to differentiate into midbrain dopaminergic neurons affected in PD. The iPSC line will be useful for disease modeling applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Best Disease is an inherited retinal dystrophy that results in progressive and irreversible central vision loss caused by mutations of BESTROPHIN1 (BEST1). We established human induced pluripotent stem cells (iPSCs) from a Best disease patient with mutations R218H and A357V in the BEST1 gene. The generated iPSCs showed pluripotency markers and three-germ layer differentiation ability in vitro. A genetic analysis revealed mutations of R218H and A357V in the iPSCs. This iPSC line will be useful for elucidating the pathomechanisms of and drug discovery for Best disease., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Mucopolysaccharidosis type I (MPS I) is a rare inherited metabolic disorder caused by defects in alpha-L-iduronidase (IDUA), a lysosomal protein encoded by IDUA gene. MPS I is a progressive multisystemic disorder with a wide range of symptoms, including skeletal abnormalities and cognitive impairment, and is characterized by a wide spectrum of severity levels caused by varied mutations in IDUA. A human iPSC line was established from an attenuated MPS I (Scheie syndrome) patient carrying an IDUA gene mutation (c.266G > A; p.R89Q). This disease-specific iPSC line will be useful for the research of MPS I., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease defined by the presence of eosinophilic hyaline intranuclear inclusions. The initial and main clinical feature of adult-onset NIID is predominantly dementia. We present herein 2 cases of sporadic adult-onset NIID with longstanding urinary disturbance prior to development of other neurological symptoms. Case 1: A 71-year-old woman was admitted after she lost consciousness while bathing. She presented slowly progressive bladder dysfunction starting at the age of 40. Recently, she complained of recurrent light-headedness on standing. Her neurological findings showed miosis, muscle weakness, rigidity, hyporeflexia, sensory disturbance, cerebellar ataxia, and orthostatic hypotension. Case 2: A 68-year-old man was admitted because of episodes of transient loss of consciousness. Ten years earlier, he had developed urinary dysfunction. His neurological findings revealed cognitive dysfunction, cerebellar ataxia, and hyporeflexia. Both patients had leukoencephalopathy and motor-sensory neuropathy. In both cases, diffusion-weighted imaging showed high-intensity signals in the corticomedurally junction; and skin biopsy samples revealed ubiquitin-positive intranuclear inclusions. Therefore, we made a diagnosis of adult-onset NIID. Although numerous cases of this disorder have been reported in the past, there were only a few cases showing the development of other neurological symptoms after longstanding urinary disturbance. Our cases suggest that it is worthwhile considering the possibility of NIID in cases with a long-term history of neurogenic bladder dysfunction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited epileptic syndrome, and it is associated with mutations of leucine-rich glioma inactivated 1 (LGI1) gene. The underlying mechanisms of ADLTE are still unknown, as human neurons are difficult to obtain as a research tool. Human induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish, and can be a promising tool to model ADLTE. Here, we report the establishment of human iPSCs from an ADLTE patient carrying LGI1 mutation (c.1418C>T, p.Ser473Leu)., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease or primary familial brain calcifications (PFBC), is a rare neurodegenerative disorder characterized by calcium deposits in basal ganglia and other brain regions, causing neuropsychiatric and motor symptoms. We established human induced pluripotent stem cells (iPSCs) from an IBGC patient. The established IBGC-iPSCs carried SLC20A2 c.1848G>A mutation (p.W616* of translated protein PiT2), and also showed typical iPSC morphology, pluripotency markers, normal karyotype, and the ability of in vitro differentiation into three-germ layers. The iPSC line will be useful for further elucidating the pathomechanism and/or drug development for IBGC., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 20-year-old dystonia patient with a GCH1 mutation (DYT5). Episomal vectors were used to introduce reprogramming factors (OCT3/4, SOX2, KLF4, L-MYC, LIN28, and p53 carboxy-terminal dominant-negative fragment) to the PBMCs. The generated iPSCs expressed pluripotency markers, and were capable of differentiating into derivates of all three germ layers in vitro. The iPSC line also showed a normal karyotype and preserved the GCH1 mutation. This cellular model can provide opportunities to perform pathophysiological studies for aberrant dopamine metabolism-related disorders., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To delineate chronological changes of cortical hyperexcitability by long-term follow-up of the amplitudes of somatosensory evoked potentials (SEPs) in patients with Japanese Unverricht-Lundborg disease (ULD)., Method: SEPs to median nerve stimulation were repeatedly examined in 7 genetically diagnosed ULD patients with the mean interval of 11.9 years. The degree of temporal changes in the amplitude of 3 early cortical components, N20, P25 and N35, to the age was analyzed