In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized.
View Article and Find Full Text PDFPolymerase chain reaction (PCR) has proven to be the gold-standard for SARS-CoV-2 detection in clinical settings. The most common approaches rely on nasopharyngeal specimens obtained from swabs, followed by RNA extraction, reverse transcription and quantitative PCR. Although swab-based PCR is sensitive, swabbing is invasive and unpleasant to administer, reducing patient compliance for regular testing and resulting in an increased risk of improper sampling.
View Article and Find Full Text PDFThe protein kinase C (PKC) family of serine/threonine kinases are pleiotropic signaling regulators and are implicated in hematopoietic signaling and development. Only one isoform however, PKCϵ, has oncogenic properties in solid cancers where it is associated with poor outcomes. Here we show that PKCϵ protein is significantly overexpressed in acute myeloid leukemia (AML; 37% of patients).
View Article and Find Full Text PDFSince mid-2020 there have been complexities and difficulties in the standardisation and administration of nasopharyngeal swabs. Coupled with the variable and/or poor accuracy of lateral flow devices, this has led to increased societal 'testing fatigue' and reduced confidence in test results. Consequently, asymptomatic individuals have developed reluctance towards repeat testing, which remains the best way to monitor COVID-19 cases in the wider population.
View Article and Find Full Text PDFThe COVID-19 pandemic, which began in 2020 is testing economic resilience and surge capacity of healthcare providers worldwide. At the time of writing, positive detection of the SARS-CoV-2 virus remains the only method for diagnosing COVID-19 infection. Rapid upscaling of national SARS-CoV-2 genome testing presented challenges: (1) Unpredictable supply chains of reagents and kits for virus inactivation, RNA extraction and PCR-detection of viral genomes.
View Article and Find Full Text PDFRecent advances in treatment options for multiple myeloma (MM) have positive impact on patient survival. However, there is a short fall of rapid and reliable assays that can predict patient response to novel agents. The anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1), are necessary for MM survival, although most myelomas are more dependent on MCL-1.
View Article and Find Full Text PDFMutations in the highly similar genes B-cell translocation gene 1 () and are identified in approximately 10-15% of non-Hodgkin lymphoma cases, which may suggest a direct involvement of and in malignant transformation. However, it is unclear whether or how disease-associated mutations impair the function of these genes. Therefore, we selected 16 BTG1 variants based on analysis.
View Article and Find Full Text PDFBackground: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells.
View Article and Find Full Text PDFAcute myeloid leukaemia (AML) is a heterogeneous clonal malignancy of hematopoietic progenitor cells. The Wnt pathway and its downstream targets are tightly regulated by β-catenin. We recently discovered a new protein, FLYWCH1, which can directly bind nuclear β-catenin.
View Article and Find Full Text PDFAcute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL-1 can cause resistance. A co-operative approach, targeting both BCL-2 and MCL-1 may therefore prove beneficial.
View Article and Find Full Text PDF: Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and preinvasive ductal carcinoma (DCIS) are desirable.
View Article and Find Full Text PDFCells from patients with acute myeloid leukemia (AML) that remain dormant and protected by stromal cells may escape effects of chemotherapy. We modeled dormancy in vitro and investigated the ability of Bcl-2 inhibitors ABT-199 and ABT-737 to overcome chemoprotection of dormant cells. CD34-enriched primary AML cells with aberrant leukemia-associated phenotypes (LAPs) were cultured on stromal cells.
View Article and Find Full Text PDFDormant leukaemia initiating cells in the bone marrow niche are a crucial therapeutic target for total eradication of acute myeloid leukaemia. To study this cellular subset we created and validated an model employing the cell line TF-1a, treated with Transforming Growth Factor β1 (TGFβ1) and a mammalian target of rapamycin inhibitor. The treated cells showed decreases in total RNA, Ki-67 and CD71, increased aldehyde dehydrogenase activity, forkhead box 03A (FOX03A) nuclear translocation and growth inhibition, with no evidence of apoptosis or differentiation.
View Article and Find Full Text PDFThe BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide.
View Article and Find Full Text PDFIntroduction: Women with polycystic ovary syndrome have a three-fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein-1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein-1 gene expression with serum lipid profiles.
View Article and Find Full Text PDFDirect co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells.
View Article and Find Full Text PDFBackground: Endometrial cancer (EC) is the most common gynaecological cancer amongst women in the UK. Although previous studies have found that women with polycystic ovary syndrome (PCOS) have at least a three-fold increase in endometrial cancer (EC) risk compared to women without PCOS, the precise molecular mechanisms which link between PCOS and EC remain unclear. It has been suggested that insulin resistance may contribute to the increased risk of EC in PCOS.
View Article and Find Full Text PDFThe aim of this proof-of-concept study was to determine the effects of three-month Metformin therapy on the expression of tumor-regulatory genes (p53, cyclin D2 and BCL-2) in the endometrium of women with polycystic ovary syndrome (PCOS). A total of 40 women, aged between 21 and 45 years with PCOS (Rotterdam criteria) were recruited. The participants were assessed at pre- and 3-month-post-Metformin therapy for the menstrual regularities, weight reduction, Ferriman Galway scores, fasting blood glucose (FBG), total cholesterol, LDL, HDL and p53, BCL-2 and cyclin D2 gene expression.
View Article and Find Full Text PDFBRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n = 1602 sporadic and n = 50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n = 1952 and n = 249).
View Article and Find Full Text PDFPhosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease activity.
View Article and Find Full Text PDFRegulation of ABCB1 (P-glycoprotein/Pgp) in AML was investigated. In a historical cohort with Pgp and transcriptional regulator expression profiling data available (n=141), FOXO1 correlated with Pgp protein expression. This was confirmed in an independent cohort (n=204).
View Article and Find Full Text PDFCurrent data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis.
View Article and Find Full Text PDFBackground: Dormant cells are characterised by low RNA synthesis. In contrast, cancer cells can be addicted to high RNA synthesis, including synthesis of survival molecules. We hypothesised that dormant cancer cells, already low in RNA, might be sensitive to apoptosis induced by RNA Polymerase II (RP2) inhibitors that further reduce RNA synthesis.
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