PanCancer analysis of somatic mutations in repetitive regions reveals recurrent mutations in snRNA U2.

Current somatic mutation callers are biased against repetitive regions, preventing the identification of potential driver alterations in these loci. We developed a mutation caller for repetitive regions, and applied it to study repetitive non protein-coding genes in more than 2200 whole-genome cases. We identified a recurrent mutation at position c.

Dual dose-related effects evoked by CCL4 on thermal nociception after gene delivery or exogenous administration in mice.

As recently described, the administration of extremely low doses (pg/kg) of CCL4 (Macrophage inflammatory protein 1β, MIP-1β) can induce antinociceptive effects in mice (García-Domínguez et al., 2019b). We describe here that hydrodynamic delivery of a plasmid containing CCL4 cDNA provokes a biphasic response consisting in an initial thermal hyperalgesic reaction for 8 days followed by analgesia at days 10-12, being both responses blocked after the administration of the CCR5 antagonist DAPTA.

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas.

The U1 spliceosomal RNA is recurrently mutated in multiple cancers.

Cancers are caused by genomic alterations known as drivers. Hundreds of drivers in coding genes are known but, to date, only a handful of noncoding drivers have been discovered-despite intensive searching. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple types of cancer, although these mutations have only been found in protein-coding splicing factors such as splicing factor 3b subunit 1 (SF3B1).

Retraction Note: NF-κB activation impairs somatic cell reprogramming in ageing.

We, the authors, are retracting this Article due to issues that have come to our attention regarding data availability, data description and figure assembly. Specifically, original numerical data are not available for the majority of the graphs presented in the paper. Although original data were available for most EMSA and immunoblot experiments, those corresponding to the published EMSA data of Supplementary Fig.

Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia.

Unlabelled: ᅟ: Matrix metalloproteinases can modulate the inflammatory response through processing of cyto- and chemokines. Among them, MMP-14 is a non-dispensable collagenase responsible for the activation of other enzymes, triggering a proteolytic cascade. To identify the role of MMP-14 during the pro-inflammatory response, wildtype and Mmp14 mice were challenged with lipopolysaccharide.

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C.

In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant.

MMP-25 Metalloprotease Regulates Innate Immune Response through NF-κB Signaling.

Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the in vivo function of this protease.

NF-κB activation impairs somatic cell reprogramming in ageing.

Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing.

Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid.

MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure.

Pleiotropic functions of the tumor- and metastasis-suppressing matrix metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice.

Introduction: Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity that has oncosuppressive actions in numerous tumor types.

Methods: We have intercrossed Mmp8-null mice with the Polyoma virus middle T oncogene-driven (MMTV-PyMT) mouse model of mammary cancer to explore the effects of loss of MMP-8 on the incidence and progression of mammary carcinomas.

Results: In this aggressive mouse model of breast cancer, loss of MMP-8 accelerated tumor onset even further, such that 90% of MMTV-PyMT; Mmp8-null female mice were tumor-bearing at the time of weaning.

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.

Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.

Effects of azacitidine on matrix metalloproteinase-9 in acute myeloid leukemia and myelodysplasia.

Matrix metalloprotease-9 (MMP9) plays a critical role in acute myeloid leukemia (AML) by increasing the invasive properties of malignant myeloblasts. The role of this enzyme in high-risk myelodysplastic diseases (MDS) and the effect of azacitidine on its expression in MDS and AML have not been studied in detail. In this work, we have analyzed the effect of different concentrations of azacitidine in two well-established, MDS-derived, acute myeloid leukemic cell lines: MOLM-13 and SKM-1.

New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment.

Processes such as cell proliferation, angiogenesis, apoptosis, or invasion are strongly influenced by the surrounding microenvironment of the tumor. Therefore, the ability to change these surroundings represents an important property through which tumor cells are able to acquire specific functions necessary for tumor growth and dissemination. Matrix metalloproteinases (MMPs) constitute key players in this process, allowing tumor cells to modify the extracellular matrix (ECM) and release cytokines, growth factors, and other cell-surface molecules, ultimately facilitating protease-dependent tumor progression.

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood.

Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome.

Accelerated aging syndromes represent a valuable source of information about the molecular mechanisms involved in normal aging. Here, we describe a progeroid syndrome that partially phenocopies Hutchinson-Gilford progeria syndrome (HGPS) but also exhibits distinctive features, including the absence of cardiovascular deficiencies characteristic of HGPS, the lack of mutations in LMNA and ZMPSTE24, and a relatively long lifespan of affected individuals. Exome sequencing and molecular analysis in two unrelated families allowed us to identify a homozygous mutation in BANF1 (c.

Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10.

Background: Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines.

Methodology And Principal Findings: To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/-) mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points.

Chemokine monocyte chemoattractant protein-3 in progressive periodontal lesions in patients with chronic periodontitis.

Background: Chemokines are central in the activation and direction of leukocyte subsets to target tissues. However, the monocyte chemoattractant protein-3 (MCP-3) has not been associated with chronic periodontitis. Chronic periodontitis is an infection showing episodic supporting tissue destruction.

Absence or inhibition of matrix metalloproteinase-8 decreases ventilator-induced lung injury.

Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators.

Plasminogen enhances neuritogenesis on laminin-1.

Proteins of the plasminogen activation system are broadly expressed throughout the nervous system, and key roles for these proteins in neuronal function have been demonstrated. Recent reports have established that plasminogen is synthesized in neuroendocrine tissues, making this protein and the proteolytic activity of the product of its activation, plasmin, available at sites separated anatomically from circulating, hepatocyte-derived plasminogen. Results with plasminogen-deficient humans and mice suggest a role for plasminogen in neuritogenesis.

Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion.

Collagenase-2 (matrix metalloproteinase-8, MMP-8) is an MMP mainly produced by neutrophils and associated with many inflammatory conditions. We have previously described that MMP-8 plays a protective role in cancer through its ability to regulate the inflammatory response induced by carcinogens. Moreover, it has been reported that experimental manipulation of the expression levels of this enzyme alters the metastatic behavior of human breast cancer cells.

Collagenase-2 deficiency or inhibition impairs experimental autoimmune encephalomyelitis in mice.

Matrix metalloproteinases (MMPs) have been implicated in a variety of human diseases, including neuroimmunological disorders such as multiple sclerosis. However, the recent finding that some MMPs play paradoxical protective roles in these diseases has made necessary the detailed study of the specific function of each family member in their pathogenesis. To determine the relevance of collagenase-2 (MMP-8) in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we have performed two different analyses involving genetic and biochemical approaches.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury.

Matrix metalloproteinase-9 (MMP-9) is released by neutrophils at the sites of acute inflammation. This enzyme modulates matrix turnover and inflammatory response, and its activity has been found to be increased after ventilator-induced lung injury. To clarify the role of MMP-9, mice lacking this enzyme and their wild-type counterparts were ventilated for 2 h with high- or low-peak inspiratory pressures (25 and 15 cmH2O, respectively).