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1.
Pigment Cell Melanoma Res ; 37(3): 363-371, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38158377

RESUMO

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture-based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co-occurred with KIT mutation and amplification. The most common pathways affected were the mitogen-activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression-free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32-19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22-15.30). Treatment with immune-checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01-0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs.


Assuntos
Neoplasias Esofágicas , Melanoma , Mutação , Humanos , Melanoma/genética , Melanoma/patologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Mutação/genética , Idoso de 80 Anos ou mais , Adulto , Biomarcadores Tumorais/genética , Prognóstico
2.
Cancer Cell Int ; 23(1): 187, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37649078

RESUMO

BACKGROUND: To date, data on the efficacy of targeted therapies for mucosal melanoma (MM) are limited. In this study, we analyzed genetic alterations according to the primary site of origin, which could provide clues for targeted therapy for MM. METHODS: We conducted a retrospective cohort study of 112 patients with MM. Targeted sequencing was performed to analyze genetic aberrations. Kaplan-Meier analysis was conducted with the log-rank test to compare the significance among subgroups. RESULTS: In total, 112 patients with MM were included according to the anatomic sites: 38 (33.9%) in the head and neck, 22 (19.6%) in the genitourinary tract, 21 (18.8%) in the anorectum, 19 (17.0%) in the esophagus, 10 (8.9%) in the uvea, and 2 (1.8%) in the small bowel. The most significantly mutated genes included BRAF (17%), KIT (15%), RAS (15%), TP53 (13%), NF1 (12%), SF3B1 (11%), GNA11 (7%), GNAQ (5%), and FBXW7 (4%). A large number of chromosomal structural variants was found. The anatomic sites of esophagus and small bowel were independent risk factors for progression-free survival (PFS, hazard ratio [HR] 4.78, 95% confidence interval [CI] 2.42-9.45, P < 0.0001) and overall survival (OS, HR 5.26, 95% CI 2.51-11.03, P < 0.0001). Casitas B-lineage lymphoma (CBL) mutants showed significantly poorer PFS and OS. In contrast, MM patients who received immune checkpoint inhibitors (ICIs) had a significantly more favorable OS (HR 0.39, 95% CI 0.20-0.75, P = 0.008). CONCLUSIONS: Our findings reveal the genetic features of patients with MM, mainly across six anatomic sites, offering a potential avenue for targeted therapies.

3.
Sci Signal ; 15(748): eabk3411, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-35998231

RESUMO

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of ß-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2G2019S mice suppressed LRRK2 expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2G2019S mice. In LRRK2G2019S mice or cultured dopaminergic neurons from LRRK2G2019S patients, treatment with itanapraced reduced LRRK2 expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Doença de Parkinson , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Camundongos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo
4.
Lung Cancer ; 160: 1-7, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364112

RESUMO

OBJECTIVES: Primary pulmonary salivary gland-type tumors (PSGTs) mainly comprise of mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), which are rare and molecularly poorly understood. This study aimed to profile the molecular alterations of PSGTs via targeted next-generation sequencing (NGS). MATERIAL AND METHODS: Immunohistochemistry was used to screen PSGTs in 32 patients and MAML2 and MYB rearrangements were detected using fluorescence in situ hybridization. 1021-Genepanel of targeted NGS was conducted to profile genomic mutations in all the PSGT patients. RESULTS: Among the 32 patients, 25 had MEC and 7 had ACC. MAML2 and MYB rearrangements were detected in 80.0% (20/25) of the MEC and 71.4% (5/7) of the ACC patients. Among the MEC patients, 10 (40.0%) had ≥1 mutation, and 6 of them had 11 isolated mutations with abundance >5%, namely NFE2L2, MYOD1, INPP4B, CCND2, SNTG1, HSPD1, TGFBR1, RBM10, NOTCH4, ASXL1, and PTPRD mutations. The remaining 4 patients had 9 mutations with abundance <5%, namely KMT2A, PDCD11, FLT1, BRCA2, APC, SLX4, FOXP1, FGFR1, and HRAS mutations. All the ACC patients had mutations, which were enriched in 5 pathways including the PI3K and NOTCH pathways, chromatin and cytoskeleton remodeling, and DNA damage. These results explain PSGTs harbor distinct driver features of MAML2 or MYB rearrangement, accompanied with wide mutational diversity with very low rate of somatic mutation. Several important pathways, including the NOTCH and PI3K pathways, and chromatin remodeling could be targeted to improve the survival in patients with ACC.


