Glycan structures are common posttranslational modifications of proteins, which serve multiple important structural roles (for instance in protein folding), but also are crucial participants in ...cell–cell communications and in the regulation of immune responses. Through the interaction with glycan‐binding receptors, glycans are able to affect the activation status of antigen‐presenting cells, leading either to induction of pro‐inflammatory responses or to suppression of immunity and instigation of immune tolerance. This unique feature of glycans has attracted the interest and spurred collaborations of glyco‐chemists and glyco‐immunologists to develop glycan‐based tools as potential therapeutic approaches in the fight against diseases such as cancer and autoimmune conditions. In this review, we highlight emerging advances in this field, and in particular, we discuss on how glycan‐modified conjugates or glycoengineered cells can be employed as targeting devices to direct tumor antigens to lectin receptors on antigen‐presenting cells, like dendritic cells. In addition, we address how glycan‐based nanoparticles can act as delivery platforms to enhance immune responses. Finally, we discuss some of the latest developments in glycan‐based therapies, including chimeric antigen receptor (CAR)‐T cells to achieve targeting of tumor‐associated glycan‐specific epitopes, as well as the use of glycan moieties to suppress ongoing immune responses, especially in the context of autoimmunity.
Glycans are macromolecules that perform crucial roles in development, in cell–cell communication, and in the regulation of immune responses. In this review, we highlight how glycans can be exploited and empowered as treatment or vaccine modalities, particularly in the fight against cancer and autoimmune diseases.
Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen‐specific humoral and cellular ...immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T‐cell immunity in the fight against cancer. The recent SARS‐CoV‐2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan‐coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as “tumor‐associated carbohydrate antigens”. Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T‐cell‐independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.
In this review, the latest advancements in development of synthetic glycoconjugate vaccines in infection and cancer have been highlighted. We provide an overview on the role of different immunogenic constructs in the modulation of immune responses in cancer and in some relevant bacterial and viral infections according to the use of different carriers, the diversity of pathological epitopes targeted, and the mode of presentation to the immune system.
Purpose: We investigated the changes in the expression of proinflammatory cytokines and related molecules in the rodent hippocampus after the induction of limbic seizures. We then studied the effects ...of pharmacologic intervention on the interleukin (IL)‐1 system on limbic seizures and the susceptibility to seizures of transgenic mice overexpressing the naturally occurring antagonist of IL‐1 (IL‐1Ra) in astrocytes.
Methods: Limbic seizures were induced in rodents by intrahippocampal injection of kainic acid or bicuculline methiodide or by electrical stimulation of the hippocampus causing status epilepticus (SE). Seizure activity was recorded by EEG analysis and behavioral observation according to Racine's scale. Cytokine expression in the hippocampus was studied by reverse transcriptase–polymerase chain reaction (RT‐PCR) followed by Southern blot quantification of the various messenger RNAs (mRNAs) and by immunocytochemistry.
Results: We found that limbic seizures rapidly and transiently enhanced IL‐1β, IL‐6, and tumor necrosis factor (TNF)‐α mRNA in the hippocampus with a peak effect at 6 h after SE. Immunoreactivity of the various cytokines was increased in glia. The increase of IL‐1Ra was delayed because the peak effect was observed at 24 h after SE. Moreover, IL‐1Ra was not produced in large excess, as during peripheral inflammation but in a molar ratio to IL‐1β of 1:1. Intrahippocampal injection of IL‐1β worsened seizure activity, whereas IL‐1Ra was a powerful anticonvulsant in various models of limbic seizures. Transgenic mice overexpressing IL‐1Ra in astrocytes were less sensitive to bicuculline‐induced seizures.
Conclusions: This study shows that limbic seizures in rodents rapidly and reversibly induce proinflammatory cytokines in glia and suggests that changes in the IL‐1Ra/IL‐1β ratio in brain may represent an effective physiopathologic mechanism to control seizures.
The purpose of this study was to assess the efficacy of buccal misoprostol to decrease uterine atony, hemorrhage, and the need for additional uterotonic agents during cesarean delivery.
