Sialyl-Tn antigen (STn) is a short O-glycan containing a sialic acid residue a2,6-linked to GalNAca-O-Ser/Thr. The biosynthesis of STn is mediated by a specific sialyltransferase termed ST6GalNAc I, which competes with O-glycans elongating glycosyltransferases and prevents cancer cells from exhibiting longer O-glycans. While weakly expressed by fetal and normal adult tissues, STn is expressed by more than 80% of human carcinomas and in all cases, STn detection is associated with adverse outcome and decreased overall survival for the patients. Because of its pan-carcinoma expression associated with an adverse outcome, an anti-cancer vaccine, named Theratope, has been designed towards the STn epitope. In spite of the great enthusiasm around this immunotherapy, Theratope failed on Phase III clinical trial. However, in lieu of missing this target, one should consider to revise the Theratope design and the actual facts. In this review, we highlight the many lessons that can be learned from this failure from the immunological standpoint, as well as from the drug design and formulation and patient selection. Moreover, an irrefutable knowledge is arising from novel immunotherapies targeting other carbohydrate antigens and STn carrier proteins, such as MUC1, that will warrantee the future development of more successful anti-STn immunotherapy strategies.

Phosphomannomutase 2 (PMM2‐CDG) is the most common congenital disorder of N‐glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2‐CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2‐CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence‐based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2‐CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2‐CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2‐CDG patients.

The mononuclear phagocyte system comprises a network of circulating monocytes and dendritic cells (DCs), and “histiocytes” (tissue-resident macrophages and DCs) that are derived in part from blood-borne monocytes and DCs. The capacity of circulating monocytes and DCs to function as the body’s first-line defense against offending pathogens greatly depends on their ability to egress the bloodstream and infiltrate inflammatory sites. Extravasation involves a sequence of coordinated molecular events and is initiated by E-selectin-mediated deceleration of the circulating leukocytes onto microvascular endothelial cells of the target tissue. E-selectin is inducibly expressed by cytokines (tumor necrosis factor-α and IL-1β) on inflamed endothelium, and binds to sialofucosylated glycan determinants displayed on protein and lipid scaffolds of blood cells. Efficient extravasation of circulating monocytes and DCs to inflamed tissues is crucial in facilitating an effective immune response, but also fuels the immunopathology of several inflammatory disorders. Thus, insights into the structural and functional properties of the E-selectin ligands expressed by different monocyte and DC populations is key to understanding the biology of protective immunity and the pathobiology of several acute and chronic inflammatory diseases. This review will address the role of E-selectin in recruitment of human circulating monocytes and DCs to sites of tissue injury/inflammation, the structural biology of the E-selectin ligands expressed by these cells, and the molecular effectors that shape E-selectin ligand cell-specific display. In addition, therapeutic approaches targeting E-selectin receptor/ligand interactions, which can be used to boost host defense or, conversely, to dampen pathological inflammatory conditions, will also be discussed.

The amount of data collected and managed in (bio)medicine is ever-increasing. Thus, there is a need to rapidly and efficiently collect, analyze, and characterize all this information. Artificial intelligence (AI), with an emphasis on deep learning, holds great promise in this area and is already being successfully applied to basic research, diagnosis, drug discovery, and clinical trials. Rare diseases (RDs), which are severely underrepresented in basic and clinical research, can particularly benefit from AI technologies. Of the more than 7000 RDs described worldwide, only 5% have a treatment. The ability of AI technologies to integrate and analyze data from different sources (e.g., multi-omics, patient registries, and so on) can be used to overcome RDs’ challenges (e.g., low diagnostic rates, reduced number of patients, geographical dispersion, and so on). Ultimately, RDs’ AI-mediated knowledge could significantly boost therapy development. Presently, there are AI approaches being used in RDs and this review aims to collect and summarize these advances. A section dedicated to congenital disorders of glycosylation (CDG), a particular group of orphan RDs that can serve as a potential study model for other common diseases and RDs, has also been included.

Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how they contribute to the tilt immune response remains poorly defined. In this study, we sought to evaluate the impact of the malignant phenotype‐associated glycan, sialyl‐Tn (STn) in the function of the key orchestrators of the immune response, the dendritic cells (DCs). In high grade bladder cancer tissue, the STn antigen is significantly overexpressed and correlated with the increased expression of ST6GALNAC1 sialyltransferase. Bladder cancer tissue presenting elevated expression of ST6GALNAC1 showed a correlation with increased expression of CD1a, a marker for bladder immature DCs and showed concomitant low levels of Th1‐inducing cytokines IL‐12 and TNF‐α. In vitro, human DCs co‐incubated with STn+ bladder cancer cells, had an immature phenotype (MHC‐II^low, CD80^low and CD86^low) and were unresponsive to further maturation stimuli. When contacting with STn⁺ cancer cells, DCs expressed significantly less IL‐12 and TNF‐α. Consistent with a tolerogenic DC profile, T cells that were primed by DCs pulsed with antigens derived from STn⁺ cancer cells were not activated and showed a FoxP3^high IFN‐γ^low phenotype. Blockade of STn antigens and of STn⁺ glycoprotein, CD44 and MUC1, in STn⁺ cancer cells was able to lower the induction of tolerance and DCs become more mature.Overall, our data suggest that STn‐expressing cancer cells impair DC maturation and endow DCs with a tolerogenic function, limiting their capacity to trigger protective anti‐tumour T cell responses. STn antigens and, in particular, STn⁺ glycoproteins are potential targets for circumventing tumour‐induced tolerogenic mechanisms.

Bacteria belonging to the Burkholderia cepacia complex (BCC) are important opportunistic pathogens that lead to respiratory infections in patients with cystic fibrosis (CF). The clinical outcome following colonization with BCC bacteria is highly variable, and so far, unpredictable. A large percentage (80 to 90%) of BCC isolates from CF patients produce the exopolysaccharide (EPS) cepacian, which has been hypothesized to play a role in the colonization and persistence of these bacteria in the CF lung. In this work, we demonstrate that although it is not required for the initiation of biofilm formation, cepacian plays a role in the establishment of thick biofilms. This conclusion was based on a comparison of the abilities of EPS-defective mutants derived from a B. cepacia mucoid CF isolate by random plasposon insertion mutagenesis and the ability of the parental strain to form biofilms. However, the systematic characterization of 108 CF isolates, corresponding to 15 distinct strains, indicated that other strain-dependent factors are also involved in the development of thick, mature biofilms. The isolates examined belonged to the species B. cepacia , B. multivorans , B. cenocepacia , and B. stabilis and were obtained during a 7-year period of surveillance from 21 CF patients receiving care at the major Portuguese CF center. Most of them (90%) were serial isolates from 12 persistently infected patients. In spite of the concept that bacteria growing in biofilms display more resistance to antibiotics and to host phagocyte killing than do planktonically growing cells, no clear correlation could be established between the ability of the various strains examined to produce EPS and/or to form biofilms in vitro and the persistence or virulence of the respiratory infections they caused in different patients.