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1.
Ann Oncol ; 35(2): 221-228, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38072158

RESUMO

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Carcinoma Basocelular , Neoplasias Cutâneas , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Proteínas Hedgehog , Ligantes , Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/induzido quimicamente , Progressão da Doença , Amidas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
2.
Nat Biomed Eng ; 3(11): 889-901, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30988472

RESUMO

Acute myelogenous leukaemia (AML) is associated with risk factors that are largely unknown and with a heterogeneous response to treatment. Here, we provide a comprehensive quantitative understanding of AML proteomic heterogeneities and hallmarks by using the AML Proteome Atlas, a proteomics database that we have newly derived from MetaGalaxy analyses, for the proteomic profiling of 205 patients with AML and 111 leukaemia cell lines. The analysis of the dataset revealed 154 functional patterns based on common molecular pathways, 11 constellations of correlated functional patterns and 13 signatures that stratify the outcomes of patients. We find limited overlap between proteomics data and both cytogenetics and genetic mutations. Moreover, leukaemia cell lines show limited proteomic similarities with cells from patients with AML, suggesting that a deeper focus on patient-derived samples is needed to gain disease-relevant insights. The AML Proteome Atlas provides a knowledge base for proteomic patterns in AML, a guide to leukaemia cell line selection, and a broadly applicable computational approach for quantifying the heterogeneities of protein expression and proteomic hallmarks in AML.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteoma/genética , Proteoma/metabolismo , Proteômica , Linhagem Celular Tumoral , Bases de Dados Factuais , Humanos , Leucemia , Mutação , Proteínas de Neoplasias/análise , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Fatores de Risco , Transcriptoma
4.
Clin Radiol ; 69(9): 939-44, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24865315

RESUMO

AIM: To investigate the correlation between implant appearance on ultrasound (US) and voiding cystourethrography (VCUG) results after dextranomer-hyaluronic acid copolymer (DxHA) injection in children with vesicoureteral reflux (VUR). MATERIALS AND METHODS: Consecutive cases of primary VUR treated by endoscopic subureteral injection of DxHA were retrospectively reviewed. All children had postoperative bladder US and VCUG with a mean interval of 34 days and 47 days after injection, respectively. VUR resolution at postoperative VCUG was considered as treatment success. Implant appearance on US was graded according to the retained volume and its location by visual inspection; it was then correlated with VCUG results using the Spearman correlation coefficient. RESULTS: A total of 36 children (56 ureters) were identified in which 38 ureters (68%) had a clearly visualized implant on postoperative US and 40 ureters (71%) showed VUR resolution. The sensitivity of implant visualization on US for predicting reflux resolution was 73% (29/40), specificity 44% (7/16), positive predictive value 76% (29/38), and negative predictive value 39% (7/18). The grade 1, grade 2, and grade 3 implant appearances showed VUR resolution in 88% (22/25), 54% (7/13), and 61% (11/18), and showed persistent VUR in 8% (2/25), 15% (2/13), and 28% (5/18), respectively (p = 0.032). CONCLUSION: The implant appearance on postoperative US showed good correlation with VCUG results in the early post-injection period. Large retained implants were associated with treatment success, while small or non-visualized implants were related to the persistent reflux.


Assuntos
Cistoscopia , Dextranos/uso terapêutico , Ácido Hialurônico/uso terapêutico , Ureter/diagnóstico por imagem , Refluxo Vesicoureteral/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções , Masculino , Valor Preditivo dos Testes , Próteses e Implantes , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Ureter/fisiopatologia , Micção , Refluxo Vesicoureteral/fisiopatologia , Refluxo Vesicoureteral/cirurgia
5.
Clin Radiol ; 69(3): e113-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24332171

