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Germline variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome ( n =536), response to neoadjuvant chemotherapy ( n =125) and platinum resistance (n= 306). Outcome was separately analyzed for women with known BRCA mutations ( n= 79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09–2.57, P =0.019, n =279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31–7.72, P =0.0106, n= 291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro . These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca 2+ -actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca 2+ concentration ([Ca 2+ ] i ), the experimental design was repeated in mice expressing podocyte-specific Ca 2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca 2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca 2+ ] i imaging in podocytes showing decreased Ca 2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca 2+ ] i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

Background In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. Methods The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). Discussion In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

The idea that the rat hippocampus stores a map of space is based on the existence of ``place cells'' that show ``location-specific'' firing. The discharge of place cells is confined with remarkable precision to a cell-specific part of the environment called the cell's ``firing field.'' We demonstrate here that firing is not nearly as reliable in the time domain as in the positional domain. Discharge during passes through the firing field was compared with a model with Poisson variance of the location-specific firing determined by the time-averaged positional firing rate distribution. Place cells characteristically fire too little or too much compared with expectations from the random model. This fundamental property of place cells is referred to as ``excess firing variance'' and has three main implications: (i) Place cell discharge is not only driven by the summation of many small, asynchronous excitatory synaptic inputs. (ii) Place cell discharge may encode a signal in addition to the current head location. (iii) The excess firing variance helps explain why the errors in computing the rat's position from the simultaneous activity of many place cells are large.

According to most textbooks, diagnostic tests with Hymenoptera venoms are reliable, and immunotherapy with these venoms in Hymenoptera-venom-allergic patients leads in near to 100% to full protection. Careful analysis of the literature shows however that the specificity of diagnostic tests is far from perfect and that both efficacy and tolerance, especially in patients receiving honeybee venom immunotherapy, are still suboptimal. The major allergens of honeybee and vespid venoms are now available in recombinant form. Preliminary trials analyzing diagnostic tests with recombinant allergens in honeybee venom allergy are promising: the specificity is clearly increased in both skin testing and in determining venom-specific IgE antibodies when compared to natural venom allergens. An important recent finding is the frequent association of severe Hymenoptera venom allergy and elevated basal serum levels of the mast-cell-specific enzyme tryptase. Elevated levels are found in up to 30% of the patients with a history of severe shock reactions following Hymenoptera stings. The current findings indicate that basal tryptase levels indicating an increased mast cell load are much more frequent than previously thought and are a risk factor for severe or even fatal sting reactions. Premedication with antihistamines in the initial phase of venom immunotherapy reduced both local and systemic allergic side effects in several controlled studies. In a retrospective analysis of one of these trials it was found that reexposure during immunotherapy resulted in significantly more systemic allergic reactions in patients on placebo than on antihistamine premedication, suggesting that initial antihistamine premedication might increase the efficacy of venom immunotherapy. Different ways of allergen modification for venom immunotherapy have been proposed. While the results with chemical modifications were not convincing, recent studies with T-cell epitope peptides from the major bee venom allergen phospholipase A 2 look promising. Patient-tailored cocktails of recombinant venom allergens or isoforms thereof may be another possibility in the future. A number of prospective studies analyzing the duration of venom immunotherapy required for long-term protection have been published in the last decade. While most patients are still fully protected 1 year after discontinuation of therapy, relapses may occur in up to 20% of patients reexposed many years after treatment. Various risk factors for such relapses have been identified.

A key feature of perception is that the interpretation of a single, continuously available stimulus can change from time to time. This aspect of perception is well illustrated by the use of ambiguous figures that can be seen in two different ways. When people view such a stimulus they almost universally describe what they are seeing as jumping between two states. If it is agreed that this perceptual phenemonon is causally linked to the activity of nerve cells, the state jumps would have to occur in conjunction with changes in neural activity somewhere in the nervous system. Our experiments suggest that hippocampal place cells are part of a perceptual system. We conducted variations of a 'cue-card rotation' experiment on rats in which the angular position of a prominent visual stimulus on the wall of cylinder is changed in the rat's presence. The three main results are that (i) place-cell firing fields remain stationary if the cue is rotated by 180 degrees, so the relation between the cue and the field is altered; (ii) firing fields rotate by 45 degrees when the cue is rotated by 45 degrees, so the relation between the field and the card is maintained; and (iii) if the cue is first rotated by 180 degrees and then rotated in a series of 45 degrees steps, the field winds up at a different angular position relative to the card when the card is back in its original position. Thus, place cells can fire in two different ways in reponse to a continuously viewed stimulus. We conclude that place cells reveal that the hippocampal mapping system also has properties expected of a perceptual system.

