Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth.

Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting.

An RGDKGE-Containing Cryptic Collagen Fragment Regulates Phosphorylation of Large Tumor Suppressor Kinase-1 and Controls Ovarian Tumor Growth by a Yes-Associated Protein-Dependent Mechanism.

The growth and spread of malignant tumors, such as ovarian carcinomas, are governed in part by complex interconnected signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms.

Mechanistic Insights into Pore Formation by an α-Pore Forming Toxin: Protein and Lipid Bilayer Interactions of Cytolysin A.

Pore forming toxins (PFTs) are the largest class of bacterial toxins playing a central role in bacterial pathogenesis. They are proteins specifically designed to form nanochannels in the membranes of target cells, ultimately resulting in cell death and establishing infection. PFTs are broadly classified as α- and β-PFTs, depending on secondary structures that form the transmembrane channel.

Correction: Mixed lineage kinase 3 promotes breast tumorigenesis via phosphorylation and activation of p21-activated kinase 1.

The original version of this Article did not acknowledge Pradeep Sathyanarayana as an author. His affiliation is Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA.

Cholesterol promotes Cytolysin A activity by stabilizing the intermediates during pore formation.

Pore-forming toxins (PFTs) form nanoscale pores across target membranes causing cell death. Cytolysin A (ClyA) from is a prototypical α-helical toxin that contributes to cytolytic phenotype of several pathogenic strains. It is produced as a monomer and, upon membrane exposure, undergoes conformational changes and finally oligomerizes to form a dodecameric pore, thereby causing ion imbalance and finally cell death.

Novel roles for podocalyxin in regulating stress myelopoiesis, Rap1a, and neutrophil migration.

Podocalyxin (Podxl) is a CD34 orthologue and cell surface sialomucin reported to have roles in renal podocyte diaphragm slit development; vascular cell integrity; and the progression of blood, breast, and prostate cancers. Roles for Podxl during nonmalignant hematopoiesis, however, are largely undefined. We have developed a Vav-Cre Podxl knockout (KO) mouse model, and report on novel roles for Podxl in governing stress myelopoiesis.

The Solvent-Exposed C-Terminus of the Cytolysin A Pore-Forming Toxin Directs Pore Formation and Channel Function in Membranes.

Pore-forming toxins (PFTs) bind to cell membranes and form nanoscale pores that allow leakage of cellular components, resulting in cell death. The water-soluble, monomeric form of these toxins shows a dramatic conformational change during pore formation, as exemplified by crystal structures of the monomer and functional pore of cytolysin A (ClyA). The solvent-exposed, C-terminal residues of the protein are essential for activity, but the mechanism by which this region regulates pore formation remains unknown.

miR-199b, a novel tumor suppressor miRNA in acute myeloid leukemia with prognostic implications.

Background: Dysregulation of miRNAs that can act as tumor suppressors or oncogenes can result in tumorigenesis. Previously we demonstrated that miR-199b was significantly downregulated in acute myeloid leukemia (AML) and targets podocalyxin and discoidin domain receptor 1. Herein we investigated the functional role of miR-199b in AML and its prognostic implications.

Copper catalyzed oxygen assisted C(CNOH)-C(alkyl) bond cleavage: a facile conversion of aryl/aralkyl/vinyl ketones to aromatic acids.

A novel copper-catalyzed aerobic oxidative C(NOH)-C(alkyl) bond cleavage reaction of aryl/aralkyl/vinyl ketones for the synthesis of aromatic/acrylic acids is described. A series of ketones having aryl/aralkyl/vinyl at the one end and methyl to any higher alkyl at the other end can be selectively cleaved and converted into the corresponding acids via oxime intermediates.

Topological defect transformation and structural transition of two-dimensional colloidal crystals across the nematic to smectic-A phase transition.

We observe that topological defects in nematic colloids are strongly influenced by the elasticity and onset of smectic layering across the nematic (N) to smectic-A (SmA) phase transition. When approaching the SmA phase from above, the nematic hyperbolic hedgehog defect that accompanies a spherical colloidal inclusion is transformed into a focal conic line in the SmA phase. This phase transformation has a strong influence on the pairwise colloidal interaction and is responsible for a structural transition of two-dimensional colloidal crystals.

Multiple myeloma presenting with a maxillary lesion as the first sign.

Multiple myeloma is a clonal neoplastic proliferation of terminally differentiated B-lymphocytes involving the skeletal system in a multifocal fashion. Its oral manifestations are less common in the maxilla than in the mandible due to the lower amount of hemopoietic bone marrow in the maxilla. We report the case of a 50-year-old man who presented with a mass in the left maxillary alveolar region with tooth mobility.

Iodine-mediated oxidative annulation for one-pot synthesis of pyrazines and quinoxalines using a multipathway coupled domino strategy.

An efficient iodine-mediated oxidative annulation of aryl acetylenes-arylethenes-aromatic ketones with 1,2-diamines for the synthesis of pyrazines and regioselective synthesis of quinoxalines is presented. A multipathway coupled domino approach has been developed for the one-pot synthesis of 1,4-diazines with high functional group compatibility.

Common features of microRNA target prediction tools.

The human genome encodes for over 1800 microRNAs (miRNAs), which are short non-coding RNA molecules that function to regulate gene expression post-transcriptionally. Due to the potential for one miRNA to target multiple gene transcripts, miRNAs are recognized as a major mechanism to regulate gene expression and mRNA translation. Computational prediction of miRNA targets is a critical initial step in identifying miRNA:mRNA target interactions for experimental validation.

miR-125a regulates cell cycle, proliferation, and apoptosis by targeting the ErbB pathway in acute myeloid leukemia.

microRNA profiling of acute myeloid leukemia patient samples identified miR-125a as being decreased. Current literature has investigated miR-125a's role in normal hematopoiesis but not within acute myeloid leukemia. Analysis of the upstream region of miR-125a identified several CpG islands.

Antagonistic flexoelectric response in liquid crystal mixtures of bent-core and rodlike molecules.

We report the measurements of the temperature variations of the flexoelastic coefficient (e(*)/K) of a host calamitic liquid crystal (RO) and its mixture with two guest bent-core (BC-120 and BC-60) liquid crystals. The bent-core (BC) molecules have different core structures and bend angles; namely, θ=/~120° and =/~60°, respectively. We find that e(*)/K is independent of temperature and decreases rapidly with increasing concentration of BC-120 molecules and changes sign from positive to negative.

Defining an EPOR- regulated transcriptome for primary progenitors, including Tnfr-sf13c as a novel mediator of EPO- dependent erythroblast formation.

Certain concepts concerning EPO/EPOR action modes have been challenged by in vivo studies: Bcl-x levels are elevated in maturing erythroblasts, but not in their progenitors; truncated EPOR alleles that lack a major p85/PI3K recruitment site nonetheless promote polycythemia; and Erk1 disruption unexpectedly bolsters erythropoiesis. To discover novel EPO/EPOR action routes, global transcriptome analyses presently are applied to interrogate EPO/EPOR effects on primary bone marrow-derived CFUe-like progenitors. Overall, 160 EPO/EPOR target transcripts were significantly modulated 2-to 21.

The effect of pioglitazone treatment on 15-epi-lipoxin A4 levels in patients with type 2 diabetes.

Objectives: Arachidonic acid-derived eicosanoids (lipoxins and 15-epilipoxins) have a major role in resolution of inflammation. 15-epi-lipoxin A(4) (15-epi-LXA(4)) is a lipid mediator with strong anti-inflammatory and inflammation-resolving effects. We examined the effect of pioglitazone therapy on plasma 15-epi-LXA(4) in patients with type 2 diabetes (T2DM).

Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2.

Sprouty proteins are established modifiers of receptor tyrosine kinase (RTK) signaling and play important roles in vasculogenesis, bone morphogenesis, and renal uteric branching. Little is understood, however, concerning possible roles for these molecular adaptors during hematopoiesis. Within erythroid lineage, Spry1 was observed to be selectively and highly expressed at CFU-e to erythroblast stages.

Viscoelasticity of ambient-temperature nematic binary mixtures of bent-core and rodlike molecules.

We report measurements of the temperature variations of physical parameters in ambient-temperature nematic liquid crystal mixtures of bent-core (BC) and rodlike molecules (5CB): birefringence Δn; static dielectric constants ε(||) and ε(⊥); splay K(11) and bend K(33) elastic constants; rotational viscosity γ(1); and diffusion coefficients D(||) and D(⊥) of a microsphere. Both Δn and ε(||) decreases rapidly with increasing BC concentration, whereas ε(⊥) remains almost constant. At a shifted temperature (e.

miR-199b-5p directly targets PODXL and DDR1 and decreased levels of miR-199b-5p correlate with elevated expressions of PODXL and DDR1 in acute myeloid leukemia.

Aberrant expression of Podocalyxin (PODXL), a CD34 orthologue, has been associated with acute myeloid leukemia (AML). Herein, via tissue microarray, we discovered elevated PODXL expression in M2, M4 and M1 FAB-subtype patients. Importantly, various investigations have linked aberrant miRNA expression with AML (1).

miR-590-5p, miR-219-5p, miR-15b and miR-628-5p are commonly regulated by IL-3, GM-CSF and G-CSF in acute myeloid leukemia.

Aberrations in IL-3, GM-CSF and G-CSF induced signaling are frequently reported in acute myeloid leukemia (AML). Herein, we utilized a unique human myeloid leukemic cell line, AML-193, which responds to all three cytokines to analyze the regulation at microRNA level. Using real-time PCR-based miRNA expression profiling, we investigated miRNA signatures regulated by IL-3, GM-CSF and G-CSF for n=704 miRNAs.

Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial.

Aims/hypothesis: Systemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).

Methods: Type 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.