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The present survey, based on a multiple-choice questionnaire, was undertaken to assess the gastrointestinal tolerance of four commercial diets from the Veterinary HPMTM diet range. The four diets were tested in 284 adult dogs over a 28-day period and compared to their usual diets. Online evaluations were performed at the beginning of the study, at the end of the 4-day diet transition, and at 7, 14 and 28 days. Digestive sensitivity with the dog's usual food was reported in 28% of the enrolled dogs. At least 94% of the pet owners declared they were satisfied with the transition to the tested diets. Average stool consistency scores with the tested diets remained steady at the optimal value of 2.2. Globally acceptable stool odour and small or normal stool volume were reported in over 70% of the dogs. Unchanged or decreased faeces odour and volume were described in more than 70% of the dogs and unchanged or increased stool consistency was reported in more than 77% of the dogs in comparison to their previous diet. Faecal consistency and stool volume were not significantly different between the different time points. The number of dogs showing flatulence was significantly lower on days 7, 14 and 28 than on day 0. In conclusion, a safe diet transition and a high digestive tolerance was reported after feeding various-sized adult dogs of different breeds with the tested Veterinary HPMTM diets. [ABSTRACT FROM AUTHOR]

The digestive tolerance of three commercial diets (Baby Dog Small & Toy, Baby Dog Large & Medium, and Junior Dog Special Large) issued from a new high proteinlow carbohydrate diet range, Veterinary HPMTM, was assessed in growing dogs through an online survey administered to 129 pet owners over a 28-day testing period, and was compared to that of the dogs' usual diets. Multiple-choice questionnaires had to be filled out at the beginning of the study, at the end of a 4-day diet transition, and after 7, 14, and 28 days. About 30% of the enrolled dogs had previously shown a digestive sensitivity with their usual food, mainly manifested as diarrhoea. In the present study, more than 94% of the pet owners were satisfied with the way the transition to the tested diets had taken place. Volume, consistency, and odour of the stools showed little change when switching diets, and were not significantly different between the different time points for each tested diet. The percentage of dogs with flatulence on days 7, 14, and 28 (except for one diet) significantly decreased compared to day 0. In conclusion, the three tested Veterinary HPMTM diets enabled a safe diet transition from numerous kinds of canine foods. The tested diets have all shown a high digestive tolerance in various-sized puppies and growing dogs of different breeds. [ABSTRACT FROM AUTHOR]

In contrast to HLA-A and -B class Ia genes that are down-regulated in human trophoblast cells, HLA-G class Ib molecules are expressed in the placenta throughout gestation. In addition to extravillous cytotrophoblast that invade the decidua basalis essentially, HLA-G was also observed in endothelial cells of fetal vessels in the chorionic villi as well as in amnion cells and amniotic fluid. Both membrane-bound and soluble HLA-G isoforms have been detected. In view of the recently published functional data showing that HLA-G: (i) has the capability to bind and present peptides; (ii) is recognized by at least three different killing inhibitory receptors; and (iii) is a regulator of HLA-E expression, we can predict that such functions are likely to be exerted by extravillous cytotrophoblast. Of particular importance will be the anti-viral function of HLA-G at this materno-fetal interface, knowing that HLA-G was shown to be expressed by thymic medullary epithelial cells. In addition to these immunological functions, due to its presence on chorionic fetal endothelial cells, we hypothesize that HLA-G could also be a regulator of chorionic villous angiogenesis. Finally, soluble HLA-G isoforms may act as specific immunosuppressors during pregnancy. [ABSTRACT FROM AUTHOR]

In contrast to HLA-A and -B class Ia genes that are down-regulated in human trophoblast cells, HLA-G class Ib molecules are expressed in the placenta throughout gestation. In addition to extravillous cytotrophoblast that invade the decidua basalis essentially, HLA-G was also observed in endothelial cells of fetal vessels in the chorionic villi as well as in amnion cells and amniotic fluid. Both membrane-bound and soluble HLA-G isoforms have been detected. In view of the recently published functional data showing that HLA-G: (i) has the capability to bind and present peptides; (ii) is recognized by at least three different killing inhibitory receptors; and (iii) is a regulator of HLA-E expression, we can predict that such functions are likely to be exerted by extravillous cytotrophoblast. Of particular importance will be the anti-viral function of HLA-G at this materno-fetal interface, knowing that HLA-G was shown to be expressed by thymic medullary epithelial cells. In addition to these immunological functions, due to its presence on chorionic fetal endothelial cells, we hypothesize that HLA-G could also be a regulator of chorionic villous angiogenesis. Finally, soluble HLA-G isoforms may act as specific immunosuppressors during pregnancy. [ABSTRACT FROM PUBLISHER]

