Characterization of a water soluble quininib prodrug that blocks metabolic activity and proliferation of multiple cancer cell lines.

Quininib is a small molecule antagonist of cysteinyl leukotriene receptor 1 (CysLT), which is increasingly recognized for its role in cancer progression. Overexpression of CysLT has been documented in colorectal cancer, renal cell carcinoma, breast cancer, and uveal melanoma (UM). However, quininib's poor aqueous solubility presents a significant barrier to its clinical development.

Translating Basic Science Discoveries into Clinical Advances: Highlights from the EACR-AACR-IACR 2024 Conference in Celebration of Irish Association for Cancer Research's 60th Anniversary.

The EACR-AACR-IACR 2024 Basic and Translational Research Conference, held in Dublin, Ireland, from 27th-29th February, 2024, marked a significant milestone as part of the 60th anniversary celebrations of the Irish Association for Cancer Research (IACR). Organized in collaboration with the European Association for Cancer Research (EACR) and the American Association for Cancer Research (AACR), this prestigious event brought together leading experts in oncology research from around the world. The conference provided a platform for cutting-edge discussions on the latest advancements in immunotherapy, drug combinations, cell-based therapies, liquid biopsies, epigenetics, tumour microenvironment, and novel drug targets.

Multi-omic biomarker panel in pancreatic cyst fluid and serum predicts patients at a high risk of pancreatic cancer development.

Integration of multi-omic data for the purposes of biomarker discovery can provide novel and robust panels across multiple biological compartments. Appropriate analytical methods are key to ensuring accurate and meaningful outputs in the multi-omic setting. Here, we extensively profile the proteome and transcriptome of patient pancreatic cyst fluid (PCF) (n = 32) and serum (n = 68), before integrating matched omic and biofluid data, to identify biomarkers of pancreatic cancer risk.

Targeting Radiation Resistance in Oesophageal Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles.

Unlabelled: Only 20-30% of oesophageal adenocarcinoma (OAC) patients achieve a complete response to neoadjuvant chemo-radiotherapy for locally advanced tumours. Enhancing the response to radiation therapy is critical for improving outcomes in this aggressive cancer. Pyrazinib (P3) is a promising compound with radiosensitizing, anti-angiogenic, anti-inflammatory, and anti-metabolic properties.

Identification of druggable targets from the interactome of the Androgen Receptor and Serum Response Factor pathways in prostate cancer.

Background: The Androgen Receptor (AR) pathway is crucial in driving the progression of prostate cancer (PCa) to an advanced state. Despite the introduction of second-generation AR antagonists, such as enzalutamide, majority of patients develop resistance. Several mechanisms of resistance have been identified, including the constitutive activation of the AR pathway, the emergence of AR spliced variants, and the influence of other signalling pathways.

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.

Ergolide mediates anti-cancer effects on metastatic uveal melanoma cells and modulates their cellular and extracellular vesicle proteomes.

Background: Uveal melanoma is a poor prognosis cancer. Ergolide, a sesquiterpene lactone isolated from , exerts anti-cancer properties. The objective of this study was to evaluate whether ergolide reduced metastatic uveal melanoma (MUM) cell survival/viability and ; and to understand the molecular mechanism of ergolide action.

Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients.

Background: The results of Aspirin prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP) are controversial.

Methods: We conducted a biomarker-based clinical study in eight FAP patients treated with enteric-coated low-dose Aspirin (100 mg daily for three months) to explore whether the drug targets mainly platelet cyclooxygenase (COX)-1 or affects extraplatelet cellular sources expressing COX-isozymes and/or off-target effects in colorectal adenomas.

Results: In FAP patients, low-dose Aspirin-acetylated platelet COX-1 at Serine529 (>70%) was associated with an almost complete inhibition of platelet thromboxane (TX) B generation ex vivo (serum TXB).

Tumor-Educated Platelet Extracellular Vesicles: Proteomic Profiling and Crosstalk with Colorectal Cancer Cells.

Background: Platelet-cancer cell interactions modulate tumor metastasis and thrombosis in cancer. Platelet-derived extracellular vesicles (EVs) can contribute to these outcomes.

