A Novel In Vitro Model of the Bone Marrow Microenvironment in Acute Myeloid Leukemia Identifies CD44 and Focal Adhesion Kinase as Therapeutic Targets to Reverse Cell Adhesion-Mediated Drug Resistance.

Background/objectives: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential.

Classification of epidermal, buccal, penile and vaginal epithelial cells using morphological characteristics measured by imaging flow cytometry.

As a result of the increased sensitivity of forensic DNA techniques, which can generate informative results from as little as a few cells, developing an understanding of the anatomical region these cells originate from is becoming more pertinent. Imaging Flow Cytometry (IFC) represents a promising method for identifying epithelial cells from different anatomical regions. This project aimed to determine whether IFC could be used to distinguish epithelial cells collected from different forensically relevant anatomical regions based on their morphology and autofluorescence.

CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer.

Background: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates.

Methods: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry.

Increased flushing frequency of a model plumbing system initially promoted the formation of viable but non culturable cells but ultimately reduced the concentration of culturable and total DNA.

is the causative agent of Legionnaires' disease, and its prevalence in potable water is a significant public health issue. Water stagnation within buildings increases the risk of However, there are limited studies investigating how stagnation arising through intermittent usage affects proliferation and the studies that are available do not consider viable but non culturable (VBNC) . This study used a model plumbing system to examine how intermittent water stagnation affects both VBNC and culturable .

Benzalkonium chloride disinfectant residues stimulate biofilm formation and increase survival of bacterial pathogens.

spp. are opportunistic human and animal pathogens found ubiquitously in marine environments. Globally, there is a predicted rise in the prevalence of spp.

The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells .

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR).

Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non-infectious uveitis.

Characterised by intraocular inflammation, non-infectious uveitis includes a large group of autoimmune and autoinflammatory diseases that either involve the eye alone or have both ocular and systemic manifestations. When non-infectious uveitis involves the posterior segment of the eye, specifically the retina, there is substantial risk of vision loss, often linked to breakdown of the inner blood-retinal barrier. This barrier is formed by non-fenestrated retinal vascular endothelial cells, reinforced by supporting cells that include pericytes, Müller cells and astrocytes.

The effect of HYPE knock-out on the AMPylome of human OSU-CLL leukemia cells.

In humans, AMPylation of cellular proteins is carried out by Huntingtin yeast-interacting protein E (HYPE), activated under conditions of endoplasmic reticulum stress, such as in cancer cells. Extracts of the human chronic lymphocytic leukemia cell line, OSU-CLL, were fractionated using immuno-precipitation with antibodies against adenosine-phosphate and then AMP-Tyr. The proteins isolated were modified with AMP, the 'AMPylome.

Effects of tumor necrosis factor-α and interleukin-1β on human retinal endothelial cells.

Uveitis, or intraocular inflammation, is a potentially blinding condition that mostly affects the working-age population. The cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, play a role in the pathogenesis of non-infectious uveitis and have been linked to the breakdown of the inner blood-retinal barrier, composed mainly of retinal endothelial cells, leading to macular oedema and vascular leakage. However, the effects of TNF-α and IL-1β on human retinal endothelial function are not fully understood.

Stagnation arising through intermittent usage is associated with increased viable but non culturable and amoeba hosts in a hospital water system.

Hospital water systems are a significant source of , resulting in the potentially fatal Legionnaires' disease. One of the biggest challenges for management within these systems is that under unfavorable conditions transforms itself into a viable but non culturable (VBNC) state that cannot be detected using the standard methods. This study used a novel method (flow cytometry-cell sorting and qPCR [VFC+qPCR] assay) concurrently with the standard detection methods to examine the effect of temporary water stagnation, on spp.

Human retinal endothelial cells express functional interleukin-6 receptor.

Background: Interleukin (IL)-6 is an inflammatory cytokine present in the eye during non-infectious uveitis, where it contributes to the progression of inflammation. There are two major IL-6 signaling pathways: classic signaling and trans-signaling. Classic signaling requires cellular expression of the IL-6 receptor (IL-6R), which exists in membrane-bound (mIL-6R) and soluble (sIL-6R) forms.

Detection and quantification of viable but non-culturable from water samples using flow cytometry-cell sorting and quantitative PCR.

is a waterborne pathogen and, as the causative agent of Legionnaires' disease, a significant public health concern. Exposure to environmental stresses, and disinfection treatments, promotes the formation of resistant and potentially infectious viable but non-culturable (VBNC) . The management of engineered water systems to prevent Legionnaires' disease is hindered by the presence of VBNC that cannot be detected using the standard culture (ISO11731:2017-05) and quantitative polymerase reaction (ISO/TS12869:2019) methods.

Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines.

Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells.

Microbial disruption in the gut promotes cerebral endothelial dysfunction.

Cerebrovascular disease is a group of conditions characterized by disorders of the cerebral vessels. Endothelial dysfunction renders the vasculature at risk of impaired blood flow and increases the potential of developing cerebrovascular disease. The gut microbiota has been recently identified as a possible risk factor of cerebrovascular disease.

Insight into del17p low-frequency subclones in chronic lymphocytic leukaemia (CLL): data from the Australasian Leukaemia and Lymphoma Group (ALLG)/CLL Australian Research Consortium (CLLARC) CLL5 trial.

The clinical significance of low-frequency deletions of 17p13 [tumour protein p53 (TP53)] in patients with chronic lymphocytic leukaemia (CLL) is currently unclear. Low-frequency del17p clones (<25%) were identified in 15/95 patients in the Australasian Leukaemia and Lymphoma Group (ALLG)/CLL Australian Research Consortium (CLLARC) CLL5 trial. Patients with low del17p, without tumour protein p53 (TP53) mutation, had significantly longer progression-free survival and overall survival durations than patients with high del17p clones.

IBL-202 is synergistic with venetoclax in CLL under in vitro conditions that mimic the tumor microenvironment.

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system.

Combination of the dual PIM/PI3-kinase inhibitor IBL-202 and venetoclax is effective in diffuse large B-cell lymphoma.

Current chemoimmunotherapy is unable to cure up to 40% of patients diagnosed with diffuse large B-cell lymphoma (DLBCL). Targeting the mechanisms by which DLBCL evades apoptosis is crucial to overcoming treatment failure in this heterogeneous disease as both current and novel treatments depend on the apoptosis of malignant cells. Despite the common overexpression of BCL-2, venetoclax is ineffective in DLBCL due to MCL-1 co-expression.

Molecular pathogenesis of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL.

Dual inhibition of MEK1/2 and AKT by binimetinib and MK2206 induces apoptosis of chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment.

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line.

The dual inhibitor of the phosphoinositol-3 and PIM kinases, IBL-202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment.

Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases.

Expression of Intracellular Reactive Oxygen Species in Hematopoietic Stem Cells Correlates with Time to Neutrophil and Platelet Engraftment in Patients Undergoing Autologous Bone Marrow Transplantation.

Reactive oxygen species (ROS) play important roles in hematopoiesis and regulate the self-renewal, migration, and myeloid differentiation of hematopoietic stem cells (HSCs). This study was conducted to determine whether ROS levels in donor HSCs correlate with neutrophil and platelet engraftment in patients after bone marrow transplantation. Cryopreserved HSC samples from 51 patients who underwent autologous transplantation were studied.

MEK1/2 inhibition by binimetinib is effective as a single agent and potentiates the actions of Venetoclax and ABT-737 under conditions that mimic the chronic lymphocytic leukaemia (CLL) tumour microenvironment.

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment.