Publications by authors named "Tomoko Tanaka"

180 Publications

Xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis.

Xenotransplantation 2021 May 6:e12693. Epub 2021 May 6.

Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Background: The clinical utility of stem cell therapy for peripheral artery disease has not been fully discussed, and one obstacle is limited donor supplies. In this study, we attempted to rescue mouse ischemic hind limb by xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells (npBM-MSCs).

Methods: Neonatal porcine bone marrow-derived mesenchymal stem cells were transplanted to ischemic hind limbs of male C57BL/6J mice (npBM-MSCs group). Mice with syngeneic transplantation of mouse BM-MSCs (mBM-MSCs group) were also prepared for comparison. The angiogenic effects were evaluated by recovery of blood flow on laser Doppler imaging, histologic findings, and genetic and protein levels of angiogenic factors.

Results: Regarding laser Doppler assessments, blood flow in the hind limb was rapidly recovered in the npBM-MSCs group, compared with that in the mBM-MSCs group (P = .016). Compared with the mBM-MSCs group, the npBM-MSCs group had early and prominent lymphangiogenesis [P < .05 on both post-operative days (PODs) 3 and 7] but had similar angiogenesis. Regarding genomic assessments, xenotransplantation of npBM-MSCs enhanced the expressions of both porcine and murine Vegfc in the hind limbs by POD 3. Interestingly, the level of murine Vegfc expression was significantly higher in the npBM-MSCs group than in the mBM-MSCs group on PODs 3 and 7 (P < .001 for both). Furthermore, the secreted VEGFC protein level was higher from npBM-MSCs than from mBM-MSCs (P < .001).

Conclusion: Xenotransplantation of npBM-MSCs contributed to the improvement of hind limb ischemia by both angiogenesis and lymphangiogenesis, especially promotion of the latter. npBM-MSCs may provide an alternative to autologous and allogeneic MSCs for stem cell therapy of critical limb ischemia.
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http://dx.doi.org/10.1111/xen.12693DOI Listing
May 2021

A case of idiopathic portal hypertension accompanying multiple hepatic nodular regenerative hyperplasia in a patient with systemic sclerosis.

Clin J Gastroenterol 2021 Apr 22. Epub 2021 Apr 22.

Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Idiopathic portal hypertension (IPH) is one of the background diseases causing nodular regenerative hyperplasia (NRH). Furthermore, IPH patients accompanied with autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), are more likely to form NRH in the liver. A 76-year-old woman had been aware of the Raynaud's phenomenon and scleroderma for the past 30 years. In this case, she presented with abdominal fullness, and her imaging analysis revealed ascites and multiple liver nodules. On Gd-EOB-DTPA enhanced magnetic resonance imaging (EOB-MRI), donut-like uptake was observed in the nodules in the hepatobiliary phase. Liver biopsy of a nodule demonstrated that it was composed of hyperplastic hepatocytes without fibrous septa, and dilated sinusoids were observed beside the nodule. Conversely, background liver showed that peripheral portal veins appeared stenotic with dense fibrosis in the portal area. The final diagnosis was that multiple NRH of the liver developed in SSc patient accompanying IPH. This case suggests that NRH may be unexpectedly diagnosed in patients with autoimmune diseases accompanying IPH.
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http://dx.doi.org/10.1007/s12328-021-01348-zDOI Listing
April 2021

Anti-relapse effect of trametinib on a local minimal residual disease neuroblastoma mouse model.

J Pediatr Surg 2021 Mar 26. Epub 2021 Mar 26.

Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Purpose: We reported the in vitro and in vivo anti-tumor effects of trametinib, an MEK inhibitor, on neuroblastoma. However, long-term trametinib administration for bulky tumors failed to prevent local relapse. In this study, we established a local minimal residual disease (L-MRD) model to develop an optimal clinical protocol.

Methods: We prepared an l-MRD model by implanting neuroblastoma cells (SK-N-AS) into the renal capsule of nude mice with total tumorectomy or sham operation 14 days later. These mice received post-operative administration of trametinib or vehicle for eight weeks. Relapse was measured once weekly. Flow cytometry was performed with SK-N-AS cells treated by trametinib.

Results: Tumorectomy+trametinib dramatically suppressed relapse, and all mice survived during trametinib administration, while other treatments failed to suppress relapse. The survival rates for other groups were 20% in sham+trametinib, 17% in tumorectomy+vehicle, and 0% in sham+vehicle. Relapse occurred in the tumorectomy+trametinib group after withdrawal of trametinib administration. Flow cytometry revealed G1 arrest in SK-N-AS cells treated with trametinib.

Conclusion: These findings suggested that trametinib was able to suppress relapse from minimal residual tumor cells. Therefore, we propose that trametinib be administered as an option for maintenance therapy after surgical and chemotherapeutic treatments for neuroblastoma in future clinical protocols.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.03.031DOI Listing
March 2021

High-mobility group box 2 protein is essential for the early phase of adipogenesis.

Biochem Biophys Res Commun 2021 Jun 13;557:97-103. Epub 2021 Apr 13.

Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Fukuoka, Japan; Seiwakai Muta Hospital, Fukuoka, Japan.

