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1.
CA Cancer J Clin ; 71(4): 315-332, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33793968

RESUMEN

Although significant improvements have been made in the outcomes of children with cancer, the pace of improvement has slowed in recent years as the limits of therapy intensification may have been reached for many pediatric cancers. Furthermore, with increasing numbers of pediatric cancer survivors, the long-term side effects of treatment have become increasingly apparent. Therefore, attention has shifted to the use of molecularly targeted agents and immunotherapies to improve the outcomes of children who are not cured by traditional cytotoxic chemotherapies and to decrease exposure to cytotoxic chemotherapy and reduce late effects. This review describes the recent progress in the treatment of children with cancer, focusing in particular on diseases in which targeted and immunotherapeutic agents have made an impact.


Asunto(s)
Oncología Médica/tendencias , Neoplasias/terapia , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Niño , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética
2.
J Pediatr Hematol Oncol ; 44(4): 147-154, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35129140

RESUMEN

Primary extrarenal Wilms tumors are rare neoplasms that are presumed to arise from metanephric or mesonephric remnants outside of the kidney. Their pathogenesis is debated but has not been studied, and there are no reports of genomic descriptions of extrarenal Wilms tumors. We describe a diffusely anaplastic extrarenal Wilms tumor that occurred in the lower abdomen and upper pelvis of a 10-year-old boy. In addition to the clinical, histopathologic, and radiologic features, we describe the cytogenetic changes and exomic profile of the tumor. The tumor showed loss of the tumor suppressor AMER1, loss of chromosome regions 1p, 16q, and 22q, gain of chromosome 8, and loss of function TP53 mutation-findings known to occur in renal Wilms tumors. This is the first description of the exomic profile of a primary extrarenal Wilms tumor. Our data indicate that primary extrarenal Wilms tumors may follow the same pathogenetic pathways that are seen in renal Wilms tumors. Finally, we describe the establishment of first ever tumor models (primary cell line and patient-derived xenograft) from an extrarenal Wilms tumor.


Asunto(s)
Neoplasias Renales , Tumor de Wilms , Niño , Femenino , Humanos , Riñón/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Mutación , Tumor de Wilms/genética , Tumor de Wilms/patología
3.
J Natl Compr Canc Netw ; 19(11): 1277-1303, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34781268

RESUMEN

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.


Asunto(s)
Enfermedad de Erdheim-Chester , Neoplasias Hematológicas , Histiocitosis de Células de Langerhans , Histiocitosis Sinusal , Adulto , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/patología , Histiocitosis Sinusal/diagnóstico , Histiocitosis Sinusal/tratamiento farmacológico , Histiocitosis Sinusal/patología , Humanos , Pronóstico
4.
Pediatr Blood Cancer ; 67(12): e28639, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32975370

RESUMEN

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date. PROCEDURE: We conducted preclinical pharmacokinetic (PK) and pharmacodynamic studies of two MEK inhibitors, trametinib and selumetinib, in two MPNST models and analyzed tumors for intratumor drug levels. We then investigated 3'-deoxy-3'-[18 F]fluorothymidine (18 F-FLT) PET imaging followed by 18 F-FDG PET/CT imaging of MPNST xenografts coupled to short-term or longer-term treatment with selumetinib focusing on PET-based imaging as a biomarker of MEK inhibition. RESULTS: Trametinib decreased pERK expression in MPNST xenografts but did not prolong survival or decrease Ki67 expression. In contrast, selumetinib prolonged survival of animals bearing MPNST xenografts, and this correlated with decreased pERK and Ki67 staining. PK studies revealed a significantly higher fraction of unbound selumetinib within a responsive MPNST xenograft model. Thymidine uptake, assessed by 18 F-FLT PET/CT, positively correlated with Ki67 expression in different xenograft models and in response to selumetinib. CONCLUSION: The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug-induced changes in pERK expression. Tumor cell proliferation assessed by 18 F-FLT PET imaging might be useful as an early response marker to targeted therapies, including MEK inhibition, where a primary effect is cell-cycle arrest.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neurofibrosarcoma/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Proteínas ras/antagonistas & inhibidores , Animales , Apoptosis , Bencimidazoles/administración & dosificación , Proliferación Celular , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neurofibrosarcoma/diagnóstico por imagen , Neurofibrosarcoma/tratamiento farmacológico , Neurofibrosarcoma/metabolismo , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Radiofármacos/farmacocinética , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Electrophoresis ; 40(9): 1353-1364, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30767247

RESUMEN

This study examined 266 individuals from various populations including African American, East Asian, South Asian, European, and mixed populations to evaluate the ForenSeq™ Signature Prep Kit Primer Mix B. Focus was placed on phenotypic and biogeographical ancestry predictions by Illumina's Universal Analysis Software (UAS). These outcomes were compared to those obtained through web-tools developed at the Erasmus Medical Center (EMC) and available from the Forensic Resource/Reference on Genetics-knowledge base (FROG-kb), as well as to eye color predictions by the 8-plex system. Due to drop-outs, predictions for eye and hair color by UAS failed for various samples in each run. By including reads below thresholds, predictions could be obtained for all samples through the web-tools. Eye and hair color predictions for African Americans, East Asians, and South Asians showed no errors. Difficulties however, were noted in intermediate (neither blue nor brown) eye color predictions. These were mitigated by the 8-plex system through exclusion of one eye color (e.g. "not brown"). Additionally, notable discrepancies were observed in hair color predictions, where some black/dark-brown haired individuals were predicted to have blond hair. Overall, ancestry predictions were more accurate by FROG-kb compared to UAS, which did not predict South Asian ancestry, particularly Indian individuals.


Asunto(s)
Color del Ojo , Color del Cabello , Grupos Raciales , Programas Informáticos , Dermatoglifia del ADN , Etnicidad , Humanos , Internet , Fenotipo
6.
Artif Organs ; 41(11): E233-E239, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29148138

RESUMEN

Cerebral palsy (CP) is the most common childhood motor disability and often results in debilitating walking abnormalities, such as flexed-knee and stiff-knee gait. Current medical and surgical treatments are only partially effective in improving gait abnormalities and may cause significant muscle weakness. However, emerging artificial walking technologies, such as step-initiated, multichannel neuromuscular electrical stimulation (NMES), can substantially improve gait patterns and promote muscle strength in children with spastic CP. NMES may also be applied to specific lumbar-sacral sensory roots to reduce spasticity. Development of tablet computer-based multichannel NMES can leverage lightweight, wearable wireless stimulators, advanced control design, and surface electrodes to activate lower-limb muscles. Musculoskeletal models have been used to characterize muscle contributions to unimpaired gait and identify high muscle demands, which can help guide multichannel NMES-assisted gait protocols. In addition, patient-specific NMES-assisted gait protocols based on 3D gait analysis can facilitate the appropriate activation of lower-limb muscles to achieve a more functional gait: stance-phase hip and knee extension and swing-phase sequence of hip and knee flexion followed by rapid knee extension. NMES-assisted gait treatment can be conducted as either clinic-based or home-based programs. Rigorous testing of multichannel NMES-assisted gait training protocols will determine optimal treatment dosage for future clinical trials. Evidence-based outcome evaluation using 3D kinematics or temporal-spatial gait parameters will help determine immediate neuroprosthetic effects and longer term neurotherapeutic effects of step-initiated, multichannel NMES-assisted gait in children with spastic CP. Multichannel NMES is a promising assistive technology to help children with spastic CP achieve a more upright, functional gait.


Asunto(s)
Corteza Cerebral/fisiopatología , Parálisis Cerebral/rehabilitación , Terapia por Estimulación Eléctrica/instrumentación , Marcha , Extremidad Inferior/inervación , Actividad Motora , Caminata , Fenómenos Biomecánicos , Parálisis Cerebral/diagnóstico , Parálisis Cerebral/fisiopatología , Terapia por Estimulación Eléctrica/métodos , Diseño de Equipo , Humanos , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento
7.
Appl Environ Microbiol ; 82(11): 3208-3216, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-26994080

RESUMEN

UNLABELLED: In the summer of 2010, Vibrio parahaemolyticus caused an outbreak in Maryland linked to the consumption of oysters. Strains isolated from both stool and oyster samples were indistinguishable by pulsed-field gel electrophoresis (PFGE). However, the oysters contained other potentially pathogenic V. parahaemolyticus strains exhibiting different PFGE patterns. In order to assess the identity, genetic makeup, relatedness, and potential pathogenicity of the V. parahaemolyticus strains, we sequenced 11 such strains (2 clinical strains and 9 oyster strains). We analyzed these genomes by in silico multilocus sequence typing (MLST) and determined their phylogeny using a whole-genome MLST (wgMLST) analysis. Our in silico MLST analysis identified six different sequence types (STs) (ST8, ST676, ST810, ST811, ST34, and ST768), with both of the clinical and four of the oyster strains being identified as belonging to ST8. Using wgMLST, we showed that the ST8 strains from clinical and oyster samples were nearly indistinguishable and belonged to the same outbreak, confirming that local oysters were the source of the infections. The remaining oyster strains were genetically diverse, differing in >3,000 loci from the Maryland ST8 strains. eBURST analysis comparing these strains with strains of other STs available at the V. parahaemolyticus MLST website showed that the Maryland ST8 strains belonged to a clonal complex endemic to Asia. This indicates that the ST8 isolates from clinical and oyster sources were likely not endemic to Maryland. Finally, this study demonstrates the utility of whole-genome sequencing (WGS) and associated analyses for source-tracking investigations. IMPORTANCE: Vibrio parahaemolyticus is an important foodborne pathogen and the leading cause of bacterial infections in the United States associated with the consumption of seafood. In the summer of 2010, Vibrio parahaemolyticus caused an outbreak in Maryland linked to oyster consumption. Strains isolated from stool and oyster samples were indistinguishable by pulsed-field gel electrophoresis (PFGE). The oysters also contained other potentially pathogenic V. parahaemolyticus strains with different PFGE patterns. Since their identity, genetic makeup, relatedness, and potential pathogenicity were unknown, their genomes were determined by using next-generation sequencing. Whole-genome sequencing (WGS) analysis by whole-genome multilocus sequence typing (wgMLST) allowed (i) identification of clinical and oyster strains with matching PFGE profiles as belonging to ST8, (ii) determination of oyster strain diversity, and (iii) identification of the clinical strains as belonging to a clonal complex (CC) described only in Asia. Finally, WGS and associated analyses demonstrated their utility for trace-back investigations.


Asunto(s)
Brotes de Enfermedades , Ostreidae/microbiología , Vibriosis/epidemiología , Vibrio parahaemolyticus/clasificación , Vibrio parahaemolyticus/aislamiento & purificación , Animales , ADN Bacteriano/genética , Electroforesis en Gel de Campo Pulsado , Genotipo , Humanos , Maryland/epidemiología , Epidemiología Molecular , Tipificación de Secuencias Multilocus , Filogenia , Análisis de Secuencia de ADN , Vibrio parahaemolyticus/genética
8.
J Anat ; 228(4): 561-8, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26712532

RESUMEN

The gastrocnemius muscle-tendon unit (MTU) is central to human locomotion. Structural variation in the human gastrocnemius MTU is predicted to affect the efficiency of locomotion, a concept most often explored in the context of performance activities. For example, stiffness of the Achilles tendon varies among individuals with different histories of competitive running. Such a finding highlights the functional variation of individuals and raises the possibility of similar variation between populations, perhaps in response to specific ecological or environmental demands. Researchers often assume minimal variation in human populations, or that industrialized populations represent the human species as well as any other. Yet rainforest hunter-gatherers, which often express the human pygmy phenotype, contradict such assumptions. Indeed, the human pygmy phenotype is a potential model system for exploring the range of ecomorphological variation in the architecture of human hindlimb muscles, a concept we review here.


Asunto(s)
Tendón Calcáneo/anatomía & histología , Ecosistema , Músculo Esquelético/anatomía & histología , Tendones/anatomía & histología , Humanos , Fenotipo
9.
PLoS Genet ; 8(2): e1002488, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22319455

RESUMEN

Overexpression or mutation of α-Synuclein is associated with protein aggregation and interferes with a number of cellular processes, including mitochondrial integrity and function. We used a whole-genome screen in the fruit fly Drosophila melanogaster to search for novel genetic modifiers of human [A53T]α-Synuclein-induced neurotoxicity. Decreased expression of the mitochondrial chaperone protein tumor necrosis factor receptor associated protein-1 (TRAP1) was found to enhance age-dependent loss of fly head dopamine (DA) and DA neuron number resulting from [A53T]α-Synuclein expression. In addition, decreased TRAP1 expression in [A53T]α-Synuclein-expressing flies resulted in enhanced loss of climbing ability and sensitivity to oxidative stress. Overexpression of human TRAP1 was able to rescue these phenotypes. Similarly, human TRAP1 overexpression in rat primary cortical neurons rescued [A53T]α-Synuclein-induced sensitivity to rotenone treatment. In human (non)neuronal cell lines, small interfering RNA directed against TRAP1 enhanced [A53T]α-Synuclein-induced sensitivity to oxidative stress treatment. [A53T]α-Synuclein directly interfered with mitochondrial function, as its expression reduced Complex I activity in HEK293 cells. These effects were blocked by TRAP1 overexpression. Moreover, TRAP1 was able to prevent alteration in mitochondrial morphology caused by [A53T]α-Synuclein overexpression in human SH-SY5Y cells. These results indicate that [A53T]α-Synuclein toxicity is intimately connected to mitochondrial dysfunction and that toxicity reduction in fly and rat primary neurons and human cell lines can be achieved using overexpression of the mitochondrial chaperone TRAP1. Interestingly, TRAP1 has previously been shown to be phosphorylated by the serine/threonine kinase PINK1, thus providing a potential link of PINK1 via TRAP1 to α-Synuclein.


Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Drosophila melanogaster/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Mitocondrias/metabolismo , Chaperonas Moleculares/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Adenosina Trifosfato/biosíntesis , Adenosina Trifosfato/genética , Animales , Supervivencia Celular/genética , Dopamina/fisiología , Neuronas Dopaminérgicas/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Células HEK293 , Proteínas HSP90 de Choque Térmico/genética , Humanos , Potencial de la Membrana Mitocondrial , Mitocondrias/genética , Chaperonas Moleculares/genética , Mutación , Estrés Oxidativo , Células PC12 , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , ARN Interferente Pequeño , Ratas , Rotenona/farmacología , alfa-Sinucleína/toxicidad
11.
J Forensic Sci ; 69(2): 391-399, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37924233

RESUMEN

Age estimation is an important component of decedent identification. When assessing adult remains, anthropologists frequently use gross examination of skeletal elements, such as clavicles, ribs, and pubic symphyses. For fleshed bodies, this requires the removal of these elements and maceration prior to analysis. A new method was developed using radiographic imaging to estimate age from degenerative changes of the lower thoracic and upper lumbar vertebrae. This technique will complement anthropological age estimation methods in young and middle-aged adults and may serve as a stand-alone method for older individuals. Digital radiographs from 240 medical examiner cases were evaluated. The sample included 120 females and 120 males between the ages of 18 and 101 years. A 3-phased scoring system was used for the target vertebrae. Transition analysis was conducted on binned average scores and a Bayesian approach was used to assign age intervals. At the 90% credible interval, individuals in Bin 1 were under 36 years of age while those in Bin 3 were over 47 years of age. Individuals in Bin 2 showed too much age variation to be informative. No significant differences were found between males and females. These findings will be especially useful in the age estimation of older adults and may eliminate the need for skeletal sampling in medicolegal cases where advanced degenerative changes are radiographically observed in the lower thoracic and/or upper lumbar vertebrae. This method was developed for use on fleshed individuals but may also be applicable to skeletonized remains.


