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1.
Cancer ; 130(14): 2416-2439, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38687639

RESUMO

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.


Assuntos
Histiocitose de Células de Langerhans , Humanos , Histiocitose de Células de Langerhans/tratamento farmacológico
2.
Oncologist ; 29(8): 723-e1093, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38873934

RESUMO

BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).


Assuntos
Mutação , Proteínas Proto-Oncogênicas B-raf , Vemurafenib , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêutico , Vemurafenib/administração & dosagem , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pré-Escolar , Neoplasias/tratamento farmacológico , Neoplasias/genética
3.
Genet Med ; 26(8): 101168, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38767058

RESUMO

PURPOSE: Professional guidelines recommend engaging adolescents and young adults (AYAs) in medical decision making (DM), including whether to undergo genomic sequencing (GS). We explored DM around GS and attitudes after return of GS results among a diverse group of AYAs with cancer and their parents. METHODS: We surveyed AYAs with cancer (n = 75) and their parents (n = 52) 6 months after receiving GS results through the Texas KidsCanSeq study. We analyzed AYAs' DM role in GS research enrollment and their satisfaction with that role. We compared AYAs' and parents' self-reported understanding of, attitudes toward, and perceived utility of the AYA's GS results. RESULTS: Most AYAs reported equally sharing DM with their parents (55%) or leading DM (36%) about GS research. Compared with their cancer care DM role, 56% of AYAs reported the same level of involvement in GS research DM, whereas 32% were more involved, and 13% were less involved (P = .011). AYAs were satisfied (99%) with their DM role regarding GS study participation. AYAs and parents had similar self-reported understanding of, attitudes toward, and perceived utility of the GS results. CONCLUSION: Our results support engaging AYAs in DM about GS research and provide insights into AYAs' DM preferences and positive attitudes toward GS.


Assuntos
Tomada de Decisões , Neoplasias , Pais , Humanos , Adolescente , Masculino , Feminino , Pais/psicologia , Adulto Jovem , Neoplasias/genética , Neoplasias/psicologia , Neoplasias/terapia , Adulto , Inquéritos e Questionários , Genômica/métodos , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde
4.
J Pediatr Hematol Oncol ; 46(5): 262-271, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38857189

RESUMO

Precision oncology incorporates comprehensive genomic profiling into the individualized clinical care of pediatric cancer patients. In recent years, comprehensive pan-cancer analyses have led to the successful implementation of genomics-based pediatric trials and accelerated approval of novel targeted agents. In addition, disease-specific studies have resulted in molecular subclassification of myriad cancer types with subsequent tailoring of treatment intensity based on the patient's prognostic factors. This review discusses the progress of the field and highlights developments that are leading to more personalized cancer care and improved patient outcomes. Increased understanding of the evolution of precision oncology over recent decades emphasizes the tremendous impact of improved genomic applications. New technologies and improved diagnostic modalities offer further promise for future advancements within the field.


Assuntos
Oncologia , Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/diagnóstico , Criança , Oncologia/métodos , Oncologia/tendências , Genômica/métodos
5.
J Genet Couns ; 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38225886

RESUMO

Access to genomic sequencing (GS) and resulting recommendations have not been well described in pediatric oncology. GS results may provide a cancer predisposition syndrome (CPS) diagnosis that warrants screening and specialist visits beyond cancer treatment, including testing or surveillance for family members. The Texas KidsCanSeq (KCS) Study evaluated implementation of GS in a diverse pediatric oncology population. We conducted semi-structured interviews (n = 20) to explore experiences of KCS patients' families around learning about a CPS diagnosis and following up on recommended care. We used qualitative content analysis to develop themes and subthemes across families' descriptions of their experiences accessing care and to understand which factors presented barriers and/or facilitators. We found participants had difficulty differentiating which follow-up care recommendations were made for their child's current cancer treatment versus the CPS. In families' access to follow-up care for CPS, organizational factors were crucial: travel time and distance were common hardships, while coordination of care to streamline multiple appointments with different providers helped facilitate CPS care. Financial factors also impacted families' access to CPS-related follow-up care: having financial assistance and insurance were facilitators for families, while costs and lack of insurance posed as barriers for patients who lost coverage during transitions from pediatric to adult care, and for adult family members who had no coverage. Factors related to beliefs and perceptions, specifically perceiving the risk as less salient to them and feeling overwhelmed with the patient's cancer care, presented barriers to follow-up care primarily for family members. Regarding social factors, competing life priorities made it difficult for families to access follow-up care, though having community support alleviated these barriers. We suggest interventions to improve coordination of cancer treatment and CPS-related care and adherence to surveillance protocols for families as children age, such as care navigators and integrating longitudinal genetic counseling into hereditary cancer centers.

