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Changes in choroidal thickness in healthy pediatric individuals: a longitudinal study

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International Journal of Ophthalmology(English edition) 2018年第7期11卷 1179-1184页

作者： Eiko Ohsugi Yoshinori Mitamura Kayo Shinomiya Masanori Niki Hiroki Sano Toshihiko Nagasawa Yukiko Shimizu Daisuke Nagasato Hitoshi Tabuchi Department of Ophthalmology Saneikai Tsukazaki Hospital Department of Ophthalmology Institute of Biomedical Sciences Tokushima University Graduate School

AIM： To investigate the changes in the choroidal thickness in healthy pediatric children in a longitudinal study, and to determine the ocular and systemic parameters that were significantly correlated with the changes in the choroidal thickness. METHODS： This study included 64 eyes of 34 healthy Japanese children with a mean age（±SD） of 4.4（±0.4）y（range, 3.6-5.8 y） at baseline. Swept-source optical coherence tomography（SS-OCT） was used to record images of the retina and choroid at the baseline and after a mean followup period of about 1.5 y. The 3 D raster scan protocol was used to construct the choroidal thickness map. Mean choroidal thickness was calculated for each of the nine sectors of the Early Treatment Diabetic Retinopathy Study grid. Best-corrected visual acuity, axial length, body height, and weight were also measured. Changes in measurements were defined as the baseline values subtracted from the values at the final visit. A generalized estimating equation was used to eliminate the effect of within-subject intereye correlations. RESULTS： The mean central choroidal thickness was significantly reduced during the follow-up period（baseline, 301.8±8.6 μm; final visit, 286.6±8.0 μm, P〈0.001）. The decrease in the choroidal thickness was greatest in the central sector, followed by the sectors of the inner and outer rings. The inner and outer rings had diameters of 1 to 3 mm and 3 to 6 mm, respectively. The changes in the choroidal thickness in the central, inner ring, and outer ring sectors were significantly and negatively correlated with the age, baseline body height, baseline body weight, and elongation of the axial length. CONCLUSION： These results indicate that the choroidal thickness among preschool-aged Japanese children decreased significantly during the follow-up period. The choroidal thinning is significantly associated with the elongation of axial length. These characteristics should be considered in the evaluation of choroidal thickness in younger children with retinochoroidal disorders.

关键词： choroidal thickness longitudinal study pediatrics swept-source optical coherence tomography

Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance

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World Journal of Diabetes 2017年第3期8卷 97-103页

作者： Tomoki Abe Katsuya Hirasaka Takeshi Nikawa Department of Nutritional Physiology Institute of Biomedical Sciences Tokushima University Graduate School graduate School of Fisheries Science and Environmental Studies Nagasaki University

Aging and overnutrition cause obesity in rodents and humans. It is well-known that obesity causes various diseases by producing insulin resistance(IR). Macrophages infiltrate the adipose tissue(AT) of obese individuals and cause chronic low-level inflammation associated with IR. Macrophage infiltration is regulated by the chemokines that are released from hypertrophied adipocytes and the immune cells in AT. Saturated fatty acids are recognized by toll-like receptor 4(TLR4) and induce inflammatory responses in AT macrophages(ATMs). The inflammatory cytokines that are released from activated ATMs promote IR in peripheral organs, such as the liver, skeletal muscle and AT. Therefore, ATM activation is a therapeutic target for IR in obesity. The ubiquitin ligase Casitas b-lineage lymphoma-b(Cbl-b) appears to potently suppress macrophage migration and activation. Cbl-b is highly expressed in leukocytes and negatively regulates signals associated with migration and activation. Cbl-b deficiency enhances ATM accumulation and IR in aging- and diet-induced obese mice. Cbl-b inhibits migration-related signals and SFA-induced TLR4 signaling in ATMs. Thus, targeting Cbl-b may be a potential therapeutic strategy to reduce the IR induced by ATM activation. In this review, we summarize the regulatory functions of Cbl-b in ATMs.

