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1.
Neurol Sci ; 45(5): 2027-2033, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38060035

RESUMEN

BACKGROUND: Mid- to late-stage Parkinson's disease (PD) is often linked with worsened and significant impairment of motor activities, but existing prognostic markers do not adequately capture the risk of loss of balance in PD patients. This study aims to develop a risk prognostic model for mid- to late-stage PD and identify prognostic factors that are indicative of impending loss of balance and falls. METHODS: The study included 307 participants of which 75 were diagnosed with idiopathic PD and 232 were neurological or non-neurological controls. Among the PD group, 46 were early-stage (Hoehn and Yahr [H&Y] = 1,2) with no significant loss of balance while 29 were mid- to late-stage (H&Y = 3,4,5) which is characterized by loss of balance and falls. Multivariable logistic regression (MLR) was used to develop a prognostic model for mid- to late-stage PD. Model discrimination was assessed by ROC curves. The model was internally validated through bootstrapping and calibration plots. RESULTS: The relevant factors identified and included in the final MLR model were shortness of breath, age, swollen joints, heme oxygenase-1 (HO-1) protein, and total salivary protein. The model had an AUC of 0.82 (95% CI = 0.71-0.92) and was well calibrated (calibration slope = 0.77, intercept = 0.03). The likelihood of shortness of breath (OR = 7.91, 95% CI = 1.63-45.12) was significantly higher among mid- to late-stage PD than early-stage. Age and total salivary protein were also significantly higher among mid- to late-stage PD. CONCLUSION: The MLR prognostic model for mid- to late-stage PD may assist physicians in identifying patients at high risk for loss of balance and falls.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Pronóstico , Equilibrio Postural/fisiología , Disnea , Proteínas y Péptidos Salivales
2.
Eur J Dent Educ ; 27(2): 360-367, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-35543311

RESUMEN

INTRODUCTION: The objective of this study was to assess an original learning intervention to train students and paediatric dentistry teachers in radiographic diagnostic accuracy of pulpo-periodontal complications in primary molars. MATERIALS AND METHODS: The learning intervention was based on 250 different randomly ordered radiographs of primary molars within three quizzes (A, B and C) for 5 sessions (S): quiz A (50 X-rays), B and C (100 X-rays) were, respectively, completed in S1 to assess the extent of agreement with 5 experts' diagnoses, in S2 and S3 (B at days 8 and 23) and in S4 and S5 (C at days 90 and 105). During S1 and at the end of S3 and S5, the participants (48 students and 16 teachers) were informed of correct diagnoses. A satisfaction questionnaire was completed by all the students. Alongside the descriptive analyses, generalised linear mixed model (GLMM) analyses assessed the odds of participants' correct diagnosis over the study duration. RESULTS: At S1, the odds of diagnostic accuracy among students were significantly lower than those among the teachers. After receiving feedback at S1, GLMM analyses showed that among all the participants, accuracy improved over time with the odds of correct diagnoses higher in S2-5 than in S1; and there were similar increases across sessions between teachers and students, except in S3, where the improvement among teachers tended to be greater than that among the students. All students were satisfied though one-third reported that quizzes with 100 radiographs felt too long. CONCLUSION: The online case-based learning was a good training format for dental education.


Asunto(s)
Educación en Odontología , Aprendizaje , Niño , Humanos , Estudiantes , Curriculum , Diente Molar/diagnóstico por imagen
3.
J Neurochem ; 157(6): 2195-2209, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32880973

RESUMEN

Heme oxygenase-1 (HO-1), a highly inducible stress protein that degrades heme to biliverdin, carbon monoxide, and free ferrous iron, is increased in blood and other biofluids of subjects with various systemic and neurological disorders. HO-1 does not contain an N-terminal signal peptide and the mechanism responsible for its secretion remains unknown. Extracellular vesicles (EVs) are membrane-bound inclusions that transport microRNAs, messenger RNAs, lipids, and proteins among diverse cellular and extracellular compartments. The objective of the current study was to determine whether EVs in human biofluids contain HO-1, and whether the latter may be transported in EVs from brain to periphery. Total, L1 cell adhesion molecule protein (L1CAM)-enriched (neuron-derived), and glutamate aspartate transporter 1 (GLAST)-enriched (astrocyte-derived) EVs were purified from five different human biofluids (saliva [n = 40], plasma [n = 14], serum [n = 10], urine [n = 10], and cerebrospinal fluid [n = 11]) using polymer precipitation and immuno-affinity-based capture methods. L1CAM-enriched, GLAST-enriched, and L1CAM/GLAST-depleted (LGD) EV, along with EV-depleted (EVD), fractions were validated by nanoparticle tracking analysis, enzyme-linked immunosorbent assay (ELISA), and western blot. HO-1 was assayed in all fractions using ELISA and western blot. The majority of HO-1 protein was localized to LGD, L1CAM-enriched, and GLAST-enriched EVs of all human biofluids surveyed after adjusting for age and sex, with little HO-1 protein detected in EVD fractions. HO-1 protein in human biofluids is predominantly localized to EV compartments. A substantial proportion of EV HO-1 in peripheral human biofluids is derived from the central nervous system and may contribute to the systemic manifestations of various neurological conditions.


