Azathioprine induction of tumors with microsatellite instability: Risk evaluation using a mouse model

Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2^wt mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2^+/− mice were found more tolerant than Msh2^wt mice to the cytotoxicity of Aza. In Msh2^+/− mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2^wt mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.     

Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells

Multidrug resistance has appeared to mitigate the efficiency of anticancer drugs and the possibility of successful cancer chemotherapy. The Hedgehog receptor Patched is a multidrug transporter expressed in several cancers and as such it represents a new target to circumvent chemotherapy resistance. We report herein that paniceins and especially panicein A hydroquinone, natural meroterpenoids produced by the Mediterranean sponge Haliclona (Soestella) mucosa, inhibit the doxorubicin efflux activity of Patched and enhance the cytotoxicity of this chemotherapeutic agent on melanoma cells in vitro. These results are supported by the molecular docking performed on the structure of the bacterial drug efflux pump AcrB and on the Patched model built from AcrB structure. Docking calculations show that panicein A hydroquinone interacts with AcrB and Patched model close to the doxorubicin binding site. This compound thus appears as the first antagonist of the doxorubicin efflux activity of Patched. The use of inhibitors of Patched drug efflux activity in combination with classical chemotherapy could represent a novel approach to reduce tumor drug resistance, recurrence and metastasis.     

BRAF mutation testing with a rapid,fully integrated molecular diagnostics system

Fast and accurate diagnostic systems are needed for further implementation of precision therapy of BRAF-mutant and other cancers. The novel Idylla^TM BRAF Mutation Test has high sensitivity and shorter turnaround times compared to other methods. We used Idylla to detect BRAF V600 mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples and compared these results with those obtained using the cobas 4800 BRAF V600 Mutation Test or MiSeq deep sequencing system and with those obtained by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory employing polymerase chain reaction–based sequencing, mass spectrometric detection, or next-generation sequencing. In one set of 60 FFPE tumor samples (15 with BRAF mutations per Idylla), the Idylla and cobas results had an agreement of 97%. Idylla detected BRAF V600 mutations in two additional samples. The Idylla and MiSeq results had 100% concordance. In a separate set of 100 FFPE tumor samples (64 with BRAF mutation per Idylla), the Idylla and CLIA-certified laboratory results demonstrated an agreement of 96% even though the tests were not performed simultaneously and different FFPE blocks had to be used for 9 cases. The Idylla^TM BRAF Mutation Test produced results quickly (sample to results time was about 90 minutes with about 2 minutes of hands on time) and the closed nature of the cartridge eliminates the risk of PCR contamination. In conclusion, our observations demonstrate that the Idylla test is rapid and has high concordance with other routinely used but more complex BRAF mutation–detecting tests.     

Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression,an effect amplified by interleukin-1β

The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium.     

Validation of a newly developed B-mode image-processing technique versus wall-tracking ultrasound for the study of wall mechanics in small-calibre arteries

Purpose: To validate a newly developed image‐processing technique for the assessment of arterial wall compliance and distensibility from non‐invasive B‐mode ultrasound compared with the invasive wall‐tracking technique. Materials and methods: Arterial wall compliance and distensibility coefficient were measured invasively by wall‐tracking with an ultrasonic transducer implanted on the vessel wall, and non‐invasively by automatic processing of B‐mode ultrasound images, with a dedicated workstation and software (IO^ 3·1, IO^DP, Paris). Measurements were performed in the normal aorta of five animals, and upstream, at the stent level, and downstream from the stent in eight other animals (immediately after stenting in six, and 3 months later in four), for a total of 35 paired measurements. Results: There was no significant difference between the two techniques for compliance but there was a significant difference in diameter (P<0·005) and distensibility (P<0·05) as external ultrasound measured the inner diameter, while wall‐tracking measured the outer diameter. Agreement between the two methods as assessed by the Bland–Altman approach was acceptable for aortic diameter, compliance and distensibility. Conclusion: Automatic processing of B‐mode ultrasound images is a reliable non‐invasive technique to assess the compliance of small‐calibre arteries.     

Fantasme d’encombrant et problématique sexuelle chez la femme et l’homme alcooliques

Although it seems possible to identify some medical, behavioral, social and cultural differences between male and female alcoholics, the authors develop in this article a metapsychological, gender independent approach. They insist on reality of a precocious phantasm of cumbersome object built by the Other. At this stage, certain children would not have got any guaranty for their existence legitimacy through a nomination allowing the distinction from their reflection in the mirror. Thus, the alcoholic could not think his own symbolic division. He would stay trapped in a sexual link that he identified as dangerous which might conduce to the false links of fraternity between alcoholic men. These metonymic links come from an identity quest or an adhesion to social conventions. Furthermore, in female alcoholics, the hidden consummation would be a mean to avoid any sexual encounter and thus any “taking position”. The drunkenness would allow to male as well as female alcoholics to be temporarily protected from their pain and would give them a false hope that one day they finally could be recognized without being obliged to encumber the Other in order to exist.     

Done or Almost Done? Improving OSCE Checklists to Better Capture Performance in Progress Tests

Construct: The impact of using nonbinary checklists for scoring residents from different levels of training participating in objective structured clinical examination (OSCE) progress tests was explored. Background: OSCE progress tests typically employ similar rating instruments as traditional OSCEs. However, progress tests differ from other assessment modalities because learners from different stages of training participate in the same examination, which can pose challenges when deciding how to assign scores. In an attempt to better capture performance, nonbinary checklists were introduced in two OSCE progress tests. The purposes of this study were (a) to identify differences in the use of checklist options (e.g., done satisfactorily, attempted, or not done) by task type, (b) to analyze the impact of different scoring methods using nonbinary checklists for two OSCE progress tests (nonprocedural and procedural) for Internal Medicine residents, and (c) to determine which scoring method is better suited for a given task. Approach: A retrospective analysis examined differences in scores (n = 119) for two OSCE progress tests (procedural and nonprocedural). Scoring methods (hawk, dove, and hybrid) varied in stringency in how they awarded marks for nonbinary checklist items that were rated as done satisfactorily, attempted, or not done. Difficulty, reliability (internal consistency), item-total correlations and pass rates were compared for each OSCE using the three scoring methods. Results: Mean OSCE scores were highest using the dove method and lowest using the hawk method. The hawk method resulted in higher item-total correlations for most stations, but there were differences by task type. Overall score reliability calculated using the three methods did not differ significantly. Pass–fail status differed as a function of scoring methods and exam type, with the hawk and hybrid methods resulting in higher failure rates for the nonprocedural OSCE and the dove method resulting in a higher failure rate for the procedural OSCE. Conclusion: The use of different scoring methods for nonbinary OSCE checklists resulted in differences in mean scores and pass–fail status. The results varied with procedural and nonprocedural OSCEs.     

Iodine Images in Dual-energy CT: Detection of Hepatic Steatosis by Quantitative Iodine Concentration Values

Hepatic steatosis is a common condition and an early manifestation of a systemic metabolic syndrome. As of today, there is no broadly accepted method for the diagnosis of hepatic steatosis in contrast-enhanced CT images. This retrospective study evaluates the potential of quantitative iodine values in portal venous phase iodine images in dual-energy CT (DECT) by measuring iodine concentrations in regions of interest (ROI) and analyzing the absolute iodine concentration of the liver parenchyma as well as three different blood-normalized iodine concentrations in a study cohort of 251 patients. An independent two sample t-test (p < 0.05) was used to compare the iodine concentrations of healthy and fatty liver. Diagnostic performance was assessed by ROC (receiver operating characteristic) curve analysis. The results showed significant differences between the average iodine concentration of healthy and fatty liver parenchyma for the absolute and for the blood-normalized iodine concentrations. The study concludes that the iodine uptake of the liver parenchyma is impaired by hepatic steatosis, and that the measurement of iodine concentration can provide a suitable method for the detection of hepatic steatosis in quantitative iodine images. Suitable thresholds of quantitative iodine concentration values for the diagnosis of hepatic steatosis are provided.     

A conceptual framework addressing the complex labour market dynamics of the work-to-retirement process

The way in which retirement is conceptualized and measured is likely to influence the research findings. The previous literature has addressed a wide range of elements related to the complex work-to-retirement process, such as early, late and partial retirement, statutory retirement, work disability and unemployment paths to retirement, or different types of bridge employment. However, conceptual clarity in terms of connections between the different elements is called for. We introduce a conceptual framework of the work-to-retirement process to guide its future measurement. Together with information on the statutory retirement age, the main elements of the framework are based on employment and pension receipt, acknowledging that these may overlap. The framework is flexible to the user, providing the possibility to add various specifications—e.g. of types of employment, types of pension receipt, unemployment, and being outside the labour force—depending on the study context and aims. The framework highlights the complexity of the work-to-retirement process, bringing forth its multifaceted, multiphased and multidirectional features. Accounting for such complexity in later-life labour market dynamics helps to elaborate what is actually addressed when investigating “retirement”. Our conceptual framework can be utilized to enhance well-defined, precise and comparable measurement of the work-to-retirement process in studies.