Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models.

Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored the urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression in this stroma-dense tumor. We generated a site-specific ADC offering high-affinity, cross-species reactivity, and efficient internalization of the anti-uPAR monoclonal antibody, FL1, carrying a potent anthracycline derivative (PNU-158692).

Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1.

Movement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis-low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactions with GPIHBP1's intrinsically disordered N-terminal tail, which harbors two acidic clusters at positions 5-12 and 19-30. This polyanionic tail provides a molecular switch that controls LPL detachment from heparan sulfate proteoglycans (HSPGs) by competitive displacement.

Distinct strategies for intravascular triglyceride metabolism in hearts of mammals and lower vertebrate species.

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1-the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen-is present in mammals but in not chickens or other lower vertebrates.

Perspectives of patient and public partners on their involvement in research.

Introduction: Patient and public involvement (PPI) in research integrates patient and public perspectives to improve research relevance and quality. The experiences of PPI partners have revealed mixed findings in countries where PPI is well established, but accounts from areas less accustomed to PPI in research are limited. This study aimed to explore the knowledge, motivations, expectations and experiences of PPI representatives in such a setting.

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This review evaluates the evidence for the use of over-the-scope clips (OTSC), topical haemostatic agents (THA), and prophylactic embolisation (PE) in patients with peptic ulcer bleeding (PUB). The use of OTSC and THA may have the potential to increase the rate of endoscopic haemostasis in PUB not responding to conventional endoscopic treatment. In patients at high risk of recurrent bleeding, the performance of PE after achieving endoscopic haemostasis can reduce the risk of rebleeding and the need for surgery.

Assessing the potential of artificial intelligence to enhance colonoscopy adenoma detection in clinical practice: a prospective observational trial.

Background/aims: This study aimed to evaluate the effectiveness of the GI Genius (Medtronic) module in clinical practice, focusing on the adenoma detection rate (ADR) during colonoscopy. Computer-aided polyp detection (CADe) systems using artificial intelligence have been shown to improve adenoma detection in controlled trials. However, the effectiveness of these systems in clinical practice has recently been questioned.

The impact of iron deficiency on patients under evaluation for colorectal cancer, a prospective cross-sectional study.

Background And Objective: Iron deficiency affects more than 60% of colorectal cancer patients at the time of diagnosis. Iron deficiency ultimately leads to anemia, but additionally, iron deficiency might impact other domains of colorectal cancer patients' health and well-being. The aim of this study was to evaluate the impact of iron deficiency on fatigue, quality of life, cognition, and physical ability in patients undergoing evaluation for colorectal cancer.

APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries.

Apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia in mice and humans. For years, the cause remained a mystery, but the mechanisms have now come into focus. Here, we review progress in defining APOA5's function in plasma triglyceride metabolism.

Laparoscopic-Assisted ERCP in Gastric Bypass Patients-No Stones Left Unturned: A Single Center Retrospective Cohort Study.

Purpose: The long-term need for biliary duct intervention following Roux-en-Y gastric bypass surgery (RYGB) is uncertain. We investigated the rate of laparoscopic assisted retrograde cholangiopancreatography (LAERCP) following RYGB. Also, the pre-LAERCP diagnostic workup together with the true rate of choledocholithiasis in patients with or without prior cholecystectomy was investigated.

Quantification of lipoprotein lipase in mouse plasma with a sandwich enzyme-linked immunosorbent assay.

To support in vivo and in vitro studies of intravascular triglyceride metabolism in mice, we created rat monoclonal antibodies (mAbs) against mouse LPL. Two mAbs, mAbs 23A1 and 31A5, were used to develop a sandwich ELISA for mouse LPL. The detection of mouse LPL by the ELISA was linear in concentrations ranging from 0.

CL-11 circulates in serum as functionally distinct isoforms.

Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway capable of interacting with collectin-10 (CL-10) and the MASPs to activate the complement cascade. Alternative splicing of the COLEC11 gene gives rise to two different isoforms found in serum (A and D). These isoforms vary in the length of their collagen-like region, which is involved in the stabilization of the trimeric subunit and the interaction with the MASPs.

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants.

