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1.
J Clin Immunol ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31903518

RESUMO

Cartilage-hair hypoplasia (CHH) is an autosomal recessive, short limb skeletal dysplasia with a variable immunologic phenotype. The spectrum of immune function ranges from clinically normal to severe combined immunodeficiency (SCID). Multiple studies have shown that abnormal immune parameters may not predict severe outcomes. Newborn screening (NBS) using T cell receptor excision circle (TREC) assay can now effectively identify infants with severe T cell deficiency who are at risk for SCID. NBS has allowed for cost-effective identification of patients with SCID and improved outcomes with hematopoietic stem cell transplant (HSCT). Ohio reports two abnormal TREC results: decreased and absent TREC. This study evaluated the laboratory and clinical differences in eight Amish patients with CHH with an abnormal TREC result on the NBS. There were four patients with absent TREC and four patients with decreased TREC. The absent TREC patients had lower CD3, CD4, naïve CD4, CD8 cells, and phytohemagglutinin (PHA)-induced lymphocyte proliferation. Three patients with absent TREC were diagnosed with SCID and two underwent successful HSCT. Patients with absent TREC experienced more CHH-related morbidity including anemia requiring transfusion, Hirschsprung's disease, and failure to thrive. No patients with decreased TREC required HSCT. Our study indicates that CHH patients with absent TREC tend to have more severe immunological and clinical phenotype than patients with decreased TREC. Confirmation of these trends in a larger group would guide providers and parents in a timely referral for HSCT, or cost-effective surveillance monitoring of children with a life-threatening illness.

2.
Pediatr Blood Cancer ; : e28126, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31850668

RESUMO

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease.

4.
Pediatr Blood Cancer ; 66(5): e27619, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30697957

RESUMO

An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like disorders, common variable immunodeficiency (CVID), CVID-like, and late-onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case-based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.

6.
Inorg Chem ; 57(22): 14178-14185, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30403341

RESUMO

In this paper, we report for the first time formation of novel manganese monocarbide (MnC) using laser-heated diamond anvil cell (LHDAC). The synthesis was carried out at high pressure-high temperature (HPHT) and subsequently quenched to ambient condition. The formation and reproducibility have been confirmed in the pressure range of 4.7 to 9.2 GPa. Employing contribution of different probes viz.X-ray diffraction (XRD), selected area electron diffraction (SAED), and ab initio electronic structure calculation, the structure of MnC was found to be ZnS type i.e. a cubic lattice with a = 4.4294(2) Å. The bulk modulus has been determined to be 170(5) GPa from in situ high-pressure X-ray diffraction (HPXRD). Hardness of ZnS type MnC is estimated from an empirical relation to be about 40 GPa, making it a potential superhard material.

7.
Blood ; 132(17): 1737-1749, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30154114

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Genótipo , Humanos , Contagem de Linfócitos , Estudos Retrospectivos
8.
Sci Rep ; 8(1): 8715, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880906

RESUMO

Pancreastatin (PST) is an endogenous peptide which regulates glucose and lipid metabolism in liver and adipose tissues. In type 2 diabetic patients, PST level is high and plays a crucial role in the negative regulation of insulin sensitivity. Novel therapeutic agents are needed to treat the diabetes and insulin resistance (IR) against the PST action. In this regard, we have investigated the PST inhibitor peptide-8 (PSTi8) action against diabetogenic PST. PSTi8 rescued PST-induced IR in HepG2 and 3T3L1 cells. PSTi8 increases the GLUT4 translocation to cell surface to promote glucose uptake in L6-GLUT4myc cells. PSTi8 treatment showed an increase in insulin sensitivity in db/db, high fat and fructose fed streptozotocin (STZ) induced IR mice. PSTi8 improved the glucose homeostasis which is comparable to metformin in diabetic mice, characterized by elevated glucose clearance, enhanced glycogenesis, enhanced glycolysis and reduced gluconeogenesis. PST and PSTi8 both were docked to the GRP78 inhibitor binding site in protein-protein docking, GRP78 expression and its ATPase activity studies. The mechanism of action of PSTi8 may be mediated by activating IRS1/2-phosphatidylinositol-3-kinase-AKT (FoxO1, Srebp-1c) signaling pathway. The discovery of PSTi8 provides a promising therapeutic agent for the treatment of metabolic diseases mainly diabetes.


Assuntos
Cromogranina A/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina , Peptídeos , Células 3T3-L1 , Animais , Cromogranina A/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Peptídeos/química , Peptídeos/farmacologia , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos
9.
J Phys Chem A ; 122(30): 6236-6242, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-29949362

RESUMO

Samples of energetic material TEX (C6H6N4O8) are studied using Raman spectroscopy and X-ray diffraction (XRD) up to 27 GPa pressure. There are clear changes in the Raman spectra and XRD patterns around 2 GPa related to a conformational change in the TEX molecule, and a phase transformation above 11 GPa. The molecular structures and vibrational frequencies of TEX are calculated by density functional theory based Gaussian 09W and CASTEP programs. The computed frequencies compare well with Raman spectroscopic results. Mode assignments are carried out using the vibrational energy distribution analysis program and are also visualized in the Materials Studio package. Raman spectra of the high pressure phases indicate that the sensitivity of these phases is more than that of the ambient phase.

10.
Blood Adv ; 2(7): 777-786, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29618462

RESUMO

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.


Assuntos
Artrite Juvenil/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Terapia de Salvação/métodos , Adolescente , Alemtuzumab/uso terapêutico , Artrite Juvenil/complicações , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressão/métodos , Lactente , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Transplante Homólogo , Resultado do Tratamento
11.
Biol Blood Marrow Transplant ; 24(7): 1527-1529, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29555312

RESUMO

Mixed chimerism and eventual graft loss occurs in a proportion of children with primary immune deficiencies receiving alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens before allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the usefulness of a CD34+ selected stem cell "boost" without conditioning to treat mixed chimerism in children and young adults who received predominantly an alemtuzumab, fludarabine, and melphalan RIC regimen for primary immune deficiencies and reported the outcomes. Patients with a primary immune deficiency disorder who were either enrolled on a prospective CD34+ boost study for treatment of mixed chimerism from 2011 to 2014 (n = 9) or treated with a CD34+ boost on a clinical basis from 2014 to 2016 (n = 3) were included in this analysis. Response to a CD34+ boost was defined as a rise in donor chimerism by ≥15% with donor chimerism of at least 20%, stabilization was defined as a rise in chimerism by <15% with donor chimerism ≥ 20%, and no response was defined as any decline in donor chimerism or need for a second HSCT after a CD34+ boost. Twelve patients received alemtuzumab, fludarabine, and melphalan. Median age was 4.5 years (range, .9 to 20.6), and median whole blood donor chimerism before the boost was 25% (range, 3% to 61%). Three patients (25%) met criteria for response, 1 patient (8%) was considered to have stabilization, and 8 patients (67%) had no response 12 months after the boost. None of the patients developed any complications from a CD34+ boost, including no acute graft-versus-host disease (GVHD). All patients are alive with a median follow-up of 32 months (range, 8 to 79). We conclude that a CD34+ selected stem cell boost can be considered for treatment of mixed chimerism after alemtuzumab, fludarabine, and melphalan RIC HSCT in children and young adults with primary immune deficiencies. Approximately one-third of patients can be expected to benefit from a CD34+ selected stem cell boost and may avoid the need for a second HSCT. Lack of any GVHD or toxicity makes a stem cell boost an attractive option compared with donor lymphocyte infusions for treatment of mixed chimerism.


Assuntos
Antígenos CD34/uso terapêutico , Quimerismo/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Masculino , Adulto Jovem
12.
J Antimicrob Chemother ; 73(6): 1651-1658, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29481593

RESUMO

Background: Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day. Objectives: We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration. Methods: Nine children, ≤10 years of age undergoing HSCT, were enrolled and received a single intravenous dose of 5 mg/kg micafungin. Blood samples were obtained for PK analysis. Micafungin plasma concentration of >0.2 mg/L was chosen for target attainment (i.e. considered adequate prophylactic concentration). In addition, a population PK model was developed based on current and our previous PK study data. We also evaluated PK model-based simulation of PK profiles and target attainment using Monte Carlo simulation, for several dosing scenarios. Results: Mean clearance was 15.3 mL/h/kg (range 11.0-21.4 mL/h/kg) and the mean elimination half-life was 11.6 h (range 7.8-16.6 h). The mean concentration at 96 h was 0.11 mg/L (range 0.03-0.26 mg/L). Eleven percent (n = 1) of patients achieved target attainment at the end of 96 h. Simulation data showed that 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies achieved at least 99% and 81% target attainment, respectively, whereas a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Conclusions: Micafungin at 5 mg/kg dosing did not achieve target attainment at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. Simulation data suggest that a dosing strategy of micafungin at 5 mg/kg every 72 h is more likely to achieve target attainment in children with a higher body weight in comparison with children with a lower body weight. A cautious approach is advisable when using a high, but less frequent, dosing strategy in very young children.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas , Micafungina/administração & dosagem , Micafungina/farmacocinética , Micoses/prevenção & controle , Administração Intravenosa , Candida/efeitos dos fármacos , Criança , Pré-Escolar , Esquema de Medicação , Drogas em Investigação , Feminino , Humanos , Lactente , Masculino , Método de Monte Carlo , Estudos Prospectivos
13.
Clin Pharmacokinet ; 57(5): 625-636, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28918602

RESUMO

BACKGROUND: High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. METHODS: A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. RESULTS: A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2 = 0.98; p < 0.01) with a mean bias of -2.2% and precision of 9.4%. A similar relationship was observed in children (R 2 = 0.99; p < 0.01). CONCLUSIONS: The developed pharmacokinetic model-based sparse sampling strategy promises to achieve the target area under the curve as part of precision dosing.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Melfalan/administração & dosagem , Modelos Biológicos , Mieloma Múltiplo/terapia , Agonistas Mieloablativos/administração & dosagem , Idoso , Área Sob a Curva , Teorema de Bayes , Coleta de Amostras Sanguíneas , Feminino , Humanos , Masculino , Melfalan/farmacocinética , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Agonistas Mieloablativos/farmacocinética
14.
Parasitology ; 145(4): 508-526, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28691653

RESUMO

Despite immense efforts, vaccine against visceral leishmaniasis has yet not been developed. Earlier our proteomic study revealed a novel protein, cofactor-independent phoshoglycerate mutase (LdiPGAM), an important enzyme in glucose metabolism, in T helper cells type 1 (Th1) stimulatory region of soluble Leishmania donovani antigen. In this study, LdiPGAM was biochemically and molecularly characterized and evaluated for its immunogenicity and prophylactic efficacy against L. donovani. Immunogenicity of recombinant LdiPGAM (rLdiPGAM) was initially assessed in naïve hamsters immunized with it by analysing mRNA expression of inducible nitric oxide (NO) synthase (iNOS) and other Th1/T helper cells type 2 cytokines, which revealed an upregulation of Th1 cytokines along with iNOS. Immunogenicity of rLdiPGAM was further evaluated in lymphocytes of treated Leishmania-infected hamsters and peripheral blood mononuclear cells of Leishmania patients in clinical remission by various parameters, viz. lymphoproliferation assay and NO production (hamsters and patients) and levels of various cytokines (patients). rLdiPGAM induced remarkable Lymphoproliferative response and NO production in treated Leishmania-infected hamsters as well as in patients and increase in interferon gamma (IFN-γ), interleukin-12 (IL-12p40) responses in Leishmania patients in clinical remission. Vaccination with rLdiPGAM exerted considerable prophylactic efficacy (73%) supported by increase in mRNA expression of iNOS, IFN-γ and IL-12p40 with decrease in transforming growth factor beta and interleukin-10. Above results indicate the importance of rLdiPGAM protein as a potential vaccine candidate against visceral leishmaniasis.


Assuntos
Antígenos de Protozoários/imunologia , Leishmania donovani/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose Visceral/prevenção & controle , Fosfoglicerato Mutase/genética , Fosfoglicerato Mutase/imunologia , Adolescente , Adulto , Animais , Antígenos de Protozoários/administração & dosagem , Antígenos de Protozoários/genética , Criança , Pré-Escolar , Cricetinae , Feminino , Humanos , Imunogenicidade da Vacina , Interferon gama/genética , Leishmania donovani/enzimologia , Vacinas contra Leishmaniose/administração & dosagem , Vacinas contra Leishmaniose/genética , Leishmaniose Visceral/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Óxido Nítrico , Fosfoglicerato Mutase/administração & dosagem , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Células Th1 , Células Th2 , Vacinação , Adulto Jovem
15.
Blood ; 130(25): 2718-2727, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29021228

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/µL, CD8 < 50 cells/µL, CD45RA < 10%, or a restricted Vß T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Reconstituição Imune , Imunodeficiência Combinada Severa/terapia , Pré-Escolar , Feminino , Genótipo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Reconstituição Imune/genética , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Estudos Prospectivos , Fatores de Risco , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Doadores de Tecidos
16.
Mol Biosyst ; 13(8): 1630-1639, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28685785

RESUMO

Human Flap endonuclease1 (FEN1) is an enzyme that is indispensable for DNA replication and repair processes and inhibition of its Flap cleavage activity results in increased cellular sensitivity to DNA damaging agents (cisplatin, temozolomide, MMS, etc.), with the potential to improve cancer prognosis. Reports of the high expression levels of FEN1 in several cancer cells support the idea that FEN1 inhibitors may target cancer cells with minimum side effects to normal cells. In this study, we used large publicly available, high-throughput screening data of small molecule compounds targeted against FEN1. Two machine learning algorithms, Support Vector Machine (SVM) and Random Forest (RF), were utilized to generate four classification models from huge PubChem bioassay data containing probable FEN1 inhibitors and non-inhibitors. We also investigated the influence of randomly selected Zinc-database compounds as negative data on the outcome of classification modelling. The results show that the SVM model with inactive compounds was superior to RF with Matthews's correlation coefficient (MCC) of 0.67 for the test set. A Maybridge database containing approximately 53 000 compounds was screened and top ranking 5 compounds were selected for enzyme and cell-based in vitro screening. The compound JFD00950 was identified as a novel FEN1 inhibitor with in vitro inhibition of flap cleavage activity as well as cytotoxic activity against a colon cancer cell line, DLD-1.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Endonucleases Flap/antagonistas & inibidores , Aprendizado de Máquina , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/enzimologia , Colo/patologia , Bases de Dados de Compostos Químicos , Descoberta de Drogas , Inibidores Enzimáticos/química , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Endonucleases Flap/genética , Endonucleases Flap/metabolismo , Expressão Gênica , Células HEK293 , Humanos , Concentração Inibidora 50 , Naftoquinonas/química , Naftoquinonas/farmacologia , Especificidade de Órgãos
17.
R Soc Open Sci ; 4(6): 170273, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28680680

RESUMO

The current communication signifies the effect of oxygen vacancies (OVs) both qualitatively and quantitatively in multiferroic BiFe0.83Ni0.17O3 by an in-depth atomic-level investigation of its electronic structure and magnetization properties, and these materials have a variety of applications in spintronics, optoelectronics, sensors and solar energy devices. Depending on the precise location of OVs, all the three types of spintronic material namely half-metallic, spin gapless semiconductor and bipolar magnetic conductor have been established in a single material for the first time and both super-exchange and double-exchange interactions are possible in accordance with the precise location of OVs. We have also calculated the vacancy formation energies to predict their thermodynamic stabilities. These results can highlight the impact and importance of OVs that can alter the multiferroic properties of materials.

18.
Chem Biol Drug Des ; 90(6): 1173-1183, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28585374

RESUMO

Dipeptidyl peptidase 4 (DPP4) is a well-known target for the antidiabetic drugs. However, currently available DPP4 inhibitor screening assays are costly and labor-intensive. It is important to create a robust in silico method to predict the activity of DPP4 inhibitor for the new lead finding. Here, we introduce an R-based Web application SVMDLF (SVM-based DPP4 Lead Finder) to predict the inhibitor of DPP4, based on support vector machine (SVM) model, predictions of which are confirmed by in vitro biological evaluation. The best model generated by MACCS structure fingerprint gave the Matthews correlation coefficient of 0.87 for the test set and 0.883 for the external test set. We screened Maybridge database consisting approximately 53,000 compounds. For further bioactivity assay, six compounds were shortlisted, and of six hits, three compounds showed significant DPP4 inhibitory activities with IC50 values ranging from 8.01 to 10.73 µm. This application is an OpenCPU server app which is a novel single-page R-based Web application for the DPP4 inhibitor prediction. The SVMDLF is freely available and open to all users at http://svmdlf.net/ocpu/library/dlfsvm/www/ and http://www.cdri.res.in/svmdlf/.


Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Interface Usuário-Computador , Sítios de Ligação , Bases de Dados de Compostos Químicos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/metabolismo , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Internet , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Máquina de Vetores de Suporte , Termodinâmica
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 184: 211-219, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28499175

RESUMO

Diisopropylammonium bromide (DIPAB) can be crystallized either in an orthorhombic (P212121) or in a monoclinic (P21) structure at room temperature depending on synthesis conditions. The non-polar orthorhombic structure exhibits a subtle, irreversible transformation into the ferroelectric monoclinic-II (m-II) phase above ~421K. At a slightly higher temperature of 426K this m-II (P21) phase reversibly transforms into a disordered, paraelectric monoclinic-I (P21/m) structure. We synthesized DIPAB in the orthorhombic structure, heated it to obtain the m-II phase and carried out a systematic study of their Raman and IR spectra. We obtained the phonon irreducible representations from factor group analysis of the orthorhombic and m-II structures based on the reported structural information. DIPAB is an organic molecular crystal, and the vibrational spectra in the intramolecular region (200-3500cm-1) of the two different phases are identical to each other, indicating weak inter-molecular interactions in both crystalline structures. In the low wavenumber region (10-150cm-1) the Raman spectra of the two phases are different due to their sensitivity to molecular environment. We also carried out first principles calculations using Gaussian 09 and CASTEP codes to analyze the vibrational frequencies. Mode assignments were facilitated by isolated molecule calculations that are also in good agreement with intramolecular vibrations, whereas CASTEP (solid state) results could explain the external modes.

20.
Phys Chem Chem Phys ; 19(20): 13316-13323, 2017 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-28492651

RESUMO

The influence of carbon concentration on the electronic and magnetic properties of C-implanted ZnO thin films has been studied using synchrotron radiation based X-ray absorption spectroscopic techniques and vibrating sample magnetometer measurements. 20 keV carbon ions were implanted in ZnO films with different fluences (2 × 1016, 4 × 1016 and 6 × 1016 ions per cm2). The pristine ZnO film shows diamagnetic behaviour while the C-implanted films exhibit room temperature ferromagnetism. Our first-principles calculations based on density functional theory show an appreciable magnetic moment only when the implanted C atom sits either in the O-site (2 µB) or in the interstitial position (1.88 µB), whereas the C atom in the Zn substitutional position does not possess any magnetic moment. X-ray absorption near edge structure analysis at the O K-edge reveals that the charge transfer from O-2p to the C-defect site causes the ferromagnetism in the C-implanted ZnO film at low fluence. However at high fluence, the implanted C replaces the lattice and produces more Zn vacancies, as evidenced by extended X-ray absorption fine structure studies at the Zn K-edge, which favors the ferromagnetism. The persistence of the implanted carbon and ferromagnetism of the C-implanted ZnO film has also been studied by isothermal annealing at 500 °C and discussed in detail.

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