RESUMO

AIM: To establish the risks of developing of hepatic tumours and to investigate their clinical and imaging findings in children with biliary atresia (BA) after Kasai portoenterostomy (Kasai). MATERIALS AND METHODS: Among 157 children who had undergone Kasai for BA over an 18 year period, patients who had newly developed hepatic tumours were identified. Patient demographics, clinical features, and imaging findings were retrospectively reviewed. RESULTS: Three male and 10 female patients (mean age 3.9 years) all (8%, of 157) had single hepatic tumours, which were confirmed in 10 explanted and three non-explanted livers. Ten (77%) were benign and three (23%) were malignant. Of the benign hepatic tumours, focal nodular hyperplasia (FNH; n = 6) was the most common, followed by regenerative nodules (n = 3) and adenoma (n = 1). All FNH appeared in young children <1 year of age and showed a subcapsular location, bulging contour, and lack of central scar. Malignant tumours included two hepatocellular carcinomas and one cholangiocarcinoma. CONCLUSION: Hepatic tumours developed in approximately 8% of children with BA after Kasai. Although benign tumours, including FNHs and regenerative nodules, were more common than malignant tumours, screening with alpha-foetoprotein (AFP) levels and regular imaging studies are the mainstay of malignant tumour detection.


Assuntos
Atresia Biliar/complicações , Atresia Biliar/cirurgia , Diagnóstico por Imagem , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Adolescente , Criança , Pré-Escolar , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Lactente , Iopamidol/análogos & derivados , Neoplasias Hepáticas/patologia , Masculino , Estudos Retrospectivos
6.
Free Radic Res ; 47(6-7): 526-34, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23607503

RESUMO

Although endothelial progenitor cells (EPCs) have been used to promote revascularization after peripheral or myocardial ischemia, excess amounts of reactive oxygen species (ROS) are often involved in senescence and apoptosis of EPCs, thereby causing defective neovascularization and reduced or failed recovery. Here, we examined the cytoprotective effect of Ecklonia cava-derived antioxidant dieckol (DK) on oxidative stress-induced apoptosis in EPCs to improve EPC bioactivity for vessel repair. Although H2O2 (10 (- 3) M) increased the intracellular ROS level in EPCs, DK (10ug/ml) pretreatment suppressed the H2O2-induced ROS increase and drastically reduced the ratios of apoptotic cells. H2O2-induced ROS increased the phosphorylation of p38 MAPK and JNK; this was inhibited by DK pretreatment. H2O2 treatment increased the phosphorylation of NF-κB, which was blocked by pretreatment with SB 203580, a p38 MAPK inhibitor, or SP 600125, a JNK inhibitor. H2O2 decreased the cellular levels of Bcl-2 and c-IAPs, cellular inhibitors of apoptosis proteins, but increased caspase-3 activation. However, all these effects were inhibited by pretreatment with DK. Injection of DK-mixed EPCs (DK + EPCs) into myocardial ischemic sites in vivo induced cellular proliferation and survival of cells at the ischemic sites and, thereby, enhanced the secretion of angiogenic cytokines at the ischemic sites. These results show that DK + EPC exhibit markedly enhanced anti-apoptotic and antioxidative capabilities, unlike that shown by EPCs alone; thus, they contribute to improved repair of ischemic myocardial injury through cell survival and angiogenic cytokine production.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Citoproteção/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Estresse Oxidativo , Células-Tronco/efeitos dos fármacos , Células Cultivadas , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
7.
Clin Radiol ; 68(6): 588-94, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23351775

