Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties

Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. Methods: Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose–response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. Results: The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. Conclusions: Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification

Gray matter imaging in multiple sclerosis: what have we learned?

At the early onset of the 20th century, several studies already reported that the gray matter was implicated in the histopathology of multiple sclerosis (MS). However, as white matter pathology long received predominant attention in this disease, and histological staining techniques for detecting myelin in the gray matter were suboptimal, it was not until the beginning of the 21st century that the true extent and importance of gray matter pathology in MS was finally recognized. Gray matter damage was shown to be frequent and extensive, and more pronounced in the progressive disease phases. Several studies subsequently demonstrated that the histopathology of gray matter lesions differs from that of white matter lesions. Unfortunately, imaging of pathology in gray matter structures proved to be difficult, especially when using conventional magnetic resonance imaging (MRI) techniques. However, with the recent introduction of several more advanced MRI techniques, the detection of cortical and subcortical damage in MS has considerably improved. This has important consequences for studying the clinical correlates of gray matter damage. In this review, we provide an overview of what has been learned about imaging of gray matter damage in MS, and offer a brief perspective with regards to future developments in this field

Localizability in κ -Minkowski spacetime

Using the methods of ordinary quantum mechanics, we study κ-Minkowski space as a quantum space described by noncommuting self-adjoint operators, following and enlarging T. Poulain and J.-C. Wallet, "κ-Poincaré invariant orientable field theories with at 1-loop: Scale-invariant couplings, preprint (2018), arXiv:1808.00350 [hep-th]. We see how the role of Fourier transforms is played in this case by Mellin transforms. We briefly discuss the role of transformations and observers

The Weyl-Mellin quantization map

In this paper, we present a quantization of the functions of spacetime, i.e. a map, analog to Weyl map, which reproduces the κ-Minkowski commutation relations, and it has the desirable properties of mapping square integrable functions into Hilbert-Schmidt operators, as well as real functions into symmetric operators. The map is based on Mellin transform on radial and time coordinates. The map also defines a deformed - product which we discuss with examples

Structural similitudes of stiffened cylinders

Similarity theory is a branch of engineering science that deals with establishing conditions of similarity among phenomena and is applied to various fields, such as structural engineering problems, vibration and impact. Tests and numerical simulation of scaled models are still a valuable design tool, whose purpose is to accurately predict the behaviour of large or small prototypes through scaling laws applied to the experimental and numerical results. The aim of this paper is to predict the behaviour of the complete and incomplete similarity of stiffened cylinders by applying distorted scaling laws of the models in similitude. The investigation is performed using models based on the finite element method within commercial software. Two classes of cylinders scaled, with different laws, and, hence, reproducing replicas (exact similitude) and avatars (distorted similitude) are investigated