Understanding of the mechanism of adipogenesis is essential for the control of obesity, which predisposes toward numerous health problems. High-mobility group box protein 2 (HMGB2) is a non-histone chromosomal protein that facilitates DNA replication, transcription, recombination, and repair. Here, we studied the role of HMGB2 in adipogenic differentiation. The expression of HMGB2 was measured at the mRNA and protein levels in cultured 3T3-L1 pre-adipocyte cells and during the process of adipogenic differentiation induced bya cocktail of insulin, 3-isobutyl-1-methylxanthine, and dexamethasone. This increased in the early phase and decreased in the late phase of differentiation. However, 3T3-L1 pre-adipocyte cells did not differentiate into adipocytes after the knockdown of HMGB2 expression by small interfering RNA (siRNA). Similarly, mesenchymal stem cells (MSCs) isolated from Hmgb2 mice did not express peroxisome proliferator-activated receptor gamma (PPARγ) in response to the adipocyte differentiation cocktail and did not differentiate. Wnt/β-catenin signaling is a negative regulator of adipogenic differentiation. We found that β-catenin expression was downregulated during 3T3-L1 adipogenic differentiation, as expected, but not when endogenous HMBG2 expression was knocked down using siRNA. These results indicate that HMGB2 plays an essential role in the early phase of the differentiation of pre-adipocytes and MSCs, and probably interacts with other regulators, such as PPARγ and Wnt/β-catenin signaling.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.149DOI Listing
June 2021

Oestrogen receptor α in T cells controls the T cell immune profile and glucose metabolism in mouse models of gestational diabetes mellitus.

Diabetologia 2021 Apr 1. Epub 2021 Apr 1.

Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.

Aims/hypothesis: The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM.

Methods: Female CD4-cre ERα (KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERα (ERα-floxed [FL]) mice were fed 60 kJ% high-fat diet (HFD) for 4 weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated.

Results: KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15 min after glucose loading: 137.3 ± 18.3 pmol/l and 40.1 ± 36.5 pmol/l, respectively; p < 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0 mmol/l × min and 2620.9 ± 122.1 mmol/l × min, respectively; p < 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4 ± 0.0% vs 0.8 ± 0.1%; p < 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of Emr1 and Tnfa in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively; p < 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines, Ahsg and Fgf21 (both were 2.4-fold higher vs FL-GDM mice; p < 0.05 and p = 0.09, respectively), with no changes in inflammatory gene expression (e.g., Tnfa and Ifng) in the liver compared with FL-GDM mice.

Conclusions/interpretation: Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.
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http://dx.doi.org/10.1007/s00125-021-05447-xDOI Listing
April 2021

Fatal Cerebral Vasospasm following a Haemophilus influenzae Meningitis in a Young Child with Ventriculoperitoneal Shunt.

Pediatr Neurosurg 2021 28;56(1):90-93. Epub 2021 Jan 28.

Division of Pediatric Neurosurgery, Department of Neurosurgery, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, Arkansas, USA.

Introduction: Despite the successful implementation of Haemophilus influenzae vaccination, invasive serotypes still lead to a fatal infection. We recently cared for a patient with a ventriculoperitoneal shunt (VPS) and H. influenzae meningitis and septicemia complicated by vasospasm. Vasospasm caused by Haemophilus central nervous system infection has not been previously reported.

Case Presentation: A 34-month-old patient with a recent VPS presented with H. influenzae meningitis and sepsis. Despite the explant of hardware, followed by maximum medical management, the patient developed stroke due to severe vasospasm, which led to diffused anoxic brain injury.

Conclusions: We aim to alert for the possible critical condition caused by H. influenzae. It is essential to treat the underlying illness, despite the presence of a VPS. Surgical implant tends to be overlooked by other subspecialists. Being vaccinated to H. influenzae does not protect from different subtypes like non-typeable H. influenzae. The cause of vasospasm remains unclear.
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http://dx.doi.org/10.1159/000512864DOI Listing
January 2021

Immunohistochemical staining of phosphorylated-ERK in post-chemotherapeutic samples is a potential predictor of the prognosis of neuroblastoma.

Pediatr Surg Int 2021 Feb 4;37(2):287-291. Epub 2021 Jan 4.

Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.

Purpose: The majority of relapsed neuroblastomas have mitogen-activated protein kinase (MAPK) pathway activating mutations. We previously showed the in vitro and in vivo anti-tumor effects of MAPK/ERK kinase (MEK) inhibitors in MAPK-activated neuroblastoma. We herein assessed the correlation between MAPK activation and the prognosis in neuroblastoma patients using phosphorylated extra-cellular signal-regulated kinase (pERK) immunohistochemistry to establish the protocol for the clinical administration of MEK inhibitors.

Methods: Neuroblastoma samples from patients treated in our hospital were immunostained with pERK. The clinical outcomes were retrospectively collected from medical records. The correlation between pERK positivity and the prognosis was analyzed.

Results: Regarding pre-chemotherapeutic specimens, there were no differences in the pERK status between tumors with a good and bad prognosis in both the nuclei and cytoplasm. Regarding post-chemotherapeutic specimens, one of eight tumors with a good prognosis and four of six tumors with a poor prognosis showed pERK-positive nuclear staining (p = 0.0909) and five of eight tumors with a good prognosis and four of six tumors with a poor prognosis showed pERK-positive cytoplasmic staining (p > 0.9999).

Conclusion: These findings suggested post-chemotherapeutic-not pre-chemotherapeutic-nuclear pERK-positive neuroblastoma tends to be associated with a poor prognosis and may be a potential therapeutic target for MEK inhibitor treatment.
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http://dx.doi.org/10.1007/s00383-020-04806-wDOI Listing
February 2021

Early-life stress induces the development of Alzheimer's disease pathology via angiopathy.

Exp Neurol 2021 Mar 10;337:113552. Epub 2020 Dec 10.

Laboratory of Neural Development, Department of Psychiatry & Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address:

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a major societal, scientific, and economic problem. Several early-life factors associated with an increased risk for the clinical diagnosis of AD have recently been identified. In the present study, we investigated the involvement of early-life stress in the pathogenesis of AD using heterozygous amyloid precursor protein (APP) mutant mice (App) and wild-type (App) mice. We found that maternal-separated App mice showed narrowing of vessels and decreased pericyte coverage of capillaries in the prefrontal cortex, while maternal-separated App mice additionally showed the impairment of cognitive function, earlier formation of Aβ plaques, increased vessel-associated microglia, and disruption of the blood-brain barrier. Substantial activation of microglia was detected in the maternal-separated App mice and maternal-separated App mice. At an early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separated App mice and maternal-separated App mice, and morphological changes in the microglia were observed in the non-maternal-separated App mice. Microglia activation induced by maternal separation in combination with the APP mutation may impair the vascular system, leading to AD progression. These findings therefore suggest that maternal separation results in the early induction of AD-related pathology via angiopathy.
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http://dx.doi.org/10.1016/j.expneurol.2020.113552DOI Listing
March 2021

Pineal cysts: Does anyone need long-term follow up?

