Genomic dissection and mutation-specific target discovery for breast cancer PIK3CA hotspot mutations.

Background: Recent advancements in high-throughput genomics and targeted therapies have provided tremendous potential to identify and therapeutically target distinct mutations associated with cancers. However, to date the majority of targeted therapies are used to treat all functional mutations within the same gene, regardless of affected codon or phenotype.

Results: In this study, we developed a functional genomic analysis workflow with a unique isogenic cell line panel bearing two distinct hotspot PIK3CA mutations, E545K and H1047R, to accurately identify targetable differences between mutations within the same gene.

An in vitro CRISPR screen of cell-free DNA identifies apoptosis as the primary mediator of cell-free DNA release.

Clinical circulating cell-free DNA (cfDNA) testing is now routine, however test accuracy remains limited. By understanding the life-cycle of cfDNA, we might identify opportunities to increase test performance. Here, we profile cfDNA release across a 24-cell line panel and utilize a cell-free CRISPR screen (cfCRISPR) to identify mediators of cfDNA release.

Direct long-acting antibodies: updating the language of RSV prevention to reflect the evolution of mAbs.

Introduction: The language of medicine is constantly evolving, typically to better describe a new understanding of disease, adjust to changing social sensibilities, or simply to reflect a new drug class or category. We address the need for an updated language around monoclonal antibodies, or "mAbs" - a widely used medical term, but one which is now too general to accurately reflect the range of mAb pharmaceuticals, their effects, and the intended patients.

Methods: The question of "what should we call a monoclonal antibody immunisation against respiratory syncytial virus (RSV) to ensure accurate understanding of the product?" was the basis for a virtual advisory panel in May 2022.

Genomic dissection and mutation-specific target discovery for breast cancer hotspot mutations.

Background: Recent advancements in high-throughput genomics and targeted therapies have provided tremendous potential to identify and therapeutically target distinct mutations associated with cancers. However, to date the majority of targeted therapies are used to treat all functional mutations within the same gene, regardless of affected codon or phenotype.

Results: In this study, we developed a functional genomic analysis workflow with a unique isogenic cell line panel bearing two distinct hotspot mutations, E545K and H1047R, to accurately identify targetable differences between mutations within the same gene.

The breast is yet to come: current and future utility of circulating tumour DNA in breast cancer.

Advances in genomic strategies and the development of targeted therapies have enabled precision medicine to revolutionise the field of oncology. Precision medicine uses patient-specific genetic and molecular information, traditionally obtained from tumour biopsy samples, to classify tumours and treat them accordingly. However, biopsy samples often fail to provide complete tumour profiling, and the technique is expensive and, of course, relatively invasive.

Hierarchical tumor heterogeneity mediated by cell contact between distinct genetic subclones.

Intratumor heterogeneity is an important mediator of poor outcomes in many cancers, including breast cancer. Genetic subclones frequently contribute to this heterogeneity; however, their growth dynamics and interactions remain poorly understood. PIK3CA and HER2 alterations are known to coexist in breast and other cancers.

Cyclin-dependent Kinase 1 and Aurora Kinase choreograph mitotic storage and redistribution of a growth factor receptor.

Endosomal trafficking of receptors and associated proteins plays a critical role in signal processing. Until recently, it was thought that trafficking was shut down during cell division. Thus, remarkably, the regulation of trafficking during division remains poorly characterized.

Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements.

Background: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated.

Results: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, and Cross-species analysis of regulatory elements suggests that -regulatory architecture is largely conserved between these highly divergent species.

Validation of anti-glucocerebrosidase antibodies for western blot analysis on protein lysates of murine and human cells.

Gaucher disease (GD) is a rare lysosomal storage disorder caused by mutations in the gene, encoding the lysosome-resident glucocerebrosidase enzyme involved in the hydrolysis of glucosylceramide. The discovery of an association between mutations in and the development of synucleinopathies, including Parkinson disease, has directed attention to glucocerebrosidase as a potential therapeutic target for different synucleinopathies. These findings initiated an exponential growth in research and publications regarding the glucocerebrosidase enzyme.

Exploring genetic modifiers of Gaucher disease: The next horizon.

Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype.

Stress-Induced Hyperglycemia in White-Throated and White-Crowned Sparrows: A New Technique for Rapid Glucose Measurement in the Field.

Organisms experience stressors, and the physiological response to these stressors is highly conserved. Acute stress activates both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, increasing epinephrine, norepinephrine, and glucocorticoids, collectively promoting glucose mobilization. While this is well characterized in mammals, the hyperglycemic response to stress in avian and nonavian reptiles has received less attention.

Establishment of lateral organ asymmetries in the invertebrate chordate, .

Background: The evolutionary emergence and diversification of the chordates appear to involve dramatic changes in organ morphogenesis along the left/right axis. However, the ancestral chordate mechanism for establishing lateral asymmetry remains ambiguous. Additionally, links between the initial establishment of lateral asymmetry and subsequent asymmetries in organ morphogenesis are poorly characterized.

Fibronectin contributes to notochord intercalation in the invertebrate chordate, Ciona intestinalis.

