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1.
Brain ; 146(10): 4233-4246, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37186601

RESUMO

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.


Assuntos
Artrogripose , Miastenia Gravis , Doenças Neuromusculares , Gravidez , Feminino , Adulto , Humanos , Imunoglobulinas Intravenosas , Receptores Colinérgicos , Miastenia Gravis/terapia , Miastenia Gravis/complicações , Autoanticorpos , Artrogripose/complicações
2.
Clin Immunol ; 255: 109755, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37673224

RESUMO

Severe eosinophilic asthma (SEA) is characterized by elevated eosinophil counts in the blood and airway mucosa. While monoclonal antibody therapies targeting interleukin-5 (IL-5) and its receptor (IL-5Rα) have improved treatment, some patients remain unresponsive. We propose an alternative approach to eliminate eosinophils using T cells by engineering IL-5Rα × CD3 bispecific T-cell engagers (bsTCEs) that target both IL-5Rα on eosinophils and CD3 on T cells. We designed different formats of IL-5Rα × CD3 bsTCEs, incorporating variations in valency, geometry, and affinity for the target antigen binding. We identified the single-chain variable fragment (scFv)-Fc format with the highest affinity toward the membrane-proximal domain of IL-5Rα in the IL-5Rα-binding arm showed the most potent cytotoxicity against IL-5Rα-expressing peripheral eosinophils by activating autologous primary T cells from healthy donors. This study proposes IL-5Rα × CD3 bsTCEs as potential alternatives for SEA treatment. Importantly, it demonstrates the first application of bsTCEs in eliminating disease-associated cells, including eosinophils, beyond cancer cells.


Assuntos
Asma , Eosinófilos , Humanos , Linfócitos T/metabolismo , Anticorpos Monoclonais/metabolismo
3.
J Transl Med ; 20(1): 517, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348371

RESUMO

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder characterized by asymmetric muscle wasting and weakness. FSHD can be subdivided into two types: FSHD1, caused by contraction of the D4Z4 repeat on chromosome 4q35, and FSHD2, caused by mild contraction of the D4Z4 repeat plus aberrant hypomethylation mediated by genetic variants in SMCHD1, DNMT3B, or LRIF1. Genetic diagnosis of FSHD is challenging because of the complex procedures required. METHODS: We applied Nanopore CRISPR/Cas9-targeted resequencing for the diagnosis of FSHD by simultaneous detection of D4Z4 repeat length and methylation status at nucleotide level in genetically-confirmed and suspected patients. RESULTS: We found significant hypomethylation of contracted 4q-D4Z4 repeats in FSHD1, and both 4q- and 10q-D4Z4 repeats in FSHD2. We also found that the hypomethylation in the contracted D4Z4 in FSHD1 is moderately correlated with patient phenotypes. CONCLUSIONS: Our method contributes to the development for the diagnosis of FSHD using Nanopore long-read sequencing. This finding might give insight into the mechanisms by which repeat contraction causes disease pathogenesis.


Assuntos
Distrofia Muscular Facioescapuloumeral , Humanos , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/diagnóstico , Proteínas de Homeodomínio/genética , Metilação de DNA/genética , Cromossomos/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo
4.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36555466

RESUMO

Immunotoxins (ITs), which are toxin-fused tumor antigen-specific antibody chimeric proteins, have been developed to selectively kill targeted cancer cells. The epidermal growth factor receptor (EGFR) is an attractive target for the development of anti-EGFR ITs against solid tumors due to its overexpression on the cell surface of various solid tumors. However, the low basal level expression of EGFR in normal tissue cells can cause undesirable on-target/off-tumor toxicity and reduce the therapeutic window of anti-EGFR ITs. Here, based on an anti-EGFR monobody with cross-reactivity to both human and murine EGFR, we developed a strategy to tailor the anti-EGFR affinity of the monobody-based ITs carrying a 24-kDa fragment of Pseudomonas exotoxin A (PE24), termed ER-PE24, to distinguish tumors that overexpress EGFR from normal tissues. Five variants of ER-PE24 were generated with different EGFR affinities (KD ≈ 0.24 nM to 104 nM), showing comparable binding activity for both human and murine EGFR. ER/0.2-PE24 with the highest affinity (KD ≈ 0.24 nM) exhibited a narrow therapeutic window of 19 pM to 93 pM, whereas ER/21-PE24 with an intermediate affinity (KD ≈ 21 nM) showed a much broader therapeutic window of 73 pM to 1.5 nM in in vitro cytotoxic assays using tumor model cell lines. In EGFR-overexpressing tumor xenograft mouse models, the maximum tolerated dose (MTD) of intravenous injection of ER/21-PE24 was found to be 0.4 mg/kg, which was fourfold higher than the MTD (0.1 mg/kg) of ER/0.2-PE24. Our study provides a strategy for the development of IT targeting tumor overexpressed antigens with basal expression in broad normal tissues by tailoring tumor antigen affinities.


