A unique serum IgG glycosylation signature predicts development of Crohn's disease and is associated with pathogenic antibodies to mannose glycan.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn's disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome-ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome-ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.

Glycome dynamics in T and B cell development: basic immunological mechanisms and clinical applications.

Glycans cover the surfaces of all mammalian cells through a process called glycosylation. Nearly all proteins and receptors that integrate the intricate series of co-stimulatory/inhibitory pathways of the immune system are glycosylated. Growing evidence indicates that the development of the immune system at the origins of T and B cell development is tightly regulated by glycosylation. In this opinion, we hypothesize that the glycome composition of developing T and B cells is developmentally regulated. We discuss how glycans play fundamental roles in lymphocyte development and how glycans early define T and B cell functionality in multiple aspects of adaptive immunity. These advances can provide opportunities for the discovery of novel disease factors and more effective candidate treatments for various conditions.

Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding.

Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.

Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player.

Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.

Colitis-associated cancer (CAC) is a major complication of inflammatory bowel disease and the molecular mechanisms underlying CAC progression are still elusive. Protein glycosylation holds a great promise for improving the understanding of CAC immunopathogenesis, opening new avenues for clinical and therapeutic interventions.

Brain Metastasis of Follicular Thyroid Carcinoma in Pregnancy: A Case Report and Literature Review.

Brain metastases (BMs) related to cancer are quite common and represent the most common brain cancer. We present a rare case of a 32-year-old female, 36 weeks pregnant, admitted to the emergency with complaints of severe headache, vomiting, and left hemiparesis associated with drowsiness. Cranial tomography showed an image suggestive of an expansive lesion in the right front-temporo-insular region with an important mass effect. The result of biopsy with immunohistochemistry was compatible with metastasis of follicular thyroid carcinoma (FTC). The knowledge of neurological characteristics in the clinical analysis of patients with thyroid carcinoma must be highly valued, both in the correct interpretation of the signs and in the early investigation through skull imaging exams.

Hábitos alimentares de acadêmicas do primeiro e do último ano de cursos de graduação em nutrição no Estado do Maranhão / Nutrition academic freshman and senior food habits in state of Maranhão

OBJECTIVE: To assess the dietary habits of freshman and senior female students in Nutrition at three institutions in the state of Maranhão. METHODS: The study included 254 students. Nutritional status was assessed by body mass index, using self-reported weight and height. Dietary intake was assessed by questionnaire "How is your food intake?" and Food Frequency Questionnaire (FFQ) by the Ministry of Health. Analyses were processed using Stata 10.0 software, using the Shapiro Wilk test, Student t test,chi- square and exact Fischer. The adopted significance level was 5%. RESULTS: The group average age was 21 years old, and it was mostly eutrophic (65.8%), with no difference between students of the first and last year (p=0.556). The most skipped meal was breakfast (16.5%), especially among the first academic year (p=0.017). The group was classified as follows: 5.1% need to make their eating habits and lifestyles healthier,73.6% need attention regarding their food intake and other associated health habits and21.3% have a healthy lifestyle. The academic graduates proved healthier than freshmen (p=0.020). The daily consumption of fruits, vegetables and dairy products was reported by only 22.4%, 44.1% and 40.2% of them, and those of the previous year showed higher proportions (p value: 0.001, 0.005, and 0.020, respectively). CONCLUSIONS: Few academic students showed nutrition showed with healthy

OBJETIVO: Avaliar os hábitos alimentares de acadêmicas do primeiro e último ano do curso de graduação em Nutrição em três instituições do estado do Maranhão, Brasil. MÉTODOS: Participaram do estudo 254 estudantes. O estado nutricional foi avaliado pelo Índice de Massa Corpórea, usando-se peso e estatura autorreferidos. Os hábitos alimentares foram avaliados pelo questionário "Como está sua alimentação?" e Questionário de Frequência Alimentar do Ministério da Saúde. As análises foram processadas no programa Stata 10.0, usando-se os testes Shapiro Wilk, t de Student, Qui-quadrado e exato de Fischer. Adotou-se o nível de significância de 5%. RESULTADOS: O grupo apresentou idade mediana de 21 anos, e era em sua maioria eutrófica (65,8%), sem diferença entre alunas do primeiro e último ano (p=0,556). A refeição mais omitida foi o desjejum (16,5%), especialmente entre as acadêmicas do primeiro ano (p=0,017). O grupo foi assim classificado: 5,1% precisam tornar sua alimentação e hábitos de vida mais saudáveis, 73,6% precisam de atenção quanto a sua alimentação e outros hábitos associados à saúde e 21,3% apresentam estilo de vida saudável. A avaliação pelo questionário 'como está sua alimentação?' apontou para uma situação mais favorável entre as alunas do último ano (p=0,020). O consumo diário de frutas, hortaliças e laticínios foi relatado por apenas 22,4%, 44,1% e 40,2% delas, respectivamente, sendo que aquelas do último ano apresentaram maiores proporções (p valor: 0,001; 0,005; e 0,020, respectivamente). CONCLUSÕES: Foi baixa a frequência de acadêmicas de Nutrição que apresentaram hábitos alimentares e estilo de vida saudáveis, sendo a situação ainda pior entre as alunas ingressantes

Polyomavirus persistence in lymphocytes: prevalence in lymphocytes from blood donors and healthy personnel of a blood transfusion centre.

BK and JC polyomaviruses (BKV and JCV) are widespread in humans and are thought to persist and reactivate under immune alterations. In addition to the kidney, lymphoid cells have been proposed as a site of latency. However, while this was shown to occur in immunocompromised patients, discordant data were published for healthy humans. To help to solve this issue, an extensive study (231 healthy subjects) was carried out on peripheral blood mononuclear cells (PBMC) from blood donors of two towns and from operators of a blood transfusion centre. To discriminate between past and recent infection, nested PCRs for BKV and JCV non-coding control region (NCCR) and VP1 DNA sequences were carried out. Twenty-two per cent of subjects had BKV NCCR, but only 7% also had BKV VP1, as detected by PCR assays of similar sensitivities; the latter positivity was found to decrease with age. In both towns, the BKV WW archetypal DDP strain, subtype I, was found. Only 0.9% of subjects contained JCV DNA, for both NCCR and VP1. Blood operators presented a statistically significant increased prevalence of BKV NCCR (3. 0-fold) and BKV VP1 (9.4-fold) sequences with respect to blood donors of comparable ages, suggesting the possibility of occupational risk of BKV (re)infection or reactivation. Since the possibility of amplifying BKV VP1 sequences from PBMC of healthy humans is lost with age, this suggests that PBMC are not a site of polyomavirus persistence in healthy individuals and that detection of BKV VP1 DNA in PBMC is probably indicative of recent infection or reactivation.

Human immunodeficiency virus infection in vitro activates naturally integrated human papillomavirus type 18 and induces synthesis of the L1 capsid protein.

Human papillomavirus (HPV) infections are prevalent in human immunodeficiency virus (HIV)-positive individuals. To highlight the effect of HIV on HPV expression, HPV-18-positive HIV-permissive HeLa-T4 cells were either infected with HIV-1 or treated with Tat or with the cytokines IL-1alpha, IL-1beta, IL-6 and TNF-alpha. The presence of HPV-18 E1 (early) and L1 (late) transcripts was then determined by dot-blot or Northern blot hybridization with E1 and L1 or with genomic HPV-18 DNA probes, respectively. Protein extracts from parallel cultures were challenged by Western blotting with an antiserum raised against an L1-beta-galactosidase hybrid protein. Results indicated that HeLa-T4 cells constitutively express E1 and L1 transcripts. When cells were infected with HIV, the amounts of E1 and L1 RNAs increased with time, followed by the de novo appearance of L1 protein. E1 and L1 transcripts were also increased, in a dose-dependent manner, by treatment of uninfected cultures with Tat or with IL-6, but were not affected by IL-1alpha, IL-1beta and TNF- alpha. Neither Tat nor IL-6 could induce L1 translation. These findings raise the hypothesis that the increase of HPV shedding and of HPV-associated diseases in HIV-infected individuals could be due in part to a direct or cytokine-mediated action of HIV, in addition to the HIV-induced immunodeficiency.