Spatial Transcriptome Mapping of the Desmoplastic Growth Pattern of Colorectal Liver Metastases by In Situ Sequencing Reveals a Biologically Relevant Zonation of the Desmoplastic Rim.

Purpose: We describe the fibrotic rim formed in the desmoplastic histopathologic growth pattern (DHGP) of colorectal cancer liver metastasis (CLM) using in situ sequencing (ISS). The origin of the desmoplastic rim is still a matter of debate, and the detailed cellular organization has not yet been fully elucidated. Understanding the biology of the DHGP in CLM can lead to targeted treatment and improve survival.

Spatial tumour gene signature discriminates neoplastic from non-neoplastic compartments in colon cancer: unravelling predictive biomarkers for relapse.

Background: Opting for or against the administration of adjuvant chemotherapy in therapeutic management of stage II colon cancer remains challenging. Several studies report few survival benefits for patients treated with adjuvant therapy and additionally revealing potential side effects of overtreatment, including unnecessary exposure to chemotherapy-induced toxicities and reduced quality of life. Predictive biomarkers are urgently needed.

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance.

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel-Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα.

Quantitation of ERK1/2 inhibitor cellular target occupancies with a reversible slow off-rate probe.

Target engagement is a key concept in drug discovery and its direct measurement can provide a quantitative understanding of drug efficacy and/or toxicity. Failure to demonstrate target occupancy in relevant cells and tissues has been recognised as a contributing factor to the low success rate of clinical drug development. Several techniques are emerging to quantify target engagement in cells; however, measurements remain challenging, mainly due to technical limitations.

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression.

Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches.

Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA.

We recently identified pathogenic β mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted β in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA.

The 1p36 Tumor Suppressor KIF 1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis.

KIF1Bβ is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1Bβ activates the Ca(2+)-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca(2+) signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease.

Tudor staphylococcal nuclease drives chemoresistance of non-small cell lung carcinoma cells by regulating S100A11.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), the major lung cancer subtype, is characterized by high resistance to chemotherapy. Here we demonstrate that Tudor staphylococcal nuclease (SND1 or TSN) is overexpressed in NSCLC cell lines and tissues, and is important for maintaining NSCLC chemoresistance.

Mature and immature microRNA ratios in cultured rat cardiomyocytes during anoxia-reoxygenation.

Background: The critical role of microRNAs (miRNAs) in the global control of gene expression in the heart has recently been postulated; however, the mechanisms of miRNA regulation in cardiac pathology are not clear.

Objective: To evaluate the levels of miR-1, miR-208a and miR-29a expressed in neonatal rat cardiomyocytes during anoxia-reoxygenation (AR).

Methods: Reverse transcription coupled with real-time polymerase chain reaction was used to evaluate the level of mature and immature miRNAs in cardiomyocyte culture during AR.

Knock-down of core proteins regulating microRNA biogenesis has no effect on sensitivity of lung cancer cells to ionizing radiation.

Recent studies underline the important role of microRNAs (miRNA) in the development of lung cancer. The main regulators of miRNA biogenesis are the ribonucleases Drosha, Dicer and Ago2. Here the role of core proteins of miRNA biogenesis machinery in the response of human non-small and small cell lung carcinoma cell lines to treatment with ionizing radiation was assessed.

Combined inhibition of DNA methyltransferase and histone deacetylase restores caspase-8 expression and sensitizes SCLC cells to TRAIL.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising drug for the treatment of tumors; however, a number of cancer cells are resistant to this cytokine. Among the mechanisms of resistance of small cell lung carcinomas (SCLCs) to TRAIL is the lack of caspase-8 expression. Although methylation of the caspase-8 promoter has been suggested as the main mechanism of caspase-8 silencing, we showed that reduction of the enzymes involved in DNA methylation, DNA methyltransferases (DNMT) 1, 3a and 3b, was not sufficient to significantly restore caspase-8 expression in SCLC cells, signifying that other mechanisms are involved in caspase-8 silencing.

Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL.

Background: TRAIL is considered as a promising anti-cancer agent, because of its ability to induce apoptosis in cancer but not in most normal cells. However, growing evidence exist that many cancer cells are resistant to its apoptotic effects. SCLC is a typical example of tumor entity where TRAIL monotherapy is not efficient.

Cardioprotective effect of 5-lipoxygenase gene (ALOX5) silencing in ischemia-reperfusion.

It is well known that 5-lipoxygenase derivates of arachidonic acid play an important pathogenic role during myocardial infarction. Therefore, the gene encoding arachidonate 5-lipoxygenase (ALOX5) appears to be an attractive target for RNA interference (RNAi) application. In experiments on cultivated cardiomyocytes with anoxia-reoxygenation (AR) and in vivo using rat model of heart ischemia-reperfusion (IR) we determined influence of ALOX5 silencing on myocardial cell death.

Effect of a low dose of proteasome inhibitor on cell death and gene expression in neonatal rat cardiomyocyte cultures exposed to anoxia-reoxygenation.

Background: Recent data suggest that low concentrations of proteasome inhibitors (PIs) are cytoprotective in models of ischemia-reperfusion injury, but the underlying mechanisms of this effect still remain unclear.

Aim: To investigate the effect of 100 nM of clasto-lactacystin beta-lactone on cell death and gene expression in neonatal rat cardiomyocytes exposed to anoxia-reoxygenation.

Methods: Fluorescent microscopy and real-time polymerase chain reaction were used to detect different types of cell death and gene expression, respectively, in neonatal rat cardiomyocyte cultures exposed to anoxia-reoxygenation.