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. RESULTS: Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity through reduced plasminogen activator inhibitor 1 activity. Macrophage polarization or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and activated protein C generation compared with macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice. CONCLUSION: Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thromboinflammatory disease.

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.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

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. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.

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. Thus, in this study, we investigated-for the first time-FKBPL's role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p < 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p < 0.01-0.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p < 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p < 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF.

Precision Medicine and Novel Therapeutic Strategies in Detection and Treatment of Cancer: Highlights from the 58th IACR Annual Conference.

Innovation in both detection and treatment of cancer is necessary for the constant improvement in therapeutic strategies, especially in patients with novel or resistant variants of cancer. Cancer mortality rates have declined by almost 30% since 1991, however, depending on the cancer type, acquired resistance can occur to varying degrees. To combat this, researchers are looking towards advancing our understanding of cancer biology, in order to inform early detection, and guide novel therapeutic approaches. Through combination of these approaches, it is believed that a more complete and thorough intervention on cancer can be achieved. Here, we will discuss the advances and approaches in both detection and treatment of cancer, presented at the 58th Irish Association for Cancer Research (IACR) annual conference.

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. We have recently shown that arginase 2 (Arg2), a mitochondrial enzyme involved in arginine metabolism, promotes the resolution of inflammation in macrophages and it is targeted by miR-155. Here, we designed and tested a target site blocker (TSB) that specifically interferes and blocks the interaction between miR-155 and Arg2 mRNA, leading to Arg2 increased expression and activity. In bone marrow-derived macrophages transfected with Arg2 TSB (in the presence or absence of the pro-inflammatory stimulus LPS), we observed an overall shift of the polarization status of macrophages toward an anti-inflammatory phenotype, as shown by significant changes in surface markers (CD80 and CD71), metabolic parameters (mitochondrial oxidative phosphorylation) and cytokines secretion (IL-1ß, IL-6, and TNF). Moreover, in an in vivo model of LPS-induced acute inflammation, intraperitoneal administration of Arg2 TSB led to an overall decrease in systemic levels of pro-inflammatory cytokines. Overall, this proof-of-concept strategy represent a promising approach to modulating macrophage phenotype.

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. Indeed, both lean mice treated with dexamethasone and obese mice with no treatment had no effect on the ex vivo colony-forming ability, mammosphere formation, or aldehyde dehydrogenase (ALDH) bright subpopulation. However, treatment of obese mice with dexamethasone resulted in a significant increase in ex vivo colony formation, mammosphere formation, ALDH bright subpopulation, and expression of pluripotency transcription factors. GC transcriptionally regulated genes were not altered in the dexamethasone-treated groups compared to treatment controls. In summary, these results provide initial evidence that obesity presents a higher risk of GC-induced cancer stemness via non-genomic GC signaling which is of potential translational significance.

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.

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. In this article, we describe the key components of the microenvironment that influence tumor development and treatment, including the microbiome, metabolism, and immune response and the progress of preclinical models to reflect these complex environments. From a psycho-social oncology perspective, we highlight expert opinion and data on the process of shared decision-making in the context of emerging cancer treatments.

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). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Thirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p<0.05). CONCLUSIONS: Exercise intervention significantly altered the expression of a number of serum biomarkers in disease-free patients who had prior treatment for esophagogastric cancer. IMPACT: Exercise rehabilitation causes a significant biological effect on serum biomarkers in esophagogastric cancer survivors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03314311).

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

Background: Overexpression of sFlt-1 or modulation of FKBPL, key antiangiogenic proteins, are important in the pathogenesis of preeclampsia. Methods: A newly developed nonviral gene-delivery system, RALA, capable of overexpressing sFlt-1 (e15a isoform) was delivered in vivo in transgenic haploinsufficient (Fkbpl+/-) mice. RALA was also used in vitro to deliver human Flt1 (hFlt1) in trophoblast cells. Results: Serum stable and nontoxic RALA/DNA-based nanoparticles induced an increase in sFlt-1 protein levels in the blood and total protein in the urine; the effect was more pronounced in Fkbpl+/- mice. In vitro, RALA-hFlt nanoparticles significantly reduced secretion of sFlt-1 in trophoblast cells. Conclusion: The RALA-based genetic nanodelivery system can be safely and effectively applied to emulate preeclampsia-like features or reduce sFlt-1 levels in vitro.

Lay abstract In this study, the investigators utilized a safe and effective approach to modulate an important circulating protein in pregnancy, sFlt-1, associated with the pregnancy complication, preeclampsia. Preeclampsia is a complex and multifactorial disease and a leading cause of death in pregnancy with no current effective treatment strategies. This is likely due to a lack of reliable preclinical models that replicate human disease. The authors demonstrate the feasibility of a new preeclampsia-like model based on the dysfunction of two key vascular proteins, sFlt-1 and FKBPL (an important protein involved in the development of new blood vessels), that could be utilized in the future for testing and development of new treatments targeting these important mechanisms in preeclampsia.

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. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.

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. Significant pathways associated with the cancer stem cell niche have been identified which interfere with the immune component of the tumour microenvironment, leading to immune surveillance evasion, dysfunction and suppression. This review aims to summarise current evidence-based knowledge on the cancer stem cell niche within the ovarian cancer tumour microenvironment and its effect on immune surveillance. Furthermore, the review seeks to understand the clinical consequences of this dynamic interaction by highlighting current therapies which target these processes.

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. Twenty-five studies were identified through systematic searches of three databases and a meta-analysis conducted using a random effects model, quantifying statistical heterogeneity. Subgroup analysis was conducted for cancer types and publication bias was assessed via funnel plots. There was high heterogeneity in meta-analysis of the studies in all cancer types, which found no association between high GR expression with overall survival (pooled unadjusted HR 1.16, 95% CI (0.89-1.50), n = 2814; pooled adjusted HR 1.02, 95% CI (0.77-1.37), n = 2355) or progression-free survival (pooled unadjusted HR 1.12, 95% CI (0.88-1.42), n = 3365; pooled adjusted HR 1.04, 95% CI (0.6-1.81), n = 582) across all cancer types. However, subgroup meta-analyses showed that high GR expression in gynaecological cancers (endometrial and ovarian) (unadjusted HR 1.83, 95% CI (1.31-2.56), n = 664) and early stage, untreated triple negative breast cancers (TNBCs) (unadjusted HR 1.73, 95% CI (1.35-2.23), n = 687) is associated with disease progression. GR expression in late stage, chemotherapy treated TNBC was not prognostic (unadjusted HR 0.76, 95% CI (0.44, 1.32), n = 287). In conclusion, high GR expression is associated with an increased risk of disease progression in gynaecological and early stage, untreated TNBC. Additional studies are required to elucidate the tumour specific function of the GR receptor in order to ensure GR antagonists target the correct patient groups.

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. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1ß in vitro. Accordingly, HIF-1α and IL-1ß are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2-/- mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

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. Data demonstrated that all six peptides complexed pEGFP-N1 to produce cationic nanoparticles <200 nm in diameter, but not all peptides resulted in successful transfection; indicating the influence of peptide design for cellular uptake and endosomal escape. Pep2, produced nanoparticles with similar characteristics and transfection efficiency to the parent peptide, RALA. However, Pep2 had issues with toxicity and a lack of pH-responsive alpha-helcity. Therefore, RALA remains the superior sequence for non-toxic gene delivery.

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. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. SETTINGS AND PARTICIPANTS: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. MAIN OUTCOME MEASURES: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. RESULTS: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. CONCLUSIONS: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

Rational design and characterisation of a linear cell penetrating peptide for non-viral gene delivery.

The design of a non-viral gene delivery system that can release a functional nucleic acid at the intracellular destination site is an exciting but also challenging proposition. The ideal gene delivery vector must be non-toxic, non-immunogenic, overcome extra- and intra-cellular barriers, protect the nucleic acid cargo from degradation with stability over a range of temperatures. A new 15 amino acid linear peptide termed CHAT was designed in this study with the goal of delivering DNA with high efficiency into cells in vitro and tissues in vivo. Rational design involved incorporation of key amino acids including arginine for nucleic acid complexation and cellular uptake, tryptophan to enhance hydrophobic interaction with cell membranes, histidine to facilitate endosomal escape and cysteine for stability and controlled cargo release. Six linear peptides were synthesised with strategic sequences and amino acid substitutions. Data demonstrated that all six peptides complexed pDNA to produce cationic nanoparticles less than 200 nm in diameter, but not all peptides resulted in successful transfection; indicating the influence of peptide design for endosomal escape. Peptide 4, now termed CHAT, was non-cytotoxic, traversed the plasma membrane of breast and prostate cancer cell lines, and elicited reporter-gene expression following intra-tumoural and intravenous delivery in vivo. CHAT presents an exciting new peptide for the delivery of nucleic acid therapeutics.

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. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism.

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. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity-metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor-adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.