Understanding the Role of the Complement System in Insulin Resistance and Metabolic Syndrome in Patients With Rheumatoid Arthritis.

OBJECTIVE: The complement system has been associated with the etiopathogenesis of rheumatoid arthritis (RA). Insulin resistance (IR) and metabolic syndrome (MetS) are prevalent among patients with RA. The aim of this study was to explore the relationship between a comprehensive evaluation of the complement system and IR, as well as MetS, in patients with RA. METHODS: A total of 339 nondiabetic patients with RA were recruited. Functional assays of the 3 complement pathways were assessed. Additionally, serum levels of the following individual components of the complement system were measured: C1q (classical); lectin (lectin); C2, C4, and C4b (classical lectin); factor D and properdin (alternative); C3 and C3a (common); C5, C5a, and C9 (terminal); as well as the factor I and C1 inhibitor regulators. IR and ß cell function indices were calculated using the homeostatic model assessment. Criteria for MetS were applied. Multivariable linear regression analysis was performed to investigate the association between the complement system and IR in patients with RA. RESULTS: Many elements of the upstream and common complement pathways, but not the functional tests of the 3 routes, correlated positively with higher levels of IR and ß cell function. However, after multivariable adjustment for factors associated with IR, these relationships were lost. Conversely, the presence of MetS in patients with RA maintained a relationship with higher levels of C1q, C4, C3, properdin, and factor I after adjusting for confounders. CONCLUSION: There is a positive correlation between the complement system and MetS among nondiabetic patients with RA. This association is independent of traditional IR factors.

The complement system is linked to insulin resistance in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients more commonly have insulin resistance (IR) than control subjects. Recent studies have revealed that the complement (C) system is not only a mediator of the immune system but is also related to the pathogenesis of atherosclerosis in the general population. Given that the C alteration is a characteristic of SLE, in the present work we set out to analyse if there is a relationship between the C system and IR in patients with SLE. METHODS: New generation functional assays of the three pathways of the C system were performed in 225 non-diabetic patients with SLE. In addition, the serum levels of inactive (C1q, C2, C3, C4, factor D), activated (C3a) and regulators (C1 inhibitor and factor H) molecules of the C system were evaluated. Insulin and C-peptide serum levels were measured, and insulin resistance and indices of beta cell function were calculated using the homeostatic model assessment (HOMA). Metabolic syndrome criteria fulfillments were applied. Multivariable linear regression analysis was performed to assess the relationship between C system and IR indices and the presence of metabolic syndrome. RESULTS: After adjusting for covariates that included traditional cardiovascular risk factors associated with IR and prednisone, serum C3a and factor H levels were positively related to higher levels of the HOMA2-IR index. Besides, in the multivariable analysis, after adjustment for covariates, serum levels of C1q and C3 associated with a higher odds ratio for the presence of metabolic syndrome. CONCLUSIONS: IR and metabolic syndrome are positively and independently related to higher serum levels of some serum C elements in patients with SLE with a predominant role of the alternative pathway elements.

Red blood cell distribution width as a surrogate biomarker of damage and disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: Red blood cell distribution width (RDW) is a measure of variability in mean corpuscular volume. Alterations in RDW can be observed in a variety of human disorders, including inflammatory, cardiovascular, and hepatic or renal diseases. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect virtually any organ in the body. In this work, our objective was to analyse how a complete characterisation of disease characteristics in a large series of patients with SLE is related to RDW values. METHODS: 284 patients with SLE and 181 age- and sex-matched healthy controls were recruited. Complete blood count including RDW was assessed. Multivariable analysis was performed to analyse the relationship between RDW and SLE disease characteristics, including composite scores of disease activity and damage. RESULTS: After multivariable adjustment, RDW was higher in patients with SLE compared to controls (beta coefficient 0.8 [95% confidence interval: 0.3-1] %, p=0.003). Several disease characteristics, such as the presence of extractable nuclear antibodies and antiphospholipid syndrome, and the use of prednisone and azathioprine, were significantly associated with higher levels of RDW after adjustment for confounders. Of note, cumulative disease damage and disease activity scores were associated with higher RDW values after controlling for covariates. CONCLUSIONS: RDW may serve as a surrogate biomarker of accrual disease damage and activity in patients with SLE.

CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.

BACKGROUND: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). METHODS: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed ß-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. RESULTS: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. CONCLUSIONS: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

Complete Description of the Three Pathways of the Complement System in a Series of 430 Patients with Rheumatoid Arthritis.

The complement (C) system is implicated in the etiopathogenesis of rheumatoid arthritis (RA). However, there is a lack of studies characterizing all three C pathways in RA patients. This study aimed to evaluate the association between an in-depth examination of the C system and RA patient characteristics, focusing on disease activity and the presence of rheumatoid factor and anti-citrullinated protein autoantibodies (ACPA). In a cohort of 430 RA patients, functional assays of the three C pathways (classical, alternative, and lectin) and serum levels of their components were assessed. Components included C1q (classical); factor D and properdin (alternative); lectin (lectin); C1-inhibitor; C2, C4, and C4b (classical and lectin); C3, C3a, and C4b (common); and C5, C5a, and C9 (terminal). A multivariable linear regression analysis showed significant positive correlations between C-reactive protein and C system proteins and functional assays, especially in the terminal and common pathways. Disease activity, measured by scores with or without acute phase reactants, positively correlated with the classical pathway functional test and terminal pathway products. Conversely, rheumatoid factor or ACPA presence was associated with lower classical pathway values and decreased C3a and C4b levels, suggesting complement depletion. In conclusion, RA disease activity increases C molecules and functional complement assays, while rheumatoid factor or ACPA positivity is linked to C consumption. Our study offers a detailed analysis of the complement system's role in RA, potentially guiding the development of more targeted and effective treatment strategies.

Relationship between Disease Characteristics and Circulating Interleukin 6 in a Well-Characterized Cohort of Patients with Systemic Lupus Erythematosus.

Interleukin-6 (IL-6) is a proinflammatory cytokine that mediates pleiotropic functions in immune responses and inflammatory diseases. The literature lacks studies, with a clinical perspective, on the relationship between IL-6 serum levels and the characteristics of the disease in patients with systemic lupus erythematosus (SLE). In the present work, we aimed to analyze the association between circulating IL-6 and disease manifestations in a well-characterized series of patients with SLE. Serum IL-6 levels and disease activity (SLEDAI-2K), severity (Katz) and damage index (SLICC-DI), complete lipid profile, and subclinical carotid atherosclerosis were evaluated in 284 patients with SLE. In addition, a complete characterization of the complement system was performed in samples from patients with SLE. A multivariate linear regression analysis was carried out to study the relationship between clinical and laboratory characteristics of the disease and IL-6 levels. Age (beta coef. 0.07 [95%CI 0.01-0.1] pg/mL, p = 0.014), C-reactive protein (beta coef. 0.21 [95%CI 0.16-0.25] pg/mL, p < 0.01), and male gender (beta coef. 2 [95%CI 0.3-0.5] pg/mL, p = 0.024), were positively associated with higher IL-6 levels in SLE patients. Most disease characteristics and damage and activity indices did not show significant relationships with IL-6. However, after multivariate analysis, IL-6 was associated with lower serum levels of HDL cholesterol (beta coef. -0.04 [95%CI -0.08-(-0.1)] pg/mL, p = 0.011), and apolipoprotein A1 (beta coef. -0.02 [95%CI -0.04-(-0.001)] pg/mL, p = 0.035). In contrast, the alternative complement cascade, C1inh, and C3a were all positively and independently associated with higher serum levels of IL-6. Moreover, stratification of the Systematic Coronary Risk Assessment 2 (SCORE2) results according to different categories of cardiovascular risk was associated with higher circulating serum IL-6 levels (beta coef. 0.2 [95%CI 0.02-0.4], pg/mL, p = 0.028). In conclusion, in a large series of SLE patients, IL-6 was not associated with disease-related features of SLE, including damage, severity, or activity indices. However, an association was found between serum IL-6 levels and circulating C3a and cardiovascular risk. Our study emphasizes the importance that IL-6 could have in cardiovascular disease and complement system disruption of SLE patients. Therapies targeting IL-6 could have a role in these two clinical manifestations of patients with SLE.

Predictive Value of Genetic Risk Scores in the Development of Colorectal Adenomas.

INTRODUCTION: Unlike colorectal cancer (CRC), few studies have explored the predictive value of genetic risk scores (GRS) in the development of colorectal adenomas (CRA), either alone or in combination with other demographic and clinical factors. METHODS: In this study, genomic DNA from 613 Spanish Caucasian patients with CRA and 829 polyp-free individuals was genotyped for 88 single-nucleotide polymorphisms (SNPs) associated with CRC risk using the MassArray™ (Sequenom) platform. After applying a multivariate logistic regression model, five SNPs were selected to calculate the GRS. Regression models adjusted by sex, age, family history of CRC, chronic use of NSAIDs, low-dose ASA, and consumption of tobacco were built in order to study the association between GRS and CRA risk. We evaluated the discriminatory capacity using the area under the receiver operating characteristic curve (AUC). The interactions between demographic information and GRS were also analyzed. RESULTS: Significant associations between high GRS values and risk of CRA for analyzed models were observed. In particular, patients with higher GRS values had 2.3-2.6-fold increase in risk of CRA compared to patients with middle values. Combining sex and age with the GRS significantly increased the discriminatory accuracy of the univariate model with GRS alone. The best model achieved an AUC value of 0.665 (95% CI: 0.63-0.69). The GRS showed a different behavior depending on sex and age. CONCLUSION: Our findings showed that, besides sex and age, GRS is an important risk factor for development of CRA and may be useful for CRC risk stratification and adaptation of screening programs.

Altered electromyographic responses to emotional and pain information in awake bruxers: case-control study.

OBJECTIVES: This study aims to investigate how emotional information and pain-related information affect the activity of the masticatory muscles in participants with awake bruxism and controls. MATERIAL AND METHODS: Different videos and texts, with positive, negative, and neutral valence or related to pain, were presented to a sample of university students, while their electromyographic (EMG) activity around the masseter muscle and their skin conductance were recorded. Two groups were selected, with 24 subjects each: one group of subjects with definitive awake bruxism (confirmed by posterior EMG activity) who also suffered from moderate jaw discomfort, and another group of subjects without bruxism. RESULTS: The results demonstrated that the subjects with definitive awake bruxism displayed greater muscular activity when presented videos and texts with negative valence, especially when related to pain, than the non-bruxist group. CONCLUSIONS: This study supports the idea that persons with bruxism who also suffer moderate levels of jaw discomfort present greater bruxism activity when watching pain-related stimuli, and to a lesser extent when watching negative stimuli. CLINICAL RELEVANCE: The increased muscular activity induced by negative and pain-related information might contribute to pain exacerbation and perpetuation in persons with bruxism who suffer from discomfort.

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms.

GLYT1 encephalopathy is a form of glycine encephalopathy caused by disturbance of glycine transport. The phenotypic spectrum of the disease has not yet been completely described, as only four unrelated families with the disorder have been reported to date. Common features of affected patients include neonatal hypotonia, respiratory failure, encephalopathy, myoclonic jerks, dysmorphic features, and musculoeskeletal anomalies. All reported affected patients harbor biallelic genetic variants in SLC6A9. SNP array together with Sanger sequencing were performed in a newborn with arthrogryposis and severe neurological impairment. The novel genetic variant c.997delC in SLC6A9 was detected in homozygous state in the patient. At protein level, the predicted change is p.(Arg333Alafs*3), which most probably results in a loss of protein function. The variant cosegregated with the disease in the family. A subsequent pregnancy with ultrasound anomalies was also affected. The proband presented the core phenotypic features of GLYT1 encephalopathy, but also a burst suppression pattern on the electroencephalogram, a clinical feature not previously associated with the disorder. Our results suggest that the appearance of this pattern correlates with higher cerebrospinal fluid glycine levels and cerebrospinal fluid/plasma glycine ratios. A detailed discussion on the possible pathophysiological mechanisms of the disorder is also provided.

Phase Entropy Analysis of Electrohysterographic Data at the Third Trimester of Human Pregnancy and Active Parturition.

Phase Entropy (PhEn) was recently introduced for evaluating the nonlinear features of physiological time series. PhEn has been demonstrated to be a robust approach in comparison to other entropy-based methods to achieve this goal. In this context, the present study aimed to analyze the nonlinear features of raw electrohysterogram (EHG) time series collected from women at the third trimester of pregnancy (TT) and later during term active parturition (P) by PhEn. We collected 10-min longitudinal transabdominal recordings of 24 low-risk pregnant women at TT (from 35 to 38 weeks of pregnancy) and P (>39 weeks of pregnancy). We computed the second-order difference plots (SODPs) for the TT and P stages, and we evaluated the PhEn by modifying the k value, a coarse-graining parameter. Our results pointed out that PhEn in TT is characterized by a higher likelihood of manifesting nonlinear dynamics compared to the P condition. However, both conditions maintain percentages of nonlinear series higher than 66%. We conclude that the nonlinear features appear to be retained for both stages of pregnancy despite the uterine and cervical reorganization process that occurs in the transition from the third trimester to parturition.

Genetic susceptibility in the development of colorectal adenomas according to family history of colorectal cancer.

Our study aimed to evaluate the relevance of genetic susceptibility in the development of colorectal adenomas (CRA) and its relationship with the presence of family history of colorectal cancer (CRC). Genomic DNA from 750 cases (first degree relatives of patients with CRC) and 750 controls (subjects with no family history of CRC) was genotyped for 99 single nucleotide polymorphisms (SNPs) previously associated with CRC/CRA risk by GWAS and candidate gene studies by using the MassArray™ (Sequenom) platform. Cases and controls were matched by gender, age and histological lesion. Eight hundred and fifty-eight patients showed no neoplastic lesions, whereas 288 patients showed low-risk adenomas, and 354 patients presented high-risk adenomas. Two SNPs (rs10505477, rs6983267) in the CASC8 gene were associated with a reduced risk of CRA in controls (log-additive models, OR: 0.67, 95%CI:0.54-0.83, and OR:0.66, 95%CI:0.54-0.84, respectively). Stratified analysis by histological lesion revealed the association of rs10505477 and rs6983267 variants with reduced risk of low- and high-risk adenomas in controls, being this effect stronger in low-risk adenomas (log-additive models, OR:0.63, 95%CI:0.47-0.84 and OR:0.64, 95%CI:0.47-0.86, respectively). Moreover, 2 SNPs (rs10795668, rs11255841) in the noncoding LINC00709 gene were significantly associated with a reduced risk of low-risk adenomas in cases (recessive models, OR:0.22, 95%CI:0.06-0.72, and OR:0.08, 95%CI:0.03-0.61) and controls (dominant models, OR:0.50, 95%CI:0.34-0.75, and OR:0.52, 95%CI:0.35-0.78, respectively). In conclusion, some variants associated with CRC risk (rs10505477, rs6983267, rs10795668 and rs11255841) are also involved in the susceptibility to CRA and specific subtypes. These associations are influenced by the presence of family history of CRC.

Undifferentiated connective tissue disease: predictors of evolution into definite disease.

OBJECTIVES: The natural evolution of undifferentiated connective tissue diseases (UCTD) has not yet been established. The aim of our study was to analyse the clinical outcomes of a cohort of UCTD patients followed in a routine outpatient setting and to establish which clinical, serological or capillaroscopy features are associated with an increased risk of evolution to definite connective tissue disease (CTD). METHODS: Data for this study were collected by a retrospective review of 758 patients referred to our hospital, between 1999 and 2008, with suspected CTD. After selection criteria, 98 patients were considered eligible and their records, laboratory findings and nailfold-capillaroscopy pattern (NCP) were analysed until clinical outcome. Three groups of patient outcomes were established: remission, UCTD, and definite CTD. Logistic regression analysis was performed to study the association of baseline clinical features, including NCP progression during monitoring, with clinical outcomes. RESULTS: After a mean follow-up of 11±3 years, 62% of the patients continued to suffer from UCTD, 24% regressed to a remission state and 14% developed definite CTD. Cytopenias (p=0.030), positivity for antibody specificities (ENA) (p=0.008), anti-Ro (p=0.036) and antiphospholipid antibodies (p=0.032), and the presence of an altered NCP (p=0.026) at baseline proved different between groups and were more frequently encountered in the group that evolved to definite CTD when compared with the others two groups. Specifically, cytopenias (odds ratio -OR- 4.20 [1.30-13.56] p=0.016), the presence of an antinuclear antibody (ANA) titre ≥1/640 (OR 7.00 [1.99-24.66], p=0.002) and anti-centromere positivity (OR 3.77 [1.03-13.79], p=0.045) at baseline and NCP progression (OR 6.63 [1.70-25.87], p=0.007) were associated with the future presence of definite CTD. CONCLUSIONS: Most patients with UCTD remain in an undifferentiated state after routine outpatient clinic follow-up. High ANA titres or the presence of cytopenias at baseline, as well as progression of NCP during follow-up, are the leading factors associated with evolution to definite CTD.