Assuntos
Carcinoma Mucoepidermoide , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Carcinoma Mucoepidermoide/genética , Fatores de Transcrição Forkhead , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Antígenos de Histocompatibilidade Menor , Mutação , Proteínas Nucleares , Fosfatidilinositol 3-Quinases , Proteínas de Ligação a RNA , Proteínas Repressoras , Glândulas Salivares
5.
Neurobiol Dis ; 153: 105313, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33636388

RESUMO

Vacuolar protein sorting protein 35 (VPS35) is a core component of the retromer complex involved in regulating protein trafficking and retrieval. Recently, a missense mutation, Asp620Asn (D620N), in VPS35 (PARK17) has been identified as a pathogenic mutation for late-onset autosomal dominant Parkinson's disease (PD). Although PD is characterized by a range of motor symptoms associated with loss of dopaminergic neurons in the substantial nigra, non-motor symptoms such as impaired hippocampal neurogenesis were observed in both PD patients and animal models of PD caused by multiple PD-linked pathogenic genes such as alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2). However, the role of the VPS35 D620N mutation in adult hippocampal neurogenesis remains unknown. Here, we showed that the VPS35 D620N mutation impaired hippocampal neurogenesis in adult transgenic mice expressing the VPS35 D620N gene. Specifically, we showed a reduction in the neural stem cell pool and neural proliferation and differentiation, retarded migration, and impaired neurite outgrowth in 3-month-old VPS35 D620N mutant mice. Moreover, we found that the VPS35 D620N mutant hyperphosphorylates amyloid precursor protein (APP) at Thr668and interacts with APP. Notably, by crossing the VPS35 D620N mutant mice with APP knockout (KO) mice, we showed that loss of APP function rescues VPS35 D620N-inhibited neurogenesis, neural migration, and maturation. Our study provides important evidence that APP is involved in the VPS35 D620N mutation in regulating adult neurogenesis, which sheds light on the pathogenic mechanisms in PD.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Hipocampo/metabolismo , Neurogênese/genética , Transtornos Parkinsonianos/genética , Proteínas de Transporte Vesicular/genética , Animais , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos
6.
Neurobiol Aging ; 95: 250-263, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32866886

RESUMO

The amyloid precursor protein (APP) intracellular domain (AICD) is a metabolic by-product of APP produced through sequential proteolytic cleavage by α-, ß-, and γ-secretases. The interaction between AICD and Fe65 has been reported to impair adult neurogenesis in vivo. However, the exact role of AICD in mediating neural stem cell fate remains unclear. To identify the role of AICD in neuronal proliferation and differentiation, as well as to clarify the molecular mechanisms underlying the role of AICD in neurogenesis, we first generated a mouse model expressing the Rosa26-based AICD transgene. AICD overexpression did not alter the spatiotemporal expression pattern of full-length APP or accumulation of its metabolites. In addition, AICD decreased the newly generated neural progenitor cell (NPC) pool, inhibited the proliferation and differentiation efficiency of NPCs, and increased cell death both in vitro and in vivo. Given that abnormal neurogenesis is often associated with depression-like behavior in adult mice, we conducted a forced swim test and tail suspension test with AICD mice and found a depression-like behavioral phenotype in AICD transgenic mice. Moreover, AICD stimulated FOXO3a transcriptional activation, which in turn negatively regulated AICD. In addition, functional loss of FOXO3a in NPCs derived from the hippocampal dentate gyrus of adult AICD transgenic mice rescued neurogenesis defects. AICD also increased the mRNA expression of FOXO3a target genes related to neurogenesis and cell death. These results suggest that FOXO3a is the functional target of AICD in neurogenesis regulation. Our study reveals the role of AICD in mediating neural stem cell fate to maintain homeostasis during brain development via interaction with FOXO3a.


Assuntos
Precursor de Proteína beta-Amiloide/fisiologia , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo/fisiologia , Neurogênese/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Hipocampo/citologia , Masculino , Camundongos Transgênicos , Neurônios/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Int J Dev Neurosci ; 35: 72-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24657285

RESUMO

Our previous studies identified a sub-population of cholinergic neurons which express nestin in the rostral part of the basal forebrain (BF) in normal adult rats. In the present study, the postnatal developmental patterns of nestin, choline acetyl transferase (ChAT) and parvalbumin (PV) positive neurons were explored by means of immunohistochemistry combined with immunofluorescence double label methods. Compared with early onset of ChAT expression (from P1) and delayed onset of PV expression (from P16), nestin positive activity was detected in the BF from P9 and co-expressed by parts of the ChAT positive neurons within the same region during the whole postnatal development process. However, ChAT and PV were not coexpressed by the neurons within the medial septum-diagonal band of Broca (MS-DBB) of BF. These results might imply a composite of separate development patterns displayed by different subpopulations of cholinergic neurons (nestin positive cholinergic neurons and nestin negative cholinergic neurons) within this region. Moreover, the topographic distribution of nestin, ChAT and PV positive neurons also showed different characteristics. In summary, our present study revealed a remarkable timing and topographic difference on the postnatal development of the nestin expression within the MS-DBB of BF compared with ChAT and PV expression. It is further suggested that nestin is re-expressed by cholinergic neurons in the BF after differentiation but not persisted from neuronal precursor cells.


Assuntos
Envelhecimento/fisiologia , Prosencéfalo Basal/fisiologia , Colina O-Acetiltransferase/metabolismo , Nestina/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Parvalbuminas/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Masculino , Nestina/classificação , Ratos , Ratos Sprague-Dawley
8.
Neurochem Int ; 56(5): 694-702, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20153393

RESUMO

This study explores recently identified neurons that express the protein nestin in the medial septum-diagonal band of Broca (MS-DBB) of adult rats and humans. These nestin positive neurons from MS-DBB are known to project to the hippocampus and frontal cortex of the brain. However, their chemical identification has not been fully elucidated. In this study, we further investigated the chemical identity of the nestin-immunoreactive (ir) neurons in rats using double immunofluorescence labeling and single cell reverse transcription polymerase chain reaction (RT-PCR) techniques. The results of double labeling showed that all nestin-ir neurons exhibited choline acetyltransferase (ChAT) immunoreactivity in the MS-DBB of the basal forebrain. Conversely, only about 43% of the ChAT-ir neurons showed nestin immunoreactivity. In addition, a vast majority of the nestin-ir neurons (95%) were nerve growth factor receptor (NGFR) positive. The nestin-ir neurons were highly distributed in the rostral and intermediated regions of the MS-DBB. Single cell RT-PCR results showed that 90% of the nestin mRNA expressed neurons displayed ChAT mRNA expression as well, but neither the mRNA of the proteins glutamic acid decarboxylases 67 (GAD67) nor vesicular glutamate transporters (VGLUTs). These results provide the first evidence that nestin-ir neurons in the basal forebrain are a subpopulation of the classic cholinergic neurons. With high NGFR proteins activated in the nestin-ir neurons, we propose that the presence of nestin in the cholinergic neurons might be related to the survival and plasticity of the cholinergic neurons.


Assuntos
Proteínas de Filamentos Intermediários/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Prosencéfalo/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Colina O-Acetiltransferase/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Glutamato Descarboxilase/metabolismo , Imuno-Histoquímica , Proteínas de Filamentos Intermediários/biossíntese , Proteínas de Filamentos Intermediários/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Nestina , Plasticidade Neuronal/fisiologia , Prosencéfalo/citologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Vesiculares de Transporte de Glutamato/metabolismo
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