RESUMO

AIM: To investigate the ultrasound findings associated with early liver transplantation (LT) after Kasai portoenterostomy (Kasai) in children with biliary atresia (BA). MATERIALS AND METHODS: Children with BA (n = 30) who underwent Kasai were classified into early LT group (n = 17, LT within 1 year after Kasai) and Kasai alone group (n = 13, alive with their native livers). Serial ultrasound (baseline and follow-up before LT or post-Kasai 1 year) images were reviewed to investigate significant ultrasound findings related to early LT using both univariate and multivariate models. Images were reviewed focusing on the hepatic artery diameter, portal vein diameter, and signs of portal hypertension. RESULTS: The hepatic artery diameters in the early LT group were significantly larger than those in the Kasai alone group both at baseline (p = 0.007) and follow-up ultrasound (p < 0.001). The portal vein diameters on follow-up ultrasound were smaller in the early LT group than the Kasai alone group (p < 0.001). On multivariate analysis, baseline hepatic artery diameter (hazard ratio, 20.4; 95% confidence interval, 3.7-110.6; p < 0.001) and the presence of splenomegaly at follow-up ultrasound (17.7; 2.6-121.8; p = 0.004) were significant predictors associated with early LT. The optimal cut-off value of the baseline hepatic artery diameter was 1.9 mm (82% sensitivity and 77% specificity). CONCLUSION: Enlarged hepatic artery at baseline ultrasound and the presence of splenomegaly at follow-up ultrasound were associated with early LT after Kasai in children with BA.


Assuntos
Atresia Biliar/cirurgia , Transplante de Fígado/diagnóstico por imagem , Portoenterostomia Hepática/métodos , Adolescente , Atresia Biliar/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Artéria Hepática/diagnóstico por imagem , Humanos , Lactente , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Transplante de Fígado/efeitos adversos , Masculino , Veia Porta/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia
8.
Clin Radiol ; 66(4): 334-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21356396

RESUMO

AIM: To describe the frequency, pattern, and outcome of chest radiographic abnormalities in children with H1N1 influenza infection. MATERIALS AND METHODS: Three hundred and fourteen paediatric patients with confirmed H1N1 influenza infection who underwent chest radiography at presentation at a single institution during the outbreak in 2009 were retrospectively reviewed. Abnormal chest radiographic findings related to acute infection were analysed in terms of frequency, pattern, and distribution. Medical records and follow-up radiographs were also reviewed to assess clinical features and outcomes. RESULTS: Chest lesions suggesting acute infection were identified in 49 (16%) patients (mean age 8.2 years, range approximately 1.8-18.5 years). The most common finding was prominent peribronchial marking (71%), followed by air-space opacity (51%) with or without volume decrease, generalized hyperinflation (24%), and pleural effusion (20%). Other minor findings included pneumomediastinum (n=2) and a nodule (n=1). Distributions were bilateral (55%) or unilateral (45%) with frequent involvement of lower (78%), and middle (59%) lung zones. Thirty-nine patients (80%) were hospitalized and six (12%) required mechanical ventilation, followed by recovery. Thirty-one out of the 33 patients that underwent follow-up radiography showed marked resolution of all radiographic abnormalities. CONCLUSION: The frequency of a chest radiographic abnormality was found to be low in children with H1N1 influenza infection. Although typical radiographic findings of a viral lower respiratory infection were more common, unilateral involvement and air-space opacity were common, often with pleural effusion. Furthermore, pulmonary lesions showed near complete resolution on follow-up radiographs in the majority of patients.


Assuntos
Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/diagnóstico por imagem , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Surtos de Doenças , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Influenza Humana/epidemiologia , Masculino , Variações Dependentes do Observador , Radiografia , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento
9.
Clin Radiol ; 66(1): 38-42, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21147297

RESUMO

AIM: To investigate the imaging and clinical findings of aberrant cervical thymus, especially validating the usefulness of ultrasound (US). MATERIALS AND METHODS: The imaging and clinical findings of 13 children with aberrant cervical thymus were reviewed. Imaging studies were investigated for the location, size, composition, and shape with special emphasis on US characteristics. Medical records were reviewed for patient demographics, clinical presentations, and management. RESULTS: There were 10 male and three female patients (age range 1 month to 12 years; mean 3 years). Nine children (69%) were younger than 1 year. The most common presenting symptom or sign was palpable, cervical, non-tender mass or swelling. The most common site was the submandibular area. The mean of the maximal diameter was 3.5 cm (range 1.5-10 cm). The composition was solid (n=12) and solid and cystic (n=1). All lesions showed well-defined, angular margins with moulding over adjacent structures. On US, the echogenicity of the solid portion was identical to that of the mediastinal thymus in all cases, demonstrating the characteristic internal echo pattern. CONCLUSION: Although rare, aberrant cervical thymus usually occurs as a well-defined, solid mass most frequently at the submandibular area in infants and young children. US is indicated as the initial imaging mode for assessment and may be the only technique required.


