Loss of Lkb1 cooperates with Braf and ultraviolet radiation, increasing melanoma multiplicity and neural-like dedifferentiation.

The mechanisms that work alongside BRAF oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal Braf activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development.

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage.

Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.

Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis.

Toward Advanced Functional Systems: Honeycomb-Like Polymeric Surfaces Incorporating Polyoxovanadates with Surface-Appended Copper-Cyclam Complexes.

In this work the immobilization of hybrid polyoxometalates (POMs) onto functional polymeric surfaces is exposed and discussed. Thus, various hybrid polymer‒inorganic films were prepared by anchoring selected hybrid POMs onto tailored polymeric surfaces that consisted of breath figures (BFs) made of polystyrene-b-poly(acrylic acid)/polystyrene (PS-b-PAA/PS) blends. Functionalization of the BF films was performed by selective arrangement of acrylic acid groups of the amphiphilic block copolymer on the surface pores because of their affinition for the water condensed during breath figure formation.

Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function.

Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD. Hence, mice lacking PARP-1 or PARP-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that PARP-1 and PARP-2 have on the cellular response to DNA damage.

Thermostructural Behavior in a Series of Lanthanide-Containing Polyoxotungstate Hybrids with Copper(II) Complexes of the Tetraazamacrocycle Cyclam: A Single-Crystal-to-Single-Crystal Transformation Study.

A series of 14 isostructural [Cu(cyclam)][{Cu(cyclam)}{(α-GeWO)Ln(HO)(OAc)}]·18HO (1-Ln, where Ln = La-Lu; cyclam = 1,4,8,11-tetraazacyclotetradecane) polyoxometalate-based hybrids reported herein represent (i) the first example of a two-dimensional covalent hybrid lattice involving the [{(α-XWO)Ln(HO)(OAc)}] archetype and (ii) the first structural characterization of such a dimeric polyoxotungste for Ln = La and Pr as well as for the combination of X = Ge and Ln = Ce, Nd, Sm, or Lu. Compounds 1-Ln have been characterized by elemental analyses, infrared spectroscopy, and thermogravimetric analysis, and their thermostructural behavior has been monitored by powder and single-crystal X-ray diffraction. The title compounds undergo two single-crystal-to-single-crystal transformations triggered by thermal dehydration leading to the [{Cu(cyclam)}{(α-GeWO)Ln(HO)(OAc)}]·4HO intermediate (2-Ln, where Ln = Eu or Er) and [Cu(cyclam)][{Cu(cyclam)}{(α-GeWO)Ln(OAc)}] (3-Ln, where Ln = Ce or Eu) final anhydrous phases, the latter evidencing a coordinatively unsaturated derivative of the dimeric archetype for the first time.

Identity Noise and Adipogenic Traits Characterize Dermal Fibroblast Aging.

During aging, stromal functions are thought to be impaired, but little is known whether this stems from changes of fibroblasts. Using population- and single-cell transcriptomics, as well as long-term lineage tracing, we studied whether murine dermal fibroblasts are altered during physiological aging under different dietary regimes that affect longevity. We show that the identity of old fibroblasts becomes undefined, with the fibroblast states present in young skin no longer clearly demarcated.

Macrophage-specific MHCII expression is regulated by a remote enhancer controlled by NFAT5.

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of and MHCII in macrophages, but not in dendritic cells and other APCs.

Constitutive Cyclin O deficiency results in penetrant hydrocephalus, impaired growth and infertility.

Cyclin O (encoded by ) is a member of the cyclin family with regulatory functions in ciliogenesis and apoptosis. Homozygous mutations have been identified in human patients with Reduced Generation of Multiple Motile Cilia (RGMC) and conditional inactivation of in the mouse recapitulates some of the pathologies associated with the human disease. These include defects in the development of motile cilia and hydrocephalus.

Thermally-Triggered Crystal Dynamics and Permanent Porosity in the First Heptatungstate-Metalorganic Three-Dimensional Hybrid Framework.

The hybrid compound [{Cu(cyclam)} (W O )]⋅15.5 H O (1) (cyclam=1,4,8,11-tetraaza-cyclotetradecane) was synthesized by reacting the {Cu(cyclam)} complex with a tungstate source in water at pH 8. Compound 1 exhibits an unprecedented three-dimensional covalent structure built of heptatungstate clusters linked through metalorganic complexes in a POMOF-like framework that displays water-filled channels.

ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82.

ΔNp63α is a critical mediator of epithelial development and stem cell function in a variety of tissues including the skin and breast, while overexpression of ΔNp63α acts as an oncogene to drive tumor formation and cancer stem cell properties in squamous cell carcinoma. However, with regards to the prostate, while ΔNp63α is expressed in the basal stem cells of the mature gland, during adenocarcinoma development, its expression is lost and its absence is used to clinically diagnose the malignant state. Surprisingly, here we identify a sub-population of bone metastatic prostate cancer cells in the PC3 cell line that express ΔNp63α.

PARP-1/PARP-2 double deficiency in mouse T cells results in faulty immune responses and T lymphomas.

The maintenance of T-cell homeostasis must be tightly regulated. Here, we have identified a coordinated role of Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in maintaining T-lymphocyte number and function. Mice bearing a T-cell specific deficiency of PARP-2 in a PARP-1-deficient background showed defective thymocyte maturation and diminished numbers of peripheral CD4 and CD8 T-cells.

