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.

Comparative microbiome analysis in cystic fibrosis and non-cystic fibrosis bronchiectasis.

BACKGROUND: Bronchiectasis is a condition characterized by abnormal and irreversible bronchial dilation resulting from lung tissue damage and can be categorized into two main groups: cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Both diseases are marked by recurrent infections, inflammatory exacerbations, and lung damage. Given that infections are the primary drivers of disease progression, characterization of the respiratory microbiome can shed light on compositional alterations and susceptibility to antimicrobial drugs in these cases compared to healthy individuals. METHODS: To assess the microbiota in the two studied diseases, 35 subjects were recruited, comprising 10 NCFB and 13 CF patients and 12 healthy individuals. Nasopharyngeal swabs and induced sputum were collected, and total DNA was extracted. The DNA was then sequenced by the shotgun method and evaluated using the SqueezeMeta pipeline and R. RESULTS: We observed reduced species diversity in both disease cohorts, along with distinct microbial compositions and profiles of antimicrobial resistance genes, compared to healthy individuals. The nasopharynx exhibited a consistent microbiota composition across all cohorts. Enrichment of members of the Burkholderiaceae family and an increased Firmicutes/Bacteroidetes ratio in the CF cohort emerged as key distinguishing factors compared to NCFB group. Staphylococcus aureus and Prevotella shahii also presented differential abundance in the CF and NCFB cohorts, respectively, in the lower respiratory tract. Considering antimicrobial resistance, a high number of genes related to antibiotic efflux were detected in both disease groups, which correlated with the patient's clinical data. CONCLUSIONS: Bronchiectasis is associated with reduced microbial diversity and a shift in microbial and resistome composition compared to healthy subjects. Despite some similarities, CF and NCFB present significant differences in microbiome composition and antimicrobial resistance profiles, suggesting the need for customized management strategies for each disease.

Expression of SmATPDases 1 and 2 in Schistosoma mansoni eggs favours IL-10 production in infected individuals.

A role of IL-10 is down-regulating T-cell responses to schistosome antigens. Since SmATPDases can be correlated to modulation of the immune response, we evaluated the expression of enzymes in S. mansoni eggs. Faecal samples were collected from 40 infected individuals to detect coding regions of the SmATPDases. The cytokines were measured in supernatants of PBMC. The analysis was performed by the global median determination and set up high producers (HP) of cytokines. Six individuals expressed SmATPDase1, six expressed SmATPDase2 and six expressed both enzymes. The group who expressed only SmATPDase1 showed a high frequency of IFN-γ, TNF IL-4 HP; individuals who expressed only SmATPDase2 showed a high frequency of IFN-γ, IL-6 and IL-4 HP; and individuals who expressed both enzymes showed a high frequency of IL-10 HP. The comparison of the IFN-γ/IL-10 ratio presented higher indices in the group who had SmATPDase 2 expression than those who had the expression of both enzymes. The positive correlation between infection intensity and IL-10 levels remained only in the positive SmATPDase group. The IL-10 is the only cytokine induced by the expression of both enzymes. Our data suggest that the expression of both enzymes seems to be a factor that modulates the host immune response by inducing high IL-10 production.

Evaluation of the ceftazidime/avibactam and meropenem susceptibility by MALDI-TOF MS directly from positive blood cultures.

The purpose of this study was to evaluate the MBT-ASTRA to determine susceptibility to ceftazidime/avibactam (CZA) and meropenem (MEM) of Enterobacterales directly from positive blood cultures (BC). Bacterial suspension was incubated with antibiotic and analyzed by MALDI-TOF MS. The relative growth was calculated and cutoff values were determined to categorize isolates as "S," "I," and "R." Klebsiella spp. with CZA 20/8 mg/L and 1.5-h incubation presented 1 (5.9%) major discrepancy and 96.3% category agreement; other species required 2.5 h for 100% category agreement. For MEM, 4 mg/L and 1.5h were necessary, demonstrating 2 (6.67%) minor discrepancies and 93.3% categorical agreement.

Rapid colorimetric polymyxin B microelution directly from positive blood bottles: because patients with serious infections should not have to wait for results of culture-based methodologies.

