Say no to drugs: Bioactive macromolecular therapeutics without conventional drugs.

The vast majority of nanomedicines (NM) investigated today consists of a macromolecular carrier and a drug payload (conjugated or encapsulated), with a purpose of preferential delivery of the drug to the desired site of action, either through passive accumulation, or by active targeting via ligand-receptor interaction. Several drug delivery systems (DDS) have already been approved for clinical use. However, recent reports are corroborating the notion that NM do not necessarily need to include a drug payload, but can exert biological effects through specific binding/blocking of important target proteins at the site of action.

Level of vital and laboratory values on arrival, and increased risk of 7-day mortality among adult patients in the emergency department: a population-based cohort study.

Objectives: The aim of the study was to provide evidence for, at which vital and laboratory values, increased risk of 7-day mortality in acute adult patients on arrival to an emergency department (ED).

Design: A population-based cohort study.

Setting: ED at Odense University Hospital, Denmark.

Use of dipeptidyl peptidase-4 inhibitors and risk of splanchnic vein thrombosis: A Danish nationwide new-user active comparator cohort study.

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors, on the basis of spontaneous adverse event reports, has recently been suspected of causing splanchnic vein thrombosis. Here, we report the results of a population-based new-user active comparator cohort study addressing this hypothesis, comparing DPP-4 inhibitor initiators (n = 75 042) with initiators of glucagon-like-peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose co-transporter-2 (SGLT2) inhibitors (n = 38 718). We estimated the hazard ratio (HR) associating DPP-4 inhibitor use with risk of splanchnic vein thrombosis using Cox regression.

Eosinophils Protect Mice From Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm.

Rationale: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease.

Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice.

Spinal cord injury (SCI) is a devastating condition consisting of an instant primary mechanical injury followed by a secondary injury that progresses for weeks to months. The cytokine tumor necrosis factor (TNF) plays an important role in the pathophysiology of SCI. We investigated the effect of myeloid TNF ablation (peripheral myeloid cells (macrophages and neutrophils) and microglia) versus central myeloid TNF ablation (microglia) in a SCI contusion model.

Doxorubicin liposomes cell penetration enhancement and its potential drawbacks for the tumor targeting efficiency.

The clinical efficacy of the PEGylated doxorubicin liposomes (PLD) is limited by low tumor accumulation and limited intra-tumoral disposition. Decoration with the cell penetration enhancers (CPEs) can increase the PLD permeability via the biological barriers, however at the expense of enhanced distribution to the non-target organs and tissues, and may interfere with their tumor accumulation and with the resulting anti-cancer effects. We investigated the effect of the surface CPE agent tetraArg-[G-1]-distearoyl glycerol (DAG-Arg) on the systemic and intra-tumoral accumulation of PLD, using a 4 T1-Luc murine orthotopic model of breast cancer, using several analytical approaches.

Severity of COVID-19 at elevated exposure to perfluorinated alkylates.

Background: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute as well.

Methods: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic.

Using a limited sampling strategy to investigate the interindividual pharmacokinetic variability in metformin: A large prospective trial.

Aims: Recently a limited sampling strategy (LSS) for determination of metformin' pharmacokinetics was developed. The LSS utilizes the plasma concentration of metformin 3 and 10 hours after oral intake of a single dose to estimate the area under the concentration-time curve up to 24 hours (AUC ). The main purpose of this study was to support the feasibility of this strategy in a large prospective trial.

Elevated Circulating Cell-Free DNA in Hemodialysis-Treated Patients Is Associated with Increased Mortality.

Background: Predicting the mortality risk of patients un-dergoing hemodialysis (HD) is challenging. Cell-free DNA (cfDNA) is released into circulation from dying cells, and its elevation is predictive of unfavorable outcome. In a pilot study, we found post-HD cfDNA level to be a predictor of all-cause mortality.

The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG.

TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity.

Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy.

Autophagy is upregulated in adipose tissue (AT) from people with obesity. We showed that activation of the calcium-sensing receptor (CaSR) elevates proinflammatory cytokines through autophagy in preadipocytes. Our aim is to understand the role of CaSR on autophagy in AT from humans with obesity.

Verification of the hemolysis index measurement: imprecision, accuracy, measuring range, reference interval and impact of implementing analytically and clinically derived sample rejection criteria.

Automated spectrophotometric measurement of hemolysis index (HI) allows rapid and cost-effective assessment of hemolysis interference. We evaluated the analytical performance of HI on two different platforms. Further, the impact of implementing analytically and clinically derived sample rejection criteria was investigated.

Hyperlipidemia does not affect development of elastase-induced abdominal aortic aneurysm in mice.

