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1.
Braz. j. oral sci ; 21: e225042, jan.-dez. 2022. ilus
Artigo em Inglês | LILACS, BBO - Odontologia | ID: biblio-1354728

RESUMO

Aim: Although bulk fill composites have been widely used as restorative material, there is no consensus regarding the best clinical protocol in terms of composite technique and adhesive system. Therefore, this clinical trial evaluated the clinical performance of bulk fill composites for class I restorations under different protocols. Methods: A randomized clinical trial including 155 class I restorations was conducted using different adhesive systems: conventional technique (phosphoric acid + conventional three-step adhesive system) (Group 1, 2 and 3); or self-etching adhesive system (Groups 4, 5 and 6). Control groups 1 and 4 were restored with conventional composite; groups 2 and 5 with low viscosity bulk fill and conventional composite as occlusal coverage; groups 3 and 6 with high viscosity bulk fill. The FDI criteria was used for clinical evaluation at baseline and after 6 months. Results: All groups showed good clinical performance. At baseline, the adhesive system did not affect postoperative hypersensitivity. After 6 months, group 5 showed a significant reduction in color and translucency; group 6 a reduction in terms of anatomical form and for postoperative sensitivity and an improvement in patient satisfaction (p<0.05). Considering the same restorative technique, the use of the self-etching adhesive system showed a significant decrease in color and translucency (p<0.05). Conclusion: All groups showed favorable clinical performance, and promising results were found for the conventional adhesive system and high viscosity bulk fill protocol


Assuntos
Ácidos Fosfóricos , Adesivos , Resinas Compostas , Restauração Dentária Permanente , Estética Dentária , Estudos Clínicos como Assunto
2.
Oncoimmunology ; 11(1): 2080328, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35756842

RESUMO

Upregulation of inhibitory receptors, such as lymphocyte activation gene-3 (LAG-3), may limit the antitumor activity of therapeutic antibodies targeting the programmed cell death protein-1 (PD-1) pathway. We describe the binding properties of ezabenlimab, an anti-human PD-1 antibody, and BI 754111, an anti-human LAG-3 antibody, and assess their activity alone and in combination. Ezabenlimab bound with high affinity to human PD-1 (KD = 6 nM) and blocked the interaction of PD-1 with PD-L1 and PD-L2. Ezabenlimab dose-dependently increased interferon-γ secretion in human T cells expressing PD-1 in co-culture with PD-L1-expressing dendritic cells. Administration of ezabenlimab to human PD-1 knock-in mice dose-dependently inhibited growth of MC38 tumors. To reduce immunogenicity, ezabenlimab was reformatted from a human IgG4 to a chimeric variant with a mouse IgG1 backbone (BI 905725) for further in vivo studies. Combining BI 905725 with anti-mouse LAG-3 antibodies improved antitumor activity versus BI 905725 monotherapy in the MC38 tumor model. We generated BI 754111, which bound with high affinity to human LAG-3 and prevented LAG-3 interaction with its ligand, major histocompatibility complex class II. In an in vitro model of antigen-experienced memory T cells expressing PD-1 and LAG-3, interferon-γ secretion increased by an average 1.8-fold versus isotype control (p = 0.027) with BI 754111 monotherapy, 6.9-fold (p < 0.0001) with ezabenlimab monotherapy and 13.2-fold (p < 0.0001) with BI 754111 plus ezabenlimab. Overall, ezabenlimab and BI 754111 bound to their respective targets with high affinity and prevented ligand binding. Combining ezabenlimab with BI 754111 enhanced in vitro activity versus monotherapy, supporting clinical investigation of this combination (NCT03156114; NCT03433898).


