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1.
Neuro Oncol ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32055852

RESUMO

Gliomas are the most common primary central nervous system tumors occurring in children and adults with neurofibromatosis type I (NF1). Over the past decade, discoveries of the molecular basis of low-grade gliomas (LGGs) have led to new approaches for diagnosis and treatments. However, these new understandings have not been fully applied to the management of NF1-associated gliomas. A consensus panel consisting of experts in NF1 and gliomas was convened to review the current molecular knowledge of NF1-associated low grade "transformed" and high-grade gliomas; insights gained from mouse models of NF1-LGGs; challenges in diagnosing and treating older patients with NF1-associated gliomas; and advances in molecular targeted treatment and potential immunologic treatment of these tumors. Next steps are recommended to advance the management and outcomes for NF1-associated gliomas.

2.
Environ Monit Assess ; 192(2): 134, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970501

RESUMO

Healthcare-acquired infections (HAIs) contribute to maternal and neonatal morbidity and mortality, especially in low- and middle-income countries (LMICs). Deficient environmental health (EH) conditions and infection prevention and control (IPC) practices in healthcare facilities (HCFs) contribute to the spread of HAIs, but microbial sampling of sources of contamination is rarely conducted nor reported in low-resource settings. The purpose of this study was to assess EH conditions and IPC practices in Malawian HCFs and evaluate how EH deficiencies contribute to pathogen exposures and HAIs, and to provide recommendations to inform improvements in EH conditions using a mixed-methods approach. Thirty-one maternity wards in government-run HCFs were surveyed in the three regions of Malawi. Questionnaires were administered in parallel with structured observations of EH conditions and IPC practices and microbial testing of water sources and facility surfaces. Results indicated significant associations between IPC practices and microbial contamination. Facilities where separate wards were not available for mothers and newborns with infections and where linens were not used for patients during healthcare services were more likely to have delivery tables with surface contamination (relative risk = 2.23; 1.49, 3.34). E. coli was detected in water samples from seven (23%) HCFs. Our results suggest that Malawian maternity wards could reduce microbial contamination, and potentially reduce the occurrence of HAIs, by improving EH conditions and IPC practices. HCF staff can use the simple, low-cost EH monitoring methods used in this study to incorporate microbial monitoring of EH conditions and IPC practices in HCFs in low-resource settings.

3.
Malar J ; 19(1): 42, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31973737

RESUMO

BACKGROUND: The humoral immune response against Anopheles salivary glands proteins in the vertebrate host can reflect the intensity of exposure to Anopheles bites and the risk of Plasmodium infection. In Colombia, the identification of exposure biomarkers is necessary due to the several Anopheles species circulating. The purpose of this study was to evaluate risk of malaria infection by measuring antibody responses against salivary glands extracts from Anopheles (Nyssorhynchus) albimanus and Anopheles (Nys.) darlingi and also against the gSG6-P1 peptide of Anopheles gambiae in people residing in a malaria endemic area in the Colombian Pacific coast. METHODS: Dried blood spots samples were eluted to measure the IgG antibodies against salivary gland extracts of An. albimanus strains STECLA (STE) and Cartagena (CTG) and An. darlingi and the gSG6-P1 peptide by ELISA in uninfected people and microscopic and submicroscopic Plasmodium carriers from the Colombia Pacific Coast. A multiple linear mixed regression model, Spearman correlation, and Mann-Whitney U-test were used to analyse IgG data. RESULTS: Significant differences in specific IgG levels were detected between infected and uninfected groups for salivary glands extracts from An. albimanus and for gSG6-P1, also IgG response to CTG and gSG6-P1 peptide were positively associated with the IgG response to Plasmodium falciparum in the mixed model. CONCLUSION: The CTG and STE An. albimanus salivary glands extracts are a potential source of new Anopheles salivary biomarkers to identify exposure to the main malaria vector and to calculate risk of disease in the Colombian Pacific coast. Also, the gSG6-P1 peptide has the potential to quantify human exposure to the subgenus Anopheles vectors in the same area.

