ABSTRACT
Cancer-associated Thrombosis (CAT) is a common complication among patients with cancer which is associated with significant morbidity and mortality. The risk of CAT varies widely depending on cancer types and treatments and its cumulative incidence increases over time. Although patients with cancer have a high risk of developing venous thromboembolism, pharmacological thromboprophylaxis is not routinely recommended for ambulatory patients receiving chemotherapy but is suggested for those deemed as high-risk. Risk assessment models can help clinicians identify ambulatory patients at high risk who would most benefit from thromboprophylaxis with low molecular weight heparin or direct oral anticoagulants (apixaban or rivaroxaban). This narrative review will summarize the data on pharmacological thromboprophylaxis in ambulatory patients with cancer, provide further insights into the safety and efficacy of different anticoagulants, and suggest implementation methods using a multidisciplinary approach leading to an optimization of preventative strategies in this patient population.
Subject(s)
Neoplasms , Venous Thromboembolism , Anticoagulants , Heparin, Low-Molecular-Weight , Humans , IncidenceABSTRACT
INTRODUCTION/OBJECTIVES: The serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) is a co-regulator of an increasing number of transcription factors and cofactors involved in DNA damage response and development. We and others have cloned HIPK2 as an interactor of the p53 oncosuppressor, and have studied the role of this interaction in cell response to stress. Nevertheless, our original cloning of HIPK2 as a p53-binding protein, was aimed at discovering partners of p53 involved in cell differentiation and development, still controversial p53 functions. To this aim, we used p53 as bait in yeast two-hybrid screening of a cDNA library from mouse embryo (day 11 postcoitus) when p53 is highly expressed. METHODS AND RESULTS: In this study, we directly explored whether HIPK2 and p53 cooperate in cell differentiation. By measuring HIPK2 expression and activity in skeletal muscle and haemopoietic differentiation, we observed inverse behaviour of HIPK2 and p53--excluding cooperation activity of these two factors in this event. However, by HIPK2 depletion experiments, we showed that drastic HIPK2 suppression promotes cell-cycle arrest by induction of the cyclin-dependent kinase inhibitor p21(Waf-1/Cip-1). HIPK2 activity is independent of DNA damage and takes place in cell-cycle-arresting conditions, such as terminal differentiation, growth factor deprivation, and G(0) resting. CONCLUSIONS: HIPK2 was found to be involved in cell-cycle regulation dependent on p21(Waf-1/Cip-1) and independent of DNA damage.
Subject(s)
Carrier Proteins/physiology , Cell Proliferation , DNA Damage , Protein Serine-Threonine Kinases/physiology , Apoptosis/physiology , Base Sequence , Blotting, Western , Bone Marrow Cells/cytology , Carrier Proteins/genetics , Cell Differentiation , Cells, Cultured , DNA Primers , Humans , Muscle, Skeletal/cytology , Protein Serine-Threonine Kinases/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
In this study, we delineate the intracellular signalling pathways modulated by a conditional v-Src tyrosine kinase that lead to unrestrained proliferation and block of differentiation of primary avian myoblasts. By inhibiting Ras-MAPK kinase and phosphatidylinositol 3-kinase with different means, we find that both pathways play crucial roles in controlling v-Src-sustained growth factor and anchorage independence for proliferation. The Ras-MAPK kinase pathway also contributes to block of differentiation independently of cell proliferation since inhibition of this pathway both in proliferating and growth-arrested v-Src-transformed myoblasts induces expression of muscle-specific genes, fusion into multinucleated myotubes and assembly of specialized contractile structures. Importantly, we find that the p38 MAPK pathway is inhibited by v-Src in myoblasts and its forced activation results in growth inhibition and expression of differentiation, indicating p38 MAPK as a critical target of v-Src in growth transformation and myogenic differentiation. Furthermore, we show that downregulation of p38 MAPK activation may occur via Ras-MAPK kinase, thus highlighting a cross-regulation between the two pathways. Finally, we report that the simultaneous inhibition of MAPK kinase and calpain, combined to activation of p38 MAPK, are sufficient to reconstitute largely the differentiation potential of v-Src-transformed myoblasts.
Subject(s)
Cell Transformation, Neoplastic/genetics , Myoblasts, Skeletal/pathology , Oncogene Protein pp60(v-src)/physiology , Signal Transduction/genetics , Animals , Cell Adhesion/physiology , Cell Differentiation/physiology , Cell Line, Transformed , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Cells, Cultured , Chick Embryo , Mitogen-Activated Protein Kinase Kinases/physiology , Models, Biological , Myoblasts, Skeletal/metabolism , Phosphatidylinositol 3-Kinases/physiology , Proto-Oncogene Proteins p21(ras)/physiology , Quail , TransfectionABSTRACT
Antennapedia homeobox peptide has been reported to enhance neurite outgrowth and branching. Thus it is of interest to investigate whether antennapedia peptide is capable of modulating the expression of genes related to different events of neuronal development. In this paper we report the enhancement of a 68 KDa neurofilament subunit, choline acetyltransferase and acetylcholinesterase expression in spinal cord neurons, elicited by antennapedia peptide. Modulation of gene expression is different with respect to each gene product analyzed, suggesting a specific action of the peptide on diverse genes controlling different events of neuronal differentiation.
