Facile route to targeted, biodegradable polymeric prodrugs for the delivery of combination therapy for malaria

A facile synthetic methodology has been developed to prepare multifaceted polymeric prodrugs that are targeted, biodegradable, and nontoxic, and used for the delivery of combination therapy. This is the first instance of the delivery of the WHO recommended antimalarial combination of lumefantrine (LUM, drug 1) and artemether (AM, drug 2) via a polymeric prodrug. To achieve this, reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization of N-vinylpyrrolidone (NVP) was conducted using a hydroxy-functional RAFT agent, and the resulting polymer was used as the macroinitiator in the ring-opening polymerization (ROP) of α-allylvalerolactone (AVL) to synthesize the biodegradable block copolymer of poly(N-vinylpyrrolidone) and poly(α-allylvalerolactone) (PVP-b-PAVL). The ω-end thiol group of PVP was protected using 2,2′-pyridyldisulfide prior to the ROP, and was conveniently used to bioconjugate a peptidic targeting ligand. To attach LUM, the allyl groups of PVP-b-PAVL underwent oxidation to introduce carboxylic acid groups, which were then esterified with ethylene glycol vinyl ether. Finally, LUM was conjugated to the block copolymer via an acid-labile acetal linkage in a “click”-type reaction, and AM was entrapped within the hydrophobic core of the self-assembled aggregates to render biodegradable multidrug-loaded micelles with targeting ability for combination therapy.The South African Research Chairs Initiative of the Department of Science and Technology (DST), the National Research Foundation (NRF) of South Africa, SARCHI: Communities of Practice in Malaria Elimination and SARChI Research Chair UID 84627 and UID 84627.http://pubs.acs.org/journal/abseba2021-10-07hj2021BiochemistryGeneticsMicrobiology and Plant Patholog

Poly(N-vinylpyrrolidone) antimalaria conjugates of membrane-disruptive peptides

The concepts of polymer–peptide conjugation and self-assembly were applied to antimicrobial peptides (AMPs) in the development of a targeted antimalaria drug delivery construct. This study describes the synthesis of α-acetal, ω-xanthate heterotelechelic poly(N-vinylpyrrolidone) (PVP) via reversible addition–fragmentation chain transfer (RAFT)-mediated polymerization, followed by postpolymerization deprotection to yield α-aldehyde, ω-thiol heterotelechelic PVP. A specific targeting peptide, GSRSKGT, for Plasmodium falciparum-infected erythrocytes was used to sparsely decorate the α-chain ends via reductive amination while cyclic decapeptides from the tyrocidine group were conjugated to the ω-chain end via thiol–ene Michael addition. The resultant constructs were self-assembled into micellar nanoaggregates whose sizes and morphologies were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro activity and selectivity of the conjugates were evaluated against intraerythrocytic P. falciparum parasites.© 2020 American Chemical Societyhttp://pubs.acs.org/journal/bomaf62021-11-06hj2021BiochemistryGeneticsMicrobiology and Plant Patholog

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

What makes some persons more prejudiced than others? Modeling the role of social dominance, empathy, social desirability, and gender

Structural equation modeling on questionnaire data showed that different kinds of prejudice (concerning sexual orientation, ethnicity, gender, and impaired develop­ment) can be represented as a general prejudice factor. Specific variability related to classical and modern prejudice only increased model fit marginally. Several causal models of the relation between key individual difference variables and prejudice were tested. Social dominance orientation had a strong, empathy a moderate, and social desirability a comparably weaker direct effect on generalized prejudice. The effects of participant gender on the generalized prejudice factor, where the men scored higher, were almost completely mediated by empathy. The importance of empathy in causal models of prejudice, and of indirect measurement of prejudice, is discussed

Ethical content of expert recommendations for end-of-life decision-making in intensive care units: A systematic review

Purpose: Intensive care unit health care professionals must be skilled in providing end-of-life care. Crucial in this kind of care is end-of-life decision-making, which is a complex process involving a variety of stakeholders and requiring adequate justification. The aim of this systematic review is to analyse papers tackling ethical issues in relation to end-of-life decision-making in intensive care units. It explores the ethical positions, arguments and principles. ----- Methods: A literature search was conducted in bibliographic databases and grey literature sources for the time period from 1990 to 2019. The constant comparative method was used for qualitative analysis of included papers in order to identify ethical content including ethical positions, ethical arguments, and ethical principles used in decision-making process. ----- Results: In the 15 included papers we have identified a total of 43 ethical positions. Ten positions were identified as substantive, 33 as procedural. Twelve different ethical principles emerged from the ethical arguments. The most frequently used principles are the principles of beneficence, autonomy and nonmaleficence. ----- Conclusions: We have demonstrated that recommendations and guidelines designed specifically by intensive or critical care experts for intensive care units promote similar ethical positions, with minimal dissenting positions

Ethical content of expert recommendations for end -of -life decision -making in intensive care units: A systematic review

PURPOSE: Intensive care unit health care professionals must be skilled in providing end-of-life care. Crucial in this kind of care is end-of-life decision-making, which is a complex process involving a variety of stakeholders and requiring adequate justification. The aim of this systematic review is to analyse papers tackling ethical issues in relation to end-of-life decision-making in intensive care units. It explores the ethical positions, arguments and principles. METHODS: A literature search was conducted in bibliographic databases and grey literature sources for the time period from 1990 to 2019. The constant comparative method was used for qualitative analysis of included papers in order to identify ethical content including ethical positions, ethical arguments, and ethical principles used in decision-making process. RESULTS: In the 15 included papers we have identified a total of 43 ethical positions. Ten positions were identified as substantive, 33 as procedural. Twelve different ethical principles emerged from the ethical arguments. The most frequently used principles are the principles of beneficence, autonomy and nonmaleficence. CONCLUSIONS: We have demonstrated that recommendations and guidelines designed specifically by intensive or critical care experts for intensive care units promote similar ethical positions, with minimal dissenting positions.status: publishe

A Paradoxical Role for Regulatory T Cells in the Tumor Microenvironment of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a poorly immunogenic cancer type that combines a low mutation burden with a strong immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) are major drivers of immune suppression but their prognostic role, particularly in gastrointestinal malignancies, remains controversial. Lymphocytic infiltration in 122 PDAC samples was assessed by multispectral immunofluorescence with anti-Keratin, -CD3, -CD8, -FOXP3 and -CD163 antibodies. Differential infiltration by Tregs was analyzed in the context of transcriptomic profiles that were available for 65 tumors. High infiltration of CD3+CD8− (mainly CD4+) T cells and, especially, of the subset expressing FOXP3 (Tregs) was associated with improved patient survival, whilst cytotoxic CD3+CD8+ T cell infiltration did not have an impact on overall survival. Transcriptomic analysis revealed three signatures in PDAC tumors comprising of epithelial-mesenchymal transition (EMT)/stromal, metabolic, and secretory/pancreatic signature. However, none of these signatures explained differences in Treg infiltration. We show that Tregs associate with improved overall survival in PDAC patients. This effect was independent of cytotoxic T cell infiltration and the transcriptomic profiles of their respective tumors. These findings provide a new layer of complexity in the study of PDAC tumor microenvironment that must be considered when developing immunotherapeutic interventions for this disease