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Herein, we report a pair of regioselective N 1- and N 2 -alkylations of a versatile indazole, methyl 5-bromo-1H-indazole-3-carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N 1- and N 2-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N 1-substituted products when cesium is present and other non-covalent interactions (NCIs) drive the N 2-product formation. Methyl 1H-indazole-7-carboxylate (18) and 1H-indazole-3-carbonitrile (21) were also subjected to the reaction conditions and their mechanisms were evaluated. The N 1- and N 2-partial charges and Fukui indices were calculated for compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways.
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PURPOSE: Mycobacterium abscessus complex (MABC) infections are increasing worldwide. Furthermore, these infections have a low treatment success rate due to their resistance to many current antibiotics. This study aimed to determine the overall in vitro activity of the tetracyclines doxycycline (DOX), minocycline (MIN), and tigecycline (TGC) against MABC clinical isolates. PATIENTS AND METHODS: A systematic review of PubMed/MEDLINE, Web of Science, and Embase was conducted up to August 28, 2023. Studies applying the drug susceptibility testing standards of the Clinical and Laboratory Standards Institute were considered. A random effects model was used to assess the total in vitro resistance rates of the MABC clinical isolates to DOX, MIN, and TGC. The I2 and Cochran's Q statistics were employed to evaluate the origins of heterogeneity. All analyses were conducted using CMA V.3 software. RESULTS: Twenty-six publications (22, 12, and 11 studies on DOX, MIN, and TGC, respectively) were included. The pooled in vitro resistance rates of the MABC clinical isolates to DOX and MIN at the breakpoint of 8 µg/mL were 93.0 % (95 % CI, 89.2 %-95.5 %) and 87.2 % (95 % CI, 76.5 %-93.4 %), respectively. In the case of TGC, the breakpoints of 2, 4, and 8 µg/mL were associated with pooled resistance rates of 2.5 % (95 % CI, 0.5 %-11.6 %), 7.2 % (95 % CI, 4.0 %-12.5 %), and 16.8 % (95 % CI, 4.7 %-45.0 %), respectively. CONCLUSION: Among the three examined tetracyclines, MABC exhibited extremely high resistance rates to DOX and MIN, thereby limiting their use in treating MABC infections. Conversely, MABC showed an increased susceptibility rate to TGC, highlighting TGC administration as a viable treatment option for patients with MABC infections.
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OBJECTIVE: This study aims to estimate the overall in vitro activity of bedaquiline (BDQ) against clinical isolates of Mycobacterium abscessus complex (MABS) and M. avium complex (MAC), considering BDQ as a repurposed drug for non-tuberculous mycobacteria (NTM) infections. METHODS: We conducted a systematic review of publications in PubMed/ MEDLINE, Web of Science, and Embase up to 15 April 2023. Studies were included if they followed the Clinical and Laboratory Standards Institute (CLSI) criteria for drug susceptibility testing (DST). Using a random effects model, we assessed the overall in vitro BDQ resistance rate in clinical isolates of MABS and MAC. Sources of heterogeneity were analysed using Cochran's Q and the I2 statistic. All analyses were performed using CMA V3.0. RESULTS: A total of 24 publications (19 reports for MABS and 11 for MAC) were included. Using 1 µg/mL and 2 µg/mL as the breakpoint for BDQ resistance, the pooled rates of in vitro BDQ resistance in clinical isolates of MABS were found to be 1.8% (95% confidence interval [CI], 0.7-4.6%) and 1.7% (95% CI, 0.6-4.4%), respectively. In the case of MAC, the pooled rates were 1.7% (95% CI, 0.4-6.9%) and 1.6% (95% CI, 0.4-6.8%) for 1 µg/mL and 2 µg/mL, respectively. CONCLUSION: This study reports the prevalence of BDQ resistance in clinical isolates of MABS and MAC. The findings suggest that BDQ holds potential as a repurposed drug for treating MABS and MAC infections.
