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Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift towards a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. Here, we explore the contribution of mechanical stretch as trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared to senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed notch signaling as a potential responsible for the epithelial-mesenchymal crosstalk, as blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair.
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BACKGROUND: The coexistence of human immunodeficiency virus (HIV) infection and inflammatory bowel disease (IBD) is uncommon. Data on the impact of HIV on IBD course and its management is scarce. AIM: To describe the IBD phenotype, therapeutic requirements and prevalence of opportunistic infections (OI) in IBD patients with a coexistent HIV infection. METHODS: Case-control, retrospective study including all HIV positive patients diagnosed with IBD in the ENEIDA registry. Patients with positive HIV serology (HIV-IBD) were compared to controls (HIV seronegative), matched 1:3 by year of IBD diagnosis, age, gender and type of IBD. RESULTS: A total of 364 patients (91 HIV-IBD and 273 IBD controls) were included. In the whole cohort, 58% had ulcerative colitis (UC), 35% had Crohn's disease (CD) and 7% were IBD unclassified. The HIV-IBD group presented a significantly higher proportion of proctitis in UC and colonic location in CD but fewer extraintestinal manifestations than controls. Regarding treatments, non-biological therapies (37.4% vs. 57.9%; P=0.001) and biologicals (26.4% vs. 42.1%; P=0.007), were used less frequently among patients in the HIV-IBD group. Conversely, HIV-IBD patients developed more OI than controls regardless of non-biological therapies use. In the multivariate analysis, HIV infection (OR 4.765, 95%CI 2.48-9.14; P<0.001) and having ≥1 comorbidity (OR 2.445, 95%CI 1.23-4.85; P=0.010) were risk factors for developing OI, while CD was protective (OR 0.372, 95%CI 0.18-0.78;P=0.009). CONCLUSIONS: HIV infection appears to be associated with a less aggressive phenotype of IBD and a lesser use of non-biological therapies and biologicals but entails a greater risk of developing OI.
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A new interactive quantum zero-knowledge protocol for identity authentication implementable in currently available quantum cryptographic devices is proposed and demonstrated. The protocol design involves a verifier and a prover knowing a pre-shared secret, and the acceptance or rejection of the proof is determined by the quantum bit error rate. It has been implemented in modified Quantum Key Distribution devices executing two fundamental cases. In the first case, all players are honest, while in the second case, one of the users is a malicious player. We demonstrate an increase of the quantum bit error rate around 25% in the latter case compared to the case of honesty. The protocol has also been validated for distances from a back-to-back setup to more than 60 km between verifier and prover. The security and robustness of the protocol has been analysed, demonstrating its completeness, soundness and zero-knowledge properties.
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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.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Neoplasias , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Estudios Prospectivos , Masculino , COVID-19/inmunología , COVID-19/prevención & control , Femenino , Persona de Mediana Edad , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , SARS-CoV-2/inmunología , Anciano , Neoplasias/inmunología , Anticuerpos Antivirales/sangre , Linfocitos T/inmunología , Inmunización Secundaria , Vacunación , Adulto , Inmunidad Humoral , Inmunoglobulina G/sangre , Huésped Inmunocomprometido , Inmunidad CelularRESUMEN
Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.
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Antifúngicos , Aspergilosis , Aspergillus , Ergosterol , Proteínas Fúngicas , Metiltransferasas , Triazoles , Animales , Metiltransferasas/metabolismo , Metiltransferasas/genética , Antifúngicos/farmacología , Aspergillus/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Ratones , Aspergilosis/microbiología , Aspergilosis/tratamiento farmacológico , Ergosterol/metabolismo , Ergosterol/biosíntesis , Triazoles/farmacología , Regulación Fúngica de la Expresión Génica , Aspergillus fumigatus/genética , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/enzimología , Aspergillus fumigatus/metabolismo , Hifa/efectos de los fármacos , Hifa/crecimiento & desarrollo , Hifa/genética , Hifa/metabolismo , Femenino , Pruebas de Sensibilidad Microbiana , Virulencia/genéticaRESUMEN
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.
