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1.
Diabetes Obes Metab ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34491605

RESUMO

AIM: To develop more effective and long-lasting antiobesity and antidiabetic therapeutics by employing novel chemical modifications of glucagon-like peptide-1 receptor (GLP-1R) agonists. METHODS: We constructed novel unimolecular dual agonists of GLP-1R and glucagon receptor prepared by linking sEx-4 and native glucagon (GCG) via lysine or triazole [sEx4-GCG(K) and sEx4-GCG(T), respectively] and evaluated their antiobesity and antidiabetic efficacy in the diabetic and obese mouse model. RESULTS: Both sEx4-GCG(K) and sEx4-GCG(T) showed the beneficial metabolic effects of GLP-1 and glucagon: they promoted weight loss and ameliorated insulin resistance and hepatic steatosis. They also increased thermogenesis in brown adipose tissue, and lipolysis and ß-oxidation in white adipose tissue, with concomitant suppression of lipogenesis. Furthermore, both dual agonists activated the 5'-AMP-activated protein kinase signalling pathway and prevented palmitate-induced oxidative stress in skeletal muscle cells. CONCLUSION: Through their complementary dual agonism, sEx4-GCG(T) and sEx4-GCG(K) induce more marked weight loss and metabolic improvements than conventional agonists, and could be developed as novel therapeutic agents for the treatment of obesity and associated metabolic disorders in humans.

2.
Nat Commun ; 12(1): 4730, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354063

RESUMO

Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Dispositivos Lab-On-A-Chip , Neurogênese/fisiologia , Organoides/crescimento & desenvolvimento , Organoides/fisiologia , Animais , Encéfalo/citologia , Meios de Cultura , Fenômenos Eletrofisiológicos , Matriz Extracelular/fisiologia , Estudos de Viabilidade , Perfilação da Expressão Gênica , Humanos , Hidrogéis , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Modelos Anatômicos , Modelos Neurológicos , Neurogênese/genética , Neuroglia/citologia , Neuroglia/fisiologia , Técnicas de Cultura de Órgãos/instrumentação , Técnicas de Cultura de Órgãos/métodos , Organoides/citologia , Suínos
3.
Neural Comput ; 33(7): 1719-1750, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34411268

RESUMO

Decoding sensory stimuli from neural activity can provide insight into how the nervous system might interpret the physical environment, and facilitates the development of brain-machine interfaces. Nevertheless, the neural decoding problem remains a significant open challenge. Here, we present an efficient nonlinear decoding approach for inferring natural scene stimuli from the spiking activities of retinal ganglion cells (RGCs). Our approach uses neural networks to improve on existing decoders in both accuracy and scalability. Trained and validated on real retinal spike data from more than 1000 simultaneously recorded macaque RGC units, the decoder demonstrates the necessity of nonlinear computations for accurate decoding of the fine structures of visual stimuli. Specifically, high-pass spatial features of natural images can only be decoded using nonlinear techniques, while low-pass features can be extracted equally well by linear and nonlinear methods. Together, these results advance the state of the art in decoding natural stimuli from large populations of neurons.

4.
Biomed Eng Lett ; 11(2): 107-115, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34150347

RESUMO

Elaborate electrodes that enable adhesion to the skin surface and effectively collect vital signs are necessitated. In recent years, various electrode materials and novel structures have been developed, and they have garnered scientific attention due to their higher sensing performances compared with those of conventional electrode-based sensors. This paper provides an overview of recent advances in biomedical sensors, focusing on the development of novel electrodes. We comprehensively review the different types of electrode materials in the context of efficient biosignal detection, with respect to material composition for flexible and wearable electrodes and novel electrode structures. Finally, we discuss recent packaging technologies in biomedical applications using flexible and wearable electrodes.

5.
Sci Rep ; 11(1): 11693, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083562

RESUMO

Insect ecdysis triggering hormones (ETHs) released from endocrine Inka cells act on specific neurons in the central nervous system (CNS) to activate the ecdysis sequence. These primary target neurons express distinct splicing variants of ETH receptor (ETHR-A or ETHR-B). Here, we characterized both ETHR subtypes in the moth Bombyx mori in vitro and mapped spatial and temporal distribution of their expression within the CNS and peripheral organs. In the CNS, we detected non-overlapping expression patterns of each receptor isoform which showed dramatic changes during metamorphosis. Most ETHR-A and a few ETHR-B neurons produce multiple neuropeptides which are downstream signals for the initiation or termination of various phases during the ecdysis sequence. We also described novel roles of different neuropeptides during these processes. Careful examination of peripheral organs revealed ETHRs expression in specific cells of the frontal ganglion (FG), corpora allata (CA), H-organ and Malpighian tubules prior to each ecdysis. These data indicate that PETH and ETH are multifunctional hormones that act via ETHR-A and ETHR-B to control various functions during the entire development-the ecdysis sequence and associated behaviors by the CNS and FG, JH synthesis by the CA, and possible activity of the H-organ and Malpighian tubules.


Assuntos
Hormônios de Inseto/metabolismo , Receptores de Peptídeos/metabolismo , Animais , Bombyx/metabolismo , Sistema Nervoso Central/metabolismo , Corpora Allata/metabolismo , Túbulos de Malpighi/metabolismo
6.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33479181

RESUMO

The link between the biological clock and reproduction is evident in most metazoans. The fruit fly Drosophila melanogaster, a key model organism in the field of chronobiology because of its well-defined networks of molecular clock genes and pacemaker neurons in the brain, shows a pronounced diurnal rhythmicity in oogenesis. Still, it is unclear how the circadian clock generates this reproductive rhythm. A subset of the group of neurons designated "posterior dorsal neuron 1" (DN1p), which are among the ∼150 pacemaker neurons in the fly brain, produces the neuropeptide allatostatin C (AstC-DN1p). Here, we report that six pairs of AstC-DN1p send inhibitory inputs to the brain insulin-producing cells, which express two AstC receptors, star1 and AICR2. Consistent with the roles of insulin/insulin-like signaling in oogenesis, activation of AstC-DN1p suppresses oogenesis through the insulin-producing cells. We show evidence that AstC-DN1p activity plays a role in generating an oogenesis rhythm by regulating juvenile hormone and vitellogenesis indirectly via insulin/insulin-like signaling. AstC is orthologous to the vertebrate neuropeptide somatostatin (SST). Like AstC, SST inhibits gonadotrophin secretion indirectly through gonadotropin-releasing hormone neurons in the hypothalamus. The functional and structural conservation linking the AstC and SST systems suggest an ancient origin for the neural substrates that generate reproductive rhythms.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Neurônios/metabolismo , Oogênese/genética , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Hormônios Juvenis/genética , Hormônios Juvenis/metabolismo , Masculino , Neurônios/citologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Reprodução/genética , Transdução de Sinais , Vitelogênese/genética
7.
J Neurogenet ; 35(1): 33-44, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33326321

RESUMO

The gastrointestinal tract in the adult Drosophila serves as a model system for exploring the mechanisms underlying digestion, absorption and excretion, stem cell plasticity, and inter-organ communication, particularly through the gut-brain axis. It is also useful for studying the cellular and adaptive responses to dietary changes, alterations in microbiota and immunity, and systematic and endocrine signals. Despite the various cell types and distinct regions in the gastrointestinal tract, few tools are available to target and manipulate the activity of each cell type and region, and their gene expression. Here, we report 353 GAL4 lines and several split-GAL4 lines that are expressed in enteric neurons (ENs), progenitors (ISCs and EBs), enterocytes (ECs), enteroendocrine cells (EEs), or/and other cell types that are yet to be identified in distinct regions of the gut. We had initially collected approximately 600 GAL4 lines that may be expressed in the gut based on RNA sequencing data, and then crossed them to UAS-GFP to perform immunohistochemistry to identify those that are expressed selectively in the gut. The cell types and regional expression patterns that are associated with the entire set of GAL4 drivers and split-GAL4 combinations are annotated online at http://kdrc.kr/index.php (K-Gut Project). This GAL4 resource can be used to target specific populations of distinct cell types in the fly gut, and therefore, should permit a more precise investigation of gut cells that regulate important biological processes.

