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1.
Nature ; 547(7663): 311-317, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28726821

RESUMO

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.


Assuntos
Análise Mutacional de DNA , Genoma Humano/genética , Meduloblastoma/classificação , Meduloblastoma/genética , Sequenciamento Completo do Genoma , Carcinogênese/genética , Proteínas de Transporte/genética , Estudos de Coortes , Metilação de DNA , Conjuntos de Dados como Assunto , Epistasia Genética , Genômica , Humanos , Terapia de Alvo Molecular , Proteínas Musculares/genética , Mutação , Oncogenes/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética
2.
Nature ; 530(7588): 57-62, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26814967

RESUMO

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica/genética , Meduloblastoma/classificação , Meduloblastoma/patologia , Fatores de Transcrição/metabolismo , Animais , Neoplasias Cerebelares/classificação , Feminino , Redes Reguladoras de Genes/genética , Genes Neoplásicos/genética , Genes Reporter/genética , Humanos , Masculino , Meduloblastoma/genética , Camundongos , Reprodutibilidade dos Testes , Peixe-Zebra/genética
3.
Sensors (Basel) ; 22(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35161777

RESUMO

Analysis of volatile organic compound (VOC) emissions using electronic-nose (e-nose) devices has shown promise for early detection of white-nose syndrome (WNS) in bats. Tricolored bats, Perimyotis subflavus, from three separate sampling groups defined by environmental conditions, levels of physical activity, and WNS-disease status were captured temporarily for collection of VOC emissions to determine relationships between these combinations of factors and physiological states, Pseudogymnoascus destructans (Pd)-infection status, and metabolic conditions. Physiologically active (non-torpid) healthy individuals were captured outside of caves in Arkansas and Louisiana. In addition, healthy and WNS-diseased torpid bats were sampled within caves in Arkansas. Whole-body VOC emissions from bats were collected using portable air-collection and sampling-chamber devices in tandem. Electronic aroma-detection data using three-dimensional Principal Component Analysis provided strong evidence that the three groups of bats had significantly different e-nose aroma signatures, indicative of different VOC profiles. This was confirmed by differences in peak numbers, peak areas, and tentative chemical identities indicated by chromatograms from dual-column GC-analyses. The numbers and quantities of VOCs present in whole-body emissions from physiologically active healthy field bats were significantly greater than those of torpid healthy and diseased cave bats. Specific VOCs were identified as chemical biomarkers of healthy and diseased states, environmental conditions (outside and inside of caves), and levels of physiological activity. These results suggest that GC/E-nose dual-technologies based on VOC-detection and analyses of physiological states, provide noninvasive alternative means for early assessments of Pd-infection, WNS-disease status, and other physiological states.


Assuntos
Quirópteros , Compostos Orgânicos Voláteis , Animais , Biomarcadores , Nariz Eletrônico , Humanos , Nariz
4.
J Environ Manage ; 321: 115921, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35987056

RESUMO

The Nepal-India transboundary region hosts one of Asia's most complex large mammal assemblages, including a small (but growing) population of Asian elephants (Elephas maximus). These elephants occur in four widespread and geographically disjunct subpopulations, and some of them undergo seasonal transboundary movements. We conducted a broad-scale evaluation of the amount and quality of elephant habitat available in the region and of functional landscape connectivity between and within subpopulations using Maxent, circuit theory, and least-cost path analysis. Habitat suitability was highly influenced by abiotic geographical factors (altitude and precipitation) and less by ecological factors (habitat heterogeneity, plant productivity) and human disturbance (distance to settlements). The region had a relatively small amount of high and optimal suitability habitat (12.6% out of 93,700 km2) but all subpopulations seem to be far from carrying capacity, suggesting ample potential for further population growth. Landscape connectivity was higher between and within the west and far-west subpopulations, which should be considered a single subpopulation. The central and ea st subpopulations, however, had low to very low between-subpopulation connectivity. Conservation priorities include maintaining the current connectivity in the west subpopulation and across the border in the east, and protecting high-quality habitats in eastern Nepal. Restoring connectivity between the central and other subpopulations is possible if the number of elephants continues growing, and it should be a long-term conservation aspiration. Maintaining and enhancing landscape connectivity in this region requires transboundary cooperation and coordination between Nepali and Indian authorities. If successful, it will bring considerable benefits for the conservation of elephants and other wildlife.


Assuntos
Elefantes , Animais , Conservação dos Recursos Naturais , Ecossistema , Humanos , Índia , Nepal
5.
J Exp Biol ; 223(Pt 6)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32054681

RESUMO

Processes associated with recovery of survivors are understudied components of wildlife infectious diseases. White-nose syndrome (WNS) in bats provides an opportunity to study recovery of disease survivors, understand implications of recovery for individual energetics, and assess the role of survivors in pathogen transmission. We documented temporal patterns of recovery from WNS in little brown bats (Myotis lucifugus) following hibernation to test the hypotheses that: (1) recovery of wing structure from WNS matches a rapid time scale (i.e. approximately 30 days) suggested by data from free-ranging bats; (2) torpor expression plays a role in recovery; (3) wing physiological function returns to normal alongside structural recovery; and (4) pathogen loads decline quickly during recovery. We collected naturally infected bats at the end of hibernation, brought them into captivity, and quantified recovery over 40 days by monitoring body mass, wing damage, thermoregulation, histopathology of wing biopsies, skin surface lipids and fungal load. Most metrics returned to normal within 30 days, although wing damage was still detectable at the end of the study. Torpor expression declined overall throughout the study, but bats expressed relatively shallow torpor bouts - with a plateau in minimum skin temperature - during intensive healing between approximately days 8 and 15. Pathogen loads were nearly undetectable after the first week of the study, but some bats were still detectably infected at day 40. Our results suggest that healing bats face a severe energetic imbalance during early recovery from direct costs of healing and reduced foraging efficiency. Management of WNS should not rely solely on actions during winter, but should also aim to support energy balance of recovering bats during spring and summer.


Assuntos
Ascomicetos , Quirópteros , Hibernação , Torpor , Animais , Nariz
6.
Nature ; 511(7510): 428-34, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25043047

RESUMO

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Variação Estrutural do Genoma/genética , Meduloblastoma/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Animais , Criança , Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Meduloblastoma/classificação , Meduloblastoma/patologia , Camundongos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo
7.
J Thromb Thrombolysis ; 44(3): 335-340, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28875371

RESUMO

Pulmonary artery (PA) catheters are routinely used for hemodynamic management in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA). Tip-associated thrombi are frequently detected and might increase the peri-operative risk in these patients. The aim of the study was to investigate the effects of low-dose heparinization before the insertion of the PA catheter on thrombus formation and thrombus weight during PEA surgery. From September 2013 to February 2015, 60 CTEPH patients undergoing PEA were included in the study and randomized into two groups of 30 patients each, including a heparin group (heparin bolus (70 IU per kg body weight) administration before PA catheter insertion) and a control group (pretreatment with placebo). During the PEA procedure the distal part of the PA catheter was drawn out of the PA and thrombus presence and weight were recorded. There were no significant differences in baseline characteristics between the two groups. Twelve patients (20%) had thrombophilic disorders. In the control group, thrombi were detected in 17 patients (57%) with a median thrombus weight of 27 mg (IQR 41). In the heparin group, tip-associated thrombi were found in five patients (17%) with a median weight of 12 mg (IQR 7). There were no bleeding complications in either group. This study demonstrates a high risk of PA catheter-related thrombi in patients with CTEPH. Prophylactic administration of low-dose heparin reduces thrombus formation and thrombus weight without an increased rate of bleeding complications.


Assuntos
Endarterectomia/métodos , Heparina/uso terapêutico , Hipertensão Pulmonar/cirurgia , Artéria Pulmonar/cirurgia , Trombose/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Catéteres/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória/métodos , Pré-Medicação/métodos , Adulto Jovem
8.
BMC Genomics ; 16: 904, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26546267

