Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival.

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

Early in life stressful events induce chronic visceral pain and changes in bladder function in adult female mice through a mechanism involving TRPV1 and alpha 1A adrenoceptors.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder with multiple phenotypes, one of which is associated with an overactive adrenergic system. OBJECTIVE: We investigated if the maternal deprivation model (MDM) in female and male mice mimics IC/BPS phenotype and if the overstimulation of alpha 1A adrenoceptor (A1AAR) and the crosstalk with transient receptor potential vanilloid-1 (TRPV1) are involved in the generation of pain and bladder functional changes. DESIGN, SETTING, AND PARTICIPANTS: C57BL/6 female and male mice were submitted to MDM. TRPV1 knockout (KO) mice were used to study TRPV1 involvement. Silodosin administration to MDM mice was used to study A1AAR involvement. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was chronic visceral pain measured by Von Frey filaments analysis (effect size: 3 for wild type, 3.9 for TRPV1 KO). Bladder changes were secondary outcome measurements. Unpaired T test, Mann-Whitney test, one-way analysis of variance followed by Newman-Keuls multiple comparisons test, and Kruskal-Wallis followed by Dunn's multiple comparisons test were used where appropriate. RESULTS AND LIMITATIONS: MDM induces pain behavior in female and not in male mice. Bladder afferents seem sensitize as MDM also increase the number of small volume spots voided, the bladder reflex activity, and urothelial damage. These changes were similarly absent after A1AAR blockade with silodosin or by TRPV1 gene KO. The main limitation is the number/type of pain tests used. CONCLUSIONS: MDM induced in female mice is able to mimic IC/BPS phenotype, through mechanisms involving A1AAR and TRPV1. Therefore, the modulation of both receptors may represent a therapeutic approach to treat IC/BPS patients.

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

Helicobacter species binding to the human gastric mucosa.

Helicobacter pylori infects half of the world population, being associated with several gastric disorders, such as chronic gastritis and gastric carcinoma. The Helicobacter genus also includes other gastric helicobacters, such as H. heilmannii¸ H. ailurogastricus, H. suis, H. felis, H. bizzozeronii, and H. salomonis. These gastric helicobacters colonize both the human and animal stomach. The prevalence of gastric non-Helicobacter pylori Helicobacter (NHPH) species in humans has been described as low, and the in vitro binding to the human gastric mucosa was never assessed. Herein, human gastric tissue sections were used for the evaluation of the tissue glycophenotype and for the binding of gastric NHPH strains belonging to different species. Histopathological evaluation showed that 37.5% of the patients enrolled in our cohort presented chronic gastritis, while the presence of neutrophil or eosinophilic activity (chronic active gastritis) was observed in 62.5% of the patients. The secretor phenotype was observed in 68.8% of the individuals, based on the expression of Lewis B antigen and binding of the UleX lectin. The in vitro binding assay showed that all the NHPH strains evaluated were able to bind, albeit in low frequency, to the human gastric mucosa. The H. heilmannii, H. bizzozeronii, and H. salomonis strains displayed the highest binding ability both to the gastric superficial epithelium and to the deep glands. Interestingly, we observed binding of NHPH to the gastric mucosa of individuals with severe chronic inflammation and intestinal metaplasia, suggesting that NHPH binding may not be restricted to the healthy gastric mucosa or slight chronic gastritis. Furthermore, the in vitro binding of NHPH strains was observed both in secretor and non-secretor individuals in a similar frequency. In conclusion, this study is the first report of the in vitro binding ability of gastric NHPH species to the human gastric mucosa. The results suggest that other glycans, besides the Lewis antigens, could be involved in the bacterial adhesion mechanism; however, the molecular intervenients remain unknown.

Influence of ventilation in H2S exposure and emissions from a gravity sewer.

This study was carried out to evaluate the effect of natural ventilation and intermittent pumping events in hydrogen sulfide and methane dynamics, in terms of system operation and risk of gas exposure. Work was conducted in a full scale gravity sewer downstream of pumping stations, in Portugal. Different ventilation rates and locations were assessed, as well as H2S removal rates and potential exposure risk, through the opening of distinct manhole covers. Increased ventilation, resulting from opening of one manhole cover, saw a 38% increase in average pipe air velocity peaks, doubling the estimated rate of air turnovers per day, accompanied by an increase of nearly 20% in H2S average removal rate. Simultaneous opening of two manhole covers induced similar airflow rates through the vent stack, but different rates throughout the pipe. H2S removal rates were also found to differ, according to location of open manholes, but also initial H2S headspace concentration. Under more unfavourable conditions, natural ventilation did not suffice in attaining recommended safety concentrations, regardless of number and location of open manhole covers. H2S concentrations above defined thresholds were verified for all studied setups. Headspace oxygen concentrations below an 18.5% asphyxiation threshold also occasionally occurred, even at manholes immediately downstream of ventilation point.

Assessment of sulfide production in a full scale wastewater sludge rising main.

Production and build-up of sulfide in wastewater systems, especially downstream of rising mains, may lead to severe odour nuisance, toxic environments and high risk of corrosion. Due to increased population migration towards cities and lower area availability for treatment facilities, rising mains for the conveyance of wastewater sludge are becoming more frequent, and research on sulfide build-up in such cases is needed. In this paper the findings of the work carried out in a full scale wastewater sludge rising main, operated during different seasons and under distinct conditions are presented (comprising both the start-up and normal operation stages of the facility). Results showed a sulfide build-up rate of 3.24 g S-2 m-2 d-1 in the summer and of 2.30 g S-2 m-2 d-1 during the winter. The ratio of sulfate reduction to sulfide production (SO4-2/S-2) was of roughly 3 to 1, as expected. Furthermore, obtained results allowed adjusting a second order polynomial empirical equation for the forecasting of sulfide build-up within the sludge rising main. The obtained equation for sludge significantly differs from existing equations obtained for wastewater. Moreover, this work also allowed obtaining new insight into the positive influence of biofilm and hydraulic retention time in the biological sulfide generation, as well as into its variation along the length of the rising main.

Release of hydrogen sulfide under intermittent flow conditions - the potential of simulation models.

For engineering purposes it is especially useful to be able to predict and control sewer corrosion rates and odor impacts as well as to design effective measures aiming to reduce effects related to hydrogen sulfide formation and release. Doing so, it is important to use modeling tools that are capable of assessing variations of dissolved oxygen, dissolved sulfide and hydrogen sulfide gas concentrations for a wide range of environmental scenarios. Two such models were assessed: AEROSEPT, an empirical formulation, and WATS, a conceptual and more complex approach. The models were applied to evaluate the effects of transitions between pressure mains and gravity sewers in the air-liquid mass transfer of hydrogen sulfide at the Ericeira sewer system in Portugal. This network is known to have odor and corrosion problems, especially during summer. Despite the unavoidable uncertainties due to the unsteady flow rate and the quantification of air velocity and turbulence, the simulation results obtained with both models have been shown to adequately predict the overall behavior of the system.

Release of hydrogen sulfide in a sewer system under intermittent flow conditions: the Eiceira case study, in Portugal.

The presence and fate of hydrogen sulfide in wastewater systems were studied in two stretches of an intercepting sewer system located in a coastal village, in Portugal. A range of hydraulic parameters were obtained and liquid and gas phase measurements were carried out, both continuously and through intensive sampling campaigns. Upstream, where flow rates were relatively low, dissolved sulfide concentrations around 12 mg S L-1 and hydrogen sulfide gas concentrations above 250 ppm were observed, along with limited corrosion damage. It is believed this is due to the low relative humidity detected along the atmosphere of the studied sewer system. Downstream, gas concentrations were always below 40 ppm. Despite that, high signs of corrosion were detected, particularly in manholes with drop structures. It is thought that condensation of spray produced by the fall is the main cause of the phenomenon. Another relevant observation was the rapid decline in dissolved sulfide contents along gravity trunk sewers following the discharge of rising mains, with loss rates as high as 40 mg S L-1 h-1. Air-flow velocities corresponded to 15-50% of wastewater flows, an observation which agrees with other authors' publications addressing relatively small pipes and moderate water flows.

Dynamic Modeling of Hydrogen Sulfide within Enclosed Environments in Biosolids Recovery Facilities.