8.
Mol Cells ; 43(12): 1011-1022, 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33293480

RESUMO

Cell type specification is a delicate biological event in which every step is under tight regulation. From a molecular point of view, cell fate commitment begins with chromatin alteration, which kickstarts lineage-determining factors to initiate a series of genes required for cell specification. Several important neuronal differentiation factors have been identified from ectopic over-expression studies. However, there is scarce information on which DNA regions are modified during induced pluripotent stem cell (iPSC) to neuronal progenitor cell (NPC) differentiation, the cis regulatory factors that attach to these accessible regions, or the genes that are initially expressed. In this study, we identified the DNA accessible regions of iPSCs and NPCs via the Assay for Transposase-Accessible Chromatin sequencing (ATACseq). We identified which chromatin regions were modified after neuronal differentiation and found that the enhancer regions had more active histone modification changes than the promoters. Through motif enrichment analysis, we found that NEUROD1 controls iPSC differentiation to NPC by binding to the accessible regions of enhancers in cooperation with other factors such as the Hox proteins. Finally, by using Hi-C data, we categorized the genes that directly interacted with the enhancers under the control of NEUROD1 during iPSC to NPC differentiation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Diferenciação Celular/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Epigênese Genética , Humanos , Células-Tronco Neurais/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/genética
9.
J Periodontal Implant Sci ; 50(6): 368-378, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33350177

RESUMO

PURPOSE: Vitamin D deficiency may cause bone loss and increased inflammation, which are well-known symptoms of periodontal disease. This study investigated whether serum 25-hydroxyvitamin D (25(OH)D) levels are associated with periodontal disease status and tooth loss. METHODS: Cross-sectional data from 5,405 individuals aged ≥50 years (2,253 males and 3,152 females) were obtained from the 2008-2010 Dong-gu study, a prospective cohort study of risk factors for chronic diseases. Periodontal examinations were conducted to evaluate the number of remaining teeth, the periodontal probing depth (PPD), the clinical attachment level (CAL), and bleeding on probing. The percentages of sites with PPD ≥4 mm and CAL ≥4 mm were recorded for each participant. The severity of periodontitis was classified using the Centers for Disease Control and Prevention and the American Academy of Periodontology case definitions. Serum 25(OH)D levels were classified as reflecting severe deficiency, deficiency, insufficiency, or sufficiency. Multivariate linear regression analysis was performed to assess the associations of serum 25(OH)D levels with periodontal parameters and the number of remaining teeth after adjusting for confounders including age, smoking status, alcohol consumption status, month of blood collection, and physical activity. Multivariate logistic regression was used to evaluate the association between serum vitamin D levels and severe periodontitis. An overall statistical analysis and a stratified analysis by sex were performed. RESULTS: Overall, the rates of severe deficiency, deficiency, insufficiency, and sufficiency were 6.5%, 67.9%, 22.4%, and 3.2%, respectively. After adjustment for confounders, vitamin D levels were directly associated with the number of remaining teeth, an association that was significant in males, but not in females. Sufficient serum 25(OH)D was associated with a low frequency of severe periodontitis. CONCLUSIONS: This population-based cross-sectional study indicates that low serum 25(OH)D is significantly associated with tooth loss and severe periodontitis in Koreans aged 50 years and older.

10.
BMC Biol ; 18(1): 167, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33187521

RESUMO

BACKGROUND: Structural variants comprise diverse genomic arrangements including deletions, insertions, inversions, and translocations, which can generally be detected in humans through sequence comparison to the reference genome. Among structural variants, insertions are the least frequently identified variants, mainly due to ascertainment bias in the reference genome, lack of previous sequence knowledge, and low complexity of typical insertion sequences. Though recent developments in long-read sequencing deliver promise in annotating individual non-reference insertions, population-level catalogues on non-reference insertion variants have not been identified and the possible functional roles of these hidden variants remain elusive. RESULTS: To detect non-reference insertion variants, we developed a pipeline, InserTag, which generates non-reference contigs by local de novo assembly and then infers the full-sequence of insertion variants by tracing contigs from non-human primates and other human genome assemblies. Application of the pipeline to data from 2535 individuals of the 1000 Genomes Project helped identify 1696 non-reference insertion variants and re-classify the variants as retention of ancestral sequences or novel sequence insertions based on the ancestral state. Genotyping of the variants showed that individuals had, on average, 0.92-Mbp sequences missing from the reference genome, 92% of the variants were common (allele frequency > 5%) among human populations, and more than half of the variants were major alleles. Among human populations, African populations were the most divergent and had the most non-reference sequences, which was attributed to the greater prevalence of high-frequency insertion variants. The subsets of insertion variants were in high linkage disequilibrium with phenotype-associated SNPs and showed signals of recent continent-specific selection. CONCLUSIONS: Non-reference insertion variants represent an important type of genetic variation in the human population, and our developed pipeline, InserTag, provides the frameworks for the detection and genotyping of non-reference sequences missing from human populations.