A Robust Open Framework Formed by Decavanadate Clusters and Copper(II) Complexes of Macrocyclic Polyamines: Permanent Microporosity and Catalytic Oxidation of Cycloalkanes.

The first decavanadate-based microporous hybrid, namely, [Cu(cyclam)][{Cu(cyclam)}2(V10O28)]·10H2O (1, cyclam = 1,4,8,11-tetraazacyclotetradecane) was prepared by reaction of (VO3)(-) anions and {Cu(cyclam)}(2+) complexes in NaCl (aq) at pH 4.6-4.7 and characterized by elemental analyses, thermogravimetry, and X-ray diffraction (powder, single-crystal) techniques.

A cellular model reflecting the phenotypic heterogeneity of mutant HRAS driven squamous cell carcinoma.

Squamous cell carcinomas have a range of histopathological manifestations. The parameters that determine this clinically observed heterogeneity are not fully understood. Here, we report the generation of a cell culture model that reflects part of this heterogeneity.

PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors.

Erythropoiesis is a tightly regulated process in which multipotential hematopoietic stem cells produce mature red blood cells. Here we show that deletion of poly(ADP-ribose) polymerase-2 (PARP-2) in mice leads to chronic anemia at steady state, despite increased erythropoietin plasma levels, a phenomenon not observed in mice lacking PARP-1. Loss of PARP-2 causes shortened lifespan of erythrocytes and impaired differentiation of erythroid progenitors.

miRNA-1 and miRNA-133a are involved in early commitment of pluripotent stem cells and demonstrate antagonistic roles in the regulation of cardiac differentiation.

miRNA-1 (miR-1) and miRNA-133a (miR-133a) are muscle-specific miRNAs that play an important role in heart development and physiopathology. Although both miRNAs have been broadly studied during cardiogenesis, the mechanisms by which miR-1 and miR-133a could influence linage commitment in pluripotent stem cells remain poorly characterized. In this study we analysed the regulation of miR-1 and miR-133a expression during pluripotent stem cell differentiation [P19.

Functionalization of Krebs-type polyoxometalates with N,O-chelating ligands: a systematic study.

The first organic derivatives of 3d-metal-disubstituted Krebs-type polyoxometalates have been synthesized under mild bench conditions via straightforward replacement of labile aqua ligands with N,O-chelating planar anions on either preformed or in situ-generated precursors. Nine hybrid clusters containing carboxylate derivatives of five- or six-membered aromatic N-heterocycles as antenna ligands have been obtained as pure crystalline phases and characterized by elemental and thermal analyses, infrared spectroscopy, and single-crystal X-ray diffraction. They all show the general formula [{M(II)L(H2O)}2(WO2)2(B-β-XW9O33)2](n-) and can be classified as follows: 1-SbM, where L = 1H-imidazole-4-carboxylate (imc), X = Sb(III), n = 12, and M(II) = Mn, Co, Ni, Zn; 1-TeM, where L = imc, X = Te(IV), n = 10, and M(II) = Mn, Co; 2-SbNi, where L = 1H-pyrazole-3-carboxylate (pzc), X = Sb(III), n = 12, and M(II) = Ni; and 3-SbM, where L = pyrazine-2-carboxylate (pyzc), X =Sb(III), n = 12, and M(II) = Co, Zn.

A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation.

Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling.

The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells.

In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors.

ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia.

Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells.

Cooperative role between p21cip1/waf1 and p27kip1 in premature senescence in glandular proliferative lesions in mice.

Cellular senescence has been considered a novel target for cancer therapy. It has also been pointed out that p21(cip1/waf1) and p27(kip1) cyclin-dependent kinase inhibitors (CKIs) play a role in cellular senescence in some tumor types. Therefore, in order to address the possibility of a cooperative role between p21 and p27 proteins in senescence in vivo we analyzed cellular senescence in spontaneous glandular proliferative lesions (adrenal, thyroid and pituitary glands) in a double-KO mice model, using γH2AX, p53, p16, PTEN and Ki67 as senescence markers.

trans-Di-aqua-bis-(pyridazine-3-carboxyl-ato-κ(2) N (2),O)cobalt(II) dihydrate.

The title compound, [Co(C5H3N2O2)2(H2O)2]·2H2O, contains a Co(II) ion on an inversion center, exhibiting an octa-hedral coordination geometry. The equatorial plane is formed by two trans-related N,O-bidentate pyridazine-3-carboxyl-ate ligands and the axial positions are occupied by two water mol-ecules. The Co(II) complex mol-ecules are stacked in a column along the a-axis direction by an O-H⋯N hydrogen bond between the non-coordinating pyridazine N atom and the coordinating water mol-ecule.

Lkb1 loss promotes tumor progression of BRAF(V600E)-induced lung adenomas.

Aberrant activation of MAP kinase signaling pathway and loss of tumor suppressor LKB1 have been implicated in lung cancer development and progression. Although oncogenic KRAS mutations are frequent, BRAF mutations (BRAF(V600E)) are found in 3% of human non-small cell lung cancers. Contrary to KRAS mutant tumors, BRAF(V600E)-induced tumors are benign adenomas that fail to progess.