Asunto(s)
Determinación de la Edad por el Esqueleto , Sínfisis Pubiana , Masculino , Femenino , Persona de Mediana Edad , Humanos , Anciano , Adolescente , Adulto Joven , Adulto , Anciano de 80 o más Años , Teorema de Bayes , Determinación de la Edad por el Esqueleto/métodos , Radiografía , Vértebras Lumbares/diagnóstico por imagen , Sínfisis Pubiana/anatomía & histología , Antropología Forense
12.
Cureus ; 15(6): e40103, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37425561

RESUMEN

Iron poisoning is a significant and potentially life-threatening condition that is commonly encountered in the emergency department. The severity of toxicity is based on the amount of iron ingested, and symptoms can range from mild gastrointestinal discomfort to multi-organ failure. Although current guidelines recommend therapy for patients with estimated ingestion of >60 mg/kg, the most useful laboratory test to determine toxicity is the serum iron level measured at four to six hours after ingestion. In this report, we present a case of a 28-year-old female who ingested a toxic dose of iron (88 mg/kg) but was only minimally symptomatic and managed with supportive care alone. The case highlights the importance of a high index of suspicion, careful clinical evaluation in patients with iron toxicity, and the need for individualized treatment decisions based on the patient's clinical presentation and laboratory values.

13.
Chemosphere ; 332: 138811, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37127196

RESUMEN

Pollution by microplastics (MPs) is a growing problem that is now well-recognized, as concerning levels of MPs have been found in drinking water, food, and even human tissues. Given the evolving understanding of their toxicological effects on human health, MPs are an area of concern requiring further study. Consequently, there is a need for greater understanding of the performance characteristics of common MP analytical methods and where possible, for standardizing methods and reporting practices. Here, we report our work comparing filtration and imaging properties of five analytical filters suitable for MP capture and analysis. We compared track-etched polycarbonate with (PCTEG) and without gold coating (PCTE), polytetrafluoroethylene (PTFE), porous silicon (PSi), and gold-coated microslit silicon nitride membranes (MSSN-Au). Four of the filter types had a nominal 1.0 µm cut-off, except for PCTEG which had a 0.8 nominal cut-off. We examined the ultrastructure of each membrane type by electron microscopy to understand how their physical properties influence filtration and imaging performance. We compared clean water filtration rates and timed volume passage for each filter in comparison to its porosity and working surface area. We further compared optical microscopy imaging properties for each filter with model MP samples in both bright-field and fluorescent modes with accompanying Nile Red staining. In terms of absolute and surface area-normalized flow rates, our measurements ranked the filters in order of MSSN-Au > PTFE > PCTE > PCTEG > PSi. Similarly, we found MSSN-Au filters compared favorably in terms of optical microscopy performance. Collectively, these data will aid practitioners when choosing analytical filters for MP surveillance and testing.


Asunto(s)
Agua Potable , Contaminantes Químicos del Agua , Humanos , Plásticos , Microplásticos , Politetrafluoroetileno , Agua Potable/análisis , Filtración/métodos , Oro/química , Microscopía , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente
14.
Front Epidemiol ; 3: 1139337, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38455900