A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and the severity of diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans and to stratify patients for targeted treatment. To date, the only imaging probe targeting uPAR that has reached clinical phase-II testing relies on a high-affinity 9-mer peptide (AE105), and several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence imaging have validated its utility and specificity in vivo.

Preoperative intravenous iron treatment - a cohort study on colorectal cancer recurrence.

Background: Intravenous (i.v.) iron treatment has been speculated to increase the malignant potential of colorectal malignancies but also to enhance the immune systems potential to fight the invasive tumor.

Inverse effects of APOC2 and ANGPTL4 on the conformational dynamics of lid-anchoring structures in lipoprotein lipase.

The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) is crucial for the delivery of dietary lipids to the heart, skeletal muscle, and adipose tissue. The processing of TRLs by LPL is regulated in a tissue-specific manner by a complex interplay between activators and inhibitors. Angiopoietin-like protein 4 (ANGPTL4) inhibits LPL by reducing its thermal stability and catalyzing the irreversible unfolding of LPL's α/β-hydrolase domain.

Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures.

Lipoprotein lipase (LPL) is secreted into the interstitial spaces by parenchymal cells and then transported into capillaries by GPIHBP1. LPL carries out the lipolytic processing of triglyceride (TG)-rich lipoproteins (TRLs), but the tissue-specific regulation of LPL is incompletely understood. Plasma levels of TG hydrolase activity after heparin injection are often used to draw inferences about intravascular LPL levels, but the validity of these inferences is unclear.

A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism.

GPIHBP1, a protein of capillary endothelial cells (ECs), is a crucial partner for lipoprotein lipase (LPL) in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1, which contains a three-fingered cysteine-rich LU (Ly6/uPAR) domain and an intrinsically disordered acidic domain (AD), captures LPL from within the interstitial spaces (where it is secreted by parenchymal cells) and shuttles it across ECs to the capillary lumen. Without GPIHBP1, LPL remains stranded within the interstitial spaces, causing severe hypertriglyceridemia (chylomicronemia).

Preoperative Intravenous Iron Treatment in Colorectal Cancer: Experience From Clinical Practice.

Introduction: Anemia is associated with increased postoperative morbidity and mortality in abdominal surgery. In clinical trials, preoperative i.v.

Electrostatic sheathing of lipoprotein lipase is essential for its movement across capillary endothelial cells.

GPIHBP1, an endothelial cell (EC) protein, captures lipoprotein lipase (LPL) within the interstitial spaces (where it is secreted by myocytes and adipocytes) and transports it across ECs to its site of action in the capillary lumen. GPIHBP1's 3-fingered LU domain is required for LPL binding, but the function of its acidic domain (AD) has remained unclear. We created mutant mice lacking the AD and found severe hypertriglyceridemia.

Optimization and Evaluation of AlF Labeling Using a NOTA-or RESCA1-Conjugated AE105 Peptide Antagonist of uPAR.

Fluorine-18 displays almost ideal decay properties for positron emission tomography (PET) and allows for large scale production. As such, simplified methods to radiolabel peptides with fluorine-18 are highly warranted. Chelation of aluminium fluoride-18 toward specific peptides represents one method to achieve this.

ANGPTL4: a new mode in the regulation of intravascular lipolysis.

Purpose Of Review: Lipoprotein lipase (LPL) is the rate-limiting enzyme for intravascular processing of circulating triglyceride-rich lipoproteins (TRLs). One emerging strategy for therapeutic lowering of plasma triglyceride levels aims at increasing the longevity of LPL activity by attenuating its inhibition from angiopoietin-like proteins (ANGPTL) 3, 4 and 8. This mini-review focuses on recent insights into the molecular mechanisms underpinning the regulation of LPL activity in the intravascular unit by ANGPTLs with special emphasis on ANGPTL4.

Expression and one-step purification of active LPL contemplated by biophysical considerations.

LPL is essential for intravascular lipid metabolism and is of high medical relevance. Since LPL is notoriously unstable, there is an unmet need for a robust expression system producing high quantities of active and pure recombinant human LPL (hLPL). We showed previously that bovine LPL purified from milk is unstable at body temperature (T is 34.