Polyploidy in chronic lymphocytic leukemia with p53 deletion detected by fish: a case report

We report a case of chronic lymphocytic leukemia with a characteristic cytogenetics finding detected by fluorescent in situ hybridization. This case has deletion in p53 gene in 50% of interphase nuclei studied in the peripheral blood and polyploidy in 30% of cells. To our knowledge polyploidy is not commonly reported with chronic lymphocytic leukemia patients

The Interplay of Youth and Care Characteristics with a Positive Social Climate in Therapeutic Residential Youth Care

Background: Limited research exists on how therapeutic residential youth care (TRC) achieves treatment outcomes. More specifically, little is known about the association between contextual factors such as treatment organization, youth characteristics, and experienced social climate in TRC. Therefore, this study aims to investigate differences between latent classes of TRC and youth characteristics and their association with a positive perceived social TRC climate. Method: We applied a person-centered approach in a cross-sectional design with a sample of 400 adolescents and 142 staff leaders. We analyzed youth and TRC characteristics in a latent class analysis and established associations with social climate for these two groupings. Results: The two types of TRC settings we found, i.e., larger TRC settings and family-style TRC settings, show small differences in social climate. These settings only differed on youth activities and staff shifts type (more cohabitation and unorganized activities outside TRC in family-style TRC). We identified four adolescent classes: A severe problems group, youth with incidental problems, family problems, and a migrant background group. The migrant background group showed the most positive perceptions of social climate, followed by youth with incidental problems, family problems, and severe problems. Conclusions: TRC staff should acknowledge how perceived social climate is connected to TRC characteristics and the heterogeneity of adolescents in care. As social climate is subjective and dynamic, a continuous dialogue about TRC social climate between staff and youth is recommended. Future research should investigate how these aspects are associated with treatment outcomes to increase our understanding of achieving positive outcomes in TRC

3-[(E)-(4-Chloro­benzyl­idene)amino]-1-phenyl­thio­urea

In the title compound, C14H12ClN3S, the dihedral angle between the terminal benzene rings is 56.6 (2)°; the benzene rings lie to the same side of the mol­ecule. The major twist in the mol­ecule occurs around the Car—N bond (ar is aromatic) [C—N—C—C = 49.9 (5)°]. The configuration about the N=C bond [1.271 (4) Å] is E. The amine H atoms lie on opposite sides of the mol­ecule with one forming an intra­molecular N—H⋯N(imine) hydrogen bond and an S(5) ring. In the crystal, centrosymmetric dimers are formed via {⋯HNC=S}2 synthons

Determinants and Outcomes of Social Climate in Therapeutic Residential Youth Care: A Systematic Review

Background: Previous studies on effectiveness of therapeutic residential youth care (TRC) have indicated that, compared to short-term effects, long-term effects are less convincing. Moreover, there is limited evidence on how TRC achieves treatment goals: TRC remains too much of a “black box”. To gain durable treatment results we need to know more about how results are achieved, rather than investigating the achieved results itself. One of the factors associated with this process of change is the social climate within TRC institutions. Up until now, no literature reviews about how social climate is affect by institution and youth characteristics, and how social climate affects outcomes has been performed. Objective: To provide an overview of the literature on associations between determinants and social climate and between social climate and outcomes in TRC. Method: We searched multiple databases with a predetermined set of search criteria in the years 1990 and March 2017. We identified 8408 studies and reduced the final sample to 36 studies. Most studies were empirical assessments with a correlational design and were conducted in Western countries. Results: Effect sizes for the studies ranged from small to large and varied between and within studies. Most associations were found between social climate and positive outcomes. The most mentioned social climate constructs were: an open climate, support, and autonomy. Conclusions: The results are challenging to summarize due to variations in the concepts and operationalizations of social climate. The organizational culture must support a social climate which is supportive, structured and caring, and provide youth with an environment to grow. A positive social climate must constantly be evaluated and recreated based on combining the perspectives of residents, staff and external perspectives

Dirac and Weyl Equations on a Lattice as Quantum Cellular Automata

A discretized time evolution of the wave function for a Dirac particle on a cubic lattice is represented by a very simple quantum cellular automaton. In each evolution step the updated value of the wave function at a given site depends only on the values at the nearest sites, the evolution is unitary and preserves chiral symmetry. Moreover, it is shown that the relationship between Dirac particles and cellular automata operating on two component objects on a lattice is indeed very close. Every local and unitary automaton on a cubic lattice, under some natural assumptions, leads in the continuum limit to the Weyl equation. The sum over histories is evaluated and its connection with path integrals and theories of fermions on a lattice is outlined.Comment: 6, RevTe

PrP(Sc)-specific antibodies with the ability to immunodetect prion oligomers.

