The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

Although FGF-2 causes the FGFR to be internalized and degraded, NCAM gets cells moving by stabilizing the receptor, promoting receptor recycling, and initiating a promigratory signaling cascade

Role of Pirh2 in Mediating the Regulation of p53 and c-Myc

Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c-Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation and proteolysis. Pirh2 mutant mice display elevated levels of c-Myc and are predisposed for plasma cell hyperplasia and tumorigenesis. Consistent with the role p53 plays in suppressing c-Myc-induced oncogenesis, its deficiency exacerbates tumorigenesis of Pirh2−/− mice. We also report that low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients' survival. Collectively, our data reveal the in vivo roles of Pirh2 in the regulation of p53 and c-Myc stability and support its role as a tumor suppressor

Exudates of <i>Picea abies</i>, <i>Pinus nigra</i>, and <i>Larix decidua</i>: Chromatographic Comparison and Pro-Migratory Effects on Keratinocytes In Vitro

Balms and resins of Picea abies, Larix decidua, and Pinus nigra are traditionally used to treat wounds. Three chromatographic techniques differing in separation capacity and technical demands were employed to distinguish among these plant exudates. A TLC method was established for fingerprint comparison, providing a quick overview of a large number of samples at low cost. HPLC-DAD (RP18) and UHPSFC-DAD (Torus 2-Picolylamin), hyphenated to ESI-MS, represented orthogonal chromatographic systems with high separation performance. The developed methods allow for the separation and detection of major and minor constituents belonging to different compound classes (phenyl carboxylic acids, lignans, diterpene resin acids). The qualitative compositions of the diterpene resin acids, the main compounds in the exudates, were comparable in all three genera. Differences were detected in the distribution of hydroxylated diterpene resin acids, pinoresinol, and hydroxycinnamic acids. The three tested chromatographic systems with varying demands on lab equipment offer appropriate tools for the quality assessment of Picea abies, Larix decidua, and Pinus nigra. The extracts were furthermore tested at three different concentrations (10 µg/mL, 3 µg/mL, and 1 µg/mL) for boosted re-epithelialization, a crucial step in the wound-healing process, in an in vitro HaCaT keratinocyte-based scratch assay. Lysophosphatidic acid (LPA, 10 µM) and extracts of several medicinal plants well known for their wound-healing properties (birch, marigold, St. John’s wort, manuka honey) were used as positive controls. Picea abies and Pinus nigra showed concentration dependency; significant activity was measured for Larix decidua at 3 µg/mL

Thalidomide Enhances the Anti-Tumor Activity of Standard Chemotherapy in a Human Melanoma Xenotransplatation Model

It has been demonstrated that thalidomide's anti-angiogenic properties result in clear anti-tumor activity in a number of human malignancies. We studied thalidomide in a human melanoma severe combined immunodeficiency mouse xenotransplantation model. Thalidomide as a single agent showed a significant tumor reduction of 46% compared with the control group. Thalidomide combined with dacarbazine treatment markedly enhanced the anti-tumor effect of chemotherapy and showed a significant tumor reduction relative to the dacarbazine-only group (61%) and even more tumor reduction (74%) compared with the control group. We also measured clearly reduced levels of tumor necrosis factor-α in the thalidomide-treated group. A significantly lower microvessel density was encountered in the thalidomide treatment groups (thalidomide alone or combined with DTIC), underscoring the anti-angiogenic effect of thalidomide as a single agent as well as in combination with chemotherapy in this model. In line with these results, we observed a nearly 3-fold increase of apoptosis for the combination of thalidomide and DTIC compared with the rate of apoptotic cells in DTIC-only-treated melanoma xenotransplants. These data underline the rationale for combining dacarbazine—a cytotoxic agent—and thalidomide—an anti-angiogenic cytostatic agent—as a promising strategy for the treatment of melanoma

Serum Expression of miR-23a-3p and miR-424-5p Indicate Specific Polycystic Ovary Syndrome Phenotypes: A Pilot Study

MicroRNAs (miRNAs) are single-stranded, non-coding RNAs that regulate mRNA expression on a post-transcriptional level. Observational studies suggest an association of serum miRNAs and polycystic ovary syndrome (PCOS), a common heterogeneous endocrinopathy characterized by hyperandrogenism (HA), oligo- or amenorrhea (OM) and polycystic ovaries. It is not known whether these miRNA profiles also differ between PCOS phenotypes. In this pilot study, we compared serum expression profiles between the four PCOS phenotypes (A–D) and analyzed them both in PCOS (all phenotypes) and in phenotypes with HA by quantitative-real-time PCR (qRT-PCR). The serum expression of miR-23a-3p was upregulated in phenotype B (n = 10) and discriminated it from phenotypes A (n = 11), C (n = 11) and D (n = 11, AUC = 0.837; 95%CI, 0.706–0.968; p = 0.006). The expression of miR-424-5p was downregulated in phenotype C (n = 11) and discriminated it from phenotypes A, B and D (AUC = 0.801; 95%CI, 0.591–1.000; p = 0.007). MiR-93-5p expression was downregulated in women with PCOS (all phenotypes, n = 42) compared to controls (n = 8; p = 0.042). Phenotypes with HA (A, B, C; n = 32) did not show differences in the analyzed expression pattern. Our data provide new insights into phenotype-specific miRNA alterations in the serum of women with PCOS. Understanding the differential hormonal and miRNA profiles across PCOS phenotypes is important to improve the pathophysiological understanding of PCOS heterogeneity