High Expression of ENO1 and Low Levels of Circulating Anti-ENO1 Autoantibodies in Patients with Myelodysplastic Neoplasms and Acute Myeloid Leukaemia.

In solid tumours, high expression of the glycolytic enzyme, α-enolase (ENO1), predicts for poor patient overall survival (OS), and circulating autoantibodies to ENO1 correlate positively with diagnosis and negatively with advanced disease. Although ENO1 is one of the most highly expressed genes in acute myeloid leukaemia (AML), its potential role as a biomarker in AML or its precursor, myelodysplastic neoplasms (MDS), has not been investigated. A meta-analysis of nine AML online datasets (n = 1419 patients) revealed that high ENO1 expression predicts for poor OS (HR = 1.

Calcium/Calmodulin-Stimulated Protein Kinase II (CaMKII): Different Functional Outcomes from Activation, Depending on the Cellular Microenvironment.

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases widely expressed in many tissues that is capable of mediating diverse functional responses depending on its cellular and molecular microenvironment. This review briefly summarises current knowledge on the structure and regulation of CaMKII and focuses on how the molecular environment, and interaction with binding partner proteins, can produce different populations of CaMKII in different cells, or in different subcellular locations within the same cell, and how these different populations of CaMKII can produce diverse functional responses to activation following an increase in intracellular calcium concentration. This review also explores the possibility that identifying and characterising the molecular interactions responsible for the molecular targeting of CaMKII in different cells in vivo, and identifying the sites on CaMKII and/or the binding proteins through which these interactions occur, could lead to the development of highly selective inhibitors of specific CaMKII-mediated functional responses in specific cells that would not affect CaMKII-mediated responses in other cells.

Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia.

Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML.

Targeting the two-pore channel 2 in cancer progression and metastasis.

The importance of Ca signaling, and particularly Ca channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored.

PARP Inhibitors and Haematological Malignancies-Friend or Foe?

Since their introduction several years ago, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have become the standard of care for breast and gynaecological cancers with gene mutations. Given that PARPi act by exploiting defective DNA repair mechanisms within tumour cells, they should be ideally suited to combatting haematological malignancies where these pathways are notoriously defective, even though mutations are rare. To date, despite promising results in vitro, few clinical trials in humans for haematological malignancies have been performed, and additional investigation is required.

A Novel Role for Brain and Acute Leukemia Cytoplasmic (BAALC) in Human Breast Cancer Metastasis.

Brain and Acute Leukemia, Cytoplasmic (BAALC) is a protein that controls leukemia cell proliferation, differentiation, and survival and is overexpressed in several cancer types. The gene is located in the chromosomal region 8q22.3, an area commonly amplified in breast cancer and associated with poor prognosis.

Regulation of Multifunctional Calcium/Calmodulin Stimulated Protein Kinases by Molecular Targeting.

Multifunctional calcium/calmodulin-stimulated protein kinases control a broad range of cellular functions in a multitude of cell types. This family of kinases contain several structural similarities and all are regulated by phosphorylation, which either activates, inhibits or modulates their kinase activity. As these protein kinases are widely or ubiquitously expressed, and yet regulate a broad range of different cellular functions, additional levels of regulation exist that control these cell-specific functions.

Assessment of evidence for or against contributions of Chlamydia pneumoniae infections to Alzheimer's disease etiology.

Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aβ peptide may be part of the brain immune response have revived longstanding contention about the possibility of causal relationships between brain pathogens and Alzheimer's disease. Research has focused on infectious pathogens that may colonize the brain such as herpes simplex type I.

Glioblastoma Multiforme: An Overview of Emerging Therapeutic Targets.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in humans and has a very poor prognosis. The existing treatments have had limited success in increasing overall survival. Thus, identifying and understanding the key molecule(s) responsible for the malignant phenotype of GBM will yield new potential therapeutic targets.

The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention.

The importance of Ca signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca/CaM complex binds and activates a variety of enzymes, including members of the multifunctional Ca/calmodulin-stimulated protein kinase (CaMK) family.

Lipidomic profiling of extracellular vesicles derived from prostate and prostate cancer cell lines.

Background: Extracellular vesicles (EVs) are produced and secreted from most cells of the body and can be recovered in biological fluids. Although there has been extensive characterisation of the protein and nucleic acid component of EVs, their lipidome has received little attention and may represent a unique and untapped source of biomarkers for prostate cancer diagnosis and prognosis.

Methods: EVs were isolated from non-tumourigenic (RWPE1), tumourigenic (NB26) and metastatic (PC-3) prostate cell lines.

Extracellular vesicles with altered tetraspanin CD9 and CD151 levels confer increased prostate cell motility and invasion.

To facilitate intercellular communication, cells release nano-sized, extracellular vesicles (EVs) to transfer biological cargo to both local and distant sites. EVs are enriched in tetraspanins, two of which (CD9 and CD151) have altered expression patterns in many solid tumours, including prostate cancer, as they advance toward metastasis. We aimed to determine whether EVs from prostate cells with altered CD9 and CD151 expression could influence cellular behaviour and increase the metastatic capabilities of non-tumourigenic prostate cells.

The Role of DNA Repair Pathways in AML Chemosensitivity.

Background: Defects in DNA repair pathways are causal factors for a plethora of solid tumours, but are only just beginning to be explored in haematological malignancies. Genomic instability, including mutations in DNA sequences, chromosomal aneuploidy, translocations and gene amplifications contribute to the development and progression of AML. Prior DNA damaging agent exposure enhances the risk of developing AML, as does inheritance of genetic syndromes that involve alterations in DNA repair pathways.

The role of Ca-calmodulin stimulated protein kinase II in ischaemic stroke - A potential target for neuroprotective therapies.

Studies in multiple experimental systems show that Ca-calmodulin stimulated protein kinase II (CaMKII) is a major mediator of ischaemia-induced cell death and suggest that CaMKII would be a good target for neuroprotective therapies in acute treatment of stroke. However, as CaMKII regulates many cellular processes in many tissues any clinical treatment involving the inhibition of CaMKII would need to be able to specifically target the functions of ischaemia-activated CaMKII. In this review we summarise new developments in our understanding of the molecular mechanisms involved in ischaemia-induced CaMKII-mediated cell death that have identified ways in which such specificity of CaMKII inhibition after stroke could be achieved.

Ischaemia- and excitotoxicity-induced CaMKII-Mediated neuronal cell death: The relative roles of CaMKII autophosphorylation at T286 and T253.

Ischaemia/excitotoxicity produces persistent activation of CaMKII (Ca-calmodulin stimulated protein kinase II) that initiates cell death. This study investigated the involvement of CaMKII phosphorylation at T286 and T253 in producing this persistent activation. In T286A-αCaMKII transgenic mice that lack the ability to phosphorylate αCaMKII at T286, transient occlusion of the middle cerebral artery for 90 min resulted in no significant difference in infarct size compared to normal littermate controls.

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells.

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional kinase that controls a range of cellular functions, including proliferation, differentiation and apoptosis. The biological properties of CaMKII are regulated by multi-site phosphorylation. However, the role that CaMKII phosphorylation plays in cancer cell metastasis has not been examined.

Activation of protein phosphatase 2A in FLT3+ acute myeloid leukemia cells enhances the cytotoxicity of FLT3 tyrosine kinase inhibitors.

Constitutive activation of the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3), via co-expression of its ligand or by genetic mutation, is common in acute myeloid leukemia (AML). In this study we show that FLT3 activation inhibits the activity of the tumor suppressor, protein phosphatase 2A (PP2A). Using BaF3 cells transduced with wildtype or mutant FLT3, we show that FLT3-induced PP2A inhibition sensitizes cells to the pharmacological PP2A activators, FTY720 and AAL(S).

Excitotoxic stimulation of brain microslices as an in vitro model of stroke.

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As such, primary or 'neuronal-like' cell culture systems are commonly utilized. While these systems are relatively easy to work with, and are useful model systems in which various functional outcomes (such as cell death) can be readily quantified, the examined outcomes and pathways in cultured immature neurons (such as excitotoxicity-mediated cell death pathways) are not necessarily the same as those observed in mature brain, or in intact tissue.

Dephosphorylation of CaMKII at T253 controls the metaphase-anaphase transition.

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional serine/threonine protein kinase that controls a range of cellular functions, including proliferation. The biological properties of CaMKII are regulated by multi-site phosphorylation and targeting via interactions with specific proteins. To investigate the role specific CaMKII phosphorylation sites play in controlling cell proliferation and cell cycle progression, we examined phosphorylation of CaMKII at two sites (T253 and T286) at various stages of the cell cycle, and also examined the effects of overexpression of wild-type (WT), T286D phosphomimic, T253D phosphomimic and T253V phosphonull forms of CaMKIIα in MDA-MB-231 breast cancer and SHSY5Y neuroblastoma cells on cellular proliferation and cell cycle progression.

αCaMKII is differentially regulated in brain regions that exhibit differing sensitivities to ischemia and excitotoxicity.

Different brain regions exhibit differing sensitivities to ischemia/excitotoxicity. Whether these differences are due to perfusion or intrinsic factors has not been established. Herein, we found no apparent association between sensitivity to ischemia/excitotoxicity and the level of expression or basal phosphorylation of calcium/calmodulin-stimulated protein kinase II (αCaMKII) or glutamate receptors.

The role of molecular regulation and targeting in regulating calcium/calmodulin stimulated protein kinases.

Calcium/calmodulin-stimulated protein kinases can be classified as one of two types - restricted or multifunctional. This family of kinases contains several structural similarities: all possess a calmodulin binding motif and an autoinhibitory region. In addition, all of the calcium/calmodulin-stimulated protein kinases examined in this chapter are regulated by phosphorylation, which either activates or inhibits their kinase activity.

Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II.

Many studies have implicated Ca²+ and calmodulin (CaM) as regulators of the cell cycle. Ca²+/CaM-stimulated proteins, including the family of multifunctional Ca²+/CaM-stimulated protein kinases (CaMK), have also been identified as mediators of cell cycle progression. CaMKII is the best-characterized member of this family, and is regulated by multi-site phosphorylation and targeting.

Enhanced oncolysis mediated by Coxsackievirus A21 in combination with doxorubicin hydrochloride.

Virotherapy is an emerging strategy for the treatment of cancer that utilizes both replication-competent and genetically modified viruses to selectively kill tumor cells. We have previously shown that Coxsackievirus A21 (CVA21), a common-cold producing enterovirus, is an effective oncolytic agent against human melanoma, prostate, and breast cancer xenografts in vivo. CVA21 specifically targets and lytically infects susceptible cells expressing the CVA21 cellular receptors, intercellular adhesion molecule-1 (ICAM-1) and decay-accelerating factor (DAF).

Regulation of CaMKII by phospho-Thr253 or phospho-Thr286 sensitive targeting alters cellular function.

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is an important mediator of synaptic function that is regulated by multi-site phosphorylation and targeting through interactions with proteins. A new phosphorylation site at Thr253 has been identified in vivo, that does not alter CaMKII activity, but does alter CaMKII function through interactions with binding proteins. To identify these proteins, as well as to examine the specific effects following Thr253 or Thr286 phosphorylation on these interactions, we developed an in vitro overlay binding assay.

Regulation of CaMKII in vivo: the importance of targeting and the intracellular microenvironment.

CaMKII (calcium/calmodulin-stimulated protein kinase II) is a multifunctional protein kinase that regulates normal neuronal function. CaMKII is regulated by multi-site phosphorylation, which can alter enzyme activity, and targeting to cellular microdomains through interactions with binding proteins. These proteins integrate CaMKII into multiple signalling pathways, which lead to varied functional outcomes following CaMKII phosphorylation, depending on the identity and location of the binding partner.