Differences in Self-Reported Food Allergy and Food-Associated Anaphylaxis by Race and Ethnicity Among SAPPHIRE Cohort Participants.

BACKGROUND: Although food allergies are considered common, relatively little is known about disparities in food allergy by race in the United States. OBJECTIVE: To evaluate differences in reported food allergy and food-associated anaphylaxis among individuals enrolled in a longitudinal cohort study from metropolitan Detroit, Michigan. METHODS: Participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) were asked about food allergies, including the inciting food and associated symptoms. Individuals were considered to have food-associated anaphylaxis if symptoms coincided with established clinical criteria. Logistic regression was used to assess whether race difference persisted after adjusting for and stratifying by potential confounders. African genetic ancestry was individually estimated among African American SAPPHIRE participants to assess whether ancestry was associated with food allergy. RESULTS: Within the SAPPHIRE cohort, African American participants were significantly more likely to report food allergy (26.1% vs 17%; P = 3.47 × 10-18) and have food-associated anaphylactic symptoms (12.7% vs 7%; P = 4.65 × 10-14) when compared with European American participants. Allergy to seafood accounted for the largest difference (13.1% vs 4.6%; P = 1.38 × 10-31). Differences in food allergy by race persisted after adjusting for potential confounders including asthma status. Among African American participants, the proportion of African ancestry was not associated with any outcome evaluated. CONCLUSION: Compared with European Americans, African Americans appear to be at higher risk for developing food allergy and food-associated anaphylaxis, particularly with regard to seafood allergy. The lack of association with genetic ancestry suggests that socioenvironmental determinants may play a role in these disparities.

Adherence to Mediterranean Diet and Depressive Symptomatology Among Boston Area Puerto Ricans.

BACKGROUND: Higher Mediterranean diet (MeD) adherence has been linked with lower depressive symptomatology, but research examining this association is limited, especially among Latinos, including mainland U.S. Puerto Ricans. Hence, we examined cross-sectional and longitudinal associations between MeD adherence and self-reported depressive symptomatology in Boston area Puerto Rican adults. METHODS: The Center for Epidemiologic Studies Depression Scale (CES-D) was used to evaluate depressive symptoms. Adherence to MeD was assessed at all 3 visits. We used multivariable linear regression for baseline cross-sectional analysis, and linear mixed effects modeling over 3 waves of follow-up for longitudinal analysis. We also assessed whether baseline MeD adherence affected 5y CES-D trajectory. We conducted sensitivity analyses among participants without diabetes, and among participants with complete MeD and CES-D measures at all visits. RESULTS: MeD adherence was significantly associated with CES-D score at baseline (ß = -2.0, 95% confidence interval [CI] -4.0, -0.04 for highest vs lowest tertile, p trend = .04) and across 3 waves (ß = -1.9, 95% CI = -3.0, -0.8 for highest vs lowest tertile, p trend = .0005). Results were similar in analyses restricted to participants without diabetes, as well as among participants with complete CES-D and MeD scores at all visits. CONCLUSIONS: While CES-D score was consistently lower in those with higher MeD adherence over 5 years of follow up, no relationship between baseline MeD adherence and 5y CES-D trajectory was observed.

Predicting death from COVID-19 using pre-existing conditions: implications for vaccination triage.

INTRODUCTION: Global shortages in the supply of SARS-CoV-2 vaccines have resulted in campaigns to first inoculate individuals at highest risk for death from COVID-19. Here, we develop a predictive model of COVID-19-related death using longitudinal clinical data from patients in metropolitan Detroit. METHODS: All individuals included in the analysis had a laboratory-confirmed SARS-CoV-2 infection. Thirty-six pre-existing conditions with a false discovery rate p<0.05 were combined with other demographic variables to develop a parsimonious prediction model using least absolute shrinkage and selection operator regression. The model was then prospectively validated in a separate set of individuals with confirmed COVID-19. RESULTS: The study population consisted of 15 502 individuals with laboratory-confirmed SARS-CoV-2. The main prediction model was developed using data from 11 635 individuals with 709 reported deaths (case fatality ratio 6.1%). The final prediction model consisted of 14 variables with 11 comorbidities. This model was then prospectively assessed among the remaining 3867 individuals (185 deaths; case fatality ratio 4.8%). When compared with using an age threshold of 65 years, the 14-variable model detected 6% more of the individuals who would die from COVID-19. However, below age 45 years and its risk equivalent, there was no benefit to using the prediction model over age alone. DISCUSSION: Using a prediction model, such as the one described here, may help identify individuals who would most benefit from COVID-19 inoculation, and thereby may produce more dramatic initial drops in deaths through targeted vaccination.

Serum Vitamin D and Depressive Symptomatology among Boston-Area Puerto Ricans.

BACKGROUND: Low vitamin D status, assessed using serum 25-hydroxyvitamin D [25(OH)D] concentration, has been associated with depression, but research among minority populations, such as Puerto Ricans is limited. We examined the association between serum 25(OH)D and self-reported depressive symptomatology across 3 waves of follow-up in a cohort of Puerto Rican adults residing in Massachusetts. OBJECTIVES: We evaluated the cross-sectional and longitudinal associations between serum 25(OH)D and self-reported depressive symptoms in the Boston Puerto Rican Health Study (BPRHS) cohort. METHODS: Participants of the BPRHS were evaluated for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Serum 25(OH)D was measured at baseline (n = 1434), year 2 (n = 1218), and year 5 (n = 914). We categorized serum 25(OH)D concentration as sufficient (≥20 ng/mL), insufficient (12 to <20 ng/mL), and deficient (<12 ng/mL). Multivariable linear regression was used for cross-sectional analyses at baseline, and repeated measures mixed effects modeling was used over 3 waves of follow-up for longitudinal analyses. We conducted sensitivity analyses in vitamin D supplement nonusers and participants with complete data on baseline serum 25(OH)D and CES-D at all 3 visits. RESULTS: Serum 25(OH)D concentration was not associated with CES-D score in cross-sectional analysis [ß = -0.85; 95% CI: -2.80, 1.10 for deficient compared with sufficient 25(OH)D; P-trend = 0.59] or in longitudinal analyses over 5 y [ß = -0.41; 95% CI: -1.95, 1.13 for deficient compared with sufficient 25(OH)D; P-trend = 0.93]. Results were similar in sensitivity analyses restricted to vitamin D supplement nonusers (n = 1371) and in analyses conducted in participants with complete measures of baseline serum 25(OH)D and CES-D score at all 3 visits (n = 887) [ß = -0.12; 95% CI: -1.98, 1.74 for deficient compared with sufficient 25(OH)D; P-trend = 0.93]. CONCLUSIONS: We did not observe a significant association between serum 25(OH)D and depressive symptomatology in the BPRHS cohort.

Serum vitamin D and cognition in a cohort of Boston-area Puerto Ricans.

Background: Vitamin D has been suggested as a protective factor for cognitive health, however results of prior studies have been mixed. To examine whether serum 25(OH)D concentration is related to cognition and cognitive decline in a study of Boston Area Puerto Ricans. Methods: We examined the association between serum 25(OH)D, cognitive function and cognitive decline in a longitudinal study of 967 Boston Area Puerto Rican adults. Results: In analyses adjusted for potential confounders, participants in the bottom quintile of 25(OH)D had similar cognitive function at baseline, as measured by a global cognitive score (mean difference: 0.09 (95% CI: -0.02, 0.19); p-trend: 0.18), and similar 2-year rates of cognitive decline (mean difference: -0.01 (95% CI: -0.09, 0.07), p-trend: 0.61) as those in the top 25(OH)D quintile. No significant associations were observed between baseline serum 25(OH)D concentration and 2-year change in individual cognitive test scores or change in executive function or memory domains. Conclusions: We observed no significant association between serum 25(OH)D and cognition in this cohort of Boston Area Puerto Ricans.

Lower Plasma Vitamin B-6 is Associated with 2-Year Cognitive Decline in the Boston Puerto Rican Health Study.

BACKGROUND: Despite its important role in cognitive development and regulation of nervous system function, vitamin B-6 has been under-studied in relation to cognitive aging. OBJECTIVE: We investigated whether plasma pyridoxal-5'-phosphate (PLP, vitamin B-6) concentrations were associated with cognitive function and subsequent cognitive decline. METHODS: In a longitudinal study of 949 participants (aged 45-75 y at baseline; 70% women) from the Boston Puerto Rican Health Study cohort, we examined the association between baseline plasma PLP and baseline cognitive function and 2-y cognitive decline. Cognitive function was assessed with an in-person 7-test cognitive battery, at baseline and 2-y follow-up. We also used logistic regression to estimate the odds of major 2-y decline in global cognitive function (defined as decline ≥1 SD below the mean), as well as decline in executive function and memory. We also used multivariable linear regression to calculate adjusted mean differences in cognitive scores, and 95% CIs, across tertiles of plasma PLP at baseline, as well as cross-sectional and longitudinal associations with individual test scores. RESULTS: In analyses adjusted for potential confounders, the OR of having a major 2-y decline in global cognitive function was 2.46 (95% CI: 1.49, 4.05; P-trend: 0.001) among participants in the lowest tertile of PLP compared with those in the top tertile of PLP. The association of PLP with cognition was stronger in participants older than 55 y at baseline (OR for bottom to top tertile: 4.58; 95% CI: 2.02, 10.35; P-interaction: 0.01) compared with those 55 y old or younger, as well as in ever smokers (OR for bottom to top tertile: 2.99; 95% CI: 1.45, 6.19; P-interaction: 0.02) compared with never smokers. CONCLUSIONS: Lower baseline plasma PLP was associated with increased odds of 2-y cognitive decline in a cohort of Boston area Puerto Ricans. The association was stronger among older participants and among ever smokers.