Assuntos
Mapeamento de Sequências Contíguas , Frequência do Gene , Genoma Humano , Mutagênese Insercional , Humanos
11.
Genes (Basel) ; 11(10)2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33050006

RESUMO

Given the difficulties of obtaining diseased cells, differentiation of neurons from patient-specific human induced pluripotent stem cells (iPSCs) with neural progenitor cells (NPCs) as intermediate precursors is of great interest. While cellular and transcriptomic changes during the differentiation process have been tracked, little attention has been given to examining spatial re-organization, which has been revealed to control gene regulation in various cells. To address the regulatory mechanism by 3D chromatin structure during neuronal differentiation, we examined the changes that take place during differentiation process using two cell types that are highly valued in the study of neurodegenerative disease - iPSCs and NPCs. In our study, we used Hi-C, a derivative of chromosome conformation capture that enables unbiased, genome-wide analysis of interaction frequencies in chromatin. We showed that while topologically associated domains remained mostly the same during differentiation, the presence of differential interacting regions in both cell types suggested that spatial organization affects gene regulation of both pluripotency maintenance and neuroectodermal differentiation. Moreover, closer analysis of promoter-promoter pairs suggested that cell fate specification is under the control of cis-regulatory elements. Our results are thus a resourceful addition in benchmarking differentiation protocols and also provide a greater appreciation of NPCs, the common precursors from which required neurons for applications in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, schizophrenia and spinal cord injuries are utilized.


Assuntos
Biomarcadores/metabolismo , Diferenciação Celular , Reprogramação Celular , Cromatina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Cromatina/genética , Genoma Humano , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia
12.
Insect Biochem Mol Biol ; 127: 103472, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32971207

RESUMO

Drosophila melanogaster sex peptide receptor (DrmSPR) is a G protein-coupled receptor (GPCR) with 'dual ligand selectivity' towards sex peptide (SP) and myoinhibitory peptides (MIPs), which are only remotely related to one another. SPR is conserved in almost all the sequenced lophotrochozoan and ecdysozoan genomes. SPRs from non-drosophilid taxa, such as those from the mosquitoes Aedes aegypti (AeaSPR), Anopheles gambiae (AngSPR), and the sea slug Aplysia californica (ApcSPR), are highly sensitive to MIP, but not to SP. To understand how Drosophila SPRs evolved their SP sensitivity while maintaining MIP sensitivity, we examined ligand selectivity in a series of chimeric GPCRs that combine domains from the SP-sensitive DrmSPR and the SP-insensitive AeaSPR. We found replacement of Pro 238 (P238) in DrmSPR with the corresponding residue from AeaSPR (L310) reduced its SP sensitivity 2.7 fold without altering its MIP sensitivity. The P238 residue located in the third extracellular loop (ECL3) is conserved in Drosophila SPRs and in SPR from the moth Bombyx mori (BomSPR), which is considerably more sensitive to SP than AeaSPR, AngSPR, or ApcSPR. We found, however, that rather than improving AeaSPR's sensitivity to SP, replacement of L310 in AeaSPR with Pro significantly reduces its MIP sensitivity. Thus, our identification of a single amino acid residue critical for SP sensitivity, but not for MIP sensitivity is an important step in clarifying how DrmSPR evolved the ability to detect SP.


Assuntos
Aedes/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Receptores de Peptídeos/genética , Aedes/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ligantes , Receptores de Peptídeos/química , Receptores de Peptídeos/metabolismo , Alinhamento de Sequência
13.
Stem Cell Rev Rep ; 16(6): 1316-1327, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32975781

RESUMO

The effects of gene body DNA methylation on gene regulation still remains highly controversial. In this study, we generated whole genome bisulfite sequencing (WGBS) data with high sequencing depth in induced pluripotent stem cell (iPSC) and neuronal progentior cell (NPC), and investigated the relationship between DNA methylation changes in CpG islands (CGIs) and corresponding gene expression during NPC differentiation. Interestingly, differentially methylated CGIs were more abundant in intragenic regions compared to promoters and these methylated intragenic CGIs (iCGIs) were associated with neuronal development-related genes. When we compared gene expression level of methylated and unmethylated CGIs in intragenic regions, DNA methylation of iCGI was positively correlated with gene expression in contrast with promoter CGIs (pCGIs). To gain insight into regulatory mechanism mediated by iCGI DNA methylation, we executed motif searching in hypermethylated iCGIs and found NEUROD1 as a hypermethylated iCGI binding transcription factor. This study highlights give rise to possibility of activating role of hypermethylation in iCGIs and involvement of neuronal development related TFs. Graphical Abstract The relationship between iCGI DNA methylation and expression of associated genes in neuronal developmental process. During iPSC to NPCdifferentiation, iCGI containing neural developmental genes show iCGI's DNA hypermethylation which is accompanied by gene activation and NEUROD1which is one of the core neuronal TFs interacts with hypermethylated iCGI regions.


