The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice

Parkin suppression induces accumulation of β-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP_swe mutant mice. We produced double mutant mice with human mutated APP_swe + partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP_swe overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK^+/− and PK^−/−, respectively), and double mutants (APP/PK^+/− and APP/PK^−/−).APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK^+/− and APP/PK^−/− mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK^+/− and APP/PK^−/− mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK^+/− and APP/PK^−/− mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK^+/− heterozygotic and homozygotic APP/PK^−/− mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK^+/− and APP/PK^−/−. Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK^−/− mice.We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP_swe mice.     

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF‐κB) in human MSCs. This pathway is activated by TNF‐α that is generated following TCR stimulation of T cells. Inhibition of NF‐κB through silencing of IκB kinase β or the TNF‐α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC‐associated NF‐κB activation primarily leads to inhibition of T‐cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF‐α/NF‐κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF‐κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.     

Twelve automated thresholding methods for segmentation of PET images: a phantom study

Tumor volume delineation over positron emission tomography (PET) images is of great interest for proper diagnosis and therapy planning. However, standard segmentation techniques (manual or semi-automated) are operator dependent and time consuming while fully automated procedures are cumbersome or require complex mathematical development. The aim of this study was to segment PET images in a fully automated way by implementing a set of 12 automated thresholding algorithms, classical in the fields of optical character recognition, tissue engineering or non-destructive testing images in high-tech structures. Automated thresholding algorithms select a specific threshold for each image without any a priori spatial information of the segmented object or any special calibration of the tomograph, as opposed to usual thresholding methods for PET. Spherical (18)F-filled objects of different volumes were acquired on clinical PET/CT and on a small animal PET scanner, with three different signal-to-background ratios. Images were segmented with 12 automatic thresholding algorithms and results were compared with the standard segmentation reference, a threshold at 42% of the maximum uptake. Ridler and Ramesh thresholding algorithms based on clustering and histogram-shape information, respectively, provided better results that the classical 42%-based threshold (p < 0.05). We have herein demonstrated that fully automated thresholding algorithms can provide better results than classical PET segmentation tools.     

Clinical assessment of non-suicidal self-injury: A systematic review of instruments

There has been an increase in the number of assessment instruments for non-suicidal self-injury (NSSI). However, previous reviews are inconsistent and do not provide a comprehensive psychometric assessment of the instruments. This study aimed to systematically assess and compare the psychometric properties of clinically relevant instruments to measure NSSI in any population. Through a systematic review guided by COSMIN and PRISMA, two searches were conducted in English and Spanish in February 2020 in 13 databases including grey literature. Of the 7,813 initial records, 152 validations were extracted. From these, 83 instruments (22 versions or adaptations) were excluded for not measuring NSSI, having no potential clinical utility or not including psychometric properties. Finally, 26 (22 versions, 35 adaptations and 19 creations) instruments measuring NSSI were included. Predominantly, the studies were North American self-reports in English for community adolescents, adaptations or versions emanating from a small number of instruments. Twenty-six indicators were categorized to assess NSSI. The most frequent instruments are structured interviews, and their indicators were related to NSSI function and topography. Evidence of validity and reliability was positive but limited. Despite the high number of instruments and diversity of evaluations, we found no instrument with sufficient evidence for clinical assessment. Findings broadly overview NSSI assessment instruments' current use and future improvement in clinical and research settings.     

Randomized, Crossover and Single-Dose Bioquivalence Study of Two Oral Desogestrel Formulations (Film-Coated Tablets of 75 μg) in Healthy Female Volunteers

Despite the increase in the substitution of branded medicinal product with generic drugs, this is a controversial issue for some pharmacological groups (such as contraceptives).The aim of the present clinical trial was to assess the bioequivalence and tolerability of two oral formulations of desogestrel.Thirty-three healthy female volunteers participated in this randomized and two-way crossover study. During two separate experimental periods, with at least four weeks of washout period, women received a single oral dose of 75 μg of desogestrel from each of the formulations (test formulation and reference formulation). Desogestrel bioavailability was determined by the measurement of 3-ketodesogestrel plasma concentration.Pharmacokinetic parameters were comparable and the 90% CI for the ratio of C_max (96.14–114.53%) and AUC_0–t (105.73–123.83%) values for the test and reference formulations fell within the established regulatory interval (80–125%). Both formulations were also comparable in terms of tolerability.From the results of this study it can be concluded that test formulation (desogestrel 75 μg, Cyndea PHARMA S.L.) is bioequivalent to the reference formulation (Cerazet® 75 μg, Organon Española S.A.).     

High polymorphism in the trisomic portion of a gastric cancer cell line

Background Genetic instability is a hallmark of malignancy, and microsatellite instability is a widely appreciated mechanism of generating genetic changes. We have recently observed four markers clustered on chromosome 20 that showed the effects of microsatellite instability in the gastric adenocarcinoma cell line SNU-1. Each affected marker had alleles of three different sizes. The aim of this study was to investigate the origin for this high-density polymorphism on a single chromosome. Methods The high polymorphism located on chromosome 20 was confirmed using 37 additional markers. To further evaluate this finding, 15 clones of the cell line were generated and then assayed with the triallelic markers. Results All told, almost a third of the markers on chromosome 20 had triallelic patterns, but only 0.3% of the markers not on chromosome 20 showed this result. The number of clones showing allelic variation was an average of 50% greater for chromosome 20 markers than for markers elsewhere. A karyotype analysis showed that the progenitor cell line of SNU-1 was trisomic for chromosome 20, and the high polymorphism on that chromosome is almost certainly due to the trisomy. Conclusions Not only are there more chromosome copies and therefore more gene copies subject to mutation in cells containing trisomy, but also more mutations may be passed on to the progeny. This elevated polymorphism increases the repertoire of genetic changes that could affect cellular growth, and may independently increase genomic instability.     

Does gender matter in glioblastoma?

Background  

The clinical outcome of glioblastoma (GBM) patients who receive radiotherapy alone or with chemotherapy is well established. However, little is known about how many patients do not receive this treatment. We consider it is important to investigate why a proportion of operated patients do not receive further treatment after surgery.     

Resistin expression and plasma concentration peak at different times during pregnancy in rats

Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5-15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin - which peaks in early pregnancy - to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy.