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Although p27 plays a central role in cell cycle regulation, its role in breast cancer prognosis is controversial. Furthermore, the p27 gene CDKN1B carries a polymorphism with unknown functional relevance. This study was designed to evaluate p27 expression and p27 genotyping with respect to early breast cancer prognosis. 279 patients with infiltrating metastasis-free breast cancer were included in this study. p27 expression was determined in tumor tissue specimens from 261 patients by immunohistochemistry. From 108 patients, the CDKN1B genotype was examined by PCR and subsequent direct sequencing. 55.2% of the tumors were considered p27 positive. p27 expression did not correlate with any of the established parameters except for nodal involvement but significantly correlated to prolonged disease-free survival. In 35% of the tumors analyzed, the CDKN1B gene showed a polymorphism at codon 109 (V109G). The V109G polymorphism correlated with greater nodal involvement. In the node-negative subgroup, V109G correlated significantly with a shortened disease-free survival. In conclusion, the determination of the CDKN1B genotype might be a powerful tool for the prognosis of patients with early breast cancer.
Large bone defects require fabricated bone constructs that consist of three main components: an artificial extracellular matrix scaffold, stem cells with the potential to differentiate into osteoblasts, and bioactive substances, such as osteoinductive growth factors to direct the growth and differentiation of cells toward osteogenic lineage within the scaffold.
The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).
Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases
(2017)
ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/peripheral cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss-of-function resulted in increased levels of H3K4me3, which co-precipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches.
When users in virtual reality cannot physically walk and self-motions are instead only visually simulated, spatial updating is often impaired. In this paper, we report on a study that investigated if HeadJoystick, an embodied leaning-based flying interface, could improve performance in a 3D navigational search task that relies on maintaining situational awareness and spatial updating in VR. We compared it to Gamepad, a standard flying interface. For both interfaces, participants were seated on a swivel chair and controlled simulated rotations by physically rotating. They either leaned (forward/backward, right/left, up/down) or used the Gamepad thumbsticks for simulated translation. In a gamified 3D navigational search task, participants had to find eight balls within 5 min. Those balls were hidden amongst 16 randomly positioned boxes in a dark environment devoid of any landmarks. Compared to the Gamepad, participants collected more balls using the HeadJoystick. It also minimized the distance travelled, motion sickness, and mental task demand. Moreover, the HeadJoystick was rated better in terms of ease of use, controllability, learnability, overall usability, and self-motion perception. However, participants rated HeadJoystick could be more physically fatiguing after a long use. Overall, participants felt more engaged with HeadJoystick, enjoyed it more, and preferred it. Together, this provides evidence that leaning-based interfaces like HeadJoystick can provide an affordable and effective alternative for flying in VR and potentially telepresence drones.