J Clin Neurosci 2021 Jan 30;83:146-151. Epub 2020 Nov 30.

Division of Division of Neurosurgery, University of Missouri, School of Medicine, United States.

Pineal cysts are a common incidental finding on brain magnetic resonance imaging (MRI) whichfrequently prompts referral to neurosurgery. Currently, a management algorithm for patientswithout hydrocephalus, Parinaud's syndrome, or pineal apoplexy is lacking.We aimed to identifypredictive factors of pineal cyst volume change andsurgical intervention by performing retrospective chart review of 98 patients between 2005 and 2018 diagnosed with pineal cysts gleaned from our Neurosurgery clinical databases.We included patients whose initial and follow-up MRIs were available in our institutional radiology system or whose surgical pathology confirmed pineal cyst after evaluation with an initial MRI. Patients' medical records were queried for presenting symptoms, demographic, management, and pineal cyst measurements. Three dimensions (anterior-posterior, rostral-caudal, transverse) of pineal cyst size were measured and converted to cyst volume (cm) for analysis. Fifty-five patients (mean age 26.09 ± 14.7 years) with pineal cysts met study criteria. Follow-up ranged from 4 months to 10 years. The indications for MR imaging included headache (81.8%) and vision problems (42%).Forty-eight patients who were observed had a mean volume change of 0.051 ± 0.862 cm [3] and median volume change of 0 cm [3] Patient symptoms, referral source, and age were not associated with changes in volume on follow-up. Aggregated number of symptoms did not differ between operative and observation patients. (p = 0.29). Pineal cyst volumes tend to remain stable over serial MR images, do not reliably correlate with symptoms, and do not typically require long-term follow-up.
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http://dx.doi.org/10.1016/j.jocn.2020.10.051DOI Listing
January 2021

Mechanism of Transplanted Islet Engraftment in Visceral White Adipose Tissue.

Transplantation 2020 12;104(12):2516-2527

Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Background: White adipose tissue (WAT) is a candidate transplantation site for islets. However, the mechanism of islet engraftment in WAT has not been fully investigated. In this study, we attempted to clarify the therapeutic effect and mechanism of islet transplantation into visceral WAT.

Methods: Two hundred mouse islets were transplanted into epididymal WAT of syngeneic diabetic mice by wrapping islets with the tissue (fat-covered group). Mice that received intraperitoneal and renal subcapsular islet transplantations were used as negative and positive control groups, respectively.

Results: The transplant efficacy, including improvements in blood glucose and plasma insulin levels and in glucose tolerance tests, of the fat-covered group was superior to the negative control group and almost equal to the positive control group. Vessel density of engrafted islets in the fat-covered group was higher than that in the positive control group. It was speculated that the mechanism of islet engraftment in WAT might consist of trapping islets in WAT, adhesion of islets via a combination of adhesion factors (fibronectin and integrin β1), and promotion of angiogenesis in islets by expression of angiogenic factors induced by adiponectin.

Conclusions: Visceral WAT is an important candidate for islet transplantation. Adhesion factors and adiponectin might contribute to islet engraftment into WAT. Further studies to elucidate the detailed mechanism are necessary.
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http://dx.doi.org/10.1097/TP.0000000000003400DOI Listing
December 2020

Bone morphogenetic protein-2 enhances gonadotropin-independent follicular development via sphingosine kinase 1.

Am J Reprod Immunol 2021 05 25;85(5):e13374. Epub 2020 Nov 25.

The president of University of Toyama, Toyama, Japan.

Problem: Pre-ovulatory mature follicles are not readily induced from gonadotropin (Gn)-independent early follicles in the poor ovarian response (POR) state, characterized by reduced number of retrieved oocytes. Bone morphogenetic protein (BMP), which is expressed in the ovary, contributes to early folliculogenesis, but its precise underlying mechanism remains unknown. The purpose of this study was to examine the effects of BMP-2 on granulosa cells (GCs) of Gn-independent early follicles.

Method Of Study: Sphingosine kinase 1 (SPHK1) localization, which produces sphingosine 1-phosphate (S1P), was examined in human early follicles by immunohistochemistry. SPHK1 mRNA levels were examined in Gn-independent bovine GCs (bGCs) and human nonluteinized granulosa cell line (HGrC1) cells. Phosphorylated Yes-associated protein (YAP) expression was evaluated by Western blot, and its localization was evaluated immunocytochemically in bGCs. Verteporfin, a selective YAP inhibitor, was used to explore the influence of YAP on BMP-2-induced bGCs proliferation.

Results: The expression of SPHK1 was observed in human GCs of primary and secondary follicles. BMP-2 significantly induced SPHK1 mRNA expression in bGCs and HGrC1 cells. Both BMP-2 and S1P decreased phosphorylated YAP protein levels and induced the nuclear translocation of YAP significantly, thereby increasing the number of bGCs by suppressing the Hippo pathway. This BMP-2-induced cell proliferation was completely blocked by verteporfin.

Conclusion: This is a first report showing that BMP-2 up-regulated SPHK1 mRNA expression in GCs and promoted GCs proliferation through Hippo pathway suppression. Thus, BMP-2 contributes to Gn-independent folliculogenesis via SPHK1, suggesting a potential therapeutic strategy for the POR patients with follicular dysgenesis.
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http://dx.doi.org/10.1111/aji.13374DOI Listing
May 2021

Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1β and islet cellular death.