PURPOSE: To evaluate the performance of the rapid colorimetric polymyxin B microelution (RCPEm) in determining polymyxin B resistance directly from Enterobacterales-positive blood cultures. METHODS: A set volume of positive blood culture bottles (diluted 1:10) was inoculated into a glucose-broth-phenol red solution (NP solution), where a polymyxin B disk was previously eluted (final concentration of 3 µg/mL). Test was read each 1 h for up to 4 h. Color change from red/orange to yellow indicated resistant isolates. Results were compared to the reference method, broth microdilution (BMD), performed from colonies grown on solid media from the same blood culture bottle. RESULTS: One hundred fifty-two Enterobacterales-positive blood cultures were evaluated, 22.4% (34/152) of them resistant to polymyxin B (including 6.6% with borderline MICs). When performing directly from positive blood cultures (RCPEm-BC), specificity and sensitivity were 99.1% and 94.1%, respectively. Of note, 79.4% (27/34) of truly resistant isolates required 3 h of incubation, compared to the 18 ± 2 h incubation that microtiter plates of BMD demand before reading can be performed. CONCLUSIONS: RCPEm directly from blood cultures has great potential to be part of the routine of clinical microbiology laboratories to establish polymyxin B susceptibility, impacting outcome of patients with bloodstream infections caused by carbapenem-resistant Enterobacterales.

Ionic Thermoelectric Generators in Vertical and Planar Topologies Based on Fluorinated Polymer Hybrid Materials with Ionic Liquids.

Ionic thermoelectrics (TEs), in which voltage generation is based on ion migration, are suitable for applications based on their low cost, high flexibility, high ionic conductivity, and wide range of Seebeck coefficients. This work reports on the development of ionic TE materials based on the poly(vinylidene fluoride-trifluoroethylene), Poly(VDF-co-TrFE), as host polymer blended with different contents of the ionic liquid, IL, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [EMIM][TFSI]. The morphology, physico-chemical, thermal, mechanical, and electrical properties of the samples are evaluated together with the TE response. It is demonstrated that the IL acts as a nucleating agent for polymer crystallization. The mechanical properties and ionic conductivity values are dependent on the IL content. A high room temperature ionic conductivity of 0.008 S cm-1 is obtained for the sample with 60 wt% of [EMIM][TFSI] IL. The TE properties depend on both IL content and device topology-vertical or planar-the largest generated voltage range being obtained for the planar topology and the sample with 10 wt% of IL content, characterized by a Seebeck coefficient of 1.2 mV K-1. Based on the obtained maximum power density of 4.9 µW m-2, these materials are suitable for a new generation of TE devices.

Stool Glycoproteomics Signatures of Pre-Cancerous Lesions and Colorectal Cancer.

Colorectal cancer (CRC) screening relies primarily on stool analysis to identify occult blood. However, its sensitivity for detecting precancerous lesions is limited, requiring the development of new tools to improve CRC screening. Carcinogenesis involves significant alterations in mucosal epithelium glycocalyx that decisively contribute to disease progression. Building on this knowledge, we examined patient series comprehending premalignant lesions, colorectal tumors, and healthy controls for the T-antigen-a short-chain O-glycosylation of proteins considered a surrogate marker of malignancy in multiple solid cancers. We found the T-antigen in the secretions of dysplastic lesions as well as in cancer. In CRC, T-antigen expression was associated with the presence of distant metastases. In parallel, we analyzed a broad number of stools from individuals who underwent colonoscopy, which showed high T expressions in high-grade dysplasia and carcinomas. Employing mass spectrometry-based lectin-affinity enrichment, we identified a total of 262 proteins, 67% of which potentially exhibited altered glycosylation patterns associated with cancer and advanced pre-cancerous lesions. Also, we found that the stool (glyco)proteome of pre-cancerous lesions is enriched for protein species involved in key biological processes linked to humoral and innate immune responses. This study offers a thorough analysis of the stool glycoproteome, laying the groundwork for harnessing glycosylation alterations to improve non-invasive cancer detection.

Aberrantly Glycosylated GLUT1 as a Poor Prognosis Marker in Aggressive Bladder Cancer.

Muscle-invasive bladder cancer (MIBC) remains a pressing health concern due to conventional treatment failure and significant molecular heterogeneity, hampering the development of novel targeted therapeutics. In our quest for novel targetable markers, recent glycoproteomics and bioinformatics data have pinpointed (glucose transporter 1) GLUT1 as a potential biomarker due to its increased expression in tumours compared to healthy tissues. This study explores this hypothesis in more detail, with emphasis on GLUT1 glycosylation patterns and cancer specificity. Immunohistochemistry analysis across a diverse set of human bladder tumours representing all disease stages revealed increasing GLUT1 expression with lesion severity, extending to metastasis, while remaining undetectable in healthy urothelium. In line with this, GLUT1 emerged as a marker of reduced overall survival. Revisiting nanoLC-EThcD-MS/MS data targeting immature O-glycosylation on muscle-invasive tumours identified GLUT1 as a carrier of short glycosylation associated with invasive disease. Precise glycosite mapping uncovered significant heterogeneity between patient samples, but also common glycopatterns that could provide the molecular basis for targeted solutions. Immature O-glycosylation conferred cancer specificity to GLUT1, laying the molecular groundwork for enhanced targeted therapeutics in bladder cancer. Future studies should focus on a comprehensive mapping of GLUT1 glycosites for highly specific cancer-targeted therapy development for bladder cancer.

