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BACKGROUND: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis. PROCEDURE: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML. RESULTS: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells. CONCLUSIONS: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.
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Biomarcadores Tumorais , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Criança , Masculino , Feminino , Prognóstico , Pré-Escolar , Adolescente , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Lactente , Taxa de Sobrevida , Seguimentos , População do Leste Asiático , Proteínas rac de Ligação ao GTPRESUMO
CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.
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Fatores de Ligação ao Core , Leucemia Mieloide Aguda , Criança , Humanos , Prognóstico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Células-Tronco Neoplásicas , Biomarcadores/metabolismo , Subunidade alfa de Receptor de Interleucina-2RESUMO
BACKGROUND: Leucine-rich repeat kinase 2 is a molecule that is responsible for familial Parkinson's disease. Our previous findings revealed that leucine-rich repeat kinase 2 is expressed in the enteric nervous system. However, which cells in the enteric nervous system express leucine-rich repeat kinase 2 and whether leucine-rich repeat kinase 2 is associated with the structure of the enteric nervous system remain unclear. The enteric nervous system is remarkable because some patients with Parkinson's disease experience gastrointestinal symptoms before developing motor symptoms. AIMS: We established a leucine-rich repeat kinase 2 reporter mouse model and performed immunostaining in leucine-rich repeat kinase 2 knockout mice. METHODS: Longitudinal muscle containing the myenteric plexus prepared from leucine-rich repeat kinase 2 reporter mice was analyzed by immunostaining using anti-green fluorescent protein (GFP) antibody. Immunostaining using several combinations of antibodies characterizing enteric neurons and glial cells was performed on intestinal preparations from leucine-rich repeat kinase 2 knockout mice. RESULTS: GFP expression in the reporter mice was predominantly in enteric glial cells rather than in enteric neurons. Immunostaining revealed that differences in the structure and proportion of major immunophenotypic cells were not apparent in the knockout mice. Interestingly, the number of biphenotypic cells expressing the neuronal and glial cell markers increased in the leucine-rich repeat kinase 2 knockout mice. Moreover, there was accumulation of α-synuclein in the knockout mice. CONCLUSIONS: Our present findings suggest that leucine-rich repeat kinase 2 is a newly recognized molecule that potentially regulates the integrity of enteric nervous system and enteric α-synuclein accumulation.
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Sistema Nervoso Entérico , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Camundongos Knockout , Neurônios , alfa-Sinucleína , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Sistema Nervoso Entérico/metabolismo , Camundongos , Neurônios/metabolismo , Plexo Mientérico/metabolismo , Neuroglia/metabolismo , FenótipoRESUMO
BACKGROUND /PURPOSE: Melasma and solar lentigo (SL) are major benign hyperpigmented lesions, and both have been shown to involve the dermal vasculature. This review discusses current knowledge regarding the clinical characteristics of dermal vascularity in melasma and SL, as well as the results of relevant molecular biological investigations. METHODS: PubMed and Google Scholar were searched in December 2023 to identify articles related to melasma, SL, and the dermal vasculature in these lesions. RESULTS: Vascular morphologies in melasma and SL have been detected by histological and non-invasive methods, including modalities such as optical coherence tomography. Biological studies have indicated that factors secreted from vascular endothelial cells, such as stem cell factor and endothelin-1, can promote melanogenesis. With respect to phototherapy, blood vessel-targeting laser treatments are expected to provide long-term suppression of pigmentation, but this regimen is only effective when dilated capillaries are visible. CONCLUSION: In both melasma and SL, clinical and experimental investigations are revealing the contributions of dermal vascularity to hyperpigmentation. More effective treatment may require identification of hyperpigmentation subtypes. In the future, knowledge of treatment (including phototherapy) is expected to accumulate through reliable and validated non-invasive measurements.