RESUMO

BACKGROUND: We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N). RESULTS: We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males of a BFMI father. The phenotype was detectable from six weeks on and was preserved after cross-fostering. RNA-seq data of liver provided evidence for higher biosynthesis and elongation of fatty acids (p = 0.00635) in obese male offspring of a BFMI mother versus lean offspring of a BFMI father. Furthermore, fatty acid degradation (p = 0.00198) and the peroxisome pathway were impaired (p = 0.00094). The circadian rhythm was affected as well (p = 0.00087). Among the highest up-regulated protein coding genes in obese males were Acot4 (1.82 fold, p = 0.022), Cyp4a10 (1.35 fold, p = 0.026) and Cyp4a14 (1.32 fold, p = 0.012), which hydroxylize fatty acids and which are known to be increased in liver steatosis. Obese males showed lower expression of the genetically imprinted and paternally expressed 3 (Peg3) gene (0.31 fold, p = 0.046) and higher expression of the androgen receptor (Ar) gene (2.38 fold, p = 0.068). Allelic imbalance was found for expression of ATP-binding cassette transporter gene Abca8b. Several of the differentially expressed genes contain estrogen response elements. CONCLUSIONS: Parent-of-origin effects during gametogenesis and/or fetal development in an obese mother epigenetically modify the transcription of genes that lead to enhanced fatty acid synthesis and impair ß-oxidation in the liver of male, but not female F1 offspring. Down-regulation of Peg3 could contribute to trigger this metabolic setting. At puberty, higher amounts of the androgen receptor and altered access to estrogen response elements in affected genes are likely responsible for male specific expression of genes that were epigenetically triggered. A suggestive lack of estrogen binding motifs was found for highly down-regulated genes in adult hepatocytes of obese F1 males (p = 0.074).


Assuntos
Obesidade/genética , Animais , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Ácidos Graxos/metabolismo , Feminino , Fígado/metabolismo , Masculino , Camundongos , Puberdade/genética
9.
BMC Genomics ; 15: 675, 2014 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-25113896

RESUMO

BACKGROUND: Gene expression analysis by RNA sequencing is now widely used in a number of applications surveying the whole transcriptomes of cells and tissues. The recent introduction of ribosomal RNA depletion protocols, such as RiboZero, has extended the view of the polyadenylated transcriptome to the poly(A)- fraction of the RNA. However, substantial amounts of intronic transcriptional activity has been reported in RiboZero protocols, raising issues regarding their potential nuclear origin and the impact on the actual sequence depth in exonic regions. RESULTS: Using HEK293 human cells as source material, we assessed here the impact of the two commonly used RNA extraction methods and of the library construction protocols (rRNA depletion versus mRNA) on 1) the relative abundance of intronic reads and 2) on the estimation of gene expression values. We benchmarked the rRNA depletion-based sequencing with a specific analysis of the cytoplasmic and nuclear transcriptome fractions, suggesting that the large majority of the intronic reads correspond to unprocessed nuclear transcripts rather than to independent transcriptional units. We show that Qiagen or TRIzol extraction methods retain differentially nuclear RNA species, and that consequently, rRNA depletion-based RNA sequencing protocols are particularly sensitive to the extraction methods. CONCLUSIONS: We could show that the combination of Trizol-based RNA extraction with rRNA depletion sequencing protocols led to the largest fraction of intronic reads, after the sequencing of the nuclear transcriptome. We discuss here the impact of the various strategies on gene expression and alternative splicing estimation measures. Further, we propose guidelines and a double selection strategy for minimizing the expression biases, without loss of information.


Assuntos
RNA Mensageiro/isolamento & purificação , Perfilação da Expressão Gênica , Biblioteca Gênica , Células HEK293 , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Splicing de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/isolamento & purificação , RNA Mensageiro/genética , Análise de Sequência de RNA , Transcriptoma
10.
PLoS Comput Biol ; 9(1): e1002875, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23365551

RESUMO

A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated genomic datasets.


Assuntos
Neoplasias da Mama/patologia , Neoplasias Ovarianas/patologia , Progressão da Doença , Feminino , Humanos , Metástase Neoplásica , Prognóstico
11.
J Chem Ecol ; 40(3): 227-35, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24532214

