Colorectal cancer (CRC) is an emerging global problem with the rapid increase in its incidence being associated with an unhealthy lifestyle. Epidemiological studies have shown that decreased levels of vitamin D3 significantly increases the risk of CRC. Furthermore, negative effects of vitamin D3 deficiency can be compensated by appropriate supplementation. Vitamin D3 was shown to inhibit growth and induce differentiation of cancer cells, however, excessive vitamin D3 intake leads to hypercalcemia. Thus, development of efficient vitamin D3 analogues with limited impact on calcium homeostasis is an important scientific and clinically relevant task. The aims of the present study were to compare the antiproliferative potential of classic vitamin D3 metabolites (1α,25(OH)2D3 and 25(OH)D3) with selected low calcemic analogues (calcipotriol and 20(OH)D3) on CRC cell lines and to investigate the expression of vitamin D-related genes in CRC cell lines and clinical samples. Vitamin D3 analogues exerted anti-proliferative effects on all CRC cell lines tested. Calcipotriol proved to be as potent as 1α,25(OH)2D3 and had more efficacy than 20-hydroxyvitamin D3. In addition, the analogs tested effectively inhibited the formation of colonies in Matrigel. The expression of genes involved in 1α,25(OH)2D3 signaling and metabolism varied in cell lines analysed, which explains in part their different sensitivities to the various analogues. In CRC biopsies, there was decreased VDR expression in tumor samples in comparison to the surgical margin and healthy colon samples (P<0.01). The present study indicates that vitamin D3 analogues which have low calcemic activity, such as calcipotriol or 20(OH)D3, are very promising candidates for CRC therapy. Moreover, expression profiling of vitamin D-related genes is likely to be a powerful tool in the planning of anticancer therapy. Decreased levels of VDR and increased CYP24A1 expression in clinical samples underline the importance of deregulation of vitamin D pathways in the development of CRC.
The transcription factor Pax7 plays a key role during embryonic myogenesis and in adult organisms in that it sustains the proper function of satellite cells, which serve as adult skeletal muscle stem cells. Recently we have shown that lack of Pax7 does not prevent the myogenic differentiation of pluripotent stem cells. In the current work we show that the absence of functional Pax7 in differentiating embryonic stem cells modulates cell cycle facilitating their proliferation. Surprisingly, deregulation of Pax7 function also positively impacts at the proliferation of mouse embryonic fibroblasts. Such phenotypes seem to be executed by modulating the expression of positive cell cycle regulators, such as cyclin E.
FIG 2: Metaphase spread with chromosome breaks (arrows), showing (a) a single break in an autosome and (b) three breaks, one in an X chromosome and two in autosomesPOLYMELIA is a rare congenital defect characterised by the presence of a supernumerary limb at different locations on the body. Depending on the body region, polymelia has been classified as notomelia, cephalomelia, thoracomelia and pygomelia (Kim and others 2001). The phenomenon of polymelia is usually associated with other congenital defects such as polydactyly (extra fingers or toes) or the presence of additional and often underdeveloped bones (Murondoti and Busayi 2001). In most cases, the extra limb is shorter and devoid of muscle tissue. The physiological attributes of the affected animal, including temperature, pulse and respiration rate, are usually normal (Hirsbrunner and others 2002). This short communication describes polymelia in a heifer, associated with frequent chromatid/chromosome breaks observed in lymphocytes cultured in vitro.A black-and-white heifer, genetically 62·5 per cent Holstein-Friesian, was born with four normal legs and one extra limb localised in a shoulder girdle between the scapulas. The supernumerary limb was smaller than the normal legs, was bent at the carpal joint and had a terminal hoof. It hung down on the left side of the animal (Fig 1a). The extra limb was attached to an underdeveloped additional scapula, which was connected to the thoracic vertebrae. The animal underwent surgery on two occasions at three and four months of age. During the first operation the additional leg was removed at the shoulder joint. During the second operation, which was performed due to unsuccessful wound healing, only a part of the extra scapula was removed at the neck of the scapula; the whole scapula was not removed due to the risk of injury to the vertebral column.The skeleton of the additional limb, according to anatomical nomenclature (Dyce and others 1987), consisted of the stylopodium (humerus), zeugopodium (radius and ulna) and autopodium, including the basipodium (carpal bones), metapodium (metacarpal bones) and acropodium (proximal, middle and distal phalanges) (Fig 1b). The stylopodium consisted of a single long bone with distinguishable epiphysial cartilage of the proximal epiphysis and three unfused skeletal elements that made up the metaphysis. The diaphysis of the stylopodium, near the epiphysis, was laterally flattened. The appearance of this bone resembled a humerus. The zeugopodium included one long bone with a cleft in the diaphysis; however, the epiphyisis and metaphysis were jointed. It was not possible to conclude whether this bone was an element of a thoracic or pelvic limb. The basipodium consisted of carpal bones that were fused in two blocks not resembling the tarsal bones (there was no talus or calcaneus). The metapodium of the extra limb had features that were not typical of this segment of the autopodium in cattle. Two bones were partially fused together (a massive one and a very thin underdeveloped bone). ...