MGL Ligand Expression Is Correlated to Lower Survival and Distant Metastasis in Cervical Squamous Cell and Adenosquamous Carcinoma.

Cervical cancer is the fourth most common cancer type in women worldwide and is characterized by a highly immune-suppressive microenvironment. Here, we describe aberrant glycosylation as a factor mediating this immunosuppressive microenvironment. Expression of a specific carbohydrate ligand for the immune-regulatory C-type lectin MGL was correlated to poor disease-specific survival and distant recurrences in squamous cell carcinoma (SCC) and adenosquamous carcinoma (ASC), the most common histological subtypes of cervical cancer. MGL ligand expression was also associated with lymph node metastasis, the absence of CD14+ myeloid cells and the presence of CD14-CD163+ myeloid cells. Indeed, expression of the MGL receptor itself could be detected on CD163+ cells, suggesting that MGL+ myeloid cells are able to interact locally with MGL ligand+ tumor cells. Additionally, MGL ligand expression correlated to the occurrence of PIK3CA mutations, the most frequently observed oncogenic alteration in cervical cancer. In conclusion, we present prognostic value for MGL ligand expression in SCC/ASC patients, which further supports an immune evasive role for the C-type lectin MGL in the tumor immune compartment.

Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3.

Colorectal cancer is the third most common cancer type worldwide. It is characterized by a high expression of aberrantly glycosylated ligands, such as the Tn antigen (GalNAcα1-Ser/Thr), which is a major ligand for the C-type lectin macrophage galactose-type lectin (MGL). We have previously determined that a high level of MGL ligands in colorectal tumors is associated with lower disease-free survival in patients with late stage disease, which we could attribute to the presence of oncogenic BRAFV600E mutations. Here we aimed to elucidate the downstream pathway of BRAFV600E governing high MGL ligand and Tn antigen expression. We focused on glycosylation-related enzymes involved in the synthesis or elongation of Tn antigen, N-acetylgalactosamine-transferases (GALNTs) and C1GalT1/COSMC, respectively. Both the activity and expression of C1GalT1 and COSMC were unrelated to the BRAF mutational status. In contrast, GALNT3, GALNT7 and GALNT12 were increased in colorectal cancer cells harboring the BRAFV600E mutation. Through CRISPR-Cas9 gene knockouts we could establish that GALNT3 increased MGL ligand synthesis in the HT29 cell line, while GALNT7 and GALNT12 appeared to have redundant roles. Together our results highlight a novel mechanistic pathway connecting BRAFV600E to aberrant glycosylation in colorectal cancer through GALNT3.

Corrigendum: Fucosylated Antigens in Cancer: An Alliance Toward Tumor Progression, Metastasis, and Resistance to Chemotherapy.

[This corrects the article on p. 39 in vol. 8, PMID: 29527514.].

Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy.

Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewisa, Lewisb, and sialyl Lewisa) and type II (H2, Lewisx, Lewisy, and sialyl Lewisx) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated expression of pertinent fucosyltransferases (FUTs). Nevertheless, the impact of fucose-containing moieties on tumor cell biology is not fully elucidated yet. Here, we review the relevance of tumor-overexpressed FUTs and their respective synthesized Lewis determinants in critical aspects associated with cancer progression, such as increased cell survival and proliferation, tissue invasion and metastasis, epithelial [corrected] to mesenchymal transition, endothelial and immune cell interaction, angiogenesis, multidrug resistance, and cancer stemness. Furthermore, we discuss the potential use of enhanced levels of fucosylation as glycan biomarkers for early prognosis, diagnosis, and disease monitoring in cancer patients.

Dietary Fiber Pectin Directly Blocks Toll-Like Receptor 2-1 and Prevents Doxorubicin-Induced Ileitis.