Methods: We characterized the medium-sized EVs (mEVs) released by thrombin-stimulated platelets of colorectal cancer (CRC) patients and healthy subjects (HS) on the capacity to induce epithelial-mesenchymal transition (EMT)-related genes and cyclooxygenase (COX)-2(), and thromboxane (TX)B production in cocultures with four colorectal cancer cell lines.

Prognostic, Diagnostic and Predictive Biomarkers in the Barrett's Oesophagus-Adenocarcinoma Disease Sequence.

Oesophageal adenocarcinoma (OAC) incidence has increased dramatically in the developed world, yet outcomes remain poor. Extensive endoscopic surveillance programs among patients with Barrett's oesophagus (BO), the precursor lesion to OAC, have aimed to both prevent the development of OAC via radiofrequency ablation (RFA) and allow earlier detection of disease. However, given the low annual progression rate and the costs of endoscopy/RFA, improvement is needed.

Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor.

Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms.

Gold nanoparticles and obese adipose tissue microenvironment in cancer treatment.

The epidemiological correlation between obesity and cancer is well characterized, but the biological mechanisms which regulate tumor development and response to therapy in obese cancer patients remain unclear. The tumor microenvironment plays an important role in protecting cancer cells by altering the delivery of anticancer therapy to the tumor tissue, reducing the efficacy of treatment. Obese tumor microenvironment provides additional benefits to the survival of tumor cells against anticancer therapies by altering the extracellular matrix composition, angiogenesis processes and the immune cells profile.

Proteome and functional decline as platelets age in the circulation.

Background: Platelets circulate in the blood of healthy individuals for approximately 7-10 days regulated by finely balanced processes of production and destruction. As platelets are anucleate we reasoned that their protein composition would change as they age and that this change would be linked to alterations in structure and function.

Objective: To isolate platelets of different ages from healthy individuals to test the hypothesis that changes in protein content cause alterations in platelet structure and function.

Extracellular vesicles from monocyte/platelet aggregates modulate human atherosclerotic plaque reactivity.

Extracellular vesicles (EVs) are emerging as key players in different stages of atherosclerosis. Here we provide evidence that EVs released by mixed aggregates of monocytes and platelets in response to TNF-α display pro-inflammatory actions on endothelial cells and atherosclerotic plaques. Tempering platelet activation with Iloprost, Aspirin or a P2Y inhibitor impacted quantity and phenotype of EV produced.

Proteomic signatures of radioresistance: Alteration of inflammation, angiogenesis and metabolism-related factors in radioresistant oesophageal adenocarcinoma.

The clinical management of locally advanced oesophageal adenocarcinoma (OAC) involves neoadjuvant chemoradiotherapy (CRT), but as radioresistance remains a major clinical challenge, complete pathological response to CRT only occurs in 20-30% of patients. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radioresistance to identify novel molecular and cellular targets of radioresistance in OAC. A total of 5785 proteins were identified of which 251 were significantly modulated in OE33R cells, when compared to OE33P.

Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response.

Radiotherapy is a regimen that uses ionising radiation (IR) to treat cancer. Despite the availability of several therapeutic options, cancer remains difficult to treat and only a minor percentage of patients receiving radiotherapy show a complete response to the treatment due to development of resistance to IR (radioresistance). Therefore, radioresistance is a major clinical problem and is defined as an adaptive response of the tumour to radiation-induced damage by altering several cellular processes which sustain tumour growth including DNA damage repair, cell cycle arrest, alterations of oncogenes and tumour suppressor genes, autophagy, tumour metabolism and altered reactive oxygen species.

Platelet-Derived Microparticles From Obese Individuals: Characterization of Number, Size, Proteomics, and Crosstalk With Cancer and Endothelial Cells.

Obesity is a risk factor for atherothrombosis and various cancers. However, the mechanisms are not yet completely clarified. We aimed to verify whether the microparticles (MPs) released from thrombin-activated platelets differed in obese and non-obese women for number, size, and proteomics cargo and the capacity to modulate the expression of (i) genes related to the epithelial to mesenchymal transition (EMT) and the endothelial to mesenchymal transition (EndMT), and (ii) cyclooxygenase (COX)-2 involved in the production of angiogenic and inflammatory mediators.

