Unintentional Weakness of Cancers: The MEK/ERK Pathway as a Double-Edged Sword.

Unintentional weakness of cancers: the MEK/ERK pathway as a double-edged sword.

Mol Cancer Res. 2013 Jul 30;
Suda K, Mitsudomi T

Recent advances in molecular target therapy have greatly improved treatment outcomes for cancers driven by oncogenic mutations. However despite initial dramatic responses, cancer cells eventually acquire resistance to these drugs, showing flexible and diverse responses. Interestingly, cancer cells may sometimes over-adapt to the environment with the drug, leading to a state in which cancer cells cannot survive without the drug. This interesting phenomenon, which can be termed as “drug dependency” or “drug addiction,” is exemplified in preclinical acquired resistance models of BRAF-mutated melanoma treated with vemurafenib and EGFR-mutated lung cancer treated with EGFR tyrosine kinase inhibitors. By comparing these two preclinical models, we noticed intriguing parallels of “drug addicted” cancers: (a) overexpression of driver oncogenes as causes of acquired resistance; (b) overexpression of driver oncogenes causing MEK-ERK hyperactivation under drug free conditions; (c) hyperactivation of the MEK-ERK pathway as critical to this “drug addiction” phenomenon; (d) ongoing dependence on the driver oncogene; and (e) morphological changes in resistant cells under drug-free conditions. In this perspective article, we focus on this interesting and weird phenomenon and discuss treatment strategies to utilize this unintentional weakness of cancers. HubMed – addiction

Update on prescription extended-release opioids and appropriate patient selection.

J Multidiscip Healthc. 2013; 6: 265-80
Brennan MJ

Chronic pain is largely underdiagnosed, often undertreated, and expected to increase as the American population ages. Many patients with chronic pain require long-term treatment with analgesic medications, and pain management may involve use of prescription opioids for patients whose pain is inadequately controlled through other therapies. Yet because of the potential for abuse and addiction, many clinicians hesitate to treat their patients with pain with potentially beneficial agents. Finding the right opioid for the right patient is the first – often complicated – step. Ensuring that patients continue to properly use the medication while achieving therapeutic analgesic effects is the long-term goal. Combined with careful patient selection and ongoing monitoring, new formulations using extended-release technologies incorporating tamper-resistant features may help combat the growing risk of abuse or misuse, which will hopefully reduce individual suffering and the societal burden of chronic pain. The objective of this manuscript is to provide an update on extended-release opioids and to provide clinicians with a greater understanding of which patients might benefit from these new opioid formulations and how to integrate the recommended monitoring for abuse potential into clinical practice. HubMed – addiction

Proteomic Approaches and Identification of Novel Therapeutic Targets For Alcoholism.

Neuropsychopharmacology. 2013 Jul 31;
Gorini G, Harris RA, Mayfield RD

Recent studies have shown that gene regulation is far more complex than previously believed and does not completely explain changes at the protein level. Therefore, the direct study of the proteome, considerably different in both complexity and dynamicity to the genome/transcriptome, has provided unique insights to an increasing number of researchers. During the past decade, extraordinary advances in proteomic techniques have changed the way we can analyze the composition, regulation and function of protein complexes and pathways underlying altered neurobiological conditions. When combined with complementary approaches, these advances provide the contextual information for decoding large datasets into meaningful biological adaptive processes. Neuroproteomics offers potential breakthroughs in the field of alcohol research by leading to a deeper understanding of how alcohol globally affects protein structure, function, interactions, and networks. The wealth of information gained from these advances can help pinpoint relevant biomarkers for early diagnosis and improved prognosis of alcoholism and identify future pharmacological targets for the treatment of this addiction.Neuropsychopharmacology accepted article preview online, 31 July 2013. doi:10.1038/npp.2013.182. HubMed – addiction

Methamphetamine Enhances Cryptococcus neoformans Pulmonary Infection and Dissemination to the Brain.

MBio. 2013; 4(4):
Patel D, Desai GM, Frases S, Cordero RJ, Deleon-Rodriguez CM, Eugenin EA, Nosanchuk JD, Martinez LR

ABSTRACT Methamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection and in vitro assays in order to critically assess the impact of METH on C. neoformans pathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotes C. neoformans dissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms. IMPORTANCE Methamphetamine (METH) is a major health threat to our society, as it adversely changes people’s behavior, as well as increases the risk for the acquisition of diverse infectious diseases, particularly those that enter through the respiratory tract or skin. This report investigates the effects of METH use on pulmonary infection by the AIDS-related fungus Cryptococcus neoformans. This drug of abuse stimulates colonization and biofilm formation in the lungs, followed by dissemination of the fungus to the central nervous system. Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus’s ability to adapt to environmental stimuli, a possible explanation for its pathogenesis. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse. HubMed – addiction

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