Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host-Guest Inclusion Complex with β-Cyclodextrin.

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies.

Efficacy of PACE4 pharmacotherapy in JHU-LNCaP-SM preclinical model of androgen independent prostate cancer.

Prostate cancer (PCa) is a complex disease progressing from in situ to invasive or metastatic tumors while also being capable of modulating its androgen dependence. Understanding how novel therapies are working across the different stages of the disease is critical for their proper positioning in the spectrum of PCa treatments. The targeting of proprotein convertase PACE4 (Paired basic Amino Acid-Cleaving Enzyme 4) has been proposed as a novel approach to treat PCa.

Climate impact from agricultural management practices in the Canadian Prairies: Carbon equivalence due to albedo change.

It is generally accepted that land use and land management practices impact climate change through sequestration of carbon in soils, but modulation of surface energy budget can also be important. Using Landsat data to characterize cropland albedos in Canada's three prairie soil zones, this study estimates the atmospheric carbon equivalent drawdown of albedo radiative forcing for three management practices: 1) moving from conventional tillage to no-till, 2) eliminating summer fallow in crop rotations, and 3) growing crops with higher albedos. In a 50-year time horizon, conversion from conventional tillage to no-till results in a total equivalent atmospheric CO (CO-eq) drawdown of 1.

Natural climate solutions for Canada.

Alongside the steep reductions needed in fossil fuel emissions, natural climate solutions (NCS) represent readily deployable options that can contribute to Canada's goals for emission reductions. We estimate the mitigation potential of 24 NCS related to the protection, management, and restoration of natural systems that can also deliver numerous co-benefits, such as enhanced soil productivity, clean air and water, and biodiversity conservation. NCS can provide up to 78.

An indicator of freeze-kill damages to fruit trees during flowering.

This paper demonstrates the use of climatological data and published information to develop a thaw-freeze/freeze-kill indicator for fruit trees during flowering. In fruit-producing regions, when budding and flowering occur before the last spring freeze, a freeze-kill event can cause substantial losses. As spring onset is occurring earlier with climate change, thaw-freeze events have the potential to become more of a hazard both in terms of current production and in terms of potential adaptation strategies.

Preparing education for the crises of tomorrow: A framework for adaptability.

The COVID-19 crisis has disrupted learning globally, exacerbating regional and global disparities that predated the pandemic. This rupture presents a unique opportunity to reimagine our educational system in times of both calm and crisis. Drawing on the work of political scientist Kathleen Thelen and economist and philosopher Amartya Sen, this article introduces a that outlines examples of flexible and equitable adaptation to change.

Influence of two management practices in the Canadian Prairies on radiative forcing.

Surface albedo and soil carbon sequestration are influenced by agricultural management practices which impact the Earth's radiation budget and climate change. In this study we investigate the impact of reduced summer fallowing and reduced tillage in the Canadian Prairies on climate change by estimating the change in radiative forcing due to albedo and soil carbon sequestration. Seasonal variations of albedo, which are dependent on agricultural management practices and soil colour in three soil zones, were derived from 10-day composite 250-m Moderate Resolution Imaging Spectroradiometer (MODIS) data.

Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors.

Recent studies in prostate cancer have identified PACE4, a proprotein convertase enzyme, as an emerging therapeutic target. Inhibition of PACE4-altCT, an oncogenic isoform of PACE4, using molecular or pharmacological approaches results in decreased cell proliferation and tumor progression in xenograft models. Although several validations have confirmed PACE4-altCT as a novel therapeutic target, the transcriptional regulation of PACE4 isoforms and mechanism of action remain a challenge.

Beef cattle production impacts soil organic carbon storage.

Grazing of natural rangeland and seeded pasture is an important feeding strategy for the Canadian beef cattle industry. As a consequence, beef cattle population has a direct influence on the proportion of land base maintained as perennial forage, which in turn changes soil organic carbon (SOC) stocks. We examined historical relationships between the net change in SOC resulting from perennial/annual crop conversion and beef cattle populations.

Assessing the effects of manure application rate and timing on nitrous oxide emissions from managed grasslands under contrasting climate in Canada.

It is uncertain whether process-based models are currently capable of simulating the complex soil, plant, climate, manure management interactions that influence soil nitrous oxide (NO) emissions from perennial cropping systems. The objectives of this study were (1) to calibrate and evaluate the DeNitrification DeComposition (DNDC) model using multi-year datasets of measured nitrous oxide (NO) fluxes, soil moisture, soil inorganic nitrogen, biomass and soil temperature from managed grasslands applied with manure slurry in contrasting climates of Canada, and (2) to simulate the impact of different manure management practices on NO emissions including slurry application i) rates (for both single vs. split); and ii) timing (e.

Intermittent agitation of liquid manure: effects on methane, microbial activity, and temperature in a farm-scale study.

Liquid manure storages are a significant source of methane (CH) emissions. Farmers commonly agitate (stir) liquid manure prior to field application to homogenize nutrients and solids. During agitation, manure undergoes mechanical stress and is exposed to the air, disrupting anaerobic conditions.

Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug.

The proprotein convertase PACE4 has been validated as a potential target to develop new therapeutic interventions in prostate cancer (PCa). So far, the most effective compound blocking the activity of this enzyme has been designed based on the structure of a small peptide Ac-LLLLRVKR-NH known as the Multi-Leu (ML) peptide. Optimization of this scaffold led to the synthesis of compound C23 (Ac-[DLeu]LLLRVK-amidinobenzylamide) with a potent in vivo inhibitory effect on the tumor growth.

Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue.

Paired basic amino acid cleaving enzyme 4 (PACE4), a serine endoprotease of the proprotein convertases family, has been recognized as a promising target for prostate cancer. We previously reported a selective and potent peptide-based inhibitor for PACE4, named the multi-Leu peptide (Ac-LLLLRVKR-NH sequence), which was then modified into a more potent and stable compound named C23 with the following structure: Ac-dLeu-LLLRVK-Amba (Amba: 4-amidinobenzylamide). Despite improvements in both in vitro and in vivo profiles of C23, its selectivity for PACE4 over furin was significantly reduced.

Increasing C-Terminal Hydrophobicity Improves the Cell Permeability and Antiproliferative Activity of PACE4 Inhibitors against Prostate Cancer Cell Lines.

The serine protease, PACE4, is a proprotein convertase that plays a substantial role in malignancy of prostate cancer. Our initial selective PACE4 inhibitor (Ac-LLLLRVKR-NH) has evolved to the current lead compound C23 (Ac-dLeu-LLLRVK-Amba), which is active both in vitro and in vivo. By screening natural residues, except Cys, in C-terminal P1' position, it was established that increasing hydrophobicity was improving cell permeability, which was directly translated into PCa cells antiproliferative activity.

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer.

Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT).

Rational Design of a Highly Potent and Selective Peptide Inhibitor of PACE4 by Salt Bridge Interaction with D160 at Position P3.

PACE4, a member of the proprotein convertases (PCs) family of serine proteases, is a validated target for prostate cancer. Our group has developed a potent and selective PACE4 inhibitor: Ac-LLLLRVKR-NH . In seeking for modifications to increase the selectivity of this ligand toward PACE4, we replaced one of its P3 Val methyl groups with a basic group capable of forming a salt bridge with D160 of PACE4.

Macrocyclization of a potent PACE4 inhibitor: Benefits and limitations.

PACE4, one of the seven members of the proprotein convertase family, plays an important role in the progression of prostate cancer. Therefore, its inhibition has become an attractive target to develop new therapies against this disease. Recently, we have developed a highly potent and selective PACE4 inhibitor, known as the multi-Leu peptide with the following sequence Ac-LLLLRVKR-NH.

Thrombin activation of protein C requires prior processing by a liver proprotein convertase.

Protein C, a secretory vitamin K-dependent anticoagulant serine protease, inactivates factors Va/VIIIa. It is exclusively synthesized in liver hepatocytes as an inactive zymogen (proprotein C). In humans, thrombin cleavage of the propeptide at PR↓ results in activated protein C (APC; residues 222-461).

Potential methane emission reductions for two manure treatment technologies.

The effect of two dairy manure treatments, solid-liquid separation (SLS) and anaerobic digestion (AD), on methane potential and the speed of production was evaluated. Assays were performed in the lab to measure methane (CH) production over 202 d from dairy manure samples taken before and after each treatment. Compared to raw manure, CH emissions on a per-L basis were reduced 81% by SLS and 59% by AD, on average.

PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression.

Breast cancer is the most frequent and deadly malignancy in women worldwide. Despite national screening programs combined with new treatments relapse rate remain high and new therapies are needed. From previous work, we identified PACE4, a member of the proprotein convertase (PCs) family of endoproteases, as a novel therapeutic target in prostate cancer.

Positional Scanning Identifies the Molecular Determinants of a High Affinity Multi-Leucine Inhibitor for Furin and PACE4.

The proprotein convertase family of enzymes includes seven endoproteases with significant redundancy in their cleavage activity. We previously described the peptide Ac-LLLLRVK-Amba that displays potent inhibitory effects on both PACE4 and prostate cancer cell lines proliferation. Herein, the molecular determinants for PACE4 and furin inhibition were investigated by positional scanning using peptide libraries that substituted its leucine core with each natural amino acid.

Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study.

Background: DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage.

Methods: The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1-2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design.

Does Fall Removal of the Dairy Manure Sludge in a Storage Tank Reduce Subsequent Methane Emissions?

When liquid manure is removed from storages for land application, "sludge" generally remains at the bottom of the tank. This may serve as an inoculum when fresh manure is subsequently added, thereby increasing methane (CH) emissions. Previous pilot-scale studies have shown that completely emptying storages can decrease CH emissions; however, no farm-scale studies have been conducted to quantify the effect of sludge removal.