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1.
Brachytherapy ; 22(5): 571-579, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37328337

RESUMO

PURPOSE: High-dose-rate brachytherapy as monotherapy (HDR-M), or as a boost combined with external beam radiotherapy (HDR-B), are both suitable treatments for intermediate-risk prostate cancer. However, data directly comparing these two approaches for men with unfavorable intermediate-risk (UIR) patients are lacking. METHODS AND MATERIALS: Patients with NCCN-defined UIR prostate cancer treated from 1997 to 2020 were identified in a prospectively maintained, single institution database. HDR-M and HDR-B patients were matched using three factors: age ±3 years; Gleason score (major and minor); and clinical T stage. Biochemical failure was defined as PSA nadir (nPSA) + 2. Available acute and chronic toxicities are additionally reported. RESULTS: A total of 247 patients were identified (170 receiving HDR-B, 77 receiving HDR-M), ultimately yielding 70 matched pairs (140 patients) for inclusion. The median followup time was 5.2 years for HDR-M compared with 9.3 years for HDR-B (p < 0.001). The two cohorts had similar calculated prostate EQD2 (HDR-B 118 Gy vs. HDR-M 115 Gy, p = 0.977). No significant differences in OS, CSS, DM, LRR, or FFBF were identified. HDR-B had an increased rate of any acute grade 2+ gastrointestinal toxicity and worse acute dysuria and diarrhea. Chronic gastrointestinal and genitourinary toxicity was similar. CONCLUSIONS: These data suggest that HDR brachytherapy as monotherapy is an effective treatment option for selected patients with unfavorable intermediate-risk prostate cancer and provides a more favorable gastrointestinal toxicity profile than HDR-B. Prospective trials should be conducted to refine the selection process for this heterogeneous cohort of patients.


Assuntos
Braquiterapia , Gastroenteropatias , Neoplasias da Próstata , Masculino , Humanos , Braquiterapia/métodos , Análise por Pareamento , Estudos Prospectivos , Neoplasias da Próstata/radioterapia , Antígeno Prostático Específico , Dosagem Radioterapêutica , Gastroenteropatias/etiologia
2.
Diabetes ; 70(12): 2947-2956, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34649926

RESUMO

Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains ß-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.


Assuntos
Peptídeo C/metabolismo , Plexo Corióideo/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Adulto , Sequência de Aminoácidos , Amiloide/análise , Amiloide/química , Amiloide/metabolismo , Animais , Autopsia , Peptídeo C/análise , Peptídeo C/química , Plexo Corióideo/química , Plexo Corióideo/patologia , Humanos , Insulina/análise , Insulina/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/análise , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/química , Ilhotas Pancreáticas/patologia , Camundongos , Proinsulina/análise , Proinsulina/química , Proinsulina/metabolismo , Isoformas de Proteínas/análise , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo
3.
JCI Insight ; 4(23)2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31647782

RESUMO

The choroid plexus (ChP) is a highly vascularized tissue found in the brain ventricles, with an apical epithelial cell layer surrounding fenestrated capillaries. It is responsible for the production of most of the cerebrospinal fluid (CSF) in the ventricular system, subarachnoid space, and central canal of the spinal cord, while also constituting the blood-CSF barrier (BCSFB). In addition, epithelial cells of the ChP (EChP) synthesize neurotrophic factors and other signaling molecules that are released into the CSF. Here, we show that insulin is produced in EChP of mice and humans, and its expression and release are regulated by serotonin. Insulin mRNA and immune-reactive protein, including C-peptide, are present in EChP, as detected by several experimental approaches, and appear in much higher levels than any other brain region. Moreover, insulin is produced in primary cultured mouse EChP, and its release, albeit Ca2+ sensitive, is not regulated by glucose. Instead, activation of the 5HT2C receptor by serotonin treatment led to activation of IP3-sensitive channels and Ca2+ mobilization from intracellular storage, leading to insulin secretion. In vivo depletion of brain serotonin in the dorsal raphe nucleus negatively affected insulin expression in the ChP, suggesting an endogenous modulation of ChP insulin by serotonin. Here, we show for the first time to our knowledge that insulin is produced by EChP in the brain, and its release is modulated at least by serotonin but not glucose.


Assuntos
Plexo Corióideo/metabolismo , Insulina/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Líquido Cefalorraquidiano/metabolismo , Células Epiteliais , Expressão Gênica , Glucose , Humanos , Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , RNA Mensageiro/metabolismo
4.
Alzheimers Res Ther ; 11(1): 39, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31060630

RESUMO

Following publication of the original article [1], the authors reported that Fig. 6 contains a mistake. The Fig. 6F is a duplicate of Fig. 6E of Braak 5.

5.
Alzheimers Res Ther ; 11(1): 28, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30902061

RESUMO

BACKGROUND: Synaptic damage precedes neuron death in Alzheimer's disease (AD). Neurexins, NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins and postsynaptic neuroligins interact with amyloid beta oligomer (AßO) deposits in damaged synapses. NRXN3 gene variants have been associated with autism, addiction, and schizophrenia, however, not fully investigated in Alzheimer's disease. In the present study, we investigated an AD association of a 3'-splicing allele of rs8019381 that produces altered expression of transmembrane or soluble NRXN3 isoforms. METHODS: We carried out RT-PCR (reverse transcription polymerase chain reaction), PCR-RFLP (PCR and restriction fragment length polymorphism), Sanger sequencing, and in situ hybridization (ISH) assays for NRXN3 neuron expression and genotyping. Genetic associations were analyzed by χ2 tests, and ISH signals were analyzed by FISH v1.0 module of Indica Labs HALO software. RESULTS: We previously identified a functional haplotype in the 3' region of neurexin 3 (NRXN3) gene that alters the expression ratios between NRXN3 transmembrane and soluble isoforms. In this study, we found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in AD postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. The splicing haplotype related to the transmembrane and soluble NRXN3 expression was associated with AD samples with P = 6.3 × 10-5 (odds ratio = 2.48) and interacted with APOE genotypes. CONCLUSIONS: We found that the SNP rs8019381 of NRXN3 that is located adjacent to splicing site #5 (SS#5) interacts with the APOE ε4 haplotype and alters NRXN3 transmembrane or soluble isoform expression in AD postmortem cortex. Dysregulation of presynaptic NRXN3 expression and splicing might increase neuron inflammation in AD brain.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encefalite/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Apolipoproteínas E/genética , Encefalite/complicações , Feminino , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo
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