6.
Pediatr Blood Cancer ; 70 Suppl 6: e30563, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37430453

RESUMO

The Developmental Therapeutics Committee (DVL) identifies and develops new agents and treatment strategies for children/adolescents with cancer, through clinical and translational research. DVL has focused on evaluating the activity of targeted therapy and has evolved from trials with multiple histology strata to biomarker-selected phase 2 trials. These trials have included single-agent studies to evaluate agents such as cabozantinib in multi-disease cohorts, to trametinib, larotrectinib, and lorvotuzumab in disease-specific cohorts, as well as the pediatric Molecular Analysis for Therapy Choice (MATCH) study including multiple single agents targeted for biomarker-selected pediatric tumors. The ongoing vision and direction of DVL is to support the disease committees of COG to develop novel agents and combinations to advance the care of children with cancer.


Assuntos
Neoplasias , Adolescente , Criança , Humanos , Neoplasias/tratamento farmacológico , Oncologia
7.
Phys Chem Chem Phys ; 25(4): 2671-2705, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36637007

RESUMO

Nanocomposite materials consist of nanometer-sized quantum objects such as atoms, molecules, voids or nanoparticles embedded in a host material. These quantum objects can be exploited as a super-structure, which can be designed to create material properties targeted for specific applications. For electromagnetism, such targeted properties include field enhancements around the bandgap of a semiconductor used for solar cells, directional decay in topological insulators, high kinetic inductance in superconducting circuits, and many more. Despite very different application areas, all of these properties are united by the common aim of exploiting collective interaction effects between quantum objects. The literature on the topic spreads over very many different disciplines and scientific communities. In this review, we present a cross-disciplinary overview of different approaches for the creation, analysis and theoretical description of nanocomposites with applications related to electromagnetic properties.

8.
Pediatr Hematol Oncol ; 40(8): 719-738, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37366551

RESUMO

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.


Assuntos
Neoplasias Encefálicas , DNA Tumoral Circulante , Humanos , Criança , DNA Tumoral Circulante/genética , Estudos de Viabilidade , Biomarcadores Tumorais , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Encefálicas/genética , Mutação
9.
Bioinformatics ; 37(8): 1164-1167, 2021 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-32821910

RESUMO

SUMMARY: Copy number variation (CNV) is an important category of unbalanced structural rearrangement. While methods for detecting CNV in high-throughput targeted sequencing have become increasingly sophisticated, dedicated tools for interactive and dynamic visualization of CNV from these data are still lacking. We describe reconCNV, a tool that produces an interactive and annotated web-based dashboard for viewing and summarizing CNVs detected in next-generation sequencing (NGS) data. reconCNV is designed to work with delimited result files from most NGS CNV callers with minor adjustments to the configuration file. The reconCNV output is an HTML file that is viewable on any modern web browser, requires no backend server, and can be readily appended to existing analysis pipelines. In addition to a standard CNV track for visualizing relative fold change and absolute copy number, the tool includes an auxiliary variant allele fraction track for visualizing underlying allelic imbalance and loss of heterozygosity. A feature to mask assay-specific technical artifacts and a direct HTML link out to the UCSC Genome Browser are also included to augment the reviewer experience. By providing a light-weight plugin for interactive visualization to existing NGS CNV pipelines, reconCNV can facilitate efficient NGS CNV visualization and interpretation in both research and clinical settings. AVAILABILITY AND IMPLEMENTATION: The source code and documentation including a tutorial can be accessed at https://github.com/rghu/reconCNV as well as a Docker image at https://hub.docker.com/repository/docker/raghuc1990/reconcnv. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Genoma , Software , Navegador
10.
Pediatr Blood Cancer ; 69(11): e29859, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35713195

