National accounting rules in a globalized world (Pro and contra) ; contra - the best of both worlds

Grundsätze ordnungsmäßiger Buchführung, Bilanztheorie, Globalisierung, GAAP (Generally Accepted Accounting Principles), Accounting theory, Globalization

Using large-scale genomics data to identify driver mutations in lung cancer: methods and challenges

Lung cancer is the commonest cause of cancer death in the world and carries a poor prognosis for most patients. While precision targeting of mutated proteins has given some successes for never- and light-smoking patients, there are no proven targeted therapies for the majority of smokers with the disease. Despite sequencing hundreds of lung cancers, known driver mutations are lacking for a majority of tumors. Distinguishing driver mutations from inconsequential passenger mutations in a given lung tumor is extremely challenging due to the high mutational burden of smoking-related cancers. Here we discuss the methods employed to identify driver mutations from these large datasets. We examine different approaches based on bioinformatics, in silico structural modeling and biological dependency screens and discuss the limitations of these approaches

Overexpression and Small Molecule-Triggered Downregulation of CIP2A in Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear.Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation

Multi-Level Targeting of the Phosphatidylinositol-3-Kinase Pathway in Non-Small Cell Lung Cancer Cells

Introduction: We assessed expression of p85 and p110a PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines. Methods: Using Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP-BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

SummaryBRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance

PHLPP : a novel family of phosphatases that are critical regulators of iIntracellular signaling pathways

A fundamental aim in cell signaling is to decipher how phosphorylation and dephosphorylation regulate cell fate. In order to achieve this goal the scientific community must have a complete understanding of the proteins involved in regulating cellular processes. To this end we have discovered a novel family of phosphatases referred to as PHLPP, (PH domain leucine-rich repeat protein phosphatase). These Ser/Thr specific phosphatases have emerged as important regulators of intracellular signaling pathways by acting as the brakes to lipid second messenger signaling. This thesis will focus on characterizing the novel phosphatase PHLPP2 and defining its role in regulation of the PI3K/Akt pathway. Second, it addresses whether these phosphatases are involved in the process of tumorigenesis. Lastly, it will examine the role of PHLPP in regulation of the related kinase, protein kinase C. In summary, this thesis is a first step in understanding the role of PHLPP in normal tissue homeostasis as well as pathophysiological state

PHLPP : a novel family of phosphatases that are critical regulators of iIntracellular signaling pathways

A fundamental aim in cell signaling is to decipher how phosphorylation and dephosphorylation regulate cell fate. In order to achieve this goal the scientific community must have a complete understanding of the proteins involved in regulating cellular processes. To this end we have discovered a novel family of phosphatases referred to as PHLPP, (PH domain leucine-rich repeat protein phosphatase). These Ser/Thr specific phosphatases have emerged as important regulators of intracellular signaling pathways by acting as the brakes to lipid second messenger signaling. This thesis will focus on characterizing the novel phosphatase PHLPP2 and defining its role in regulation of the PI3K/Akt pathway. Second, it addresses whether these phosphatases are involved in the process of tumorigenesis. Lastly, it will examine the role of PHLPP in regulation of the related kinase, protein kinase C. In summary, this thesis is a first step in understanding the role of PHLPP in normal tissue homeostasis as well as pathophysiological state

New Therapeutic Opportunities for the Treatment of Squamous Cell Carcinomas: A Focus on Novel Driver Kinases

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome’s distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases

Protein kinase signaling networks in cancer

Protein kinases orchestrate the activation of signalling cascades in response to extracellular and intracellular stimuli to control cell growth, proliferation, and survival. The complexity of the numerous intracellular signalling pathways is highlighted by the number of kinases encoded by the human genome (539) and the plethora of phosphorylation sites identified in phosphoproteomic studies. Perturbation of these signalling networks by mutations or abnormal protein expression underlies the cause of many diseases including cancer. Recent RNAi screens and cancer genomic sequencing studies have revealed that many more kinases than anticipated contribute to tumorigenesis and are potential targets for inhibitor drug development intervention. This review will highlight recent insights into known pathways essential for tumorigenesis and discuss exciting new pathways for therapeutic intervention

PHLiPPing the switch on Akt and protein kinase C signaling

The Ser/Thr specific-phosphatase PHLPP (Pleckstrin Homology (PH) domain leucine-rich repeat protein phosphatase) provides “the brakes” for Akt and protein kinase C (PKC) signaling. The two isoforms of this recently discovered family, PHLPP1 and PHLPP2, control the amplitude and duration of signaling of Akt and PKC by catalyzing the dephosphorylation of the hydrophobic phosphorylation motif, a C-terminal phosphorylation switch that controls the activity of these kinases. Aberrant regulation of either kinase accompanies many diseases, notably diabetes and cancer. By specifically dephosphorylating the hydrophobic motif, PHLPP controls the degree of agonist-evoked signaling by Akt and the cellular levels of PKC. This review focuses on the function of PHLPP1 and PHLPP2 in modulating signaling by Akt and PKC