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1.
Int J Gynecol Cancer ; 2024 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-39244209

RESUMEN

OBJECTIVE: In the phase 2 OVARIO trial (NCT03326193) investigating niraparib-bevacizumab first-line maintenance, median progression-free survival was 14.2 months (95% confidence interval (CI) 8.6 to 16.8) for patients with homologous recombination (HR)-proficient (HRp) epithelial ovarian cancer, and 12.1 months (95% CI8.0-not evaluated) for patients with undefined HR status. However, real-world data are limited for patients who receive niraparib-bevacizumab first-line maintenance therapy. The COMB1NE study describes real-world clinical outcomes (time to treatment discontinuation; time to next treatment) in patients with epithelial ovarian cancer who received niraparib-bevacizumab first-line maintenance, regardless of first-line bevacizumab use. METHODS: This real-world, retrospective study used a US nationwide electronic health record-derived deidentified database. Eligible patients were 18 years or older at initial epithelial ovarian cancer diagnosis and initiated niraparib-bevacizumab first-line maintenance (January 1, 2017-September 2, 2022) following first-line treatment. The index date was the start of first-line maintenance. Patients were followed until death, last clinical activity, or end of study, whichever occurred first. Time to treatment discontinuation and time to next treatment, a proxy for real-world progression-free survival, were estimated using the Kaplan-Meier method. RESULTS: Among 59 included patients, the median age was 67 years (interquartile range (IQR) 61-76), and 81.4% had stage III/IV epithelial ovarian cancer at diagnosis. Overall, 83.1% of patients had BRCA wild-type with either HRp or HR status unknown disease. Median time to treatment discontinuation of first-line maintenance was 11.8 months (95% CI 8.7 to 13.5). Median time to next treatment was 14.1 months (95% CI 11.3 to 16.6). At 6 months after index, 77.9% of patients had not initiated second-line treatment; at 12 months, 61.3% had not. CONCLUSION: In this real-world study of patients receiving niraparib-bevacizumab first-line maintenance, the majority of whom had HRp/HR status unknown, the median time to next treatment was consistent with observed progression-free survival in patients with similar HR status in the OVARIO study.

2.
Int J Gynecol Cancer ; 34(7): 1041-1050, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38950925

RESUMEN

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.


Asunto(s)
Indazoles , Neoplasias Ováricas , Piperidinas , Supervivencia sin Progresión , Humanos , Femenino , Indazoles/uso terapéutico , Indazoles/administración & dosificación , Piperidinas/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano
3.
Gastric Cancer ; 26(3): 415-424, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36943511

RESUMEN

BACKGROUND: The phase 3 CheckMate 649 established superior overall survival of nivolumab in combination with chemotherapy (NIVO + chemo) compared with chemotherapy (chemo) alone as a first-line treatment for patients with Her2-negative advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). This post hoc trial analysis aimed to evaluate the benefit of NIVO + chemo using quality-adjusted time without symptoms or toxicity (Q-TWiST) to further account for quality of life (QoL) in different health states depending on disease progression and treatment toxicity. METHODS: Using data from CheckMate 649, we evaluated the quality-adjusted survival gain associated with NIVO + chemo compared with chemo alone among all randomized patients and repeated similar analyses among those with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Relative Q-TWiST gains of ≥ 10% were predefined as clinically important. RESULTS: In all randomized patients, those receiving NIVO + chemo had a mean Q-TWiST gain of 1.8 (95% CI 0.9, 2.7) months compared with those receiving chemo alone. The relative Q-TWiST gain was estimated to be 12.8%. Patients with PD-L1 CPS ≥ 5 had greater quality-adjusted survival gain from NIVO + chemo with an estimated Q-TWiST gain of 2.8 (95% CI 1.5, 4.1) months, representing a relative gain of 20.6%. Subgroup analyses and sensitivity analyses with various QoL utility values yielded consistent findings in favor of NIVO + chemo compared with chemo alone. Q-TWiST gain from NIVO + chemo increased with longer duration of follow-up. CONCLUSIONS: NIVO + chemo was associated with a statistically significant and clinically important gain in quality-adjusted survival compared with chemo alone among previously untreated patients with advanced GC/GEJC/EAC.


Asunto(s)
Adenocarcinoma , Neoplasias Gástricas , Humanos , Nivolumab/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/etiología , Calidad de Vida , Antígeno B7-H1 , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/etiología , Unión Esofagogástrica , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
4.
Pediatr Nephrol ; 38(10): 3297-3308, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37140708

RESUMEN

BACKGROUND: In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity). METHODS: Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes. RESULTS: We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth. CONCLUSION: LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Síndrome Nefrótico , Nacimiento Prematuro , Femenino , Humanos , Niño , Recién Nacido , Adulto , Síndrome Nefrótico/complicaciones , Estudios de Cohortes , Peso al Nacer , Neptuno , Nacimiento Prematuro/epidemiología , Recién Nacido de Bajo Peso , Glomeruloesclerosis Focal y Segmentaria/patología , Proteinuria/etiología , Proteinuria/complicaciones , Apolipoproteína L1/genética
5.
J Biol Chem ; 296: 100125, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33243834

RESUMEN

Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in the growth medium, which extends both replicative and chronological life span (CLS). We found that conditioned media collected from stationary-phase CR cultures extended CLS when supplemented into nonrestricted (NR) cultures, suggesting a potential cell-nonautonomous mechanism of CR-induced life span regulation. Chromatography and untargeted metabolomics of the conditioned media, as well as transcriptional responses associated with the longevity effect, pointed to specific amino acids enriched in the CR conditioned media (CRCM) as functional molecules, with L-serine being a particularly strong candidate. Indeed, supplementing L-serine into NR cultures extended CLS through a mechanism dependent on the one-carbon metabolism pathway, thus implicating this conserved and central metabolic hub in life span regulation.


Asunto(s)
Restricción Calórica , Carbono/metabolismo , Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Ciclo Celular/fisiología , Medios de Cultivo , Replicación del ADN , Longevidad , Metaboloma , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/crecimiento & desarrollo
6.
Am J Physiol Heart Circ Physiol ; 323(6): H1376-H1387, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36367690

RESUMEN

Phospholipase Cε (PLCε) is a phospholipase C isoform with a wide range of physiological functions. It has been implicated in aortic valve disorders, but its role in frequently associated aortic disease remains unclear. To determine the role of PLCε in thoracic aortic aneurysm and dissection (TAAD) we used PLCε-deficient mice, which develop aortic valve insufficiency and exhibit aortic dilation of the ascending thoracic aorta and arch without histopathological evidence of injury. Fourteen days of infusion of Plce1+/+ and Plce1-/- mice with angiotensin II (ANG II), which induces aortic dilation and dissection, led to sudden death secondary to ascending aortic dissection in 43% of Plce1-/- versus 5% of Plce1+/+ mice (P < 0.05). Medial degeneration and TAAD were detected in 80% of Plce1-/- compared with 10% of Plce1+/+ mice (P < 0.05) after 4 days of ANG II. Treatment with ANG II markedly increased PLCε expression within the ascending aortic adventitia. Total RNA sequencing demonstrated marked upregulation of inflammatory and fibrotic pathways mediated by interleukin-1ß, interleukin-6, and tumor necrosis factor-α. In silico analysis of whole exome sequences of 258 patients with type A dissection identified 5 patients with nonsynonymous PLCE1 variants. Our data suggest that PLCε deficiency plays a role in the development of TAAD and aortic insufficiency.NEW & NOTEWORTHY We describe a novel phenotype by which PLCε deficiency predisposes to aortic valve insufficiency and ascending aortic aneurysm, dissection, and sudden death in the setting of ANG II-mediated hypertension. We demonstrate PLCE1 variants in patients with type A aortic dissection and aortic insufficiency, suggesting that PLCE1 may also play a role in human aortic disease. This finding is of very high significance because it has not been previously demonstrated that PLCε directly mediates aortic dissection.


