A rare case of melanosis of the hard palate mucosa in a patient with chronic myeloid leukemia

Imatinib Mesylate, also known as Gleevec or ST1-571, is a tyrosine-kinase inhibitor used as the gold standard medication for the chronic myeloid leukemia (CML); Imatinib has indeed deeply revolutionized the CML therapy allowing most patients to have a good quality of life. Despite its beneficial effects, Imatinib has significant side effects such as mucosal pigmentation. A 72-year-old female having an Imatinib induced mucosal pigmentation is presented: she has been treated with Imatinib since 2003 and only in 2014 discovered, during a routine dental visit, having a pigmented lesion on her hard palate mucosa. Histopathologically, the lesion shows the deposition of fine dark brown spherical bodies within the lamina propria and cloaked in between the collagen fibers. There was no sign of inflammation, hyperplasia, or hemorrhage in the tissu

Cancer 2.0: A Summary of Recent Research

Outlines findings on Internet access and use among cancer patients compared with other chronic disease patients, the demand for health information online, the role of social network sites, and implications for cancer treatment and research

Complex Systems Analysis of Arrested Neural Cell Differentiation during Development and Analogous Cell Cycling Models in Carcinogenesis

A new approach to the modular, complex systems analysis of nonlinear dynamics of arrested neural cell Differentiation--induced cell proliferation during organismic development and the analogous cell cycling network transformations involved in carcinogenesis is proposed. Neural tissue arrested differentiation that induces cell proliferation during perturbed development and Carcinogenesis are complex processes that involve dynamically inter-connected biomolecules in the intercellular, membrane, cytosolic, nuclear and nucleolar compartments. Such 'dynamically inter-connected' biomolecules form numerous inter-related pathways referred to as 'molecular networks'. One such family of signaling pathways contains the cell cyclins. Cyclins are proteins that link several critical pro-apoptotic and other cell cycling/division components, including the tumor suppressor gene TP53 and its product, the Thomsen-Friedenreich antigen (T antigen), Rb, mdm2, c-Myc, p21, p27, Bax, Bad and Bcl-2, which play major roles in various neoplastic transformations of many tissues. The novel theoretical analysis presented here is based on recently published studies of arrested cell differentiation that normally leads to neural system formation during early developmental stages; the perturbed development may involve cyclin signaling and cell cycling responsible for rapidly induced cell proliferation without differentiation into neural cells in such experimental studies; special emphasis in this modular model is placed upon the roles of cyclins D1 and E, and does suggest novel clinical trials as well as rational therapies of cancer through re-establishment of cell cycling inhibition in metastatic cancer cells. Cyclins are proteins that are often over-expressed in cancerous cells (Dobashi et al., 2004). They may also be over-expressed in cells whose differentiation is arrested during the early stages of organismic development, leading to increased cell proliferation instead of differentiation into specialized tissues such as those forming the neural system. Cyclin-dependent kinases (CDK), their respective cyclins, and inhibitors of CDKs (CKIs) were identified as instrumental components of the cell cycle-regulating machinery. In mammalian cells the complexes of cyclins D1, D2, D3, A and E with CDKs are considered motors that drive cells to enter and pass through the “S” phase. Cell cycle regulation is a critical mechanism governing cell division and proliferation, and it is finely regulated by the interaction of cyclins with CDKs and CKIs, among other molecules (Morgan et al., 1995). A categorical and Topos framework for Łukasiewicz Algebraic Logic models of nonlinear dynamics in complex functional genomes and cell interactomes is also proposed. Łukasiewicz Algebraic Logic models of genetic networks and signaling pathways in cells are formulated in terms of nonlinear dynamic systems with n-state components that allow for the generalization of previous logical models of both genetic activities and neural networks. An algebraic formulation of varying 'next-state' functions is extended in a Łukasiewicz-Topos with an n-valued Łukasiewicz Algebraic Logic subobject classifier description that represents non-random and nonlinear network activities as well as their transformations in developmental processes and carcinogenesis. Important aspects of Cell Cycling, the Control of Cell Division,and the Neoplastic Transformation in Carcinogenesis are being considered and subjected to algebraic-logico- relational, and computer-aided investigations. The essential roles of various levels of c-Myc, p27 quasi-complete inhibition/blocking, TP53 and/or p53 inactivation, as well as the perpetual hTERT activation of Telomerase biosynthesis are pointed out as key conditions for Malignant Cell transformations and partial re-differentiation leading to various types of cancer such as lung, breast,skin, prostate and colon. Rational Clinical trials, Individualized Medicine and the potential for optimized Radio-, Chemo-, Gene-, and Immuno- therapies of Cancers are suggested on the basis of integrated complex systems biology modeling of oncogenesis, coupled with extensive genomic/proteomic and interactomic High-throughput/high-sensitivity measurements of identified, sorted cell lines that are being isolated from malignant tumors of patients undergoing clinical trials with adjuvant signaling drug therapies. The implications of the cyclin model for abnormal neural development during early development are being considered in this model that may lead to explanations of subsequent cognitive changes associated with abnormal neural cell differentiation in environmentally-affected embryos. This new model may also be relevant to detecting the onset of senescing neuron transformations in Alzheimer's and related diseases of the human brain in ageing populations at risk

Novartis and the United Nations Global Compact Initiative

The spirit of the Global Compact found fertile ground and has become an integral part of Novartis corporate strategy since the enterprise was formed by the merger of the two large Swiss pharmaceutical companies, Sandoz and Ciba, in 1996. Following a four-year concentration on economic consolidation and performance, Daniel Vasella (Chairman and CEO) signed the Global Compact. Together, productivity-based economic performance and a proactive approach to the expectations of society are envisioned as the key to long-term corporate success in the rapidly integrating global economic, political, and social environment of today’s large multinational corporation. This paper outlines the Novartis strategy and its implementation including the coalescing role of the Global Compact in the drive for sustainable corporate development. Following a review of extending corporate strategy to incorporate social concerns into the economic business model, the process of implementing the strategy will be assessed. In part three, specific examples of this strategic positioning will be outlined.http://deepblue.lib.umich.edu/bitstream/2027.42/39911/3/wp526.pd

An Exploratory Analysis of Pharmaceutical Price Disparities and Their Implications Among Six Developed Nations

In our study of 43 drugs, prescription drug prices in several wealthy nations (Australia, Canada, France, Germany, and the U.K.) were much lower than in the U.S. on average, well below relative per capita GDP. There was relatively little difference among the five foreign nations. All this is consistent with previous research. After separating less-unique from more unique drugs, however, important new findings emerged. Relative prices for less-unique drugs, which are subject to strong competition, were at about half the U.S. level. We suggest that this reflects the exercise of monopsony power that does not exist in the U.S., where buyers as well as sellers compete. On the other hand, relative prices for highly unique drugs tended to be approximately proportional to per capita GDP or higher. Remarkably, biotech drugs were priced at or above U.S. levels in Canada and France

An Exploratory Analysis of Pharmaceutical Price Disparities and Their Implications Among Six Developed Nations

In our study of 43 drugs, prescription drug prices in several wealthy nations (Australia, Canada, France, Germany, and the U.K.) were much lower than in the U.S. on average, well below relative per capita GDP. There was relatively little difference among the five foreign nations. All this is consistent with previous research. After separating less-unique from moreunique drugs, however, important new findings emerged. Relative prices for less-unique drugs, which are subject to strong competition, were at about half the U.S. level. We suggest that this reflects the exercise of monopsony power that does not exist in the U.S., where buyers as well as sellers compete. On the other hand, relative prices for highly unique drugs tended to be approximately proportional to per capita GDP or higher. Remarkably, biotech drugs were priced at or above U.S. levels in Canada and France. These results carry uneasy implications for the future of pharmaceutical research. The follow-on drugs that make therapeutic classes competitive also amplify the incentives to conduct new R&D within these classes even as R&D incentives for pioneer brands disappear with the approach of patent expiration. Our results suggest that price controls operate to blunt these incentives for follow-on drug research, leaving most of the burden to U.S. purchasers. Because these follow-on R&D results are often extremely valuable, the implications merit substantial concern. In contrast, biotech drug prices in foreign nations appear to be above profit-maximizing levels, which we suggest is caused by political forces in the U.S., while foreign revenues, as one would expect, are very low. This, too, undermines research incentives, especially for creating highly innovative drugs.

Novartis and the United Nations Global Compact Initiative

The spirit of the Global Compact found fertile ground and has become an integral part of Novartis corporate strategy since the enterprise was formed by the merger of the two large Swiss pharmaceutical companies, Sandoz and Ciba, in 1996. Following a four-year concentration on economic consolidation and performance, Daniel Vasella (Chairman and CEO) signed the Global Compact. Together, productivity-based economic performance and a proactive approach to the expectations of society are envisioned as the key to long-term corporate success in the rapidly integrating global economic, political, and social environment of today’s large multinational corporation. This paper outlines the Novartis strategy and its implementation including the coalescing role of the Global Compact in the drive for sustainable corporate development. Following a review of extending corporate strategy to incorporate social concerns into the economic business model, the process of implementing the strategy will be assessed. In part three, specific examples of this strategic positioning will be outlined.Novartis, Pharmaceutical Industry, UN Global Compact, Gleevec, Novartis Institute for Tropical Diseases

Identification of Potent Leads for Human cAMP Dependent Protein Kinase Catalytic Subunit Alpha: A Strategic Application of Virtual Screening for Cancer Therapeutics

The advancement in therapeutic applications focused on specific macromolecular compounds of deregulated cell signaling pathways bestowed novel approach to design the ligands as drug molecules against several life threatening diseases such as Cancer. In humans, protein kinase A is one of the important kinases those were involved in cell signaling mechanism. cAMP, G-proteins and ATP molecules were required for activation of protein kinase A (PKA), upon activation, PKA catalytic subunits (PRKACA,PRKACB and PRKACG) undergoes many cellular functions like cell proliferations, cell cycle regulation, and survival of cells through acting on many substrates. Overexpression of extracellular cAMP dependent protein kinase A catalytic subunits (PRKACA) causes severe tumorgenesis in different organs (prostate gland, breast, lungs and pancreas) leading to cancer. High throughput virtual screening was implemented herein to identify the potent leads for human PRKACA that stimulates chronic form of cancers. In silico functional and phylogenetic analysis of PRKACA protein provided enough evidences towards its cancer stimulating nature. The human PRKACA crystal structure in complex with inhibitor ‘796’ (PDB ID: 2GU8) was optimized in Maestro v9.0 and the amino acid residues constituting inhibitor interaction site were determined. Fifteen published inhibitors were selected including HA1077, Flavopiridol, Roscovitine, MLN-518, PP2 and Gleevec which were already in clinical trials for high throughput screening at Ligand.Info database. An in house library of 5388 compounds was designing from the above screening procedure were prepared in LigPrep for molecular docking with human PRKACA. Maestro Glide docking from lesser to higher stringency towards minor steric classes were applied subsequently to the prepared ligand dataset against a grid around centroid of the identified inhibitor interaction site of human PRKACA and 21 lead molecules with good docking scores were obtained. Lead ‘1’ (Leptosidin) with relatively least docking score (-11.02 Kcal/mol) compared to other 20 lead molecules and 15 published inhibitors delineates it as potentially the best competitive inhibitor among all. The promising inhibitory activity of Leptosidin is further supported from analysis of binding orientations of human PRKACA- Leptosidin complex deciphering the Lead 1 blocks the active site residues Thr51, Glu121, Val123, Glu127 and Thr183 by forming hydrogen bond. Thus, Leptosidin could be futuristic perspective chemical compound to design drug molecule against human PRKACA in numerous cancers, however, further in vitro and in vivo studies were required to verify the computational strategic prediction of PKA holoenzyme against cancer therapeutics

The efficiency of multi-target drugs: the network approach might help drug design

Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug design paradigm will depend not only on a new generation of computer models to identify the correct multiple hits and their multi-fitting, low-affinity drug candidates but also on more efficient in vivo testing.Comment: 6 pages, 2 figures, 1 box, 38 reference

A research-inspired laboratory sequence investigating acquired drug resistance

Here, we present a six-session laboratory exercise designed to introduce students to standard biochemical techniques in the context of investigating a high impact research topic, acquired resistance to the cancer drug Gleevec. Students express a Gleevec-resistant mutant of the Abelson tyrosine kinase domain, the active domain of an oncogenic protein implicated in chronic myelogenous leukemia, and investigate the kinase activity of wild type and mutant enzyme in the presence of two cancer drugs. Techniques covered include protein expression, purification, and gel analysis, kinase activity assays, and protein structure viewing. The exercises provide students with a hands-on understanding of the impact of biochemistry on human health, and demonstrate their potential as the next generation of investigators.Howard Hughes Medical Institut