Patients who ...underwent cesarean delivery were assigned randomly to either 200-μg misoprostol or placebo placed in the buccal space. A dilute intravenous oxytocin infusion was given to all patients at delivery of the placenta. The primary outcome variable was the need for additional uterotonic agents.
A total of 352 women received random assignments. Demographic and intrapartum characteristics were similar between the groups. More women in the placebo group required 1 additional uterotonic agent (43% vs 26%;
P < .01; relative risk, 1.3; 95% CI, 1.10, 1.50). There was not a difference between the groups in the incidence of postpartum hemorrhage or a difference in preoperative and postoperative hemoglobin level.
Buccal misoprostol reduces the need for additional uterotonic agents during cesarean delivery.
To compare oral rofecoxib with intravenous magnesium sulfate as a tocolytic.
This was a randomized study of patients who were between 22 and 34 weeks of gestation with preterm labor. Patients were ...randomly assigned to receive either daily oral rofecoxib (50 mg) or intravenous magnesium sulfate for a maximum of 48 hours. Outcome variables included delay of delivery for 48 hours and the incidence of side effects. Data were analyzed by using the Student t test, Mann-Whitney U test, chi(2) test, and repeated-measures analysis of variance. Sample size calculations were based on previous studies of tocolytic efficacy.
Two hundred fourteen patients were randomly assigned (105 received rofecoxib and 109 received magnesium sulfate). Delivery was delayed for 48 hours in 95 (90.4%) and 96 (88%) of the patients in the rofecoxib and magnesium sulfate groups, respectively (relative risk 0.97; 95% confidence interval 0.89, 1.06). To show a statistically significant benefit in delay of delivery past 48 hours, a total of 2,686 patients would be required in each group. There was no difference between the groups over the course of the study in cervical dilatation, amniotic fluid index, or cervical length by vaginal ultrasonography. The median hospital days on the original admission were also similar at 2 for both groups (P =.10). There was a higher reported incidence of maternal side effects in the magnesium sulfate group (relative risk 1.81; 95% confidence interval 1.07, 3.06). There was no difference in the incidence of neonatal side effects.
There was no difference between oral rofecoxib and intravenous magnesium sulfate in arresting preterm labor.
To assess the efficacy of buccal misoprostol to decrease bleeding after vaginal delivery.
This was a randomized study of patients between 22 weeks and 42 weeks of gestation with anticipated vaginal ...delivery. Patients were given either a 200-mug misoprostol tablet or placebo in the buccal space at the time of cord clamping. A continuous dilute intravenous oxytocin infusion was given to all patients at delivery of the placenta. Postpartum hemorrhage was defined as blood loss exceeding 500 mL. Sample size calculations based on previous studies assumed a 13% incidence of postpartum hemorrhage in the control group. To show a statistically significant reduction of postpartum hemorrhage a total of 1,604 patients would be required in each group.
A total of 848 patients were enrolled and 756 randomly assigned, 377 in the misoprostol group and 379 in the placebo group. Demographic, antepartum, and intrapartum characteristics were similar between the groups. The incidence of postpartum hemorrhage, 3% compared with 5%, (relative risk 0.65, 95% confidence interval 0.33-1.29, P = .22), mean estimated blood loss, 322 compared with 329 mL, (P = .45), and mean minutes of the third stage of labor, 6.7 compared with 6.9 (P = .52) were similar between the groups, misoprostol and placebo, respectively. Hemoglobin difference before and after delivery, need for second or third uterotonic agent, and all measured neonatal variables including birth weights, and umbilical cord pH were similar between the groups.
Buccal misoprostol at cord clamping is no more effective than placebo in reducing postpartum hemorrhage.
OBJECTIVE:
To determine whether serial oral misoprostol shortens the third stage of labor in second-trimester pregnancy loss.
METHODS:
This was a randomized, double-blind, placebo-controlled study of ...women between 13 and 28 weeks’ gestation admitted for spontaneous or induced pregnancy termination. Subjects were randomized to receive either misoprostol (200 μg) or placebo orally every hour for a maximum of three doses if the placenta had not delivered spontaneously within 10 minutes of the fetus. A dilute oxytocin infusion was given to women in both groups. The patients were managed expectantly until intervention was required or up to 6 hours when curettage was scheduled.
RESULTS:
One hundred eighteen women were randomized to misoprostol and 119 randomized to placebo. Fifty-eight (49%) and 55 (46%) of the misoprostol and placebo groups, respectively, did not receive their medication (P = .65, χ2 test). There was no difference between the groups with regard to demographic features, method of pregnancy termination, or gestational age. Sixty-seven (57%) and 62 (52%) of the misoprostol and placebo groups, respectively, completed the third stage of labor within 2 hours (P = .47, χ2 test). There was no statistically significant difference in the median time from fetus to placenta (60 versus 91 minutes in the misoprostol versus placebo group, P = .57, Mann-Whitney U test). There was no difference between the groups in the incidence of hemorrhage, need for transfusion, or curettage rate.
CONCLUSION:
The therapeutic use of oral misoprostol in the third stage of labor in second-trimester pregnancy loss does not reduce the time to complete spontaneous placental delivery.
Multivalency plays a major role in biological processes and particularly in the relationship between pathogenic microorganisms and their host that involves protein-glycan recognition. These ...interactions occur during the first steps of infection, for specific recognition between host and bacteria, but also at different stages of the immune response. The search for high-affinity ligands for studying such interactions involves the combination of carbohydrate head groups with different scaffolds and linkers generating multivalent glycocompounds with controlled spatial and topology parameters. By interfering with pathogen adhesion, such glycocompounds including glycopolymers, glycoclusters, glycodendrimers and glyconanoparticles have the potential to improve or replace antibiotic treatments that are now subverted by resistance. Multivalent glycoconjugates have also been used for stimulating the innate and adaptive immune systems, for example with carbohydrate-based vaccines. Bacteria present on their surfaces natural multivalent glycoconjugates such as lipopolysaccharides and S-layers that can also be exploited or targeted in anti-infectious strategies.
In this work, we have discovered that the Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc trisaccharide, a fragment of the B antigen Type‐1, is a new ligand of two C‐type lectin receptors (CLRs) i. e. DCAR and Mincle ...which are key players in different types of autoimmune diseases. Accordingly, we report here on a straightforward methodology to access pure Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc trisaccharide. A spacer with a terminal primary amine group was included at the reducing end of the GlcNAc residue thus ensuring the further functionalization of the trisaccharide Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc.
The identification and synthesis of a new ligand for two C‐type lectin receptors, i. e. dendritic cell activating receptor (DCAR) and macrophage‐inducible C‐type lectin (Mincle), are described.
The potential benefits of active school travel (AST) are widely recognized, yet there is consistent evidence of a systematic decline in the use of active modes of transportation to school since the ...middle part of the 20th century. This study explored parental accounts of the school travel mode choice decision-making process.
Thirty-seven parents of children (17 who walked; 20 who were driven) from four elementary schools in Toronto, Canada participated in semi-structured interviews. The schools varied with respect to walkability of the built environment and socio-economic status. Thematic analysis of interview transcripts identified a two-stage decision-making process.
An initial decision concerned the issue of escorting or chauffeuring a child to/from school. This decision appeared to be primarily influenced by concerns about traffic, the child's personal safety, and the child's maturity and cognitive ability regarding navigating his/her way to/from school safely. Following the escort decision, parents considered mode choice, typically selecting what they perceived to be the easiest and most convenient way to travel. The ascription of convenience to the various modes of transportation was influenced by perceptions of travel time and/or distance to/from school. Convenience became a particularly salient theme for parents who found it necessary to complete multi-activity trip chains.
The school travel mode choice decision process is complex. Future research and practice should continue to address safety concerns that are typically the focus of active school transport initiatives while addressing more explicitly the behavioural cost of competing mode choices.
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