Vascular senescence and leak are features of the early breakdown of the blood-brain barrier in Alzheimer's disease models.

Alzheimer's disease (AD) is an age-related disease, with loss of integrity of the blood-brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD.

Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells.

Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response.

Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement of MPM cell sensitivity to chemotherapy drug treatment following microRNA (miRNA) transfection in MPM cell lines, albeit not for all tested miRNAs.

Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7.

MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours.

Deletion of kif3a in CK19 positive cells leads to primary cilia loss, biliary cell proliferation and cystic liver lesions in TAA-treated mice.

Background & Aims: Loss of primary cilia in epithelial cells is known to cause cystic diseases of the liver and kidney. We have previously shown that during experimental and human cirrhosis that primary cilia were predominantly expressed on biliary cells in the ductular reaction. However, the role of primary cilia in the pathogenesis of the ductular reaction is not fully understood.

Genomic Deletion of and Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures.

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose.

Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression.

Purpose: Deregulated MYC drives oncogenesis in many tissues yet direct pharmacologic inhibition has proven difficult. MYC coordinately regulates polyamine homeostasis as these essential cations support MYC functions, and drugs that antagonize polyamine sufficiency have synthetic-lethal interactions with MYC Neuroblastoma is a lethal tumor in which the MYC homologue MYCN, and ODC1, the rate-limiting enzyme in polyamine synthesis, are frequently deregulated so we tested optimized polyamine depletion regimens for activity against neuroblastoma.

Experimental Design: We used complementary transgenic and xenograft-bearing neuroblastoma models to assess polyamine antagonists.

Cilengitide inhibits attachment and invasion of malignant pleural mesothelioma cells through antagonism of integrins αvβ3 and αvβ5.

Malignant pleural mesothelioma (MPM) is an almost invariably fatal, asbestos-related malignancy arising from the mesothelial membrane lining the thoracic cavities. Despite some improvements in treatment, therapy is not considered curative and median survival following diagnosis is less than 1 year. Although still classed as a rare cancer, the incidence of MPM is increasing, and the limited progress in treating the disease makes the identification of new therapies a priority.

ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma.

Introduction: Epigenetic inactivation of tumor suppressor genes is involved in the development of malignant pleural mesothelioma (MPM). ZIC1, a potential tumor suppressor gene involved in regulating cell growth and apoptosis, was investigated in MPM cell lines and tumors.

Methods: ZIC1 expression and promoter methylation were evaluated in MPM cell lines and tumor samples by quantitative polymerase chain reaction (PCR), Combined Bisulfite Restriction Analysis, and methylation-specific PCR.

Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg.

Fanconi anemia (FA) is a heritable disease characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. The 15 identified FA genes operate in a molecular pathway to preserve genomic integrity. Within this pathway the FA core complex operates as an ubiquitin ligase that activates the complex of FANCD2 and FANCI to coordinate DNA repair.

ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma.

Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis.

Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma.

Overexpression of the human MYCN oncogene driven by a tyrosine hydroxylase promoter causes tumours in transgenic mice that recapitulate the childhood cancer neuroblastoma. To establish an in vitro model to study this process, a series of isogenic cell lines were developed from these MYCN-driven murine tumours. Lines were established from tumours arising in homozygous and hemizygous MYCN transgenic mice.

In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice.

Fanconi anemia (FA) is a rare autosomal recessive disease, characterized by bone marrow failure and cancer predisposition. So far, 8 complementation groups have been identified, although mutations in FANCA account for the disease in the majority of FA patients. In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the main phenotypic characteristics of the bone marrow (BM) progenitors using retroviral vectors.

Characterization, expression and complex formation of the murine Fanconi anaemia gene product Fancg.

Background: Fanconi anaemia (FA) is an autosomal recessive chromosomal instability disorder. Six distinct FA disease genes have been identified, the products of which function in an integrated pathway that is thought to support a nuclear caretaker function. Comparison of FA gene characteristics in different species may help to unravel the molecular function of the FA pathway.

Knockout mouse model for Fxr2: a model for mental retardation.

Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Fmr1 knockout mice exhibit a phenotype with some similarities to humans, such as macro-orchidism and behavioral abnormalities. Two homologs of FMRP have been identified, FXR1P and FXR2P.

Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice.

Fanconi anemia (FA) is a heterogeneous autosomal recessive chromosomal instability syndrome associated with diverse developmental abnormalities, progressive bone marrow failure and a predisposition to cancer. Spontaneous chromosomal breakage and hypersensitivity to DNA cross-linking agents characterize the cellular FA phenotype. The gene affected in FA complementation group G patients was initially identified as XRCC9, for its ability to partially correct the cellular phenotype of the Chinese hamster ovary (CHO) cell mutant UV40.