👤 Morten C Moe

Recent studies have highlighted the deleterious role of high phosphate intake in hypertension via sympathetic overactivation, yet the underlying mechanisms remain unclear. Dietary phosphate loading triggers physiologic release of FGF23 (fibroblast growth factor-23) from the bone to maintain phosphate homeostasis. Both FGF23 and FGF receptors (FGFRs) are present in the central nervous system, but their role in neural control of blood pressure during phosphate loading is unknown. We investigated central FGF23/FGFR signaling in high-phosphate diet-induced sympathetic dysregulation of blood pressure in rats. FGF23 protein levels were measured by immunoprecipitation, immunoblotting, and immunohistochemistry. FGF23 translocation into the brain was determined by injecting infrared-labeled FGF23 intravenously into anesthetized Sprague-Dawley rats. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction were measured in decerebrate Sprague-Dawley rats treated with either a normal 0.6% phosphate diet (NP) or a high 1.2% phosphate diet (HP) for 12 weeks before and after intracerebroventricular (ICV) administration of FGFR signaling inhibitors. Excess phosphate intake significantly increased FGF23 protein levels in the brainstem (HP versus NP, Our data reveal a novel pathophysiologic paradigm of high-phosphate diet-induced sympathoexcitation and hypertension by FGF23 crossing into the brain, possibly acting via FGFR4. Show less

Activation of the acute-phase cascade (APC) has been correlated with outcomes in various cancers, including head and neck squamous cell carcinoma (HNSCC). Primary drivers of the APC are the cytokines within the interleukin-6 (IL-6) and IL-1 families. Plasma levels of IL-6 family cytokines/soluble receptors (IL-6, IL-27, IL-31, OSM, CNTF, soluble (s-)gp130, s-IL-6Rα) and IL-1 family members (IL-1RA, s-IL-33Rα) were determined at diagnosis for 87 human papillomavirus (HPV)-negative (-) HNSCC patients. We then studied the 5-year Disease-Specific Survival (DSS) and Overall Survival (OS). Increased plasma levels of IL-6 ( Show less

Early innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c Show less

C-reactive protein (CRP) has a prognostic impact in head and neck squamous cell carcinoma (HNSCC). However, the acute phase reaction involves many other proteins depending on its inducing events, including various cytokines that can function as reaction inducers. In the present study, we compared the pretreatment acute phase cytokine profile for 144 patients with potentially curative HNSCC. We investigated the systemic levels of interleukin (IL)6 family mediators (glycoprotein (gp130), IL6 receptor (R)α, IL6, IL27, IL31, oncostatin M (OSM), ciliary neurotrophic factor (CNTF)), IL1 subfamily members (IL1R antagonist (A), IL33Rα), and tumor necrosis factor (TNF)α. Patient subsets identified from this 10-mediator profile did not differ with regard to disease stage, human papilloma virus (HPV) status, CRP levels, or death cause. Increased CRP, IL6, and IL1RA levels were independent markers for HNSCC-related death in the whole patient population. Furthermore, gp130, IL6Rα, and IL31 were suggested to predict prognosis among tumor HPV-negative patients. Only IL6 predicted survival in HPV-positive patients. Finally, we did a clustering analysis of HPV-negative patients based on six acute phase mediators that showed significant or borderline association with prognosis in Kaplan-Meier analyses; three subsets could then be identified, and they differed in survival ( Show less

Uveal melanoma (UM) has a high propensity for metastatic spread, and approximately 40-50% of patients die of metastatic disease. Metastases can be found at the time of diagnosis but also several years after the tumor has been removed. The survival of disseminated cancer cells is known to be linked to anchorage independence, anoikis resistance, and an adaptive cellular metabolism. The cultivation of cancer cells as multicellular tumor spheroids (MCTS) by anchorage-independent growth enriches for a more aggressive phenotype. The present study examines the differential gene expression of adherent cell cultures, non-adherent MCTS cultures, and uncultured tumor biopsies from three patients with UM. We elucidate the biochemical differences between the culture conditions to find whether the culture of UM as non-adherent MCTS could be linked to an anchorage-independent and more aggressive phenotype, thus unravelling potential targets for treatment of UM dissemination. The various culture conditions were evaluated with microarray analysis, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), RNAscope, immunohistochemistry (IHC), and transmission electron microscopy (TEM) followed by gene expression bioinformatics. The MCTS cultures displayed traits associated with anoikis resistance demonstrated by The MCTS cultures displayed traits associated with anoikis resistance, a metabolic shift toward a lipogenic profile, and upregulation of SSXs, related to the PcG proteins. Show less

The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome 6 using a canine whole genome radiation hybrid panel. There is close linkage between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been observed in humans and other mammalian species. The gene responsible for the human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2 and PKD1 in humans, and is also syntenic in the dog. We further demonstrate linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6). Show less

The neuronal ceroid lipofuscinoses (NCL) are a group of fatal autosomal recessive neurodegenerative diseases occurring in human and some domesticated animal species. A canine form of the disease (CNCL) has been extensively studied in a Norwegian colony of inbred English setters since 1960. A resource family developed for genetic mapping and comprising 170 individuals was typed for 103 genetic markers. Linkage analysis showed three genetic markers to be linked to the disease locus with the closest marker at a distance of about 3 CM. Two other loci were linked with these markers making a linkage group of five genetic markers. The linkage group spanned a distance of 54 CM. Two genes for human forms of the disease, CLN2 and CLN3, have been identified and mapped to human chromosome 11p15 and 16p12, respectively. The present study did not indicate any linkage between CNCL and the canine CLN3 homologue or to homologues of markers for genes that map close to human CLN2. Show less