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Lopez, G.

Publications and source records attributed to Lopez, G..

25 records · Page 2Linked to original sources
bioRxiv2019

Cell-to-cell Mathematical modeling of arrhythmia phenomena in excitable media

In this document are modeled arrhythmias with cellular automaton and ordinary differential equations systems. With an aperiodic, self-similar distribution of two-dimensional arrangement of cells, it is possible to simulate such phenomena as fibrillation, fluttering and a sequence of fibrillation-fluttering. The topology of the cytoarchitecture of a network of cells may determine the initiation and development of arrhythmias.

cell biology↗
bioRxiv2019

Structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma exhibits a relative paucity of somatic single nucleotide variants (SNVs) and small insertions and deletions (indels) compared to adult cancers. Here, we assessed the contribution of somatic structural variation (SV) in neuroblastoma using a combination of whole genome sequencing (WGS; n=135) and single nucleotide polymorphism (SNP) genotyping (n=914) of matched tumor-normal pairs. Our study design allowed for orthogonal validation and replication across platforms. SV frequency, type, and localization varied significantly among high-risk tumors. MYCN non-amplified high-risk tumors harbored an increased SV burden overall, including a substantial excess of tandem-duplication events across the genome. Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder (ASD). The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% of MYCN non-amplified high-risk tumors based on WGS and 10% in the SNP array cohort. Expression of SHANK2 was low across human-derived neuroblastoma cell lines and high-risk neuroblastoma tumors. Forced expression of SHANK2 in neuroblastoma cell models resulted in significant growth inhibition (P=2.62x10-2 to 3.4x10-5) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.08x10-13 to 2.38x10-30). These data further define the complex landscape of structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of SHANK2, are key mediators of tumorigenesis in this childhood cancer.

cancer biology↗
bioRxiv2019

Genomic landscape of 261 childhood cancer patient-derived xenograft models

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.\n\nHighlightsO_LIMultiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) models\nC_LIO_LIPediatric patient derived xenografts faithfully recapitulate relapsed disease\nC_LIO_LIInferred TP53 pathway inactivation correlates with pediatric cancer copy number burden\nC_LIO_LISomatic mutational signatures predict impaired DNA repair across multiple histologies\nC_LI

genomics↗
bioRxiv2019

High prevalence of precocious menarche in Puerto Barrios, Guatemala

BackgroundAge of menarche is variable between women with a median age of 14 years old worldwide, and averages ranging from 12-13 years old in developed countries to 15-16 years old in low and middle-income countries. Precocious menarche, occurring before age 11, is rare, with a prevalence of 1.4 to 2.3% in most worldwide populations. Precocious menarche is poorly understood but is associated with early puberty and is a risk factor for pre-teen birth. In studying HPV prevalence in Latin America, we identified a community with a very high rate of precocious menarche. Objective(s)Describe the patterns of precocious menarche in Guatemala. Study DesignReproductive histories were collected from 3385 cancer-free women at the time of routine Pap smear from 4 sites in Guatemala including hospitals in Guatemala City and Puerto Barrios, Izabal. Statistical analyses included determination of the age-specific prevalence of menarche and linear regression to determine the effect of year of birth, study site, number of births and miscarriages, on the age at menarche. ResultsCompared with a low prevalence of precocious menarche observed in Guatemala City (3.1%, 88/2834), we observed a high prevalence of precocious menarche in the city of Puerto Barrios, Izabal, Guatemala (88%, 486/551). We observed a high prevalence of precocious menarche in Puerto Barrios across all age groups. In contrast in Guatemala City, the median age at menarche declined from the age of 14 in 50-60-year-old women to 13 in women under 40 years of age. Hospital records show that the occurrence of both miscarriage and pregnancy under age 14 is substantially higher in Izabal. In addition, the main public hospital in Puerto Barrios accounts for a high fraction of the early pregnancies and miscarriages seen in Guatemala. ConclusionsIn Puerto Barrios, Izabal, Guatemala, the prevalence of menarche before age 11 is dramatically elevated compared to Guatemala City and substantially higher than other worldwide populations. We observed precocious menarche in Puerto Barrios in all age groups examined, indicating that this condition has been common for decades. This finding is supported by the comparatively higher occurrence of early pregnancy and miscarriage in Puerto Barrios compared with Guatemala City. The cause is unknown, but precocious menarche is associated with adverse reproductive outcome in young women and warrants further investigation.

epidemiology↗
bioRxiv2017

Low-Cost HPV Screening And The Prevalence Of Cervical Infection In Asymptomatic Populations In Guatemala

BackgroundA low cost and accurate method for detecting high-risk (HR) HPV is important to permit HPV testing for cervical cancer prevention. We validated a low-cost commercially available HPV method (H13, Hybribio, Hong Kong) and determined the distribution of HPV infections in over 1717 cancer-free women in Guatemala.\n\nMethodsH13 results were compared with two more established HPV tests: (Xpert (Cepheid) and SPF10-LIPA25 (DDL)) in 40 mainly known positive specimens. HR-HPV was detected in cervical samples from 1717 cancer-free women receiving Pap smears using the Hybribio realtime PCR assay of 13 HR types. Selected HPV positive samples were sequenced to determine viral type.\n\nResultsThe Hybribio H13 Assay showed 93% identical results with Xpert, and 89% with SPF10-LIPA25. A total of 13% (226/1717) of women tested HPV+. The highest prevalence was found in younger women (<30 years, 22 %) and older ones ([&ge;]60 years, 15%). The six most common HR-HPV types among the 148 HPV+ typed were HPV16 (22%), HPV18 (11%), HPV39 (11%), HPV58 (10%), HPV52 (8%), and HPV45 (8%).\n\nConclusionsThe Hybribio Assay was low cost, and accurate in testing for HR-HPV infection. As in most places, HPV16 was the most prevalent HR type in Guatemala and the age-specific prevalence curve peaked in younger ages.\n\nHighlightsO_LIA low cost and accurate method, Hybribio Assay, could be used for CC testing in low income regions.\nC_LIO_LIA total of 13% of cancer-free women were HPV+ and positivity was associated with younger age (<30 years old) in Guatemala.\nC_LIO_LIHPV16 was the major prevalent type.\nC_LI

molecular biology↗
bioRxiv2016

Cell-to-cell Modelling of the inter-phase between Atrial and Sinoatrial Anisotropic Heterogeneous Nets

AO_SCPCAPBSTRACTC_SCPCAPThe transition between Sinoatrial cells and Atrial cells in the Heart is not fully undefirst ood. Here we focus in cell-to-cell mathematical models involving typical Sinoatrial cells and Atrial cells connected with experimentally observed conductance values exclusively. We are interested mainly in the geometry of the microstructure of the conduction paths in the Sinoatrial Node. We show with some models that appropriate source-sink relationships between Atrial and Sinoatrial cells may occur according to certain geometric arrangements.

bioengineering↗