Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.

Background: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.

TERT RNAscope analysis of sub-centimetric papillary thyroid carcinomas and synchronous lymph node metastases.

Background: Sub-centrimetric papillary thyroid carcinomas usually have a good prognosis with a cancer specific survival of > 99%, however in up to 65% of patients, lymph node metastases can be observed. Molecular alterations in BRAF, TERT and TP53 are associated with worse clinicopathological outcome in patients with papillary thyroid carcinoma.

Material And Methods: Twenty-two cases of papillary thyroid carcinomas measuring ≤ 1 cm with synchronous lymph node metastases were examined regarding morphological patterns and immunohistochemical status of p53, Ki-67, and BRAF V600E status.

-FISH Evaluation Algorithm: Proposal of a Simplified Method.

MET amplifications (METamp) occur in 5% of NSCLC and represent in most case mechanisms of resistance to ALK and/or EGFR-targeted therapies. METamp detection can be performed using different techniques, although Fluorescence In-Situ Hybridization (FISH) remains the gold-standard, especially in the context of subclonality. To date current evaluation algorithms of MET amplifications are time consuming.

Prevalence and potential biological role of TERT amplifications in ALK translocated adenocarcinoma of the lung.

Aims: The advent of specific ALK-targeting drugs has radically changed the outcome of patients with ALK translocated non-small-cell lung cancer (NSCLC). However, emerging resistance to treatment with ALK inhibitors in these patients remains a major concern. In previous studies, we analysed two ALK+ patient cohorts (TP53 wild-type/TP53 mutated) in terms of copy number alterations.

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors.

Background: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI and later the 2nd -generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy.

The nucleic acid binding protein YB-1-controlled expression of CXCL-1 modulates kidney damage in liver fibrosis.

Acute kidney injury is a common complication of advanced liver disease and increased mortality of these patients. Here, we analyzed the role of Y-box protein-1 (YB-1), a nucleic acid binding protein, in the bile duct ligation model of liver fibrosis and monitored liver and subsequent kidney damage. Following bile duct ligation, both serum levels of liver enzymes and expression of hepatic extracellular matrix components such as type I collagen were significantly reduced in mice with half-maximal YB-1 expression (Yb1) as compared to their wild-type littermates.

Advance of theragnosis biomarkers in lung cancer: from clinical to molecular pathology and biology.

One distinct molecular subtype of non-small cell lung cancer (NSCLC) is defined by rearrangement of the anaplastic lymphoma kinase (). The increasing knowledge over the last years has enabled the continuous improvement of ALK inhibitors; however, resistance in these patients remains a major concern. In this review, we summarize recent findings in +-adenocarcinoma of the lung, highlighting the role of mutations in this specific cancer type and suggest new diagnostic strategies for the future, in order to improve patient's outcome.

Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies.

Although non-small-cell lung cancer is a leading cause of cancer-related deaths, the molecular characterization and classification of its genetic alterations has drastically changed treatment options and overall survival within the last few decades. In particular, tyrosine kinase inhibitors targeting specific molecular alterations, among other MET, have greatly improved the prognosis of non-small-cell lung cancer patients. Here, we compare the genomic background of a subset of non-small-cell lung cancer cases harboring either a MET high-level amplification (n = 24) or a MET exon 14 skipping mutation (n = 26), using next-generatison sequencing, fluorescence in situ hybridization, immunohistochemistry, and Nanostring nCounter technology.

YB-1 increases glomerular, but decreases interstitial fibrosis in CNI-induced nephropathy.

Calcineurin inhibitors (CNIs) are a cornerstone of the current treatment in solid organ transplantation and autoimmune disease. However, CNIs also bear deleterious effects as they cause glomerular and tubulointerstitial fibrosis in the kidney. We recently identified Y-box protein-1 (YB-1) as a novel downstream effector of CNI-signaling in the cytoplasm of glomerular cells.

Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations.

The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse.

Comparison of Blood Collection Tubes from Three Different Manufacturers for the Collection of Cell-Free DNA for Liquid Biopsy Mutation Testing.

The improvement in sensitive techniques has allowed the detection of tumor-specific aberrations in circulating tumor (ct) DNA. Amplification-refractory mutation system PCR has been used for the analysis of ctDNA to detect resistance-causing mutations in the epidermal growth factor receptor gene (eg, EGFR T790M) in lung cancer patients. So far, Streck tubes have been widely used as standard blood collection tubes.

Therapeutic nuclear shuttling of YB-1 reduces renal damage and fibrosis.

Virtually all chronic kidney diseases progress towards tubulointerstitial fibrosis. In vitro, Y-box protein-1 (YB-1) acts as a central regulator of gene transcription and translation of several fibrosis-related genes. However, it remains to be determined whether its pro- or antifibrotic propensities prevail in disease.

Cold shock protein YB-1 is involved in hypoxia-dependent gene transcription.

Hypoxia-dependent gene regulation is largely orchestrated by hypoxia-inducible factors (HIFs), which associate with defined nucleotide sequences of hypoxia-responsive elements (HREs). Comparison of the regulatory HRE within the 3' enhancer of the human erythropoietin (EPO) gene with known binding motifs for cold shock protein Y-box (YB) protein-1 yielded strong similarities within the Y-box element and 3' adjacent sequences. DNA binding assays confirmed YB-1 binding to both, single- and double-stranded HRE templates.

Calcineurin-mediated YB-1 dephosphorylation regulates CCL5 expression during monocyte differentiation.

Y-box (YB) protein-1 serves as a master regulator in gene transcription and mRNA translation. YB-1 itself is regulated at various levels, e.g.

YB-1 is an early and central mediator of bacterial and sterile inflammation in vivo.

In vitro studies identified Y-box-binding protein (YB)-1 as a key regulator of inflammatory mediators. In this study, we observed increased levels of secreted YB-1 in sera from sepsis patients. This led us to investigate the in vivo role of YB-1 in murine models of acute peritonitis following LPS injection, in sterile renal inflammation following unilateral ureteral obstruction, and in experimental pyelonephritis.

Y-box binding protein-1 mediates profibrotic effects of calcineurin inhibitors in the kidney.

The immunosuppressive calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus are widely used in transplant organ recipients, but in the kidney allograft, they may cause tubulointerstitial as well as mesangial fibrosis, with TGF-β believed to be a central inductor. In this study, we report that the cold-shock protein Y-box binding protein-1 (YB-1) is a TGF-β independent downstream effector in CsA- as well as in tacrolimus- but not in rapamycin-mediated activation of rat mesangial cells (rMCs). Intracellular content of YB-1 is several-fold increased in MCs following CNI treatment in vitro and in vivo in mice.