RESUMEN

Introduction: High-level prenatal and childhood arsenic (As) exposure characteristic of several regions in Asia (e.g., Bangladesh), may impact motor function. However, the relationship between lower-level arsenic exposure (characteristic of other regions) and motor development is largely unstudied, despite the potential for deficient motor skills in childhood to have adverse long-term consequences. Thus, we sought to investigate the association between prenatal As exposure and motor function among 395 children in the New Hampshire Birth Cohort Study, a rural cohort from northern New England. Methods: Prenatal exposure was estimated by measuring maternal urine speciated As at 24-28 weeks of gestation using high-performance liquid chromatography (HPLC) inductively coupled plasma mass spectrometry (ICP-MS) and summing inorganic As, monomethylarsonic acid, and dimethylarsinic acid to obtain total urinary As (tAs). Motor function was assessed with the Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) at a mean (SD) age of 5.5 (0.4) years. Results: Children who completed this exam were largely reported as white race (97%), born to married mothers (86%) with a college degree or higher (67%). The median (IQR) gestational urine tAs concentration was 4.0 (5.0) µg/L. Mean (SD) BOT-2 scores were 48.6 (8.4) for overall motor proficiency and 48.2 (9.6) for fine manual control [standard score = 50 (10)], and were 16.3 (5.1) for fine motor integration and 12.5 (4.1) for fine motor precision [standard score = 15 (5)]. We found evidence of a non-linear dose response relationship and used a change-point model to assess the association of tAs with overall motor proficiency and indices of fine motor integration, fine motor precision, and their composite, fine manual control, adjusted for age and sex. In models adjusted for potential confounders, each doubling of urine tAs decreased overall motor proficiency by -3.3 points (95% CI: -6.1, -0.4) for tAs concentrations greater than the change point of 9.5 µg/L and decreased fine motor integration by -4.3 points (95% CI: -8.0, -0.6) for tAs concentrations greater than the change point of 17.0 µg/L. Discussion: In summary, we found that levels of prenatal As exposure above an empirically-derived threshold (i.e., the change point) were associated with decrements in childhood motor development in a US population.

15.
iScience ; 26(11): 108171, 2023 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-37915590

RESUMEN

Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poorer overall outcome. Of 117 primary leukemia samples obtained, successful engraftment and serial passage in mice were achieved in 82 samples (70%). Hispanic patient samples engrafted at a rate (51/73, 70%) that was similar to non-Hispanic patient samples (31/45, 70%). With a new algorithm to remove mouse contamination in multi-omics datasets including methylation data, we found PDX models faithfully reflected somatic mutations, copy-number alterations, RNA expression, gene fusions, whole-genome methylation patterns, and immunophenotypes found in primary tumor (PT) samples in the first 50 reported here. This cohort of characterized PDX childhood leukemias represents a valuable resource in that germline DNA sequencing has allowed the unambiguous determination of somatic mutations in both PT and PDX.

16.
Nat Commun ; 14(1): 7600, 2023 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-37990009

RESUMEN

Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.


Asunto(s)
Neoplasias , Animales , Niño , Humanos , Xenoinjertos , Neoplasias/genética , Neoplasias/patología , Transcriptoma/genética , Mutación , Modelos Animales de Enfermedad , Genómica/métodos , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Sci Rep ; 12(1): 12369, 2022 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-35858951

RESUMEN

Museums displaying artifacts of the human struggle against oppression are often caught in their own internal struggle between presenting factual and unbiased descriptions of their collections, or relying on testament of survivors. Often this quandary is resolved in favor of what can be verified, not what is remembered. However, with improving instrumentation, methods and informatic approaches, science can help uncover evidence able to reconcile memory and facts. Following World War II, thousands of small, cement-like disks with numbers impressed on one side were found at concentration camps throughout Europe. Survivors claimed these disks were made of human cremains; museums erred on the side of caution-without documentation of the claims, was it justifiable to present them as fact? The ability to detect species relevant biological material in these disks could help resolve this question. Proteomic mass spectrometry of five disks revealed all contained proteins, including collagens and hemoglobins, suggesting they were made, at least in part, of animal remains. A new protein/informatics approach to species identification showed that while human was not always identified as the top contributor, human was the most likely explanation for one disk. To our knowledge, this is the first demonstration of protein recovery from cremains. Data are available via ProteomeXchange with identifier PXD035267.


Asunto(s)
Campos de Concentración , Animales , Artefactos , Europa (Continente) , Humanos , Proteómica , Segunda Guerra Mundial
18.
Womens Health Rep (New Rochelle) ; 3(1): 274-280, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35262066

RESUMEN

Introduction: Although regular exercise is recommended during non-complicated pregnancies to promote maternal and fetal/infant health, estimates suggest that only 15% of expectant mothers achieve current exercise recommendations. Although lack of motivation and fear related to potential fetal injury are often cited as reasons for not engaging in regular physical activity/exercise during pregnancy, less is understood about individual attitudes and practice habits of obstetrician and gynecologists (OB/GYNs) regarding exercise recommendations that may influence patient engagement in exercise during pregnancy. Purpose: To describe the attitudes, knowledge, and clinical practice of OB/GYNs regarding exercise during pregnancy. Methods: Surveys were sent via U.S. mail to 950 practicing OB/GYNs identified via publicly available databases. The survey included 11 questions regarding demographic information, exercise physiology knowledge, as well as their attitudes and clinical practice recommendations regarding exercise during pregnancy. Results: One hundred thirty-nine completed surveys were returned (14.6% response rate). Ninety-four percent of physicians surveyed agreed that there are benefits of exercise during pregnancy and/or the benefits of exercise during pregnancy outweigh the risks. Ninety-eight percent of physicians surveyed reported that they (or their medical staff) routinely advise their patients to exercise during pregnancy and 46% reported discussing exercise guidelines related to time, intensity, and type of exercise. Only 13% of physicians surveyed reported taking a semester-long exercise physiology course, yet 27% of physicians surveyed reported developing personalized exercise prescriptions for all (6%) or some (21%) of their patients. Conclusions: Low exercise engagement among expectant mothers does not appear to be due to a lack of guidance or negative views of OB/GYNs regarding exercise during pregnancy.

19.
Artículo en Inglés | MEDLINE | ID: mdl-35933111

RESUMEN

Rhabdomyosarcoma (RMS) is a childhood sarcoma composed of myoblast-like cells, which suggests a defect in terminal skeletal muscle differentiation. To explore potential defects in the differentiation program, we searched for mRNA splicing variants in genes encoding transcription factors driving skeletal muscle lineage commitment and differentiation. We studied two RMS cases and identified altered splicing resulting in "skipping" the second of three exons in MYOD1. RNA-Seq data from 42 tumors and additional RMS cell lines revealed exon 2 skipping in both MYOD1 and MYF5 but not in MYF6 or MYOG. Complementary molecular analysis of MYOD1 mRNA found evidence for exon skipping in 5 additional RMS cases. Functional studies showed that so-called MYODΔEx2 protein failed to robustly induce muscle-specific genes, and its ectopic expression conferred a selective advantage in cultured fibroblasts and an RMS xenograft. In summary, we present previously unrecognized exon skipping within MYOD1 and MYF5 in RMS, and we propose that alternative splicing can represent a mechanism to alter the function of these two transcription factors in RMS.

20.
Sci Rep ; 12(1): 15914, 2022 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-36151130

RESUMEN

The ocean is experiencing unprecedented rapid change, and visually monitoring marine biota at the spatiotemporal scales needed for responsible stewardship is a formidable task. As baselines are sought by the research community, the volume and rate of this required data collection rapidly outpaces our abilities to process and analyze them. Recent advances in machine learning enables fast, sophisticated analysis of visual data, but have had limited success in the ocean due to lack of data standardization, insufficient formatting, and demand for large, labeled datasets. To address this need, we built FathomNet, an open-source image database that standardizes and aggregates expertly curated labeled data. FathomNet has been seeded with existing iconic and non-iconic imagery of marine animals, underwater equipment, debris, and other concepts, and allows for future contributions from distributed data sources. We demonstrate how FathomNet data can be used to train and deploy models on other institutional video to reduce annotation effort, and enable automated tracking of underwater concepts when integrated with robotic vehicles. As FathomNet continues to grow and incorporate more labeled data from the community, we can accelerate the processing of visual data to achieve a healthy and sustainable global ocean.


Asunto(s)
Inteligencia Artificial , Aprendizaje Automático , Animales , Biota , Bases de Datos Factuales , Océanos y Mares
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