Assuntos
Coristoma/diagnóstico , Timo , Criança , Pré-Escolar , Coristoma/diagnóstico por imagem , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Pescoço , Tomografia Computadorizada por Raios X , Ultrassonografia
10.
Oncogene ; 30(11): 1329-40, 2011 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-21057542

RESUMO

Dysregulation of cyclin D2 contributes to the pathogenesis of multiple myeloma, and can occur through translocations that activate MAF/MAFB or MMSET/FGFR3. However, cyclin D2 induction can also be seen in the absence of such translocations, such as in patients with hyperdiploid disease, through unknown mechanisms. In UniGene cluster data-mining and ECgene analysis, we found that zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel transcription factor, is overrepresented in this malignancy, and three consensus ZKSCAN3 binding sites were found in the cyclin D2 promoter. Analysis of a panel of myeloma cell lines, primary patient samples and datasets from Oncomine and the Multiple Myeloma Genomics Portal (MMGP) revealed expression of ZKSCAN3 messenger RNA (mRNA) in a majority of samples. Studies of cell lines by western blotting, and of primary tissue microarrays by immunohistochemistry, showed ZKSCAN3 protein expression in a majority, and in a manner that paralleled messenger levels in cell lines. ZKSCAN3 overexpression was associated with increased gene copy number or genomic DNA gain/amplification in a subset based on analysis of data from the MMGP, and from fluorescence in situ hybridization studies of cell lines and primary samples. Overexpression of ZKSCAN3 induced cyclin D2 promoter activity in a MAF/MAFB-independent manner, and to an extent that was influenced by the number of consensus ZKSCAN3 binding sites. Moreover, ZKSCAN3 protein expression correlated with cyclin D2 levels in cell lines and primary samples, and its overexpression induced cyclin D2. Conversely, ZKSCAN3 suppression using small hairpin RNAs (shRNAs) reduced cyclin D2 levels, and, importantly, inhibited myeloma cell line proliferation. Finally, ZKSCAN3 was noted to specifically bind to oligonucleotides representing sequences from the cyclin D2 promoter, and to the endogenous promoter itself in myeloma cells. Taken together, the data support the conclusion that ZKSCAN3 induction represents a mechanism by which myeloma cells can induce cyclin D2 dysregulation, and contribute to disease pathogenesis.


Assuntos
Ciclina D2/metabolismo , Mieloma Múltiplo/genética , Fatores de Transcrição/metabolismo , Sequência de Bases , Sítios de Ligação/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Silenciamento de Genes , Humanos , Fator de Transcrição MafB/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética , Transfecção , Translocação Genética
11.
Clin Radiol ; 64(3): 256-64, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19185655