Assuntos
Diferenciação Celular/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Linhagem da Célula/genética , Epigênese Genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo
14.
Math Biosci Eng ; 17(4): 2970-2983, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32987511

RESUMO

Computational models and inverse dynamic optimization methods are used to predict in-vivo spinal loading. Spinal force is conventionally predicted using the constant loading path method, which is based on the concept that the physiological directions of the spine loads follow the same path of the spinal curve. However, the global convergence optimization method, in which the instantaneous center of rotation of the joint should be also predicted, is necessary for accurate prediction of joint forces of the human body. In this study, we investigate the joint forces, instantaneous centers of rotation, and muscle forces of the human lumbar spine using both global convergence optimization method and constant loading path method during flexion, upright standing, and extension postures. The joint forces predicted using the constant loading path method were 130%, 234%, and 253% greater than those predicted using the global convergence optimization method for the three postures. The instantaneous centers of rotation predicted using the global convergence optimization method were segment level-dependent and moved anteriorly in the flexion and posteriorly in the extension, whereas those predicted using the constant loading path method moved posteriorly in both the flexion and extension. The data indicated that compared to the global convergence optimization method, the constant loading path method introduces additional constraints to the spinal joint model, and thus, it results in greater joint and muscle forces.


Assuntos
Vértebras Lombares , Postura , Fenômenos Biomecânicos , Humanos , Amplitude de Movimento Articular , Rotação
15.
Exp Mol Med ; 52(9): 1550-1563, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879421

RESUMO

Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento
16.
J Clin Invest ; 130(10): 5370-5379, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32663196

RESUMO

Chronic inflammation is deeply involved in various human disorders, such as cancer, neurodegenerative disorders, and metabolic disorders. Induction of epigenetic alterations, especially aberrant DNA methylation, is one of the major mechanisms, but how it is induced is still unclear. Here, we found that expression of TET genes, methylation erasers, was downregulated in inflamed mouse and human tissues, and that this was caused by upregulation of TET-targeting miRNAs such as MIR20A, MIR26B, and MIR29C, likely due to activation of NF-κB signaling downstream of IL-1ß and TNF-α. However, TET knockdown induced only mild aberrant methylation. Nitric oxide (NO), produced by NOS2, enhanced enzymatic activity of DNA methyltransferases (DNMTs), methylation writers, and NO exposure induced minimal aberrant methylation. In contrast, a combination of TET knockdown and NO exposure synergistically induced aberrant methylation, involving genomic regions not methylated by either alone. The results showed that a vicious combination of TET repression, due to NF-κB activation, and DNMT activation, due to NO production, is responsible for aberrant methylation induction in human tissues.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Dioxigenases/metabolismo , Animais , Dioxigenases/genética , Modelos Animais de Doenças , Regulação para Baixo , Epigênese Genética , Gastrite/genética , Gastrite/metabolismo , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Helicobacter felis/patogenicidade , Helicobacter pylori , Humanos , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Regulação para Cima
17.
J Clin Med ; 9(6)2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32466515

RESUMO

The impact of body mass index (BMI) on postoperative nausea and vomiting (PONV) is controversial, and few studies have focused on their relationship. We investigated the effects of BMI on PONV, taking into account other PONV risk factors. We analyzed adults over the age of 18 years who received general anesthesia between 2015 and 2019, using propensity score matching. Before propensity score matching, odds ratios (ORs) for PONV were lower for overweight (OR, 0.91; 95% confidence interval (CI), 0.87-0.96; p < 0.0001) or obese patients (OR, 0.77; 95% CI, 0.71-0.84; p < 0.0001) than for normal-BMI patients. After matching, the ORs for PONV of overweight (OR, 0.89; 95% CI, 0.80-0.98; p = 0.016) and obese patients (OR, 0.71; 95% CI, 0.63-0.79; p < 0.0001) were low. However, the ORs of underweight patients did not differ from those of normal-BMI patients, irrespective of matching. Therefore, the incidence of PONV may be lower among adults with a higher­than­normal BMI.

18.
Nat Genet ; 52(6): 594-603, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32451460

RESUMO

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.


Assuntos
Linhagem da Célula , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Colorretais/patologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Análise de Sequência de RNA , Análise de Célula Única , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
19.
World Neurosurg ; 143: 553-556, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31954886

RESUMO

OBJECTIVE: The double microcatheter technique (DMT) is a common technique for treating intracranial aneurysms with endovascular coiling. The DMT is usually performed with 6 Fr guiding catheters. However, to the best of our knowledge, this technique using 5 Fr guiding catheters has not been reported. We report a DMT using a 5 Fr guiding catheter and the thoughts and tenets to make this possible. METHODS: An 84-year-old woman had presented with a subarachnoid hemorrhage caused by rupture of a broad-necked aneurysm on the origin of the left posterior inferior cerebellar artery. We decided to use the DMT for coil embolization. However, because of the tortuous and calcified vessels from the femoral artery to the vertebral artery (VA), placement of a 6 Fr guiding catheter within the left VA failed. Therefore, we changed the guiding catheter to a 5 Fr Chaperon guiding catheter, which has the largest inner diameter of the 5 Fr guiding catheters. It was successfully navigated to the left VA, and we performed the DMT using Headway Duo and Prowler 10 microcatheters. Coil embolization was successfully completed without any complications. RESULTS: DMT using a 5 Fr guiding catheter can be performed if the sum of the largest outer diameters of the 2 microcatheters is less than the inner diameter of the 5 Fr guiding catheter. CONCLUSIONS: The DMT using a 5 Fr guiding catheter can be performed if the sum of the outer diameters of the 2 microcatheters is less than the inner diameter of the 5 Fr guiding catheter. This technique could be a safe and effective option for treatment of broad-necked aneurysms, especially in the case of an elderly patient with tortuous vasculature or posterior circulation.


Assuntos
Aneurisma Roto/terapia , Cateteres , Embolização Terapêutica/instrumentação , Procedimentos Endovasculares/instrumentação , Aneurisma Intracraniano/terapia , Idoso de 80 Anos ou mais , Feminino , Humanos
20.
J Korean Neurosurg Soc ; 62(5): 536-544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31484229

RESUMO

OBJECTIVE: The objective of this study was to evaluatelong-term radiologic prognosis and characteristics of in-stent stenosis (ISS) after stent assisted coiling (SAC) for cerebral aneurysm and analyze its risk factors. METHODS: Radiological records of 362 cases of SAC during 10 years were retrospectively reviewed. Patients were included in this study if they had follow-up angiogram using catheter selected angiography at least twice. All subjected were followed up from 12 months to over 30 months. Of 120 patients, 123 aneurysms were enrolled. Patient data including age, sex, aneurysm size, neck size, procedural complication, kinds of stent, ISS associated symptom, ruptured state, location of ISS, degree of ISS, radiologic prognosis of ISS, follow-up period of time, and medical comorbidities such as hypertension, diabetes mellitus (DM), dyslipidemia, and smoking were collected.Statistical comparisons of group clinical characteristics were conducted for the total population. RESULTS: Among 123 casesof aneurysm, 22 cases (17.9%) of ISS were revealed on follow-up angiography. Multiple stenting was performed in three cases and intra-procedural rupture occurred in two cases. Most cases were asymptomatic and symptomatic stenosis was identified in only one case. Sixteen cases were ruptured aneurysm. Mild stenosis was observed in 11 cases. Moderate stenosis was found in eight cases and severe stenosis was identified in three cases. Mean timing of identification of ISS was 8.90 months. The most common type was proximal type. Most cases were improved or not changed on follow-up angiography. Only one case was aggravated from mild stenosis to occlusion of parent artery. Mean follow-up period was 44.3 months. We compared risk factors and characteristic between ISS group and non-ISS group using univariate analysis. Multiple stenting was performed for three cases (13.6%) of the ISS group and four cases (4.0%) of the non-ISS group, showing no statistical difference between the two groups (p=0.108). Additionally, the proportion of patients who had more than two risk factors among four medical risk factors (hypertension, DM, dyslipidemia, and smoking) was higher in the ISS group than that in the non-ISS group, the difference between the two was not statistically significant either (31.8% vs. 12.9%, p=0.05). CONCLUSION: Clinical course and long-term prognosis of ISS might be benign. Most cases of ISS could be improved or not aggravated. Control of medical co-morbidity might be important. To the best of our knowledge, our study had more cases with longer follow-up period of time than other reports.

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