Asunto(s)
Aneurisma de la Aorta Ascendente , Aneurisma de la Aorta Torácica , Aneurisma de la Aorta , Disección Aórtica , Insuficiencia de la Válvula Aórtica , Hipertensión , Humanos , Ratones , Animales , Insuficiencia de la Válvula Aórtica/genética , Ratones Endogámicos C57BL , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/patología , Disección Aórtica/genética , Angiotensina II , Muerte Súbita , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo
7.
Am J Kidney Dis ; 79(6): 807-819.e1, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-34864148

RESUMEN

RATIONALE & OBJECTIVE: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). EXPOSURE: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. OUTCOME: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. ANALYTICAL APPROACH: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. RESULTS: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. LIMITATIONS: Low prevalence of some descriptors and biopsy at a single time point. CONCLUSIONS: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Enfermedades Renales , Nefrosis Lipoidea , Síndrome Nefrótico , Progresión de la Enfermedad , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Enfermedades Renales/complicaciones , Nefrosis Lipoidea/patología , Síndrome Nefrótico/patología , Pronóstico , Estudios Prospectivos , Proteinuria/patología , Transcriptoma
8.
J Neurosci ; 40(48): 9186-9209, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33097637

RESUMEN

Neurons within the spinal cord are sensitive to environmental relations and can bring about a behavioral modification without input from the brain. For example, rats that have undergone a thoracic (T2) transection can learn to maintain a hind leg in a flexed position to minimize exposure to a noxious electrical stimulation (shock). Inactivating neurons within the spinal cord with lidocaine, or cutting communication between the spinal cord and the periphery (sciatic transection), eliminates the capacity to learn, which implies that it depends on spinal neurons. Here we show that these manipulations have no effect on the maintenance of the learned response, which implicates a peripheral process. EMG showed that learning augments the muscular response evoked by motoneuron output and that this effect survives a sciatic transection. Quantitative fluorescent imaging revealed that training brings about an increase in the area and intensity of ACh receptor labeling at the neuromuscular junction (NMJ). It is hypothesized that efferent motoneuron output, in conjunction with electrical stimulation of the tibialis anterior muscle, strengthens the connection at the NMJ in a Hebbian manner. Supporting this, paired stimulation of the efferent nerve and tibialis anterior generated an increase in flexion duration and augmented the evoked electrical response without input from the spinal cord. Evidence is presented that glutamatergic signaling contributes to plasticity at the NMJ. Labeling for vesicular glutamate transporter is evident at the motor endplate. Intramuscular application of an NMDAR antagonist blocked the acquisition/maintenance of the learned response and the strengthening of the evoked electrical response.SIGNIFICANCE STATEMENT The neuromuscular junction (NMJ) is designed to faithfully elicit a muscular contraction in response to neural input. From this perspective, encoding environmental relations (learning) and the maintenance of a behavioral modification over time (memory) are assumed to reflect only modifications upstream from the NMJ, within the CNS. The current results challenge this view. Rats were trained to maintain a hind leg in a flexed position to avoid noxious stimulation. As expected, treatments that inhibit activity within the CNS, or disrupt peripheral communication, prevented learning. These manipulations did not affect the maintenance of the acquired response. The results imply that a peripheral modification at the NMJ contributes to the maintenance of the learned response.


Asunto(s)
Conducta Animal/fisiología , Sistema Nervioso Central/fisiología , Unión Neuromuscular/fisiología , Animales , Condicionamiento Clásico , Condicionamiento Operante/fisiología , Vías Eferentes/fisiología , Electromiografía , Miembro Posterior/inervación , Miembro Posterior/fisiología , Aprendizaje/fisiología , Masculino , Placa Motora/fisiología , Neuronas Motoras/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Colinérgicos/fisiología , Nervio Ciático/fisiología , Médula Espinal/fisiología
9.
Future Oncol ; 17(22): 2940-2949, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33849296