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Hiperpigmentação , Lentigo , Melanose , Transtornos de Fotossensibilidade , Humanos , Células Endoteliais , Lentigo/patologia , Melanose/terapia , Melanose/patologia , FototerapiaRESUMO
OBJECTIVES: The purpose of this study was to noninvasively confirm the characteristics of the dermal vasculature in patients with solar lentigo (SL) and determine any association with the efficacy of picosecond-domain laser (PSL) treatment. METHODS: Thirteen facial SL lesions in 11 Asian female patients were included in this study and evaluated over 12 weeks. An Nd:YAG laser was used at 532 nm and 750 ps. Skin color and morphological structure were evaluated by ANTERA-3D® and optical coherence tomography (OCT), respectively. To analyze the vascularity in the upper dermis, an OCT angiography (OCTA) algorithm was applied to the OCT data. RESULTS: After PSL treatment, significant improvement in both hyperpigmentation and abnormally thickened epidermis was observed, but the efficacy varied for each lesion. There was a significant correlation between the change in the melanin index due to PSL treatment and preoperative vascular density in the upper dermis. CONCLUSIONS: To the best of our knowledge, this is the first report to demonstrate a correlation between the efficacy of PSL treatment of SL lesions and the vascularity in the upper dermis. Methods to evaluate the vasculature in the upper dermis may be useful for preoperative prediction of the efficacy of PSL treatment for SL lesions.
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Lasers de Estado Sólido , Lentigo , Humanos , Feminino , Tomografia de Coerência Óptica , Lentigo/diagnóstico por imagem , Lentigo/radioterapia , Lentigo/cirurgia , Lasers de Estado Sólido/uso terapêutico , Derme , Angiografia , Resultado do TratamentoRESUMO
The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%-40% of cases. Novel genetic factors for pediatric AML need to be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF-ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF-ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF-ITDs were found in exon 13 and shared a duplicated region. UBTF-ITD was more frequently detected in patients with trisomy 8, FLT3-ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3-ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF-ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML-05 cohort revealed that patients with UBTF-ITD had worse outcomes than those without UBTF-ITD (3-year event-free survival, 20% vs. 55%; 3-year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF -ITD had a poor prognosis resulting in early events (relapse or non-complete remission) within 1 year. Our findings suggest that UBTF-ITD may be a novel and significant prognostic factor for pediatric patients with AML.
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Leucemia Mieloide Aguda , Adulto , Criança , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Prognóstico , Recidiva , TrissomiaRESUMO
Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML.
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Leucemia Mieloide Aguda , Humanos , Criança , Mutação , Leucemia Mieloide Aguda/patologia , Prognóstico , Estimativa de Kaplan-Meier , Proteína Supressora de Tumor p53/genética , Transportador de Glucose Tipo 5/genética , Ubiquitina-Proteína Ligases/genética , Proteínas de Ligação a Retinoblastoma/genéticaRESUMO
OBJECTIVES: Hallux valgus is associated with tarsometatarsal arthritis; its pathophysiology remains unknown. Therefore, we aimed to elucidate the relationship between arthritis of the second and third tarsometatarsal joints and incongruity of the first tarsometatarsal joint in the sagittal plane. METHODS: Forty-three patients (64 feet) with hallux valgus who underwent surgery at University Hospital Kyoto Prefectural University of Medicine were included and divided into two groups: control (without second and third tarsometatarsal joint degeneration) and osteoarthritis (with second and third tarsometatarsal joint degeneration). Intergroup comparisons of the incongruity of the first tarsometatarsal joint in the sagittal plane, age, body mass index, hallux valgus angle, first-second intermetatarsal angle, metatarsus adductus angle, Meary's angle, and calcaneal pitch angle were performed. RESULTS: The proportion of patients with incongruity of the first tarsometatarsal joint was significantly higher in the osteoarthritis group than in the control group. Logistic regression analysis identified incongruity of the first tarsometatarsal joint and metatarsus adductus angle as significant related factors for arthritis of the second and third tarsometatarsal joints. CONCLUSIONS: Incongruity of the first tarsometatarsal joint in the sagittal plane was involved in the development of arthritis of the second and third tarsometatarsal joints in patients with hallux valgus.
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Hallux Valgus , Ossos do Metatarso , Metatarso Varo , Osteoartrite , Humanos , Hallux Valgus/complicações , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Metatarso Varo/complicações , Articulações do Pé , Ossos do Metatarso/diagnóstico por imagem , Ossos do Metatarso/cirurgia , Osteoartrite/complicações , Osteoartrite/diagnóstico por imagem , Osteoartrite/cirurgiaRESUMO
The jamming transition is a nonequilibrium critical phenomenon, which governs characteristic mechanical properties of jammed soft materials, such as pastes, emulsions, and granular matters. Both experiments and theory of jammed soft materials have revealed that the complex modulus measured by conventional macrorheology exhibits a characteristic frequency dependence. Microrheology is a new type of method to obtain the complex modulus, which transforms the microscopic motion of probes to the complex modulus through the generalized Stokes relation (GSR). Although microrheology has been applied to jammed soft materials, its theoretical understanding is limited. In particular, the validity of the GSR near the jamming transition is far from obvious since there is a diverging length scale lc, which characterizes the heterogeneous response of jammed particles. Here, we study the microrheology of jammed particles by theory and numerical simulation. First, we develop a linear response formalism to calculate the response function of the probe particle, which is transformed to the complex modulus via the GSR. Then, we apply our formalism to a numerical model of jammed particles and find that the storage and loss modulus follow characteristic scaling laws near the jamming transition. Importantly, the observed scaling law coincides with that in macrorheology, which indicates that the GSR holds even near the jamming transition. We rationalize this equivalence by asymptotic analysis of the obtained formalism and numerical analysis on the displacement field of jammed particles under a local perturbation.