关键词： Casitas b 系 lymphoma-b 胰岛素抵抗巨噬细胞肥胖像使用费的受体 4

Hepatitis D virus infection, replication and cross-talk with the hepatitis B virus

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World Journal of Gastroenterology 2014年第40期20卷 14589-14597页

作者： Chi-Ruei Huang Szecheng John Lo institute of Microbiology and Immunology National Yang-Ming University Department and institute of biomedical sciences College of Medicine Chang Gung University Graduate Institute of Biomedical Sciences College of Medicine Chang Gung University

Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a single open reading frame(ORF)and requires HBV supplying surface antigens(HBsAgs)to assemble a new HDV virion.During HDV replication,two isoforms of a delta antigen,a small delta antigen(SDAg)and a large delta antigen(LDAg),are produced from the same ORF of the HDV genome.The SDAg is required for HDV replication,whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA.Various clinical outcomes of HBV/HDV dual infection have been reported,but the molecular interaction between HBV and HDV is poorly understood,especially regarding howHBV and HDV compete with HBsAgs for assembling virions.In this paper,we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export.Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications(PTMs),including acetylation,phosphorylation,and isoprenylation,we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling,LDAg PTMs,and nuclear export mechanisms in this review.

关键词： Hepatitis B virus Hepatitis D virus Posttranslatio

Deep-learning classifier with ultrawide-field fundus ophthalmoscopy for detecting branch retinal vein occlusion

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International Journal of Ophthalmology(English edition) 2019年第1期12卷 94-99页

作者： Daisuke Nagasato Hitoshi Tabuchi Hideharu Ohsugi Hiroki Masumoto Hiroki Enno Naofumi Ishitobi Tomoaki Sonobe Masahiro Kameoka Masanori Niki Yoshinori Mitamura Department of Ophthalmology Saneikai Tsukazaki Hospital Rist Inc Department of Ophthalmology Institute of Biomedical SciencesTokushima University Graduate School

AIM: To investigate and compare the efficacy of two machine-learning technologies with deep-learning(DL) and support vector machine(SVM) for the detection of branch retinal vein occlusion(BRVO) using ultrawide-field fundus images. METHODS: This study included 237 images from 236 patients with BRVO with a mean±standard deviation of age 66.3±10.6 y and 229 images from 176 non-BRVO healthy subjects with a mean age of 64.9±9.4 y. Training was conducted using a deep convolutional neural network using ultrawide-field fundus images to construct the DL model. The sensitivity, specificity, positive predictive value(PPV), negative predictive value(NPV) and area under the curve(AUC) were calculated to compare the diagnostic abilities of the DL and SVM models. RESULTS: For the DL model, the sensitivity, specificity, PPV, NPV and AUC for diagnosing BRVO was 94.0%(95%CI: 93.8%-98.8%), 97.0%(95%CI: 89.7%-96.4%), 96.5%(95%CI: 94.3%-98.7%), 93.2%(95%CI: 90.5%-96.0%) and 0.976(95%CI: 0.960-0.993), respectively. In contrast, for the SVM model, these values were 80.5%(95%CI: 77.8%-87.9%), 84.3%(95%CI: 75.8%-86.1%), 83.5%(95%CI: 78.4%-88.6%), 75.2%(95%CI: 72.1%-78.3%) and 0.857(95%CI: 0.811-0.903), respectively. The DL model outperformed the SVM model in all the aforementioned parameters(P<0.001). CONCLUSION: These results indicate that the combination of the DL model and ultrawide-field fundus ophthalmoscopy may distinguish between healthy and BRVO eyes with a high level of accuracy. The proposed combination may be used for automatically diagnosing BRVO in patients residing in remote areas lacking access to an ophthalmic medical center.