RESUMO

BACKGROUND: The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). PROCEDURE: We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. RESULTS: There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at-risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis. CONCLUSION: Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Encefálicas , Criança , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Humanos , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicas Hereditárias
11.
J Pathol ; 255(1): 52-61, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34086347

RESUMO

The myogenic differentiation 1 gene (MYOD1) p.L122R somatic mutation was first discovered in a subset of clinically aggressive embryonal rhabdomyosarcomas and has since been described in both pediatric and adult spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about the clinical, molecular, and histopathological features of these tumors in children. In order to further characterize the genomic and clinical features of pediatric MYOD1-mutant sarcomas, we evaluated a cohort of soft-tissue sarcoma patients treated at Texas Children's Hospital. Tumor DNA was subjected to next-generation panel sequencing and/or Sanger sequencing of the MYOD1 hotspot mutation. The MYOD1 p.L122R mutation was identified in six tumors, with a variant allele fraction greater than 0.8 in three cases, suggestive of loss of heterozygosity. One sclerosing rhabdomyosarcoma lacking the MYOD1 hotspot mutation was observed to have a MYOD1 copy number gain, also with evidence of loss of heterozygosity. Cancer gene panel sequencing revealed potentially targetable alterations in six of seven (86%) patients with MYOD1 alterations, including four patients with an alteration in the PI3K-AKT pathway: two hotspot PIK3CA mutations and deletions in PTEN and TSC2. On histopathologic review, MYOD1-altered tumors exhibited spindle and/or round cells and varying degrees of hyaline sclerosis. At last follow-up, six patients had died of disease and the seventh progressed early and was subsequently lost to follow-up. Both pre- and post-therapy patient-derived xenograft models were generated from one patient's tumor. These models were confirmed to harbor the MYOD1 and PIK3CA mutations seen in the primary tumor and were shown to be sensitive to PI3K/mTOR inhibition in vitro and in vivo. In conclusion, this study adds to recent reports describing the clinicopathologic and genomic features of MYOD1-altered soft-tissue sarcomas in children, including dismal prognosis and potential molecular targets for therapy. The novel preclinical models developed will facilitate further biological and preclinical study of this rare and aggressive tumor. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Proteína MyoD/genética , Rabdomiossarcoma/genética , Neoplasias de Tecidos Moles/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adolescente , Animais , Antineoplásicos/farmacologia , Criança , Feminino , Genômica , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Mutação , Quinolinas/farmacologia , Rabdomiossarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Adulto Jovem
12.
Proc Biol Sci ; 288(1946): 20202754, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33653144

RESUMO

Humans are rapidly changing the marine environment through a multitude of effects, including increased greenhouse gas emissions resulting in warmer and acidified oceans. Elevated CO2 conditions can cause sensory deficits and altered behaviours in marine organisms, either directly by affecting end organ sensitivity or due to likely alterations in brain chemistry. Previous studies show that auditory-associated behaviours of larval and juvenile fishes can be affected by elevated CO2 (1000 µatm). Here, using auditory evoked potentials (AEP) and micro-computer tomography (microCT) we show that raising juvenile snapper, Chrysophyrs auratus, under predicted future CO2 conditions resulted in significant changes to their hearing ability. Specifically, snapper raised under elevated CO2 conditions had a significant decrease in low frequency (less than 200 Hz) hearing sensitivity. MicroCT demonstrated that these elevated CO2 snapper had sacculus otolith's that were significantly larger and had fluctuating asymmetry, which likely explains the difference in hearing sensitivity. We suggest that elevated CO2 conditions have a dual effect on hearing, directly effecting the sensitivity of the hearing end organs and altering previously described hearing induced behaviours. This is the first time that predicted future CO2 conditions have been empirically linked through modification of auditory anatomy to changes in fish hearing ability. Given the widespread and well-documented impact of elevated CO2 on fish auditory anatomy, predictions of how fish life-history functions dependent on hearing may respond to climate change may need to be reassessed.


Assuntos
Dióxido de Carbono , Água do Mar , Animais , Peixes , Audição , Humanos , Concentração de Íons de Hidrogênio , Oceanos e Mares
13.
Pediatr Blood Cancer ; 68(1): e28741, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33009870

RESUMO

BACKGROUND: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. METHODS: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. RESULTS: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. CONCLUSIONS: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Papilar/patologia , DNA de Neoplasias/análise , Neoplasias Pulmonares/secundário , Mutação , Análise de Sequência de RNA/métodos , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Carcinoma Papilar/genética , Criança , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Neoplasias Pulmonares/genética , Metástase Linfática , Masculino , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genética , Adulto Jovem
14.
Phys Chem Chem Phys ; 22(20): 11362-11373, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32373792

RESUMO

Considering ice-premelting on a quartz rock surface (i.e. silica) we calculate the Lifshitz excess pressures in a four layer system with rock-ice-water-air. Our calculations give excess pressures across (1) ice layer, (2) water layer, and (3) ice-water interface for different ice and water layer thicknesses. We analyse equilibrium conditions where the different excess pressures take zero value, stabilized in part by repulsive Lifshitz interactions. In contrast to previous investigations which considered varying thickness of only one layer (ice or water), here we present theory allowing for simultaneous variation of both layer thicknesses. For a given total thickness of ice and water, this allows multiple alternative equilibrium solutions. Consequently the final state of a system will depend on initial conditions and may explain variation in experimental measurements of the thicknesses of water and ice layers.

15.
Genet Med ; 21(12): 2791-2797, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31186522

RESUMO

PURPOSE: We describe parental perceptions of and experiences with genomic sequencing (GS) in the care of seriously ill children. Understanding parents' perspectives is vital for clinicians caring for children, given the uptake of genomic technologies into clinical practice. METHODS: Longitudinal, semistructured interviews were conducted with parents of pediatric cancer patients who underwent exome sequencing (ES) as a part of the BASIC3 study. Interviews were conducted at baseline, one to eight months after results disclosure, and approximately one year after disclosure. Using thematic qualitative analysis, parent interviews were coded with both inductive and deductive approaches. RESULTS: Before receiving genomic information, parents indicated that they saw ES as something responsible parents would agree to if their child had cancer. Some parents talked about the possibility of sequencing affecting feelings of culpability for their child's cancer, worrying that they passed on a cancer-causing gene or made parenting decisions that caused the disease. However, after receiving their child's ES results many reported feeling relieved of guilt and worry, and felt they had fulfilled parental duties by agreeing to ES for their child. CONCLUSION: These results reveal a layer of meaning that parents associate with GS that may inform clinicians' approach to care.


Assuntos
Testes Genéticos/ética , Poder Familiar/psicologia , Pais/psicologia , Adulto , Tomada de Decisões/ética , Revelação/ética , Feminino , Genômica , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estudos Longitudinais , Masculino , Neoplasias/genética , Análise de Sequência , Comportamento Social , Responsabilidade Social
16.
Langmuir ; 35(12): 4218-4223, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30821464

RESUMO

Gas bubbles in a water-filled cavity move upward because of buoyancy. Near the roof, additional forces come into play, such as Lifshitz, double layer, and hydrodynamic forces. Below uncharged metallic surfaces, repulsive Lifshitz forces combined with buoyancy forces provide a way to trap micrometer-sized bubbles. We demonstrate how bubbles of this size can be stably trapped at experimentally accessible distances, the distances being tunable with the surface material. By contrast, large bubbles (≥100 µm) are usually pushed toward the roof by buoyancy forces and adhere to the surface. Gas bubbles with radii ranging from 1 to 10 µm can be trapped at equilibrium distances from 190 to 35 nm. As a model for rock, sand grains, and biosurfaces, we consider dielectric materials such as silica and polystyrene, whereas aluminium, gold, and silver are the examples of metal surfaces. Finally, we demonstrate that the presence of surface charges further strengthens the trapping by inducing ion adsorption forces.

17.
Pediatr Blood Cancer ; 66(7): e27745, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30977242

RESUMO

BACKGROUND: Pediatric hepatocellular carcinoma (HCC) is a rare liver tumor in children with a poor prognosis. Comprehensive molecular profiling to understand the underlying genomic drivers of this tumor has not been completed, and it is unclear whether nonfibrolamellar pediatric HCC is more genomically similar to hepatoblastoma or adult HCC. PROCEDURE: To characterize the molecular landscape of these tumors, we analyzed a cohort of 15 pediatric non-FL-HCCs by sequencing a panel of cancer-associated genes and conducting copy-number and gene-expression analyses. RESULTS: We detected multiple types of molecular alterations in Wnt signaling genes, including APC inversion, AMER1 somatic mutation, and most commonly CTNNB1 intragenic deletions. There were multiple alterations to the telomerase pathway via TERT activation or ATRX mutation. Therapeutically targetable activating mutations in MAPK/ERK signaling pathway genes, including MAPK1 and BRAF, were detected in 20% of tumors. TP53 mutations occurred far less frequently in our pediatric HCC cohort than reported in adult cohorts. Tumors arising in children with underlying liver disease were found to be molecularly distinct from the remainder and lacking detectable oncogenic drivers, as compared with those arising in patients without a history of underlying liver disease; the majority of both types were positive for glypican-3, another potential therapeutic target. CONCLUSION: Our study revealed pediatric HCC to be a molecularly heterogeneous group of tumors. Those non-FL-HCC tumors arising in the absence of underlying liver disease harbor genetic alterations affecting multiple cancer pathways, most notably Wnt signaling, and share some characteristics with adult HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Sistema de Sinalização das MAP Quinases/genética , Mutação , Proteínas de Neoplasias/genética , Adolescente , Adulto , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Proteínas de Neoplasias/metabolismo
18.
Cancer ; 124(12): 2607-2620, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29624648

RESUMO

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.


Assuntos
Neoplasias Encefálicas/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Osteopontina/líquido cefalorraquidiano , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biópsia , Encéfalo/patologia , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Células-Tronco Hematopoéticas/patologia , Histiocitose de Células de Langerhans/líquido cefalorraquidiano , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Recém-Nascido , Leucócitos Mononucleares/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Adulto Jovem
19.
Hepatology ; 65(1): 104-121, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27775819

RESUMO

Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large-scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity. CONCLUSION: Analysis of immunohistochemical assays using antibodies targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis; our results pave the way for clinical collaborative studies to validate candidate biomarkers and test their potential to improve outcome for HB patients. (Hepatology 2017;65:104-121).


Assuntos
Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Regulação Neoplásica da Expressão Gênica , Genômica , Hepatoblastoma/classificação , Humanos , Neoplasias Hepáticas/classificação , Prognóstico
20.
Blood ; 128(21): 2533-2537, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27729324

RESUMO

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207+ dendritic cells with constitutively activated ERK. Mutually exclusive somatic mutations in MAPK pathway genes have been identified in ∼75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. To elucidate mechanisms of ERK activation in the remaining 25% of patients, we performed whole-exome sequencing (WES, n = 6), targeted BRAF sequencing (n = 19), and/or whole-transcriptome sequencing (RNA-seq, n = 6) on 24 LCH patient samples lacking BRAF-V600E or MAP2K1 mutations. WES and BRAF sequencing identified in-frame BRAF deletions in the ß3-αC loop in 6 lesions. RNA-seq revealed one case with an in-frame FAM73A-BRAF fusion lacking the BRAF autoinhibitory regulatory domain but retaining an intact kinase domain. High levels of phospho-ERK were detected in vitro in cells overexpressing either BRAF fusion or deletion constructs and ex vivo in CD207+ cells from lesions. ERK activation was resistant to BRAF-V600E inhibition, but responsive to both a second-generation BRAF inhibitor and a MEK inhibitor. These results support an emerging model of universal ERK-activating genetic alterations driving pathogenesis in LCH. A personalized approach in which patient-specific alterations are identified may be necessary to maximize benefit from targeted therapies for patients with LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ativação Enzimática/genética , Feminino , Histiocitose de Células de Langerhans/enzimologia , Humanos , Lactente , Masculino , Proteínas de Fusão Oncogênica/metabolismo , Domínios Proteicos , Proteínas Proto-Oncogênicas B-raf/metabolismo
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