RESUMO
Anti-spike receptor binding domain (S-RBD) antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which best correlates with virus-neutralizing antibody is useful for estimating the period of protection and identifying the timing of additional booster doses. Long-term transition of the S-RBD antibody titer and the antibody responses among healthy individuals remain unclear. In the present study, therefore, we monitored the S-RBD antibody titers of 16 healthcare workers every 4 weeks for 76 weeks after vaccination with a fourth dose of mRNA-1273 (Moderna) following three doses of BNT162b2 (Pfizer/BioNTech) using two commercial automated immunoassays (Roche and Abbott). Two antibody responses to the vaccine were similar with an up-down change before and after the second (weeks 3), third (weeks 40) and fourth (week 72) vaccinations, but the titer did not fall below the assay's positivity threshold in any individual. The peak level of the geometric mean titer (GMT) in the Roche assay was highest after the third vaccination, and that in Abbott assay was highest after the fourth vaccination but almost equal to that after the third vaccination. Both the geometric mean fold rise (GMFR) demonstrated by the Roche and Abbott assays were highest after the third vaccination. Antibody titers determined by the Roche and Abbott assays showed a positive strong correlation (correlation coefficient: 0.70 to 0.99), but the ratio (Roche/Abbott) of antibodies demonstrated by both assays increased 0.46- to 8.26-fold between weeks 3 and 76. These findings will be helpful for clinicians when interpreting results for SARS-CoV-2 antibody levels and considering future vaccination strategies.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19 , Vacina BNT162 , COVID-19/diagnóstico , COVID-19/prevenção & controle , Imunoensaio , Anticorpos Antivirais , Pessoal de Saúde , Vacinação , RNA MensageiroRESUMO
We conducted two-year seroprevalence surveys of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies among outpatients and healthcare workers (HCWs) at Ehime University Hospital. Data were collected for outpatients and HCWs in June 2020 (1st survey), December 2020 (2nd survey), July 2021 (3rd survey), and December 2021 (4th survey), focusing on demographics, occupation, and the seroprevalence of anti-SARS-CoV-2 antibodies. Blood samples were obtained from randomly selected outpatients who visited our hospital for medical care and HCWs undergoing regular medical checks with opt-out informed consent. SARS-CoV-2 antibody positivity was evaluated using two laboratory-based quantitative tests. The total number of participants enrolled was 6,369 (1st survey: 1,000 outpatients and 743 HCWs, 2nd survey: 1,000 outpatients and 407 HCWs, 3rd survey: 1,000 outpatients and 804 HCWs, 4th survey: 1,000 outpatients and 415 HCWs). The prevalence of SARS-CoV-2 antibodies among outpatients and HCWs was 0-0.1% and 0-0.124% during the research period, respectively, and changed little over time. These findings suggest that the magnitude of COVID-19 infection during the pandemic among outpatients and HCWs in this rural hospital might have been small.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , COVID-19/epidemiologia , Pessoal de Saúde , Humanos , Japão/epidemiologia , Pacientes Ambulatoriais , Estudos SoroepidemiológicosRESUMO
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma ß-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.
Assuntos
Peso Corporal/efeitos dos fármacos , Butileno Glicóis/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Leptina/farmacologia , Obesidade/tratamento farmacológico , Ácido 3-Hidroxibutírico/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Butileno Glicóis/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Obesos , Obesidade/metabolismoRESUMO
BACKGROUND: Zinc-finger E-box-binding homeobox 1 (ZEB1) is an important regulator of epithelial-mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR-200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT-mediated acquired resistance to gefitinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear. METHODS: PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as "gefitinib-resistant persisters" (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib. RESULTS: GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR-200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR-200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133- and BMI1-positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR-mutant NSCLC patients with gefitinib resistance. CONCLUSIONS: ZEB1 plays an important role in gefitinib-resistant lung CSCs with EMT features via regulation of miR-200c and BMI1.
Assuntos
Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10-7, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10-3, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10-3), Taiwanese (P = 1.1 × 10-3), and European populations (P = 5.2 × 10-4). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (Pmeta = 1.2 × 10-9, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.
Assuntos
Agranulocitose/genética , Antitireóideos/uso terapêutico , Doença de Graves/tratamento farmacológico , Cadeias HLA-DRB1/genética , Agranulocitose/induzido quimicamente , Agranulocitose/patologia , Alelos , Antitireóideos/efeitos adversos , Feminino , Frequência do Gene , Estudos de Associação Genética , Doença de Graves/complicações , Doença de Graves/genética , Doença de Graves/patologia , Haplótipos/genética , Humanos , Japão/epidemiologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Fatores de RiscoRESUMO
PURPOSE: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) ß-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFß expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified. METHODS: We investigated the in vitro effect of tranilast on ECM production and TGFß/SMAD2 pathway in TGFß2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin. RESULTS: Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFß2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFß, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice. CONCLUSION: These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFß/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.
Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Proteína Smad2/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Bleomicina , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Estrutura Molecular , Proteína Smad2/metabolismo , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta/metabolismo , ortoaminobenzoatosRESUMO
Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes. To investigate the role of HMGCR in the development of ß-cells and glucose homeostasis, we deleted Hmgcr in a ß-cell-specific manner by using the Cre-loxP technique. Mice lacking Hmgcr in ß-cells (ß-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both ß-cell mass and insulin secretion. Ki67-positive cells were reduced in ß-KO mice at P9; thus, ß-cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (Ngn3), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of ß-cell-associated genes, such as insulin, pancreatic and duodenal homeobox 1 (Pdx1), and MAF BZIP transcription factor A (Mafa) in the islets from ß-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of ß-cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of ß-cells in mice.
Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Células Secretoras de Insulina/enzimologia , Insulina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Glicemia , Diabetes Mellitus , Comportamento Alimentar , Teste de Tolerância a Glucose , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hidroximetilglutaril-CoA Redutases/genética , Hiperglicemia , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell-specific reduction of HMG-CoA reductase (Hmgcr m-/m- ), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr m-/m- mice than in control Hmgcr fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr m-/m- and Hmgcr fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell-specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell-specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Células Mieloides/metabolismo , Obesidade/induzido quimicamente , Tecido Adiposo/patologia , Animais , Glicemia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Regulação Enzimológica da Expressão Gênica , Hidroximetilglutaril-CoA Redutases/genética , Inflamação/induzido quimicamente , Insulina/sangue , Macrófagos , Camundongos , Camundongos KnockoutRESUMO
The synthesis of highly acidic metal-organic frameworks (MOFs) has attracted significant research interest in recent years. We report here the design of a strongly Lewis acidic MOF, ZrOTf-BTC, through two-step transformation of MOF-808 (Zr-BTC) secondary building units (SBUs). Zr-BTC was first treated with 1 M hydrochloric acid solution to afford ZrOH-BTC by replacing each bridging formate group with a pair of hydroxide and water groups. The resultant ZrOH-BTC was further treated with trimethylsilyl triflate (Me3SiOTf) to afford ZrOTf-BTC by taking advantage of the oxophilicity of the Me3Si group. Electron paramagnetic resonance spectra of Zr-bound superoxide and fluorescence spectra of Zr-bound N-methylacridone provided a quantitative measurement of Lewis acidity of ZrOTf-BTC with an energy splitting (ΔE) of 0.99 eV between the πx* and πy* orbitals, which is competitive to the homogeneous benchmark Sc(OTf)3. ZrOTf-BTC was shown to be a highly active solid Lewis acid catalyst for a broad range of important organic transformations under mild conditions, including Diels-Alder reaction, epoxide ring-opening reaction, Friedel-Crafts acylation, and alkene hydroalkoxylation reaction. The MOF catalyst outperformed Sc(OTf)3 in terms of both catalytic activity and catalyst lifetime. Moreover, we developed a ZrOTf-BTC@SiO2 composite as an efficient solid Lewis acid catalyst for continuous flow catalysis. The Zr centers in ZrOTf-BTC@SiO2 feature identical coordination environment to ZrOTf-BTC based on spectroscopic evidence. ZrOTf-BTC@SiO2 displayed exceptionally high turnover numbers (TONs) of 1700 for Diels-Alder reaction, 2700 for epoxide ring-opening reaction, and 326 for Friedel-Crafts acylation under flow conditions. We have thus created strongly Lewis acidic sites in MOFs via triflation and constructed the MOF@SiO2 composite for continuous flow catalysis of important organic transformations.
