Immune response against the SARS-CoV-2 spike protein in cancer patients after COVID-19 vaccination during the Omicron wave: a prospective study.

BACKGROUND: Cancer patients often have weakened immune systems, resulting in a lower response to vaccines, especially those receiving immunosuppressive oncological treatment (OT). We aimed to assess the impact of OT on the humoral and T-cell response to the B.1 lineage and Omicron variant following COVID-19 vaccination in patients with solid and hematological neoplasms. METHODS: We conducted a prospective study on cancer patients, stratified into OT and non-OT groups, who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. The outcomes measured were the humoral (anti-SARS-CoV-2 S IgG titers and ACE2-S interaction inhibition capacity) and cellular (SARS-CoV-2 S-specific T-cell spots per million PBMCs) responses against the B.1 lineage and Omicron variant. These responses were evaluated four weeks after the second dose (n = 98) and eight weeks after the booster dose (n = 71). RESULTS: The humoral response after the second vaccine dose against the B.1 lineage and Omicron variant was significantly weaker in the OT group compared to the non-OT group (q-value<0.05). A booster dose of the mRNA-1273 vaccine significantly improved the humoral response in the OT group, making it comparable to the non-OT group. The mRNA-1273 vaccine, designed for the original Wuhan strain, elicited a weaker humoral response against the Omicron variant compared to the B.1 lineage, regardless of oncological treatment or vaccine dose. In contrast, T-cell responses against SARS-CoV-2, including the Omicron variant, were already present after the second vaccine dose and were not significantly affected by oncological treatments. CONCLUSIONS: Cancer patients, particularly those receiving immunosuppressive oncological treatments, should require booster doses and adapted COVID-19 vaccines for new SARS-CoV-2 variants like Omicron. Future studies should evaluate the durability of the immune response and the efficacy of individualized regimens.

The protective effect of dietary folate intake on gastric cancer is modified by alcohol consumption: A pooled analysis of the StoP Consortium.

Dietary folate intake has been identified as a potentially modifiable factor of gastric cancer (GC) risk, although the evidence is still inconsistent. We evaluate the association between dietary folate intake and the risk of GC as well as the potential modification effect of alcohol consumption. We pooled data for 2829 histologically confirmed GC cases and 8141 controls from 11 case-control studies from the international Stomach Cancer Pooling Consortium. Dietary folate intake was estimated using food frequency questionnaires. We used linear mixed models with random intercepts for each study to calculate adjusted odds ratios (OR) and 95% confidence interval (CI). Higher folate intake was associated with a lower risk of GC, although this association was not observed among participants who consumed >2.0 alcoholic drinks/day. The OR for the highest quartile of folate intake, compared with the lowest quartile, was 0.78 (95% CI, 0.67-0.90, P-trend = 0.0002). The OR per each quartile increment was 0.92 (95% CI, 0.87-0.96) and, per every 100 µg/day of folate intake, was 0.89 (95% CI, 0.84-0.95). There was a significant interaction between folate intake and alcohol consumption (P-interaction = 0.02). The lower risk of GC associated with higher folate intake was not observed in participants who consumed >2.0 drinks per day, ORQ4v Q1 = 1.15 (95% CI, 0.85-1.56), and the OR100 µg/day = 1.02 (95% CI, 0.92-1.15). Our study supports a beneficial effect of folate intake on GC risk, although the consumption of >2.0 alcoholic drinks/day counteracts this beneficial effect.

Dietary intake of vitamin C and gastric cancer: a pooled analysis within the Stomach cancer Pooling (StoP) Project.

BACKGROUND: Previous studies suggest that dietary vitamin C is inversely associated with gastric cancer (GC), but most of them did not consider intake of fruit and vegetables. Thus, we aimed to evaluate this association within the Stomach cancer Pooling (StoP) Project, a consortium of epidemiological studies on GC. METHODS: Fourteen case-control studies were included in the analysis (5362 cases, 11,497 controls). We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between dietary intake of vitamin C and GC, adjusted for relevant confounders and for intake of fruit and vegetables. The dose-response relationship was evaluated using mixed-effects logistic models with second-order fractional polynomials. RESULTS: Individuals in the highest quartile of dietary vitamin C intake had reduced odds of GC compared with those in the lowest quartile (OR: 0.64; 95% CI: 0.58, 0.72). Additional adjustment for fruit and vegetables intake led to an OR of 0.85 (95% CI: 0.73, 0.98). A significant inverse association was observed for noncardia GC, as well as for both intestinal and diffuse types of the disease. The results of the dose-response analysis showed decreasing ORs of GC up to 150-200 mg/day of vitamin C (OR: 0.54; 95% CI: 0.41, 0.71), whereas ORs for higher intakes were close to 1.0. CONCLUSIONS: The findings of our pooled study suggest that vitamin C is inversely associated with GC, with a potentially beneficial effect also for intakes above the currently recommended daily intake (90 mg for men and 75 mg for women).

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Reproductive factors, hormonal interventions, and gastric cancer risk in the Stomach cancer Pooling (StoP) Project.

BACKGROUND: Gastric cancer incidence is higher in men, and a protective hormone-related effect in women is postulated. We aimed to investigate and quantify the relationship in the Stomach cancer Pooling (StoP) Project consortium. METHODS: A total of 2,084 cases and 7,102 controls from 11 studies in seven countries were included. Summary odds ratios (ORs) and 95% confidence intervals (CIs) assessing associations of key reproductive factors and menopausal hormone therapy (MHT) with gastric cancer were estimated by pooling study-specific ORs using random-effects meta-analysis. RESULTS: A duration of fertility of ≥ 40 years (vs. < 20), was associated with a 25% lower risk of gastric cancer (OR = 0.75; 95% CI: 0.58-0.96). Compared with never use, ever, 5-9 years and ≥ 10 years use of MHT in postmenopausal women, showed ORs of 0.73 (95% CI: 0.58-0.92), 0.53 (95% CI: 0.34-0.84) and 0.71 (95% CI: 0.50-1.00), respectively. The associations were generally similar for anatomical and histologic subtypes. CONCLUSION: Our results support the hypothesis that reproductive factors and MHT use may lower the risk of gastric cancer in women, regardless of anatomical or histologic subtypes. Given the variation in hormones over the lifespan, studies should address their effects in premenopausal and postmenopausal women. Furthermore, mechanistic studies may inform potential biological processes.

TNFAIP3-interacting protein 1 polymorphisms and their association with symptomatic human respiratory syncytial virus infection and bronchiolitis in infants younger than one year from South Africa: A case-control study.

OBJECTIVES: This study analyzed the association of TNFAIP3-interacting protein 1 (TNIP1) polymorphisms with the symptomatic human respiratory syncytial virus (HRSV) infection and bronchiolitis in infants. METHODS: A case-control study was conducted involving 129 hospitalized infants with symptomatic HRSV infection (case group) and 161 healthy infants (control group) in South Africa (2016-2018). Six TNIP1 polymorphisms (rs869976, rs4958881, rs73272842, rs3792783, rs17728338, and rs999011) were genotyped. Genetic associations were evaluated using logistic regression adjusted by age and gender. RESULTS: Both rs73272842 G and rs999011 C alleles were associated with reduced odds for symptomatic HRSV infection (adjusted odd ratio [aOR] = 0.68 [95% confidence interval {CI} = 0.48-0.96] and aOR = 0.36 [95% CI = 0.19-0.68], respectively] and bronchiolitis (aOR = 0.71 [95% CI = 0.50-1.00] and aOR = 0.38 [95% CI = 0.22-0.66], respectively). The significance of these associations was validated using the BCa Bootstrap method (P <0.05). The haplotype GC (composed of rs73272842 and rs999011) was associated with reduced odds of symptomatic HRSV infection (aOR = 0.53 [95% CI = 0.37-0.77]) and bronchiolitis (aOR = 0.62 [95% CI = 0.46-0.84]), which were validated by the BCa Bootstrap method (P = 0.002 for both). CONCLUSION: TNIP1 rs73272842 G allele and rs999011 C allele were associated with reduced odds of symptomatic HRSV infection and the development of bronchiolitis in infants, suggesting that TNIP1 polymorphisms could impact susceptibility to HRSV illness.

Consumption of aspartame and other artificial sweeteners and risk of cancer in the Spanish multicase-control study (MCC-Spain).

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (

A deficient immune response to SARS-CoV-2 in the nasopharynx is associated with severe COVID-19 pneumonia.

OBJECTIVES: We analyzed the expression of inflammatory and antiviral genes in the nasopharynx of SARS-CoV-2 infected patients and their association with the severity of COVID-19 pneumonia. METHODS: We conducted a cross-sectional study on 223 SARS-CoV-2 infected patients. Clinical data were collected from medical records, and nasopharyngeal samples were collected in the first 24 hours after admission to the emergency room. The gene expression of eight proinflammatory/antiviral genes (plasminogen activator urokinase receptor [PLAUR], interleukin [IL]-6, IL-8, interferon [IFN]-ß, IFN-stimulated gene 15 [ISG15], retinoic acid-inducible gene I [RIG-I], C-C motif ligand 5 [CCL5], and chemokine C-X-C motif ligand 10 [CXCL10]) were quantified by real-time polymerase chain reaction. Outcome variables were: (i) pneumonia; (ii) severe pneumonia or acute respiratory distress syndrome. Statistical analysis was performed using multivariate logistic regression analyses. RESULTS: We enrolled 84 mild, 88 moderate, and 51 severe/critical cases. High expression of PLAUR (adjusted odds ratio [aOR] = 1.25; P = 0.032, risk factor) and low expression of CXCL10 (aOR = 0.89; P = 0.048, protective factor) were associated with pneumonia. Furthermore, lower values of ISG15 (aOR = 0.88, P = 0.021), RIG-I (aOR = 0.87, P = 0.034), CCL5 (aOR = 0.73, P <0.001), and CXCL10 (aOR = 0.84, P = 0.002) were risk factors for severe pneumonia/acute respiratory distress syndrome. CONCLUSION: An unbalanced early innate immune response to SARS-CoV-2 in the nasopharynx, characterized by high expression of PLAUR and low expression of antiviral genes (ISG15 and RIG-I), and chemokines (CCL5 and CXCL10), was associated with COVID-19 severity.

Blunted circadian variation of blood pressure in individuals with neurofibromatosis type 1.

BACKGROUND: Cardiovascular events such as myocardial infarction and stroke are life-threatening complications associated with Neurofibromatosis type 1 (NF1). As previous studies observed an association between cardiovascular events and the loss of circadian variations of blood pressure, we investigated the 24 h circadian rhythm of blood pressure (BP) in 24 NF1 patients (10 males and 14 females, with a mean age of 39.5 years ± 14 years) by using ambulatory blood pressure monitoring (ABPM). RESULTS: Only one-third of the patient were dippers, 50% were non-dippers, and 17% were risers. Reduced variability of systolic and diastolic nocturnal blood pressure was observed in NF1 patients compared with several studies of normotensive individuals (p = 0.024). In NF1 patients, the blunted systolic nocturnal decline was significantly associated with the number of neurofibromas (p = 0.049) and the presence of a plexiform neurofibroma (p = 0.020). CONCLUSIONS: Most NF1 patients in this study showed a "non-dipper" pattern with a blunted nocturnal BP decline, which is considered an independent risk factor for cardiovascular events in normotensive and hypertensive individuals. Periodic monitoring of BP should be included in NF1 follow-up guidelines to diagnose masked hypertension or a non-dipper/riser pattern which would significantly increase the morbidity and mortality of NF1 patients to implement therapeutic strategies.

