Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Applications of morphometric and diffusion tensor magnetic resonance imaging to the study of brain abnormalities in the alcoholism spectrum.

Background: The International Conference on Applications of Neuroimaging to Alcoholism was held at Yale University in New Haven, CT, in January 2004. The following is a brief summary of the contributions of five speakers who presented their work during the magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) session. Methods: This session addressed how MRI and DTI are used to assess macro- and microstructural brain alterations in alcoholism. Structural MRI methods can address regional gray and white matter volumetric/ morphometric abnormalities, and DTI methods can address microstructural disruptions of white matter tracts. These methods can be applied across the spectrum of alcoholism to elucidate distinct brain abnormalities underlying clinical subtypes, to disentangle brain volume deficits that precede, from those that follow, the onset of alcoholic drinking in chronic alcoholics, and to examine effects of prenatal alcohol exposures on brain development in children. The presentations highlighted recent scientific findings and methodological advances in these areas. Results: Disease-specific probabilistic atlases, designed to reflect the unique anatomy and physiology of particular clinical subpopulations, can be developed for alcoholism. Such an atlas can be used to identify efficiently patterns of altered structure or function in alcoholism and can guide algorithms for knowledge-based image analysis. DTI is sensitive to constraints on the random diffusion of water molecules in axons, allowing assessment of white matter tract integrity in neuropsychiatric diseases, including alcoholism. Recent MRI and DTI data were presented showing region-specific brain abnormalities at both macro- and microstructural levels that varied differentially according to sex, time of alcohol exposure in life, and alcoholism subtype. Conclusion: The International Conference on Applications of Neuroimaging to Alcoholism brought together leading experts in MRI and DTI techniques to discuss their applications to the study of alcoholism. The extant and new imaging technologies provide us with multiple modalities to study the brain in vivo. These noninvasive tools enable us to monitor the time course of alcohol effects on the brain and to characterize macro- and microstructural brain abnormalities across the full spectrum of alcoholism, including its precursors and its sequelae

Applications of morphometric and diffusion tensor magnetic resonance imaging to the study of brain abnormalities in the alcoholism spectrum.

Background: The International Conference on Applications of Neuroimaging to Alcoholism was held at Yale University in New Haven, CT, in January 2004. The following is a brief summary of the contributions of five speakers who presented their work during the magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) session. Methods: This session addressed how MRI and DTI are used to assess macro- and microstructural brain alterations in alcoholism. Structural MRI methods can address regional gray and white matter volumetric/ morphometric abnormalities, and DTI methods can address microstructural disruptions of white matter tracts. These methods can be applied across the spectrum of alcoholism to elucidate distinct brain abnormalities underlying clinical subtypes, to disentangle brain volume deficits that precede, from those that follow, the onset of alcoholic drinking in chronic alcoholics, and to examine effects of prenatal alcohol exposures on brain development in children. The presentations highlighted recent scientific findings and methodological advances in these areas. Results: Disease-specific probabilistic atlases, designed to reflect the unique anatomy and physiology of particular clinical subpopulations, can be developed for alcoholism. Such an atlas can be used to identify efficiently patterns of altered structure or function in alcoholism and can guide algorithms for knowledge-based image analysis. DTI is sensitive to constraints on the random diffusion of water molecules in axons, allowing assessment of white matter tract integrity in neuropsychiatric diseases, including alcoholism. Recent MRI and DTI data were presented showing region-specific brain abnormalities at both macro- and microstructural levels that varied differentially according to sex, time of alcohol exposure in life, and alcoholism subtype. Conclusion: The International Conference on Applications of Neuroimaging to Alcoholism brought together leading experts in MRI and DTI techniques to discuss their applications to the study of alcoholism. The extant and new imaging technologies provide us with multiple modalities to study the brain in vivo. These noninvasive tools enable us to monitor the time course of alcohol effects on the brain and to characterize macro- and microstructural brain abnormalities across the full spectrum of alcoholism, including its precursors and its sequelae

Applications of Morphometric and Diffusion Tensor Magnetic Resonance Imaging to the Study of Brain Abnormalities in the Alcoholism Spectrum

Background: The International Conference on Applications of Neuroimaging to Alcoholism was held at Yale University in New Haven, CT, in January 2004. The following is a brief summary of the contributions of five speakers who presented their work during the magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) session. Methods: This session addressed how MRI and DTI are used to assess macro- and microstructural brain alterations in alcoholism. Structural MRI methods can address regional gray and white matter volumetric/morphometric abnormalities, and DTI methods can address microstructural disruptions of white matter tracts. These methods can be applied across the spectrum of alcoholism to elucidate distinct brain abnormalities underlying clinical subtypes, to disentangle brain volume deficits that precede, from those that follow, the onset of alcoholic drinking in chronic alcoholics, and to examine effects of prenatal alcohol exposures on brain development in children. The presentations highlighted recent scientific findings and methodological advances in these areas. Results: Disease-specific probabilistic atlases, designed to reflect the unique anatomy and physiology of particular clinical subpopulations, can be developed for alcoholism. Such an atlas can be used to identify efficiently patterns of altered structure or function in alcoholism and can guide algorithms for knowledge-based image analysis. DTI is sensitive to constraints on the random diffusion of water molecules in axons, allowing assessment of white matter tract integrity in neuropsychiatric diseases, including alcoholism. Recent MRI and DTI data were presented showing region-specific brain abnormalities at both macro- and microstructural levels that varied differentially according to sex, time of alcohol exposure in life, and alcoholism subtype. Conclusion: The International Conference on Applications of Neuroimaging to Alcoholism brought together leading experts in MRI and DTI techniques to discuss their applications to the study of alcoholism. The extant and new imaging technologies provide us with multiple modalities to study the brain in vivo. These noninvasive tools enable us to monitor the time course of alcohol effects on the brain and to characterize macro- and microstructural brain abnormalities across the full spectrum of alcoholism, including its precursors and its sequelae