Pulmonary manifestations of systemic karyomegaly

Over 40 years ago, abnormal enlargement of the nucleus of tubular epithelial cells was reported in a rare distinct hereditary chronic interstitial nephritis, karyomegalic interstitial nephritis (KIN). Here, we report the second case of systemic karyomegaly with pulmonary manifestations and present a detailed characterization of the karyomegalic cells in lung parenchyma. A 59-year-old woman who was diagnosed with KIN developed renal failure and eventually received a renal transplant later evaluated for chronic and progressive restrictive lung disease. The KIN diagnosis prompted us to carefully examine her lung parenchyma. Karyomegalic cells were identified in the alveolar epithelium, interstitium, as well as, in the vascular wall. Viral serological and biochemical blood analyses were negative. We consider that the pulmonary manifestations of karyomegaly expands the differential diagnosis of interstitial lung disease in patients with KIN.Funding Agencies|Swedish Cancer Research; Vastra Gotalandregionen; Swedish Society of Pathology</p

Blocking the Cleavage of Filamin A by Calpain Inhibitor Decreases Tumor Cell Growth

Background/Aim: Filamin A (FLNA) is the most abundant and widely expressed isoform of filamin in human tissues. It is cleaved by calpain at the hinge 1 and 2 domains, producing a 90-kDa carboxyl-terminal fragment (FLNA(CT)). Recently, it has been shown that FLNA(CT) mediates cell signaling and transports transcription factors into the cell nucleus. However, the significance of cleavage of FLNA by calpain has not been studied in cancer cell growth. Calpeptin is a chemical inhibitor of both calpain 1 and 2 that cleaves FLNA. In this study, we questioned if inhibiting calpain using calpeptin would decrease tumor cell proliferation, migration, invasion, and colony formation. Materials and Methods: Human melanoma (A7), prostate cancer (PC3), mouse fibrosarcoma (T241) and endothelial (MS1) cells were assayed for proliferation, migration, invasion and colony formation after treatment with calpeptin. Cell lysates were immunoblotted for FLNA and FLNA(CT). Results: Calpeptin treatment of these cells resulted in a decreased production of FLNA(CT). Calpeptin-treated human and mouse tumor cells displayed impaired proliferation, migration, and colony formation. Conclusion: These data suggest that the cleavage of FLNA by calpain is an important cellular event in the regulation of tumor cell growth

Filamin A mediates HGF/c-MET signaling in tumor cell migration

Deregulated hepatocyte growth factor (HGF)/c-MET axis has been correlated with poor clinical outcome and drug resistance in may human cancers. Identification of novel regulatory mechanisms influencing HGF/c-MET signaling may therefore be necessary to develop more effective cancer therapies. In our study, we show that multiple human cancer tissues and cells express filamin A (FLNA), a large cytoskeletal actin-binding protein, and expression of c-MET is significantly reduced in human tumor cells deficient for FLNA. The FLNA-deficient tumor cells exhibited poor migrative and invasive ability in response to Kg. On the other hand, the anchorage-dependent and independent tumor cell proliferation was not altered by HGF. The FLNA-deficiency specifically attenuated the activation of the c-MET downstream signaling molecule AKT in response to HGF stimulation. Furthermore, FLNA enhanced c-MET promoter activity by its binding to SMAD2. The impact of FLNA deficiency on c-NET expression and HGF-mediated cell migration in human tumor cells was confirmed in primary mouse embryonic fibroblasts deficient for Flna. These data suggest that FLNA is one of the important regulators of c-MET signaling and HGF-induced tumor cell migration

IGL-1 as a preservation solution in intestinal transplantation: a multicenter experience

Intestinal transplantation (ITx) is a life-saving procedure for complicated intestinal failure. It is still characterized by a high risk of infection and rejection(1). Of all organs, the intestine is the most vulnerable to ischemia reperfusion injury (IRI) and the associated crosstalk between the innate and adaptive immune response can trigger rejection(2). A crucial factor in limiting IRI is the organ preservation phase. Currently, static cold storage with University of Wisconsin (UW) solution is the gold standard, although other solutions such as HTK (Histidine-Tryptophan-Ketoglutarate) have also been reported (3). Due to low numbers, randomized controlled trials are difficult to organize in this field.status: publishe

Targeting filamin A reduces K-RAS-induced lung adenocarcinomas and endothelial response to tumor growth in mice

Background: Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. less thanbrgreater than less thanbrgreater thanMethods: First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. less thanbrgreater than less thanbrgreater thanResults: Knockout of Flna significantly reduced K-RAS-induced lung tumor formation and the proliferation of oncogenic K-RAS-expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.Funding Agencies|The Swedish Society of Medicine||The Assar Gabrielsson Foundation||The Sahlgrenska University Hospital||The Swedish Research Council||The Swedish Cancer Society||</p

Open Access

Targeting filamin A reduces K-RAS-induce

The Risk-Associated Long Noncoding RNA NBAT-1 Controls Neuroblastoma Progression by Regulating Cell Proliferation and Neuronal Differentiation

Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptonnes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors

Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies