Precision Oncology, Artificial Intelligence, and Novel Therapeutic Advancements in the Diagnosis, Prevention, and Treatment of Cancer: Highlights from the 59th Irish Association for Cancer Research (IACR) Annual Conference.

Advancements in oncology, especially with the era of precision oncology, is resulting in a paradigm shift in cancer care. Indeed, innovative technologies, such as artificial intelligence, are paving the way towards enhanced diagnosis, prevention, and personalised treatments as well as novel drug discoveries. Despite excellent progress, the emergence of resistant cancers has curtailed both the pace and extent to which we can advance.

The Concise Guide to PHARMACOLOGY 2023/24: Enzymes.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.

Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability.

Background: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.

Objectives: We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.

Methods: We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease.

Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets.

Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC.

FK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility.

Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation.

Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype.

Macrophages are plastic cells playing a crucial role in innate immunity. While fundamental in responding to infections, when persistently maintained in a pro-inflammatory state they can initiate and sustain inflammatory diseases. Therefore, a strategy that reprograms pro-inflammatory macrophages toward an anti-inflammatory phenotype could hold therapeutic potential in that context.

Dexamethasone promotes breast cancer stem cells in obese and not lean mice.

Obesity is highly prevalent in breast cancer patients and is associated with increased recurrence and breast cancer-specific mortality. Glucocorticoids (GC) are used as an adjuvant in cancer treatment and are associated with promoting breast cancer metastasis through activation of stemness-related pathways. Therefore, we utilized the synergetic allograft E0771 breast cancer model to investigate if treatment with GCs had differential effects on promoting cancer stem cells in lean and diet-induced obese mice.

Characterizing and Exploiting Tumor Microenvironments to Optimize Treatment Outcomes.

Our understanding of cancer initiation, progression, and treatment is continually progressing through dedicated research achieved through laboratory investigation, clinical trials, and patient engagement. The importance and complexity of the microenvironment and its role in tumor development and behavior is pivotal to the understanding of tumor growth and the best course of treatment. The 57th Irish Association for Cancer Research (IACR) Annual Conference collected key researchers, clinicians, and patient advocates together to highlight and discuss the recognized importance of the microenvironment and treatment advances in cancer.

Effect of the Rehabilitation Program, ReStOre, on Serum Biomarkers in a Randomized Control Trial of Esophagogastric Cancer Survivors.

Background: The Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial.

Methods: Patients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education).

Educating pharmacy students through a pandemic: Reflecting on our COVID-19 experience.

The impact of the COVID-19 pandemic on pharmacy education worldwide has been immense, affecting students, educators and regulatory agencies. Pharmacy programmes have had to rapidly adapt in their delivery of education, maintaining standards while also ensuring the safety of all stakeholders. In this commentary, we describe the challenges, compromises and solutions adopted by our institution throughout the pandemic, the lessons learnt, adaptive measures taken, and strategies to develop and future-proof our curricula.

Non-viral gene delivery utilizing RALA modulates sFlt-1 secretion, important for preeclampsia.

Overexpression of sFlt-1 or modulation of FKBPL, key antiangiogenic proteins, are important in the pathogenesis of preeclampsia. A newly developed nonviral gene-delivery system, RALA, capable of overexpressing sFlt-1 (e15a isoform) was delivered in transgenic haploinsufficient () mice. RALA was also used to deliver human Flt1 (hFlt1) in trophoblast cells.

FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function.

Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail.

The Cancer Stem Cell Niche in Ovarian Cancer and Its Impact on Immune Surveillance.

Ovarian cancer is an aggressive gynaecological cancer with extremely poor prognosis, due to late diagnosis as well as the development of chemoresistance after first-line therapy. Research advances have found stem-like cells present in ovarian tumours, which exist in a dynamic niche and persist through therapy. The stem cell niche interacts extensively with the immune and non-immune components of the tumour microenvironment.

Prognostic Significance of Glucocorticoid Receptor Expression in Cancer: A Systematic Review and Meta-Analysis.

In solid malignancies, the glucocorticoid receptor (GR) signalling axis is associated with tumour progression and GR antagonists are in clinical development. Therefore, GR expression may be a useful potential prognostic or predictive biomarker for GR antagonist therapy in cancer. The aim of this review is to investigate if GR expression in tumours is predictive of overall survival or progression free survival.

Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages.

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation.

Rational design and characterisation of an amphipathic cell penetrating peptide for non-viral gene delivery.

RALA is a cationic amphipathic peptide which has shown great promise as an efficient, multifunctional delivery system for the delivery of nucleic acids. Rational peptide design was utilised in this study to understand the essential amino acids required for delivery and if any improvements to the RALA peptide could be made. Six amphipathic peptides were synthesised with strategic sequences and amino acid substitutions to reduce peptide sequence, while maintaining the functional characteristics of RALA including amphipathicity, alpha-helicity and pH responsiveness for endosomal escape.

Obesity and Cancer Metastasis: Molecular and Translational Perspectives.

Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival.

FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease.

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non-diabetic subjects with/without CVD, matched for age, BMI and gender.

FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention.

FK506 binding (FKBP) proteins are part of the highly conserved immunophilin family and its members have fundamental roles in the regulation of signalling pathways involved in inflammation, adaptive immune responses, cancer and developmental biology. The original member of this family, FKBP12, is a well-known binding partner for the immunosuppressive drugs tacrolimus (FK506) and sirolimus (rapamycin). FKBP12 and its analog, FKBP12.

Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment.

Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.

Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.

Design And Intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia.

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.

Background: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours.

Methods: In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting.

Delivery of RALA/siFKBPL nanoparticles via electrospun bilayer nanofibres: An innovative angiogenic therapy for wound repair.

FK506-binding protein-like (FKBPL) has previously been shown to inhibit angiogenesis viain vitro and in vivo experimentation. Thus, it was proposed that the delivery of a siRNA targeting FKBPL could hold great potential in promoting angiogenesis for advanced wound healing applications. An effective delivery system has been utilised to encapsulate the siFKBPL to form nanoparticles, thereby improving cellular entry and eliciting a potent angiogenic response.