Assuntos
Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Animais , Anticorpos Bloqueadores , Anticorpos Monoclonais/farmacologia , Estudos Clínicos como Assunto , Inibidores de Checkpoint Imunológico , Interferon gama , Ligantes , Camundongos
3.
Sci Rep ; 12(1): 10517, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35732870

RESUMO

Sensitive serological testing is essential to estimate the proportion of the population exposed or infected with SARS-CoV-2, to guide booster vaccination and to select patients for treatment with anti-SARS-CoV-2 antibodies. The performance of serological tests is usually evaluated at 14-21 days post infection. This approach fails to take account of the important effect of time on test performance after infection or exposure has occurred. We performed parallel serological testing using 4 widely used assays (a multiplexed SARS-CoV-2 Nucleoprotein (N), Spike (S) and Receptor Binding Domain assay from Meso Scale Discovery (MSD), the Roche Elecsys-Nucleoprotein (Roche-N) and Spike (Roche-S) assays and the Abbott Nucleoprotein assay (Abbott-N) on serial positive monthly samples collected as part of the Co-STARs study ( www.clinicaltrials.gov , NCT04380896) up to 200 days following infection. Our findings demonstrate the considerable effect of time since symptom onset on the diagnostic sensitivity of different assays. Using a time-to-event analysis, we demonstrated that 50% of the Abbott nucleoprotein assays will give a negative result after 175 days (median survival time 95% CI 168-185 days), compared to the better performance over time of the Roche Elecsys nucleoprotein assay (93% survival probability at 200 days, 95% CI 88-97%). Assays targeting the spike protein showed a lower decline over the follow-up period, both for the MSD spike assay (97% survival probability at 200 days, 95% CI 95-99%) and the Roche Elecsys spike assay (95% survival probability at 200 days, 95% CI 93-97%). The best performing quantitative Roche Elecsys Spike assay showed no evidence of waning Spike antibody titers over the 200-day time course of the study. We have shown that compared to other assays evaluated, the Abbott-N assay fails to detect SARS-CoV-2 antibodies as time passes since infection. In contrast the Roche Elecsys Spike Assay and the MSD assay maintained a high sensitivity for the 200-day duration of the study. These limitations of the Abbott assay should be considered when quantifying the immune correlates of protection or the need for SARS-CoV-2 antibody therapy. The high levels of maintained detectable neutralizing spike antibody titers identified by the quantitative Roche Elecsys assay is encouraging and provides further evidence in support of long-lasting SARS-CoV-2 protection following natural infection.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , COVID-19/diagnóstico , Estudos Clínicos como Assunto , Humanos , Nucleoproteínas , Sensibilidade e Especificidade
4.
Blood Cancer J ; 12(5): 80, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595730

RESUMO

Pirtobrutinib (LOXO-305), a reversible inhibitor of Bruton's tyrosine kinase (BTK), was designed as an alternative strategy to treat ibrutinib-resistant disease that develops due to C481 kinase domain mutations. The clinical activity of pirtobrutinib has been demonstrated in CLL, but the mechanism of action has not been investigated. We evaluated pirtobrutinib in 4 model systems: first, MEC-1, a CLL cell line overexpressing BTKWT, BTKC481S, or BTKC481R; second, murine models driven by MEC-1 overexpressing BTKWT or BTKC481S; third, in vitro incubations of primary CLL cells; and finally, CLL patients during pirtobrutinib therapy (NCT03740529, ClinicalTrials.gov). Pirtobrutinib inhibited BTK activation as well as downstream signaling in MEC-1 isogenic cells overexpressing BTKWT, BTKC481S, or BTKC481R. In mice, overall survival was short due to aggressive disease. Pirtobrutinib treatment for 2 weeks led to reduction of spleen and liver weight in BTKWT and BTKC481S cells, respectively. In vitro incubations of CLL cells harboring wild-type or mutant BTK had inhibition of the BCR pathway with either ibrutinib or pirtobrutinib treatment. Pirtobrutinib therapy resulted in inhibition of BTK phosphorylation and downstream signaling initially in all cases irrespective of their BTK profile, but these effects started to revert in cases with other BCR pathway mutations such as PLCG2 or PLEKHG5. Levels of CCL3 and CCL4 in plasma were marginally higher in patients with mutated BTK; however, there was a bimodal distribution. Both chemokines were decreased at early time points and mimicked BCR pathway protein changes. Collectively, these results demonstrate that pirtobrutinib is an effective BTK inhibitor for CLL harboring wild-type or mutant BTK as observed by changes in CCL3 and CCL4 biomarkers and suggest that alterations in BCR pathway signaling are the mechanism for its clinical effects. Long-term evaluation is needed for BTK gatekeeper residue variation along with pathologic kinase substitution or mutations in other proteins in the BCR pathway.


Assuntos
Leucemia Linfocítica Crônica de Células B , Tirosina Quinase da Agamaglobulinemia , Animais , Estudos Clínicos como Assunto , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais
5.
Yonsei Med J ; 63(5): 413-421, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35512743

RESUMO

PURPOSE: Platelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel. MATERIALS AND METHODS: Searching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them. RESULTS: Nine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (*2 or *3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively. CONCLUSION: The PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734028.


Assuntos
Doença da Artéria Coronariana , Stents Farmacológicos , Estudos Clínicos como Assunto , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/cirurgia , Citocromo P-450 CYP2C19/genética , Genótipo , Humanos , Testes de Função Plaquetária
6.
Antimicrob Agents Chemother ; 66(6): e0021522, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35604212

RESUMO

Dolutegravir-based regimens are recommended as first-line therapy for HIV in low- and middle-income countries where tuberculosis is the most common opportunistic infection. Concurrent HIV/tuberculosis treatment is challenging because of drug-drug interactions. Our analysis aimed to characterize dolutegravir's population pharmacokinetics when coadministered with rifampicin and assess alternative dolutegravir dosing regimens. We developed a population pharmacokinetic model of dolutegravir in NONMEM with data from two healthy-volunteer studies (RADIO and ClinicalTrials.gov identifier NCT01231542) and validated it with data from the INSPIRING study, which consisted of participants living with HIV. The model was developed with 817 dolutegravir plasma concentrations from 41 participants. A 2-compartment model with first-order elimination and lagged absorption best described dolutegravir's pharmacokinetics. For a typical 70-kg individual, we estimated a clearance, absorption rate constant, central volume, and peripheral volume of 1.03 L/h, 1.61 h-1, 12.7 L, and 3.85 L, respectively. Rifampicin coadministration increased dolutegravir clearance by 144% (95% confidence interval [CI], 126 to 161%). Simulations showed that when 50 or 100 mg once-daily dolutegravir is coadministered with rifampicin in 70-kg individuals, 71.7% and 91.5% attain trough concentrations above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (PA-IC90), respectively. The model developed from healthy-volunteer data describes patient data reasonably well but underpredicts trough concentrations. Although 50 mg of dolutegravir given twice daily achieves target concentrations in more than 99% of individuals cotreated with rifampicin, 100 mg of dolutegravir, once daily, in the same population is predicted to achieve satisfactory pharmacokinetic target attainment. The efficacy of this regimen should be investigated since it presents an opportunity for treatment simplification.


Assuntos
Infecções por HIV , Tuberculose , Estudos Clínicos como Assunto , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Oxazinas/farmacocinética , Piperazinas , Piridonas/uso terapêutico , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico
7.
BMJ Open ; 12(5): e059234, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35613803

