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In the last decade, there has been a surge in developing immunotherapies to enhance the immune system's ability to eliminate tumor cells. Bispecific antibodies known as T cell engagers (TCEs) present an attractive strategy in this pursuit. TCEs aim to guide cytotoxic T cells toward tumor cells, thereby inducing a strong activation and subsequent tumor cell lysis. In this study, we investigated the activity of different TCEs on both conventional alpha-beta (αβ) T cells and unconventional gamma delta (γδ) T cells. TCEs were built using camelid single-domain antibodies (VHHs) targeting the tumor-associated antigen CEACAM5 (CEA), together with T cell receptor chains or a CD3 domain. We show that Vγ9Vδ2 T cells display stronger in vitro antitumor activity than αβ T cells when stimulated with a CD3xCEA TCE. Furthermore, restricting the activation of fresh human peripheral T cells to Vγ9Vδ2 T cells limited the production of protumor factors and proinflammatory cytokines, commonly associated with toxicity in patients. Taken together, our findings provide further insights that γδ T cell-specific TCEs hold promise as specific, effective, and potentially safe molecules to improve antitumor immunotherapies., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.

Elevated expression of the c -MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c -MYC protein levels in a MYC- amplified cell line led to the discovery of a compound series that phenocopies c -MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c -MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.

Purpose: Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of nonalloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, in vitro and in vivo , in the absence of any prior sensitization., Experimental Design: Through functional and transcriptomic analyses, we extensively characterized the immunoreactivity of human Vγ9Vδ2 T lymphocytes against various primary GBM cultures directly derived from patient tumors., Results: We evidenced that GBM cells displaying a mesenchymal signature are spontaneously eliminated by allogeneic human Vγ9Vδ2 T lymphocytes, a reactivity process being mediated by γδ T-cell receptor (TCR) and tightly regulated by cellular stress-associated NKG2D pathway. This led to the identification of highly reactive Vγ9Vδ2 T lymphocyte populations, independently of a specific TCR repertoire signature. Moreover, we finally provide evidence of immunotherapeutic efficacy in vivo , in the absence of any prior tumor cell sensitization., Conclusions: By identifying pathways implicated in the selective natural recognition of mesenchymal GBM cell subtypes, accounting for 30% of primary diagnosed and 60% of recurrent GBM, our results pave the way for novel targeted cellular immunotherapies., (©2019 American Association for Cancer Research.)

Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required. Adoptive transfer(s) of immune effector cells, including allogeneic human Vγ9Vδ2 T lymphocytes, represent attractive targets for efficiently and safely tracking tissue-invading tumor cells and controlling tumor dissemination in the organism. Our study describes the establishment of robust and physiological orthotopic model of human EOC in mouse, that includes surgical resection (ovariectomy) and chemotherapy, which are ineluctably accompanied by a fatal peritoneal carcinosis recurrence. Through a complementary set of in vitro and in vivo experiments, we provide here a preclinical proof of interest of the antitumor efficiency of adoptive transfers of allogeneic human Vγ9Vδ2 T lymphocytes against EOC, in association with surgical debulking and standard chemotherapies (i.e., taxanes and platinum salts). Moreover, our results indicate that chemo- and immunotherapies can be combined to improve the antitumor efficiency of immunotherapeutic lines. Altogether, these results further pave the way for next-generation antitumor immunotherapies, based on local administrations of human allogeneic human Vγ9Vδ2 T lymphocytes, in association with standard treatments., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Inadequate oral care in long-term care (LTC) facilities compromises the quality of life of residents. This study assessed oral care knowledge of, and challenges experienced by, nurses and allied nursing staff (ANS) in a LTC facility in Canada. Dentists and nursing staff used the findings to implement strategies for improved care. Using a sequential mixed method design, data on oral care knowledge and practices were collected using self-administered questionnaires (n = 114) and focused groups (n = 39). Data were analyzed using descriptive statistics and thematic analysis. While participants (>80%) felt knowledgeable and confident in providing oral care, they desired improved skills to overcome resistive behavior, communication, and wanted adapted oral care materials. Implemented strategies included skills-acquisition workshop, oral care posters, and oral health champion. Overall, our interprofessional collaboration increased awareness of the need for oral care training, and implemented strategies to help nursing staff overcome barriers in providing care., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Progresses in childhood cancer treatment, diagnosis, and management have resulted in childhood cancer survival rates of over 80%. However, this therapeutic success comes with a heavy price: two-thirds of childhood cancer survivors will be affected by further complications, including cardiovascular and metabolic diseases. Adequate nutrition during cancer treatment is essential to ensure the child's optimal development, improve tolerance to treatments, and can contribute to lower the risk of developing cardiometabolic diseases. Side effects of cancer treatments can negatively impact children's nutritional intake and eating behaviors. Involving the families of childhood cancer patients in educational workshops could be a promising avenue to promote healthy eating during and after cancer treatment., Objective: The objectives of this study were to develop, validate, and implement a family-based nutrition education and cooking workshop curriculum in a pediatric oncology setting that addresses the nutritional issues encountered during treatments while promoting the adoption of healthy eating habits for the prevention of long-term cardiometabolic effects., Methods: The workshops were developed and validated following an 8-step iterative process, including a review of the literature and consultations with a steering committee. An evaluation tool was also developed. A nonrandomized study protocol was elaborated to implement the workshops and measure their impact. The themes of the 6 research- and practice-based lessons are as follows: meal fortification during cancer treatment, changes in taste during cancer therapy and their impact on children, adapting diet to eating-related side effects of treatments, nutritional support during cancer treatment, Mediterranean diet and health, and planning quick and economic meals. The validation process included consultations with the institution's clinical nutrition professionals. Self-administered post questionnaires were developed according to the content of each workshop to measure short-term outcomes, namely, participants' perception of knowledge acquisition, behavioral intention, and satisfaction. Medium-term outcomes that will be evaluated are participants' anthropometric profile, quality of the diet, and circulating biomarkers of metabolic health., Results: The project was funded in 2016 and enrollment will be completed in 2021. Data analysis is currently under way and the first results are expected to be submitted for publication in 2019., Conclusions: This research- and practice-based nutrition education and cooking demonstration curriculum could be a valuable complement to a multidisciplinary lifestyle intervention for the prevention of long-term cardiometabolic complications in childhood cancer., (©Cynthia Chaput, Sabrina Beaulieu-Gagnon, Véronique Bélanger, Simon Drouin, Laurence Bertout, Lucie Lafrance, Cinthia Olivier, Marthe Robitaille, Caroline Laverdière, Daniel Sinnett, Marie Marquis, Valérie Marcil. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 09.01.2018.)

Histone methyltransferases (HMT) catalyze the methylation of histone tail lysines, resulting in changes in gene transcription. Misregulation of these enzymes has been associated with various forms of cancer, making this target class a potential new area for the development of novel chemotherapeutics. EZH2 is the catalytic component of the polycomb group repressive complex (PRC2), which selectively methylates histone H3 lysine 27 (H3K27). EZH2 is overexpressed in prostate, breast, bladder, brain, and other tumor types and is recognized as a molecular marker for cancer progression and aggressiveness. Several new reagents and assays were developed to aid in the identification of EZH2 inhibitors, and these were used to execute two high-throughput screening campaigns. Activity assays using either an H3K27 peptide or nucleosomes as substrates for methylation are described. The strategy to screen EZH2 with either a surrogate peptide or a natural substrate led to the identification of the same tractable series. Compounds from this series are reversible, are [(3)H]-S-adenosyl-L-methionine competitive, and display biochemical inhibition of H3K27 methylation.

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice., (Copyright 2009 Elsevier Ltd. All rights reserved.)

A novel series of potent and selective alpha(v)beta(3)/alpha(v)beta(5) dual( )()inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the guanidinium mimetics and the corresponding central templates. Guanidinium mimetics with enhaced rigidity (i.e., (2-pyridylamino)propoxy versus the 2-(6-methylamino-2-pyridyl)ethoxy) led to improved activity toward alpha(v)beta(3). Exemplary oral bioavailability in mice was achieved using the indole central scaffold. Although, oral bioavailability was maintained when the indole molecular core was replace with the bioisosteric benzofuran or benzothiophene ring systems, it was found to not significantly impact the integrin activity or selectivity. However, the indole series displayed the best in vivo pharmacokinetic properties. Thus, the indole series was selected for further structure-activity relationships to obtain more potent alpha(v)beta(3)/alpha(v)beta(5) dual antagonist with improved oral bioavailability.

/ It has been suggested that the general public should be moreinvolved in environmental policy and decision making. It is important forthem to realize that they will have to live with the consequences ofenvironmental policies and decisions. Consequently, policy makers shouldconsider the concerns and opinions of the general public before makingdecisions on environmental issues. This raises questions such as: How can weintegrate the perceptions and reactions of the general population inenvironmental decisions? What kind of public participation should weconsider? In the present study, using a new regional ecosystem model, weattempted to integrate these aspects in its decision making model byincluding the formation of an advisory committee to resolve problems relatedto waste management. The advisory committee requested the activeparticipation of representatives from all levels of the community: economic,municipal, and governmental intervenors; environmental groups; and citizens.Their mandates were to examine different management strategies available inthe region, considering all the interdisciplinary aspects of each strategy,elaborate recommendations concerning the management strategies that are mostsuitable for all, and collaborate in communication of the information to thegeneral population. The results showed that at least in small municipalitiessuch an advisory committee can be a powerful tool in environmental decisionmaking. Conditions required for a successful consultation process, such aseveryday lay language and the presence of a facilitator other than ascientific expert, are discussed.KEY WORDS: Public consultation; Environmental policies;Interdisciplinary aspects; Municipal sewage sludge management; Generalpopulation; Decision-making process

Heparin is a highly sulfated long-chain glycosaminoglycan utilized extensively for its anticoagulation properties, which has found widespread use as a general affinity ligand. The polysaccharide is composed of repeating units of uronic acid and glucosamine with great variability in sequence within the chain. The high degree of sulfation imparts strong acidity to the molecule and it may bond with many compounds simply by ionic interaction. In addition, it has been established that heparin contains certain specific monosaccharide sequences which act as unique binding sites for some proteins. For utilization as a biospecific affinity ligand it has been reported that heparin may optimally be immobilized by a single point of attachment through a terminal sugar residue. This method of immobilization allows unrestricted access to sequences within the polysaccharide chain required for biospecific interaction. Heparin immobilized to beaded agarose by single point attachment through its terminal formyl moiety was prepared. Chromatographic performance characteristics were evaluated using thrombin and antithrombin III as model compounds and elution profiles are presented. Additionally, stability of attachment was directly compared to several other commercially available supports. In conclusion, this end-point attached affinity matrix demonstrates high capacity and good stability compared with that of other methods of preparation.

Objective: The objective of this pilot study was to determine the number of patients required for a randomized controlled trial of spinal manipulation for neck pain and to determine if there is a relationship between pain and range of motion (ROM) in the cervical spine., Design: Fifty consecutive outpatients were studied in a pretest-posttest design without long-term follow-up., Setting: The patients were taken from a primary cae outpatient teaching clinic specializing in back pain., Patients: All patients had unilateral neck pain without neurological deficit. The patients were selected as a consecutive sample., Intervention: All the patients received a single cervical manipulation., Main Outcome Measures: Prior to and immediately after the treatment, cervical ROM was recorded on a goniometer, and pain intensity was rated on the 101-point numerical rating scale., Results: The results show an increase in all planes of post-treatment ROM and a decrease in post-treatment pain scores. Partial correlations between post-treatment ROM and 101-point numerical rating scale scores reveal a significant relationship between a decrease in pain and an increase in cervical rotation (p < .005)., Conclusions: Since the results of this pilot study are not controlled, they cannot be seen as proof supporting the clinical efficacy of manipulation for neck pain. However, the correlation between an increase in cervical rotation and a decrease in pain is clinically instructive. In addition, the outcome measures used in this study could prove to be useful in the design of future randomized controlled trials of cervical manipulation.

Facial consummatory responses reflecting ingestive and aversive perceptions were studied and quantified in rats chronically implanted with gastric and oral catheters. A gustatory stimulus of 50 microliters of 1.75 mol.1-1 sucrose was injected into the mouth every 5 min during 60 min. At time zero, 1.7 ml of 3.3 mol.1-1 glucose was injected into the stomach. Typical ingestive facial consummatory responses were observed in response to sweet stimuli prior to the gastric load. Aversive consummatory responses were observed in response to sweet stimuli after the glucose gastric load (negative alliesthesia). The rats were then fasted until they had lost about 14% of their body weight (from 411 +/- 34 g to 353 +/- 28 g). When lean, the rats were subjected to the same gustatory session as in the control period described above. In lean rats the gastric load of glucose was not followed by negative alliesthesia in response to sweet oral stimuli. In the last part of the experiment the rats were fed ad lib and they recovered their initial body weight. When the rats were subjected again to the same gustatory sessions, the gastric load was followed by negative alliesthesia in response to sweet stimuli. Thus, after recovering their initial body weight, the rats displayed the same response as in the control sessions prior to losing weight. These results in rats parallel results obtained in human subjects, and reinforce the hypothesis of the existence of a ponderostat regulating body mass.