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Antituberculosos , Diarilquinolinas , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Complexo Mycobacterium avium , Diarilquinolinas/farmacologia , Humanos , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/genética , Mycobacterium abscessus/isolamento & purificação , Complexo Mycobacterium avium/efeitos dos fármacos , Complexo Mycobacterium avium/isolamento & purificação , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antituberculosos/farmacologia , Farmacorresistência Bacteriana , Infecção por Mycobacterium avium-intracellulare/microbiologiaRESUMO
BACKGROUND: Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown promise in managing neuromyelitis optica spectrum disorders (NMOSD) by depleting B cells and reducing relapses. However, there is no consensus on the optimal RTX dosing regimen, and genetic factors, such as FCGR3A-V158F polymorphism, may influence treatment outcomes. This study investigates how FCGR3A-V158F genotypes influence RTX efficacy in Chinese NMOSD patients under varying dosing regimens and aims to optimize treatment protocols. METHODS: We conducted a retrospective analysis of 25 Chinese NMOSD patients treated with RTX, grouped into standardized and low-dosage regimens. FCGR3A-V158F genotypes were determined, and treatment responses were evaluated, including relapse rates, time to first relapse (TFR), B-cell depletion, dose adjustments, and treatment retention. RESULTS: Among all patients, 15 received standardized dosages, while 10 received varied induction doses (500 mg to 1200 mg) in low-dose regimens. For FCGR3A-V158F genotypes, 15 had the FF genotype, and 10 were V carriers (3 VV genotype, 7 VF genotype). Regardless of dosing, FF genotype patients had a higher relapse rate post-RTX treatment compared to V carriers (P < 0.05). None of the 3 VV genotype patients in either dose group experienced relapses post-RTX. In both dose groups, FF genotype patients had significantly shorter TFR and required more RTX dose adjustments post-RTX treatment compared to V carriers in the standardized dosage group (P < 0.05). FF genotype patients in the low dosage group were more likely to experience insufficient B-cell depletion, had lower treatment retention rates, and more discontinuations than V carriers in the standardized dosage group (P < 0.05). Insufficient B-cell depletion significantly predicted clinical relapses after RTX treatment (P < 0.05). In survival analysis, FF genotype patients, regardless of dosing, experienced earlier relapses post-RTX treatment (P < 0.05). CONCLUSIONS: This study highlights the importance of RTX dosage selection in NMOSD treatment, particularly for FCGR3A-FF genotype patients. Standard-dose RTX therapy with vigilant monitoring of peripheral blood B-cell levels is recommended for these individuals to optimize treatment efficacy.
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Fatores Imunológicos , Neuromielite Óptica , Receptores de IgG , Rituximab , Humanos , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/genética , Receptores de IgG/genética , Rituximab/administração & dosagem , Feminino , Adulto , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Fatores Imunológicos/administração & dosagem , Adulto Jovem , China , Genótipo , Polimorfismo de Nucleotídeo Único , População do Leste AsiáticoRESUMO
Background: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disorder with cycles of escalating relapse. Rates of diagnosis in the elderly are increasing. Therapeutic decision-making is more challenging in elderly patients due to multiple comorbidities and high risk of drug-induced side effects. Objective: This retrospective study assessed the efficacy and safety of standard plasma exchange (PLEX) treatment in an elderly population with NMOSD. Design: Seventy-six patients with NMOSD who received PLEX were apportioned to two groups as either elderly (⩾60 years, n = 26) or young (<60 years) at the time of the first procedure. Methods: Therapeutic response was judged according to functional recovery at 6 months, as reflected by Expanded Disability Status Scale (EDSS) and visual outcome scale (VOS) scores. Results: The mean age of the 26 elderly patients was 67.7 ± 7.9 years (range 60-87 years); the population was predominantly female (88.5%). PLEX sessions were generally well tolerated among the elderly. Compared with the young patients, the elderly had significantly more comorbidities and concomitant medications. Twenty-four (96.0%) elderly patients showed functional improvement at 6 months after PLEX, of which 15 (60.0%) experienced moderate-to-marked improvement. Six months after the initial PLEX treatment, the patients overall experienced a significant improvement in EDSS and VOS scores. Logistic regression showed that severe optic neuritis attack was a significant independent prognostic factor associated with poor PLEX response. The groups were comparable regarding overall or serious adverse events. The rate of transient hypotension was significantly higher in the elderly compared with the young. Conclusion: PLEX is an effective and safe therapy for elderly patients with NMOSD and should be considered a treatment option during NMOSD attacks. In the elderly, preventive measures against hypotension are recommended before PLEX.
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Background: Elderly-onset neuromyelitis optica spectrum disorder (NMOSD) is a rare entity that poses a therapeutic challenge. We report a case of elderly-onset NMOSD with mutant FCGR3A genotype who was successfully treated with ofatumumab after multiple episodes of relapse. Case Report: The patient was a 67-year-old woman who was diagnosed with NMOSD with high disease activity. She experienced six episodes of relapse over a period of 2 years despite immunosuppressant therapy with intravenous rituximab (RTX), oral steroids, mycophenolate mofetil, and tacrolimus. At the last relapse, she was unable to walk and developed immunosuppressant-induced hypogammaglobulinemia. Based on the insufficient B cell depletion and FCGR3A-FF genotype carrier, the patient was diagnosed as RTX non-responder. After subcutaneous ofatumumab plus intravenous immunoglobulin replacement therapy, she was able to walk independently, and experienced no further relapse. Ofatumumab was well-tolerated, and sufficiently depleted the circulating B cells. Conclusion: Ofatumumab might be an effective alternative in RTX-unresponsive NMOSD, and seems to be safe in elderly patients.