Dietary carbohydrate fibers are known to prevent immunological diseases common in Western countries such as allergy and asthma but the underlying mechanisms are largely unknown. Until now beneficial effects of dietary fibers are mainly attributed to fermentation products of the fibers such as anti-inflammatory short-chain fatty acids (SCFAs). Here, we found and present a new mechanism by which dietary fibers can be anti-inflammatory: a commonly consumed fiber, pectin, blocks innate immune receptors. We show that pectin binds and inhibits, toll-like receptor 2 (TLR2) and specifically inhibits the proinflammatory TLR2-TLR1 pathway while the tolerogenic TLR2-TLR6 pathway remains unaltered. This effect is most pronounced with pectins having a low degree of methyl esterification (DM). Low-DM pectin interacts with TLR2 through electrostatic forces between non-esterified galacturonic acids on the pectin and positive charges on the TLR2 ectodomain, as confirmed by testing pectin binding on mutated TLR2. The anti-inflammatory effect of low-DM pectins was first studied in human dendritic cells and mouse macrophages in vitro and was subsequently tested in vivo in TLR2-dependent ileitis in a mouse model. In these mice, ileitis was prevented by pectin administration. Protective effects were shown to be TLR2-TLR1 dependent and independent of the SCFAs produced by the gut microbiota. These data suggest that low-DM pectins as a source of dietary fiber can reduce inflammation through direct interaction with TLR2-TLR1 receptors.

ß2→1-Fructans Modulate the Immune System In Vivo in a Microbiota-Dependent and -Independent Fashion.

It has been shown in vitro that only specific dietary fibers contribute to immunity, but studies in vivo are not conclusive. Here, we investigated degree of polymerization (DP) dependent effects of ß2→1-fructans on immunity via microbiota-dependent and -independent effects. To this end, conventional or germ-free mice received short- or long-chain ß2→1-fructan for 5 days. Immune cell populations in the spleen, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) were analyzed with flow cytometry, genome-wide gene expression in the ileum was measured with microarray, and gut microbiota composition was analyzed with 16S rRNA sequencing of fecal samples. We found that ß2→1-fructans modulated immunity by both microbiota and microbiota-independent effects. Moreover, effects were dependent on the chain-length of the ß2→1-fructans type polymer. Both short- and long-chain ß2→1-fructans enhanced T-helper 1 cells in PPs, whereas only short-chain ß2→1-fructans increased regulatory T cells and CD11b-CD103- dendritic cells (DCs) in the MLN. A common feature after short- and long-chain ß2→1-fructan treatment was enhanced 2-alpha-l-fucosyltransferase 2 expression and other IL-22-dependent genes in the ileum of conventional mice. These effects were not associated with shifts in gut microbiota composition, or altered production of short-chain fatty acids. Both short- and long-chain ß2→1-fructans also induced immune effects in germ-free animals, demonstrating direct effect independent from the gut microbiota. Also, these effects were dependent on the chain-length of the ß2→1-fructans. Short-chain ß2→1-fructan induced lower CD80 expression by CD11b-CD103- DCs in PPs, whereas long-chain ß2→1-fructan specifically modulated B cell responses in germ-free mice. In conclusion, support of immunity is determined by the chemical structure of ß2→1-fructans and is partially microbiota independent.

Particulate ß-glucans synergistically activate TLR4 and Dectin-1 in human dendritic cells.

SCOPE: The major receptor for ß(1-3)-glucans on immune cells is considered to be Dectin-1 receptor. Particulate ß-glucans induce stronger immune responses than soluble ß-glucans by clustering of Dectin-1 receptors. Here, it was hypothesized that activation of other pattern recognition receptors such as Toll-like receptor 4 (TLR4) can also contribute to enhanced activity of immune cells after exposure to particulate ß-glucans. METHODS AND RESULTS: To test this hypothesis, reporter cell lines were designed expressing TLR4 with either Dectin-1A or Dectin-1B, that is, one of the two transcript variants of human Dectin-1 receptors. Enhanced NF-κB activation was observed after stimulation with particulate ß-glucans in both Dectin-1A-TLR4 and the Dectin-1B-TLR4 cell lines. This was different with soluble ß-glucans, which enhanced activation in Dectin-1A-TLR4 cell lines but not in Dectin-1B-TLR4 cells. The synergistic activation of TLR4 and Dectin-1 by particulate ß-glucans was confirmed in human dendritic cells. The effects of particulate ß-glucan induced TLR4 binding were regulatory as blocking TLR4 enhanced pro-inflammatory cytokine IL-23, IL-4, IL-6, and TNF-α production. CONCLUSION: These results suggest that TLR4 and Dectin-1 are synergistically activated by particulate ß-glucans, wherein TLR4 activates an immune regulatory pathway in human dendritic cells. Our data suggest that ß-glucan is an immune regulatory ligand for TLR4.

Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer.

The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1α). In this report we demonstrate that Rab25 regulates HIF-1α protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1α protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1ß re-sensitised cells to cisplatin in vitro and reduced tumour formation of A2780-Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1α at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer.

Arabinoxylan activates Dectin-1 and modulates particulate ß-glucan-induced Dectin-1 activation.

SCOPE: Arabinoxylan is one of the most commonly consumed dietary fiber. Immunomodulation by arabinoxylan is documented but the mechanisms by which these immune-effects are accomplished are unknown. METHODS AND RESULTS: By applying reporter cell lines for Toll-like receptors (TLRs) and Dectin-1, we demonstrated that arabinoxylan interacts with Dectin-1 receptors and not with TLRs. Arabinoxylan activates Dectin-1 to a similar magnitude as soluble ß-glucans. Soluble ß-glucans are known to inhibit the particulate ß-glucan-induced activation of Dectin-1. As arabinoxylan is also soluble, the inhibiting capacity of arabinoxylan on particulate ß-glucan-activated Dectin-1 cell lines was studied. It was found that this inhibition was similar to that of soluble ß-glucan and was caused predominantly by inhibition of the Dectin-1A transcript variant. The Dectin-1 inhibitory function of arabinoxylan was further confirmed in human dendritic cells that demonstrated reduced production of IL-10 and TNF-α. The production of the antifungal cytokines IL-4 and IL-23 were increased in dendritic cells stimulated with arabinoxylan and particulate ß-glucan. In contrast to soluble ß-glucan, arabinoxylan did not enhance production of IL-10, TNF-α, and IL-23. CONCLUSION: Arabinoxylan activates Dectin-1 and supports antifungal immune responses in human dendritic cells. The mode of action of arabinoxylan is similar but not identical to that of soluble ß-glucans.

DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1.

In between the period of transplantation and revascularization, pancreatic islets are exposed to low-oxygen and low-nutrient conditions. In the present study we mimicked those conditions in vitro to study the involvement of different cell death processes, release of danger-associated molecular patterns (DAMP), and associated in vitro immune activation. Under low-oxygen and low-nutrient conditions, apoptosis, autophagy and necroptosis occur in human islets. Necroptosis is responsible for DAMP-release such as dsDNA, uric acid, and HMGB1. The sensors of the innate immune system able to recognize these DAMPs are mainly TLR, NOD receptors, and C-type lectins. By using cell-lines with a non-functional adaptor molecule MyD88, we were able to show that the islet-derived DAMPs signal mainly via TLR. Immunoisolation in immunoprotective membranes reduced DAMP release and immune activation via retention of the relative large DAMPs in the capsules. Another effective strategy was suppressing necroptosis using the inhibitor nec-1. Although the effect on cell-survival was minor, nec-1 was able to reduce the release of HMGB1 and its associated immune activation. Our data demonstrate that in the immediate post-transplant period islets release DAMPs that in vitro enhance responses of innate immune cells. DAMP release can be reduced in vitro by immunoisolation or intervention with nec-1.

The impact of dietary fibers on dendritic cell responses in vitro is dependent on the differential effects of the fibers on intestinal epithelial cells.

SCOPE: In the present study, the direct interaction of commonly consumed fibers with epithelial or dendritic cells (DCs) was studied. METHODS AND RESULTS: The fibers were characterized for their sugar composition and chain length profile. When in direct contact, fibers activate DCs only mildly. This was different when DCs and fibers were co-cultured together with supernatants from human epithelial cells (Caco spent medium). Caco spent medium enhanced the production of IL-12, IL-1Ra, IL-6, IL-8, TNF-α, MCP-1 (monocyte chemotactic protein), and MIP-1α but this was strongly attenuated by the dietary fibers. This attenuating effect on proinflammatory cytokines was dependent on the interaction of the fibers with Toll-like receptors as it was reduced by Pepinh-myd88. The interaction of galacto-oligosaccharides, chicory inulin, wheat arabinoxylan, barley ß-glucan with epithelial cells and DCs led to changes in the production of the Th1 cytokines in autologous T cells, while chicory inulin, and barley ß-glucan reduced the Th2 cytokine IL-6. The Treg-promoting cytokine IL-10 was induced by galacto-oligosaccharides whereas chicory inulin decreased the IL-10 production. CONCLUSIONS: Our results suggest that dietary fibers can modulate the host immune system not only by the recognized mechanism of effects on microbiota but also by direct interaction with the consumer's mucosa. This modulation is dietary fiber type dependent.