Intake of Proton-Pump Inhibitors and Gastric Cancer within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: A potential association between proton-pump inhibitors (PPI) and gastric cancer remains undefined. Thus, we aimed to evaluate such association within the Stomach cancer Pooling (StoP) Project. METHODS: Data from five case-control studies of the StoP Project were included (1,889 cases and 6,517 controls). We assessed the impact of different exposure definitions, specifically any reported use of PPIs and exposure definitions based on the duration of PPI intake. Additionally, we modeled the dose-response relationship between the cumulative duration of PPI intake and gastric cancer. RESULTS: Significant associations between PPI intake and gastric cancer, both overall and in the stratified analyses, were limited to exposure definitions based on short durations of intake. The overall odds ratio (OR) for any reported PPI intake was 1.78 [95% confidence interval (CI): 0.76-4.14]. In the dose-response analysis, the ORs of gastric cancer were found to be higher for short durations of PPI intake (6 months: OR 3.26; 95% CI: 2.40-4.42; one year: OR 2.14; 95% CI: 1.69-2.70; 2 years: OR 1.50; 95% CI: 1.22-1.85; 3 years: OR 1.27; 95% CI: 1.03-1.56), with the association becoming not significant for durations longer than 3 years. CONCLUSIONS: Our findings suggest that the observed association between PPIs and gastric cancer might be mainly due to reverse causality. IMPACT: The results of this study suggest that PPIs are a safe therapeutic choice regarding their effect on the occurrence of gastric cancer. See related commentary by Richman and Leiman, p. 1127.

EGFR-mutated advanced lung cancer. Data from a single institution, the Hospital of Leon, in Spain.

INTRODUCTION: 10-16% of non-small cell lung cancer (NSCLC) cases have the epidermal growth factor receptor (EGFR) amplified and/or mutated. Studies show that EGFR tyrosine kinase inhibitors (TKIs) significantly prolong progression-free survival (PFS) in patients with advanced NSCLC compared to those treated with platinum-based chemotherapy (CT) doublets. Our aim is to perform a real-world survival analysis of patients treated with TKI as first-line therapy at the Hospital of Leon (CAULE) in Spain. The impact on global survival rates and responses to clinical and histopathological factors were also analyzed. MATERIAL AND METHODS: We retrospectively reviewed patients diagnosed with EGFR-mutated NSCLC who received treatment with EGFR-TKI in the Department of Oncology at the University of Leon Health Center complex between March 2011 and June 2018. Data was analyzed with Kaplan-Meier and Cox regression models to show overall survival (OS), progression-free survival (PFS), and the associated variables. RESULTS: 53 patients were included in the study, 50% (n = 27) were treated with gefitinib, 32% (n = 18) with erlotinib and 10% (n = 6) with afatinib. The median OS and PFS were 27.7 months (95% CI: 21-33.8 months) and 18 months (95% CI 14.25-21.89 months), respectively. The variables associated with OS and with PFS were exon19 deletion as a protective factor and presence of extrathoracic metastasis as a risk factor. The most frequent adverse effects were rash, diarrhea, asthenia, and conjunctivitis. CONCLUSIONS: Real-world analysis of this data confirms that treatment with TKI is beneficial for patients diagnosed with EGFR-mutated NSCLC. Our OS outcomes were similar to those reported in clinical trials.

Adult height and risk of gastric cancer: a pooled analysis within the Stomach cancer Pooling Project.

BACKGROUND: The association between height and risk of gastric cancer has been studied in several epidemiological studies with contrasting results. The aim of this study is to examine the association between adult height and gastric cancer within a large pooled analysis of case-control studies members of the Stomach cancer Pooling (StoP) Project consortium. METHODS: Data from 18 studies members of the StoP consortium were collected and analyzed. A multivariable logistic regression model was used to estimate the study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between 10-cm increase in height and risk of gastric cancer. Age, sex, tobacco smoking, alcohol consumption, social class, geographical area and Helicobacter pylori (H. pylori ) status were included in the regression model. Resulting estimates were then pooled with random-effect model. Analyses were conducted overall and in strata of selected variables. RESULTS: A total of 7562 cases and 19 033 controls were included in the analysis. The pooled OR was 0.96 (95% CI 0.87-1.05). A sensitivity analysis was performed restricting the results to the studies with information on H. pylori status, resulting in an OR of 0.97 (95% CI 0.79-1.20). CONCLUSION: Our study does not support a strong and consistent association between adult height and gastric cancer.