Assuntos
Antineoplásicos , Imunotoxinas , Neoplasias , Humanos , Camundongos , Animais , Imunotoxinas/farmacologia , Imunotoxinas/uso terapêutico , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Anticorpos , Antígenos de Neoplasias , Neoplasias/tratamento farmacológico
5.
Neurol Sci ; 40(1): 67-73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30232672

RESUMO

Miller Fisher syndrome (MFS) is characterized by a clinical triad of ophthalmoplegia, ataxia, and areflexia, and is closely associated with serum anti-GQ1b antibody. Although the clinical triad is the cardinal diagnostic clue, a variety of other symptoms and signs beyond the triad have been reported. To elucidate the frequency and characteristics of atypical clinical manifestations of MFS, we recruited 38 patients with MFS and evaluated the symptoms or signs beyond the classic triad. Eleven (29%) of 38 patients had atypical clinical manifestations of MFS such as headache (n = 6), delayed facial palsy (n = 3), divergence insufficiency (n = 2), and taste impairment (n = 2). Headache was localized to the periorbital (n = 3), temporal (n = 2), or whole (n = 1) area. Only one of them showed bilateral papilledema and an elevated opening pressure in cerebrospinal fluid analysis. Delayed facial palsy developed after the other signs have reached nadir (n = 1) or started to improve (n = 2), and did not follow a pattern of descending paralysis with other cranial neuropathies. Two patients showed divergence insufficiency without external ophthalmoplegia, and another two had taste impairment over the entire tongue without the other signs of facial and glossopharyngeal nerve involvements. Our study shows that approximately 30% of MFS patients can have atypical clinical manifestations beyond the classic triad. These results reflect the broad clinical spectrum of MFS, and might be associated with the presence of additional antiganglioside antibodies besides anti-GQ1b in patients with MFS.


Assuntos
Paralisia Facial/diagnóstico , Gangliosídeos , Síndrome de Miller Fisher/diagnóstico , Oftalmoplegia/diagnóstico , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Diagnóstico Diferencial , Paralisia Facial/sangue , Paralisia Facial/epidemiologia , Feminino , Gangliosídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Miller Fisher/sangue , Síndrome de Miller Fisher/epidemiologia , Oftalmoplegia/sangue , Oftalmoplegia/epidemiologia , Adulto Jovem
7.
Muscle Nerve ; 58(2): 235-244, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29669168

RESUMO

INTRODUCTION: Congenital myopathies are muscle diseases characterized by specific histopathologic features, generalized hypotonia from birth, and perinatal complications, although some cases develop during childhood or, rarely, in adulthood. We undertook this study to characterize congenital myopathies among patients registered at our institution. METHODS: Clinical, histopathologic, and genetic features were evaluated in 34 patients recruited for this study. RESULTS: The majority of patients experienced a childhood onset, and no disease-related mortality was recorded during follow-up. Functional outcomes were no better for those with late-onset disease, indicating later disease progression can be significant. Nemaline myopathy was the most frequent pathology, followed by central core disease and centronuclear myopathy. Among the 18 (54.5%) genetically confirmed patients, NEB and RYR1 mutations were the most common, followed by DNM2 mutations. DISCUSSION: This study shows features not previously reported and suggests that congenital myopathy should be considered an important issue among adult patients. Muscle Nerve 58: 235-244, 2018.


Assuntos
Miotonia Congênita/patologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Dinamina II , Dinaminas/genética , Feminino , Humanos , Lactente , Masculino , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/genética , Mutação , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Miopatias Congênitas Estruturais/congênito , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miopatia da Parte Central/congênito , Miopatia da Parte Central/genética , Miopatia da Parte Central/patologia , Miotonia Congênita/genética , República da Coreia , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Resultado do Tratamento , Adulto Jovem
8.
Biochem Biophys Res Commun ; 482(4): 843-848, 2017 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-27888104

RESUMO

In this study, we examined whether the peroxisome proliferator-activated receptor γ (PPARγ) agonists, ciglitazone (CGZ) and troglitazone (TGZ), induce cell death in human cervical cancer HeLa cells. The cells were treated with a range of CGZ or TGZ doses for 24 or 48 h. Low concentrations of CGZ (≤10 µM) or TGZ (≤20 µM) had no effect on cell viability whereas higher doses induced cell death in a time- and dose-dependent manner as evidenced by the detection of activated caspase-3 and PARP cleavage. Treatment with the PPARγ antagonist GW9662 followed by PPARγ agonists did not increase CGZ- or TGZ-induced cell death, indicating that PPARγ agonists induced HeLa cell death independently of PPARγ. Moreover, ERK1/2 activation was observed at a CGZ concentration of 25 µM and a TGZ concentration of 35 µM, both of which induced cell death. To elucidate the role of ERK1/2 activated by the two PPARγ agonists, the effect of U0126, an inhibitor of ERK1/2, on PPARγ-agonist-induced cell death was examined. Treatment with 10 or 20 µM U0126 followed by CGZ or TGZ induced the down-regulation of ERK1/2 activity and a decrease in Bcl-2 expression accompanied by the collapse of mitochondrial membrane potential, which in turn significantly enhanced CGZ- or TGZ-induced apoptotic cell death. Our results suggest that PPARγ agonists are capable of inducing apoptotic cell death in HeLa cells independently of PPARγ and that inhibition of ERK1/2 activity offers a strategy to enhance the cytotoxicity of PPARγ agonists in the treatment of cervical cancer.


Assuntos
Antineoplásicos/farmacologia , Cromanos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Apoptose/efeitos dos fármacos , Butadienos/farmacologia , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colo do Útero/citologia , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Feminino , Células HeLa , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Nitrilas/farmacologia , PPAR gama/metabolismo , Troglitazona , Neoplasias do Colo do Útero/metabolismo
9.
Nanotechnology ; 28(47): 475302, 2017 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-28961147

RESUMO

In this report, we introduce a method utilizing ion-assisted aerosol lithography to stack 3D nanostructures vertically. The stacked 3D nanostructures exhibit extraordinary optical properties: the double layer 3D nanostructures show more than 5-fold increased surface enhanced Raman scattering intensities compared to their single layer counterpart. This unusual enhancement of Raman intensity implies the existence of additional vertical hotspots formed by interlayer cavity effects between the lower and upper nanostructures. Allowing for full three-dimensional control in nanofabrication, this work provides a reliable way to create complex-shaped advanced optical nanostructures with non-intuitive bulk optical properties.

10.
Korean J Physiol Pharmacol ; 21(4): 439-447, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28706458

RESUMO

Myotonia congenita (MC) is a genetic disease that displays impaired relaxation of skeletal muscle and muscle hypertrophy. This disease is mainly caused by mutations of CLCN1 that encodes human skeletal muscle chloride channel (CLC-1). CLC-1 is a voltage gated chloride channel that activates upon depolarizing potentials and play a major role in stabilization of resting membrane potentials in skeletal muscle. In this study, we report 4 unrelated Korean patients diagnosed with myotonia congenita and their clinical features. Sequence analysis of all coding regions of the patients was performed and mutation, R47W and A298T, was commonly identified. The patients commonly displayed transient muscle weakness and only one patient was diagnosed with autosomal dominant type of myotonia congenita. To investigate the pathological role of the mutation, electrophysiological analysis was also performed in HEK 293 cells transiently expressing homo- or heterodimeric mutant channels. The mutant channels displayed reduced chloride current density and altered channel gating. However, the effect of A298T on channel gating was reduced with the presence of R47W in the same allele. This analysis suggests that impaired CLC-1 channel function can cause myotonia congenita and that R47W has a protective effect on A298T in relation to channel gating. Our results provide clinical features of Korean myotonia congenita patients who have the heterozygous mutation and reveal underlying pathophyological consequences of the mutants by taking electrophysiological approach.

11.
J Hum Genet ; 61(9): 775-80, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27225851

RESUMO

This study aimed to develop a new set of screening criteria that is easily applicable and highly sensitive for the detection of patients at high risk of Fabry disease (FD) among hypertrophic cardiomyopathy (HCM) patients. We prospectively studied 273 consecutive unrelated patients who were referred to HCM clinic for unknown left ventricular hypertrophy. Among the 273 patients, we selected 65 high-risk patients who fulfilled at least one of our newly proposed screening criteria. All 273 patients were assayed for plasma α-galactosidase A (α-GAL A) activity. The new screening criteria were: (1) atypical HCM, (2) history or presence of documented arrhythmia, (3) short PR interval defined as <120 ms on electrocardiogram, and (4) symptoms of autonomic dysfunction. From this screening study, three unrelated patients (4.6%; 2 females and 1 male) were newly diagnosed with FD using α-GAL A activity and mutation analysis of the GLA gene. Using the screening method based on the newly proposed criteria, the prevalence of FD in our HCM population was 4.6% if at least one criterion was met and 18.8% if ⩾3 criteria were met. Therefore, our proposed criteria are easily applicable and highly sensitive for classifying patients at high risk of FD from HCM patients.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/etiologia , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Adulto , Idoso , Biomarcadores , Análise Mutacional de DNA , Gerenciamento Clínico , Ecocardiografia , Eletrocardiografia , Doença de Fabry/complicações , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , alfa-Galactosidase/sangue , alfa-Galactosidase/genética
12.
Muscle Nerve ; 53(3): 479-84, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26562614

RESUMO

INTRODUCTION: Mutations in the gene encoding nebulin (NEB) are known to cause several types of congenital myopathy including recessive nemaline myopathy and distal nebulin myopathy. Core-rod myopathy has recently been reported to be another type of NEB-related myopathy, and is pathologically characterized by the coexistence of cores and nemaline rods within muscle fibers. METHODS: We describe 2 patients with core-rod myopathy who were analyzed genetically by whole exome sequencing and evaluated clinically and pathologically. Findings were compared with those of patients with the disease of other genetic causes. RESULTS: Three NEB mutations were identified, 2 of which were novel. Mild clinical features, unusual patterns of muscle involvement, and atypical pathological findings were observed. CONCLUSIONS: We propose that the clinical and pathological spectrum of core-rod myopathy should be widened. A significant amount of residual nebulin expression is believed to contribute to the much milder phenotype exhibited by the patients we describe here.


Assuntos
Proteínas Musculares/genética , Músculo Esquelético/patologia , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Adenosina Trifosfatases/metabolismo , Adulto , Criança , Creatina Quinase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons , Humanos , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/diagnóstico por imagem , Radiografia , Tomógrafos Computadorizados
13.
Cell Biochem Funct ; 34(1): 16-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26778408

RESUMO

In this study, we investigated the effect of cell density on the proliferation activity of human mesenchymal stem cells (MSCs) derived from adipose tissue (AT-MSCs) over time in culture. Passage #4 (P4) and #12 (P12) AT-MSCs from two donors were plated at a density of 200 (culture condition 1, CC1) or 5000 (culture condition 2, CC2) cells cm(-2) . After 7 days of incubation, P4 and P12 AT-MSCs cultured in CC1 were thin and spindle-shaped, whereas those cultured in CC2 had extensive cell-to-cell contacts and an expanded cell volume. In addition, P4 and P12 AT-MSCs in CC1 divided more than three times, while those in CC2 divided less than once on average. Flow cytometric analysis using 5(6)-carboxyfluorescein diacetate N-succinimidyl ester dye showed that the fluorescence intensity of AT-MSCs was lower in CC1 than in CC2. Furthermore, expression of proliferation-associated genes, such as CDC45L, CDC20A and KIF20A, in P4 AT-MSCs was higher in CC1 than in CC2, and this difference was also observed in P12 AT-MSCs. These data demonstrated that cell culture density affects the proliferation activity of MSCs, suggesting that it is feasible to design a strategy to prepare suitable MSCs using specific culture conditions.


Assuntos
Tecido Adiposo/citologia , Proliferação de Células , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/metabolismo , Contagem de Células , Técnicas de Cultura de Células , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Citometria de Fluxo , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Células-Tronco Mesenquimais/metabolismo
14.
Biochem Biophys Res Commun ; 463(4): 894-9, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26074143

RESUMO

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, is a promising new strategy for the treatment of cancer. However, aberrant PI3K/Akt/mTOR survival signaling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. In the present study, we showed that the Akt/mTOR inhibitor RAD001 (everolimus) induced cell death in a dose-dependent manner and enhanced TRAIL-induced apoptosis in human leukemic Jurkat T cells, which show PI3K/Akt/mTOR pathway activation and basal expression levels of death receptor (DR) 5 (TRAIL-R2). Investigation of the effect of RAD001 treatment on the expression of TRAIL receptors (TRAIL-Rs) in Jurkat T cells showed that RAD001 significantly upregulated DR5 by up to 51.22%, but not other TRAIL-Rs such as DR4 (TRAIL-R1), decoy receptor (DcR) 1 (TRAIL-R3), and DcR2 (TRAIL-R4). Pretreatment with DR5:Fc chimera abrogated the RAD001-induced increase of TRAIL cytotoxicity, indicating that the upregulation of DR5 by RAD001 plays a role in enhancing the susceptibility of Jurkat T cells to TRAIL. Our results indicate that combination treatment with RAD001 and TRAIL may be a novel therapeutic strategy in leukemia.


Assuntos
Antineoplásicos/farmacologia , Leucemia/patologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Sirolimo/análogos & derivados , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Regulação para Cima/efeitos dos fármacos , Apoptose/fisiologia , Relação Dose-Resposta a Droga , Everolimo , Humanos , Células Jurkat , Leucemia/fisiopatologia , Sirolimo/farmacologia
15.
Neurol Sci ; 36(4): 599-605, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25388776

RESUMO

Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of the enzyme acid glucosidase alfa (GAA). Recently, enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA) became clinically available, and is expected to modify the clinical course in LOPD of various stages. In this study, we evaluated the efficacy and adverse events of ERT for 48 weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features, including muscular and pulmonary function, were assessed, and rhGAA was infused every 2 weeks. Then, patients were examined at every 12-week interval for evaluation of changes in motor and pulmonary function for 48 weeks along with adverse reactions to ERT. The muscular and pulmonary function of the patients varied depending on the baseline condition of the patient after 48 weeks of ERT. However, the overall function of the patients showed stabilization of the disease rather than the improvement seen in infantile-onset Pompe disease. This is the first clinical study on ERT of Korean LOPD patients. Results of our study showed stabilization of muscular and pulmonary function in LOPD patients for 48 weeks with a favorable prognosis for patients who received early diagnosis and ambulatory patients. One of our patients developed a serious anaphylactic reaction, which necessitated the cessation of further ERT. Therefore, our study shows that early diagnosis and ERT are important in preventing further deterioration of the disease.


Assuntos
Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/terapia , Adulto , Glicemia , Criança , Creatina Quinase/sangue , Feminino , Seguimentos , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Projetos Piloto , Estudos Retrospectivos
16.
J Res Med Sci ; 19(8): 792-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25422667

RESUMO

Hereditary inclusion body myopathy (hIBM) is an adult-onset hereditary myopathy, usually with distal onset and quadriceps sparing. This myopathy is autosomal recessive and associated to UPD-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene mutations. In this study, we report a novel GNE homozygous point mutation c.1834T>G that results in amino acid substitution of cysteine 612 to glutamine in an Iranian patient. This mutation is located in exon 10 within the kinase domain of the protein.

17.
J Clin Neurol ; 20(1): 67-77, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38179634

RESUMO

BACKGROUND AND PURPOSE: Advances in serological tests are transforming the classification of idiopathic inflammatory myopathy (IIM). The new criteria suggested by the 119th European Neuromuscular Center international workshop divide IIM cases into four main diseases according to clinical and pathological findings, adding immune-mediated necrotizing myositis and nonspecific myositis to the classic categories of polymyositis and dermatomyositis. METHODS: Seventy one cases of IIM with sufficient available clinical and pathological data were reviewed to be reclassified according to the new criteria. RESULTS: Most of the cases previously classified as polymyositis (77.8%, 35/45) were reclassified as immune-mediated necrotizing myopathy. The results of myositis-specific antibodies matched well with the new clinicopathological classification. CONCLUSIONS: This new clinicopathological classification for IIM in combination with serological test results could be applied to our previous case series. Adoption of the new criteria will lead to a better understanding of the disease and hence new therapeutic insights.

18.
Int J Biol Macromol ; 278(Pt 1): 134668, 2024 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-39137851

RESUMO

Immunotoxins (ITs) are recombinant chimeric proteins that combine a protein toxin with a targeting moiety to facilitate the selective delivery of the toxin to cancer cells. Here, we present a novel strategy to enhance the cytosolic access of ITs by promoting their dissociation from target receptors under the reducing conditions of the endocytic pathway. We engineered monobodySS, a human fibronectin type III domain-based monobody with disulfide bond (SS)-containing paratopes, targeting receptors such as EGFR, EpCAM, Her2, and FAP. MonobodySS exhibited SS-dependent target receptor binding with a significant reduction in binding under reducing conditions. We then created monobodySS-based ITs carrying a 25 kDa fragment of Pseudomonas exotoxin A (PE25), termed monobodySS-PE25. These ITs showed dose-dependent cytotoxicity against target receptor-expressing cancer cells and a wider therapeutic window due to higher efficacy at lower doses compared to controls with SS reduction inhibited. ERSS/28-PE25, with a KD of 28 nM for EGFR, demonstrated superior tumor-killing potency compared to ER/21-PE25, which lacks an SS bond, at equivalent and lower doses. In vivo, ERSS/28-PE25 outperformed ER/21-PE25 in suppressing tumor growth in EGFR-overexpressing xenograft mouse models. This study presents a strategy for developing solid tumor-targeting ITs using SS-containing paratopes to enhance cytosolic delivery and antitumor efficacy.

19.
Ann Hematol ; 92(12): 1595-602, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23835655

RESUMO

To overcome the limitations of allogeneic hematopoietic stem cell transplantation (HSCT), we conducted a study to identify a strategy for enhancing hematopoietic stem cell (HSC) engraftment during HSCT. Co-transplantation experiments with mesenchymal stem cells (MSCs) derived from adult human tissues including bone marrow (BM), adipose tissue (AT), and umbilical cord blood (CB) were conducted. We showed that AT-MSCs and CB-MSCs enhanced the engraftment of HSCs as effectively as BM-MSCs in NOD/SCID mice, suggesting that AT-MSCs and CB-MSCs can be used as alternative stem cell sources for enhancing the engraftment and homing of HSCs. CB-MSCs derived from different donors showed different degrees of efficacy in enhancing the engraftment of HSCs. The most effective CB-MSCs showed higher proliferation rates and secreted more MCP-1, RANTES, EGF, and VEGF. Our results suggest that AT-MSCs and CB-MSCs could be alternative stem cell sources for co-transplantation in HSCT. Furthermore, in terms of MSCs' heterogeneity, characteristics of each population of MSCs are considerable factors for selecting MSCs suitable for co-transplantation with HSC.


Assuntos
Sobrevivência de Enxerto/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Mesenquimais/fisiologia , Tecido Adiposo/citologia , Tecido Adiposo/fisiologia , Tecido Adiposo/transplante , Animais , Células da Medula Óssea/fisiologia , Proliferação de Células , Células Cultivadas , Sangue Fetal/fisiologia , Sangue Fetal/transplante , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
20.
Clin Auton Res ; 23(2): 105-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23152140

RESUMO

Primary erythromelalgia (EM) is an autosomal dominant disorder caused by mutations of SCN9A. It is clinically characterized by reddish discoloration and episodic burning sensation of distal extremities triggered by warmth. We report a 49-year-old male with primary EM caused by SCN9A mutation (p.F216S), in whom an autonomic reflex screening test revealed a mild sudomotor dysfunction.


Assuntos
Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/genética , Eritromelalgia/complicações , Eritromelalgia/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Sequência de Bases , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem
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