The molecular background of the most frequent intersexuality syndrome in dogs (female-to-male sex reversal with the female karyotype and a lack of the SRY gene) is unknown. In this article, new cases of this syndrome are described in two unrelated American Staffordshire terrier dogs and one miniature pinscher dog subjected to cytogenetic and molecular analysis due to the presence of an enlarged clitoris. One dog was operated on and histological studies of the gonads revealed a testicular structure without signs of spermatogenesis, but the uterus wall appeared to be normal. All three dogs had female chromosome complements and lacked the Y-linked genes SRY and ZFY. Eight fragments, representing the vast majority of the coding sequence of the SOX9 gene, and two fragments of the 5' flanking region of this gene were analyzed. The studied fragments had identical DNA sequences when comparing the intersexual dogs with GenBank sequences (AY237827; NW139883). Thus a mutation in the coding sequence as well as the promoter region of the SOX9 gene might be excluded as a cause of this type of intersexuality. The importance of further studies of the 5' flanking region of this gene is discussed.
The RAS pathway is central to epidermal homeostasis, and its activation in tumors or in Rasopathies correlates with hyperproliferation. Downstream of RAS, RAF kinases are actionable targets regulating keratinocyte turnover; however, chemical RAF inhibitors paradoxically activate the pathway, promoting epidermal proliferation. We generated mice with compound epidermis-restricted BRAF/RAF1 ablation. In these animals, transient barrier defects and production of chemokines and Th2-type cytokines by keratinocytes cause a disease akin to human atopic dermatitis, characterized by IgE responses and local and systemic inflammation. Mechanistically, BRAF and RAF1 operate independently to balance MAPK signaling: BRAF promotes ERK activation, while RAF1 dims stress kinase activation. In vivo, JNK inhibition prevents disease onset, while MEK/ERK inhibition in mice lacking epidermal RAF1 phenocopies it. These results support a primary role of keratinocytes in the pathogenesis of atopic dermatitis, and the animals lacking BRAF and RAF1 in the epidermis represent a useful model for this disease.DOI: http://dx.doi.org/10.7554/eLife.14012.001
The dual-specificity kinases MEK1 and MEK2 act downstream of RAS/RAF to induce ERK activation, which is generally considered protumorigenic. Activating MEK mutations have not been discovered in leukemia, in which pathway activation is caused by mutations in upstream components such as RAS or Flt3. The anti-leukemic potential of MEK inhibitors is being tested in clinical trials; however, downregulation of MEK1 promotes Eμ-Myc-driven lymphomagenesis and MEK1 ablation induces myeloproliferative disease in mice, raising the concern that MEK inhibitors may be inefficient or counterproductive in this context. We investigated the role of MEK1 in the proliferation of human leukemic cell lines and in retroviral models of leukemia. Our data show that MEK1 suppression via RNA interference and genomic engineering does not affect the proliferation of human leukemic cell lines in culture; similarly, MEK1 ablation does not impact the development of MYC-driven leukemia in vivo. In contrast, MEK1 ablation significantly reduces tumorigenesis driven by Nras alone or in combination with Myc. Thus, while MEK1 restricts proliferation and tumorigenesis in some cellular and genetic contexts, it cannot be considered a tumor suppressor in the context of leukemogenesis. On the contrary, its role in NRAS-driven leukemogenesis advocates the use of MEK inhibitors, particularly in combination with PI3K/AKT inhibitors, in hematopoietic malignancies involving RAS activation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.