RESUMEN
Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.
Asunto(s)
Variación Estructural del Genoma/genética , Genómica/métodos , Neoplasias/genética , Inversión Cromosómica/genética , Cromotripsis , Variaciones en el Número de Copia de ADN/genética , Reordenamiento Génico/genética , Genoma Humano/genética , Humanos , Mutación/genética , Secuenciación Completa del Genoma/métodosRESUMEN
Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations1. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure2. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one (cis) outcome corresponded to the copying and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells.
Asunto(s)
Proteína BRCA1 , Proteína BRCA2 , Aberraciones Cromosómicas , Reparación del ADN , Neoplasias , Humanos , Proteína BRCA1/deficiencia , Proteína BRCA1/genética , Proteína BRCA2/deficiencia , Proteína BRCA2/genética , Inversión Cromosómica , Reparación del ADN/genética , Neoplasias/genética , Translocación Genética/genética , Recombinación Homóloga , Análisis Citogenético , Aberraciones Cromosómicas/clasificaciónRESUMEN
Compositional tunability, an indispensable parameter for modifying the properties of materials, can open up new applications for van der Waals (vdW) layered materials such as transition-metal dichalcogenides (TMDCs). To date, multielement alloy TMDC layers are obtained via exfoliation from bulk polycrystalline powders. Here, we demonstrate direct deposition of high-entropy alloy disulfide, (VNbMoTaW)S2, layers with controllable thicknesses on free-standing graphene membranes and on bare and hBN-covered Al2O3(0001) substrates via ultra-high-vacuum reactive dc magnetron sputtering of the VNbMoTaW target in Kr and H2S gas mixtures. Using a combination of density functional theory calculations, Raman spectroscopy, X-ray diffraction, scanning transmission electron microscopy coupled with energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy, we determine that the as-deposited layers are single-phase, 2H-structured, and 0001-oriented (V0.10Nb0.16Mo0.19Ta0.28W0.27)S2.44. Our synthesis route is general and applicable for heteroepitaxial growth of a wide variety of TMDC alloys and potentially other multielement alloy vdW compounds with the desired compositions.
RESUMEN
Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
Asunto(s)
Genotipo , Leiomiosarcoma/genética , Mutación , Fusión de Oncogenes , Neoplasias Uterinas/genética , Animales , Antineoplásicos/uso terapéutico , Femenino , Humanos , Leiomiosarcoma/tratamiento farmacológico , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida/métodos , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Neoplasias Uterinas/tratamiento farmacológicoRESUMEN
BACKGROUND: 'Next-generation' (NGS) sequencing has wide application in medical genetics, including the detection of somatic variation in cancer. The Ion Torrent-based (IONT) platform is among NGS technologies employed in clinical, research and diagnostic settings. However, identifying mutations from IONT deep sequencing with high confidence has remained a challenge. We compared various computational variant-calling methods to derive a variant identification pipeline that may improve the molecular diagnostic and research utility of IONT. RESULTS: Using IONT, we surveyed variants from the 409-gene Comprehensive Cancer Panel in whole-section tumors, intra-tumoral biopsies and matched normal samples obtained from frozen tissues and blood from four early-stage non-small cell lung cancer (NSCLC) patients. We used MuTect, Varscan2, IONT's proprietary Ion Reporter, and a simple subtraction we called "Poor Man's Caller." Together these produced calls at 637 loci across all samples. Visual validation of 434 called variants was performed, and performance of the methods assessed individually and in combination. Of the subset of inspected putative variant calls (n=223) in genomic regions that were not intronic or intergenic, 68 variants (30%) were deemed valid after visual inspection. Among the individual methods, the Ion Reporter method offered perhaps the most reasonable tradeoffs. Ion Reporter captured 83% of all discovered variants; 50% of its variants were visually validated. Aggregating results from multiple packages offered varied improvements in performance. CONCLUSIONS: Overall, Ion Reporter offered the most attractive performance among the individual callers. This study suggests combined strategies to maximize sensitivity and positive predictive value in variant calling using IONT deep sequencing.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Análisis de Secuencia de ADN , Programas InformáticosRESUMEN
OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors. METHODS: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components. RESULTS: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity. CONCLUSIONS: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.
Asunto(s)
Carcinosarcoma/patología , Neoplasias Uterinas/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinosarcoma/genética , Transición Epitelial-Mesenquimal , Femenino , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Uterinas/genéticaRESUMEN
Hispanics with acute leukemias have poorer outcomes than non-Hispanic whites (NHWs), despite an increased likelihood of favorable prognostic features. We reviewed medical records from 167 children ages 0-18 years diagnosed with de novo AML over an 18-year period at Texas Children's Cancer Center, among whom 129 self-identified as Hispanic or NHW. Although Hispanics were significantly more likely to have the favorable prognostic cytogenetic feature t(8;21) (P = 0.04), the expected survival benefit was not observed. This lack of survival benefit was primarily due to significantly poorer event-free and overall survival among Hispanics treated with upfront stem cell transplantation after achieving first clinical remission (P = 0.008).
