Platelet release of Vascular Endothelial Growth Factor (VEGF) in patients undergoing chemotherapy for breast cancer

<p>Abstract</p> <p>Background</p> <p>Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. In this study we investigated the changes in serum and plasma VEGF, together with platelet release of VEGF and related these to the development of VTE at 3 months.</p> <p>Methods</p> <p>Serum and plasma VEGF, together with platelet release of VEGF were measured prior to chemotherapy and at 24 hours; four-, eight days and three months following commencement of chemotherapy in early and advanced breast cancer patients and in age and sex matched controls. Duplex ultrasound imaging was performed after one month or if symptomatic.</p> <p>Results</p> <p>Of 123 patients 9.8% developed VTE within three months. Serum and plasma VEGF were increased in advanced breast cancer as was platelet release of VEGF. Prior to chemotherapy a 100 μg/ml increase in serum VEGF was associated with a 40% increased risk of VTE, while a 10 μg/ml increase in plasma VEGF was associated with a 20% increased risk of VTE. Serum VEGF showed a different response to chemotherapy in those who developed VTE.</p> <p>Conclusion</p> <p>A group of patients at risk of VTE could be identified, allowing targeted thrombopropylaxis. Whether or not the response in VEGF during chemotherapy has any angiogenic significance remains to be elucidated.</p

Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses

Hyaluronan (HA) is a large nonsulfated glycosaminoglycan and an important regulator of angiogenesis, in particular, the growth and migration of vascular endothelial cells. We have identified some of the key intermediates responsible for induction of mitogenesis and wound recovery. Treatment of bovine aortic endothelial cells with oligosaccharides of hyaluronan (o-HA) resulted in rapid tyrosine phosphorylation and plasma membrane translocation of phospholipase C1 (PLC1). Cytoplasmic loading with inhibitory antibodies to PLC1, G, and Gi/o/t/z inhibited activation of extracellular-regulated kinase 1/2 (ERK1/2). Treatment with the Gi/o inhibitor, pertussis toxin, reduced o-HA-induced PLC1 tyrosine phosphorylation, protein kinase C (PKC) and 1/2 membrane translocation, ERK1/2 activation, mitogenesis, and wound recovery, suggesting a mechanism for o-HA-induced angiogenesis through G-proteins, PLC1, and PKC. In particular, we demonstrated a possible role for PKC in mitogenesis and PKC1/2 in wound recovery. Using antisense oligonucleotides and the Ras farnesylation inhibitor FTI-277, we showed that o-HA-induced bovine aortic endothelial cell proliferation, wound recovery, and ERK1/2 activation were also partially dependent on Ras activation, and that o-HA-stimulated tyrosine phosphorylation of the adapter protein Shc, as well as its association with Sos1. Binding of Src to Shc was required for its activation and for Ras-dependent activation of ERK1/2, cell proliferation, and wound recovery. Neither Src nor Ras activation was inhibited by pertussis toxin, suggesting that their activation was independent of heterotrimeric G-proteins. However, the specific Src kinase inhibitor PP2 inhibited G subunit co-precipitation with PLC1, suggesting a possible role for Src in activation of PLC1 and interaction between two distinct o-HA-induced signaling pathways

Gamma radiation induced variations in corn marigold (Glebionis segetum) and their RAPD-based genetic relationship

The present investigation was conducted during the kharif season of 2010-2012 to study hormesis, morphological and biochemical attributes associated with mutation and purification of novel types in corn marigold. The seeds of Glebionis segetum were treated with gamma rays (Source 60Co) at the dose of 20, 40, 60, 80 and 100 Gy were sown in the field along with control (un-irradiated seeds). Low doses of gamma irradiation resulted in hormesis and induced encouraging novelties, while the higher doses induced higher degree of abnormalities which led to mortality. The M2 seeds were sown to observe their characters and mutants in each population. Five promising mutants, viz. S1-S3 at 20 Gy and S4-S5 at 40 Gy gamma irradiation treatments were tagged, screened and checked for stability of characters for genetic study and possible uses of the traits. RAPD molecular marker technique was used for the study of genetic divergence and establishment of distinctiveness or similarity between the mutants developed as a result of mutagenic treatment

A microarray study of gene and protein regulation in human and rat brain following middle cerebral artery occlusion

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Altered gene expression is an important feature of ischemic cerebral injury and affects proteins of many functional classes. We have used microarrays to investigate the changes in gene expression at various times after middle cerebral artery occlusion in human and rat brain.[Results]: Our results demonstrated a significant difference in the number of genes affected and the time-course of expression between the two cases. The total number of deregulated genes in the rat was 335 versus 126 in the human, while, of 393 overlapping genes between the two array sets, 184 were changed only in the rat and 36 in the human with a total of 41 genes deregulated in both cases. Interestingly, the mean fold changes were much higher in the human. The expression of novel genes, including p21-activated kinase 1 (PAK1), matrix metalloproteinase 11 (MMP11) and integrase interactor 1, was further analyzed by RT-PCR, Western blotting and immunohistochemistry. Strong neuronal staining was seen for PAK1 and MMP11.[Conclusion]: Our findings confirmed previous studies reporting that gene expression screening can detect known and unknown transcriptional features of stroke and highlight the importance of research using human brain tissue in the search for novel therapeutic agents.This work was supported by the Higher Education Funding Council for England (HEFCE) and the Research Institute for Health and Social Change (RIHSC).Peer reviewe

TNFα down-regulates CD105 expression in vascular endothelial cells: a comparative study with TGFß1

The vascular endothelium participates in angiogenesis, inflammation and the immune response, which are modulated by vasoactive cytokines such as tumour necrosis factor-α (TNFα) and transforming growth factor-ß1 (TGFß1). CD105 is a component of the TGFß receptor complex and is abundantly expressed in activated/injured endothelium where it is implicated in multiple cellular processes. Up-regulation of CD105 in synovial cells of rheumatoid arthritis and psoriatic lesions implies a possible role in the pathogenesis of such inflammatory disorders. The pro-inflammatory cytokine, TNFα, and anti-inflammatory cytokine, TGFß1, regulate multiple cellular processes such as proliferation, differentiation and apoptosis. Our hypothesis is that CD105 gene expression in endothelial cells is regulated by the multifunctional cytokines TNFα and TGFß1. By using human dermal microvascular endothelial cells the present study has shown that long-term treatment with TNFα (0.1-5 ng/ml) elicited a concentration- and time-dependent significant suppression (over 50% reduction) in CD105 protein levels. The observations that no significant alterations in the CD105 mRNA levels or in the CD105 promoter activity were found and that the potent inhibitor of NFÎB, PDTC, did not affect the TNFα action suggest that CD105 down-regulation by TNF· is not at the transcriptional level. In contrast to TNFα, TGFß1 significantly elevated CD105 protein and mRNA expression (<2-fold increase) through activation of its promoter activity. From these data we conclude that TNFα and TGFß1 exert opposing effects on CD105 expression in human vascular endothelial cells and that CD105 is enmeshed in the network of signal pathways modulating multiple cellular functions

CD105 prevents apoptosis in hypoxic endothelial cells

CD105, a marker of endothelial cells, is abundantly expressed in tissues undergoing angiogenesis and is a receptor for transforming growth factorß. The pivotal role of CD105 in the vascular system was demonstrated by the severe vascular defects that occur in CD105-knockout mice, but the exact mechanisms for CD105 regulation of vascular development have not been fully elucidated. In light of the function of CD105 and the importance of hypoxia in neovascularisation, we speculated that CD105 is involved in hypoxia-initiated angiogenesis. Using tissue-cultured human microvascular endothelial cells, we have investigated the effects of hypoxic stress on CD105 gene expression. Hypoxia induced a significant increase in membrane-bound and secreted CD105 protein levels. CD105 mRNA and promoter activity were also markedly elevated, the latter returning to the basal level after 16 hours of hypoxic stress. Hypoxia induced cell cycle arrest at the G0/G1 phases and massive cell apoptosis after 24 hours through a reduction in the Bcl-2 to Bax ratio, downregulation of Bcl-XL and Mcl-1, and upregulation of caspase-3 and caspase-8. The consequence of CD105 upregulation was revealed using an antisense approach and a TUNEL assay. Suppression of CD105 increased cell apoptosis under hypoxic stress in the absence of TGFß1. Furthermore, hypoxia and TGFß1 synergistically induced apoptosis in the CD105-deficient cells but not in the control cells. We conclude that hypoxia is a potent stimulus for CD105 gene expression in vascular endothelial cells, which in turn attenuates cell apoptosis and thus contributes to angiogenesis

What Indian working class is saying about the COVID-19 pandemic: concerns and reactions

This is an exploratory research highlighting the concerns and reactions of Indian working-class people towards the COVID-19. It was observed that most of the Indian working-class people were seriously concerned about the pandemic and responded well to the measures suggested by the Governments and other agencies in a big way. Most of the respondents believed the pandemic will be effectively controlled across the globe within one year. Word cloud and other data visualization techniques were used to analyze the reactions of the Indian working class towards the Central and State government’s initiatives to contain COVID-19. In the word cloud of the top 150 popular words for both central and state governments Lockdown, People and Government have taken the central stage. The word streaming analysis suggests the intense relationship among the most frequent words in the dataset. For the central government, it was social distancing and for state government, it was social distancing and relationship between central and state governments. The sentiment analysis for both central and state government was neutral, mostly. The researchers are of the view that the research will provide a deeper insight into human perception and behavior towards the measures initiated by the Central and State Governments in any similar difficult situations. Further the concerns identified may be taken into consideration by the Government while designing the policy measures and other interventions by the Government

Functional analysis of alternative isoforms of the transcription factor PAX3 in melanocytes in vitro

Transcription factor PAX3 has seven isoforms of which PAX3c has been studied extensively whereas the functions of the other isoforms are less well known. Here, we found that PAX3 isoforms in a stable transfection system have different biological functions in mouse melanocytes in vitro. PAX3a and PAX3b had negative effects on melanocyte proliferation but had no discernable effect on melanocyte growth in soft agar. PAX3a did not affect cell migration and apoptosis but PAX3b reduced migration and accelerated apoptosis. PAX3c and PAX3d promoted cell proliferation, migration, transformation, and survival. PAX3e reduced melanocyte growth; transformation and migration were unchanged and apoptosis was increased in vitro. PAX3g did not influence cell proliferation or apoptosis. Cells expressing PAX3g were able to grow in soft agar but migration was reduced. PAX3h increased cell proliferation, migration, survival, and transformation. These functional studies have advanced our understanding of the effects of PAX3 isoforms in melanocytes and their potential contribution in tumorigenesis