Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer

Background Malignant melanoma is an aggressive tumor of the skin and seems to be resistant to current therapeutic approaches. Melanocytic transformation is thought to occur by sequential accumulation of genetic and molecular alterations able to activate the Ras/Raf/MEK/ERK (MAPK) and/or the PI3K/AKT (AKT) signalling pathways. Specifically, mutations of B-RAF activate MAPK pathway resulting in cell cycle progression and apoptosis prevention. According to these findings, MAPK and AKT pathways may represent promising therapeutic targets for an otherwise devastating disease. Result Here we show a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. Overall, this computational approach may accelerate the drug discovery process and encourages the identification of novel pathway activators with consequent development of novel antioncogenic compounds to overcome tumor cell resistance to conventional therapeutic agents. The source code of the various versions of the model are available as S1 Archive

Alcoholic Pancreatitis: Pathogenesis, Incidence and Treatment with Special Reference to the Associated Pain

Alcoholic pancreatitis continues to stir up controversy. One of the most debated points is whether from onset it is a chronic disease or whether it progresses to a chronic form after repeated episodes of acute pancreatitis. Histological studies on patients with alcoholic pancreatitis have shown that the disease is chronic from onset and that alcoholic acute pancreatitis occurs in a pancreas already damaged by chronic lesions. Genetic factors may also play a role in the pathogenesis of alcoholic disease. The incidence of chronic alcoholic pancreatitis seems to have decreased in the last twenty years. Finally, recent therapeutic studies which have shown medical or surgical approaches capable of reducing the pain episodes in chronic pancreatitis patients will be described

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Impulsivity traits and Facebook addiction in young people and the potential mediating role of coping styles

Impulsivity traits are important predictors of substance use problems and behavioural addictions such as online gaming. However, little is known about to what extent the two related neuropsychological systems of rash impulsiveness and reward drive contribute to Facebook addiction, or the mechanisms of impulsivity risk. The aim of this study was to examine the role of emotion-focused and avoidance coping as potential mediators of the link between rash impulsiveness and Facebook addiction, while controlling for reward drive. Participants (N = 244) were young people aged 18–25 years recruited from the first-year undergraduate research participant pool and via convenience sampling which involved the first author sharing the study on his Facebook page. Participants completed online, validated measures of Facebook addiction, emotion-focused and avoidant coping styles, rash impulsiveness and reward drive. Results showed that when controlling for reward drive, emotion-focused coping mediated the association between rash impulsiveness and Facebook addiction. Results also showed that rash impulsiveness but not reward drive was directly associated with Facebook addiction. These findings have implications for designing targeted cognitive behavioural treatments that consider biologically-based personality factors such as rash impulsiveness and cognitive factors such as emotion-focused coping to reduce harmful levels of Facebook addiction

Perfusion Imaging In Acute Traumatic Brain Injury

Traumatic brain injury (TBI) is a significant problem worldwide and neuroimaging plays a critical role in diagnosis and management. Recently, perfusion neuroimaging techniques have been explored in TBI to determine and characterize potential perfusion neuroimaging biomarkers to aid in diagnosis, treatment, and prognosis. In this article, computed tomography (CT) bolus perfusion, MR imaging bolus perfusion, MR imaging arterial spin labeling perfusion, and xenon CT are reviewed with a focus on their applications in acute TBI. Future research directions are also discussed

Neuroimaging of Traumatic Brain Injury

The purpose of this article is to review conventional and advanced neuroimaging techniques performed in the setting of traumatic brain injury (TBI). The primary goal for the treatment of patients with suspected TBI is to prevent secondary injury. In the setting of a moderate to severe TBI, the most appropriate initial neuroimaging examination is a noncontrast head computed tomography (CT), which can reveal life-threatening injuries and direct emergent neurosurgical intervention. We will focus much of the article on advanced neuroimaging techniques including perfusion imaging and diffusion tensor imaging and discuss their potentials and challenges. We believe that advanced neuroimaging techniques may improve the accuracy of diagnosis of TBI and improve management of TBI