关键词： automatic diagnosis branch retinal vein occlusion deep learning machine-learning technology ultrawide-field fundus ophthalmoscopy

PARP inhibitors as precision medicine for cancer treatment

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National Science Review 2017年第4期4卷 576-592页

作者： Yi Du Hirohito Yamaguchi Jennifer L.Hsu Mien-Chie Hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical University Department of Biotechnology Asia University Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical UniversityTaichung

Personalized or precision medicine is an emerging treatment approach tailored to individuals or certain groups of patients based on their unique characteristics. These types of therapies guided by biomarkers tend to be more effective than traditional approaches, especially in cancer. The inhibitor against poly(ADP-ribose) polymerase(PARP), olaparib(Lynparza, Astra Zeneca), which was approved by the US Food and Drug Administration(FDA) in 2014, demonstrated efficacy specifically for ovarian cancer patients harboring mutations in BRCA genes, which encode proteins in DNA double-strand break repairs.However, the response to PARP inhibitors has been less encouraging in other cancer types that also carry defects in the BRCA genes. Thus, furthering our understanding of the underlying mechanism of PARP inhibitors and resistance is critical to improve their efficacy. In this review, we summarize the results of preclinical studies and the clinical application of PARP inhibitors, and discuss the future direction of PARP inhibitors as a potential marker-guided personalized medicine for cancer treatment.

关键词： PARP inhibitor kinase DNA damage precision medicine combination therapy

Multifunctional to multistage delivery systems: The evolution of nanoparticles for biomedical applications

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Chinese Science Bulletin 2012年第31期57卷 3961-3971页

作者： MARTINEZ Jonathan O BROWN Brandon S QUATTROCCHI Nicoletta EVANGELOPOULOS Michael FERRARI Mauro TASCIOTTI Ennio Department of Nanomedicine The Methodist Hospital Research Institute graduate School of biomedical sciences The University of Texas at Houston

Nanomaterials are advancing in several directions with significant progress being achieved with respect to their synthesis, functionalization and biomedical application. In this review, we will describe several classes of prototypical nanocarriers, such as liposomes, silicon particles, and gold nanoshells, in terms of their individual function as well as their synergistic use. Active and passive targeting, photothermal ablation, and drug controlled release constitute some of the crucial functions identified to achieve a medical purpose. Current limitations in targeting, slow clearance, and systemic as well as local toxicity are addressed in reference to the recent studies that attempted to comprehend and solve these issues. The demand for a more sophisticated understanding of the impact of nanomaterials on the body and of their potential immune response underlies this discussion. Combined components are then discussed in the setting of multifunctional nanocarriers, a class of drug delivery systems we envisioned, proposed, and evolved in the last 5 years. In particular, our third generation of nanocarriers, the multistage vectors, usher in the new field of nanomedicine by combining several components onto multifunctional nanocarriers characterized by emerging properties and able to achieve synergistic effects.

关键词：生物医学应用纳米粒子多功能传递系统演变多级药物控制释放纳米载体

‘Hide-then-hit’to explain the importance of genotypic polymorphism of DNA repair genes in determining susceptibility to cancer

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分子细胞生物学报:英文版 2011年第1期3卷 59-65页

作者： Pei-Ei Wu Chen-Yang Shen institute of biomedical sciences Academia SinicaTaipei 11529 graduate institute of Environmental Science China Medical UniversityTaichong 40402

have been suggested to account for different risk of developing cancers.In this review article,on the basis of breast cancer formation as a model,we propose a‘hide-then-hit’hypothesis indicating the importance of escaping checkpoint surveillance for sub-optimal DNA repair variants to cause cancer.Therefore,only cells with subtle defects in repair capacity arising from low-penetrance variants of DNA repair genes would have the opportunity to grow and accumulate the genetic changes needed for cancer formation,without triggering cell-cycle checkpoint surveillance.Furthermore,distinct from high-penetrance alleles,these polymorphic alleles of DNA repair genes would predispose carriers to a higher risk of developing cancer but would not necessarily cause cancer.To examine this,we simultaneously genotyped multiple SNPs of cell-cycle checkpoint genes and the DNA repair genes.Support for the hypothesis came from observations that breast cancer risk associated with variant genotypes of DNA repair genes became more significant in the subgroups of women with specific genotypic statuses of checkpoint genes.This‘hide-then-hit’hypothesis is certainly needed to be confirmed by biological evidence in which a cause–effect relationship has to be established.However,based on this,possible gene–gene interaction is considered to play an important role in modifying the cancer risk associated with genotypic polymorphism of DNA repair gene in different study populations.