Asunto(s)
Leucemia Mieloide Aguda/epidemiología , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Hispánicos o Latinos , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Población BlancaRESUMEN
Electrospun nanofibers exhibit a significant potential in the synthesis of nanostructured materials, thereby offering a promising avenue for enhancing the efficacy of wound care. The present study aimed to investigate the wound-healing potential of two biomacromolecules, PCL-Gelatin nanofiber adhered with bone marrow-derived mesenchymal stem cells (BMSCs). Characterisation of the nanofiber revealed a mean fiber diameter ranging from 200 to 300 nm, with distinctive elemental peaks corresponding to polycaprolactone (PCL) and gelatin. Additionally, BMSCs derived from bone marrow were integrated into nanofibers, and their wound-regenerative potential was systematically evaluated through both in-vitro and in-vivo methodologies. In-vitro assessments substantiated that BMSC-incorporated nanofibers enhanced cell viability and crucial cellular processes such as adhesion, and proliferation. Subsequently, in-vivo studies were performed to demonstrate the wound-healing efficacy of nanofibers. It was observed that the rate of wound healing of BMSCs incorporated nanofibers surpassed both, nanofiber and BMSCs alone. Furthermore, histomorphological analysis revealed accelerated re-epithelization and improved wound contraction in BMSCs incorporated nanofiber group. The fabricated nanofiber incorporated with BMSCs exhibited superior wound regeneration in animal model and may be utilised as a wound healing patch.
Asunto(s)
Gelatina , Células Madre Mesenquimatosas , Nanofibras , Poliésteres , Andamios del Tejido , Cicatrización de Heridas , Nanofibras/química , Células Madre Mesenquimatosas/citología , Gelatina/química , Poliésteres/química , Animales , Andamios del Tejido/química , Ratas , Proliferación Celular , Células de la Médula Ósea/citología , Supervivencia Celular , Adhesión Celular , MasculinoRESUMEN
Lower airway club cells (CCs) serve the dual roles of a secretory cell and a stem cell. Here, we probe how the CC fate is regulated. We find that, in response to acute perturbation of Notch signaling, CCs adopt distinct fates. Although the vast majority transdifferentiate into multiciliated cells, a "variant" subpopulation (v-CCs), juxtaposed to neuroepithelial bodies (NEBs; 5%-10%) and located at bronchioalveolar duct junctions (>80%), does not. Instead, v-CCs transition into lineage-ambiguous states but can revert to a CC fate upon restoration of Notch signaling and repopulate the airways with CCs and multiciliated cells. The v-CC response to Notch inhibition is dependent on localized activation of ß-catenin in v-CCs. We propose that the CC fate is stabilized by canonical Notch signaling, that airways are susceptible to perturbations to this pathway, and that NEBs/terminal bronchioles comprise niches that modulate CC plasticity via ß-catenin activation to facilitate airway repair post Notch inhibition.
RESUMEN
BACKGROUND: The amniotic membrane (AM) has shown immense potential in repairing wounds due to its great regenerative qualities. Although the role of AM as a biological scaffold in repairing wounds has been studied well, the tissue regenerative potential of AM-derived mesenchymal stem cells (MSCs) and conditioned media (CM) derived from it remains to be discovered as of now. Here, we examined the wound healing abilities of fresh and frozen thawed rabbit AM (rAM) along with the MSCs and their lyophilised CM in rabbits challenged with skin wounds. METHODS: To elucidate the role of rAM-MSCs and its CM in repairing the wound, we isolated it from the freshly derived placenta and characterised their differentiation potential by performing an in vitro tri-lineage differentiation assay besides other standard confirmations. We compared the wound repair capacities of rAM-MSCs and lyophilised CM with the fresh and cryopreserved AM at different timelines by applying them to excision wounds created in rabbits. RESULTS: By monitoring wound contractions and tissue histology of wounded skin at different time points after the application, we observed that rAM-MSCs and rAM-MSC-derived CM significantly promoted wound closure compared to the control group. We also observed that the wound closure capacity of rAM-MSCs and rAM-MSC-derived CM is as efficient as fresh and cryopreserved rAM. CONCLUSION: Our findings suggest that rAM-MSCs and rAM-MSC derived CM can be effectively used to treat skin wounds in animals and correctly delivered to the damaged tissue using AM as a bioscaffold, either fresh or frozen.