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Agamaglobulinemia , Neuromielite Óptica , Feminino , Humanos , Idoso , Neuromielite Óptica/tratamento farmacológico , Rituximab/uso terapêutico , Rituximab/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Agamaglobulinemia/tratamento farmacológico , Imunossupressores/uso terapêutico , Genótipo , Recidiva , Receptores de IgGRESUMO
Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50,000 individuals worldwide. Berotralstat (BCX7353) is the only small molecule approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, we also identified a novel series of small molecules containing a quaternary carbon as potent and orally bioavailable Plasma Kallikrein (PKal) inhibitors. Lead compound was identified as a potent inhibitor following a detailed lead optimization process that balanced the lipophilic efficiency (LipE) and pharmacokinetic (PK) profile.
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Angioedemas Hereditários , Calicreína Plasmática , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Antivirais/uso terapêutico , Carbono , Humanos , Estados UnidosRESUMO
The three complement pathways comprising the early phase of the complement system (the classical, lectin, and alternative pathways) act together with the innate and adaptive immune systems to protect against foreign entities and maintain tissue homeostasis. While these systems are normally under tight regulatory control, several diseases have been reported to correlate with uncontrolled activation and amplification of the alternative pathway, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. Complement FactorD (CFD), a serine protease, is the rate-limiting enzyme for the activity of alternative pathway. CFD activates the alternative pathway by cleaving Complement Factor B complexed to C3b (C3bB) to generate alternative pathway C3 convertase (C3bBb). In our search for novel CFD inhibitors with therapeutic potential, we employed a hot-spot analysis of an ensemble of apo and holo CFD structures. This analysis identified potential pharmacophore features that aided in the design of a series of compounds based on an l-proline core. While these compounds inhibited CFD in an esterolytic assay (for example, a proline-based compound, IC50 = 161 nM), the pharmacokinetic (PK) properties were poor. A strategy of scaffold hopping via ring opening led to a novel series of acyclic compounds, with subsequent structure-based ligand design and lead optimization producing several novel CFD inhibitors. One of these inhibitors, 1-(2-((2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-5-(3-methyl-3-(1-methylpiperidin-4-yl)ureido)-1H-indazole-3-carboxamide, showed good potency with IC50s of 37 nM in the esterolytic assay and 30 nM in a hemolytic assay and PK assessments following oral administration to rats revealed a Cmax of 113 ng/mL and an AUC0-24h of 257 hr.ng/mL.
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Fator D do Complemento , Serina Endopeptidases , Ratos , Animais , Fator D do Complemento/metabolismo , Hemólise , LigantesRESUMO
BACKGROUND AND OBJECTIVE: To present 6 new cases with Homer-3 antibodies that expand their clinical spectra and to evaluate the effect of immunotherapy. METHODS: Patients with suspected autoimmune cerebellar disorder were tested for rare autoimmune cerebellar ataxia (ACA) antibodies (anti-Tr(DNER)/Zic4/ITPR1/Homer-3/NCDN/PKCγ/PCA-2/AP3B2/mGluR1/ATP1A3 antibodies) using both cell-based and tissue-based assays. Patients with positive serum or CSF results who were diagnosed with ACA were registered and followed up. This study reports and analyzes cases with Homer-3 antibodies. RESULTS: Of the serum and CSF samples of 750 patients tested, 6 were positive for Homer-3 antibodies. All manifested subacute or insidious-onset cerebellar ataxia. Furthermore, 2 patients each exhibited encephalopathy, myeloradiculopathy, REM sleep behavior disorder, and autonomic dysfunction. Brain magnetic resonance images were normal (n = 1) or revealed cerebellar atrophy (n = 1), cerebellum and pons atrophy with the hot cross bun sign (n = 2), and bilateral cerebral abnormalities (n = 2). Definite leukocytosis was identified in the CSF of 2 patients, protein concentration elevation was observed in the CSF of 1 patient, and oligoclonal bands were present in 2 patients. All patients received immunotherapy, including corticosteroid, IV immunoglobulin, plasma exchange, and mycophenolate mofetil, after which the residual disability was still severe (modified Rankin Scale score ≥3 at the last follow-up in 4 patients and final Scale for the Assessment and Rating of Ataxia scores of 12-29), although 4 patients partially improved and 1 patient stabilized. The remaining 1 patient continued to deteriorate after repeated immunotherapy. Two patients relapsed. DISCUSSION: Disorders associated with Homer-3 antibody can mimic multiple system atrophy with cerebellar features in both clinical and radiologic aspects. Accurate identification of autoimmune-mediated cases is critical. Timely, comprehensive immunotherapy is warranted, given the possibility of long-term clinical benefit.
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Autoanticorpos , Doenças Autoimunes do Sistema Nervoso , Ataxia Cerebelar , Proteínas de Arcabouço Homer/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/patologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/imunologia , Ataxia Cerebelar/patologia , Ataxia Cerebelar/fisiopatologia , China , Progressão da Doença , Feminino , Humanos , Fatores Imunológicos/farmacologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50â¯000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older.
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Angioedemas Hereditários/tratamento farmacológico , Calicreínas/antagonistas & inibidores , Pirazóis/química , Pirazóis/farmacologia , Administração Oral , Domínio Catalítico , Desenho de Fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
Inhibition of MER receptor tyrosine kinase (MERTK) causes direct tumor cell killing and stimulation of the innate immune response. Therefore, MERTK has been identified as a therapeutic target in a wide variety of human tumors. Clinical trials targeting MERTK have recently been initiated, however, none of these drugs are MERTK-specific. Herein, we present the discovery of a highly MERTK-selective inhibitor UNC5293 (24). UNC5293 has subnanomolar activity against MERTK with an excellent Ambit selectivity score (S50 (100 nM) = 0.041). It mediated potent and selective inhibition of MERTK in cell-based assays. Furthermore, it has excellent mouse PK properties (7.8 h half-life and 58% oral bioavailability) and was active in bone marrow leukemia cells in a murine model.
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Inibidores de Proteínas Quinases/farmacologia , c-Mer Tirosina Quinase/antagonistas & inibidores , Administração Oral , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos NOD , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , c-Mer Tirosina Quinase/metabolismoRESUMO
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
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Inibidores Enzimáticos/química , Isocitrato Desidrogenase/antagonistas & inibidores , Piridonas/química , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Meia-Vida , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Mutagênese Sítio-Dirigida , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Piridinas/uso terapêutico , Piridonas/metabolismo , Piridonas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: The area postrema syndrome (APS) is a unique diagnostic criterion for neuromyelitis optica spectrum disorders (NMOSD). However, APS has rarely been reported in cases of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Case presentation: A 36-year-old woman presented with APS and clinical features of diffuse central nervous system involvement during the early stage of the disease. Owing to the absence of serum aquaporin 4 antibodies, she was initially misdiagnosed as a case of seronegative NMOSD. However, the distinct neuroimaging characteristics [symmetrical small punctuate gadolinium enhancing lesions (pepper-like)], typical clinical/radiological relapse, and intense steroid-dependence in this case, prompted us to correct the diagnosis as probable CLIPPERS. To prevent relapse, long-term oral steroids and an immunosuppressive agent were administered. Conclusions: CLIPPERS may present as APS, and should be considered in the differential diagnosis of NMOSD.
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Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose uptake inhibitor. Due to the hydrolytic instability of the ester linkage we have prepared a series of isosteres of the ester moiety. Of all of the isosteres prepared, the amine linkage showed the most promise. Several additional analogues of the amine-linked compounds were also prepared to improve the overall activity.
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Antineoplásicos/síntese química , Ésteres/síntese química , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Glucose/metabolismo , Amidas/química , Aminas/química , Antineoplásicos/farmacologia , Metabolismo dos Carboidratos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/farmacologia , Glicólise/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Ácidos Ftálicos/química , Relação Estrutura-Atividade , Sulfonas/química , Sulfóxidos/químicaRESUMO
OBJECTIVE: To clarify the existence of monophasic neuromyelitis optica spectrum disorders (NMOSD) and to identify predictive factors of long-term relapse-free form. METHODS: We retrospectively analyzed 289 Chinese patients with NMOSD. Selected subjects were divided into three groups based on the time interval between disease onset and the first relapse, if any. Clinical and imaging data were acquired from each patient's medical record and evaluated as predictive factors for NMOSD. RESULTS: In total, none of the participating patients exhibited a monophasic form of NMOSD. Rather, 241 patients were selected for relapse tendency analysis; 143 (59.3%) patients relapsed within the first year, 66 (27.4%) during 1-5 years, and 32 (13.3%) beyond 5 years. Such onset symptoms as optic neuritis (ON) and non-longitudinally extensive transverse myelitis (LETM) were independent prognostic factors for a prolonged remission interval (P < 0.05). The relapse rate was bi-modal for ON patients in the first year (47.9%) and beyond 5 years (24.0%) after disease onset, respectively. However, most TM and area postrema syndrome (APS) patients experienced an attack within the first year (61.3% for TM and 76.9% for APS). A survival analysis showed that attacks with APS (P < 0.0001) and TM (P < 0.05) have a significantly higher risk of early relapse than with ON and that seropositive aquaporin-4 antibody may shorten the relapse interval for all onset symptoms (P < 0.0001). CONCLUSIONS: Our study indicated that the monophasic form of NMOSD may not exist when a sufficient follow-up period is considered. Onset phenotypes with ON, non-APS, or non-LETM attacks had a lower risk of early relapse.
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Progressão da Doença , Neuromielite Óptica/classificação , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/fisiopatologia , Adolescente , Adulto , Idoso , China , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Adulto JovemRESUMO
This study aimed to investigate the underlying pathological muscle damage in neuromyelitis optica spectrum disorder (NMOSD) patients without muscular symptoms. We prospectively enrolled 15 patients with aquaporin 4 (AQP4) antibody seropositive NMOSD and 16 patients with non-NMOSD diseases as a control group. Biceps biopsy samples from 18 patients were examined. Six NMOSD patients exhibited inflammatory lesions/edema in lower muscles on muscle MRI. On histopathological examination, NMOSD samples showed significantly decreased IgG-targeting AQP4 expression on sarcolemma compared with non-NMOSD samples in terms of the area of positive staining and integrated optical density. Muscle biopsy can support the differential diagnosis of NMOSD.
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Aquaporina 4/sangue , Neuromielite Óptica/sangue , Neuromielite Óptica/diagnóstico por imagem , Sarcolema/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/biossíntese , Aquaporina 4/genética , Diagnóstico Diferencial , Feminino , Expressão Gênica , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Neuromielite Óptica/genética , Estudos Prospectivos , Sarcolema/genéticaRESUMO
OBJECTIVE: To explore the clinical, electrophysiological and imaging features of a patient with Krabbe disease caused by GALC mutation. METHODS: A comprehensive analysis including clinical investigation and genetic testing was carried out. RESULTS: The patient presented with peripheral neuropathy with electrophysiological anomaly suggestive of asymmetric demyelinating neuropathy. Brain imaging revealed leukoencephalopathy. Genetic analysis has identified compound heterozygous mutations in exons 5 and 11 of the GALC gene, namely c.461C>A and c.1244G>A. CONCLUSION: Krabbe disease is a group of disorders featuring substantial phenotypic heterogeneity. Genetic and enzyme testing has become indispensable for accurate diagnosis for this disease.
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Galactosilceramidase/genética , Leucodistrofia de Células Globoides/genética , Doenças do Sistema Nervoso Periférico/etiologia , Análise Mutacional de DNA , Testes Genéticos , Humanos , Leucodistrofia de Células Globoides/complicações , MutaçãoRESUMO
Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.
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Linfoma não Hodgkin/enzimologia , Linfoma de Efusão Primária/enzimologia , Terapia de Alvo Molecular , Proteoma/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/virologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro. The potency and selectivity of 19 for MERTK over FLT3 were confirmed in cell-based assays using human cancer cell lines. Compound 19 had favorable pharmacokinetic properties in mice. Phosphorylation of MERTK was decreased by 75% in bone marrow leukemia cells from mice treated with 19 compared to vehicle-treated mice.
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Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , c-Mer Tirosina Quinase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Metilação , Camundongos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Distribuição Tecidual , c-Mer Tirosina Quinase/química , c-Mer Tirosina Quinase/metabolismoRESUMO
To facilitate the diagnosis of anti-NMDAR encephalitis presenting with brain lesions in unconventional locations (BLUL) on MRI, we retrospectively analyzed forty-five Chinese patients. Eighteen (40.0%) of their MRI initially exhibited one or more BLUL. These locations predominantly included cerebral gray matter (cortex, basal ganglia and thalamus), as well as white matter and brainstem. Due to these BLUL, thirteen (72.2%) patients were originally misdiagnosed with other diseases and developed poor clinical and imaging outcomes. Therefore, anti-NMDAR encephalitis has unpredictable MRI findings that easily obscure its diagnosis and cause serious sequelae. Anti-NMDAR antibody tests are highly recommended in patients with BLUL.