Sci Rep 2020 10 21;10(1):17920. Epub 2020 Oct 21.

Department of Regenerative Medicine and Transplantation, Fukuoka University, 7-45-1 Nanakuma Jonan-ku, Fukuoka, 814-0180, Japan.

Early rejection is a critical issue to be overcome to achieve successful islet transplantation. NLRP3 inflammasome is a protein complex that mediates the maturation of pro-interleukin (IL)-1β and pro-IL-18 to IL-1β and IL-18, respectively, which induce cellular death. Here, we investigated the impact of NLRP3 inflammasome and the effect of its inhibition by MCC950 in a rodent model of islet transplantation. We assessed the therapeutic effects of MCC950, a specific inhibitor of NLRP3 inflammasome, on gene expression, islet survival ratio and viability, and islet transplantation in mice. NLRP3 inflammasome-related gene (Nlrp3 and Il1b) expression was upregulated in islets stimulated with proinflammatory cytokines and suppressed when incubated with MCC950. Survival ratio and viability of incubated islets were reduced by cytokine stimulation and improved by MCC950. Regarding islet transplantation, the number of apoptotic cells in transplanted islets was reduced by MCC950. Furthermore, the expression of IL-1β in transplanted islets, migration of macrophages around islets, and fluctuation of blood glucose levels were suppressed by MCC950. Our study revealed that NLRP3 inflammasome worsened the therapeutic outcomes of islet transplantation and that MCC950 administration improved glycaemic control in syngeneic mice that underwent islet transplantation by inhibiting inflammation, which suppressed islet death.
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http://dx.doi.org/10.1038/s41598-020-74786-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578017PMC
October 2020

A case report: resolution of Chiari I malformation after helmet therapy for deformational brachycephaly.

Childs Nerv Syst 2020 Oct 3. Epub 2020 Oct 3.

Department of Neurosurgery, University of Arkansas for Medical Sciences, 4301 W Markham St. #503, Little Rock, AR, 72205, USA.

Positional plagiocephaly is the most common cause of cranial asymmetry. Deformational brachycephaly denotes a head shape characterized by occipital flattening and increased bilateral width, which can also be caused by external deformation of the moldable infant cranium in positional bilateral posterior plagiocephaly. There are reports of craniosynostosis associated with Chiari I malformation (CIM), possibly caused by decreased posterior fossa volume and related to increased intracranial pressure. To the best of our knowledge, this is only the second case report demonstrating acquired CIM in a child with positional brachycephaly. Of note, the fact that the CIM resolved after helmet therapy could support the hypothesis that CIM is associated with decreased volume of the posterior fossa. However, these two conditions may be independent of one another. More research is needed to identify an association between the two conditions.
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http://dx.doi.org/10.1007/s00381-020-04906-xDOI Listing
October 2020

Increased Incidence of Ophthalmologic Findings in Children With Concurrent Isolated Nonsyndromic Metopic Suture Abnormalities and Deformational Cranial Vault Asymmetry.

Cleft Palate Craniofac J 2021 04 15;58(4):497-504. Epub 2020 Sep 15.

Division of Plastic Surgery and Department of Child Health, University of Missouri School of Medicine, MO, USA.

Objective: The purpose of this project was to study the incidence of ophthalmologic findings which are known to be risk factors for amblyopia in children who have coexisting metopic suture abnormalities and deformational plagiocephaly (DP) and brachycephaly (DB).

Design: Institutional Review Board-approved retrospective study reviewing records of a consecutive cohort of children under 2 years of age with metopic suture abnormalities and cranial vault asymmetries seen in both the plastic surgery and ophthalmology clinics from 2007 to 2017.

Setting: Institutional tertiary care center with all care in plastic surgery under the senior author and the standard of care accepted in pediatric ophthalmology under one of two ophthalmologists.

Patients: After application of exclusion criteria, 76 children diagnosed with metopic suture abnormalities and DP/DB were included in the study. Patients with severe trigonocephaly, other suture involvement, syndromic diagnoses, and primary ocular disorders were excluded.

Main Outcome Measures: Describe the incidences of refractive errors (astigmatism, hyperopia, and myopia), anisometropia, strabismus, and amblyopia within the study population.

Results: In our patient population, the rates of amblyopia (17.1%) and strabismus (15.8%) are higher than the general pediatric population rates of 1.5% to 1.8% and 2.4% to 3.6%, respectively. Overall, 47.4% had significant refractive error: 28.9% with astigmatism, 15.8% with hyperopia, 5.3% with myopia, and 10.5% with anisometropia.

Conclusions: In our patient population, children with coexisting metopic suture abnormalities and DP or DB had significant risk for amblyopia, strabismus, and refractive errors.
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http://dx.doi.org/10.1177/1055665620954739DOI Listing
April 2021

Electrophysiological Effects of Transcranial Direct Current Stimulation on Neural Activity in the Rat Motor Cortex.

Front Neurosci 2020 30;14:495. Epub 2020 Jun 30.

Department of Information Medicine, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Kodaira, Japan.

Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the neuronal membrane potential. We have previously documented a sustainable increase in extracellular dopamine levels in the rat striatum of cathodal tDCS, suggesting that cathodal tDCS enhances the neuronal excitability of the cortex. In the present study, we investigated changes in neuronal activity in the cerebral cortex induced by tDCS at the point beneath the stimulus electrode in anesthetized rats . Multiunit recordings were performed to examine changes in neuronal activity before and after the application of tDCS. In the cathodal tDCS group, multiunit activity (indicating the collective firing rate of recorded neuronal populations) increased in the cerebral cortex. Both anodal and cathodal tDCS increased the firing rate of isolated single units in the cerebral cortex. Significant differences in activity were observed immediately following stimulation and persisted for more than an hour after stimulation. The primary finding of this study was that both anodal and cathodal tDCS increased neuronal activity in the rat cerebral cortex underneath the stimulus electrode.
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http://dx.doi.org/10.3389/fnins.2020.00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340144PMC
June 2020

Safe diagnostic management of malignant mediastinal tumors in the presence of respiratory distress: a 10-year experience.