RESUMEN

Background: Chemotherapy (CT) alone was previously standard first-line (1L) therapy for metastatic non-small-cell lung cancer (NSCLC) but alternative treatments, including immunotherapy (I-O), are now available. Patients & methods: In this retrospective study, adults with stage IV NSCLC who initiated 1L treatment between 1 August 2018 and 31 December 2019 and had ≥2 visits were identified in the Flatiron database. Patients were followed up until 30 June 2020. Baseline characteristics and treatment patterns were described by treatment group: CT, I-O + CT, I-O monotherapy and other. Results: Approximately 20% of patients received 1L CT in the 2018-2019 timeframe studied; these patients tended to have squamous histology and low (≤49%) programmed death ligand-1 expression. Conclusion: A proportion of patients with metastatic NSCLC still receive 1L CT despite the availability and widespread use of I-O therapies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia/estadística & datos numéricos , Neoplasias Pulmonares/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/análisis , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos
10.
Kidney Int ; 98(6): 1502-1518, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33038424

RESUMEN

COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cell-specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2-infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19-related kidney damage.


Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , Nefropatías Diabéticas/metabolismo , Túbulos Renales Proximales/metabolismo , SARS-CoV-2/metabolismo , Adulto , Anciano , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , COVID-19/complicaciones , COVID-19/virología , Estudios de Casos y Controles , Nefropatías Diabéticas/tratamiento farmacológico , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Interacciones Huésped-Patógeno , Humanos , Túbulos Renales Proximales/efectos de los fármacos , Masculino , Persona de Mediana Edad
11.
PLoS Biol ; 14(5): e1002462, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27168400

RESUMEN

The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del), results in functional expression defect of the CF transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (ΔF670) in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects. Genome-wide phenotypic (phenomic) analysis of the Yor1-ΔF670 biogenesis identified several modifier genes of mRNA processing and translation, which conferred oligomycin resistance to yeast. Silencing of orthologues of these candidate genes enhanced the ΔF508-CFTR functional expression at the apical PM in human CF bronchial epithelia. Although knockdown of RPL12, a component of the ribosomal stalk, attenuated the translational elongation rate, it increased the folding efficiency as well as the conformational stability of the ΔF508-CFTR, manifesting in 3-fold augmented PM density and function of the mutant. Combination of RPL12 knockdown with the corrector drug, VX-809 (lumacaftor) restored the mutant function to ~50% of the wild-type channel in primary CFTRΔF508/ΔF508 human bronchial epithelia. These results and the observation that silencing of other ribosomal stalk proteins partially rescue the loss-of-function phenotype of ΔF508-CFTR suggest that the ribosomal stalk modulates the folding efficiency of the mutant and is a potential therapeutic target for correction of the ΔF508-CFTR folding defect.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Proteínas Ribosómicas/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Aminopiridinas/farmacología , Benzodioxoles/farmacología , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Bronquios/patología , Células Cultivadas , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/patología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/química , Células Epiteliales/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Ensayos Analíticos de Alto Rendimiento , Humanos , Factor 2 de Elongación Peptídica/genética , Factor 2 de Elongación Peptídica/metabolismo , Pliegue de Proteína , Estabilidad Proteica , ARN Interferente Pequeño , Proteínas Ribosómicas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Levaduras/genética
12.
Kidney Int ; 94(4): 795-808, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30093081

RESUMEN

Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Since new technologies allow us to better evaluate changes in systemic and renal JAK-STAT activity as it relates to kidney function, we examined this in 106 patients with biopsy-proven FSGS compared to 47 healthy control individuals. Peripheral immune function was assessed in peripheral blood mononuclear cells by phosphoflow studies before and after cytokine stimulation. Kidney JAK-STAT activity was measured by immunofluorescence and by transcriptomics. A STAT1 activity score was calculated by evaluating message status of downstream targets of pSTAT 1. Peripheral blood mononuclear cells were found to be upregulated in terms of pSTAT production at baseline in FSGS and to have limited reserve to respond to various cytokines. Increased staining for components of the JAK-STAT system in FSGS by microscopy was found. Furthermore, we found transcriptomic evidence for activation of JAK-STAT that increased pSTAT 1 and pSTAT 3 in glomerular and tubulointerstitial sections of the kidney. Some of these changes were associated with the likelihood of remission of proteinuria and progression of disease. JAK-STAT signaling is altered in patients with FSGS as compared to healthy controls with activated peripheral immune cells, increased message in the kidney and increased activated proteins in the kidney. Thus, our findings support immune activation in this disease and point to the JAK-STAT pathway as a potential target for treatment of FSGS.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/inmunología , Humanos , Janus Quinasa 1/sangre , Janus Quinasa 1/genética , Janus Quinasa 2/sangre , Janus Quinasa 2/genética , Glomérulos Renales/metabolismo , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Fosforilación , Factor de Transcripción STAT1/sangre , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT3/sangre , Transducción de Señal , Transcriptoma , Adulto Joven
13.
Value Health ; 21(2): 229-238, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29477405

RESUMEN

OBJECTIVE: To identify which specifications and approaches to model selection better predict health preferences, the International Academy of Health Preference Research (IAHPR) hosted a predictive modeling competition including 18 teams from around the world. METHODS: In April 2016, an exploratory survey was fielded: 4074 US respondents completed 20 out of 1560 paired comparisons by choosing between two health descriptions (e.g., longer life span vs. better health). The exploratory data were distributed to all teams. By July, eight teams had submitted their predictions for 1600 additional pairs and described their analytical approach. After these predictions had been posted online, a confirmatory survey was fielded (4148 additional respondents). RESULTS: The victorious team, "Discreetly Charming Econometricians," led by Michal Jakubczyk, achieved the smallest χ2, 4391.54 (a predefined criterion). Its primary scientific findings were that different models performed better with different pairs, that the value of life span is not constant proportional, and that logit models have poor predictive validity in health valuation. CONCLUSIONS: The results demonstrated the diversity and potential of new analytical approaches in health preference research and highlighted the importance of predictive validity in health valuation.


Asunto(s)
Conducta de Elección , Estado de Salud , Longevidad , Prioridad del Paciente/psicología , Conducta Competitiva , Colaboración de las Masas , Humanos , Modelos Estadísticos , Años de Vida Ajustados por Calidad de Vida
14.
Qual Life Res ; 27(3): 725-733, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29264776

RESUMEN

PURPOSE: Summarizing patient-reported outcomes (PROs) on a quality-adjusted life year (QALY) scale is an essential component to any economic evaluation comparing alternative medical treatments. While multiple studies have compared PRO items and instruments based on their psychometric properties, no study has compared the preference-based summary of the EQ-5D-3L and Patient Reported Outcomes Measurement Information System (PROMIS-29) instruments. As part of this comparison, a major aim of this manuscript is to transform PROMIS-29 utility values to an EQ-5D-3L scale. METHODS: A nationally representative survey of 2623 US adults completed the 29-item PROMIS health profile instrument (PROMIS-29) and the 3-level version of the EQ-5D instrument (EQ-5D-3L). Their responses were summarized on a health utility scale using published estimates. Using regression analysis, PROMIS-29 and EQ-5D-3L utility weights were compared with each other as well as with self-reported general health. RESULTS: PROMIS-29 utility weights were much lower than the EQ-5D-3L weights. However, a correlation coefficient of 0.769 between the utility values of the two instruments suggests that the main discordance is simply a difference in scale between the measures. It is also possible to map PROMIS-29 utility weights onto an EQ-5D-3L scale. EQ-5D-3L losses equal .1784 × (PROMIS-29 Losses).7286. CONCLUSIONS: The published estimates of the PROMIS-29 produce lower utility values than many other health instruments. Mapping the PROMIS-29 estimates to an EQ-5D-3L scale alleviates this issue and allows for a more straightforward comparison between the PROMIS-29 and other common health instruments.


Asunto(s)
Análisis Costo-Beneficio/métodos , Medición de Resultados Informados por el Paciente , Psicometría/métodos , Años de Vida Ajustados por Calidad de Vida , Adulto , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Autoinforme , Encuestas y Cuestionarios
15.
Matern Child Health J ; 22(12): 1780-1788, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29995297

RESUMEN

Objectives Examining the association between maternal smoking and losses in childhood health-related quality of life due to behavior problems provides parents and policymakers another tool for the valuation of smoking cessation during pregnancy. Methods Using the National Longitudinal Survey of Youth 1979 Child and Young Adult data, this study retrospectively examined a cohort of 4114 women and 8668 children. In addition to questions focusing on maternal smoking and general demographics, each survey included the Behavior Problems Index (BPI), a 28-item questionnaire with six subscales measuring childhood behavior problems (antisocial behavior, anxiousness/depression, headstrongness, hyperactivity, immature dependency, and peer conflict/social withdrawal). Responses to the BPI, completed by mothers with children ages 4-14, were summarized on a QALY scale using published preference weights. Results Children whose mothers smoked during pregnancy experience additional QALY losses of 0.181, on average, per year due to increased behavior problems. Boys suffered larger QALY losses associated with maternal smoking (0.242) compared to girls (0.119; p value = .021), regardless of age. Moreover, heavier smoking during pregnancy (i.e., 1 or more packs/day) was associated with larger QALY losses (0.282; p-value < .001). Conclusions for Practice These findings illustrate the burden of maternal smoking during pregnancy on child health, namely behavioral problems. The losses in QALYs may be incorporated into economic evaluations for smoking cessation interventions during pregnancy. Future research will investigate how maternal smoking following childbirth is associated with child QALYs.


Asunto(s)
Trastornos de la Conducta Infantil/etiología , Madres/psicología , Efectos Tardíos de la Exposición Prenatal , Años de Vida Ajustados por Calidad de Vida , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Niño , Preescolar , Depresión/etiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Embarazo , Problema de Conducta
16.
J Am Soc Nephrol ; 28(10): 2931-2945, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28720684

RESUMEN

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/etiología , Glomérulos Renales/crecimiento & desarrollo , Adaptación Fisiológica , Animales , Peso Corporal , Ciclo Celular , Enalapril , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Glomérulos Renales/patología , Masculino , Tamaño de los Órganos , Podocitos/fisiología , Distribución Aleatoria , Ratas Endogámicas F344 , Estrés Fisiológico , Transcriptoma
17.
FASEB J ; 30(3): 1247-62, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26606940

RESUMEN

The ABCC transporter subfamily includes pumps, the long and short multidrug resistance proteins (MRPs), and an ATP-gated anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). We show that despite their thermodynamic differences, these ABCC transporter subtypes use broadly similar mechanisms to couple their extracellular gates to the ATP occupancies of their cytosolic nucleotide binding domains. A conserved extracellular phenylalanine at this gate was a prime location for producing gain of function (GOF) mutants of a long MRP in yeast (Ycf1p cadmium transporter), a short yeast MRP (Yor1p oligomycin exporter), and human CFTR channels. Extracellular gate mutations rescued ATP binding mutants of the yeast MRPs and CFTR by increasing ATP sensitivity. Control ATPase-defective MRP mutants could not be rescued by this mechanism. A CFTR double mutant with an extracellular gate mutation plus a cytosolic GOF mutation was highly active (single-channel open probability >0.3) in the absence of ATP and protein kinase A, each normally required for CFTR activity. We conclude that all 3 ABCC transporter subtypes use similar mechanisms to couple their extracellular gates to ATP occupancy, and highly active CFTR channels that bypass defects in ATP binding or phosphorylation can be produced.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Unión Proteica/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfato/genética , Secuencia de Aminoácidos , Sitios de Unión/genética , Línea Celular , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células HEK293 , Humanos , Activación del Canal Iónico/genética , Mutación/genética , Fosforilación/genética , Estructura Terciaria de Proteína
18.
Matern Child Health J ; 20(4): 862-9, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26645618