Woodchips in stand-off pads for wintering cows have been applied in countries like Ireland and New Zealand. Their primary role is to protect soils by effectively filtering nutrients during wet conditions, while ensuring a healthy and comfortable environment for the cows. The stand-off pad concept has the potential to be adopted in Canada to provide year-long outdoor access to tie-stall dairy cows. The objective of this study was to evaluate the effect of alternative filtering materials and bed aeration under controlled laboratory conditions. Twelve biofilter columns (0.3 m in diameter and 1-m high) were installed in 12 environmentally-controlled chambers (1.2-m wide by 2.4-m long), and divided into four treatments: a bed of conventional woodchips or an alternative mix of organic materials (sphagnum peat moss, woodchips and biochar) with and without aeration (flux rate set at 0.6 m 3 /min/m 2 ). Approximately 0.6 L of semi-synthetic dairy manure and 1 L of tap water were poured on the biofilters during two experimental periods of 4 weeks, simulating the effect of either winter or summer conditions (room temperature below or over 10 °C) on the retention of nutrients and fecal bacteria. Results showed that the alternative biofilters under both summer and winter conditions were more efficient in removing COD, SS, TN, and NO 3 -N than conventional biofilters (maximum efficiencies of 97.6%, 99.7%, 96.4%, and 98.4%, respectively). Similarly for E. coli, they achieved a minimum concentration of 1.8 Log 10  CFU/100 ml. Conventional biofilters were more efficient for PO 4 -P removal with a maximum efficiency of 88.2%. Aeration did not have any significant effect under the tested temperature conditions. Additional factors such as media adaptation time as well as aeration flow during this period should be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Elizabeth Alvarez Chavez reports financial support was provided by Laval University. Elizabeth Alvarez Chavez reports financial support was provided by Research and Development Institute for the Agri-Environment. Elizabeth Alvarez Chavez reports financial support was provided by Quebec Ministry of Agriculture Fisheries and Food., (Copyright © 2023. Published by Elsevier Ltd.)

Cationic polymers such as polyethylenimine (PEI) have found a pervasive place in laboratories across the world as gene delivery agents. However, their applications are not limited to this role, having found a place as delivery agents for drugs, in complexes known as polymer-drug conjugates (PDCs). Yet a potentially underexplored domain of research is in their inherent potential as anti-cancer therapeutic agents, which has been indicated by several studies. Even more interesting is the recent observation that certain polycations may present a significantly greater toxicity towards the clinically important cancer stem cell (CSC) niche than towards more differentiated bulk tumour cells. These cells, which possess the stem-like characteristics of self-renewal and differentiation, are highly implicated in cancer drug resistance, tumour recurrence and poor clinical prognosis. The search for compounds which may target and eliminate these cells is thus of great research interest. As such, the observation in our previous study on a PEI-based PDC which showed a considerably higher toxicity of PEI towards glioblastoma CSCs (GSCs) than on more differentiated glioma (U87) cells led us to investigate other cationic polymers for a similar effect. The evaluation of the toxicity of a range of different types of polycations, and an investigation into the potential source of GSC's sensitivity to such compounds is thus described.

Our multicentric, masked, controlled and randomised study aimed to assess the efficacy and safety of Suprelorin® 4.7 mg (Virbac, Carros, France) regarding oestrus prevention in prepubertal intact bitches. Twelve- to eighteen-week-old females (n = 83) were allocated either a deslorelin implant (n = 62) or 0.9% sodium chloride (n = 21) group. Clinical assessment (heat signs), 17β oestradiol and progesterone assays, and vaginal cytology were performed at day (D)0, D7, D21, month (M)3 and M6 after product administration, and were then performed every other month until reaching puberty. Trained owners assessed heat signs between each veterinary visit. All bitches (n = 83) reached puberty before M30. Deslorelin significantly extended the median time to sexual maturity when compared to the control group (377 days versus 217 days after D0, p < 0.0001). Three females, implanted between 16 and 18 weeks of age, expressed an induced oestrus. Additional descriptive data, collected over a 24 month-period, showed functional reproductive abilities in both deslorelin (n = 52) and control (n = 21) groups once puberty was achieved. In conclusion, Suprelorin® 4.7 mg seems to be an effective and safe option for postponing the onset of oestrus when administered to prepubertal female dogs aged from 12 to 16 weeks.

Cancer stem cells (CSCs) represent a difficult to treat cellular niche within tumours due to their unique characteristics, which give them a high propensity for resistance to classical anti-cancer treatments and the ability to repopulate the tumour mass. An attribute that may be implicated in the high rates of recurrence of certain tumours. However, other characteristics specific to these cells, such as their high dependence on mitochondria, may be exploited for the development of new therapeutic agents that are effective against the niche. As such, a previously described phosphorescent N-heterocyclic carbene iridium(III) compound which showed a high level of cytotoxicity against classical tumour cell lines with mitochondria-specific effects was studied for its potential against CSCs. The results showed a significantly higher level of activity against several CSC lines compared to non-CSCs. Mitochondrial localisation and superoxide production were confirmed. Although the cell death involved caspase activation, their role in cell death was not definitive, with a potential implication of other, non-apoptotic pathways shown. A cytostatic effect of the compound was also displayed at low mortality doses. This study thus provides important insights into the mechanisms and the potential for this class of molecule in the domain of anti-CSC therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The difficulty involved in the treatment of many tumours due to their recurrence and resistance to chemotherapy is tightly linked to the presence of cancer stem cells (CSCs). This CSC sub-population is distinct from the majority of cancer cells of the tumour bulk. Indeed, CSCs have increased mitochondrial mass that has been linked to increased sensitivity to mitochondrial targeting compounds. Thus, a platinum-based polyethylenimine (PEI) polymer-drug conjugate (PDC) was assessed as a potential anti-CSC therapeutic since it has previously displayed mitochondrial accumulation. Our results show that CSCs have increased specific sensitivity to the PEI carrier and to the PDC. The mechanism of cell death seems to be necrotic in nature, with an absence of apoptotic markers. Cell death is accompanied by the induction of a protective autophagy. The interference in the balance of this pathway, which is highly important for CSCs, may be responsible for a partial reversion of the stem-like phenotype observed with prolonged PEI and PDC treatment. Several markers also indicate the cell death mode to be capable of inducing an anti-cancer immune response. This study thus indicates the potential therapeutic perspectives of polycations against CSCs.

Animal welfare concerns have been a challenging issue for producers and international marketing. In laying hen production, cage-free systems (CFS) have been identified as an alternative to ensure the laying hens' well-being. Nevertheless, in CFS, important environmental issues have been reported, decreasing indoor air quality. Environmental control strategies (ECS) have been designed to enhance indoor air quality in CFSs. However, little information exists about the effect of these ECSs on natural animal behaviors. Four strategies and one control were tested in an experimental CFS, previously designed to track behavioral variables using video recordings over seven time-lapses of 1 hour per day. Spatial occupancy (SO) and laying hen behaviors (LHB) were registered. One statistical analysis was applied to evaluate the effect of ECS on SO and LHB using a multinomial response model. Results show lower chances to use litter area within the reduction of litter allowance treatment (T17) ( p < 0.05). Neither the four ECSs nor the control implemented in this experiment affected the natural behaviors of the hens. However, stress patterns and high activity were reported in the T17 treatment. This study shows that it is possible to use these ECSs without disrupting laying hens' natural behaviors.

A chronic antigenic stimulation is believed to sustain the leukemogenic development of chronic lymphocytic leukemia (CLL) and most of lymphoproliferative malignancies developed from mature B cells. Reproducing a proliferative stimulation ex vivo is critical to decipher the mechanisms of leukemogenesis in these malignancies. However, functional studies of CLL cells remains limited since current ex vivo B cell receptor (BCR) stimulation protocols are not sufficient to induce the proliferation of these cells, pointing out the need of mandatory BCR co-factors in this process. Here, we investigated benefits of several BCR co-stimulatory molecules (IL-2, IL-4, IL-15, IL-21 and CD40 ligand) in multiple culture conditions. Our results demonstrated that BCR engagement (anti-IgM ligation) concomitant to CD40 ligand, IL-4 and IL-21 stimulation allowed CLL cells proliferation ex vivo. In addition, we established a proliferative advantage for ZAP70 positive CLL cells, associated to an increased phosphorylation of ZAP70/SYK and STAT6. Moreover, the use of a tri-dimensional matrix of methylcellulose and the addition of TLR9 agonists further increased this proliferative response. This ex vivo model of BCR stimulation with T-derived cytokines is a relevant and efficient model for functional studies of CLL as well as lymphoproliferative malignancies.

The high interest in N -Heterocyclic platinum carbene complexes in cancer research stems from their high cytotoxicity to human cancer cells, their stability, as well as their ease of functionalization. However, the development of these new molecules as anticancer agents still faces multiple challenges, in particular solubility in aqueous media. Here, we synthesized platinum-NHC bioconjugates that combine water-solubility and cytotoxicity by using polyethyleneimine as polymer carrier. We showed on 8 different types of cells that the activity of these conjugates is modulated by the size of the polymer and the overall density of metal ions onto polymer chains. Using HCT116 cells, the conjugates displayed an effective activity after only 45 min of exposure in vitro correlated with a quick uptake by the cells as shown by the use of various fluorescent-tagged derivatives.

Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL) appears as an interesting candidate for targeted cancer therapy as it induces apoptosis in cancer cells without toxicity to normal cells. TRAIL elicits apoptosis through agonist death receptor TRAIL-R1 and TRAIL-R2 engagement. Nevertheless, recombinant soluble TRAIL and monoclonal antibodies against these receptors demonstrated insufficient efficacy in clinical trials. This may be explained by the cell-type dependency of the apoptotic response, itself influenced by the effect on ligand binding mode of factors such as the level of receptor oligomerization or glycosylation. To investigate the relation between binding mode and signaling, we used previously described synthetic divalent and monovalent peptides specific for TRAIL-R2. We measured their pro-apoptotic activity on three cancer cell lines sensitive to rhTRAIL induced-apoptosis and monitored their cell-surface binding kinetics. The two divalent peptides bound with strong affinity to TRAIL-R2 expressed on B lymphoma BJAB cells and induced a high degree of apoptosis. By contrast, the same peptides bound weakly to TRAIL-R2 expressed at the surface of the human colon cancer HCT116 or T lymphoma Jurkat cell lines and did not induce their apoptosis. Cross-linking experiments suggest that these differences could be afforded by variations in the TRAIL-R2 oligomerization state at cell surface before ligand addition. Moreover divalent peptides showed a different efficiency in BJAB apoptosis induction, and kinetic distribution analysis of the BJAB binding curves suggested subtle differences in binding mechanisms. Thus our data support a relation between the cell-surface binding mode of the peptides and their pro-apoptotic activity. In this case the precise characterization of ligand binding to the surface of living cells would be predictive of the therapeutic potential of TRAIL-R2 synthetic ligands prior to clinical trials., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Physical oncology is an emerging paradigm which recognizes tissue mechanics, per se, as an active modulator of tumorigenesis, treatment resistance and clinical outcome, mediated by mechanosignaling pathways, matrix remodeling and physical barriers to drugs. The tumor microenvironment displays abnormal physical properties in comparison to healthy tissue which contribute to cancer progression and resistance to current treatments. Physical aberrancies comprise the chaotic organization of tumor vasculature, an increased interstitial pressure, an increased solid stress, hypoxia, an abundant extracellular matrix and a progressive stiffening of solid tumors. The physical barriers in tumors are of critical importance, as tissue mechanics compromises drug delivery, reduces immune cell infiltration and promotes disease aggressiveness. All these physical hallmarks of cancer, although not fully understood, are inspiring new anticancer strategies aiming to target and normalize the physical anomalies of solid tumors, particularly in the field of nanomedicine. Here we summarize the recent paradigm shift of physical oncology and review some of the proposed strategies using nanomaterials to tackle the tumor microenvironment and its aberrant physical properties. Nanomedicine might harness the features of the tumor microenvironment in order to improve nanoparticle and drug delivery, or propose nano-agents that can be activated on demand to achieve a tailored spatio-temporal modulation of the tumor microenvironment, reduce tumor pressure and stiffness and alleviate the resistance to current treatments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Heat stress negatively affects the health and performance of dairy cows, resulting in considerable economic losses for the industry. In future years, climate change will exacerbate these losses by making the climate warmer. Physical modification of the environment is considered to be the primary means of reducing adverse effects of hot weather conditions. At present, to reduce stressful heat exposure and to cool cows, dairy farms rely on shade screens and various forms of forced convection and evaporative cooling that may include fans and misters, feed-line sprinklers, and tunnel- or cross-ventilated buildings. However, these systems have been mainly tested in subtropical areas and thus their efficiency in humid continental climates, such as in the province of Québec, Canada, is unclear. Therefore, this study reviewed the available cooling applications and assessed their potential for northern regions. Thermal stress indices such as the temperature-humidity index (THI) were used to evaluate the different cooling strategies.