BMC Pediatr 2020 06 10;20(1):292. Epub 2020 Jun 10.

Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan.

Background: The fundamental treatment for patients with pediatric malignant mediastinal tumors is chemotherapy. Therefore, accurate diagnosis is essential for selecting the appropriate chemotherapeutic regimen. However, malignant mediastinal tumors occasionally cause respiratory distress, and biopsies under general anesthesia are dangerous for such patients as invasive mechanical ventilation can aggravate airway obstruction caused by mass effect. In this study, we reviewed our 10-year diagnostic experience to evaluate the efficacy of our practices and confirm a safe diagnostic protocol for future patients.

Methods: We retrospectively reviewed medical records of children with malignant mediastinal tumors diagnosed at Nagoya University Hospital from 2007 to 2018 who demonstrated respiratory distress. Respiratory distress included dyspnea, massive pleural effusion, wheezing, and hypoxemia owing to tumors. Data on sex, age at onset, primary symptoms, location of tumor, management strategy (especially the method of diagnosis and definitive diagnosis), clinical course, prognosis during the acute phase (within 3 months from the onset of respiratory symptoms), and long-term outcome were collected.

Results: Twelve pediatric patients met the review criteria. There were seven anterior mediastinal tumors and five posterior mediastinal tumors. All anterior mediastinal tumors were diagnosed via bone marrow smear, thoracentesis, or core needle biopsy while maintaining spontaneous breathing. Regarding posterior tumors, two patients were diagnosed via a core needle biopsy and lymph node excisional biopsy under spontaneous breathing. Two cases were initially diagnosed solely using tumor markers. One patient with severe tracheal compression underwent tumor resection with extracorporeal membrane oxygenation stand-by. No patient died of diagnostic procedure-related complications.

Conclusions: In 11 of the 12 cases reviewed, safe and accurate tumor diagnosis was accomplished without general anesthesia. A diagnostic strategy without general anesthesia considering the tumor location proved to be useful.
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http://dx.doi.org/10.1186/s12887-020-02183-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285522PMC
June 2020

Which sleep hygiene factors are important? comprehensive assessment of lifestyle habits and job environment on sleep among office workers.

Sleep Health 2020 06 28;6(3):288-298. Epub 2020 Apr 28.

Department of Psychiatry, Tokyo Medical University, Tokyo, Japan.

Background: Although several lifestyle habits are associated with sleep, it is unclear which factors are important. Among office workers, the effect of job environment should also be considered. The multivariate analyses on the effects of lifestyle habits and job environment on sleep among office workers was conducted.

Methods: A cross-sectional survey of 6,342 employees from 29 companies was conducted in 2017-2019. Complete responses and informed consent were provided by 5,640 participants. The survey examined demographic variables, sleep schedules, Pittsburgh Sleep Quality Index (PSQI), Brief Job Stress Questionnaire (BJSQ), and lifestyle habits.

Results: Mean values were as follows: age, 36.9 years (±10.2); PSQI, 6.52 (±2.83); and total sleep time, 6h06m (±1h40m) on work days and 7h39m (±1h58m) on free days. After adjusting for job environment and demographic variables, irregular meal time (1.45-2.86), not eating vegetables every day (1.35), nightcap (2.74-3.55), weight gain (1.20-1.42), lack of sunlight in the morning in the bedroom (1.48-1.60), waking up before dawn (2.18), electronic display use in bed (1.50), and daily caffeine intake (1.27) were significantly associated with sleep disturbance. Irregular meal time (1.51-2.37), lack of morning breakfast (1.74-2.95), having dinner within 2 hours before bed time (0.49-0.64), not eating vegetables every day (1.52), lack of sunlight exposure in the morning (1.43-2.01), and caffeine use every day (1.42) were also associated with eveningness (p<.01).

Conclusion: Each sleep hygiene factor had a different effect size. Sleep hygiene interventions to promote worker sleep health should prioritize factors in accordance with effect size.
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http://dx.doi.org/10.1016/j.sleh.2020.02.001DOI Listing
June 2020

Estrogen regulates sex-specific localization of regulatory T cells in adipose tissue of obese female mice.

PLoS One 2020 2;15(4):e0230885. Epub 2020 Apr 2.

Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.

Regulatory T cells (Treg) play essential roles in maintaining immune homeostasis. Resident Treg in visceral adipose tissue (VAT-Treg) decrease in male obese mice, which leads to the development of obesity-associated chronic inflammations and insulin resistance. Although gender differences in immune responses have been reported, the effects of the difference in metabolic environment on VAT-Treg are unclear. We investigated the localization of VAT-Treg in female mice in comparison with that in male mice. On a high-fat diet (HFD), VAT-Treg decreased in male mice but increased in female mice. The increase was abolished in ovariectomized and HFD-fed mice, but was restored by estrogen supplementation. The IL33 receptor ST2, which is important for the localization and maturation of VAT-Treg in males, was reduced in CD4+CD25+ T cells isolated from gonadal fat of obese mice of both genders, suggesting that a different system exists for VAT-Treg localization in females. Extensive analysis of chemokine expression in gonadal fat and adipose CD4+CD25+T cells revealed several chemokine signals related to female-specific VAT-Treg accumulation such as CCL24, CCR6, and CXCR3. Taken together, the current study demonstrated sexual dimorphism in VAT-Treg localization in obese mice. Estrogen may attenuate obesity-associated chronic inflammation partly through altering chemokine-related VAT-Treg localization in females.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230885PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117686PMC
July 2020

Activation of overexpressed glucagon-like peptide-1 receptor attenuates prostate cancer growth by inhibiting cell cycle progression.

J Diabetes Investig 2020 Sep 9;11(5):1137-1149. Epub 2020 Apr 9.

Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Fukuoka, Japan.

Aims/introduction: Incretin therapy is a common treatment for type 2 diabetes mellitus. We have previously reported an anti-prostate cancer effect of glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4. The attenuation of cell proliferation in the prostate cancer cell line was dependent on GLP-1R expression. Here, we examined the relationship between human prostate cancer severity and GLP-1R expression, as well as the effect of forced expression of GLP-1R using a lentiviral vector.

Materials And Methods: Prostate cancer tissues were extracted by prostatectomy and biopsy. GLP-1R was overexpressed in ALVA-41 cells using a lentiviral vector (ALVA-41-GLP-1R cells). GLP-1R expression was detected by immunohistochemistry and quantitative polymerase chain reaction. Cell proliferation was examined by growth curves and bromodeoxyuridine incorporation assays. Cell cycle distribution and regulators were examined by flow cytometry and western blotting. In vivo experiments were carried out using a xenografted model.

Results: GLP-1R expression levels were significantly inversely associated with the Gleason score of human prostate cancer tissues. Abundant GLP-1R expression and functions were confirmed in ALVA-41-GLP-1R cells. Exendin-4 significantly decreased ALVA-41-GLP-1R cell proliferation in a dose-dependent manner. DNA synthesis and G1-to-S phase transition were inhibited in ALVA-41-GLP-1R cells. SKP2 expression was decreased and p27Kip1 protein was subsequently increased in ALVA-41-GLP-1R cells treated with exendin-4. In vivo experiments carried out by implanting ALVA-41-GLP-1R cells showed that exendin-4 decreased prostate cancer growth by activation of GLP-1R overexpressed in ALVA41-GLP-1R cells.

Conclusions: Forced expression of GLP-1R attenuates prostate cancer cell proliferation by inhibiting cell cycle progression in vitro and in vivo. Therefore, GLP-1R activation might be a potential therapy for prostate cancer.
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http://dx.doi.org/10.1111/jdi.13247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477521PMC
September 2020

Extension of Survival in Bilaterally Adrenalectomized Mice by Implantation of SF-1/Ad4BP-Induced Steroidogenic Cells.

Endocrinology 2020 03;161(3)

Department of Endocrinology and Diabetes Mellitus, Fukuoka University, Fukuoka, Japan.

Mesenchymal stroma/stem cells (MSCs) exist in adult tissues, such as adipose tissue and bone marrow, and differentiate into cells of multiple lineages. In previous studies, we found that MSCs differentiate into steroidogenic cells by forced expression of steroidogenic factor 1 (SF-1)/adrenal 4 binding protein (Ad4BP), the master regulator of steroidogenesis and differentiation of pituitary gonadotrophs, adrenal glands, and gonads. In this study, SF-1/Ad4BP-induced steroidogenic cells derived from mouse adipose tissue-derived MSCs (ADSCs) were implanted under the kidney capsule of bilateral adrenalectomized (bAdx) mice. bAdx mice did not survive after 7 days. However, 4 of 9 bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, 1 of 10 bAdx mice transplanted with control ADSCs, and bAdx mice transplanted with an adrenal gland survived for 30 days. Plasma corticosterone levels in bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells and control ADSCs were 5.41 ± 2.26 ng/mL (mean ± SEM) and undetectable at 7 days after implantation, respectively. After removal of the kidney bearing the graft from the surviving mice at 30 days after implantation, plasma corticosterone was not detected in any of the samples. Immunohistochemical staining revealed SF-1/Ad4BP-positive cells under the capsule of the kidney. Although we performed an adrenocorticotropin (ACTH) loading test on bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, ACTH responsiveness was not observed. Implantation of steroidogenic cells derived from ADSCs into bAdx mice increased the basal plasma corticosterone level and extended the survival of bAdx mice, suggesting the capability of restoring steroidogenic cells by cell transplantation therapy for adrenal insufficiency.
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http://dx.doi.org/10.1210/endocr/bqaa007DOI Listing
March 2020

Plastid-targeted forms of restriction endonucleases enhance the plastid genome rearrangement rate and trigger the reorganization of its genomic architecture.

Plant J 2020 06 13;102(5):1042-1057. Epub 2020 Feb 13.

Genome Engineering Program, Strategic Research Division, Toyota Central R&D Laboratories, Inc., Nagakute, Aichi, 480-1192, Japan.

Plant cells have acquired chloroplasts (plastids) with a unique genome (ptDNA), which developed during the evolution of endosymbiosis. The gene content and genome structure of ptDNAs in land plants are considerably stable, although those of algal ptDNAs are highly varied. Plant cells seem, therefore, to be intolerant of any structural or organizational changes in the ptDNA. Genome rearrangement functions as a driver of genomic evolutionary divergence. Here, we aimed to create various types of rearrangements in the ptDNA of Arabidopsis genomes using plastid-targeted forms of restriction endonucleases (pREs). Arabidopsis plants expressing each of the three specific pREs, i.e., pTaqI, pHinP1I, and pMseI, were generated; they showed the leaf variegation phenotypes associated with impaired chloroplast development. We confirmed that these pREs caused double-stranded breaks (DSB) at their recognition sites in ptDNAs. Genome-wide analysis of ptDNAs revealed that the transgenic lines exhibited a large number of rearrangements such as inversions and deletions/duplications, which were dominantly repaired by microhomology-mediated recombination and microhomology-mediated end-joining, and less by non-homologous end-joining. Notably, pHinP1I, which recognized a small number of sites in ptDNA, induced drastic structural changes, including regional copy number variations throughout ptDNAs. In contrast, the transient expression of either pTaqI or pMseI, whose recognition site numbers were relatively larger, resulted in small-scale changes at the whole genome level. These results indicated that DSB frequencies and their distribution are major determinants in shaping ptDNAs.
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http://dx.doi.org/10.1111/tpj.14687DOI Listing
June 2020

Estimation of Motor Impairment and Usage of Upper Extremities during Daily Living Activities in Poststroke Hemiparesis Patients by Observation of Time Required to Accomplish Hand Dexterity Tasks.

Biomed Res Int 2019 7;2019:9471921. Epub 2019 Nov 7.

Department of Rehabilitation Medicine, The Jikei University School of Medicine, Tokyo, Japan.

Aim: This study evaluated whether specific actual performance could accurately predict body function levels and upper limb use in the real-life functioning of poststroke hemiparesis patients to aid in choosing the most appropriate rehabilitation exercises.

Methods: We measured the time taken for poststroke patients to move small objects with the paralyzed hand and investigated how the measurement could estimate upper extremity motor impairment and hand usage during activities of daily living (ADL). We examined 86 stroke patients (age 66 ± 16 years) whose upper extremity motor paralysis was measured using the Fugl-Meyer assessment (FMA) and Southampton Hand Assessment Procedure (SHAP), and patient-reported ADL was investigated using the Jikei Assessment Scale for Motor Impairment in Daily Living (JASMID). To identify the time required to perform each SHAP item, we employed a linear regression analysis. The prediction formula was used in the linear regression analysis, and the coefficient of determination () was applied to compare each component item score that was obtained with the predicted values derived from the linear regression analysis.

Results: The most easily accomplished task was Heavy Power in the SHAP. The between the SHAP Heavy Power item score and the FMA scores was moderate ( = 0.344, < 0.0001), whereas the with the JASMID score was low ( = 0.126, < 0.001).

Conclusions: By measuring the time it takes for poststroke hemiparesis patients to hold and move an object, we developed a prediction formula for upper extremity motor function and hand dexterity.
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http://dx.doi.org/10.1155/2019/9471921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885294PMC
April 2020

Laparoscopic lateral pelvic lymph node dissection for lower rectal cancer treated with preoperative chemoradiotherapy.

Surg Endosc 2020 03 18;34(3):1425-1431. Epub 2019 Oct 18.

Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Laparoscopic lateral pelvic lymph node dissection (LLND) has been reported to be feasible; however, studies comparing the outcomes of laparoscopic LLND with that of open LLND following preoperative chemoradiotherapy (CRT) are limited.

Methods: Between November 2005 and October 2017, 38 patients with locally advanced rectal cancer underwent total mesorectal excision and LLND following preoperative CRT at Kobe University Hospital. The data of the patients who underwent open LLND (OP group, n = 19) and laparoscopic LLND (LAP group, n = 19) were retrospectively collected and compared.

Results: The operative time was significantly longer in the LAP group compared with that in the OP group. However, the volume of blood loss was significantly higher, and transfusion was more frequently performed in the OP group than in the LAP group. The number of LLNs harvested in the LAP group was significantly higher than that in the OP group. The prevalence of perineal wound infection and bowel obstruction was significantly higher in the OP group than in the LAP group. However, no significant differences were observed between the groups in terms of 5-year overall survival, relapse-free survival, and local recurrence-free survival.

Conclusions: Laparoscopic LLND is feasible and safe for patients with rectal cancer who were treated with preoperative CRT. Compared with open LLND, laparoscopic LLND might have several advantages such as higher yields of dissected LLNs and lower incidences of perineal wound infection and bowel obstruction.
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http://dx.doi.org/10.1007/s00464-019-07224-9DOI Listing
March 2020

Novel mesenchymal stem cell delivery system as targeted therapy against neuroblastoma using the TH-MYCN mouse model.

J Pediatr Surg 2019 Dec 30;54(12):2600-2605. Epub 2019 Aug 30.

Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: Mesenchymal stem cells (MSCs) are reported to migrate toward damaged tissues or tumors. We previously reported the in vivo short-term (1 day) tumor-homing effect of xenogeneic human MSCs (hMSCs) using the TH-MYCN mouse neuroblastoma model (MYCN-TgM). In this study, we analyzed the long-term tumor-homing effect of allogeneic mouse MSCs (mMSCs) and explored the antitumor effect and drug delivery function of mMSCs.

Methods: mMSCs were administered intraperitoneally (i.p.) to MYCN-TgM and traced by an in vivo imaging system (IVIS). We administered green fluorescent protein (GFP)-transduced mMSCs into MYCN-TgM i.p. and examined the cell survival by immunohistochemistry. We also administered interferon beta-transduced mMSCs (mMSCs-IFN-β) to MYCN-TgM i.p. and measured the concentration of IFN-β in the tumor and organs by an enzyme-linked immunosorbent assay (ELISA). The survival curves of MYCN-TgM administered every week was analyzed.

Results: The IVIS revealed the accumulation of fluorescence was observed in the tumor both in vivo and after excision. Immunohistochemistry using anti-GFP antibody revealed that the mMSCs existed within the tumor until 14 days but not in the organs. The ELISA showed increased concentrations of IFN-β only in the tumors, with the values gradually diminishing over 14 days. The mMSCs-IFN-β group survived significantly longer than the control group (p < 0.03), while the mMSCs-alone group did not show a survival advantage.

Conclusions: Allogeneic mMSCs showed a homing ability for mouse neuroblastoma and existed within the tumor for as long as two weeks. This may be a candidate drug delivery vehicle for antitumor agents against neuroblastoma.

Level Of Evidence:
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http://dx.doi.org/10.1016/j.jpedsurg.2019.08.023DOI Listing
December 2019

Therapeutic strategy for thoracoscopic repair of esophageal atresia and its outcome.

Pediatr Surg Int 2019 Oct 9;35(10):1071-1076. Epub 2019 Aug 9.