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Consumo de Bebidas Alcohólicas , Ácido Fólico , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/prevención & control , Neoplasias Gástricas/epidemiología , Ácido Fólico/administración & dosificación , Consumo de Bebidas Alcohólicas/efectos adversos , Femenino , Masculino , Estudios de Casos y Controles , Persona de Mediana Edad , Anciano , Dieta , Adulto , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.
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Antifúngicos , Aspergillus fumigatus , Ergosterol , Proteínas Fúngicas , Hidroximetilglutaril-CoA Reductasas , Triazoles , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/metabolismo , Aspergillus fumigatus/genética , Antifúngicos/farmacología , Triazoles/farmacología , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Ergosterol/metabolismo , Ergosterol/biosíntesis , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hidroximetilglutaril-CoA Reductasas/genética , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Farmacorresistencia Fúngica/genética , Farmacorresistencia Fúngica/efectos de los fármacos , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Pruebas de Sensibilidad Microbiana , Esterol 14-Desmetilasa/metabolismo , Esterol 14-Desmetilasa/genética , Humanos , MutaciónRESUMEN
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).
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Ácido Ascórbico , Neoplasias Gástricas , Masculino , Humanos , Femenino , Neoplasias Gástricas/prevención & control , Dieta , Frutas , Verduras , Estudios de Casos y Controles , Ingestión de Alimentos , Factores de RiesgoRESUMEN
BACKGROUND: Delayed cholecystectomy in patients with symptomatic gallstone disease is associated with recurrence. Limited data on the recurrence patterns and the factors that determine them are available. OBJECTIVE: We aimed to determine the pattern of relapse in each symptomatic gallstone disease (acute pancreatitis, cholecystitis, cholangitis, symptomatic choledocholithiasis, and biliary colic) and determine the associated factors. METHODS: RELAPSTONE was an international multicenter retrospective cohort study. Patients (n = 3016) from 18 tertiary centers who suffered a first episode of symptomatic gallstone disease from 2018 to 2020 and had not undergone cholecystectomy during admission were included. The main outcome was relapse-free survival. Kaplan-Meier curves were used in the bivariate analysis. Multivariable Cox regression models were used to identify prognostic factors associated with relapses. RESULTS: Mean age was 76.6 [IQR: 59.7-84.1], and 51% were male. The median follow-up was 5.3 months [IQR 2.1-12.4]. Relapse-free survival was 0.79 (95% CI: 0.77-0.80) at 3 months, 0.71 (95% CI: 0.69-0.73) at 6 months, and 0.63 (95% CI: 0.61-0.65) at 12 months. In multivariable analysis, older age (HR = 0.57; 95% CI: 0.49-0.66), sphincterotomy (HR = 0.58, 95% CI: 0.49-0.68) and higher leukocyte count (HR = 0.79; 95% CI: 0.70-0.90) were independently associated with lower risk of relapse, whereas higher levels of alanine aminotransferase (HR = 1.22; 95% CI: 1.02-1.46) and multiple cholelithiasis (HR = 1.19, 95% CI: 1.05-1.34) were associated with higher relapse rates. CONCLUSION: The relapse rate is high and different in each symptomatic gallstone disease. Our independent predictors could be useful for prioritizing patients on the waiting list for cholecystectomies.
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Coledocolitiasis , Pancreatitis , Humanos , Masculino , Anciano , Femenino , Estudios Retrospectivos , Enfermedad Aguda , Pancreatitis/etiología , Factores de Riesgo , Coledocolitiasis/diagnóstico , Coledocolitiasis/epidemiología , Coledocolitiasis/cirugía , RecurrenciaRESUMEN
In this study, two distinct in vitro infection models of Aspergillus fumigatus, using murine macrophages (RAW264.7) and human lung epithelial cells (A549), were employed to identify the genes important for fungal adaptation during infection. Transcriptomic analyses of co-incubated A. fumigatus uncovered 140 fungal genes up-regulated in common between both models that, when compared with a previously published in vivo transcriptomic study, allowed the identification of 13 genes consistently up-regulated in all three infection conditions. Among them, the maiA gene, responsible for a critical step in the L-phenylalanine degradation pathway, was identified. Disruption of maiA resulted in a mutant strain unable to complete the Phe degradation pathway, leading to an excessive production of pyomelanin when this amino acid served as the sole carbon source. Moreover, the disruption mutant exhibited noticeable cell wall abnormalities, with reduced levels of ß-glucans within the cell wall but did not show lack of chitin or mannans. The maiA-1 mutant strain induced reduced inflammation in primary macrophages and displayed significantly lower virulence in a neutropenic mouse model of infection. This is the first study linking the A. fumigatus maiA gene to fungal cell wall homeostasis and virulence.
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Aspergillus fumigatus , Proteínas Fúngicas , Animales , Humanos , Ratones , Aspergillus fumigatus/metabolismo , Pared Celular/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Homeostasis , Virulencia/genéticaRESUMEN
Quantum-key-distribution (QKD) networks are gaining importance and it has become necessary to analyze the most appropriate methods for their long-distance interconnection. In this paper, four different methods of interconnecting remote QKD networks are proposed. The methods are used to link three different QKD testbeds in Europe, located in Berlin, Madrid, and Poznan. Although long-distance QKD links are only emulated, the methods used can serve as a blueprint for the secure interconnection of distant QKD networks in the future. Specifically, the presented approaches combine, in a transparent way, different fiber and satellite physical media, as well as common standards of key delivery interfaces. The testbed interconnections are designed to increase the security by utilizing multipath techniques and multiple hybridizations of QKD and post-quantum cryptography (PQC) algorithms.
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Aspergillus fumigatus is a major invasive mold pathogen and the most frequent etiologic agent of invasive aspergillosis. The currently available treatments for invasive aspergillosis are limited in both number and efficacy. Our recent work has uncovered that the ß-glucan synthase inhibitors, the echinocandins, are fungicidal against strains of A. fumigatus with defects in septation initiation network (SIN) kinase activity. These drugs are known to be fungistatic against strains with normal septation. Surprisingly, SIN kinase mutant strains also failed to invade lung tissue and were significantly less virulent in immunosuppressed mouse models. Inhibiting septation in filamentous fungi is therefore an exciting therapeutic prospect to both reduce virulence and improve current antifungal therapy. However, the SIN remains understudied in pathogenic fungi. To address this knowledge gap, we characterized the putative regulatory components of the A. fumigatus SIN. These included the GTPase, SpgA, it's two-component GTPase-activating protein, ByrA/BubA, and the kinase activators, SepM and MobA. Deletion of spgA, byrA, or bubA resulted in no overt septation or echinocandin susceptibility phenotypes. In contrast, our data show that deletion of sepM or mobA largely phenocopies disruption of their SIN kinase binding partners, sepL and sidB, respectively. Reduced septum formation, echinocandin hypersusceptibility, and reduced virulence were generated by loss of either gene. These findings provide strong supporting evidence that septa are essential not only for withstanding the cell wall disrupting effects of echinocandins but are also critical for the establishment of invasive disease. Therefore, pharmacological SIN inhibition may be an exciting strategy for future antifungal drug development.IMPORTANCESepta are important structural determinants of echinocandin susceptibility and tissue invasive growth for the ubiquitous fungal pathogen Aspergillus fumigatus. Components of the septation machinery therefore represent promising novel antifungal targets to improve echinocandin activity and reduce virulence. However, little is known about septation regulation in A. fumigatus. Here, we characterize the predicted regulatory components of the A. fumigatus septation initiation network. We show that the kinase activators SepM and MobA are vital for proper septation and echinocandin resistance, with MobA playing an essential role. Null mutants of mobA displayed significantly reduced virulence in a mouse model, underscoring the importance of this pathway for A. fumigatus pathogenesis.
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Aspergilosis , Aspergillus fumigatus , Animales , Ratones , Equinocandinas/farmacología , Antifúngicos/metabolismo , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , HongosRESUMEN
Adequate glycemic control is key to prevent morbi-mortality from type 2 diabetes (T2D). Despite the increasing availability of novel, effective, and safe medications for the treatment of T2D, and periodically updated guidelines on its management, the overall rate of glycemic goal attainment remains low (around 50%) and has not improved in the past decade. Therapeutic inertia (TI), defined as the failure to advance or de-intensify medical therapy when appropriate to do so, has been identified as a central contributor to the lack of progress in the rates of HbA1c goal attainment. The time to treatment intensification in patients not meeting glycemic goals has been estimated to be between 1 and 7 years from the time HbA1c exceeded 7%, and often, even when an intervention is carried out, it proves insufficient to achieve glycemic goals, which led to the concept of intensification inertia. Therefore, finding strategies to overcome all forms of TI in the management of T2D is a fundamental initiative, likely to have an enormous impact in health outcomes for people with T2D. There are several factors that have been described in the literature leading to TI, including clinician-related, patient-related, and healthcare system-related factors, which are discussed in this review. Likewise, several interventions addressing TI had been tested, most of them proving limited efficacy. Within the most effective interventions, there appear to be two common factors. First, they involve a team-based effort, including nurses, pharmacists, and diabetes educators. Second, they were built upon a framework based on results of qualitative studies conducted in the same context where they were later implemented, as will be discussed in this article. Given the complex nature of TI, it is crucial to use a research method that allows for an in-depth understanding of the phenomenon. Most of the literature on TI is focused on quantitatively describing its consequences; unfortunately, however, not many study groups have undertaken qualitative studies to deeply investigate the drivers of TI in their diverse contexts. This is particularly true in the United States, where there is an abundance of publications exploring the effects of different strategies to overcome TI in type 2 diabetes, but a severe shortage of qualitative studies aiming to truly understand the phenomenon.
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Whereas aging is a whole-organism process, senescence is a cell mechanism that can be triggered by several stimuli. There is increasing evidence that critical conditions activate cell senescence programs irrespective of patient's age. In this review, we briefly describe the basic senescence pathways and the consequences of their activation in critically ill patients. The available evidence suggests a paradigm in which activation of senescence can be beneficial in the short term by rendering cells resistant to apoptosis, but also detrimental in a late phase by inducing a pro-inflammatory and pro-fibrotic state. Senescence can be a therapeutic target. The use of drugs that eliminate senescent cells (senolytics) or the senescence-associated phenotype (senomorphics) will require monitoring of these cell responses and identification of therapeutic windows to improve the outcome of critically ill patients.
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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.
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Neoplasias Colorrectales , Carne Roja , Humanos , Interacción Gen-Ambiente , Carne Roja/efectos adversos , Carne/efectos adversos , Factores de Riesgo , Neoplasias Colorrectales/genéticaRESUMEN
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.
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Neoplasias Gástricas , Masculino , Humanos , Femenino , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiología , Factores de Riesgo , Premenopausia , IncidenciaRESUMEN
Asexual spores are the main vehicle used by fungi to disperse to new niches. The Eurotiomycete Aspergillus nidulans is the main reference for the study of the genetic/molecular control of asexual development. In this species, Flb proteins control the expression of the master gene brlA, and thus, loss-of-function mutations in flb (upstream developmental activation [UDA]) genes block brlA transcription and, consequently, the production of conidiophores, the structures bearing asexual spores known as conidia. However, the aconidial phenotype of specific flb mutants, such as that of the ΔflbB strain, is reverted under salt-stress conditions. Previously, we generated a collection of second-site mutants of ΔflbB unable to conidiate on culture medium supplemented with NaH2PO4 (0.65 M). Here, we identified a Gly347Stop mutation within flpA as responsible for the FLIP57 phenotype and characterized the role of the putative cyclin FlpA and the remaining putative components of the C-terminal domain kinase-1 (CTDK-1) complex in A. nidulans and Aspergillus fumigatus. FlpA, Stk47, and FlpB are necessary (i) for timely germination, (ii) in the transition from metulae to phialides (the cells generating conidia) during conidiophore development, and (iii) for the development of sexual structures (cleistothecia) in A. nidulans. The three proteins are nuclear, and the nucleoplasmic localization of Stk47 depends on the activity of FlpA, which correlates with the retention of Stk47 by FlpA in pull-down assays. Overall, this work links the putative CTDK-1 complex of aspergilli with growth and developmental control. Identification of a mutation in flpA as inhibitor of conidiation in A. nidulans and functional characterization of FlpA, Stk47 and FlpB as putative members of the C-terminal domain kinase complex CTDK-1 in A. nidulans and A. fumigatus.IMPORTANCEAspergillus fumigatus has been included by the World Health Organization in the priority list of fungal pathogens because (i) it causes 90% of invasive aspergillosis cases, with a high mortality rate, and (ii) infections are becoming increasingly resistant to azole antifungals. A. nidulans is an opportunistic pathogen and a saprotroph which has served during the last 80 years as a reference system for filamentous fungi. Here, we characterized the role in morphogenesis and development of the putative transcriptional cyclin/kinase complex CTDK-1 in both aspergilli. The null mutants of the corresponding genes showed delayed germination, aberrant conidiophore development, and inhibition of cleistothecia production. While in higher eukaryotes this complex is formed only by a cyclin and a kinase, the fungal complex would incorporate a fungal-specific third component, FlpB, which would enable the interaction between the kinase (Stk47) and the cyclin (FlpA) and may be used as a target for antifungals.
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Monitoring of the mental health status of the population and assessment of its determinants are 2 of the most relevant pillars of public mental health, and data from population health surveys could be instrumental to support them. Although these surveys could be an important and suitable resource for these purposes, due to different limitations and challenges, they are often relegated to the background behind other data sources, such as electronic health records. These limitations and challenges include those related to measurement properties and cross-cultural validity of the tools used for the assessment of mental disorders, their degree of representativeness, and possible difficulties in the linkage with other data sources. Successfully addressing these limitations could significantly increase the potential of health surveys in the monitoring of mental disorders and ultimately maximize the impact of the relevant policies to reduce their burden at the population level. The widespread use of data from population health surveys, ideally linked to electronic health records data, would enhance the quality of the information available for research, public mental health decision-making, and ultimately addressing the growing burden of mental disorders.
Asunto(s)
Trastornos Mentales , Salud Poblacional , Humanos , Salud Mental , Trastornos Mentales/epidemiología , Encuestas Epidemiológicas , Registros Electrónicos de SaludRESUMEN
BACKGROUND: Assessing the prevalence of clinically relevant depressive symptoms and their possible variation by country and over time could be a valuable resource to inform the development of public health policies and preventive resources to reduce mental health burden. We aimed to assess cross-national differences in the point prevalence of clinically relevant depressive symptoms in Europe in 2018-20, and to evaluate point prevalence differences between countries and over time between 2013-15 and 2018-20. METHODS: In this population-based study, data from participants in the second and third waves of the European Health Interview Survey (EHIS-2 from 2013 to 2015 and EHIS-3 from 2018 to 2020) from 30 European countries were used (n=542â580). From the total sample, 283â692 participants belonging to EHIS-3 were included in the study (52·4% women and 47·5% men). The non-response in EHIS-3 ranged by country, from 12% to 78%. Point prevalence of clinically relevant depressive symptoms was evaluated using a cutoff score of 10 or more for the 8-item version of the Patient Health Questionnaire. Crude prevalence ratios and adjusted prevalence ratios (aPRs) were obtained to assess differences in the prevalence between countries and over time within countries. FINDINGS: The point prevalence of clinically relevant depressive symptoms in Europe in 2018-20 was 6·54% (95% CI 6·34-6·73), ranging across countries from 1·85% (1·53-2·17) in Greece to 10·72% (10·04-11·40) in Sweden. Compared with the other European countries, those with the lowest aPRs were Greece, Serbia, and Cyprus and those with the highest aPRs were Belgium, Slovenia, and Croatia. A small but significant increase in the prevalence between EHIS-2 and EHIS-3 was observed (aPR 1·11 [1·07-1·14]). A wide variability over time in the point prevalence within countries was observed, ranging from an aPR of 0·63 (0·54-0·74) in Hungary to 1·88 (1·53-2·31) in Slovenia. INTERPRETATION: This study, based on large and representative datasets and a valid and reliable screening tool for the assessment of depression, indicates that the point prevalence of clinically relevant depressive symptoms in Europe from 2013 to 2020 remains relatively stable, with wide variability between countries. These findings could be considered a baseline for monitoring the prevalence of clinically relevant depressive symptoms in Europe, and could inform policy for the development of preventive strategies for depression both at a country and European level. FUNDING: Center for Biomedical Research in Epidemiology and Public Health Network and AGAUR.