A Systems Biology Approach to Understanding the Pathophysiology of High-Grade Serous Ovarian Cancer: Focus on Iron and Fatty Acid Metabolism.

Ovarian cancer (OVC) is the most lethal of the gynecological malignancies, with diagnosis often occurring during advanced stages of the disease. Moreover, a majority of cases become refractory to chemotherapeutic approaches. Therefore, it is important to improve our understanding of the molecular dependencies underlying the disease to identify novel diagnostic and precision therapeutics for OVC. Cancer cells are known to sequester iron, which can potentiate cancer progression through mechanisms that have not yet been completely elucidated. We developed an algorithm to identify novel links between iron and pathways implicated in high-grade serous ovarian cancer (HGSOC), the most common and deadliest subtype of OVC, using microarray gene expression data from both clinical sources and an experimental model. Using our approach, we identified several links between fatty acid (FA) and iron metabolism, and subsequently developed a network for iron involvement in FA metabolism in HGSOC. FA import and synthesis pathways are upregulated in HGSOC and other cancers, but a link between these processes and iron-related genes has not yet been identified. We used the network to derive hypotheses of specific mechanisms by which iron and iron-related genes impact and interact with FA metabolic pathways to promote tumorigenesis. These results suggest a novel mechanism by which iron sequestration by cancer cells can potentiate cancer progression, and may provide novel targets for use in diagnosis and/or treatment of HGSOC

Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors

<p>Abstract</p> <p>Background</p> <p>Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, <it>SOSTDC1 </it>and <it>MEOX2</it>, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor.</p> <p>Methods</p> <p>To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of <it>SOSTDC1 </it>in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of <it>SOSTDC1 </it>genetic aberrations on SOSTDC1 protein levels and signaling.</p> <p>Results</p> <p>Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected <it>SOSTDC1</it>. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected <it>SOSTDC1</it>. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of <it>SOSTDC1 </it>LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization.</p> <p>Conclusions</p> <p>This study shows that genetic aberrations near <it>SOSTDC1 </it>are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of <it>SOSTDC1 </it>LOH, however, did not correspond with changes in SOSTDC1 protein levels or signaling regulation. Although our conclusions are limited by sample size, we suggest that an alternative mechanism such as epigenetic silencing of <it>SOSTDC1 </it>may be a key contributor to the reduced SOSTDC1 mRNA and protein levels observed in renal cancer.</p

Amyloid peptide β1-42 induces integrin αIIbβ3 activation, platelet adhesion and thrombus formation in a NADPH oxidase-dependent manner

This is the final version. Available on open access from Hindawi Publishing Corporation via the DOI in this recordThe progression of Alzheimer’s dementia is associated with neurovasculature impairment, which includes inflammation, microthromboses, and reduced cerebral blood flow. Here, we investigate the effects of β amyloid peptides on the function of platelets, the cells driving haemostasis. Amyloid peptide β1-42 (Aβ1-42), Aβ1-40, and Aβ25-35 were tested in static adhesion experiments, and it was found that platelets preferentially adhere to Aβ1-42 compared to other Aβ peptides. In addition, significant platelet spreading was observed over Aβ1-42, while Aβ1-40, Aβ25-35, and the scAβ1-42 control did not seem to induce any platelet spreading, which suggested that only Aβ1-42 activates platelet signalling in our experimental conditions. Aβ1-42 also induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other Aβ peptides did not. The molecular mechanism of Aβ1-42 was investigated by flow cytometry, which revealed that this peptide induces a significant activation of integrin αIIbβ3, but does not induce platelet degranulation (as measured by P-selectin membrane translocation). Finally, Aβ1-42 treatment of human platelets led to detectable levels of protein kinase C (PKC) activation and tyrosine phosphorylation, which are hallmarks of platelet signalling. Interestingly, the NADPH oxidase (NOX) inhibitor VAS2870 completely abolished Aβ1-42-dependent platelet adhesion in static conditions, thrombus formation in physiological flow conditions, integrin αIIbβ3 activation, and tyrosine- and PKC-dependent platelet signalling. In summary, this study highlights the importance of NOXs in the activation of platelets in response to amyloid peptide β1-42. The molecular mechanisms described in this manuscript may play an important role in the neurovascular impairment observed in Alzheimer’s patients.Alzheimer´s Research UKBritish Heart FoundationNational Institute for Health Research (NIHR

Amyloid peptide β 1-42 induces integrin α IIb β 3 activation, platelet adhesion, and thrombus formation in a NADPH Oxidase-Dependent Manner

The progression of Alzheimer's dementia is associated with neurovasculature impairment, which includes inflammation, microthromboses, and reduced cerebral blood flow. Here, we investigate the effects of β amyloid peptides on the function of platelets, the cells driving haemostasis. Amyloid peptide β1-42 (Aβ1-42), Aβ1-40, and Aβ25-35 were tested in static adhesion experiments, and it was found that platelets preferentially adhere to Aβ1-42 compared to other Aβ peptides. In addition, significant platelet spreading was observed over Aβ1-42, while Aβ1-40, Aβ25-35, and the scAβ1-42 control did not seem to induce any platelet spreading, which suggested that only Aβ1-42 activates platelet signalling in our experimental conditions. Aβ1-42 also induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other Aβ peptides did not. The molecular mechanism of Aβ1-42 was investigated by flow cytometry, which revealed that this peptide induces a significant activation of integrin αIIbβ3, but does not induce platelet degranulation (as measured by P-selectin membrane translocation). Finally, Aβ1-42 treatment of human platelets led to detectable levels of protein kinase C (PKC) activation and tyrosine phosphorylation, which are hallmarks of platelet signalling. Interestingly, the NADPH oxidase (NOX) inhibitor VAS2870 completely abolished Aβ1-42-dependent platelet adhesion in static conditions, thrombus formation in physiological flow conditions, integrin αIIbβ3 activation, and tyrosine- and PKC-dependent platelet signalling. In summary, this study highlights the importance of NOXs in the activation of platelets in response to amyloid peptide β1-42. The molecular mechanisms described in this manuscript may play an important role in the neurovascular impairment observed in Alzheimer's patients

Combined lymphocyte/monocyte count, D-dimer and iron status predict COVID-19 course and outcome in a long-term care facility

Background: The Sars-CoV-2 can cause severe pneumonia with multiorgan disease; thus, the identification of clinical and laboratory predictors of the progression towards severe and fatal forms of this illness is needed. Here, we retrospectively evaluated and integrated laboratory parameters of 45 elderly subjects from a long-term care facility with Sars-CoV-2 outbreak and spread, to identify potential common patterns of systemic response able to better stratify patients’ clinical course and outcome. Methods: Baseline white blood cells, granulocytes’, lymphocytes’, and platelets’ counts, hemoglobin, total iron, ferritin, D-dimer, and interleukin-6 concentration were used to generate a principal component analysis. Statistical analysis was performed by using R statistical package version 4.0. Results: We identified 3 laboratory patterns of response, renamed as low-risk, intermediate-risk, and high-risk, strongly associated with patients’ survival (p &lt; 0.01). D-dimer, iron status, lymphocyte/monocyte count represented the main markers discriminating high- and low-risk groups. Patients belonging to the high-risk group presented a significantly longer time to ferritin decrease (p: 0.047). Iron-to-ferritin-ratio (IFR) significantly segregated recovered and dead patients in the intermediate-risk group (p: 0.012). Conclusions: Our data suggest that a combination of few laboratory parameters, i.e. iron status, D-dimer and lymphocyte/monocyte count at admission and during the hospital stay, can predict clinical progression in COVID-19

TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

T cell immunoglobulin-domain and mucin-domain (TIM) proteins constitute a receptor family that was identified first on kidney and liver cells; recently it was also shown to be expressed on T cells. TIM-1 and -3 receptors denote different subsets of T cells and have distinct regulatory effects on T cell function. Ferritin is a spherical protein complex that is formed by 24 subunits of H- and L-ferritin. Ferritin stores iron atoms intracellularly, but it also circulates. H-ferritin, but not L-ferritin, shows saturable binding to subsets of human T and B cells, and its expression is increased in response to inflammation. We demonstrate that mouse TIM-2 is expressed on all splenic B cells, with increased levels on germinal center B cells. TIM-2 also is expressed in the liver, especially in bile duct epithelial cells, and in renal tubule cells. We further demonstrate that TIM-2 is a receptor for H-ferritin, but not for L-ferritin, and expression of TIM-2 permits the cellular uptake of H-ferritin into endosomes. This is the first identification of a receptor for ferritin and reveals a new role for TIM-2

Primate rhythmic categories analyzed on an individual basis

Rhythm is a fundamental feature characterizing communicative displays, and recent studies showed that primate songs encompass categorical rhythms falling on small integer ratios observed in humans. We individually assessed the presence and sexual dimorphism of rhythmic categories, analyzing songs emitted by 39 wild indris. Considering the intervals between the units given during each song, we extracted 13556 interval ratios and found three peaks (at around 0.33, 0.47, and 0.70). Two peaks indicated rhythmic categories corresponding to small integer ratios (1:1, 2:1). All individuals showed a peak at 0.70, and most showed those at 0.47 and 0.33. In addition, we found sex differences in the peak at 0.47 only, with males showing lower values than females. This work investigates the presence of individual rhythmic categories in a non-human species; further research may highlight the significance of rhythmicity and untie selective pressures that guided its evolution across species, including humans

The Indris have got rhythm! Timing and pitch variation of a primate song examined between sexes and age classes

A crucial, common feature of speech and music is that they show non-random structures over time. It is an open question which of the other species share rhythmic abilities with humans, but in most cases the lack of knowledge about their behavioral displays prevents further studies. Indris are the only lemurs who sing. They produce loud howling cries that can be heard at several kilometers, in which all members of a group usually sing. We tested whether overlapping and turn-taking during the songs followed a precise pattern by analysing the temporal structure of the individuals' contribution to the song. We found that both dominants (males and females) and non-dominants influenced the onset timing one another. We have found that the dominant male and the dominant female in a group overlapped each other more frequently than they did with the non-dominants. We then focused on the temporal and frequency structure of particular phrases occurring during the song. Our results show that males and females have dimorphic inter-onset intervals during the phrases. Moreover, median frequencies of the unit emitted in the phrases also differ between the sexes, with males showing higher frequencies when compared to females. We have not found an effect of age on the temporal and spectral structure of the phrases. These results indicate that singing in indris has a high behavioral flexibility and varies according to social and individual factors. The flexible spectral structure of the phrases given during the song may underlie perceptual abilities that are relatively unknown in other non-human primates, such as the ability to recognize particular pitch patterns