Hydrogen sulfide emissions from wastewater affect human health and equipment durability, thus presenting a complex issue for utilities. Several VOC emission models have been used before to predict H2S in collection systems and water resources recovery operations, even if with restrictions. By contrast, fewer studies focus on biosolids emissions and modelling. This paper presents a dynamic modelling approach to predict H2S concentration in a tank headspace of a wastewater biosolids recovery facility. Data from one of the largest Portuguese water resources recovery facilities was collected under different facility operating modes. The developed model adequately predicted H2S concentration, with R2 values of 0.89 and 0.78, for different periods of the year, thus showing how modelling may reliably contribute to utility operation decisions.

Advanced Vestibular Schwannoma: A Case of Optic Disc Oedema without Hydrocephalus.

A wide range of pathologies can cause papilloedema. Vestibular schwannoma is a benign and slow-growing tumour that causes symptoms and findings on ophthalmic examination when the diagnostic is delayed. The authors report a case of a 64-year-old male who presented with bilateral disc oedema secondary to a vestibular schwannoma grade 4. Obstructive hydrocephalus was not evident. The authors suggest that cerebrospinal fluid protein may have a role in the formation of optic disc oedema. A right suboccipital craniectomy was performed to remove the tumour, leading to secondary facial palsy.

Preliminary Insights into the Antigenotoxic Potential of Lemon Essential Oil and Olive Oil in Human Peripheral Blood Mononuclear Cells.

Lemon essential oil, derived from Citrus limon, possesses diverse health-promoting properties, including antioxidant, antimicrobial, and mood-enhancing effects. Despite its traditional use in aromatherapy and complementary medicine, there is a need for comprehensive investigations into its therapeutic potential, particularly in mitigating DNA damage and supporting health in palliative care settings. This study aimed to evaluate the antigenotoxic effects of lemon essential oil in human peripheral blood mononuclear cells and to explore its potential applications in palliative care. Treatment with lemon essential oil significantly reduced DNA damage, with 1% w/v with 3.13% DNA in tail demonstrating greater efficacy. Furthermore, lemon essential oil attenuated streptonigrin-induced DNA damage, suggesting a potential protective effect against oxidative stress, especially at 3% w/v, with 11.81% DNA in tail. Compared to olive oil treatment, the DNA damage was significantly lower with streptonigrin treatment alone, which had 47.06% DNA in tail, while the olive oil treatment resulted in 36.88% DNA in tail. These results can be attributed to the main constituents: limonene in lemon essential oil and oleic acid in olive oil. These results suggest a potential role in mitigating oxidative stress and supporting genomic stability. Further research is warranted to elucidate the mechanisms of action and clinical applications in palliative care.

Exploring Aromatherapy as a Complementary Approach in Palliative Care: A Systematic Review.

Background: Palliative care, a cornerstone of comprehensive healthcare, prioritizes quality of life for individuals with life-threatening illnesses. Aromatherapy, with its holistic approach and patient-reported benefits, emerges as a promising complementary therapy for managing symptoms and enhancing well-being in palliative care. Objective: The objective of this systematic review is to assess the efficacy of aromatherapy interventions in symptom management, with a focus on pain, anxiety, nausea, and sleep disturbances among palliative care patients. Design: A comprehensive search was conducted across various databases to identify relevant studies. Eligibility criteria were applied, resulting in the inclusion of eight studies for analysis. The review assessed the efficacy of aromatherapy interventions, primarily through massage, in symptom management. Variations in intervention procedures and outcome measures were noted, necessitating a critical examination of the findings. Results: The review's findings suggest promising outcomes associated with aromatherapy in palliative care. Aromatherapy interventions demonstrated significant efficacy in reducing pain, anxiety, nausea, and improving sleep quality among patients. However, considerable heterogeneity was observed across studies, highlighting the need for standardized methodologies and larger-scale trials. Conclusion: This systematic review underscores the potential of aromatherapy as a complementary intervention in palliative care. While the findings support its efficacy in symptom management, methodological inconsistencies across studies warrant further research. Standardized approaches and larger trials are essential to validate the tailored effectiveness of aromatherapy for different symptoms encountered in palliative care, ultimately enhancing its clinical utility and integration into therapeutic practices.

Predictive factors for dose reduction and discontinuation of nintedanib in fibrotic interstitial lung diseases: Real life data.

Nintedanib, an intracellular inhibitor targeting multiple tyrosine kinases, has emerged as a standard treatment for various fibrotic lung diseases. Despite its efficacy, side effects such as nausea, diarrhea, and hepatotoxicity often lead to dose reduction or discontinuation. In this retrospective analysis at an university hospital's interstitial lung disease clinic, we aimed to identify baseline characteristics associated with dose adjustment or treatment discontinuation. Of the 58 patients included, 41.4% maintained the full nintedanib dose, while 31.0% required dosage reduction, and 27.6% discontinued treatment due to adverse events, predominantly gastrointestinal and hepatotoxic effects. Multivariate analysis revealed body surface area (BSA) as an independent and significant baseline risk factor (adjusted Odds Ratio [aOR] 0.22), suggesting a 78% decreased chance of requiring dose modification for every decimal point increase in BSA. A BSA cutoff of ≤1.73 m [2] exhibited a sensitivity of 73% and specificity of 91.7%, with significant impact on one-year survival under full-dose treatment (p < 0.001). Lower BSA was associated with early onset adverse effects, particularly gastrointestinal, supporting the need for regular clinical monitoring. The study emphasizes the importance of recognizing baseline factors to ensure the safety and tolerability of nintedanib, thereby preventing the progression of pulmonary fibrosis. These findings contribute to the evolving understanding of nintedanib management in fibrotic interstitial lung diseases, guiding clinicians in personalized treatment approaches.

Orogenital and anal infection by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and other sexually transmitted infections in men who have sex with men in Lisbon.

BACKGROUND: Men who have sex with men (MSM) are at risk for sexually transmitted infections (STIs), but more data on extragenital carriage are needed. AIM: We assessed the genital and extragenital prevalence of bacterial and other STIs in MSM in a Lisbon sexual health clinic. METHODS: We screened oral, anal, and urine samples of MSM visiting the GAT-CheckpointLX clinic June 2017-December 2021 for Chlamydia trachomatis (including lymphogranuloma venereum, LGV), Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, Mycoplasma hominis, Ureaplasma urealyticum, and U. parvum. Ano-oro-genital lesions were tested for LGV, Treponema pallidum, and Herpes Simplex Virus. Blood was tested for HIV and T. pallidum antibodies. RESULTS: N. gonorrhoeae was found in 16.6% of the MSM followed by C. trachomatis (13.2%), M. genitalium (10.3%) and T. vaginalis (0.2%). The most frequent occurrence was anorectal (C. trachomatis, M. genitalium) and oral (N. gonorrhoeae). We found high carriage of U. urealyticum (36.1%) and M. hominis (22.1%). LGV was detected in 21.8% of chlamydia-positive anorectal swabs. Syphilis was detected in 22.6% of tested MSM, while 13.8% had HIV. Gonorrhoea and chlamydia were significantly more prevalent in MSM with concomitant HIV or syphilis. CONCLUSION: The substantial extragenital prevalence of bacterial STIs in MSM, and HIV and syphilis coinfections, suggest screening has value in identifying hidden carriage and in contributing for providing better care.

Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease.

The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabA's binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.

Monitoring of SARS-CoV-2 Specific Antibodies after Vaccination.

Vaccination is considered the most important measure to control the COVID-19 pandemic. Extensive follow-up studies with distinct vaccines and populations are able to promote robust and reliable data to better understand the effectiveness of this pharmacologic strategy. In this sense, we present data regarding binding and neutralizing (achieved by surrogate ELISA assay) antibodies throughout time, from vaccinated and previously infected (PI) health care workers (HCW) in Portugal. We analyzed serum samples of 132 HCW, who were vaccinated and with previous SARS-CoV-2 infection. Samples were collected before vaccination (baseline, M1), at second dose vaccine uptake (M2), and 25-70 days (M3) and 150-210 days (M4) after the second dose for vaccinated individuals. The IgG (anti-RBD/S) antibody geometric mean titers found on vaccinated HCW at M2 (GM = 116.1 BAU/mL; CI: 92.3-146.1) were significantly higher than those found on PI HCW at recruitment (M1) (GM = 35.9 BAU/mL; CI:15.4-83.4), and the neutralizing antibodies (nAb) were similar between these groups, of 93.2 UI/mL (95% CI 73.2-118.5) vs. 84.1 UI/mL (95% CI 40.4-155.9), respectively. We detected around 10-fold higher IgG (anti-RBD/S) antibodies titers in M3 when compared with M2, with a slight but significant decrease in titers from 36 days after the second dose vaccine uptake. The increase of nAb titers was correlated with IgG (anti-RBD/S) antibodies titers; however, in contrast to IgG (anti-RBD/S) antibodies titers, we did not detect a decrease in the nAb titer 36 days after a second vaccine dose uptake. At M4, a decrease of 8-fold in binding IgG (anti-RBD/S) and nAb was observed. No significant differences in antibody titers were observed by sex, age or chronic diseases. Our results suggest that IgG (anti-RBD/S) antibodies titers and nAb titers could be correlated, but an ongoing follow up of the cohort is required to better understand this correlation, and the duration of the immune response.

Presence of Helicobacter Species in Gastric Mucosa of Human Patients and Outcome of Helicobacter Eradication Treatment.

The genus Helicobacter is composed of bacteria that colonize both the human and animal gastrointestinal tract. Helicobacter pylori infects half of the world's population, causing various disorders, such as gastritis, duodenitis and gastric cancer. Additionally, non-Helicobacter pylori Helicobacter species (NHPH) are commonly found in the stomach of pigs, dogs and cats. Most of these species have zoonotic potential and prevalence rates of 0.2-6.0%, and have been described in human patients suffering from gastric disorders undergoing a gastric biopsy. The aim of this study was to determine the occurrence of Helicobacter spp. in the stomach of patients with gastric cancer (n = 17) and obese (n = 63) patients. Furthermore, the outcome of the Helicobacter eradication treatment and the current infection status was evaluated. Overall, based on the genus-specific PCR followed by sequencing, DNA from Helicobacter spp. was detected in 46.3% of the patients, including single infections with H. pylori in 43.8% of the patients and mixed infections with H. pylori and canine- or feline-associated H. felis in 2.5%. About 32.5% of the patients had been subjected to previous Helicobacter eradication therapy and the triple standard therapy was the most frequent scheme (42.3%). In 48.0% of the patients who received eradication treatment, bacteria were still detected, including one mixed infection. In 23.1% of the patients who reported that a subsequent test had been performed to confirm the elimination of the bacteria, Helicobacter were still detected. In conclusion, although in a smaller percentage, NHPH may also be present in the human stomach. Thus, specific NHPH screening should be included in the diagnostic routine. The continued presence of H. pylori in the stomach of patients recently subjected to eradication schemes raises questions about the efficacy of the current Helicobacter treatments.

Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes.

Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.

SARS-CoV-2 seroprevalence in Portugal following the third epidemic wave: results of the second National Serological Survey (ISN2COVID-19).

BACKGROUND: Integrated approaches to surveillance of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection are important for public health actions. The 2nd National Serological Survey (ISN2COVID-19) aimed to characterize the extent of SARS-CoV-2 infection and vaccine-induced response in the Portuguese population following the third epidemic wave and the launch of the vaccination campaign. METHODS: A cross-sectional study was performed using data on 8463 Portuguese 1-79 years of age, collected in February and March, 2021. SARS-CoV-2 IgM and IgG (anti-nucleoprotein and anti-spike) antibodies were determined in serum samples using Abbott Architect chemiluminescent microparticle assays. Post-infection and vaccine-induced seroprevalence with 95% confidence intervals (95%CI) were estimated in the overall sample and stratified by population characteristics. RESULTS: The estimated seroprevalence was 15.5% (95%CI:14.6-16.5%), of which 13.5% (95%CI: 12.6-14.4%) was attributable to natural infection and 2.0% (95%CI:1.7-2.4%) to vaccination. The lowest seroprevelence was observed in persons aged 70-79 years (8.9% 95%CI:6.8-11.6), while seroprevalence in children (14.3%; 95%CI:11.5-17.6%) and adolescents (12.9%; 95%CI:10.5-15.7%) was similar to that of persons aged between 20 and 69 years. Of seropositive individuals, 22.6% (95%CI:19.7-25.9%) did not report any symptoms in 6 months prior to interview. Of persons with completed vaccination (2-doses), 98.6% (95%CI: 93.0-99.7%) had specific IgG (anti-S) antibodies. CONCLUSIONS: After the third epidemic wave, the post-infection SARS-CoV-2 seroprevalence was 1.7 times higher than the cumulative incidence based on PCR-testing, but was higher (2.7 times) in children may be due to the high proportion of asymptomatic and mild infections.