TNF receptor superfamily members (TNFRSF) such as CD40, Fas and TRAIL receptor 2 (TRAILR2) participate to the adaptive immune response by eliciting survival, proliferation, differentiation and/or cell death signals. The balance between these signals determines the fate of the immune response. It was previously reported that these receptors are able to self-assemble in the absence of ligand through their extracellular regions. However, the role of this oligomerization is not well understood, and none of the proposed hypotheses take into account potential hetero-association of receptors. Using CD40 as bait in a flow cytometry Förster resonance energy transfer assay, TNFRSF members with known functions in B cells were probed for interactions. Both Fas and TRAILR2 associated with CD40. Immunoprecipitation experiments confirmed the interaction of CD40 with Fas at the endogenous levels in a BJAB B-cell lymphoma cell line deficient for TRAILR2. TRAILR2-expressing BJAB cells displayed a robust CD40-TRAILR2 interaction at the expense of the CD40-Fas interaction. The same results were obtained by proximity ligation assay, using TRAILR2-positive and -negative BJAB cells and primary human B cells. Expression of the extracellular domains of Fas or TRAILR2 with a glycolipid membrane anchor specifically reduced the intrinsic signalling pathway of CD40 in 293T cells. Conversely, BJAB cells lacking endogenous Fas or TRAILR2 showed an increased NF-κB response to CD40L. Finally, upregulation of TRAILR2 in primary human B cells correlated with reduced NF-κB activation and reduced proliferation in response to CD40L. Altogether, these data reveal that selective interactions between different TNFRSF members may modulate ligand-induced responses upstream signalling events.

DR4 (Death Receptor 4) and DR5 (Death Receptor 5) are two potential targets for cancer therapy due to their ability to trigger apoptosis of cancer cells, but not normal ones, when activated by their cognate ligand TRAIL (TNF related apoptosis-inducing ligand). Therapies based on soluble recombinant TRAIL or agonist antibodies directed against one of the receptors are currently under clinical trials. However, TRAIL-R positive tumor cells are frequently resistant to TRAIL induced apoptosis. The precise mechanisms of this resistance are still not entirely understood. We have previously reported on synthetic peptides that bind to DR5 (TRAILmim/DR5) and induce tumor cell apoptosis in vitro and in vivo. Here, we showed that while hexameric soluble TRAIL is able to efficiently kill the DR5 positive lymphoma Jurkat or the carcinoma HCT116, these cells are resistant to apoptosis induced by the divalent form of TRAILmim/DR5 and are poorly sensitive to apoptosis induced by an anti-DR5 agonist monoclonal antibody. This resistance can be restored by the cross-linking of anti-DR5 agonist antibody but not by the cross-linking of the divalent form of TRAILmim/DR5. Interestingly, the divalent form of TRAILmim/DR5 that induced apoptosis of DR5 positive BJAB cells, acts as an inhibitor of TRAIL-induced apoptosis on Jurkat and HCT116 cells. The rapid internalization of DR5 observed when treated with divalent form of TRAILmim/DR5 could explain the antagonist activity of the ligand on Jurkat and HCT116 cells but also highlights the independence of the mechanisms responsible for internalization and activation when triggering the DR5 apoptotic cascade.

Oncolytic virotherapy is an emergent promising therapeutic approach for the treatment of cancer. We have constructed a vaccinia virus (WR strain) deleted for thymidine kinase (TK) and ribonucleotide reductase (RR) genes that expressed the fusion suicide gene FCU1 derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We evaluated this construct (VV-FCU1) in the orthotopic model of renal carcinoma (RenCa). Systemic administration of VV-FCU1 resulted in orthotopic tumor growth inhibition, despite temporary expression of viral proteins. VV-FCU1 treatment was associated with an infiltration of tumors by CD8 + T lymphocytes and a decrease in the proportion of infiltrating Tregs, thus modifying the ratio of CD8 + /CD4 + Treg in favor of CD8 + cytotoxic T cells. We demonstrated that VV-FCU1 treatment prolonged survival of animals implanted with RenCa cells in kidney. Depletion of CD8 + T cells abolished the therapeutic effect of VV-FCU1 while depletion of CD4 + T cells enhanced its protective activity. Administration of the prodrug 5-fluorocytosine (5-FC) resulted in a sustained control of tumor growth but did not extend survival. This study shows the importance of CD4 + and CD8 + T cells in vaccinia virus-mediated oncolytic virotherapy and suggests that this approach may be evaluated for the treatment of human renal cell carcinoma.

We present here the synthetic routes and the experimental data (NMR and MS spectra) for model reactions for copper-free Huisgen 1,4-cycloaddition, Staudinger ligation and for addition of a dithiol on a dibromomaleimide ring. Starting materials were synthesized from the commercially available 4-chlorophenethylamine, previously described 2-(cyclooct-2-yn-1-yloxy)acetic acid, 1-fluorocyclooct-2-ynecarboxylic acid, commercial 2-(diphenylphosphino)terephthalic acid 1-methyl 4-pentafluorophenyl diester and dibromomaleimide. In all cases, the expected compounds were obtained with good yield (50% to quantitative). A novel synthesis of the lipid anchor DOGP3NH2 is also described. These data were used as basis for the study reported in the article "Smart Tools and Orthogonal Click-like Reactions onto Small Unilamellar Vesicles" in Chemistry and Physics of Lipids [1].

Background: Intestinal phosphate binders, uremic toxin binders and some other types of supplements are an integral part of the management of chronic kidney disease (CKD) in various species, including cats. This pathology in domestic carnivores requires life-long nutritional and medical management. In this context, the compliance of owners and patients cannot be achieved without an adequate level of palatability for oral medication or supplementation. Knowing that hyporexia and anorexia are among the most commonly seen clinical signs in cats suffering from CKD this is already, in itself, a serious obstacle to acceptable compliance in sick animals. The aim of the present study was to investigate the palatability of four commercially available products designed for cats suffering from CKD: Ipakitine® (Vetoquinol, France), Azodyl® (Vetoquinol, USA), Renalzin® (Bayer, France), Rubenal® (Vetoquinol, France) and an additional recently developed product: Pronefra® (Virbac, France). The study was performed with a group of previously-characterised cats, all living in an enriched and well-being securing environment of an independent centre housing panels of pets expert in palatability measurement. In total 172 monadic testings were performed. The palatability of each product was assessed by measuring their rates of prehension and consumption, and the consumption proportions were also analysed., Results: The most palatable presentation (based on useful consumption) was Pronefra®, which was significantly higher than Azodyl® (p = 0.046), Ipakitine® (p < 0.0001), Renalzin® (p < 0.0001) and Rubenal® (p < 0.0001). The product with the highest rate of prehension was also Pronefra®, which was significantly higher than Azodyl® (p = 0.0019), Ipakitine® (p = 0.0023), Renalzin® (p = 0.0008) and Rubenal® (p < 0.0001)., Conclusion: Pronefra® was the most palatable presentation tested, meaning it may be useful for improving ease of supplementation in CKD cats.