and compared with that of healthy subjects., Results: Their clinical course was almost stable during the follow-up period, namely cessation of generalized tonic-clonic seizures and little or no progression of myoclonus. SEP amplitudes of P25 and N35 were enlarged in all patients and were gradually decreased with aging in ULD on average. The degree of temporal changes of P25 and N35 in ULD was similar or even lower than that of healthy subjects., Conclusion: Enlarged but relatively stable SEP amplitudes had a consistency with so-called self-limited clinical course in Japanese ULD. SEP amplitude could be one of the surrogate markers of the degree of cortical hyperexcitability in ULD during the long-term follow-up period., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To delineate long-term change of cortical excitability by measuring somatosensory evoked potentials (SEPs) in patients with Unverricht-Lundborg disease (ULD)., Methods: SEPs to median nerve stimulation were repeatedly examined in two genetically proven ULD patients manifesting stable condition over 16 years, namely disabling but non-progressive myoclonus and cessation of generalised tonic-clonic seizures., Results: In both patients, five sets of early cortical components were identified 16 years ago: two tangential components of N20-P20 and P30-N30 and three radial components of P25, N35 and N40. Cortical SEPs were regarded as abnormally enhanced 'giant' based on the N35 amplitude (>mean+3 SD of normal controls). The bimodal negative peaks of N35 and N40 showed different spatial distribution: N35 maximum in the central area and N40 in the centro-parietal area. At present, N35 remained giant while N40 disappeared in both patients., Conclusions: It is possible that currently preserved giant SEPs at least at N35 reflect disabling cortical myoclonus and that disappearance of N40 might reflect a lesser degree of increased cortico-cortical connectivity and/or decreased cortical hyperexcitability in the association cortices. It might possibly have resulted in the disappearance of GTCSs., Significance: We delineated long-term change of giant SEP in ULD., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To test the hypothesis that loss of molar support causes increased stress and strain in the periodontal structures surrounding the premolars, and to assess the influence of denture use on stress distribution., Methods: Subjects included female patients with unilateral and bilateral loss of mandibular molar teeth and controls with complete dentition (n=7 in each group). The subjects included had normal dentition mesial to the edentulous region and use of a lower free-end saddle removable partial denture. Occlusal contacts were registered in vivo, and a patient-specific finite element model was constructed for each subject based on morphological measurements of the diagnostic cast and radiographs. The maximum bite force on each tooth was then used to calculate the stress and strain on the cortical and the cancellous bone., Results: Mean maximum bite force and maximum principal stress and strain on periodontal tissues of the second premolars were significantly higher in the bilateral molar loss group than those in the other groups (p<0.05). The increase in stress could not be prevented by wearing dentures. The mean maximum stress and strain per bite force were relatively constant among the groups, indicating that the increased maximum stress and strain in the bilateral molar loss group was attributed to the higher maximum bite force., Conclusions: The results suggest that the periodontium surrounding the most posteriorly located occluding premolars may become sensitive to bilateral loss of molar support when patients exhibit higher maximum bite forces.

Autoimmune autonomic ganglionopathy (AAG) is a disorder defined by antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia. We report two patients with chronically progressing dysautonomia with Sjögren's syndrome (SS). The first case showed elevated titer of ganglionic acetylcholine receptor (AChR) antibody and improved with oral intake of prednisolone. In contrast, the second case showed no elevation of ganglionic AChR antibody titer and had poor response to immunomodulatory therapy. These two cases indicate that chronic AAG may be treatable by immunomodulatory therapy, and have relevance to SS.

Natural killer (NK) cell-mediated cytotoxicity is triggered by multiple activating receptors associated with the signaling adaptor protein DNAX activation protein 12/killer cell-activating receptor-associated protein (DAP12/KARAP). Here, we show that one of these receptors, NKp44, is present on a subset of natural interferon-producing cells (IPCs) in tonsils. NKp44 expression can also be induced on blood IPCs after in vitro culture with interleukin 3 (IL-3). Crosslinking of NKp44 does not trigger IPC-mediated cytotoxicity but, paradoxically, inhibits interferon alpha (IFN-alpha) production by IPCs in response to cytosine-phosphate-guanosine (CpG) oligonucleotides. We find that IPCs in tonsils are in close contact with CD8+ T cells and demonstrate that a subset of memory CD8+ T cells produces IL-3. Therefore, IL-3-mediated induction of NKp44 on IPCs may be an important component of the ongoing crosstalk between the innate and adaptive immune response that allows memory CD8+ T cells to control the IPC response to virus.