Follow-Up of Patients After Total Pancreatectomy and Islet Cell Autotransplantation at Off-Site Islet Isolation Facility.

CONTEXT: Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis (CP). Islet autotransplantation (IAT) allows for the preservation of beta cells to prevent complications of long-term diabetes. OBJECTIVE: Our study follows TPIAT recipients for up to 12 years to determine the efficacy of the procedure completed with an off-site islet isolation facility. METHODS: Patient demographics, mixed meal tolerance test measures, glycosylated hemoglobin, insulin requirements, and homeostatic model assessment for insulin resistance values were collected prior to surgery and at the most recent follow-up assessment. RESULTS: Forty-four patients (median age, 46.0 years; range, 20-78 years) underwent TPIAT for CP. At an overall median follow-up time of 845.5 days (range, 195-4470 days) 8 patients were insulin independent and 36 patients were insulin dependent. At the most recent follow-up time point, islet yield per kilogram was the strongest indicator of insulin independence. Homeostatic model assessment for insulin resistance values were comparable between insulin independent and dependent cohorts. CONCLUSIONS: Our long-term follow-up data suggest that IAT can effectively reduce insulin requirements and improve postoperative glycemic control.

Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19.

MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G > C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients (< 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18-2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

Meat Intake, Cooking Methods, Doneness Preferences and Risk of Gastric Adenocarcinoma in the MCC-Spain Study.

BACKGROUND: The association of meat intake with gastric adenocarcinoma is controversial. We examined the relation between white, red, and processed meat intake and gastric adenocarcinoma, considering doneness preference and cooking methods, by histological subtype and anatomical subsite. METHODS: MCC-Spain is a multicase-control study that included 286 incident gastric adenocarcinoma cases and 2993 controls who answered a food-frequency questionnaire. The association of gastric adenocarcinoma with meat intake, doneness preference and cooking methods was assessed using binary multivariate logistic regression mixed models and a possible interaction with sex was considered. Multinomial logistic regression models were used to estimate risk by tumor subsite (cardia vs. non-cardia) and subtype (intestinal vs. diffuse). Sensitivity analyses were conducted comparing models with and without data on Helicobacter pylori infection. RESULTS: The intake of red and processed meat increased gastric adenocarcinoma risk (OR for one serving/week increase (95% CI) = 1.11 (1.02;1.20) and 1.04 (1.00;1.08), respectively), specifically among men and for non-cardia and intestinal gastric adenocarcinoma. Those who consume well done white or red meat showed higher risk of non-cardia (white: RRR = 1.57 (1.14;2.16); red: RRR = 1.42 (1.00;2.02)) and intestinal tumors (white: RRR = 1.69 (1.10;2.59); red: RRR = 1.61 (1.02;2.53)) than those with a preference for rare/medium doneness. Stewing and griddling/barbequing red and white meat, and oven baking white meat, seemed to be the cooking methods with the greatest effect over gastric adenocarcinoma. The reported associations remained similar after considering Helicobacter pylori seropositivity. CONCLUSIONS: Reducing red and processed meat intake could decrease gastric adenocarcinoma risk, especially for intestinal and non-cardia tumors. Meat cooking practices could modify the risk of some gastric cancer subtypes.

Effect of the use of prediagnosis hormones on breast cancer prognosis: MCC-Spain study.