Nucleic acid diagnostics is dominated by fluorescence-based assays that use complex and expensive enzyme-based target or signal-amplification procedures 1 , 2 , 3 , 4 , 5 , 6 . Many clinical diagnostic applications will require simpler, inexpensive assays that can be done in a screening mode. We have developed a 'spot-and-read' colorimetric detection method for identifying nucleic acid sequences based on the distance-dependent optical properties of gold nanoparticles. In this assay, nucleic acid targets are recognized by DNA-modified gold probes, which undergo a color change that is visually detectable when the solutions are spotted onto an illuminated glass waveguide. This scatter-based method enables detection of zeptomole quantities of nucleic acid targets without target or signal amplification when coupled to an improved hybridization method that facilitates probe-target binding in a homogeneous format. In comparison to a previously reported absorbance-based method 7 , this method increases detection sensitivity by over four orders of magnitude. We have applied this method to the rapid detection of mecA in methicillin-resistant Staphylococcus aureus genomic DNA samples.

Eine ausreichende Versorgung mit Sauerstoff ist für den zellulären Energiehaushalt und damit für die Funktion aller Organe von herausragender Bedeutung. Dies gilt insbesondere für die Niere, welche sich durch eine hohe Sauerstoffversorgung und -ausschöpfung auszeichnet. So spielt eine Minderversorgung mit Sauerstoff sowohl bei der Entwicklung eines akuten Nierenversagens als auch bei der Progression einer chronischen Niereninsuffizienz (CNI) eine wichtige Rolle. In der Anpassung an ein hypoxisches Milieu kommen evolutionär konservierte Signalwege zum Einsatz, welche mittels Umstellung des Metabolismus einerseits und durch Verbesserung der Sauerstoffversorgung andererseits zelluläres Überleben und den Erhalt der Organfunktion gewährleisten. Hierbei sind insbesondere hypoxieinduzierbare Transkriptionsfaktoren (HIF) bedeutsam. Hypoxie-Signaling kann jedoch nicht nur als Antwort auf Sauerstoffmangel gesehen werden, sondern erhöht darüber hinaus die zelluläre Stressresistenz. Diese Tatsache zeigt sich im Tierversuch als Schutz vor akutem Nierenversagen durch sogenannte hypoxische Konditionierung. Im folgenden Übersichtsartikel beschreiben wir die Grundlagen von renaler Gewebshypoxie und Hypoxie- Signaling sowie potenzielle therapeutische Ansätze.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth. Although it is evident that 1,25(OH)2D3 inhibits growth of both estrogen receptor alpha-positive [ER alpha(+)] and -negative [ER alpha(-)] breast cancer cells, the cellular pathways contributing to these effects remain unclear. We studied the gene expression patterns in ER alpha(+) MCF-7 and ER alpha(-) MDA MB 231 human breast cancer cells following 1,25(OH)2D3 treatment, using cDNA expression arrays. Both cell lines showed a significant induction of the 1,25(OH)2D3-dependent 24-hydroxylase gene, a marker for the actions of 1,25(OH)2D3. In MCF-7 cells, 51 genes were up-regulated and 19 genes were down-regulated. The up-regulated genes encoded cell adhesion molecules, growth factors/modulators, steroid receptors/co-activators, cytokines, kinases and transcription factors. Of the up-regulated genes, 40% were implicated in cell cycle regulation and apoptosis and included cyclin G1 and cyclin I, p21-activated kinase-1 (PAK-1), p53, retinoblastoma like-2 [Rb2 (p130)], insulin-like growth factor binding protein-5 (IGFBP5) and caspases. Among the down-regulated genes were ER alpha, growth factors, cytokines and several kinases. Some of these results were confirmed by real-time PCR. In MDA MB 231 cells, 20 genes were up-regulated and 13 genes were down-regulated. Very few genes directly implicated in cell cycle regulation were up-regulated. The matrix metalloproteinases formed a major class of genes that were down-regulated in the MDA MB 231 cells. Seven genes were commonly up-regulated in both cell lines and these included transforming growth factor (TGFbeta2) and Rb2 (p130). In conclusion, the gene expression profiles of the two cell lines studied were different with a few overlapping genes suggesting that different cellular pathways might be regulated by 1,25(OH)2D3 to exert its growth inhibitory effects in ER alpha(+) and ER alpha(-) cells.