关键词： DNA repair genotype polymorphism

Increased PIT1 and PIT2 Expression in Streptozotocin (STZ)-induced Diabetic Mice Contributes to Uptake of iAs^((V))

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biomedical and Environmental sciences 2017年第11期30卷 792-801页

作者： YU Sha Li XU Ling Fei WU Jun Xia YAO Chen Juan HU Qiao Yun ZHANG Chun Xue ZHAO Xin Yuan WEI Hai Yan WANG Xiao Ke CHEN Gang Department of Environmental Health School of Public Health Nantong University Department of Molecular Oral Physiology Institute of Biomedical Sciences Tokushima University Graduate School

Objective This study aimed to investigate the susceptibility of mice with streptozotocin（STZ）-induced diabetes mellitus（TIDM） to the uptake of pentavalent inorganic arsenic（iAs^V） and the possible molecular mechanism. Methods TIDM was induced in mice by STZ. TIDM and normal mice were treated with 15.0 mg/kg Na2HAsO4·12H2O by intragastric administration. Then, the concentrations of arsenic in various tissues were measured by atomic fluorescence spectrometry. The gene expression levels of Pit1 and Pit2 were quantified by real-time RT-PCR, and their protein levels were detected by Western blotting in mouse heart, kidney, and liver tissues. Results The concentrations of arsenic in STZ-induced TIDM mouse tissues were higher at 2 h after intragastric administration of Na2HAsO4·12H2O. Compared with the levels in normal mice, PIT1 and PIT2, which play a role in the uptake of iAs^V, were upregulated in the livers and hearts of TIDM mice. PIT1 but not PIT2 was higher in TIDM mouse kidneys. The upregulation of Pit1 and Pit2 expression could be reversed by insulin treatment. Conclusion The increased uptake of iAs^V in TIDM mouse tissues may be associated with increased PIT1 and/or PIT2 expression.

关键词： Type I diabetes mellitus Pentavalent inorganic arsenic Uptake Phosphate cotransporters

The CBP/p300 histone acetyltransferases function as plant-specific MEDIATOR subunits in Arabidopsis

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Journal of Integrative Plant Biology 2021年第4期63卷 755-771页

作者： Jing Guo Long Wei Shan-Shan Chen Xue-Wei Cai Yin-Na Su Lin Li She Chen Xin-Jian He National institute of Biological sciences Beijing 102206China graduate School of Peking Union Medical College Beijing 100730China Tsinghua institute of Multidisciplinary biomedical Research Tsinghua UniversityBeijing 100084China

In eukaryotes,MEDIATOR is a conserved multisubunit complex that links transcription factors and RNA polymerase II and that thereby facilitates transcriptional initiation.Although the composition of MEDIATOR has been well studied in yeast and mammals,relatively little is known about the composition of MEDIATOR in plants.By affinity purification followed by mass spectrometry,we identified 28 conserved MEDIATOR subunits in Arabidopsis thaliana,including putative MEDIATOR subunits that were not previously validated.Our results indicated that MED34,MED35,MED36,and MED37 are not Arabidopsis MEDIATOR subunits,as previously proposed.Our results also revealed that two homologous CBP/p300 histone acetyltransferases,HAC1 and HAC5(HAC1/5)are in fact plant-specific MEDIATOR subunits.The MEDIATOR subunits MED8 and MED25(MED8/25)are partially responsible for the association of MEDIATOR with HAC1/5,MED8/25 and HAC1/5 co-regulate gene expression and thereby affect flowering time and floral development.Our in vitro observations indicated that MED8 and HAC1 form liquid-like droplets by phase separation,and our in vivo observations indicated that these droplets co-localize in the nuclear bodies at a subset of nuclei.The formation of liquid-like droplets is required for MED8 to interact with RNA polymerase II.In summary,we have identified all of the components of Arabidopsis MEDIATOR and revealed the mechanism underlying the link of histone acetylation and transcriptional regulation.

关键词： complex development flowering time histone acetylation MEDIATOR phase separation transcription