RESUMO

INTRODUCTION: Application of non-invasive positive airway pressure may provoke laryngeal responses that obstruct the airways, especially in patients with disturbed laryngeal control. To control and adjust for this, transnasal fibre-optic laryngoscopy (TFL) is used to visualise laryngeal movements during therapeutic interventions. Being an invasive procedure, this may be unpleasant for patients. The aim of this study is to evaluate if ultrasound (US) imaging of the larynx may be used as an alternative less invasive diagnostic tool for evaluating the upper airway responses to non-invasive ventilation (NIV) and mechanical insufflation-exsufflation (MI-E). METHODS AND ANALYSIS: This protocol presents an experimental cross-sectional study of a novel method to study laryngeal responses in adult healthy volunteers (n=30). The participants will be assessed with simultaneous TFL and laryngeal US imaging (anterior and lateral approaches) during NIV and MI-E therapy. Additionally, airflow and pressure signals will be registered during the procedures. The primary outcome is whether laryngeal US is a feasible method to study laryngeal responses and, if so, to compare the laryngeal responses visualised with TFL and US. The participants' perception of the examinations will be recorded. Secondary outcomes include airflow curve shapes and calculated ventilation volumes during the interventions. ETHICS AND DISSEMINATION: The study has been approved by The Regional Committee for Medical Research Ethics in Norway, and registered in ClinicalTrials.gov. Results will be disseminated through peer-reviewed journals, presentation of scientific abstracts at international medical conventions and oral presentations in relevant medical conventions. TRIAL REGISTRATION NUMBER: NCT04586855.


Assuntos
Laringe , Ventilação não Invasiva , Adulto , Estudos Clínicos como Assunto , Tosse , Estudos Transversais , Humanos , Laringoscopia/métodos , Laringe/diagnóstico por imagem , Ultrassonografia
8.
Cancer Chemother Pharmacol ; 89(5): 671-682, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35397664

RESUMO

PURPOSE: To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor. METHODS: The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12-40 mg), intensive and sparse oral data (12-360 mg single-dose, 40-500 mg once daily, and 240-840 mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600 mg). RESULTS: Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600 mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex. CONCLUSION: The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect. CLINICALTRIALS: GOV: Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534).


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Estudos Clínicos como Assunto , Citocromo P-450 CYP1A2 , Feminino , Humanos , Indóis , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética
9.
Microbiol Spectr ; 10(2): e0216721, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35412356

RESUMO

The SARS-CoV-2 coronavirus, which causes COVID-19, uses a viral surface spike protein for host cell entry and the human cell-surface transmembrane serine protease, TMPRSS2, to process the spike protein. Camostat mesylate, an orally available and clinically used serine protease inhibitor, inhibits TMPRSS2, supporting clinical trials to investigate its use in COVID-19. A one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for camostat and the active metabolite FOY-251 was developed, incorporating TMPRSS2 reversible covalent inhibition by FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. The model predicts that 95% inhibition of TMPRSS2 is required for 50% inhibition of viral entry efficiency. For camostat 200 mg dosed four times daily, 90% inhibition of TMPRSS2 is predicted to occur but with only about 40% viral entry inhibition. For 3-fold higher camostat dosing, marginal improvement of viral entry rate inhibition, up to 54%, is predicted. Because respiratory tract viral load may be associated with negative outcome, even modestly reducing viral entry and respiratory tract viral load may reduce disease progression. This modeling also supports medicinal chemistry approaches to enhancing PK/PD and potency of the camostat molecule. IMPORTANCE Strategies to repurpose already-approved drugs for the treatment of COVID-19 has been attractive since the beginning of the pandemic. Camostat mesylate, a serine protease inhibitor approved in Japan for the treatment of acute exacerbations of chronic pancreatitis, inhibits TMPRSS1, a host cell surface serine protease essential for SARS-CoV-2 viral entry. In vitro experiments provided data suggesting that camostat might be effective in the treatment of COVID-19. Multiple clinical trials were planned to test the hypothesis that camostat would be beneficial for treating COVID-19 (for example, clinicaltrials.gov, NCT04353284). The present work used a one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) mathematical model for camostat and the active metabolite FOY-251, incorporating TMPRSS2 reversible covalent inhibition by FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. This work is valuable to guide further development of camostat mesylate and possible medicinal chemistry derivatives for the treatment of COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/tratamento farmacológico , Estudos Clínicos como Assunto , Ésteres , Guanidinas , Humanos , Serina Proteases , Inibidores de Serino Proteinase/farmacologia , Inibidores de Serino Proteinase/uso terapêutico , Glicoproteína da Espícula de Coronavírus
11.
Antimicrob Agents Chemother ; 66(4): e0225121, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35315687

RESUMO

Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes. Drugs that induce or inhibit CYP3A, P-glycoprotein, and BCRP may affect temsavir concentrations. Understanding potential drug-drug interactions (DDIs) following fostemsavir coadministration with antiretrovirals approved for HIV-1-infected treatment-experienced patients, including darunavir plus cobicistat (DRV/c) or DRV plus low-dose ritonavir (DRV/r) and etravirine, is clinically relevant. Open-label, single-sequence, multiple-dose, multicohort DDI studies were conducted in healthy participants (n = 46; n = 32). The primary objective was to assess the effects of DRV/r, etravirine, DRV/r plus etravirine, cobicistat, and DRV/c on temsavir systemic exposures; safety was a secondary objective. Compared with fostemsavir alone, coadministration with DRV/r increased the temsavir maximum observed plasma concentration (Cmax), area under the concentration-time curve in one dosing interval (AUCtau), and plasma trough concentration (Ctau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir Cmax, AUCtau, and Ctau by ∼50% each. DRV/r plus etravirine increased the temsavir Cmax, AUCtau, and Ctau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir Cmax, AUCtau, and Ctau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir Cmax, AUCtau, and Ctau by 79%, 97%, and 124%, respectively. Fostemsavir with all combinations was generally well tolerated. No dose adjustment is required for fostemsavir when coadministered with strong CYP3A inhibitors, P-glycoprotein inhibitors, and modest inducers, including regimens with DRV/r, DRV/c, cobicistat, etravirine, and DRV/r plus etravirine based on the therapeutic margin for temsavir (ClinicalTrials.gov registration no. NCT02063360 and NCT02277600).


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Pró-Fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Fármacos Anti-HIV/uso terapêutico , Estudos Clínicos como Assunto , Cobicistat/farmacocinética , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Voluntários Saudáveis , Humanos , Proteínas de Neoplasias , Nitrilas , Organofosfatos , Piperazinas , Pró-Fármacos/farmacologia , Pirimidinas , Ritonavir
12.
Front Endocrinol (Lausanne) ; 13: 812568, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250870

RESUMO

BACKGROUND: Puberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex® Growth Forum Database (Eu-IGFD) Registry (NCT00903110). METHODS: The Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. RESULTS: This analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3-13.0) cm/year in boys and 6.8 (1.3-9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. CONCLUSION: Children and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.


Assuntos
Fator de Crescimento Insulin-Like I , Adolescente , Criança , Estudos Clínicos como Assunto , Feminino , Transtornos do Crescimento , Perda Auditiva Neurossensorial , Humanos , Fator de Crescimento Insulin-Like I/deficiência , Masculino , Proteínas Recombinantes , Sistema de Registros
13.
Clin. transl. oncol. (Print) ; 24(3): 597-604, marzo 2022.
Artigo em Inglês | IBECS | ID: ibc-203554

RESUMO

BackgroundPrognosis of breast cancer (BC) patients differs considerably and identifying reliable prognostic biomarker(s) is imperative. With evidence that the microbiome plays a critical role in the response to cancer therapies, we aimed to identify a cancer microbiome signature for predicting the prognosis of BC patients.MethodsThe TCGA BC microbiome data (TCGA-BRCA-microbiome) was downloaded from cBioPortal. Univariate and multivariate Cox regression analyses were used to examine association of microbial abundance with overall survival (OS) and to identify a microbial signature for creating a prognostic scoring model. The performance of the scoring model was assessed by the area under the ROC curve (AUC). Nomograms using the microbial signature, clinical factors, and molecular subtypes were established to predict OS and progression-free survival (PFS).ResultsAmong 1406 genera, the abundances of 94 genera were significantly associated with BC patient OS in TCGA-BRCA-microbiome dataset. From that set we identified a 15-microbe prognostic signature and developed a 15-microbial abundance prognostic scoring (MAPS) model. Patients in low-risk group significantly prolong OS and PFS as compared to those in high-risk group. The time-dependent ROC curves with MAPS showed good predictive efficacy both in OS and PFS. Moreover, MAPS is an independent prognostic factor for OS and PFS over clinical factors and PAM50-based molecular subtypes and superior to the previously published 12-gene signature. The integration of MAPS into nomograms significantly improved prognosis prediction.ConclusionMAPS was successfully established to have independent prognostic value, and our study provides a new avenue for developing prognostic biomarkers by microbiome profiling.


Assuntos
Humanos , Feminino , Neoplasias Unilaterais da Mama/microbiologia , Neoplasias Unilaterais da Mama/mortalidade , Microbiota , Biomarcadores , Nomogramas , Estudos Clínicos como Assunto , Taxa de Sobrevida
14.
Fisioterapia (Madr., Ed. impr.) ; 44(2): 119-122, mar.-abr. 2022. tab
Artigo em Espanhol | IBECS | ID: ibc-203752

RESUMO

Objetivo: Determinar la efectividad del tratamiento con punción seca para eliminar el síndrome de dolor miofascial en una paciente con gonartrosis y puntos gatillo no miofasciales activos en el compartimento medial de la rodilla. Material y métodos: Mujer de 69 años con osteoartritis generalizada e importante deformidad en genu varum de ambas rodillas. Se valora mediante palpación la presencia de puntos dolorosos en el compartimento medial de la rodilla más limitada, y son tratados con punción seca mediante la técnica de inserciones múltiples rápidas de Hong. Resultados: Se realiza un seguimiento de 4 semanas de tratamiento mientras se registran los datos relacionados con la percepción del dolor al inicio de la técnica, durante la misma y tras ella, y se objetiva la evolución del umbral de dolor a la presión en los puntos más dolorosos del compartimento medial de cada visita. Al finalizar el estudio, se demuestra la eficacia analgésica tras el análisis del registro. Conclusiones: La técnica de inserciones múltiples rápidas de Hong sobre los puntos gatillo no miofasciales de una rodilla con degeneración medial provocada por osteoartritis es eficaz en el tratamiento del dolor y, por tanto, en el aumento de la calidad de vida de la paciente, debiendo considerarse como una opción de tratamiento válida a la hora de abordar su cuadro clínico.(AU)


Objective: To determine the effectiveness of treatment with dry needling to eliminate myofascial pain syndrome in a patient with gonarthrosis and active non-myofascial trigger points in the medial compartment of her knee. Material and methods: A 69-year-old woman with generalized osteoarthritis and significant genu varum deformity of both knees. In the medial knee compartment, the tender points of the more limited knee were palpated and treated with dry needling using Hong's rapid multiple insertion technique. Results: A 4-week follow-up of treatment was carried out, and the data relating to the perception of pain were recorded at the beginning of the technique, during and after it, along with the evolution of the pressure pain threshold in the most painful points in the medial compartment during each visit. At the end of the study, analgesic efficacy was proven, after analysis of the records. Conclusions: Hong's rapid multiple needle insertion technique in the non-myofascial trigger points of the knee with medial degeneration caused by osteoarthritis was effective in the treatment of pain and, therefore, improved the quality of life of the patient, so it should be considered a valid treatment option in her rheumatological disease.(AU)


Assuntos
Humanos , Feminino , Idoso , Punções , Osteoartrite do Joelho , Síndromes da Dor Miofascial , Estudos Clínicos como Assunto , Mulheres
15.
J Neural Eng ; 19(2)2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35234665

RESUMO

Objective.The article aims at addressing 2 challenges to step motor brain-computer interface (BCI) out of laboratories: asynchronous control of complex bimanual effectors with large numbers of degrees of freedom, using chronic and safe recorders, and the decoding performance stability over time without frequent decoder recalibration.Approach.Closed-loop adaptive/incremental decoder training is one strategy to create a model stable over time. Adaptive decoders update their parameters with new incoming data, optimizing the model parameters in real time. It allows cross-session training with multiple recording conditions during closed loop BCI experiments. In the article, an adaptive tensor-based recursive exponentially weighted Markov-switching multi-linear model (REW-MSLM) decoder is proposed. REW-MSLM uses a mixture of expert (ME) architecture, mixing or switching independent decoders (experts) according to the probability estimated by a 'gating' model. A Hidden Markov model approach is employed as gating model to improve the decoding robustness and to provide strong idle state support. The ME architecture fits the multi-limb paradigm associating an expert to a particular limb or action.Main results.Asynchronous control of an exoskeleton by a tetraplegic patient using a chronically implanted epidural electrocorticography (EpiCoG) recorder is reported. The stable over a period of six months (without decoder recalibration) eight-dimensional alternative bimanual control of the exoskeleton and its virtual avatar is demonstrated.Significance.Based on the long-term (>36 months) chronic bilateral EpiCoG recordings in a tetraplegic (ClinicalTrials.gov, NCT02550522), we addressed the poorly explored field of asynchronous bimanual BCI. The new decoder was designed to meet to several challenges: the high-dimensional control of a complex effector in experiments closer to real-world behavior (point-to-point pursuit versus conventional center-out tasks), with the ability of the BCI system to act as a stand-alone device switching between idle and control states, and a stable performance over a long period of time without decoder recalibration.


Assuntos
Interfaces Cérebro-Computador , Exoesqueleto Energizado , Estudos Clínicos como Assunto , Eletrocorticografia/métodos , Espaço Epidural , Humanos , Modelos Lineares
17.
Front Immunol ; 13: 746889, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185868

RESUMO

Organ transplants have been a life-saving form of treatment for many patients who are facing end stage organ failure due to conditions such as diabetes, hypertension, various congenital diseases, idiopathic diseases, traumas, and other end-organ failure. While organ transplants have been monumental in treatment for these conditions, the ten year survival and long-term outcome for these patients is poor. After receiving the transplant, patients receive a multi-drug regimen of immunosuppressants. These drugs include cyclosporine, mTOR inhibitors, corticosteroids, and antibodies. Polyclonal antibodies, which inhibit the recipient's B lymphocytes, and antibodies targeting host cytokine inhibitors which prevent activation of B cells by T cells. Use of these drugs suppresses the immune system and increases the risk of opportunistic pathogen infections, tumors, and further damage to the transplanted organs and vasculature. Many regulatory mechanisms are present in organs to prevent the development of autoimmune disease, and Tregs are central to these mechanisms. Tregs secrete suppressive cytokines such as IL-10, TGF-B, and IL-35 to suppress T cells. Additionally, Tregs can bind to target cells to induce cell cycle arrest and apoptosis and can inhibit induction of IL-2 mRNA in target T cells. Tregs also interact with CTLA-4 and CD80/CD86 on antigen presenting cells (APCs) to prevent their binding to CD28 present on T cells. Due to their various immunosuppressive capabilities, Tregs are being examined as a possible treatment for patients that receive organ transplants to minimize rejection and prevent the negative outcomes. Several studies in which participants were given Tregs after undergoing organ transplantations were reviewed to determine the efficacy and safety of using Tregs in solid organ transplantation to prevent adverse outcomes.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Órgãos/métodos , Linfócitos T Reguladores/imunologia , Doenças Autoimunes/terapia , Estudos Clínicos como Assunto , Rejeição de Enxerto/imunologia , Humanos
18.
Autoimmun Rev ; 21(5): 103060, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35114404