4.
Acta Neuropathol ; 139(2): 259-271, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31802236

RESUMO

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

5.
Ann Clin Transl Neurol ; 6(12): 2555-2565, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797581

RESUMO

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

6.
J Atten Disord ; : 1087054719894384, 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31838937

RESUMO

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

8.
Phys Rev E ; 100(5-1): 052145, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31869903

RESUMO

We investigate ionic criticality on the basis of a specially devised spherical model that accounts both for Coulomb and nonionic forces in binary systems. We show in detail here the consequences of the entanglement of density and charge correlation functions G_{NN} and G_{ZZ} on criticality and screening. We also show on this soluble model how, because of electroneutrality, the long-range Coulomb interactions do not change the universality class of criticality in the model driven primarily by sufficiently attractive nonionic interactions. Near criticality, G_{NN} and G_{ZZ} are fully decoupled in charge symmetric systems. However, in more realistic nonsymmetric models, charge and density fluctuations couple in leading order so that the charge and density correlation lengths diverge asymptotically in a similar way. Similarly, the Stillinger-Lovett sum rule, which characterizes a conducting fluid, is violated at criticality in nonsymmetric models when the critical-point density-decay exponent η vanishes. In addition, if quantum effects are accounted for semiclassically by incorporating algebraically decaying interactions, G_{ZZ} decays only as a power law in the whole phase space, contrary to the usually expected exponential Debye screening. We expect these results on this soluble toy model to be general and to reveal general mechanisms ruling ionic criticality.

9.
Health Policy Plan ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722372

RESUMO

Many healthcare facilities (HCFs) in low-income countries experience unreliable connectivity to energy sources, which adversely impacts the quality of health service delivery and provision of adequate environmental health services. This assessment explores the status and consequences of energy access through interviews and surveys with administrators and healthcare workers from 44 HCFs (central hospitals, district hospitals, health centres and health posts) in Malawi. Most HCFs are connected to the electrical grid but experience weekly power interruptions averaging 10 h; less than one-third of facilities have a functional back-up source. Inadequate energy availability is associated with irregular water supply and poor medical equipment sterilization; it adversely affects provider safety and contributes to poor lighting and working conditions. Some challenges, such as poor availability and maintenance of back-up energy sources, disproportionately affect smaller HCFs. Policymakers, health system actors and third-party organizations seeking to improve energy access and quality of care in Malawi and similar settings should address these challenges in a way that prioritizes the specific needs of different facility types.

10.
J Clin Oncol ; 37(35): 3446-3454, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31626572

RESUMO

PURPOSE: Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. PATIENTS AND METHODS: Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers. RESULTS: Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. CONCLUSION: High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

11.
Vaccine ; 37(44): 6601-6608, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31562003

RESUMO

Centralized reminder/recall (C-R/R) is an evidence-based strategy for increasing vaccination rates that uses a population-level database such as a state immunization information system (IIS) to send notifications across large geographic areas. IISs are usually based in state public health departments, which could initiate C-R/R. While C-R/R is a promising strategy, the factors influencing its initiation and sustainment are not clear. Utilizing qualitative content analysis methodology and interviews with key stakeholders involved in or knowledgeable about C-R/R, we examined the characteristics of these initiatives and factors influencing their success. We identified and spoke with managers and senior leaders across IISs, health plans, health systems, pharmaceutical companies, and advocacy organizations and focused especially on C-R/R activities within IISs. Several considerations were determined important to C-R/R success: decision-making, stakeholder buy-in, partnerships, funding, data and technology, evaluation, and message content. Salient barriers were costs and lack of funding, poor contact data quality (i.e. telephone number, home address), and messaging that is either overly broad or too specific. Pertinent facilitators of C-R/R included notifying health providers in advance of an initiative, conducting a rigorous post-reminder/recall evaluation, and engaging a range of partners. Partnerships were important to stakeholders for multiple reasons including technical assistance, resource sharing, and sharing of best practices. Overall, our results illustrate the many opportunities to advance C-R/R through further collaboration within and across public health departments and potentially via public-private partnerships.

12.
Pediatr Blood Cancer ; 66(12): e27972, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31512390

RESUMO

BACKGROUND: Radiotherapy is often deferred in very young children with medulloblastoma, in favor of more intense chemotherapy and stem cell rescue; however, posterior fossa radiation has been shown to improve overall survival (OS) and event-free survival compared with adjuvant chemotherapy alone. This study was performed to assess the OS, recurrence-free survival (RFS), patterns of failure, and clinical toxicity for children aged five and under who received focal proton radiation to the tumor bed alone. PROCEDURE: From 2010 to 2017, 14 patients with newly diagnosed medulloblastoma at one institution received tumor bed irradiation following surgery and chemotherapy. The median age of the patients was 40 months (range, 10.9-62.9 months). RESULTS: With a median follow-up of 54 months, four patients relapsed: three within the central nervous system (CNS) outside of the posterior fossa, and one within the tumor bed after subtotal resection. All relapses occurred within 28 months after the completion of radiation therapy. Five-year OS and RFS for this cohort of patients were 84% (95% CI, 48%-96%) and 70% (95% CI, 38%-88%), respectively. One patient experienced significant tumor regrowth soon after completion of radiation, autopsy showed viable tumor and necrosis near and within the brainstem, with relation to radiation unknown; however, no other acute clinical toxicities greater than grade 2 were observed in this group of patients. In the nine patients with available performance status follow-up, no significant changes in Lansky performance status were observed. CONCLUSIONS: Five-year OS and RFS following tumor bed irradiation in young children with medulloblastoma appear to be improved compared with other studies that forego the use of radiation therapy in this patient population. This approach should be further investigated in young children with medulloblastoma.

13.
J Clin Oncol ; 37(32): 3050-3058, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31532722

RESUMO

PURPOSE: Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents. METHODS: We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non-NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children's Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures. RESULTS: In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors (P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children's Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9). CONCLUSION: Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

14.
J Synchrotron Radiat ; 26(Pt 5): 1790-1796, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31490171

RESUMO

A multimodal imaging instrument has been developed that integrates scanning near-field optical microscopy with nanofocused synchrotron X-ray diffraction imaging. The instrument allows for the simultaneous nanoscale characterization of electronic/near-field optical properties of materials together with their crystallographic structure, facilitating the investigation of local structure-property relationships. The design, implementation and operating procedures of this instrument are reported. The scientific capabilities are demonstrated in a proof-of-principle study of the insulator-metal phase transition in samarium sulfide (SmS) single crystals induced by applying mechanical pressure via a scanning tip. The multimodal imaging of an in situ tip-written region shows that the near-field optical reflectivity can be correlated with the heterogeneously transformed structure of the near-surface region of the crystal.

15.
Parasit Vectors ; 12(1): 436, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500667

RESUMO

BACKGROUND: The common bed bug, Cimex lectularius, is an obligatory blood-feeding ectoparasite that requires a blood meal to molt and produce eggs. Their frequent biting to obtain blood meals and intimate association with humans increase the potential for disease transmission. However, despite more than 100 years of inquiry into bed bugs as potential disease vectors, they still have not been conclusively linked to any pathogen or disease. This ecological niche is extraordinarily rare, given that nearly every other blood-feeding arthropod is associated with some type of human or zoonotic disease. Bed bugs rely on the bacteria Wolbachia as an obligate endosymbiont to biosynthesize B vitamins, since they acquire a nutritionally deficient diet, but it is unknown if Wolbachia confers additional benefits to its bed bug host. In some insects, Wolbachia induces resistance to viruses such as Dengue, Chikungunya, West Nile, Drosophila C and Zika, and primes the insect immune system in other blood-feeding insects. Wolbachia might have evolved a similar role in its mutualistic association with the bed bug. In this study, we evaluated the influence of Wolbachia on virus replication within C. lectularius. METHODS: We used feline calicivirus as a model pathogen. We fed 40 bed bugs from an established line of Wolbachia-cured and a line of Wolbachia-positive C. lectularius a virus-laden blood meal, and quantified the amount of virus over five time intervals post-feeding. The antibiotic rifampicin was used to cure bed bugs of Wolbachia. RESULTS: There was a significant effect of time post-feeding, as the amount of virus declined by ~90% over 10 days in both groups, but no significant difference in virus titer was observed between the Wolbachia-positive and Wolbachia-cured groups. CONCLUSIONS: These findings suggest that other mechanisms are involved in virus suppression within bed bugs, independent of the influence of Wolbachia, and our conclusions underscore the need for future research.


Assuntos
Percevejos-de-Cama/microbiologia , Percevejos-de-Cama/virologia , Calicivirus Felino/crescimento & desenvolvimento , Calicivirus Felino/isolamento & purificação , Interações Microbianas , Carga Viral , Wolbachia/crescimento & desenvolvimento , Animais
16.
Neurology ; 93(10): e964-e967, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31363058

RESUMO

OBJECTIVE: To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children. METHODS: A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed. RESULTS: The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%). CONCLUSIONS: Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.


Assuntos
Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromina 2/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
17.
Arthrosc Tech ; 8(6): e597-e603, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31334016

RESUMO

Rotator cuff tears are increasing in frequency in the aging population and are a common issue seen by orthopaedic surgeons. In patients with large, multi-tendon rotator cuff tears or retears, treatment can be challenging. Failure rates of up to 90% have been reported for rotator cuff repair (RCR) of large, multi-tendon tears. Biological augmentation has been an area of interest because of the distinctly different biology of the repaired tendon compared with the native tendon. These biological differences affect the ultimate tensile properties of the repair and may contribute to gap formation and the high failure rate of repairs. RCR with allograft augmentation is a technique that shows potential benefit to healing and preventing retears. Arthroscopic augmentation of RCRs can be challenging. The technique described in this Technical Note illustrates a simple and easily reproducible method for augmenting RCRs with human acellular dermal allograft.

18.
Lancet Oncol ; 20(7): 1011-1022, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31151904

RESUMO

BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

19.
Nat Neurosci ; 22(7): 1182-1195, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209381

RESUMO

Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To systematically profile morpho-electric properties of mammalian neurons, we established a single-cell characterization pipeline using standardized patch-clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly accessible online database, the Allen Cell Types Database, to display these datasets. Intrinsic physiological properties were measured from 1,938 neurons from the adult laboratory mouse visual cortex, morphological properties were measured from 461 reconstructed neurons, and 452 neurons had both measurements available. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We established a taxonomy of morphologically and electrophysiologically defined cell types for this region of the cortex, with 17 electrophysiological types, 38 morphological types and 46 morpho-electric types. There was good correspondence with previously defined transcriptomic cell types and subclasses using the same transgenic mouse lines.


Assuntos
Conjuntos de Dados como Assunto , Neurônios/classificação , Córtex Visual/citologia , Potenciais de Ação , Animais , Forma Celular , Bases de Dados Factuais , Genes Reporter , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Transcriptoma , Córtex Visual/fisiologia
20.
Drug Metab Dispos ; 47(7): 724-731, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028057

RESUMO

Midazolam is a widely used index substrate for assessing effects of xenobiotics on CYP3A activity. A previous study involving human hepatocytes showed the primary route of midazolam metabolism, 1'-hydroxylation, shifted to N-glucuronidation in the presence of the CYP3A inhibitor ketoconazole, which may lead to an overprediction of the magnitude of a xenobiotic-midazolam interaction. Because ketoconazole is no longer recommended as a clinical CYP3A inhibitor, indinavir was selected as an alternate CYP3A inhibitor to evaluate the contribution of the N-glucuronidation pathway to midazolam metabolism. The effects of indinavir on midazolam 1'-hydroxylation and N-glucuronidation were first characterized in human-derived in vitro systems. Compared with vehicle, indinavir (10 µM) inhibited midazolam 1'-hydroxylation by recombinant CYP3A4, human liver microsomes, and high-CYP3A activity cryopreserved human hepatocytes by ≥70%; the IC50 obtained with hepatocytes (2.7 µM) was within reported human unbound indinavir Cmax (≤5 µM). Midazolam N-glucuronidation in hepatocytes increased in the presence of indinavir in both a concentration-dependent (1-33 µM) and time-dependent (0-4 hours) manner (by up to 2.5-fold), prompting assessment in human volunteers (n = 8). As predicted by these in vitro data, indinavir was a strong inhibitor of the 1'-hydroxylation pathway, decreasing the 1'-hydroxymidazolam/midazolam area under the plasma concentration versus time curve (AUC)0-12h ratio by 80%. Although not statistically significant, the midazolam N-glucuronide/midazolam AUC0-12h ratio increased by 40%, suggesting a shift to the N-glucuronidation pathway. The amount of midazolam N-glucuronide recovered in urine increased 4-fold but remained <10% of the oral midazolam dose (2.5 mg). A powered clinical study would clarify whether N-glucuronidation should be considered when assessing the magnitude of a xenobiotic-midazolam interaction.

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