Background And Aims: Hyperlipidemia is a suggested risk factor for abdominal aortic aneurysm (AAA). However, whether hyperlipidemia is causally involved in AAA progression remains elusive. Here, we tested the hypothesis that hyperlipidemia aggravates AAA formation in the widely used porcine pancreatic elastase (PPE) model of AAA in mice with varying levels of plasma lipids.

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice.

Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr genotype to the different domains of behavior.

Depletion of ASK1 blunts stress-induced senescence in adipocytes.

Increasing energy expenditure via induction of browning in white adipose tissue has emerged as a potential strategy to treat obesity and associated metabolic complications. We previously reported that ASK1 inhibition in adipocytes protected from high-fat diet (HFD) or lipopolysaccharide (LPS)-mediated downregulation of UCP1 both and . Conversely, adipocyte-specific ASK1 overexpression attenuated cold-induction of UCP-1 in inguinal fat.

Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) has increasing worldwide incidence but when unresectable lacks curative options. Treatment with a kinase inhibitor Sorafenib (Sf), while initially effective, results in only short increases in patient survival, thus there is a need for improved treatment regimens. Numerous treatment regimens have been explored wherein Sf is combined with other agents, such as non-toxic botanicals like Curcumin or Silibinin.

Postponement of cardiovascular outcomes by statin use: A systematic review and meta-analysis of randomized clinical trials.

Objective: To estimate the average outcome postponement (gain in days to an event) for cardiovascular outcomes in a meta-analysis of randomized, controlled statin trials, including any myocardial infarction, any stroke and cardiovascular death.

Design: Systematic review of large randomized, placebo-controlled trials of statin use, including a random-effects meta-analysis of all included trials.

Data Sources: We searched MEDLINE (15 July 2019) and ClinicalTrials.

Cell-free DNA concentration in patients with clinical or mammographic suspicion of breast cancer.

Mammography has a crucial role in the detection of breast cancer (BC), yet it is not limitation-free. We hypothesized that the combination of mammography and cell-free DNA (cfDNA) levels may better discriminate patients with cancer. This prospective study included 259 participants suspected with BC before biopsy.

Oxidant-induced glutathionylation at protein disulfide bonds.

Disulfide bonds are a key determinant of protein structure and function, and highly conserved across proteomes. They are particularly abundant in extracellular proteins, including those with critical structural, ligand binding or receptor function. We demonstrate that oxidation of protein disulfides induces polymerization, and results in oxygen incorporation into the former disulfide via thiosulfinate generation.

Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients.

Objective: Pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic enzyme by its ability to locally increase insulin-like growth factor (IGF) activity through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. This study aimed to investigate IGFBP-4, PAPP-A, and STC2 as local regulators of IGF bioactivity in the cardiac microenvironment by comparing levels in the pericardial fluid with those in the circulation of patients with cardiovascular disease.

Primate differential redoxome (PDR) - A paradigm for understanding neurodegenerative diseases.

Despite different phenotypic manifestations, mounting evidence points to similarities in the molecular basis of major neurodegenerative diseases (ND). CNS has evolved to be robust against hazard of ROS, a common perturbation aerobic organisms are confronted with. The trade-off of robustness is system's fragility against rare and unexpected perturbations.

Causes of Vitamin K Deficiency in Patients on Haemodialysis.

A low vitamin K status is common in patients on haemodialysis, and this is considered one of the reasons for the accelerated atherosclerosis in these patients. The vitamin is essential in activation of the protein Matrix Gla Protein (MGP), and the inactive form, dp-ucMGP, is used to measure vitamin K status. The purpose of this study was to investigate possible underlying causes of low vitamin K status, which could potentially be low intake, washout during dialysis or inhibited absorption capacity.

Affinity Capture Enrichment versus Affinity Depletion: A Comparison of Strategies for Increasing Coverage of Low-Abundant Human Plasma Proteins.

In the present study, we evaluated four small molecule affinity-based probes based on agarose-immobilized benzamidine (ABA), O-Phospho-L-Tyrosine (pTYR), 8-Amino-hexyl-cAMP (cAMP), or 8-Amino-hexyl-ATP (ATP) for their ability to remove high-abundant proteins such as serum albumin from plasma samples thereby enabling the detection of medium-to-low abundant proteins in plasma samples by mass spectrometry-based proteomics. We compared their performance with the most commonly used immunodepletion method, the Multi Affinity Removal System Human 14 (MARS14) targeting the top 14 most abundant plasma proteins and also the ProteoMiner protein equalization method by label-free quantitative liquid chromatography tandem mass spectrometry (LC-MSMS) analysis. The affinity-based probes demonstrated a high reproducibility for low-abundant plasma proteins, down to picomol per mL levels, compared to the Multi Affinity Removal System (MARS) 14 and the Proteominer methods, and also demonstrated superior removal of the majority of the high-abundant plasma proteins.