Acetylsalicylic Acid Exhibits Antitumor Effects in Esophageal Adenocarcinoma Cells In Vitro and In Vivo.

BACKGROUND AND AIM: Recent observational studies have shown therapeutic benefits of acetylsalicylic acid (ASA) in several types of cancer. We examined whether ASA exerts antitumor activity in esophageal adenocarcinoma (EAC). METHODS: Human EAC cells (OE33) were treated with ASA (0-5 mM) to evaluate proliferation, apoptosis, and migration. In vivo model: OE33-derived tumors were subcutaneously implanted into athymic mice which were allocated to ASA (5 or 50 mg/kg/day)/vehicle (5-6 animals/group). Tumor growth was assessed every 2-3 days, and after 40 days, mice were euthanized. Plasma drug levels were determined by high-performance liquid chromatography. Histological and immunohistochemical (Ki67, activated caspase-3) analysis of tumors were performed. The effect of ASA on tumor prostaglandin E2 (PGE2) levels was also evaluated. RESULTS: In vitro cell proliferation and migration were significantly inhibited while apoptosis increased (p < 0.05) by ASA. Although ASA did not induce tumor remission, tumor progression was significantly lower in ASA-treated mice when compared to non-treated animals (478 % in mice treated with 5 mg/kg/day ASA vs. 2696 % control; 748 % in mice treated with 50 mg/kg/day ASA vs. 2670 % control). Maximum tumor inhibition was 92 and 85 %, respectively. This effect was associated with a significant decrease of proliferation index in tumors. ASA 5 mg/kg/day did not modify tumor PGE2 levels. Whereas tumor PGE2 content in mice treated with ASA 50 mg/kg was lower than in control mice, the difference was not significant. CONCLUSION: Although these results need to be confirmed in other EAC cells, our data suggest a role for ASA in the treatment of this tumor.

Association of PSCA rs2294008 gene variants with poor prognosis and increased susceptibility to gastric cancer and decreased risk of duodenal ulcer disease.

Two recent genome-wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori infection-related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR-TaqMan assays. H. pylori infection [odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45-15.33] and nonsteroidal anti-inflammatory drugs (OR: 6.54; 95% CI: 3.19-12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33-0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63-2.34), smoking (OR: 1.93; 95% CI: 1.54-2.61), family history of GC (OR: 2.83; 95% CI: 2.01-3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07-1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12-1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16-1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse-type GC (hazard ratio: 1.85; 95% CI: 1.12-3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse-type of GC in Caucasians.

Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study.

BACKGROUND: The optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC. METHODS: Patients received intravenous irinotecan 175 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) (800 mg/m(2) for patients >65 years of age) twice daily on days 2-8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks. RESULTS: Seventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1-11. CONCLUSION: Our study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009.

Isolated deafness in multiple sclerosis patients.

Isolated cranial nerve involvement in multiple sclerosis (MS) patients is not frequent. Deafness is considered to be uncommon in MS patients. We have reviewed the sensorineural hearing loss episodes that had been thoroughly investigated in our hospital in the last 5 years. We present three cases of sensorineural hearing loss in patients with MS and compare them with other previously reported and discuss this uncommon symptom. The cases that we present were firstly evaluated by an otolaryngologist. A lesion is seen at the root-entry zone of the eighth cranial nerve in only one case, but no lesions are seen in the other cases. A retrocochlear demyelinating disorder was demonstrated in the two patients in whom brainstem auditory evoked potentials were performed. All patients recovered at least partially their hearing functions.

Genetic susceptibility and gastric cancer risk: the importance of meta-analyses as a statistical tool.

Gastric cancer (GC) is a complex disease and a worldwide health burden due to its high prevalence and poor prognosis. A deeper knowledge of the factors involved in the development and progression of GC could help to identify subpopulations at risk that therefore require surveillance or early treatment strategies. Current research is based on the study of genetic variants that confer a higher risk of GC and their interactions with environmental exposure. Recently, meta-analysis has emerged as an important statistical method involving pooling of data from individual association studies to increase statistical power and obtain more conclusive results. Given the importance of chronic inflammation in the process of gastric carcinogenesis, the present article reviews the most recent meta-analyses of the contribution of cytokine gene polymorphisms to GC risk.

GastricAITool: A Clinical Decision Support Tool for the Diagnosis and Prognosis of Gastric Cancer.

BACKGROUND/OBJECTIVE: Gastric cancer (GC) is a complex disease representing a significant global health concern. Advanced tools for the early diagnosis and prediction of adverse outcomes are crucial. In this context, artificial intelligence (AI) plays a fundamental role. The aim of this work was to develop a diagnostic and prognostic tool for GC, providing support to clinicians in critical decision-making and enabling personalised strategies. METHODS: Different machine learning and deep learning techniques were explored to build diagnostic and prognostic models, ensuring model interpretability and transparency through explainable AI methods. These models were developed and cross-validated using data from 590 Spanish Caucasian patients with primary GC and 633 cancer-free individuals. Up to 261 variables were analysed, including demographic, environmental, clinical, tumoral, and genetic data. Variables such as Helicobacter pylori infection, tobacco use, family history of GC, TNM staging, metastasis, tumour location, treatment received, gender, age, and genetic factors (single nucleotide polymorphisms) were selected as inputs due to their association with the risk and progression of the disease. RESULTS: The XGBoost algorithm (version 1.7.4) achieved the best performance for diagnosis, with an AUC value of 0.68 using 5-fold cross-validation. As for prognosis, the Random Survival Forest algorithm achieved a C-index of 0.77. Of interest, the incorporation of genetic data into the clinical-demographics models significantly increased discriminatory ability in both diagnostic and prognostic models. CONCLUSIONS: This article presents GastricAITool, a simple and intuitive decision support tool for the diagnosis and prognosis of GC.

Relationship between the complement system and serum lipid profile in patients with rheumatoid arthritis.

Background: The complement system has been linked to the etiopathogenesis of rheumatoid arthritis (RA). Patients with RA exhibit a dysregulated profile of lipid molecules, which has been attributed to the inflammation present in the disease. In this study, we aimed to evaluate the association between a comprehensive assessment of the complement system and the lipid profile of patients with RA. Methods: 430 patients with RA were recruited. New-generation techniques were employed to conduct functional assays of the three pathways of the complement system. Serum levels of various complement components such as C1q, factor D, properdin, lectin, C1-inhibitor, C2, C4, C4b, C3, C3a, C5, C5a, and C9 were assessed. Furthermore, a complete pattern of lipid molecules was measured including high (HDL), low-density lipoproteins (LDL), and lipoprotein (a). Multivariable linear regression analysis was conducted to investigate the association between the complement system and lipid profile in RA patients. Results: After multivariable analysis, several noteworthy associations emerged between the complement system and lipid molecules. Notably, complement components most strongly linked to the lipid profile were C1q and properdin, representing the upstream classical and alternative pathways, along with C3 from the common cascade. These associations demonstrated significance and positivity concerning total cholesterol, LDL, atherogenic index, apolipoprotein B, and lipoprotein(a), suggesting a connection with an unfavorable lipid profile. Interestingly, complement functional assays of the three pathways and activated products such as C3a and C5a showed no correlation with the lipid pattern. Conclusion: The correlation between the complement system and lipid molecule patterns is pronounced in patients with RA. This relationship is predominantly positive and primarily associated with upstream complement components rather than activated ones.