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

Purpose: Thoracoscopic repair can be safely performed in most types of congenital esophageal atresia (EA), including in patients with long gap EA or very low birth weight. Accordingly, we performed single- or multistage thoracoscopic repair for various EA types. We aimed to report our therapeutic strategy for thoracoscopic radical surgery for treating EA and its outcome.

Methods: Outcomes of radical surgeries for treating congenital EA at our institute from 2013 to 2018 were retrospectively evaluated.

Results: Thirty-eight radical surgeries were evaluated: 3 Gross type-A, 1 type-B, 30 type-C, 1 type-D, and 3 type-E. The cervical approach was performed in 5 cases and thoracoscopic esophageal anastomosis in 33, including 26 single-stage (all type-C) and 7 multistage surgeries (3 type-A, 3 type-C, and 1 type-D). There were no cases of thoracotomies or intraoperative thoracoscopic surgery complications. Three cases of minor leakage were conservatively resolved. Three postoperative chylothorax surgeries (9%) and seven balloon dilatations (21%) for anastomotic stenosis were performed.

Conclusion: Thoracoscopic radical surgery for treating EA, including single- and multistage procedures, can be performed, except in type-E cases or when the end of the proximal esophagus is located higher than the clavicle.
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http://dx.doi.org/10.1007/s00383-019-04541-xDOI Listing
October 2019

Efficacy of and prognosis after steroid pulse therapy in patients with poor reduction of jaundice after laparoscopic Kasai portoenterostomy.

Pediatr Surg Int 2019 Oct 8;35(10):1059-1063. Epub 2019 Aug 8.

Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Purpose: High-dose postoperative steroid therapy after Kasai portoenterostomy is reported to improve jaundice clearance and a strong anti-inflammatory activity might prevent fibrous tissue formation which is often observed at the porta hepatis in revision surgery. We started steroid pulse therapy for the patients with cessation of decrease in jaundice and aimed to evaluate the efficacy in this study.

Methods: The demographics and outcomes of patients who underwent laparoscopic Kasai portoenterostomy and received steroid pulse therapy within 2 months postoperatively between September 2014 and December 2018 were retrospectively reviewed; the therapy was determined successful when the serum total bilirubin level decreased to or below two-thirds of the pre-therapy level after 2 weeks. Patient data in the successful group were compared with those in the unsuccessful group.

Results: Steroid pulse therapy was successful in seven of 16 patients (43.8%). The percentage of patients whose serum total bilirubin level decreased to normal was significantly higher in the successful group at 3 months (85.7% vs. 11.1%, P = 0.0028) and after all (100% vs. 33.3%, P = 0.011).

Conclusions: Steroid pulse therapy was effective for some patients. Unsuccessful cases may have little chances of jaundice clearance; revision Kasai portoenterostomy would be a good option.
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http://dx.doi.org/10.1007/s00383-019-04537-7DOI Listing
October 2019

Neoadjuvant Chemotherapy Increases PD-L1 Expression and CD8 Tumor-infiltrating Lymphocytes in Esophageal Squamous Cell Carcinoma.

Anticancer Res 2019 Aug;39(8):4539-4548

Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Background/aim: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP).

Patients And Methods: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8 tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors.

Results: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8 TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8 TIL density, was not significantly associated with patient survival in ESCC patients.

Conclusion: NAC-FP induced PD-L1 expression on ICs and CD8 TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.
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http://dx.doi.org/10.21873/anticanres.13631DOI Listing
August 2019

Neoadjuvant Chemotherapy Increases PD-L1 Expression and CD8 Tumor-infiltrating Lymphocytes in Esophageal Squamous Cell Carcinoma.

Anticancer Res 2019 Aug;39(8):4539-4548

Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Background/aim: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP).

Patients And Methods: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8 tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors.

Results: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8 TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8 TIL density, was not significantly associated with patient survival in ESCC patients.

Conclusion: NAC-FP induced PD-L1 expression on ICs and CD8 TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.
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http://dx.doi.org/10.21873/anticanres.13631DOI Listing
August 2019

Response to the Question of Dr Huppmann: Regarding an Unusual Presentation of a Cervical Paraspinal Leiomyoma in an Adolescent Female.

Pediatr Dev Pathol 2019 10 27;22(5):500. Epub 2019 Jun 27.

Department of Pathology & Anatomical Sciences, School of Medicine, University of Missouri, Columbia, Missouri.

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http://dx.doi.org/10.1177/1093526619856842DOI Listing
October 2019

Combined treatment with DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice.

Biochem Biophys Rep 2019 Jul 19;18:100640. Epub 2019 Apr 19.

Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Fukuoka, Japan.

Incretin therapy has emerged as one of the most popular medications for type 2 diabetes. We have previously reported that the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin attenuates neointima formation after vascular injury in non-diabetic mice. In the present study, we examined whether combined treatment with linagliptin and the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin attenuates neointima formation in diabetic mice after vascular injury. Diabetic mice were treated with 3 mg/kg/day linagliptin and/or 30 mg/kg/day empagliflozin from 5 to 10 weeks of age. Body weight was significantly decreased by empagliflozin and the combined treatment. Blood glucose levels and glucose tolerance test results were significantly improved by empagliflozin and the combined treatment, but not by linagliptin. An insulin tolerance test suggested that linagliptin and empagliflozin did not improve insulin sensitivity. In a model of guidewire-induced femoral artery injury in diabetic mice, neointima formation was significantly decreased in mice subjected to combined treatment. In an assay using rat aortic smooth muscle cells (RASMC), 100, 500, or 1000 nM empagliflozin significantly decreased the RASMC number in a dose-dependent manner. A further significant reduction in RASMC proliferation was observed after combined treatment with 10 nM linagliptin and 100 nM empagliflozin. These data suggest that combined treatment with the DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice and smooth muscle cell proliferation .
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http://dx.doi.org/10.1016/j.bbrep.2019.100640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477163PMC
July 2019