15-Deoxy-Δ-Prostaglandin J Modifies Components of the Proteasome and Inhibits Inflammatory Responses in Human Endothelial Cells.

15-Deoxy-Δ-prostaglandin J (15d-PGJ) is an electrophilic lipid mediator derived from PGD with potent anti-inflammatory effects. These are likely to be due to the covalent modification of cellular proteins, a reactive α,β-unsaturated carbonyl group in its cyclopentenone ring. This study was carried out to identify novel cellular target(s) for covalent modification by 15d-PGJ and to investigate the anti-inflammatory effects of the prostaglandin on endothelial cells (EC).

Milk-derived bioactive peptides and their health promoting effects: a potential role in atherosclerosis.

Bioactive peptides derived from milk proteins are food components that, in addition to their nutritional value, retain many biological properties and have therapeutic effects in several health disorders, including cardiovascular disease. Amongst these, atherosclerosis is the underlying cause of heart attack and strokes. It is a progressive dyslipidaemic and inflammatory disease where accumulation of oxidized lipids and inflammatory cells leads to the formation of an atherosclerotic plaque in the vessel wall.

Conjugated linoleic acid induces an atheroprotective macrophage MΦ2 phenotype and limits foam cell formation.

Background: Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds.

Milk-derived bioactive peptides inhibit human endothelial-monocyte interactions via PPAR-γ dependent regulation of NF-κB.

Background: Milk-derived bioactive peptides retain many biological properties and have therapeutic effects in cardiovascular disorders such as atherosclerosis. Under inflammatory conditions the expression of endothelial cells adhesion molecules is induced, increasing monocyte adhesion to human vessel wall, a critical step in the pathogenesis of atherosclerosis. In the present work we explored the effects of milk-derived bioactive peptides on the expression of the inflammatory phenotype of human endothelial cells and their effects on monocyte adherence to endothelial cells.

Conjugated linoleic acid targets β2 integrin expression to suppress monocyte adhesion.

Chronic recruitment of monocytes and their subsequent migration through the activated endothelium contribute to atherosclerotic plaque development. Integrin-mediated leukocyte adhesion is central to this process. Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis via modulation of monocyte/macrophage function.

Proteomic identification of the candidate target proteins of 15-deoxy-delta12,14-prostaglandin J2.

15-Deoxy-delta12, 14-prostaglandin J(2) (15d-PGJ(2)) is an endogenous anti-inflammatory lipid derived from PGD(2). One potential mechanism for its activity is the covalent modification of cellular proteins, via a reactive α,β-unsaturated carbonyl group in its cyclopentenone ring, which in turn alters protein function. In order to identify the candidate target proteins covalently modified by 15d-PGJ(2) in human aortic endothelial cell (EC), EC was treated with biotinylated-15d-PGJ(2), the modified proteins extracted by Neutravidin affinity-purification and the proteins identified by LTQ Orbitrap mass spectrometer.

Proteomics: bases for protein complexity understanding.

In the post genomic era we became aware that the genomic sequence and protein functions cannot be correlated. One gene can encode multiple protein functions mainly because of mRNA splice variants, post translational modifications (PTM) and moonlighting functions. To study the whole population of proteins present in a cell to a specific time point and under defined conditions it is necessary to investigate the proteome.

The anti-inflammatory prostaglandin 15-deoxy-delta(12,14)-PGJ2 inhibits CRM1-dependent nuclear protein export.

The signaling molecule 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been described as the "anti-inflammatory prostaglandin." Here we show that substrates of the nuclear export receptor CRM1 accumulate in the nucleus in the presence of 15d-PGJ(2), identifying this prostaglandin as a regulator of CRM1-dependent nuclear protein export that can be produced endogenously. Like leptomycin B (LMB), an established fungal CRM1-inhibitor, 15d-PGJ(2) reacts with a conserved cysteine residue in the CRM1 sequence.