OBJECTIVE: To extend knowledge about the long-term use of hormones in hormone therapy or oral contraception as prognostic factors in breast cancer. METHODS: The MCC-Spain project is a cohort of 1,685 women with incident breast cancer recruited in Spain. Recruitment was carried out between 2007 and 2010, and the follow-up finished in December 2017. The impact of hormone therapy or oral contraception on breast cancer prognosis was analyzed considering year of birth and menopausal status (1,095 women [65%] were postmenopausal). Hazard ratios (HRs) were estimated using Cox regression models. Death by any cause was considered as the event, and hormone therapy or oral contraception were analyzed as regressors. RESULTS: Oral contraception use for less than 5 years shows an HR of 1.10 (95% CI, 0.75 to 1.62), whereas use for 5 or more years shows an HR of 1.46 (95% CI, 0.95 to 2.25), with a P trend of 0.01, showing a dose-dependent response. Regarding hormone therapy and restricting the analysis to postmenopausal women born between1940 and 1959, where most hormone therapy (consumption) is concentrated, the results did not show any trend. CONCLUSION: Concerning oral contraception use, our results demonstrate that their use is related to poor prognosis in breast cancer. However, research in this field is limited and controversial, indicating the need for more research in this area. Regarding hormone therapy consumption, our results indicate no association with better prognosis, which contradicts what has previously been published.

Increased serum concentrations of estrogen-induced growth factors Midkine and FGF2 in NF1 patients with plexiform neurofibroma.

Neurofibromatosis type 1 (NF1) predisposes to the development of dermal and plexiform neurofibromas and serum of NF1 patients stimulates neurofibroma proliferation in vitro. This study aimed to determine whether, in NF1 patients, serum levels of midkine (MK) and fibroblast growth factor 2 (FGF2) were associated with the number and/or type of neurofibromas. In addition, their concentrations were correlated with serum levels of dehydroepiandrosterone sulfate (DHEAS), a neurosteroid secreted by the peripheral nervous system. We performed a case control-study and measured, by ELISA assay, serum concentrations of MK, FGF2, and DHEAS in 20 NF1 patients and 30 controls. We found increased serum levels of MK and FGF2 in NF1 patients between 30 and 50 years old. Their concentrations were significantly higher in NF1 patients with plexiform neurofibromas than in controls (P=0.003 for MK and P=0.008 for FGF2). As an underlying hormonal regulation was suspected, DHEAS serum levels were measured but no difference was observed between patients and controls. We also observed a strong association between MK and FGF2 levels (P=0.0001) in NF1 patients and controls. In conclusion, we point out MK and FGF2 as biomarkers for plexiform neurofibroma in NF1 patients. As both growth factors are estrogen-responsive genes and neurofibromin is a co-repressor of estrogen receptor alpha activity, we suggest that the increased serum levels of MK and FGF2 observed in NF1 patients might be due to estradiol hypersensitivity.

Allium vegetables intake and the risk of gastric cancer in the Stomach cancer Pooling (StoP) Project.

BACKGROUND: The role of allium vegetables on gastric cancer (GC) risk remains unclear. METHODS: We evaluated whether higher intakes of allium vegetables reduce GC risk using individual participant data from 17 studies participating in the "Stomach cancer Pooling (StoP) Project", including 6097 GC cases and 13,017 controls. Study-specific odds ratios (ORs) were pooled using a two-stage modelling approach. RESULTS: Total allium vegetables intake was inversely associated with GC risk. The pooled OR for the highest versus the lowest study-specific tertile of consumption was 0.71 (95% confidence interval, CI, 0.56-0.90), with substantial heterogeneity across studies (I2 > 50%). Pooled ORs for high versus low consumption were 0.69 (95% CI, 0.55-0.86) for onions and 0.83 (95% CI, 0.75-0.93) for garlic. The inverse association with allium vegetables was evident in Asian (OR 0.50, 95% CI, 0.29-0.86) but not European (OR 0.96, 95% CI, 0.81-1.13) and American (OR 0.66, 95% CI, 0.39-1.11) studies. Results were consistent across all other strata. CONCLUSIONS: In a worldwide consortium of epidemiological studies, we found an inverse association between allium vegetables and GC, with a stronger association seen in Asian studies. The heterogeneity of results across geographic regions and possible residual confounding suggest caution in results interpretation.

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.