RESUMEN

OBJECTIVES: To estimate the prevalence and losses in quality-adjusted life years (QALYs) associated with 20 child health conditions. METHODS: Using data from the 2009-2010 National Survey of Children with Special Health Care Needs, preference weights were applied to 14 functional difficulties to summarize the quality of life burden of 20 health conditions. RESULTS: Among the 14 functional difficulties, "a little trouble with breathing" had the highest prevalence (37.1 %), but amounted to a loss of just 0.16 QALYs from the perspective of US adults. Though less prevalent, "a lot of behavioral problems" and "chronic pain" were associated with the greatest losses (1.86 and 3.43 QALYs). Among the 20 conditions, allergies and asthma were the most prevalent but were associated with the least burden. Muscular dystrophy and cerebral palsy were among the least prevalent and most burdensome. Furthermore, a scatterplot shows the association between condition prevalence and burden. CONCLUSIONS: In child health, condition prevalence is negatively associated with quality of life burden from the perspective of US adults. Both should be considered carefully when evaluating the appropriate role for public health prevention and interventions.


Asunto(s)
Salud Infantil , Costo de Enfermedad , Pediatría , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Adolescente , Niño , Preescolar , Enfermedad Crónica/epidemiología , Niños con Discapacidad/estadística & datos numéricos , Educación Especial/economía , Educación Especial/estadística & datos numéricos , Femenino , Estado de Salud , Humanos , Discapacidades para el Aprendizaje/epidemiología , Masculino , Prevalencia , Estados Unidos
19.
J Biol Chem ; 289(29): 19942-57, 2014 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-24876383

RESUMEN

ATP-binding cassette (ABC) transporters are an ancient family of transmembrane proteins that utilize ATPase activity to move substrates across cell membranes. The ABCC subfamily of the ABC transporters includes active drug exporters (the multidrug resistance proteins (MRPs)) and a unique ATP-gated ion channel (cystic fibrosis transmembrane conductance regulator (CFTR)). The CFTR channel shares gating principles with conventional ligand-gated ion channels, but the allosteric network that couples ATP binding at its nucleotide binding domains (NBDs) with conformational changes in its transmembrane helices (TMs) is poorly defined. It is also unclear whether the mechanisms that govern CFTR gating are conserved with the thermodynamically distinct MRPs. Here we report a new class of gain of function (GOF) mutation of a conserved proline at the base of the pore-lining TM6. Multiple substitutions of this proline promoted ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-ß,γ-imidodiphosphate (AMP-PNP). TM6 proline mutations exhibited additive GOF effects when combined with a previously reported GOF mutation located in an outer collar of TMs that surrounds the pore-lining TMs. Each TM substitution allosterically rescued the ATP sensitivity of CFTR gating when introduced into an NBD mutant with defective ATP binding. Both classes of GOF mutations also rescued defective drug export by a yeast MRP (Yor1p) with ATP binding defects in its NBDs. We conclude that the conserved TM6 proline helps set the energy barrier to both CFTR channel opening and MRP-mediated drug efflux and that CFTR channels and MRP pumps utilize similar allosteric mechanisms for coupling conformational changes in their translocation pathways to ATP binding at their NBDs.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/química , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/química , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Adenilil Imidodifosfato/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Secuencia Conservada , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Células HEK293 , Humanos , Activación del Canal Iónico , Modelos Moleculares , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Prolina/química , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Homología de Secuencia de Aminoácido
20.
Oncol Ther ; 12(3): 465-475, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38965204

RESUMEN

INTRODUCTION: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. METHODS: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011-30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan-Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). RESULTS: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60-72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7-25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0-53.9 days). Median TTD was 9.3 months (95% CI 6.1-11.3 months). Median TTNT was 12.9 months (95% CI 11.5-19.0 months). CONCLUSIONS: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC.

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