Background: Genomic analysis has upended chordate phylogeny, placing the tunicates as the sister group to the vertebrates. This taxonomic rearrangement raises questions about the emergence of a tunicate/vertebrate ancestor.

Results: Characterization of developmental genes uniquely shared by tunicates and vertebrates is one promising approach for deciphering developmental shifts underlying acquisition of novel, ancestral traits.

Mitotic Membrane Turnover Coordinates Differential Induction of the Heart Progenitor Lineage.

In response to microenvironmental cues, embryonic cells form adhesive signaling compartments that influence survival and patterning. Dividing cells detach from the surrounding matrix and initiate extensive membrane remodeling, but the in vivo impact of mitosis on adhesion-dependent signaling remains poorly characterized. We investigate in vivo signaling dynamics using the invertebrate chordate, Ciona intestinalis.

The challenge of offering long-acting antipsychotic therapies: a preliminary discourse analysis of psychiatrist recommendations for injectable therapy to patients with schizophrenia.

Objective: To characterize patterns of communication in the offer of long-acting injectable (LAI) antipsychotic medication made by psychiatrists to patients with schizophrenia by (1) examining the style and content of their interaction and (2) determining how these may have driven the ultimate response to recommendations for LAI therapy.

Method: This was an observational study conducted at 10 community mental health centers in 3 waves from July 2010 to May 2011. The final dataset for discourse analysis was 33 recorded conversations in which a psychiatrist offered an injectable antipsychotic to a patient with schizophrenia.

Heart genetics in a small package, exploiting the condensed genome of Ciona intestinalis.

Defects in the initial establishment of cardiogenic cell fate are likely to contribute to pervasive human congenital cardiac abnormalities. However, the molecular underpinnings of nascent cardiac fate induction have proven difficult to decipher. In this review we explore the participation of extracellular, cellular and nuclear factors in comprehensive specification networks.

Matrix adhesion polarizes heart progenitor induction in the invertebrate chordate Ciona intestinalis.

Cell-matrix adhesion strongly influences developmental signaling. Resulting impacts on cell migration and tissue morphogenesis are well characterized. However, the in vivo impact of adhesion on fate induction remains ambiguous.

Initial deployment of the cardiogenic gene regulatory network in the basal chordate, Ciona intestinalis.

The complex, partially redundant gene regulatory architecture underlying vertebrate heart formation has been difficult to characterize. Here, we dissect the primary cardiac gene regulatory network in the invertebrate chordate, Ciona intestinalis. The Ciona heart progenitor lineage is first specified by Fibroblast Growth Factor/Map Kinase (FGF/MapK) activation of the transcription factor Ets1/2 (Ets).

Cytoskeletal polarity mediates localized induction of the heart progenitor lineage.

Cells must make appropriate fate decisions within a complex and dynamic environment. In vitro studies indicate that the cytoskeleton acts as an integrative platform for this environmental input. External signals regulate cytoskeletal dynamics and the cytoskeleton reciprocally modulates signal transduction.

A single GATA factor plays discrete, lineage specific roles in ascidian heart development.

GATA family transcription factors are core components of the vertebrate heart gene network. GATA factors also contribute to heart formation indirectly through regulation of endoderm morphogenesis. However, the precise impact of GATA factors on vertebrate cardiogenesis is masked by functional redundancy within multiple lineages.

Spatio-temporal intersection of Lhx3 and Tbx6 defines the cardiac field through synergistic activation of Mesp.

Mesp encodes a bHLH transcription factor required for specification of the cardiac mesoderm in Ciona embryos. The activities of Macho-1 and beta-catenin, two essential maternal determinants, are required for Mesp expression in the B7.5 blastomeres, which constitute the heart field.

The transcription/migration interface in heart precursors of Ciona intestinalis.

Gene regulatory networks direct the progressive determination of cell fate during embryogenesis, but how they control cell behavior during morphogenesis remains largely elusive. Cell sorting, microarrays, and targeted molecular manipulations were used to analyze cardiac cell migration in the ascidian Ciona intestinalis. The heart network regulates genes involved in most cellular activities required for migration, including adhesion, cell polarity, and membrane protrusions.

Movers and shakers: evolution and development of the mesoderm.

Groundbreaking research in a wide variety of organisms has begun to address fundamental questions regarding the evolutionary origin of mesoderm and how patterning of this emergent tissue layer has played a central role in the diversification of metazoan body plans. However, attempts to synthesize this growing body of research have been limited. To address this perceived gap, a symposium entitled "Movers and Shakers: The Evolution and Development of Mesoderm" was held at the 2006 Society for Integrative and Comparative Biology Conference in Orlando, Florida.

FoxF is essential for FGF-induced migration of heart progenitor cells in the ascidian Ciona intestinalis.

Heart development requires precise coordination of morphogenetic movements with progressive cell fate specification and differentiation. In ascidian embryos, FGF/MAPK-mediated activation of the transcription factor Ets1/2 is required for heart tissue specification and cell migration. We found that FoxF is one of the first genes to be activated in heart precursors in response to FGF signaling.