Asunto(s)
Líquidos Corporales/enzimología , Vesículas Extracelulares/enzimología , Hemo-Oxigenasa 1/metabolismo , Adulto , Anciano , Biomarcadores/metabolismo , Líquidos Corporales/química , Vesículas Extracelulares/química , Femenino , Hemo-Oxigenasa 1/análisis , Humanos , Masculino , Persona de Mediana Edad
4.
Stat Med ; 40(4): 998-1020, 2021 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-33210315

RESUMEN

For a continuous time-to-event outcome and an expensive-to-measure exposure, we develop a pooling design and propose a likelihood-based approach to estimate the hazard ratios (HRs) of a Cox proportional hazards (PH) model. Our proposed approach fits a PH model based on pooled exposures with individually observed time-to-event outcomes. The design and estimation exploits the equivalence of the conditional logistic likelihood functions arising from a matched case-control study and the partial likelihood function of a riskset-matched, nested case-control (NCC) subset of a cohort study. To create the pools, we first focus on an NCC subcohort. Pools are formed at random while keeping the matching intact. Pool-level exposure and confounders are then evaluated and used in the likelihood to estimate the HR and the standard error of the estimates. The estimators are MLEs, provide consistent estimates of the individual-level HRs, and are asymptotically normal. Our simulation results indicate that the pooled estimates are comparable to the estimates obtained from the NCC subcohort. The units of analysis for the pooled design are the pools and not the individual participants. Hence the effective sample size is reduced. Therefore, the variance of the HR estimate increases with increasing poolsize. However, this variance inflation in small samples can be offset by including more matched controls per case within the NCC subcohort. An application is demonstrated with the Second Manifestations of ARTerial disease (SMART) study.


Asunto(s)
Modelos de Riesgos Proporcionales , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Funciones de Verosimilitud , Análisis de Supervivencia
5.
Mov Disord ; 35(3): 468-477, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31800144

RESUMEN

BACKGROUND: Parkinson's disease (PD) is the most common movement disorder among adults, affecting 2% of the world population older than 65 years of age. No diagnostic biomarker for routine use in clinical settings currently exists. Dysregulation of microRNAs (miRNAs) has been implicated in various neurodegenerative conditions, including PD. Distinct miRNAs have been demonstrated to be involved in the regulation of α-synuclein, a key player in PD pathogenesis; miR-153 and miR-223 are downregulated in the brain and serum of parkinsonian GFAP.HMOX1 transgenic mice where they directly regulate α-synuclein. OBJECTIVE: To ascertain whether salivary miR-153 and miR-223 are similarly downmodulated in, and may serve as diagnostic biomarkers of, idiopathic PD. METHODS: Using reverse transcriptase quantitative polymerase chain reaction, miR-153 and miR-223 levels were evaluated in the saliva of 77 non-neurological controls and 83 PD patients. Levels of heme oxygenase-1 and α-synuclein were measured using enzyme-linked immunosorbent assay. Analyses were adjusted by age, sex, medication exposure, disease duration, and relevant comorbidities. RESULTS: Log-transformed expression levels of miR-153 and miR-223 were significantly decreased in the saliva of human PD patients in comparison with nonneurological controls. The miRNA expression levels did not change as a function of disease progression (Hoehn and Yahr staging). The area under the receiver operating characteristic curve separating controls from PD patients was 79% (95% confidence interval, 61%-96%) for miR-153 and 77% (95% confidence interval, 59%-95%) for miR-223. The ratios of miRNAs to oligomeric α-synuclein, total α-synuclein, or heme oxygenase-1 protein did not improve accuracy of the test. CONCLUSION: Salivary miR-153 and miR-223 levels may serve as useful, noninvasive, and relatively inexpensive diagnostic biomarkers of idiopathic PD. © 2019 International Parkinson and Movement Disorder Society.


Asunto(s)
MicroARNs , Enfermedad de Parkinson , Adulto , Biomarcadores , Humanos , MicroARNs/genética , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Curva ROC , alfa-Sinucleína
6.
Oncologist ; 23(11): 1269-e125, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29853657

RESUMEN

LESSONS LEARNED: The combination of the antiangiogenic agent ziv-aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested.Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens. BACKGROUND: Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single-arm phase I study evaluating the combination of ziv-aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib. METHODS: Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non-small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv-aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28-day cycle. RESULTS: Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events. CONCLUSION: The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.


Asunto(s)
Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Sarcoma/tratamiento farmacológico , Triazoles/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Masculino , Neoplasias/patología , Proteínas Recombinantes de Fusión/farmacología , Sarcoma/patología , Triazoles/farmacología
7.
Invest New Drugs ; 36(2): 230-239, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28808818

RESUMEN

Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities.


Asunto(s)
Benzodioxoles/farmacocinética , Metabolómica , Chaperonas Moleculares/metabolismo , Purinas/farmacocinética , Adulto , Anciano , Benzodioxoles/administración & dosificación , Benzodioxoles/efectos adversos , Benzodioxoles/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Metaboloma , Persona de Mediana Edad , Purinas/administración & dosificación , Purinas/efectos adversos , Purinas/sangre , Resultado del Tratamiento , Adulto Joven
8.
Patterns (N Y) ; 5(4): 100946, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38645766

RESUMEN

Data bias is a major concern in biomedical research, especially when evaluating large-scale observational datasets. It leads to imprecise predictions and inconsistent estimates in standard regression models. We compare the performance of commonly used bias-mitigating approaches (resampling, algorithmic, and post hoc approaches) against a synthetic data-augmentation method that utilizes sequential boosted decision trees to synthesize under-represented groups. The approach is called synthetic minority augmentation (SMA). Through simulations and analysis of real health datasets on a logistic regression workload, the approaches are evaluated across various bias scenarios (types and severity levels). Performance was assessed based on area under the curve, calibration (Brier score), precision of parameter estimates, confidence interval overlap, and fairness. Overall, SMA produces the closest results to the ground truth in low to medium bias (50% or less missing proportion). In high bias (80% or more missing proportion), the advantage of SMA is not obvious, with no specific method consistently outperforming others.

9.
Stat Methods Med Res ; 33(1): 96-111, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38093410

RESUMEN

Analyses of distributed data networks of rare diseases are constrained by legitimate privacy and ethical concerns. Analytical centers (e.g. research institutions) are thus confronted with the challenging task of obtaining data from recruiting sites that are often unable or unwilling to share personal records of participants. For time-to-event data, recently popularized disclosure techniques with privacy guarantees (e.g., Differentially Private Generative Adversarial Networks) are generally computationally expensive or inaccessible to applied researchers. To perform the widely used Cox proportional hazards regression, we propose an easy-to-implement privacy-preserving data analysis technique by pooling (i.e. aggregating) individual records of covariates at recruiting sites under the nested case-control sampling framework before sharing the pooled nested case-control subcohort. We show that the pooled hazard ratio estimators, under the pooled nested case-control subsamples from the contributing sites, are maximum likelihood estimators and provide consistent estimates of the individual level full cohort HRs. Furthermore, a sampling technique for generating pseudo-event times for individual subjects that constitute the pooled nested case-control subsamples is proposed. Our method is demonstrated using extensive simulations and analysis of the National Lung Screening Trial data. The utility of our proposed approach is compared to the gold standard (full cohort) and synthetic data generated using classification and regression trees. The proposed pooling technique performs to near-optimal levels comparable to full cohort analysis or synthetic data; the efficiency improves in rare event settings when more controls are matched on during nested case-control subcohort sampling.


Asunto(s)
Privacidad , Proyectos de Investigación , Humanos , Modelos de Riesgos Proporcionales , Estudios de Cohortes , Estudios de Casos y Controles
10.
Cancer Chemother Pharmacol ; 93(3): 177-189, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38010394

RESUMEN

PURPOSE: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2­negative, locally advanced or metastatic breast cancer. Because knowledge of the pharmacodynamic (PD) effects of talazoparib in patients has been limited to studies of PARP enzymatic activity (PARylation) in peripheral blood mononuclear cells, we developed a study to assess tumoral PD response to talazoparib treatment (NCT01989546). METHODS: We administered single-agent talazoparib (1 mg/day) orally in 28-day cycles to adult patients with advanced solid tumors harboring (suspected) deleterious BRCA1 or BRCA2 mutations. The primary objective was to examine the PD effects of talazoparib; the secondary objective was to determine overall response rate (ORR). Tumor biopsies were mandatory at baseline and post-treatment on day 8 (optional at disease progression). Biopsies were analyzed for PARylation, DNA damage response (γH2AX), and epithelial‒mesenchymal transition. RESULTS: Nine patients enrolled in this trial. Four of six patients (67%) evaluable for the primary PD endpoint exhibited a nuclear γH2AX response on day 8 of treatment, and five of six (83%) also exhibited strong suppression of PARylation. A transition towards a more mesenchymal phenotype was seen in 4 of 6 carcinoma patients, but this biological change did not affect γH2AX or PAR responses. The ORR was 55% with the five partial responses lasting a median of six cycles. CONCLUSION: Intra-tumoral DNA damage response and inhibition of PARP enzymatic activity were confirmed in patients with advanced solid tumors harboring BRCA1/2 mutations after 8 days of talazoparib treatment.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Adulto , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Leucocitos Mononucleares , Ftalazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/genética
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