RESUMO
The Lewis acidity of metal-organic frameworks (MOFs) has attracted much research interest in recent years. We report here the development of two quantitative methods for determining the Lewis acidity of MOFs-based on electron paramagnetic resonance (EPR) spectroscopy of MOF-bound superoxide (O2â¢-) and fluorescence spectroscopy of MOF-bound N-methylacridone (NMA)-and a simple strategy that significantly enhances MOF Lewis acidity through ligand perfluorination. Two new perfluorinated MOFs, Zr6-fBDC and Zr6-fBPDC, where H2fBDC is 2,3,5,6-tetrafluoro-1,4-benzenedicarboxylic acid and H2fBPDC is 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldicarboxylic acid, were shown to be significantly more Lewis acidic than nonsubstituted UiO-66 and UiO-67 as well as the nitrated MOFs Zr6-BDC-NO2 and Zr6-BPDC-(NO2)2. Zr6-fBDC was shown to be a highly active single-site solid Lewis acid catalyst for Diels-Alder and arene C-H iodination reactions. Thus, this work establishes the important role of ligand perfluorination in enhancing MOF Lewis acidity and the potential of designing highly Lewis acidic MOFs for fine chemical synthesis.
RESUMO
BACKGROUND: Causative mutations cannot be identified in the majority of Asian patients with suspected maturity-onset diabetes of the young (MODY). OBJECTIVES: To elucidate the genetic basis of Japanese patients with MODY-like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes. SUBJECTS: A total of 263 Japanese patients with early-onset, non-obese, MODY-like diabetes mellitus referred to Osaka City General Hospital for diagnosis. METHODS: Mutational analysis of the four major MODY genes (GCK, HNF1A, HNF4A, HNF1B) by Sanger sequencing. Mutation-positive and mutation-negative patients were further analyzed for clinical features. RESULTS: Mutations were identified in 103 (39.2%) patients; 57 mutations in GCK; 29, HNF1A; 7, HNF4A; and 10, HNF1B. Contrary to conventional diagnostic criteria, 18.4% of mutation-positive patients did not have affected parents and 8.2% were in the overweight range (body mass index [BMI] >85th percentile). HOMA-IR at diagnosis was elevated (>2) in 15 of 66 (22.7%) mutation-positive patients. Compared with mutation-positive patients, mutation-negative patients were significantly older (P = 0.003), and had higher BMI percentile at diagnosis (P = 0.0006). Interestingly, maternal inheritance of diabetes was significantly more common in mutation-negative patients (P = 0.0332) and these patients had significantly higher BMI percentile as compared with mutation-negative patients with paternal inheritance (P = 0.0106). CONCLUSIONS: Contrary to the conventional diagnostic criteria, de novo diabetes, overweight, and insulin-resistance are common in Japanese patients with mutation-positive MODY. A significant fraction of mutation-negative patients had features of early-onset type 2 diabetes common in Japanese, and non-Mendelian inheritance needs to be considered for these patients.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fatores Nucleares de Hepatócito/genética , Herança Materna , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Quinases do Centro Germinativo , Humanos , Japão/epidemiologia , Masculino , Adulto JovemRESUMO
Transcription factors PAX9 and MSX1 play crucial roles in the development of permanent teeth at the bud stage, and their loss-of-function variants have been associated with congenital tooth agenesis. We sequenced the coding regions of the PAX9 and MSX1 genes from nine patients with non-syndromic tooth agenesis, and identified a missense mutation, P20L, of PAX9 in a single familial case involving three patients in two generations. Identical mutation was previously reported by other authors, but has not been characterized in detail. The mutation was located in a highly conserved N-terminal subdomain of the paired domain and co-segregated as a heterozygote with tooth agenesis. The patients showed defects primarily in the first and second molars, which is typical for cases attributable to PAX9 mutation. Luciferase reporter assay using the 2.3-kb promoter region of BMP4 and electrophoretic mobility shift assay using the CD19-2(A-ins) sequence revealed that P20L substitution eliminated most of the transactivation activity and specific DNA binding activity of PAX9 under the experimental conditions we employed, while some residual activity of the mutant was evident in the former assay. The hypomorphic nature of the variant may explain the relatively mild phenotype in this case, as compared with other PAX9 pathogenic variants such as R26W.
Assuntos
Anodontia/genética , Fator de Transcrição PAX9/genética , Adolescente , Adulto , Animais , Proteína Morfogenética Óssea 4/genética , Células COS , Chlorocebus aethiops , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Humanos , Fator de Transcrição MSX1/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Fator de Transcrição PAX9/química , Fator de Transcrição PAX9/fisiologia , Linhagem , Estrutura Terciária de ProteínaRESUMO
Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.