The development of antibodies with binding capacity towards soluble oligomeric forms of PrPSc recognised in the aggregation process in early stage of the disease would be of paramount importance in diagnosing prion diseases before extensive neuropathology has ensued. As blood transfusion appears to be efficient in the transmission of the infectious prion agent, there is an urgent need to develop reagents that would specifically recognize oligomeric forms of the abnormally folded prion protein, PrPSc.To that end, we show that anti-PrP monoclonal antibodies (called PRIOC mAbs) derived from mice immunised with native PrP-coated microbeads are able to immunodetect oligomers/multimers of PrPSc. Oligomer-specific immunoreactivity displayed by these PRIOC mAbs was demonstrated as large aggregates of immunoreactive deposits in prion-permissive neuroblastoma cell lines but not in equivalent non-infected or prn-p(0/0) cell lines. In contrast, an anti-monomer PrP antibody displayed diffuse immunoreactivity restricted to the cell membrane. Furthermore, our PRIOC mAbs did not display any binding with monomeric recombinant and cellular prion proteins but strongly detected PrPSc oligomers as shown by a newly developed sensitive and specific ELISA. Finally, PrioC antibodies were also able to bind soluble oligomers formed of Aβ and α-synuclein. These findings demonstrate the potential use of anti-prion antibodies that bind PrPSc oligomers, recognised in early stage of the disease, for the diagnosis of prion diseases in blood and other body fluids

Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention since it has been associated with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate how the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Initially individual beta-sheets form with random orientations, which subsequently tend to align into protofilaments as their lengths increases. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-β1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (P<0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-β1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-β1 and BMP2 in an auto- and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment

Xanthene Food Dye, as a Modulator of Alzheimer's Disease Amyloid-beta Peptide Aggregation and the Associated Impaired Neuronal Cell Function

Alzheimer's disease (AD) is the most common form of dementia. AD is a degenerative brain disorder that causes problems with memory, thinking and behavior. It has been suggested that aggregation of amyloid-beta peptide (Aβ) is closely linked to the development of AD pathology. In the search for safe, effective modulators, we evaluated the modulating capabilities of erythrosine B (ER), a Food and Drug Administration (FDA)-approved red food dye, on Aβ aggregation and Aβ-associated impaired neuronal cell function.In order to evaluate the modulating ability of ER on Aβ aggregation, we employed transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assay, and immunoassays using Aβ-specific antibodies. TEM images and ThT fluorescence of Aβ samples indicate that protofibrils are predominantly generated and persist for at least 3 days. The average length of the ER-induced protofibrils is inversely proportional to the concentration of ER above the stoichiometric concentration of Aβ monomers. Immunoassay results using Aβ-specific antibodies suggest that ER binds to the N-terminus of Aβ and inhibits amyloid fibril formation. In order to evaluate Aβ-associated toxicity we determined the reducing activity of SH-SY5Y neuroblastoma cells treated with Aβ aggregates formed in the absence or in the presence of ER. As the concentration of ER increased above the stoichiometric concentration of Aβ, cellular reducing activity increased and Aβ-associated reducing activity loss was negligible at 500 µM ER.Our findings show that ER is a novel modulator of Aβ aggregation and reduces Aβ-associated impaired cell function. Our findings also suggest that xanthene dye can be a new type of small molecule modulator of Aβ aggregation. With demonstrated safety profiles and blood-brain permeability, ER represents a particularly attractive aggregation modulator for amyloidogenic proteins associated with neurodegenerative diseases

RNA Aptamers Generated against Oligomeric Aβ40 Recognize Common Amyloid Aptatopes with Low Specificity but High Sensitivity

Aptamers are useful molecular recognition tools in research, diagnostics, and therapy. Despite promising results in other fields, aptamer use has remained scarce in amyloid research, including Alzheimer's disease (AD). AD is a progressive neurodegenerative disease believed to be caused by neurotoxic amyloid β-protein (Aβ) oligomers. Aβ oligomers therefore are an attractive target for development of diagnostic and therapeutic reagents. We used covalently-stabilized oligomers of the 40-residue form of Aβ (Aβ40) for aptamer selection. Despite gradually increasing the stringency of selection conditions, the selected aptamers did not recognize Aβ40 oligomers but reacted with fibrils of Aβ40, Aβ42, and several other amyloidogenic proteins. Aptamer reactivity with amyloid fibrils showed some degree of protein-sequence dependency. Significant fibril binding also was found for the naïve library and could not be eliminated by counter-selection using Aβ40 fibrils, suggesting that aptamer binding to amyloid fibrils was RNA-sequence-independent. Aptamer binding depended on fibrillogenesis and showed a lag phase. Interestingly, aptamers detected fibril formation with ≥15-fold higher sensitivity than thioflavin T (ThT), revealing substantial β-sheet and fibril formation undetected by ThT. The data suggest that under physiologic conditions, aptamers for oligomeric forms of amyloidogenic proteins cannot be selected due to high, non-specific affinity of oligonucleotides for amyloid fibrils. Nevertheless, the high sensitivity, whereby aptamers detect β-sheet formation, suggests that they can serve as superior amyloid recognition tools