Objectives: KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK.
View Article and Find Full Text PDFAm J Med Genet C Semin Med Genet
December 2019
The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590).
View Article and Find Full Text PDFBackground: This study aimed to evaluate outcome of children on chronic peritoneal dialysis (PD) with a concurrent colostomy.
Methods: Patients were identified through the International Pediatric Peritoneal Dialysis Network (IPPN) registry. Matched controls were randomly selected from the registry.
Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated.
View Article and Find Full Text PDFTemporal lobe epilepsy is the most common and often drug-resistant type of epilepsy in the adult and aging populations and has great diversity in etiology, electro-clinical manifestations, and comorbidities. Kindling through repeated brief stimulation of limbic structures is a commonly used model of temporal lobe epilepsy. Particularly, extended kindling can induce spontaneous recurrent seizures in several animal species.
View Article and Find Full Text PDFThe kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer's disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test).
View Article and Find Full Text PDFThe blood-brain barrier (BBB) protects the brain from the toxic side effects of drugs and exogenous molecules. However, it is crucial that medications developed for neurological disorders cross into the brain in therapeutic concentrations. Understanding the BBB interaction with drug molecules based on physicochemical property space can guide effective and efficient drug design.
View Article and Find Full Text PDFThe impacts of invertebrate RNA virus population dynamics on virulence and infection outcomes are poorly understood. Deformed wing virus (DWV), the main viral pathogen of honey bees, negatively impacts bee health, which can lead to colony death. Despite previous reports on the reduction of DWV diversity following the arrival of the parasitic mite Varroa destructor, the key DWV vector, we found high genetic diversity of DWV in infested United States honey bee colonies.
View Article and Find Full Text PDFBreast tumor stratification by recurrence-risk is critical for deciding patient treatment. Here an approach combining cancer pathways microarray data complemented by RNA in situ hybridization (ISH) was investigated as a means for recurrence marker discovery and visualization in pathology specimens. LncRNA and mRNA expressions in breast carcinomas with low (n = 8) vs intermediate/high (n = 10) recurrence-scores as estimated by 21-gene assay and pathology review were compared by microarray assay.
View Article and Find Full Text PDFBackground: Ovarian cancer is often diagnosed in advanced stages, when survival is poor. Treatment advances have been made, but are inconsistently implemented. Our purpose was to project the maximum life expectancy gains that could be achieved in women with stage IIIC epithelial ovarian cancer if the implementation of available chemotherapy regimens could be optimized.
View Article and Find Full Text PDFArthropods often have obligate relationships with symbiotic microbes, and recent investigations have demonstrated that such host-microbe relationships could be exploited to suppress natural populations of vector carrying mosquitos. Strategies that target the interplay between agricultural pests and their symbionts could decrease the burden caused by agricultural pests; however, the lack of comprehensive genomic insights into naturally occurring microbial symbionts presents a significant bottleneck. Here we employed amplicon surveys, genome-resolved metagenomics, and scanning electron microscopy to investigate symbionts of the wheat stem sawfly (), a major pest that causes an estimated $350 million dollars or more in wheat yield losses in the northwestern United States annually.
View Article and Find Full Text PDFThe use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology.
View Article and Find Full Text PDFCoffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS.
View Article and Find Full Text PDFThe northern tamarisk beetle Diorhabda carinulata (Desbrochers) was approved for release in the United States for classical biological control of a complex of invasive saltcedar species and their hybrids (Tamarix spp.). An aggregation pheromone used by D.
View Article and Find Full Text PDFGene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in , and (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity.
View Article and Find Full Text PDFContact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts.
View Article and Find Full Text PDFBackground: We have previously demonstrated in vitro cytotoxicity of mesothelin-chimeric antigen receptor autologous T cells against pancreatic cancer cells using lentiviral vectors, but these vectors pose safety concerns. Here, we incorporated Sleeping Beauty and minicircle design enhancements into interleukin-2-secreting natural NK-92MI cells to eliminate both bacterial and viral components and address inhibition by the tumor microenvironment.
Methods: Parental (conventional deoxyribonucleic acid)-mesothelin-chimeric antigen receptor and minicircle-mesothelin-chimeric antigen receptor vectors were electroporated into NK-92MI cells and engraftment was visualized by immunofluorescence analysis with protein-L staining.
Synthesized digital mammography (SM) was developed to replace digital mammography (DM) in digital breast tomosynthesis (DBT) imaging to reduce radiation dose. This survey assessed utilization and attitudes regarding SM in DBT screening. The study was institutional review board exempt.
View Article and Find Full Text PDFImportance: Following recent US Food and Drug Administration approval, adoption of whole slide imaging in clinical settings may be imminent, and diagnostic accuracy, particularly among challenging breast biopsy specimens, may benefit from computerized diagnostic support tools.
Objective: To develop and evaluate computer vision methods to assist pathologists in diagnosing the full spectrum of breast biopsy samples, from benign to invasive cancer.
Design, Setting, And Participants: In this diagnostic study, 240 breast biopsies from Breast Cancer Surveillance Consortium registries that varied by breast density, diagnosis, patient age, and biopsy type were selected, reviewed, and categorized by 3 expert pathologists as benign, atypia, ductal carcinoma in situ (DCIS), and invasive cancer.
Background: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability.
View Article and Find Full Text PDFJ Pediatr Ophthalmol Strabismus
July 2019
Background: Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the Population-based Research Optimizing Screening through Personalized Regimens consortium.
View Article and Find Full Text PDFBackground Cardiovascular disease is a major cause of morbidity and mortality in children with chronic kidney disease. We sought to determine the prevalence of cardiovascular risk factors in children with glomerular disease and to describe current practice patterns regarding risk factor identification and management. Methods and Results Seven-hundred sixty-one children aged 0 to 17 years with any of 4 biopsy-confirmed primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy/vasculitis) were enrolled at a median of 16 months from glomerular disease diagnosis in the multicenter prospective Cure Glomerulonephropathy Network study.
View Article and Find Full Text PDFIntroduction: The Affordable Care Act (ACA) expanded Medicaid eligibility to persons with income up to 138% of the federal poverty line. We investigated how Medicaid expansion (ME) impacted the access to cancer-specific surgical care in the US.
Methods: We used a nationwide population-based database (SEER) to identify patients with the 8 most prevalent cancers between 2007 and 2015.