RESUMO

AIM: To investigate the imaging and clinical findings of central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RTs) in children. MATERIALS AND METHODS: The computed tomography (CT) and magnetic resonance imaging (MRI) findings and clinical records of 16 children with CNS AT/RTs were retrospectively reviewed. Tumour location, size, composition, enhancement pattern, peritumoural oedema, signal intensity (SI) on MRI and CT attenuation were evaluated. RESULTS: A total of 17 lesions from 16 patients (median age 2.3 years, age range 0.7-15 years) were included in the evaluation. Tumour location was infratentorial for 11 lesions and supratentorial for six lesions. The mean diameter of the largest dimension for a tumour was 4 cm. The tumour was mainly solid in 65% of cases, and solid and cystic or cystic and solid in 35% of cases. The solid component of the tumours had a homogeneous iso SI (n=15) on T2-weighted MRI images and iso SI (n=14) on T1-weighted images. Moderate to strong enhancement of the solid component was noted in most cases. In spite of a large tumour size, peritumoural oedema was minimal or mild except in four cases. Rapid growth of the tumour was demonstrated in three cases. Seven patients died from tumour progression, with a mean survival time of 8.4 months (range 2-12 months). CONCLUSION: Although the AT/RTs had non-specific imaging findings, the tumours tended to be large in size, have iso SI on T1 and T2-weighted MR images with prominent enhancement, and relatively mild peritumoural oedema. Rapid growth of the tumour was seen during the follow-up period.


Assuntos
Neoplasias Encefálicas/diagnóstico , Tumor Rabdoide/diagnóstico , Adolescente , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Lactente , Coreia (Geográfico) , Imageamento por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos , Tumor Rabdoide/patologia , Tomografia Computadorizada por Raios X/métodos
13.
Acta Psychiatr Scand ; 118(3): 200-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18699953

RESUMO

OBJECTIVE: Dopamine dysregulation has been implicated in the pathophysiology of schizophrenia. The present study was performed to examine whether unaffected relatives at high genetic risk of schizophrenia have dopamine dysregulation in comparison with healthy controls. METHOD: Eleven unaffected relatives from families with two or more first- or second-degree relatives with schizophrenia (n = 9) or with a monozygotic schizophrenic twin (n = 2) and 11 age- and sex-matched controls were examined using positron emission tomography (PET) with [(11)C] raclopride. Subjects also underwent extensive neuropsychological testing. RESULTS: Subjects with high genetic risk showed a loss of asymmetry of D(2) receptors in the putamen in comparison with healthy controls. In addition, they showed significantly poorer performance on neuropsychological tests than controls. CONCLUSION: Our results suggest that dopamine dysregulation and neuropsychological dysfunction may be present in subjects at high genetic risk of schizophrenia. However, further studies are required to confirm these findings.


Assuntos
Família/psicologia , Lateralidade Funcional/genética , Predisposição Genética para Doença/psicologia , Putamen/fisiopatologia , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Feminino , Marcadores Genéticos/genética , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Tomografia por Emissão de Pósitrons/métodos , Adulto Jovem
14.
J Med Genet ; 45(7): 411-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18310264

RESUMO

BACKGROUND: Mutations in the SLC26A4 gene are responsible for Pendred syndrome and non-syndromic hearing loss (DFNB4). This study analysed non-synonymous SLC26A4 mutations newly identified in East Asians, as well as three common mutations in Caucasians, to characterise their molecular pathogenic mechanisms and to explore the possibility of rescuing their processing defects. METHODS: A total of 11 non-synonymous disease associated mutations were generated and their effects on protein processing and on ion transporting activities were examined. RESULTS: Most of the mutations caused retention of the SLC26A4 gene product (pendrin) in the intracellular region, while wild-type pendrin reached the plasma membrane. Accordingly, these mutations abolished complex glycosylation and Cl(-)/HCO(3)(-) exchange activities of pendrin. However, significant heterogeneity in the processing of mutant pendrin molecules was observed. Each mutant protein exhibited a different cellular localisation, a different degree of N-glycosylation, and a different degree of sensitivity to the treatments that rescue processing defects. For example, H723R-pendrin, the most common mutation in East Asians, was mostly expressed in endoplasmic reticulum (ER), and its defects in protein processing and ion transporting activities were restored considerably by low temperature incubation. On the other hand, L236P-pendrin, the most common mutation in Caucasians, was mainly in the centrosomal region and was temperature insensitive. CONCLUSION: These results indicate that the processing of pendrin mutant protein is determined by mutant specific mechanisms, and that a mutant specific method would be required to rescue the conformational defects of each folding mutant.


Assuntos
Perda Auditiva Neurossensorial/genética , Proteínas de Membrana Transportadoras/genética , Antiportadores de Cloreto-Bicarbonato/metabolismo , DNA Complementar/química , DNA Complementar/genética , Variação Genética , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Immunoblotting , Proteínas de Membrana Transportadoras/biossíntese , Proteínas de Membrana Transportadoras/metabolismo , Mutagênese Sítio-Dirigida , Mutação , Reação em Cadeia da Polimerase , Transportadores de Sulfato , Transfecção
16.
Acta Psychiatr Scand ; 116(3): 211-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17655563

RESUMO

OBJECTIVE: The aim was to investigate the white matter abnormalities of drug-naïve patients with obsessive-compulsive disorder (OCD) using diffusion tensor-imaging and the white matter changes in the patients after pharmacotherapy. METHOD: Thirteen drug-naïve OCD patients and 13 age- and sex-matched healthy comparison subjects were examined using diffusion tensor-imaging and structural magnetic resonance imaging. Measurements were made in OCD patients before and after 12 weeks of citalopram treatment. RESULTS: Compared with controls, the drug-naïve OCD patients showed significant increases in fractional anisotropy (FA) in the corpus callosum, the internal capsule and white matter in the area superolateral to the right caudate. The increases in FA were mostly no longer observed in patients after 12 weeks of treatment compared with controls. CONCLUSION: Our findings suggest that white matter alterations are associated with the pathophysiology of OCD, and the abnormalities may be partly reversible with pharmacotherapy.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Encéfalo/efeitos dos fármacos , Citalopram/uso terapêutico , Imagem de Difusão por Ressonância Magnética , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Adulto , Anisotropia , Antidepressivos de Segunda Geração/efeitos adversos , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Citalopram/efeitos adversos , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Dominância Cerebral/fisiologia , Feminino , Análise de Fourier , Humanos , Cápsula Interna/efeitos dos fármacos , Cápsula Interna/patologia , Masculino , Fibras Nervosas Mielinizadas/patologia , Transtorno Obsessivo-Compulsivo/diagnóstico , Tálamo/efeitos dos fármacos , Tálamo/patologia
17.
Clin Pharmacol Ther ; 81(2): 252-8, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17259948

RESUMO

YKP1358 is a novel serotonin (5-HT(2A)) and dopamine (D(2)) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D(2) receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D(2) receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [(11)C]raclopride. The D(2) receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D(2) receptor occupancy by YKP1358 increased to 53-83% at 2 h, and then decreased afterwards, ranging from 40-64% at 5 h to 20-51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D(2) receptor occupancy that was well predicted by a sigmoid E(max) model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D(2) receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D(2) receptor occupancy.


Assuntos
Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Antagonistas de Dopamina/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/metabolismo , Administração Oral , Adulto , Algoritmos , Alcaloides/administração & dosagem , Alcaloides/sangue , Alcaloides/farmacocinética , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Área Sob a Curva , Radioisótopos de Carbono , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/sangue , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Masculino , Modelos Biológicos
18.
Abdom Imaging ; 29(4): 491-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15136893

RESUMO

The purposes of this essay are to illustrate the technology overview and theoretical benefits of real-time compound ultrasonography (US) and to present our preliminary clinical experience in the evaluation of normal and diseased abdomens. The application of compounding principles to real-time US and its recent reintroduction into mainstream commercial systems have offered new opportunities for its clinical application to the routine examination of the abdomen. In our early preliminary experience, this technique effectively suppressed many of the US artifacts, better depicted the margin or boundary of the lesion, and increased contrast resolution or lesion conspicuity. Therefore, we believe that real-time compound US is a promising technique that may enhance the diagnostic confidence of the examination in the evaluation of normal and diseased abdomens.