RESUMO

OBJECTIVE: As with drug-induced lupus, some drugs may induce an antiphospholipid syndrome (APS). With the always growing numbers of new molecules, the list of the liable treatments evolves rapidly. We herein analyzed VigiBase, the international pharmacovigilance database, to identify drugs suspected of inducing APS. METHODS: All the reported cases associated with "anti-phospholipid syndrome" using the preferred term level of medDRA (dictionary of regulated drug activity) when associated with anti-phospholipid antibodies in VigiBase were analyzed. For each treatment, a Bayesian disproportionality indicator (i.e. information component, IC) was calculated. A drug was significantly associated with APS if the 95% lower-end of the IC credibility interval was positive (IC025 > 0). Drugs with potential protopathic bias were excluded. RESULTS: From 01/11/2000 to 25/07/2021, 790 reports of suspected drug-induced APS were found in VigiBase. After excluding drugs reported by a single country and drugs with protopathic bias, fourteen drugs (n = 359 reports) were associated with APS with an IC0 25 > 0. These drugs were hormons: ethinylestradiol-etonogestrel and drospirenone-ethynilestradiol; platelet growth factors: eltrombopag, romiplostim; vaccines: Human Papillomavirus vaccine, hepatitis A and B vaccines and typhoid vaccine; antibiotics: minocycline; nonstreroidal anti-inflammatory: rofecoxib; biotherapy: interferon beta-1-a, etanercept; anti-hypertensive drug: hydralazine; bisphosphonates: alendronic acid and antipsychotic: olanzapine. The mean age at diagnosis of drug-induced APS was 39.2 years [29.3;47.9] and there were 63.5% of female patients. The mean delay from first exposition to drug-induced APS was 19.7 months [4.5; 38.8]. Drug-induced APS was reported as a severe side effect in 66.3% of cases: 8.4% with a life-threatening event and 2.5% of death (n = 9). A third (n = 118, 32.9%) pulmonary embolism events were reported and 4.2% (15) cerebral infarctions. 14.8% (53) cases were associated with a systemic lupus, a sub-analysis without lupus cases showed the same severity of cases. CONCLUSION: This study identified 14 drugs potentially associated with drug-induced APS that may prove useful in the investigational work-up in any new diagnosis of APS. TRIAL REGISTRATION NUMBER: NCT03994302.


Assuntos
Síndrome Antifosfolipídica , Adulto , Síndrome Antifosfolipídica/induzido quimicamente , Teorema de Bayes , Estudos Clínicos como Assunto , Etanercepte/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Organização Mundial da Saúde
19.
Molecules ; 27(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35209150

RESUMO

Stevia rebaudiana Bertoni is a perennial shrub from Paraguay that is nowadays widely cultivated, since it is increasingly being utilized as a sugar substitute in various foodstuffs due to its sweetness and minimal caloric content. These properties of the plant's derivatives have spurred research on their biological activities revealing a multitude of benefits to human health, including antidiabetic, anticariogenic, antioxidant, hypotensive, antihypertensive, antimicrobial, anti-inflammatory and antitumor actions. To our knowledge, no recent reviews have surveyed and reported published work solely on the latter. Consequently, our main objective was to present a concise, literature-based review of the biological actions of stevia derivatives in various tumor types, as studied in in vitro and in vivo models of the disease. With global cancer estimates suggesting a 47% increase in cancer cases by 2040 compared to 2020, the data reviewed in this article should provide a better insight into Stevia rebaudiana and its products as a means of cancer prevention and therapy within the context of a healthy diet.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Stevia/química , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Estudos Clínicos como Assunto , Modelos Animais de Doenças , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/metabolismo , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Glucosídeos/química , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Concentração Inibidora 50 , Redes e Vias Metabólicas , Estrutura Molecular , Relação Estrutura-Atividade , Edulcorantes
20.
Molecules ; 27(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35209100

RESUMO

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson's disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Animais , Agonistas dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/química , Canais de Cálcio/classificação , Canais de Cálcio/genética , Estudos Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Resultado do Tratamento
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