Having Fun in Learning Formal Specifications

There are many benefits in providing formal specifications for our software. However, teaching students to do this is not always easy as courses on formal methods are often experienced as dry by students. This paper presents a game called FormalZ that teachers can use to introduce some variation in their class. Students can have some fun in playing the game and, while doing so, also learn the basics of writing formal specifications in the form of pre- and post-conditions. Unlike existing software engineering themed education games such as Pex and Code Defenders, FormalZ takes the deep gamification approach where playing gets a more central role in order to generate more engagement. This short paper presents our work in progress: the first implementation of FormalZ along with the result of a preliminary users' evaluation. This implementation is functionally complete and tested, but the polishing of its user interface is still future work

Correction to:Positron emission tomography in the diagnosis and follow-up of transthyretin amyloid cardiomyopathy patients: A systematic review (European Journal of Nuclear Medicine and Molecular Imaging, (2023), 51, 1, (93-109), 10.1007/s00259-023-06381-3)

The authors regret that the name of J. H. van ’t Oever was incorrectly presented as J. H. A. van ’t Oever in the original article. The original article has been corrected. The original article can be found at https://doi.org/10.1007/s00259-023-06381-3.</p

Positron emission tomography in the diagnosis and follow-up of transthyretin amyloid cardiomyopathy patients:A systematic review

Purpose: Transthyretin (ATTR) amyloidosis is a progressive protein misfolding disease with frequent cardiac involvement. This review aims to determine the value of PET in diagnosis, assessment of disease progression or treatment response and its relation to clinical outcome in follow-up of ATTR amyloid cardiomyopathy (ATTR-CM) patients. Methods: Medline, Cochrane Library, Embase and Web of Science databases were searched, from the earliest date available until December 2022, for studies investigating the use of PET in ATTR-CM patients. Studies containing original data were included, except for case reports. Risk of bias was assessed by QUADAS-2. Results: Twenty-one studies were included in this systematic review, investigating five different tracers: carbon-11 Pittsburgh compound B ([11C]PIB), fluorine-18 Florbetaben ([18F]FBB), fluorine-18 Florbetapir ([18F]FBP), fluorine-18 Flutemetamol ([18F]FMM) and fluorine-18 Sodium Fluoride (Na[18F]F). In total 211 ATTR amyloidosis patients were included. A majority of studies concluded that [11C]PIB, [18F]FBP and Na[18F]F can distinguish ATTR amyloidosis patients from controls, and that [11C]PIB and Na[18F]F, but not [18F]FBP, can distinguish ATTR-CM patients from patients with cardiac light chain amyloidosis. Evidence on the performance of [18F]FBB and [18F]FMM was contradictory. No studies on the use of PET in follow-up were found. Conclusion: [11C]PIB, Na[18F]F and [18F]FBP can be used to diagnose cardiac amyloidosis, although [18F]FBP may not be suitable for the distinction of different types of amyloid cardiomyopathy. No studies on PET in the follow-up of ATTR amyloidosis patients were found. Future research should focus on the use of these PET tracers in the follow-up of ATTR amyloidosis patients.</p

TGF-beta-induced endothelial to mesenchymal transition is determined by a balance between SNAIL and ID factors

Endothelial-to-mesenchymal transition (EndMT) plays an important role in embryonic development and disease progression. Yet, how different members of the transforming growth factor-beta (TGF-beta) family regulate EndMT is not well understood. In the current study, we report that TGF-beta 2, but not bone morphogenetic protein (BMP)9, triggers EndMT in murine endothelial MS-1 and 2H11 cells. TGF-beta 2 strongly upregulates the transcription factor SNAIL, and the depletion of Snail is sufficient to abrogate TGF-beta 2-triggered mesenchymal-like cell morphology acquisition and EndMT-related molecular changes. Although SLUG is not regulated by TGF-beta 2, knocking out Slug also partly inhibits TGF-beta 2-induced EndMT in 2H11 cells. Interestingly, in addition to SNAIL and SLUG, BMP9 stimulates inhibitor of DNA binding (ID) proteins. The suppression of Id1, Id2, or Id3 expression facilitated BMP9 in inducing EndMT and, in contrast, ectopic expression of ID1, ID2, or ID3 abrogated TGF-beta 2-mediated EndMT. Altogether, our results show that SNAIL is critical and indispensable for TGF-beta 2-mediated EndMT. Although SLUG is also involved in the EndMT process, it plays less of a crucial role in it. In contrast, ID proteins are essential for maintaining endothelial traits and repressing the function of SNAIL and SLUG during the EndMT process. These data suggest that the control over endothelial vs. mesenchymal cell states is determined, at least in part, by a balance between the expression of SNAIL/SLUG and ID proteins.Cancer Signaling networks and Molecular Therapeutic

Primary Polyomavirus Infection, Not Reactivation, as the Cause of Trichodysplasia Spinulosa in Immunocompromised Patients

Classic human polyomaviruses (JC and BK viruses) become pathogenic when reactivating from latency. For the rare skin disease trichodysplasia spinulosa, we show that manifestations of the causative polyomavirus (TSPyV) occur during primary infection of the immunosuppressed host. High TSPyV loads in blood and cerebrospinal fluid, sometimes coinciding with cerebral lesions and neuroendocrine symptoms, marked the acute phase of trichodysplasia spinulosa, whereas initiation and maturation of TSPyV seroresponses occurred in the convalescent phase. TSPyV genomes lacked the rearrangements typical for reactivating polyomaviruses. These findings demonstrate the clinical importance of primary infection with this rapidly expanding group of human viruses and explain the rarity of some novel polyomavirus-associated diseases.Peer reviewe

CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients ≥60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients