Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact.

Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors.

Background: Although differentiation therapy can cure some hematologic malignancies, its curative potential remains unrealized in solid tumors. This is because conventional computational approaches succumb to the thunderous noise of inter-/intratumoral heterogeneity. Using colorectal cancers (CRCs) as an example, here we outline a machine learning(ML)-based approach to track, differentiate, and selectively target cancer stem cells (CSCs).

Breast Cancers That Disseminate to Bone Marrow Acquire Aggressive Phenotypes through CX43-related Tumor-Stroma Tunnels.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact.

COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis.

Background: In the aftermath of Covid-19, some patients develop a fibrotic lung disease, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.

COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis.

Background: In the aftermath of Covid-19, some patients develop a fibrotic lung disease, i.e., ost- OVID-19 ung isease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.

GIV/Girdin, a non-receptor modulator for Gαi/s, regulates spatiotemporal signaling during sperm capacitation and is required for male fertility.

For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of conditional knockout (cKO) mice and cell-penetrating peptides, we show that GIV (), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility.

Loss of Thy-1 may reduce lung regeneration after pneumonectomy in mice.

Background: Lung regeneration plays an important role in lung repair after injury. It is reliant upon proliferation of multiple cell types in the lung, including endothelium, epithelium, and fibroblasts, as well as remodeling of the extracellular matrix.

Methods: Lung regeneration following injury progresses via an initial inflammatory response during which macrophages clear the tissue of cellular debris.

Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif.

Loss of Thy-1 expression in fibroblasts correlates with lung fibrogenesis; however, the clinical relevance of therapeutic targeting of myofibroblasts via Thy-1-associated pathways remains to be explored. Using single (self-resolving) or repetitive (nonresolving) intratracheal administration of bleomycin in type 1 collagen-GFP reporter mice, we report that Thy-1 surface expression, but not mRNA, is reversibly diminished in activated fibroblasts and myofibroblasts in self-resolving fibrosis. However, Thy-1 mRNA expression is silenced in lung with nonresolving fibrosis following repetitive bleomycin administration, associated with persistent activation of αv integrin.

Transforming growth factor beta 1 induces methylation changes in lung fibroblasts.

Idiopathic pulmonary fibrosis is a complex disease of unknown etiology. Environmental factors can affect disease susceptibility via epigenetic effects. Few studies explore global DNA methylation in lung fibroblasts, but none have focused on transforming growth factor beta-1 (TGF-β1) as a potential modifier of the DNA methylome.

Integrating multiomics longitudinal data to reconstruct networks underlying lung development.

A comprehensive understanding of the dynamic regulatory networks that govern postnatal alveolar lung development is still lacking. To construct such a model, we profiled mRNA, microRNA, DNA methylation, and proteomics of developing murine alveoli isolated by laser capture microdissection at 14 predetermined time points. We developed a detailed comprehensive and interactive model that provides information about the major expression trajectories, the regulators of specific key events, and the impact of epigenetic changes.

Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation.

Bone marrow-derived mesenchymal stem cells (MSC) have been promoted for multiple therapeutic applications. Many beneficial effects of MSCs are paracrine, dependent on extracellular vesicles (EVs). Although MSC-derived EVs (mEVs) are beneficial for acute lung injury and pulmonary fibrosis, mechanisms of mEV uptake by lung fibroblasts and their effects on myofibroblastic differentiation have not been established.

Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution.

Thy-1-negative lung fibroblasts are resistant to apoptosis. The mechanisms governing this process and its relevance to fibrotic remodeling remain poorly understood. By using either sorted or transfected lung fibroblasts, we found that Thy-1 expression is associated with downregulation of anti-apoptotic molecules Bcl-2 and Bcl-xL, as well as increased levels of cleaved caspase-9.

Selecting the most appropriate time points to profile in high-throughput studies.

Biological systems are increasingly being studied by high throughput profiling of molecular data over time. Determining the set of time points to sample in studies that profile several different types of molecular data is still challenging. Here we present the Time Point Selection () method that solves this combinatorial problem in a principled and practical way.

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes.

The molecular mechanisms that control the temporal and lineage-specific accessibility, as well as the rearrangement frequency of V(H) genes for V(H)-to-DJ(H) recombination, are not fully understood. We previously found a positive correlation between the extent of histone acetylation and the differential rearrangement frequency of individual V(H) genes. Here, we demonstrated that poorly rearranging V(H) genes are more highly associated with histone H3 dimethylated at lysine 9, a marker of repressive chromatin, than frequently rearranging V(H) genes.

Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.

Immunoglobulin rearrangement from variable heavy chain (V(H)) to diversity (D)-joining heavy chain (J(H)), which occurs exclusively in B lineage cells, is impaired in mice deficient for the B lineage-specific transcription factor Pax5. Conversely, ectopic Pax5 expression in thymocytes promotes the rearrangement of D(H)-proximal V(H)7183 genes. In exploring the mechanism for Pax5 regulation of V(H)-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V(H) gene segments.

The extent of histone acetylation correlates with the differential rearrangement frequency of individual VH genes in pro-B cells.

During B lymphocyte development, Ig heavy and L chain genes are assembled by V(D)J recombination. Individual V, D, and J genes rearrange at very different frequencies in vivo, and the natural variation in recombination signal sequence does not account for all of these differences. Because a permissive chromatin structure is necessary for the accessibility of VH genes for VH to DJH recombination, we hypothesized that gene rearrangement frequency might be influenced by the extent of histone modifications.

Many levels of control of V gene rearrangement frequency.

V, D, and J gene segments rearrange at very different frequencies. As with most biological systems, there are multiple levels of control of V gene recombination frequency, and here we review some of the work from our laboratory that addresses these various control mechanisms. One of the important factors that affect non-random V gene rearrangement frequency is the natural heterogeneity in recombination signal sequences (RSSs).

Development of a microarray assay that measures hybridization stoichiometry in moles.

Microarray data is most useful when it can be compared with other genetic detection technologies. In this report, we designed a microarray assay format that transforms raw data into a defined scientific unit (i.e.

Characterization of a thyroid-specific and cyclic adenosine monophosphate-responsive enhancer far upstream from the human sodium iodide symporter gene.

We describe the cloning and characterization of a human sodium iodide (NIS) upstream enhancer (NUE). This putative enhancer was cloned based on its sequence homology (69% identity) to the rat NUE. A 296 base pair (bp) genomic DNA fragment, which is located 9000 bp upstream from the human hNIS gene, was amplified by polymerase chain reaction (PCR) and inserted into a luciferase reporter gene in front of both the homologous NIS promoter and the heterologous SV40 promoter.