Assuntos
Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/citologia , Fator 3 de Transcrição de Octâmero/fisiologia , Quinazolinas/química , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/genética , Éxons , Feminino , Gefitinibe , Deleção de Genes , Glicoproteínas/metabolismo , Humanos , Hipóxia , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Microscopia de Fluorescência , Mutação , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Peptídeos/metabolismo , Fenótipo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Bromoderma is a rare skin disorder caused by bromide intake. It presents as single or multiple papillomatous nodules or plaques, and ulcers studded with small pustules on the face or limbs. The clinical features of bromoderma are similar to those of pyoderma gangrenosum. A 41-year-old Japanese woman was diagnosed with pyoderma gangrenosum 11 years prior to presentation. Pyoderma had repeatedly appeared over her entire body despite treatment. She also frequently complained of syncopal episodes. She was admitted to our hospital after loss of consciousness and an episode of generalized convulsion. Laboratory tests revealed a negative serum anion gap and hyperchloremia. Her serum bromide level was significantly elevated, suggesting bromide intoxication. The patient had a 10-year history of high serum bromide levels. After the intake of bromide-containing sedatives was stopped, there was no recurrence of pyoderma in the absence of treatment. In conclusion, this case was diagnosed as bromoderma with commercial sedative-induced bromide intoxication. Although the US Food and Drug Administration have banned the use of bromides, over-the-counter (OTC) treatments containing bromides are still used in Japan and other countries. Long-term use of OTC medicines containing bromvalerylurea may result in the development of bromoderma. If unclarified neurological or psychiatric symptoms are associated with pyoderma, we propose measurement of the patient's serum chloride concentration. Determination of hyperchloremia is helpful for the diagnosis of chronic intoxication with bromides.
Assuntos
Brometos/efeitos adversos , Bromisoval/efeitos adversos , Toxidermias/patologia , Hipnóticos e Sedativos/efeitos adversos , Medicamentos sem Prescrição/efeitos adversos , Pioderma Gangrenoso/patologia , Doenças Raras/patologia , Equilíbrio Ácido-Base , Adulto , Anorexia Nervosa/tratamento farmacológico , Biópsia , Brometos/administração & dosagem , Brometos/sangue , Bromisoval/sangue , Bromisoval/uso terapêutico , Cloretos/sangue , Ciclosporina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Toxidermias/sangue , Toxidermias/etiologia , Eritema/induzido quimicamente , Eritema/tratamento farmacológico , Eritema/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/uso terapêutico , Medicamentos sem Prescrição/análise , Prednisolona/uso terapêutico , Pioderma Gangrenoso/tratamento farmacológico , Doenças Raras/sangue , Doenças Raras/induzido quimicamente , Convulsões/etiologia , Síncope/etiologia , Suspensão de TratamentoRESUMO
The focal form of congenital hyperinsulinism (CHI) is characterized by a cluster of abnormal insulin-oversecreting ß cells within a restricted area of the pancreas. Although identification of the focal lesion is very important in the management of CHI, it has been reported that imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI) scans, or angiography, are not helpful in identifying the focal lesion. Currently, fluorine-18-L-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET) is believed to be the only imaging modality that can identify the focal lesions. In this report, however, we present a case of a 7-month-old girl with the focal form of CHI, caused by a loss-of-function mutation in the ABCC8 gene, whose lesion was clearly visible as a hyperenhancing nodule on contrast-enhanced CT and dynamic MRI imaging.
Assuntos
Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/genética , Mesilato de Imatinib/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Repressoras/genética , Antineoplásicos/uso terapêutico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 4/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Leucemia , Masculino , Pessoa de Meia-Idade , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor ß1 (TGFß1). Inhibition of hypoxia-inducible factor 1α (HIF1α) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Antígenos CD , Caderinas/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Progressão da Doença , Fibronectinas/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Metástase Neoplásica , Oxigênio/metabolismo , Fenótipo , Transdução de Sinais , Vimentina/metabolismo , CicatrizaçãoRESUMO
A 57-year-old woman, who had undergone hysterectomy for uterine myoma 11 years earlier presented with cystic, nodular and cavitary lesions simultaneously visible on computed tomography images of the chest. Histological examinations of both the resected lung and past "myoma" specimens demonstrated that the original uterine tumor was a low-grade endometrial stromal sarcoma (ESS) that had metastasized to the lungs. No previous reports have described the coexistence of cystic, nodular and cavitary lesions with pulmonary metastasis of ESS; however, we successfully correlated the radiologic appearance with the corresponding pathologic findings. Medroxyprogesterone acetate therapy has effectively kept the patient asymptomatic for approximately five years.
Assuntos
Neoplasias do Endométrio/patologia , Neoplasias Pulmonares/secundário , Sarcoma do Estroma Endometrial/secundário , Diagnóstico Diferencial , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Pessoa de Meia-Idade , Pneumonectomia/métodos , Tomografia por Emissão de Pósitrons , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/cirurgia , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios XRESUMO
Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.