Following a subcutaneous injection of adrenaline (300 mug/kg), blood-glucose levels were lower in rats treated chronically with adrenaline (300 mug/kg twice a day for 28 days) than in control rats during at least 2.5 h after the injection. To explain this difference of response, the turnover rate of glucose was measured in control and adrenaline-treated rats during adrenaline infusion (0.75 mug/kg- minus 1 min- minus 1), with [U- minus 14C]glucose as tracer. It was found that the rate of appearance of glucose was greater in the control than in the adrenaline-treated group after a 120-min infusion of adrenaline. The rate of disappearance of glucose in the treated rats increased during the first 60 min of infusion and stayed at this elevated level for a subsequent 2 h, whereas in the control rats, it remained unchanged at the beginning of adrenaline infusion and significantly increased only during the second and third hours of infusion. In addition, the metabolic- clearance rate of glucose was not modified by adrenaline in the treated group, but in the control group, the initial clearance rate was significantly less than in the treated group, and decreased during the first hour of adrenaline infusion even though blood glucose reached values of 244 mg/100 ml. ,rom these data, it is suggested that rats adapt to a chronic exogenous supply of adrenaline by a reduced increase in glucose production in response to adrenaline infusion and a better glucose utilization, which possibly indicates a decrease in the inhibitory effect of adrenaline on insulin secretion.

Dynorphin-(1-13) (Dyn-(1-13)) and various analogs substituted in positions 8 and 10 were synthesized by the solid-phase technique and analyzed for their ability to inhibit the electrically evoked contraction of the guinea pig ileum (GPI) and to compete with the binding of [3H]-ethylketocyclazocine (EKC, kappa ligand), [3H]-[D-Ala2, MePhe4-Gly-ol5]-enkephalin (DAGO, mu ligand) and [3H]-[D-Ser2, Thr6]-Leu-enkephalin (DSLET, delta ligand) to membrane preparations of the guinea pig cerebellum or rat brain. Introduction of Ala in position 8 decreased the activity of the peptide on the GPI by 50% but induced a 2.22-fold increase in its affinity for the kappa receptor ([3H]-EKC binding displacement from guinea pig cerebellum; Ki of 0.05 nM as compared with 0.11 nM for Dyn-(1-13)). On the other hand, the ability of [Ala8] Dyn-(1-13) to displace the binding of [3H]-DSLET from rat brain membranes was decreased by a factor of 1.7 while its affinity for the mu receptor was not greatly affected ([3H]-DAGO displacement; Ki of 0.44 nM as compared with 0.50 nM for Dyn-(1-13)). Replacement of position 8 by D-Ala caused similar changes in the activity of the peptide but the increase in its affinity for the kappa site was somewhat smaller (Ki of 0.08 nM as compared with 0.11 nM). [D-Pro10]-Dyn-(1-13) was equipotent to [Ala8]-Dyn-(1-13) in the GPI but its affinity for the mu binding site was decreased by a factor of 2.7 as compared with Dyn-(1-13).(ABSTRACT TRUNCATED AT 250 WORDS)

A 3-h noradrenaline (NA) infusion (1.5 microgram kg-1 min-1) produced a sustained enhanced oxygen consumption (O2 cons.) in cold-adapted rats. Plasma free fatty acid (FFA) levels were elevated by NA in control and in cold-adapted rats, but to lesser extent in cold-adapted rats; the increase was maintained at a plateau in both groups during the entire period of NA infusion. A 1-h nicotinic acid (Nic A) infusion (1.5 mg kg-1 min-1) added to the NA infusion inhibited the calorigenic response to NA in cold-adapted rats and reduced the elevated plasma FFA concentration in control and in cold-adapted rats to values below basal levels. However, when the Nic A infusion was stopped, the O2 cons. was increased again in cold-adapted rats by the uninterrupted NA infusion, without the simultaneous increase of the plasma FFA concentration; the plasma FFA concentration was maintained in cold-adapted rats below basal values and merely brought back to basal levels in control rats. From these results, it is suggested that plasma FFA are not an essential substrate to the calorigenic response to NA observed in cold-adapted rats, as 85% of the response can occur when the plasma FFA concentration is very low.