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Non-steroidal anti-inflammatory drugs (NSAIDs), which are antipyretics and analgesics, cause gastrointestinal disorders, such as inflammation and ulcers. To prescribe NSAIDs more safely, it is important to clarify the mechanism of NSAID-induced gastrointestinal mucosal injury. However, there is a paucity of studies on small intestinal mucosal damage by NSAIDs, and it is currently unknown whether inflammation and ulceration also occur in the small intestine, and whether mediators are involved in the mechanism of injury. Therefore, in this study, we created an animal model in which small intestinal mucosal injury was induced using NSAIDs (indomethacin; IDM). Focusing on the dynamics of immune regulatory factors related to the injury, we aimed to elucidate the pathophysiological mechanism involved. We analyzed the pathological changes in the small intestine, the expression of immunoregulatory factors (cytokines), and identified cytokine secretion and expression cells from isolated lamina propria mononuclear cells (LPMCs). Ulcers were formed in the small intestine by administering IDM. Although the mRNA expression levels of IL-1ß, IL-6, and TNFα were decreased on day 7 after IDM administration, IL-13 mRNA levels increased from day 3 after IDM administration and remained high even on day 7. The IL-13 mRNA expression and the secretion of IL-13 were increased in small intestinal LPMCs isolated from the IDM-treated group. In addition, we confirmed that IL-13 was expressed in CD4-positive T cells. These results provided new evidence that IL-13 production from CD4-positive T cells in the lamina propria of the small intestine contributes to NSAID-induced mucosal injury.
Assuntos
Interleucina-13 , Úlcera , Animais , Interleucina-13/genética , Interleucina-13/metabolismo , Úlcera/metabolismo , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/metabolismo , Intestino Delgado/metabolismo , Mucosa Intestinal/metabolismo , Fatores Imunológicos/metabolismo , Inflamação/metabolismo , RNA Mensageiro/metabolismoRESUMO
Osteoblasts participate in both bone formation through the synthesis of extracellular matrix and osteoclast differentiation through the expression of osteoclast differentiation factor. Osteoblasts communicate with each other via gap junctions (GJ), which enable small molecules, such as cAMP, to move to adjacent cells. Therefore, we focused on the role of cAMP propagation between osteoblasts via GJ in the osteoclast-supporting activity of osteoblasts. Osteoclast-supporting activity was evaluated by a co-culture system of osteoblasts with bone marrow-derived mononuclear cells. In this system, ablation of Gja1, a gene encoding connexin 43, in osteoblasts promoted osteoclastogenesis induced by prostaglandin E2 (PGE2). A phosphodiesterase 4 inhibitor increased both osteoclastogenesis and the intracellular cAMP concentration ([cAMP]i) in osteoblasts. Individual cell analysis of [cAMP]i in osteoblasts revealed different responses of each osteoblast to PGE2. Moreover, measurement of real-time [cAMP]i demonstrated cAMP movement from cell to cell via GJ. The inhibition of GJ resulted in the upregulation of [cAMP]i in osteoblasts stimulated by PGE2. This study suggested that GJ intercellular communication exerts protective effects against excess osteoclastogenesis via cAMP movement between osteoblasts.
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RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Criança , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , PrognósticoRESUMO
KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1-RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)-AML patients. The 5 year event-free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%-69.4%] vs. 74.7% [95% CI, 63.0%-83.2%] P-value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%-NA vs. 89.7% [95% CI, 69.6%-96.8%] P-value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF-AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1-RUNX1T1-positive AML.
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Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/epidemiologia , Masculino , Mutação Puntual , Reação em Cadeia da Polimerase , Análise de SobrevidaRESUMO
By genetic manipulations, we study the roles played by insulin-producing cells (IPCs) in the brain and their target, the corpora allata (CA), for reproductive dormancy in female Drosophila melanogaster, which is induced by exposing them to a combination of low temperature (11°C), short-day photoperiod (10L:14D) and starvation (water only) for 7 days immediately after eclosion (dormancy-inducing conditions). Artificial inactivation of IPCs promotes, whereas artificial activation impedes, the induction of reproductive dormancy. A transcriptional reporter assay reveals that the IPC activity is reduced when the female flies are exposed to dormancy-inducing conditions. The photoperiod sensitivity of reproductive dormancy is lost in pigment-dispersing factor (pdf), but not cry, mutants, suggesting that light input to IPCs is mediated by pdf-expressing neurons. Genetic manipulations to upregulate and downregulate insulin signaling in the CA, a pair of endocrine organs that synthesize the juvenile hormone (JH), decrease and increase the incidence of reproductive dormancy, respectively. These results demonstrate that the IPC-CA axis constitutes a key regulatory pathway for reproductive dormancy.
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Corpora Allata/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Hormônios Juvenis/biossíntese , Reprodução/genética , Estresse Fisiológico/genética , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Regulação para Baixo , Proteínas de Drosophila/genética , Feminino , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Hormônios Juvenis/genética , Transdução de Sinais/genética , Regulação para CimaRESUMO
The molecular and cellular mechanism for clearance of dead neurons was explored in the developing Drosophila optic lobe. During development of the optic lobe, many neural cells die through apoptosis, and corpses are immediately removed in the early pupal stage. Most of the cells that die in the optic lobe are young neurons that have not extended neurites. In this study, we showed that clearance was carried out by cortex glia via a phagocytosis receptor, Draper (Drpr). drpr expression in cortex glia from the second instar larval to early pupal stages was required and sufficient for clearance. Drpr that was expressed in other subtypes of glia did not mediate clearance. Shark and Ced-6 mediated clearance of Drpr. The Crk/Mbc/dCed-12 pathway was partially involved in clearance, but the role was minor. Suppression of the function of Pretaporter, CaBP1 and phosphatidylserine delayed clearance, suggesting a possibility for these molecules to function as Drpr ligands in the developing optic lobe.
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Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Lobo Óptico de Animais não Mamíferos/metabolismo , Transdução de Sinais , Animais , Corpo Celular/metabolismo , Morte Celular , Larva/citologia , Fosfatidilserinas/metabolismo , Pupa/citologiaRESUMO
Although infants (age <1 year) with acute myeloid leukaemia (AML) have unique characteristics and are vulnerable to chemotherapy, children aged 1-2 years with AML may have characteristics similar to that of infants. Thus, we analysed 723 paediatric AML patients treated on the Japanese AML99 and AML-05 trials to identify characteristics of younger children. We identified patients aged <3 years (the younger group) as a distinct subgroup. KMT2A-rearrangement (KMT2A-R), CBFA2T3-GLIS2, CBFB-MYH11 and NUP98-KDM5A were frequently found in the younger group. Prognostic analyses revealed poor 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) in patients with CBFA2T3-GLIS2 (42%, 17% and 83%, respectively) and those with NUP98-KDM5A (33%, 17% and 83%, respectively). Additionally, we identified KMT2A-R and CBFB-MYH11 as age-specific prognostic markers. Regarding KMT2A-R, the younger group had significantly better OS, EFS and CIR than the older group (aged 3 to <18 years) (P = 0·023, 0·011 and <0·001, respectively). Conversely, concerning CBFB-MYH11, the younger group had significantly poor EFS and CIR than the older group (each P < 0·001), suggesting that certain molecular markers are linked to different prognoses according to age. Therefore, we characterized patients <3 years as a distinct subgroup of paediatric AML.
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Rearranjo Gênico , Leucemia Mieloide Aguda , Proteínas de Neoplasias/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Early in the development of the central nervous system, progenitor cells undergo a shape change, called apical constriction, that triggers the neural plate to form a tubular structure. How apical constriction in the neural plate is controlled and how it contributes to tissue morphogenesis are not fully understood. In this study, we show that intracellular calcium ions (Ca2+) are required for Xenopus neural tube formation and that there are two types of Ca2+-concentration changes, a single-cell and a multicellular wave-like fluctuation, in the developing neural plate. Quantitative imaging analyses revealed that transient increases in Ca2+ concentration induced cortical F-actin remodeling, apical constriction and accelerations of the closing movement of the neural plate. We also show that extracellular ATP and N-cadherin (cdh2) participate in the Ca2+-induced apical constriction. Furthermore, our mathematical model suggests that the effect of Ca2+ fluctuations on tissue morphogenesis is independent of fluctuation frequency and that fluctuations affecting individual cells are more efficient than those at the multicellular level. We propose that distinct Ca2+ signaling patterns differentially modulate apical constriction for efficient epithelial folding and that this mechanism has a broad range of physiological outcomes.
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Cálcio/metabolismo , Polaridade Celular , Espaço Intracelular/metabolismo , Morfogênese , Tubo Neural/citologia , Tubo Neural/metabolismo , Xenopus laevis/embriologia , Actinas/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Espaço Extracelular/metabolismo , Imageamento Tridimensional , Modelos Lineares , Modelos Biológicos , Placa Neural/citologia , Placa Neural/metabolismoRESUMO
AIM: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. METHODS: In total, 28 Child-Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2-week administration of lenvatinib. RESULTS: The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2 ) did not change after the 2-week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). CONCLUSIONS: Considering that this was a short-term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.
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BACKGROUND: Ultraviolet (UV) irradiation to skin induces biological responses to protect and heal the wounded tissue. Cutaneous blood vessels play an important role in maintaining skin homeostasis, by inducing angiogenesis and vasodilation. However, the vascular dynamics in vivo, such as morphological changes over time and their depth dependency, are not fully understood. METHODS: Ten Asian males were enrolled in this study and received UV (UVA + UVB) irradiation at two minimal erythema dose (MED) to the inner upper arm. Changes in epidermal thickness and vascular structures associated with UV irradiation were evaluated over time for 28 days by optical coherence tomography angiography (OCTA). This technique enables non-invasive visualization of three-dimensional vascular networks in human skin based on OCT assessment of skin structures with near-infrared light. RESULTS: Notable dilation of vascular structures and increases in epidermal thickness were observed after UV irradiation. Vessel density was markedly increased from the papillary dermis to the upper reticular dermis at a depth of 200 µm. These increases in vascular density showed significant persistence even at 28 days after UV irradiation. CONCLUSION: We visualized the vascular structural changes caused by UV irradiation and revealed that the effects of a single UV irradiation at 2 MED persisted for up to 28 days after exposure. The OCTA technique allows not only the in situ assessment of micro-vasculature in human skin but also its monitoring of vascular dynamics over time.
Assuntos
Angiografia/métodos , Vasos Sanguíneos/diagnóstico por imagem , Eritema/diagnóstico por imagem , Pele/diagnóstico por imagem , Raios Ultravioleta/efeitos adversos , Adulto , Vasos Sanguíneos/patologia , Dilatação Patológica/diagnóstico por imagem , Epiderme/metabolismo , Epiderme/patologia , Eritema/etiologia , Eritema/patologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/metabolismo , Masculino , Pele/patologia , Pigmentação da Pele/efeitos da radiação , Fatores de Tempo , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: In chronic lateral ankle instability (CLAI), the instability of the ankle joint results in repeated microtrauma to the articular cartilage. How the lesion condition or stage is affected by the presence of lateral instability in medial osteochondral lesions of the talus (OLT) is unclear. We aimed to examine whether CLAI is associated with the size and staging of medial OLT on radiographs, magnetic resonance (MR) images, and arthroscopy. METHODS: Forty-five patients with medial OLTs in 45 ankles were reviewed. Radiographs were assessed for damage and lesion classification. The tibio-talar tilting angle (TTA) was measured. The patients were divided into two groups: the CLAI group and the stable group. The lesion classification on radiographs, MR images, and arthroscopy, and size on MR images were statistically compared. RESULTS: The CLAI group had a mean TTA of 8.15 ± 3.41°, whereas the stable group had a mean TTA of 2.24 ± 1.64°. The CLAI group had a lower clinical score than the stable group at the initial visit to our clinic. The CLAI group presented with lesions of significantly shorter longitudinal and transverse diameters. Stages of medial OLT on radiographs, MR images, and arthroscopic evaluation were earlier in the CLAI group than those in the stable group. CONCLUSIONS: Patients with CLAI presented in the early stages of OLT and had significantly smaller lesions than those without CLAI. The patients without CLAI may be selected for surgery at an early phase.