RESUMO

Pilosebaceous units found in the mammalian integument are composed of a hair follicle, the proximal portion of the hair shaft, a sebaceous gland, and the erector pili muscle. Pilosebaceous units release protective oils, or sebum, by holocrine secretion onto skin and hair through rupturing of sebocytes. Sebum is composed largely of polar and neutral lipids including glycerolipids, free fatty acids, sterols, wax esters, sterol esters, and squalene. In addition to these lipid classes, there is a small proportion of ionic/anionic glycerophospholipids (GPs). Composition of GPs on hair is rarely addressed despite their broad biological activities as signaling molecules and membrane stability. Furthermore, knowledge on GP composition in bats is lacking. Bat GP composition is important to document due to GP roles ranging from decreasing drag during migration to interaction with the integumentary microbiome. In this study, we analyzed GP molecular composition with liquid chromatography electrospray ionization tandem mass spectrometry and compared GP content to previous literature. A total of 152 GPs were detected. Broad GP classes identified include lysophosphatidylcholine, phosphatidylcholine (PC), lysophosphatidylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and phosphatidylglycerol, with PC being the most abundant class. The acyl components were consistent with fatty acid methyl esters and triacylglyceride moieties found in Eastern red bat sebum. Glycerophospholipid proportions of the hair surface were different from a previous study on bat lung surfactants. This study determined the broad class and molecular species of bat sebum GPs that may be used in future ecological studies in vespertilionid bats.


Assuntos
Quirópteros/metabolismo , Glicerofosfolipídeos/análise , Espectrometria de Massas por Ionização por Electrospray , Animais , Glicerofosfolipídeos/isolamento & purificação , Cabelo/metabolismo , Extração Líquido-Líquido
12.
Chem Biodivers ; 10(12): 2122-32, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24327437

RESUMO

White-nose syndrome (WNS) is a fungal disease caused by Pseudogymnoascus destructans and is devastating North American bat populations. Sebaceous lipids secreted from host integumentary tissues are implicated in the initial attachment and recognition of host tissues by pathogenic fungi. We are interested in determining if ratios of lipid classes in sebum can be used as biomarkers to diagnose severity of fungal infection in bats. To first establish lipid compositions in bats, we isolated secreted and integral lipid fractions from the hair and wing tissues of three species: big brown bats (Eptesicus fuscus), Eastern red bats (Lasiurus borealis), and evening bats (Nycticeius humeralis). Sterols, FFAs, MAGs, and squalene were derivatized as trimethylsilyl esters, separated by gas chromatography, and identified by mass spectrometry. Ratios of sterol to squalene in different tissues were determined, and cholesterol as a disease biomarker was assessed. Free sterol was the dominant lipid class of bat integument. Squalene/sterol ratio is highest in wing sebum. Secreted wing lipid contained higher proportions of saturated FFAs and MAGs than integral wing or secreted hair lipid. These compounds are targets for investigating responses of P. destructans to specific host lipid compounds and as biomarkers to diagnose WNS.


Assuntos
Quirópteros/metabolismo , Ácidos Graxos não Esterificados/análise , Cromatografia Gasosa-Espectrometria de Massas , Monoglicerídeos/análise , Esqualeno/análise , Esteróis/análise , Animais , Ascomicetos/fisiologia , Biomarcadores/análise , Quirópteros/microbiologia , Cabelo/química , Cabelo/metabolismo , Sebo/química , Sebo/metabolismo , Compostos de Trimetilsilil/química , Asas de Animais/química , Asas de Animais/metabolismo
13.
Cancers (Basel) ; 14(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35406521

RESUMO

Metastasis-Associated in Colon Cancer 1 (MACC1) is a strong prognostic biomarker inducing proliferation, migration, invasiveness, and metastasis of cancer cells. The context of MACC1 dysregulation in cancers is, however, still poorly understood. Here, we investigated whether chromosomal instability and somatic copy number alterations (SCNA) frequently occurring in CRC contribute to MACC1 dysregulation, with prognostic and predictive impacts. Using the Oncotrack and Charité CRC cohorts of CRC patients, we showed that elevated MACC1 mRNA expression was tightly dependent on increased MACC1 gene SCNA and was associated with metastasis and shorter metastasis free survival. Deep analysis of the COAD-READ TCGA cohort revealed elevated MACC1 expression due to SCNA for advanced tumors exhibiting high chromosomal instability (CIN), and predominantly classified as CMS2 and CMS4 transcriptomic subtypes. For that cohort, we validated that elevated MACC1 mRNA expression correlated with reduced disease-free and overall survival. In conclusion, this study gives insights into the context of MACC1 expression in CRC. Increased MACC1 expression is largely driven by CIN, SCNA gains, and molecular subtypes, potentially determining the molecular risk for metastasis that might serve as a basis for patient-tailored treatment decisions.

15.
Biosensors (Basel) ; 10(2)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069963

RESUMO

The development of new C-320 electronic-nose (e-nose) methods for pre-symptomatic detection of White-Nose Syndrome (WNS) in bats has required efficacy studies of instrument capabilities to discriminate between major sources of volatile organic compounds (VOCs) derived from clinical samples. In this phase-2 study, we further tested this e-nose for capabilities to distinguish between bat species based on differences in whole-body VOC emissions. Live healthy individuals of nine bat species were temporarily captured outside of caves in Arkansas and Louisiana. VOC emissions from bats were collected using newly developed portable air collection and sampling-chamber devices in tandem. Sensor-array output responses to bat VOC emissions were compared to those of 22 pure VOC analytical standards from five chemical classes. Distinct smellprint signatures were produced from e-nose analyses of VOC metabolites derived from individual bat species. Smellprint patterns were analyzed using 2-dimensional and 3-dimensional Principal Component Analysis (PCA) to produce aroma map plots showing effective discrimination between bat species with high statistical significance. These results demonstrate potential instrument efficacy for distinguishing between species-specific, bat-derived VOC metabolite emissions as major components of clinical samples collected from bats in caves for disease detection prior to symptom development. This study provided additional information required to fully test the efficacy of a portable e-nose instrument for diagnostic applications in subsequent phase-3 testing of noninvasive, early WNS disease detection in intra-cave hibernating bats.


Assuntos
Nariz Eletrônico/normas , Animais , Quirópteros , Compostos Orgânicos Voláteis/análise
16.
Blood Adv ; 4(17): 4052-4064, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32853382

RESUMO

Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Amidoidrolases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Linfócitos B , Moléculas de Adesão Celular , Criança , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Ligadas por GPI , Células-Tronco Hematopoéticas , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos
17.
Cancer Cell ; 36(6): 630-644.e9, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31735627

RESUMO

The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia.


Assuntos
Proteína p300 Associada a E1A/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas de Ligação a DNA/genética , Humanos , Translocação Genética
18.
Cancer Cell ; 36(2): 123-138.e10, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31303423

RESUMO

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 21 , Subunidade beta Comum dos Receptores de Citocinas/genética , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Leucemia Mieloide/genética , Reação Leucemoide/genética , Mutação , Animais , Modelos Animais de Doenças , Progressão da Doença , Síndrome de Down/diagnóstico , Fator de Transcrição GATA1/metabolismo , Regulação Leucêmica da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/patologia , Reação Leucemoide/diagnóstico , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Fenótipo , Transcrição Gênica
19.
Cancer Cell ; 34(6): 996-1011.e8, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30537516

RESUMO

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Transcriptoma , Adulto , Biomarcadores Tumorais/metabolismo , Evolução Molecular , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Risco , Sequenciamento Completo do Genoma/métodos
20.
Ecology ; 88(2): 306-14, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17479749

RESUMO

We studied litter size variation in a population of Richardson's ground squirrels (Spermophilus richardsonii) in Alberta, Canada, from 1987 to 2004. Litter size at first emergence of juveniles from the natal burrow ranged from 1 to 14; the most common litter sizes, collectively accounting for 41.0% of 999 litters, were 6 and 7. The number of offspring surviving to adulthood (attained on emergence from hibernation as yearlings) increased with increasing litter size, a result that was not predicted by Lack's "optimal litter size" hypothesis, Mountford's "cliff-edge" effect, or the "bad-years" effect. Contrary to the negative effects predicted by the "cost of reproduction" hypothesis, litter size had no significant influence on survival of mothers to the subsequent year or on the size of the subsequent litter. Rather, our results best fit the predictions of the "individual optimization" hypothesis, which suggests that litter size is determined by the body condition and environmental circumstances of each mother. Supporting this hypothesis, survival of individual offspring was not significantly associated with litter size. Additionally, year-to-year changes in maternal body mass at mating were positively associated with concurrent changes in litter size (r = 0.56), suggesting that litter size depends on the body condition of the mother. Because the mean number of recruits to adulthood increased as litter size increased (r2 = 0.96) and litter size increased with maternal condition, offspring productivity was greater for mothers in better body condition.


Assuntos
Tamanho da Ninhada de Vivíparos/fisiologia , Sciuridae/fisiologia , Animais , Feminino , Taxa de Sobrevida
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