Bone marrow senescence and the microenvironment of hematological malignancies

Senescence is the irreversible arrest of cell proliferation that has now been shown to play an important role in both health and disease. With increasing age senescent cells accumulate throughout the body, including the bone marrow and this has been associated with a number of age-related pathologies including malignancies. It has been shown that the senescence associated secretory phenotype (SASP) creates a pro-tumoural environment that supports proliferation and survival of malignant cells. Understanding the role of senescent cells in tumor development better may help us to identify new treatment targets to impair tumor survival and reduce treatment resistance. In this review, we will specifically discuss the role of senescence in the aging bone marrow (BM) microenvironment. Many BM disorders are age-related diseases and highly dependent on the BM microenvironment. Despite advances in drug development the prognosis particularly for older patients remains poor and new treatment approaches are needed to improve outcomes for patients. In this review, we will focus on the relationship of senescence and hematological malignancies, how senescence promotes cancer development and how malignant cells induce senescence

Front-line glioblastoma chemotherapeutic temozolomide is toxic to Trypanosoma brucei and potently enhances melarsoprol and eflornithine

Sleeping sickness is an infectious disease that is caused by the protozoan parasite Trypanosoma brucei. The second stage of the disease is characterised by the parasites entering the brain. It is therefore important that sleeping sickness therapies are able to cross the blood-brain barrier. At present, only three medications for chemotherapy of the second stage of the disease are available. As these trypanocides have serious side effects and are difficult to administer, new and safe anti-trypanosomal brain-penetrating drugs are needed. For these reasons, the anti-glioblastoma drug temozolomide was tested in vitro for activity against bloodstream forms of T. brucei. The concentration of the drug required to reduce the growth rate of the parasites by 50% was 29.1 μM and to kill all trypanosomes was 125 μM. Importantly, temozolomide did not affect the growth of human HL-60 cells up to a concentration of 300 μM. Cell cycle analysis revealed that temozolomide induced DNA damage and subsequent cell cycle arrest in trypanosomes exposed to the compound. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, the interactions of temozolomide with the trypanocides eflornithine and melarsoprol, respectively, was determined. Both combinations were found to produce an additive effect. In conclusion, these results together with well-established pharmacokinetic data provide the basis for in vivo studies and potentially for clinical trials of temozolomide in the treatment of T. brucei infections and a rationale for its use in combination therapy, particularly with eflornithine or melarsoprol

Embedding Outreach into the Undergraduate Science Curriculum – Everyone's a Winner

This article summarizes the authors' experience of developing and delivering undergraduate modules in Science Communication. The modules address two needs: resourcing science outreach activities for children in Years 5-7, and developing transferable skills (oral and written communication, team working, time management) to enhance student employability and engagement.Keywords:  Employability, outreach, transferable skill

Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

The Role of PI3K Isoforms in Regulating Bone Marrow Microenvironment Signaling Focusing on Acute Myeloid Leukemia and Multiple Myeloma

Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of various blood cancers, less is understood about the complex microenvironment of the bone marrow (BM), which is known to be a key player in the pathogenesis of chronic lymphocytic leukaemia (CLL), AML and MM. This niche acts as a sanctuary for the cancerous cells, protecting them from chemotherapeutics and encouraging clonal cell survival. It does this by upregulating a plethora of signalling cascades within the malignant cell, with the phosphatidylinositol-3-kinase (PI3K) pathway taking a critical role. This review will focus on how the PI3K pathway influences disease progression and the individualised role of the PI3K subunits. We will also summarise the current clinical trials for PI3K inhibitors and how these trials impact the treatment of blood cancers

Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL

Nuclear magnetic resonance applied to problems of molecular motion in solids

The discovery of nuclear magnetic resonance in bulk matter in 1945 has led to advances in several branches of physics. One of the most interesting applications of these new techniques has been to problems of the solid state, where information about molecular motion and thermal relaxation effects can be obtained. It is with this field of research that the nuclear magnetic resonance absorption experiments reported in this thesis are concerned. The general theory of nuclear magnetic absorption is developed first and the relevant apparatus and experiment methods are then described. The design and performance of a large permanent magnet made especially for nuclear resonance work is considered and experiments on suitable solids are reported and discussed in the final section

Effects of temperature on the β-phase depletion in MCrAlYs: a modelling and experimental study towards designing new bond coat alloys

This paper investigates the effects of varied temperature conditions on the kinetics of β-phase depletion in MCrAlYs by DICTRA diffusion simulations and experimental observations. A commercially available MCrAlY composition and two modelled compositions were examined at temperature regimes of 1000 °C, 1100 °C and 1200 °C. A previously developed temperature-dependent oxidation model was used at the boundary to examine the β-phase depletion kinetics at different temperatures. The oxide growth kinetics and the corresponding Al flux were calculated based on the oxidation model. The MCrAlY phase equilibrium calculations were conducted in Thermo-Calc and the oxidation-diffusion simulations were carried out using the finite difference diffusion software, DICTRA. It was found that the MCrAlYs exhibit a predominantly dual-phase γ + β structure at 1000 °C and above. It was revealed that varying the temperature had a strong effect on the β-phase depletion in low Al-content MCrAlYs from DICTRA simulations and available experimental measurements. In addition, it was demonstrated from the diffusion simulations that MCrAlYs with high Al content exhibit an enhanced lifetime in maintaining the two-phase structure with less β-phase depletion at high temperatures due to the high Al and β-phase content