Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle

Altered multisensory temporal integration in obesity

Eating is a multisensory behavior. The act of placing food in the mouth provides us with a variety of sensory information, including gustatory, olfactory, somatosensory, visual, and auditory. Evidence suggests altered eating behavior in obesity. Nonetheless, multisensory integration in obesity has been scantily investigated so far. Starting from this gap in the literature, we seek to provide the first comprehensive investigation of multisensory integration in obesity. Twenty male obese participants and twenty male healthy-weight participants took part in the study aimed at describing the multisensory temporal binding window (TBW). The TBW is defined as the range of stimulus onset asynchrony in which multiple sensory inputs have a high probability of being integrated. To investigate possible multisensory temporal processing deficits in obesity, we investigated performance in two multisensory audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Results showed a wider TBW in obese participants as compared to healthy-weight controls. This holds true for both the simultaneity judgment and the temporal order judgment tasks. An explanatory hypothesis would regard the effect of metabolic alterations and low-grade inflammatory state, clinically observed in obesity, on the temporal organization of brain ongoing activity, which one of the neural mechanisms enabling multisensory integration

Dose-related effects of alcohol on cognitive functioning

We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18–45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test(TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties.Mathew J. Dry, Nicholas R. Burns, Ted Nettelbeck, Aaron L. Farquharson and Jason M. Whit

Depression is the main determinant of quality of life in multiple sclerosis : a classification-regression (CART) study

PURPOSE: Quality of life in multiple sclerosis has been often measured through the SF-36 questionnaire. In this study, validation of the SF-36 summary scores, its 'physical' component, and its 'mental' component was attempted by exploring the joint predictive power of disability (EDSS score), of anxiety and depression (HADS-A and -D scores, respectively), and of disease duration, progression type, age, gender and marital status. METHOD: The sample consisted of 75 patients suffering from multiple sclerosis admitted to an inpatient rehabilitation unit. The interplay between potential predictors was assessed through a particular regression model (classification and regression tree, CART). Two main advantages of this technique are its robustness with respect to distributional assumptions (rarely met by scores coming in from questionnaires) and its sensitivity to high-order interactions, between independent variables, difficult to detect through conventional multiple regression. RESULTS: Predictive variables for physical component of the SF-36 were EDSS and HADS-D (36.8% variance explanation). The only predictive variable for mental component of SF-36 was HADS-D (39.1% variance explanation). CONCLUSION: Results confirm previous findings showing that in patients with multiple sclerosis quality of life is heavily determined by person's mood, whatever his/her neurological or functional severity. The usefulness and validity of the SF-36 as an index representative of quality of life is debatable, as long as depression explains much of its variance. Further refinement of quality of life definition and measurement is worth further psychometric and statistical research.Purpose. Quality of life in multiple sclerosis has been often measured through the SF-36 questionnaire. In this study, validation of the SF-36 summary scores, its 'physical' component, and its 'mental' component was attempted by exploring the joint predictive power of disability (EDSS score), of anxiety and depression (HADS-A and -D scores, respectively), and of disease duration, progression type, age, gender and marital status. Method. The sample consisted of 75 patients suffering from multiple sclerosis admitted to an inpatient rehabilitation unit. The interplay between potential predictors was assessed through a particular regression model (classification and regression tree, CART). Two main advantages of this technique are its robustness with respect to distributional assumptions (rarely met by scores coming in from questionnaires) and its sensitivity to high-order interactions, between independent variables, difficult to detect through conventional multiple regression. Results. Predictive variables for physical component of the SF-36 were EDSS and HADS-D (36.8% variance explanation). The only predictive variable for mental component of SF-36 was HADS-D (39.1% variance explanation). Conclusion. Results confirm previous findings showing that in patients with multiple sclerosis quality of life is heavily determined by person's mood, whatever his/her neurological or functional severity. The usefulness and validity of the SF-36 as an index representative of quality of life is debatable, as long as depression explains much of its variance. Further refinement of quality of life definition and measurement is worth further psychometric and statistical research

A functional variant in the gene 3 ' untranslated region regulates HSP70 expression and is a potential candidate for insulin resistance-related abnormalities

[No abstract available

Detection of small (≤2 cm) HCC in cirrhotic patients: added value of diffusion MR-imaging

Objectives To evaluate the usefulness of the diffusion-weighted sequence in the detection of small (≤2 cm) hepatocellular carcinoma (HCC) in patients with cirrhosis. Methods Seventy cirrhotic patients with 93 HCCs underwent MR-Imaging at 1.5 T. MR acquisitions comprised unenhanced T1- and T2-weighted images and post-contrast Gd-BOPTA-enhanced T1W GRE-3D images acquired after approximately 25, 60, 180 s (dynamic phases) and 90 min (hepatobiliary phase). DWI was performed by a SSEPI sequence (b values 0, 50, 400, 800 s/mm2). Quantitative analysis was performed to establish significant difference of ADC values of benign lesions compared with that of HCC. Sensitivity, specificity, positive and negative predictive values and diagnostic accuracy of two different protocols with and without diffusion MRI sequence were also calculated and compared each other. Results A good inverse correlation was found between reference standard and ADC values (ρ = −0.688). The mean ADC value of HCC was significantly lower than the mean value of benign focal liver lesions (p < 0.0001). No significant difference was reported in term of sensitivity, specificity, PPV, NPV and diagnostic accuracy between the two datasets. A trend to a better sensitivity was found when DWI images were considered. Conclusions The adjunction of DWI does not significantly improve the diagnostic accuracy in the detection of small HCC