Assuntos
Abdome/diagnóstico por imagem , Ultrassonografia/métodos , Abdome/anatomia & histologia , Humanos , Aumento da Imagem/métodos , Ilustração Médica , Fatores de Tempo , Ultrassonografia/instrumentação
19.
Abdom Imaging ; 28(5): 617-23, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14628862

RESUMO

BACKGROUND: We assessed computed tomographic (CT) features of postoperative complications and recurrent tumors in gastric cancer patients who underwent radical surgery. METHODS: We performed a retrospective study of 397 patients who had undergone radical surgery for the treatment of gastric carcinoma and underwent postoperative CT in our institution over a 2-year period. Patients were assigned to one of two groups: group A consisted of 47 patients who underwent CT for complications in the early postoperative period, and group B consisted of 355 patients who underwent CT for evidence of tumor recurrence during the follow-up period. We classified recurrent tumors into four categories: local recurrence, lymph node metastasis, peritoneal seeding, and remote metastasis. RESULTS: In group A, localized fluid collections or abscesses in the surgical bed were found in 38 patients (81%) and usually involved the left subphrenic area (74%) or the superior recess of the lesser sac (47%). In group B, recurrent tumors were found in 196 patients (55%). Among these, lymph node metastasis was the most common pattern (52%), followed by peritoneal seeding (44%), local recurrence (40%), and remote metastasis (37%). CONCLUSION: CT after radical surgery for the treatment of gastric carcinoma frequently shows postoperative complications or tumor recurrence. Familiarity with the common postoperative complications and patterns of the tumor recurrence is a prerequisite to accurate interpretation of CT findings in these patients.


Assuntos
Recidiva Local de Neoplasia/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Radiografia Intervencionista , Neoplasias Gástricas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia
20.
Abdom Imaging ; 28(3): 326-32, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12719902

RESUMO

BACKGROUND: We investigated the radiologic findings and clinical course of focal eosinophilic infiltration in the liver. METHODS: We retrospectively reviewed computed tomographic (CT) and sonographic scans in 20 patients (18 male, two female; mean age, 50 years) with pathologically or clinically proven focal eosinophilic infiltration in the liver by two experienced radiologists in our institute from August 1995 to June 1999. We also correlated radiologic findings with peripheral eosinophil count. Radiologic and clinical findings during the follow-up (range, 2-49 months; mean, 19.5 months) also were analyzed. RESULTS: Clinical symptoms and signs included abdominal pain (n = 4), easy fatigability (n = 3), weight loss (n = 1), and peripheral eosinophilia (n = 19). Twelve patients were asymptomatic. On sonographic examinations, all lesions were seen as focal, low echoic nodules. On CT, the lesions appeared isoattenuated or low attenuated in the arterial phase and low attenuated in the portal phase, except one case that showed high attenuation in the arterial phase. The margins of most lesions appeared poorly defined. Lesions were single (n = 9) and multiple: two to five (n = 6), six to 10 (n = 3), and more than 10 (n = 2). Each lesion was smaller than 2 cm; only one was 4 cm in diameter. The distribution of the lesion was subcapsular in 14 patients and central in five. Diffuse dissemination was observed in one. Eosinophil-associated abnormality was not present in other abdominal organ in all cases. The peripheral eosinophil count correlated closely with the number but not with the size of lesions. Sixteen patients who had follow-up images showed complete (n = 14) or partial regression of the lesions with a decrease in size (n = 1) or number (n = 1) after 2-22 months (mean, 6.4 months). CONCLUSION: Focal eosinophilic infiltration in the liver had somewhat characteristic radiologic findings on sonography and CT. In the correct clinical context of peripheral eosinophilia and self-limited course, these radiologic findings may be helpful in differentiating this condition from other focal hepatic lesions.


Assuntos
Eosinofilia/diagnóstico por imagem , Iohexol/análogos & derivados , Hepatopatias/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Meios de Contraste , Eosinófilos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
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