RESUMO
BACKGROUND: The appropriate surgical procedure for patients with upper third early gastric cancer is controversial. We compared total gastrectomy (TG) with proximal gastrectomy (PG) in this patient population. METHODS: A multicenter, non-randomized trial was conducted, with patients treated with PG or TG. We compared short- and long-term outcomes between these procedures. RESULTS: Between 2009 and 2014, we enrolled 254 patients from 22 institutions; data from 252 were included in the analysis. These 252 patients were assigned to either the PG (n = 159) or TG (n = 93) group. Percentage of body weight loss (%BWL) at 1 year after surgery, i.e., the primary endpoint, in the PG group was significantly less than that of the TG group (- 12.8% versus - 16.9%; p = 0.0001). For short-term outcomes, operation time was significantly shorter for PG than TG (252 min versus 303 min; p < 0.0001), but there were no group-dependent differences in blood loss and postoperative complications. For long-term outcomes, incidence of reflux esophagitis in the PG group was significantly higher than that of the TG group (14.5% versus 5.4%; p = 0.02), while there were no differences in the incidence of anastomotic stenosis between the two (5.7% versus 5.4%; p = 0.92). Overall patient survival rates were similar between the two groups (3-year survival rates: 96% versus 92% in the PG and TG groups, respectively; p = 0.49). CONCLUSIONS: Patients who underwent PG were better able to control weight loss without worsening the prognosis, relative to those in the TG group. Optimization of a reconstruction method to reduce reflux in PG patients will be important.
Assuntos
Gastrectomia/métodos , Neoplasias Gástricas/cirurgia , Estômago/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica , Feminino , Gastrectomia/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Duração da Cirurgia , Prognóstico , Estudos Prospectivos , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do Tratamento , Redução de PesoRESUMO
BACKGROUND: Although a third of gastroesophageal reflux disease (GERD) patients are refractory to proton pump inhibitor (PPI) therapy, the underlying mechanism of the refractoriness remains unclear. We compared the level of gastric acid suppression during PPI treatment between responders and non-responders by directly measuring gastric acid secretion in GERD patients taking PPIs. METHODS: Seventy-five consecutive patients receiving standard-dose PPI therapy for GERD were prospectively recruited, irrespective of persistent GERD symptoms. They were asked about their GERD symptoms using a validated questionnaire, and simultaneously underwent both a routine endoscopic examination and a gastric acid secretory testing using an endoscopic gastrin test. Associations between residual gastric acid secretion during PPI treatment and persistent GERD symptoms were analyzed by a logistic regression analysis. RESULTS: Overall, 26 of 75 (34.7%) patients were judged to be positive for persistent GERD symptoms. The patients with and without persistent symptoms showed similar gastric acid secretion levels (1.3 [1.3] mEq/10 min vs. 1.4 [2.0] mEq/10 min). Sufficient gastric acid suppression, defined as < 0.6, was not significantly associated with persistent GERD symptoms (odds ratio 1.1, 95% confidence interval 0.40-3.5). CONCLUSIONS: This study provided solid evidence to support that the gastric acid suppression level during PPI treatment does not differ between patients with and without persistent GERD symptoms. The insignificant role of residual gastric acid in the persistent GERD symptoms suggests that the use of medications other than those that enhance gastric acid inhibitory effects would be an essential approach for the management of PPI-refractory GERD.
Assuntos
Refluxo Gastroesofágico , Inibidores da Bomba de Prótons , Progressão da Doença , Ácido Gástrico , Refluxo Gastroesofágico/diagnóstico , Humanos , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
BACKGROUND: Although many new disease entities of autoimmune bullous disease (AIBD) have recently been recognized, satisfactory immunological diagnostic methods and comprehensive classifications for various AIBDs have not been established. OBJECTIVES: To identify immunological diagnostics and comprehensive classifications for AIBDs. METHODS: We selected and examined 4774 patients with various AIBDs from our cohort of 5063 patients with difficult AIBDs, whose sera and information were sent for our diagnostic method from other institutes in either Japan or other countries over the last 19 years. We examined the sera by our immunological diagnostic methods including various immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay tests to make final diagnoses. RESULTS: By our immunological diagnostic methods, we successfully made final diagnoses for approximately three-quarters of the difficult cases of AIBD, although the remaining cases could not be diagnosed. Using the results, we suggest the most extensive and newest classification of AIBDs, and also propose the most efficient algorithm of immunological tests for the diagnosis of various AIBDs. CONCLUSIONS: The results in this study of 4774 patients with various AIBDs indicate that our immunological diagnostic method is useful for making diagnoses for most patients with AIBD. However, we need further improvements including new immunological techniques to establish more satisfactory methods.
Assuntos
Doenças Autoimunes/diagnóstico , Testes Imunológicos/métodos , Dermatopatias Vesiculobolhosas/diagnóstico , Autoanticorpos/metabolismo , Doenças Autoimunes/classificação , Doenças Autoimunes/imunologia , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Dermatopatias Vesiculobolhosas/classificação , Dermatopatias Vesiculobolhosas/imunologiaRESUMO
BACKGROUND: Despite the established pathogenic role of anti-desmoglein (Dsg) antibodies in classical pemphigus, the significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc) is at present unknown. No consistent immunoassay for immunoglobulin (Ig) G autoantibodies to Dscs has been developed. OBJECTIVES: The aim of this study was to develop reliable assays to detect anti-Dsc autoantibodies. METHODS: We expressed soluble recombinant proteins (RPs) of human Dsc1-3 in mammalian cells and examined sera of various types of pemphigus, including 79 paraneoplastic pemphigus (PNP) sera, by novel enzyme-linked immunosorbent assays (ELISAs) using the RPs. We also performed ELISAs of Dsc baculoproteins and used the complementary DNA (cDNA) transfection method, and compared the results with those of mammalian ELISAs. RESULTS: Through mammalian ELISAs, IgG autoantibodies to Dsc1, Dsc2 and Dsc3 were detected in 16.5%, 36.7% and 59.5% of PNP sera, respectively, and considerable numbers of pemphigus herpetiformis (PH) and pemphigus vegetans (PVeg) sera reacted strongly with Dsc1 and Dsc3. Mammalian ELISAs were highly specific and more sensitive than baculoprotein ELISAs or the cDNA transfection method. Several Dsc-positive sera, particularly PH sera, showed no reactivity with Dsgs. The reactivity of PNP serum and PVeg serum with Dscs was not abolished by pre-absorption with Dsg RPs. CONCLUSIONS: The results of these novel ELISAs indicated that IgG anti-Dsc autoantibodies were frequently detected and potentially pathogenic in nonclassical pemphigus.
Assuntos
Autoanticorpos/sangue , Desmocolinas/imunologia , Pênfigo/imunologia , DNA Complementar/análise , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Imunoglobulina G/sangue , Imunoprecipitação/métodos , Curva ROC , Proteínas Recombinantes , TransfecçãoRESUMO
OBJECTIVE: Psychological stress is known to have a negative effect on a large number of skin diseases. However, there is little research on the relationship between psychological stress and the epidermal permeability barrier function (EPBF) of healthy individuals. We hypothesize that psychological stress deteriorates EPBF and aimed to investigate this relationship. METHODS: Psychological stress was assessed using salivary alpha-amylase (sAmy; KIU L(-1) ), and chromogranin A level corrected with total protein (CgAP; pmol mg(-1) protein) as psychological stress biomarkers. Measurements were obtained from 16 healthy female students during two periods of presumed higher stress (final examinations and returning from a long vacation), and a period considered as a control. The EPBF level was evaluated by measuring transepidermal water loss (TEWL; g m(-2) h(-1) ). The TEWL was measured three times: just before (TEWL [Intact]), immediately after (TEWL [Str]) and 4 h after (TEWL [4 h]) barrier disruption by tape stripping. The rate of barrier disruption was evaluated by comparing the difference between the TEWL [Intact] and the TEWL [Str] (delta-BD: g m(-2) h(-1) ). The recovery was assessed by comparing the difference between the TEWL [Intact] and TEWL [4 h] (delta-RE: g m(-2) h(-1) ). RESULTS: The subjects demonstrated a significant increase in the sAmy value after the long vacation compared with the control. There was no change in the CgAP value between the groups. Meanwhile, the EPBF level showed significant deterioration during both higher stress periods. There was a significant increase in delta-BD and delta-RE after the long vacation. CONCLUSIONS: The results indicate the possibility that psychological stress causes a decline in EPBF and deterioration in barrier disruption and recovery. Furthermore, it implies a relationship between psychological stress and the exacerbation or protracted healing of skin disease.
Assuntos
Epiderme/fisiopatologia , Estresse Psicológico , HumanosRESUMO
BACKGROUND: Drug-induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP. OBJECTIVES: To characterize clinical and immunological profiles in patients with DIP. METHODS: We studied 17 Japanese patients with DIP who were treated at Kurume University Hospital or who consulted from other hospitals between 1997 and 2012. Complicated diseases, clinical and histopathological manifestations, responsible drugs and findings in immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), immunoblotting (IB) and prognosis were analysed. RESULTS: Eight of the 17 patients with DIP showed pemphigus foliaceus-like appearance, three showed pemphigus herpetiformis-like appearance, and six showed atypical bullous lesions. Responsible drugs were thiol-containing drugs in 16 patients (bucillamine in nine cases, d-penicillamine in four cases, and cetapril, thiopronine and captopril in one patient each), and a nonthiol drug, sulfasalazine, in one patient. By ELISAs and/or IB analyses, nine patients reacted only with desmoglein 1 (Dsg1), four reacted with Dsg1 and Dsg3, and four showed no specific reactivity. By IB of normal human epidermal extracts, in addition to positive reactivity with Dsg1, four patients with no detectable malignancy showed paraneoplastic pemphigus-like reactivity with the 210-kDa envoplakin and the 190-kDa periplakin. Four cases showed anti-Dsg3 antibodies without mucosal lesions. While 11 cases recovered after discontinuation of the causative drugs, six patients had a very protracted or intractable disease course, and might develop true pemphigus. CONCLUSIONS: The present study indicated that the majority of the patients with DIP studied showed a pemphigus foliaceus-type phenotype with anti-Dsg1 autoantibodies, caused by thiol-containing drugs.
Assuntos
Toxidermias/etiologia , Pênfigo/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Desmogleína 1/imunologia , Toxidermias/metabolismo , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Pênfigo/imunologiaRESUMO
BACKGROUND: The purpose of this study was to evaluate the efficacy of superselective cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with the squamous cell carcinoma of maxillary sinus (SCC-MS). METHODS: Between 1999 and 2010, 54 patients were given superselective intra-arterial infusions of cisplatin (100-120 mg m(-2) per week) with simultaneous intra-venous infusions of thiosulfate to neutralise cisplatin toxicity and conventional radiotherapy (65-70 Gy). RESULTS: One patient (1.9%) was diagnosed with T2, 14 (25.9%) with T3, 27 (50%) with T4a, and 12 (22.2%) with T4b disease. Lymph-node involvement was present in 12 patients (22.2%). During the median follow-up period of 6.4 years, the 5-year local progression-free and overall survival rates were 65.8 and 67.9% for all patients, respectively. No patient died as a result of treatment toxicity or experienced a cerebrovascular accident. Osteonecrosis (n=5), brain necrosis (n=1), and ocular/visual problems (n=14) were observed as late adverse reactions. CONCLUSION: We have shown excellent overall survival and local progression-free rate in SCC-MS patients treated by RADPLAT with acceptable rates of acute and late toxicity. A multi-institutional trial is needed to prove that this strategy is a feasible and effective approach for the treatment of SCC-MS.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias do Seio Maxilar/tratamento farmacológico , Neoplasias do Seio Maxilar/radioterapia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Quimiorradioterapia , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/efeitos adversos , Recidiva , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de SobrevidaRESUMO
A 79-year-old Japanese woman presented with severe recalcitrant erosions on her oral mucosa, resembling paraneoplastic pemphigus. Using indirect immunofluorescence, we detected IgA antibodies against the cell surface, and both IgG and IgA antibodies against the basement membrane zone. Immunoblotting showed that the IgG antibodies reacted weakly with bullous pemphigoid 230 and periplakin, whereas the IgA antibodies did not react with any antigen. IgA antibodies to both desmoglein (Dsg)1 and Dsg3 were detected by ELISA. IgA antibodies to desmocollin (Dsc)3 were also detected by using cDNAs for human Dsc1-3 transfected into COS-7 cells. Despite treatment with oral prednisolone, high-dose intravenous immunoglobulin and double-filtration plasmapheresis, the skin lesions remained active, and the patient died from bronchiolitis obliterans-like respiratory failure. Despite extensive investigations and postmortem examination, no underlying neoplasms were found. The complex immunopathological findings probably played an important role in the development of the patient's unusual clinical features.
Assuntos
Membrana Basal/imunologia , Caderinas de Desmossomos/imunologia , Imunoglobulina A/imunologia , Neoplasias Bucais/imunologia , Síndromes Paraneoplásicas/imunologia , Penfigoide Bolhoso/imunologia , Idoso , Desmocolinas/imunologia , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Evolução Fatal , Feminino , Humanos , Imunoglobulina G/imunologiaAssuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Asma/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Asma/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
BACKGROUND: Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the 'desmoglein (Dsg) compensation theory'. Dsg3 and Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti-Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti-Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus. OBJECTIVES: We present five Japanese patients with pemphigus who deviate from this theory, i.e. all patients showed oral lesions (three also had cutaneous lesions) and reacted only with Dsg1, but not with Dsg3, by enzyme-linked immunosorbent assay. METHODS: To confirm whether the unique clinical phenotypes in our patients were due to a different immunological profile from that in classical pemphigus, we examined the reactivity of the patient sera by immunoprecipitation-immunoblotting analysis using five Dsg1/Dsg2 domain-swapped molecules. RESULTS: The sera of two patients who had only oral lesions tended to react with the extracellular (EC) 5 domain of Dsg1, the domain that is considered nonpathogenic in classical pemphigus foliaceus. Sera of three patients with mucocutaneous lesions reacted with EC1 domain or with both EC1 and EC2 domains of Dsg1, like classical pemphigus foliaceus. CONCLUSIONS: These results indicate that antigenic diversity of anti-Dsg1 antibodies in these patients may cause the unique oral mucosal and cutaneous lesions, although further studies are required to elucidate the pathomechanisms.
Assuntos
Autoanticorpos/metabolismo , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Doenças da Boca/imunologia , Pênfigo/imunologia , Idoso , DNA Complementar , Feminino , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa Bucal , Pênfigo/sangue , Transfecção/métodosRESUMO
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an autosomal recessive skin disease caused by mutations in the type VII collagen gene (COL7A1), resulting in detachment of the entire epidermis due to loss or hypoplasticity of the anchoring fibrils that normally secure the basement membrane to the underlying dermis. Trauma-induced blistering is often complicated by chronic erosions and scarring. From that perspective, pregnancy in RDEB might be considered an indication for elective caesarean section in a bid to minimize perineal blistering. To date, only four cases of pregnancy and delivery in patients with RDEB have been reported. CASES: We report three more women, each with RDEB-generalized other (RDEB-GO), all of whom had successful vaginal deliveries without major cutaneous or mucosal complications. One woman also had a second child, by vaginal delivery, indicating a lack of vaginal stenosis after the first birth. CONCLUSIONS: These cases show that RDEB-GO is not an absolute primary indication for elective caesarean section and that, perhaps surprisingly, genital/perineal blistering and scarring are not inevitable consequences of childbirth. Moreover, breastfeeding is also feasible in women with RDEB-GO.
Assuntos
Parto Obstétrico/métodos , Epidermólise Bolhosa Distrófica/patologia , Complicações na Gravidez , Adulto , Aleitamento Materno , Feminino , Humanos , Gravidez , Resultado da Gravidez , VaginaRESUMO
The origin and transmission routes of atypical bovine spongiform encephalopathy (BSE) remain unclear. To assess whether the biological and biochemical characteristics of atypical L-type BSE detected in Japanese cattle (BSE/JP24) are conserved during serial passages within a single host, 3 calves were inoculated intracerebrally with a brain homogenate prepared from first-passaged BSE/JP24-affected cattle. Detailed immunohistochemical and neuropathologic analysis of the brains of second-passaged animals, which had developed the disease and survived for an average of 16 months after inoculation, revealed distribution of spongiform changes and disease-associated prion protein (PrP(Sc)) throughout the brain. Although immunolabeled PrP(Sc) obtained from brain tissue was characterized by the presence of PrP plaques and diffuse synaptic granular accumulations, no stellate-type deposits were detected. Western blot analysis suggested no obvious differences in PrP(Sc) molecular mass or glycoform pattern in the brains of first- and second-passaged cattle. These findings suggest failures to identify differences in mean incubation period and biochemical and neuropathologic properties of the BSE/JP24 prion between the first and second passages in cattle.
Assuntos
Encéfalo/patologia , Encefalopatia Espongiforme Bovina/transmissão , Proteínas PrPSc/metabolismo , Animais , Western Blotting/veterinária , Encéfalo/metabolismo , Bovinos , Encefalopatia Espongiforme Bovina/metabolismo , Encefalopatia Espongiforme Bovina/patologia , Feminino , Glicosilação , Imuno-Histoquímica/veterinária , Proteínas PrPSc/análise , Conformação Proteica , Estabilidade Proteica , Inoculações SeriadasRESUMO
This policy statement, which is the fourth of a series of documents being prepared by the Asia-Oceania Federation of Organizations for Medical Physics Committees Professional Development Committee, gives guidance on how member countries could develop a continuing professional development system for ensuring that its clinical medical physicists are up-to-date in their knowledge and practice. It is not intended to be prescriptive as there are already several CPD systems successfully operated by AFOMP member countries and elsewhere that vary considerably in scope and structure according to local culture, practice and legislation but all of which are capable of ensuring that physicists are up-to-date. It is intended to be advisory and set out options for member countries to develop their individual CPD systems.
Assuntos
Currículo/normas , Educação Continuada/normas , Física Médica/normas , Guias de Prática Clínica como Assunto , Competência Profissional/normas , Ásia , OceaniaRESUMO
We report on the results of a high-resolution angle-resolved photoemission study on the ordered surface alloy CePt(5). The temperature dependence of the spectra show the formation of the coherent low-energy heavy-fermion band near the Fermi level. These experimental data are supported by a multiband model calculation in the framework of the dynamical mean-field theory.
RESUMO
AFOMP recognizes that clinical medical physicists should demonstrate that they are competent to practice their profession by obtaining appropriate education, training and supervised experience in the specialties of medical physics in which they practice, as well as having a basic knowledge of other specialties. To help its member countries to achieve this, AFOMP has developed this policy to provide guidance when developing medical physicist education and training programs. The policy is compatible with the standards being promoted by the International Organization for Medical Physics and the International Medical Physics Certification Board.
Assuntos
Educação Médica/normas , Física Médica/educação , Medicina/normas , Ásia , Certificação/organização & administração , Escolaridade , Humanos , Guias de Prática Clínica como Assunto , Sociedades/organização & administraçãoRESUMO
Glomerular hyperfiltration is observed in an early stage of kidney diseases including diabetic nephropathy. A better understanding of pathophysiological changes in glomerular hyperfiltration is essential for development of new therapies to prevent kidney disease progression. In this study, we investigated glomerular changes including glomerular filtration rate (GFR) and glomerular size in the Spontaneously Diabetic Torii (SDT) fatty rat, an obese type 2 diabetic model, and we also evaluated pharmacological effects of the sodium glucose cotransporter 2 inhibitor dapagliflozin on the renal lesions. Dapagliflozin was administered to SDT fatty rats from 5 to 17 weeks of age. Blood and urinary biochemical parameters were periodically measured. GFR was determined by transdermal GFR monitor at 16 weeks of age and histopathological analysis was performed at 17 weeks of age. SDT fatty rat developed severe hyperglycemia and exhibited pathophysiological abnormalities in the kidney, such as an increased GFR, glomerular hypertrophy and tissue lesions. Dapagliflozin achieved good glycemic control during the experimental period, inhibited the increase in GFR, and improved histopathological abnormalities in tubules. These results suggest that the SDT fatty rat is a useful model for analyzing the pathogenesis of diabetic nephropathy during its early stage and dapagliflozin improves not only hyperglycemia but also glomerular hyperfiltration and tubule lesions in SDT fatty rat.
Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/etiologia , Glucosídeos/farmacologia , Hiperglicemia/patologia , Obesidade/complicações , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Hiperglicemia/tratamento farmacológico , Masculino , Obesidade/genética , Ratos , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1-4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a(-/-) mice, but did stimulate/costimulate proliferation of these cells from Stat5a(+/+), Stat5b(-/-), and Stat5b(+/+) mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Proteínas do Leite , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Transdução de Sinais , Transativadores/fisiologia , Animais , Células COS , Divisão Celular , Linhagem Celular , Fatores Estimuladores de Colônias/farmacologia , Humanos , Janus Quinase 1 , Janus Quinase 2 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Tirosina Quinases/fisiologia , Fator de Transcrição STAT5 , Proteínas Supressoras de Tumor , Tirosina Quinase 3 Semelhante a fmsRESUMO
AIM: Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signalling, is a novel therapeutic target for type 2 diabetes mellitus. We evaluated in vitro and in vivo the pharmacological profiles of a new PTP1B inhibitor, JTT-551: monosodium ({[5-(1,1-dimethylethyl)thiazol-2-yl]methyl} {[(4-{4-[4-(1-propylbutyl)phenoxy]methyl}phenyl)thiazol-2-yl]methyl}amino)acetate. METHODS: PTP1B inhibitory activity and the inhibition mode were assayed with p-nitrophenyl phosphate as a substrate, and the selectivity of JTT-551 against other PTPs, including T-cell protein tyrosine phosphatase (TCPTP), CD45 protein tyrosine phosphatase (CD45) and leucocyte common antigen-related protein tyrosine phosphatase (LAR), was evaluated. Glucose uptake with JTT-551 treatment was evaluated in L6 rat skeletal myoblasts (L6 cells). In the in vivo study, we investigated the effects on insulin receptor (IR) phosphorylation and blood chemical parameters with JTT-551 administration in ob/ob mice and db/db mice. RESULTS: JTT-551 showed an inhibitory effect on PTP1B with a Ki value of 0.22 microM, and a mixed-type inhibition mode. Ki values of TCPTP, CD45 and LAR were 9.3, 30 or higher and 30 or higher microM, respectively, and JTT-551 exhibited clear selectivity against the other PTPs. Moreover, JTT-551 increased the insulin-stimulated glucose uptake in L6 cells. A single administration of JTT-551 in ob/ob mice enhanced the IR phosphorylation of liver and reduced the glucose level. In db/db mice, chronic administration showed a hypoglycaemic effect without an acceleration of body weight gain. CONCLUSIONS: JTT-551, a newly developed PTP1B inhibitor, improves glucose metabolism by enhancement of insulin signalling and could be useful in the treatment of type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/enzimologia , Glicina/farmacologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Obesos , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Receptor de Insulina/metabolismo , Transdução de SinaisRESUMO
Tomato yellow leaf curl disease, caused by the begomovirus Tomato yellow leaf curl virus (TYLCV; family Geminiviridae), is an economically important disease of tomato (Solanum lycopersicum L.) that can be very destructive in tropical and subtropical regions (1). In October 2009, tomato plants showing stunted new growth, interveinal chlorosis, and upward curling of leaf margins were reported by a residential gardener in Wailuku, on the island of Maui. Similar symptoms were observed in approximately 200 tomato plants at a University of Hawaii research farm in Poamoho, on the island of Oahu in November 2009. The similarity between these symptoms and those of tomato yellow leaf curl disease and the presence of whiteflies (Bemisia spp.), the vector of TYLCV, suggested the causal agent was a geminivirus such as TYLCV. Total nucleic acids were extracted from a tomato plant sample from Wailuku and Poamoho and used in a PCR assay with degenerate primers PAR1c715 and PAL1v1978 for geminivirus detection (4). The ~1.5-kbp amplicon expected to be produced from a geminivirus template was generated from the symptomatic tomato plant samples but not from a greenhouse-grown control tomato plant. The amplicons were cloned by the pGEM-T Easy vector (Promega, Madison, WI). Three clones from each sample were sequenced, revealing 97 to 99% nucleotide identity to TYLCV sequences in GenBank and a 98.9% nucleotide identity between the Wailuku (Accession No. GU322424) and Poamoho (Accession No. GU322423) isolates. A multiplex PCR assay for the detection and discrimination between the IL and Mld clades of TYLCV was also performed on these isolates (2). A ~0.8-kbp amplicon was generated from both isolates confirming the presence of TYLCV and their inclusion into the TYLCV-IL clade (2). Seven symptomatic and three asymptomatic tomato plant samples from Poamoho were tested for TYLCV using a squash-blot hybridization assay (3) utilizing a digoxigenin-labeled probe derived from the ~1.5-kbp PCR amplicon. All symptomatic tomato plants and one asymptomatic tomato plant were found to be infected with TYLCV. How the virus entered Hawaii and how long it has been present is unknown. The most plausible route is through infected plant material such as an asymptomatic alternative host rather than viruliferous whiteflies. It appears TYLCV is not a recent introduction into Hawaii since the Wailuku gardener observed similar disease symptoms for a few years before submitting samples for testing. In January 2010, TYLCV was also detected in two commercial tomato farms on Oahu, posing a serious threat to the state's $10 million annual tomato crop. References: (1) H. Czosnek and H. Laterrot. Arch. Virol. 142:1392, 1997. (2) P. Lefeuvre et al. J. Virol. Methods 144:165, 2007. (3) N. Navot et al. Phytopathology 79:562, 1989. (4) M. R. Rojas et al. Plant Dis. 77:340, 1993.
RESUMO
This document is the second of a series of policy statements being issued by the Asia-Oceania Federation of Organizations for Medical Physics (AFOMP). The document was developed by the AFOMP Professional Development Committee (PDC) and was released by the AFOMP Council in 2009. The main purpose of the document is to give guidance as to how many medical physicists are required to staff a radiation oncology department. Strict guidelines are difficult to define as work practices vary from country-to-country and from hospital-to-hospital. A calculation scheme is presented to aid in estimating medical physics staffing requirements that is primarily based on equipment levels and patient numbers but also with allowances for staff training, professional development and leave requirements.