Asunto(s)
Amnios , Células Madre Mesenquimatosas , Cicatrización de Heridas , Animales , Conejos , Femenino , Células Madre Mesenquimatosas/citología , Diferenciación Celular , Medios de Cultivo Condicionados/farmacología , Trasplante de Células Madre Mesenquimatosas/métodos , Piel/lesiones , Piel/patología , Embarazo , Modelos Animales de Enfermedad , Células Cultivadas , Trasplante HomólogoRESUMEN
In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGESNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGECNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGESNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition.
Asunto(s)
ADN Tumoral Circulante , Variaciones en el Número de Copia de ADN , Aprendizaje Automático , Neoplasia Residual , Carga Tumoral , Humanos , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Neoplasia Residual/genética , Secuenciación Completa del Genoma , Neoplasias/genética , Neoplasias/sangre , Neoplasias/terapia , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patologíaRESUMEN
OBJECTIVES: Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. CASE PRESENTATION: We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. CONCLUSIONS: Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA.
Asunto(s)
Acidosis Tubular Renal , Acidosis , Síndrome de Fanconi , Raquitismo , Niño , Humanos , Acidosis Tubular Renal/complicaciones , Bicarbonatos/metabolismo , Acidosis/complicaciones , Equilibrio Ácido-Base , Síndrome de Fanconi/complicaciones , Raquitismo/complicacionesRESUMEN
Human behaviour reflects cognitive abilities. Human cognition is fundamentally linked to the different experiences or characteristics of consciousness/emotions, such as joy, grief, anger, etc., which assists in effective communication with others. Detection and differentiation between thoughts, feelings, and behaviours are paramount in learning to control our emotions and respond more effectively in stressful circumstances. The ability to perceive, analyse, process, interpret, remember, and retrieve information while making judgments to respond correctly is referred to as Cognitive Behavior. After making a significant mark in emotion analysis, deception detection is one of the key areas to connect human behaviour, mainly in the forensic domain. Detection of lies, deception, malicious intent, abnormal behaviour, emotions, stress, etc., have significant roles in advanced stages of behavioral science. Artificial Intelligence and Machine learning (AI/ML) has helped a great deal in pattern recognition, data extraction and analysis, and interpretations. The goal of using AI and ML in behavioral sciences is to infer human behaviour, mainly for mental health or forensic investigations. The presented work provides an extensive review of the research on cognitive behaviour analysis. A parametric study is presented based on different physical characteristics, emotional behaviours, data collection sensing mechanisms, unimodal and multimodal datasets, modelling AI/ML methods, challenges, and future research directions.
RESUMEN
Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure.
Asunto(s)
Neoplasias de la Mama , Genómica , Humanos , Femenino , Genómica/métodos , Análisis de Secuencia de ADN/métodos , Genoma Humano/genética , Aberraciones Cromosómicas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Variación Estructural del Genoma/genéticaRESUMEN
Immune checkpoint blockade (ICB) has transformed the treatment of metastatic cancer but is hindered by variable response rates. A key unmet need is the identification of biomarkers that predict treatment response. To address this, we analyzed six whole exome sequencing cohorts with matched disease outcomes to identify genes and pathways predictive of ICB response. To increase detection power, we focus on genes and pathways that are significantly mutated following correction for epigenetic, replication timing, and sequence-based covariates. Using this technique, we identify several genes (BCLAF1, KRAS, BRAF, and TP53) and pathways (MAPK signaling, p53 associated, and immunomodulatory) as predictors of ICB response and develop the Cancer Immunotherapy Response CLassifiEr (CIRCLE). Compared to tumor mutational burden alone, CIRCLE led to superior prediction of ICB response with a 10.5% increase in sensitivity and a 11% increase in specificity. We envision that CIRCLE and more broadly the analysis of recurrently mutated cancer genes will pave the way for better prognostic tools for cancer immunotherapy.
Asunto(s)
Inmunoterapia , Neoplasias , Biomarcadores de Tumor/metabolismo , Humanos , Inmunoterapia/métodos , Mutación , Neoplasias/genética , Neoplasias/terapia , Secuenciación del ExomaRESUMEN
We investigate the spatiotemporal dynamics and control of an epidemic using a partial differential equation (PDE) based Susceptible-Latent-Infected-Recovered (SLIR) model. We first validate the model using empirical COVID-19 data corresponding to a period of 45 days from the state of Ohio, United States. Upon optimizing the model parameters in the learning phase of the analysis using actual infection data from a period of the first 30 days, we then find that the model output closely tracks the actual data for the next 15 days. Next, we introduce a control input into the model to represent the Non-Pharmaceutical Intervention of social distancing. Implementing the control using two distinct schemes, we find that in both cases the control input is able to significantly mitigate the infection spread. In addition to opening a novel pathway towards the characterization, analysis and implementation of Non-Pharmaceutical Interventions across multiple geographical scales using Control frameworks, our results highlight the importance of first-principles based PDE models in understanding the spatiotemporal dynamics of epidemics triggered by novel pathogens.
Asunto(s)
COVID-19 , Epidemias , COVID-19/epidemiología , COVID-19/prevención & control , Epidemias/prevención & control , Humanos , Ohio , Distanciamiento Físico , SARS-CoV-2 , Estados Unidos/epidemiologíaRESUMEN
High-order three-dimensional (3D) interactions between more than two genomic loci are common in human chromatin, but their role in gene regulation is unclear. Previous high-order 3D chromatin assays either measure distant interactions across the genome or proximal interactions at selected targets. To address this gap, we developed Pore-C, which combines chromatin conformation capture with nanopore sequencing of concatemers to profile proximal high-order chromatin contacts at the genome scale. We also developed the statistical method Chromunity to identify sets of genomic loci with frequencies of high-order contacts significantly higher than background ('synergies'). Applying these methods to human cell lines, we found that synergies were enriched in enhancers and promoters in active chromatin and in highly transcribed and lineage-defining genes. In prostate cancer cells, these included binding sites of androgen-driven transcription factors and the promoters of androgen-regulated genes. Concatemers of high-order contacts in highly expressed genes were demethylated relative to pairwise contacts at the same loci. Synergies in breast cancer cells were associated with tyfonas, a class of complex DNA amplicons. These results rigorously link genome-wide high-order 3D interactions to lineage-defining transcriptional programs and establish Pore-C and Chromunity as scalable approaches to assess high-order genome structure.
Asunto(s)
Secuenciación de Nanoporos , Nanoporos , Andrógenos , Cromatina/genética , Humanos , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: To assess the direct annual health care costs for children and adolescents with Down syndrome in Western Australia and to explore the variation in health care use including respite, according to age and disease profile. STUDY DESIGN: Population-based data were derived from a cross-sectional questionnaire that was distributed to all families who had a child with Down syndrome as old as 25 years of age in Western Australia. RESULTS: Seventy-three percent of families (363/500) responded to the survey. Mean annual cost was $4209 Australian dollars ($4287 US dollars) for direct health care including hospital, medical, pharmaceutical, respite and therapy, with a median cost of $1701. Overall, costs decreased with age. The decline in costs was a result of decreasing use of hospital, medical, and therapy costs with age. Conversely, respite increased with age and also with dependency. Health care costs were greater in all age groups with increasing dependency and for an earlier or current diagnosis of congenital heart disease. Annual health care costs did not vary with parental income, including cost of respite. CONCLUSIONS: Direct health care costs for children with Down syndrome decrease with age to approximate population costs, although costs of respite show an increasing trend.
Asunto(s)
Síndrome de Down/economía , Costos de la Atención en Salud/estadística & datos numéricos , Adolescente , Factores de Edad , Australia/epidemiología , Niño , Preescolar , Estudios Transversales , Evaluación de la Discapacidad , Personas con Discapacidad , Síndrome de Down/epidemiología , Femenino , Cardiopatías Congénitas/economía , Cardiopatías Congénitas/epidemiología , Humanos , Hidroterapia/economía , Lactante , Recién Nacido , Masculino , Terapia Ocupacional/economía , Visita a Consultorio Médico/economía , Visita a Consultorio Médico/estadística & datos numéricos , Modalidades de Fisioterapia/economía , Cuidados Intermitentes/economía , Logopedia/economía , Encuestas y Cuestionarios , Natación/economía , Adulto JovenRESUMEN
We study the spatiotemporal dynamics of an epidemic spread using a compartmentalized PDE model. The model is validated using COVID-19 data from Hamilton County, Ohio, USA. The model parameters are estimated using a month of recorded data and then used to forecast the infection spread over the next ten days. The model is able to accurately estimate the key dynamic characteristics of COVID-19 spread in the county. Additionally, a stability analysis indicates that the model is robust to disturbances and perturbations which, for instance, could be used to represent the effects of super spreader events. We also use the modeling framework to analyse and discuss the impact of Non-pharmaceutical interventions (NPIs) for mitigation of infection. Our results suggest that such models can yield useful short and medium term predictive characterization of an epidemic spread in a restricted geographical region and also help formulate effective NPIs for mitigation. The results also signify the importance of further research into the accurate analytical representation of specific NPIs and hence their dampening effects on an infection spread.
RESUMEN
RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.