Metachronous lesions after gastric endoscopic submucosal dissection: first assessment of the FAMISH prediction score.

BACKGROUND: Surveillance after gastric endoscopic submucosal dissection (ESD) is recommended for all patients owing to the persistent risk of metachronous gastric lesions (MGLs). We developed and validated a prediction score to estimate MGL risk after ESD for early neoplastic gastric lesions, to define an individualized and cost-saving approach. METHODS: Clinical predictors and a risk score were derived from meta-analysis data. A retrospective, single-center, cohort study including patients with ≥ 3 years of standardized surveillance after ESD was conducted for score validation. Predictive accuracy of the score by the area under the receiver operating characteristic curve (AUC) was assessed and cumulative probabilities of MGL were estimated. RESULTS: The risk score (0-9 points) included six clinical predictors (scored 0-3): positive family history of gastric cancer, older age, male sex, corpus intestinal metaplasia, synchronous gastric lesions, and persistent Helicobacter pylori infection (FAMISH). The study population included 263 patients. The MGL rate was 16 %. The score diagnostic accuracy for predicting MGL at 3 years' follow-up, measured by the AUC, was 0.704 (95 %CI 0.603-0.806). At 3 years and a cutoff < 2, the score achieved maximal sensitivity and negative predictive value; 15 % of patients could be assigned to a low-risk group, in which the progression to MGL was significantly lower than for the high-risk group (P = 0.04). CONCLUSION: The FAMISH score might be a useful tool to accurately identify patients with low-to-intermediate risk for MGL at 3 years of follow-up who could have surveillance intervals extended to reduce the burden of care.

Detection of polymyxins resistance among Enterobacterales: evaluation of available methods and proposal of a new rapid and feasible methodology.

BACKGROUND: Fast and accurate detection of polymyxins resistance is necessary as they remain the last resources to treat infections caused by Carbapenem-resistant Enterobacterales in many regions. We evaluated the rapid colorimetric polymyxin B elution (RCPE) and developed its miniaturized version, RCPE microelution (RCPEm), aiming to detect polymyxins resistance among Enterobacterales. METHODS: The methodologies consist of exposing the bacterial population in a solution (NP solution) where polymyxin B disks were previously eluted to obtain a concentration of 2 µg/mL for RCPE and 3 µg/mL for RCPEm. RESULTS: Two hundred sixty-seven Enterobacterales were evaluated, 90 (33.7%) resistant to polymyxin B by broth microdilution. It was observed 0.6% of major error (ME) by RCPE, with a specificity of 99.4%. The miniaturized version (RCPEm) presented the same ME and specificity values, but slightly higher sensitivity (97.8% vs. 95.6%) with 2.2% of very major error (VME). CONCLUSIONS: RCPE and RCPEm proved to be useful alternatives to determine polymyxin B susceptibility in clinical microbiology laboratories, presenting low cost, being easy to perform, and demanding short incubation time.

Overcoming a stubborn patent foramen ovale.

Transesophageal echocardiography (TEE) with agitated saline contrast ("bubble study") is the gold standard for detection of patent foramen ovale (PFO). Standard provocative maneuvers help facilitate right-to-left shunting necessary for diagnosing PFO but may be difficult to implement during TEE. Hypovolemia related to preprocedural fasting may challenge detection of PFO in TEE, and additional optimization measures such as fluid replenishment with passive leg raise (PLR) can enhance PFO detection. We present a 57-year-old male with history of cryptogenic stroke and stubborn PFO which during TEE bubble study responded only to ample fluid replenishment with PLR following a period of prolonged preprocedural fasting.

Trends and complications associated with acute new-onset heart failure: a National Readmissions Database-based cohort study.

Literature regarding recent trends and outcomes of acute new-onset heart failure (AHF) with preserved ejection fraction (AHFpEF) and reduced ejection fraction (AHFrEF) is limited. The objective of this study is to study the outcomes of AHFpEF and AHFrEF in the USA. Data from the National Readmissions Database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the USA, representing more than 95% of the national population, were analyzed for hospitalization visits for acute heart failure. ICD-9 and ICD-10 codes were used to identify AHF. A total of 2,559,102 adult index AHF patients (mean age 70.79 ± 14.58 years, 49.4% females), 1,028,970 (40.2%) AHFpEF and 1,330,999 (52%) AHFrEF, were recorded in the National Readmissions Database for the years 2016-2018. A total of 152,465 (5.96%) acute heart failure, 47,271 (4.6%) AHFpEF and 91,973 (6.91%) AHFrEF, died during hospitalization, and 45,810 (1.9%) were readmitted in 30 days among alive discharges. Higher complication rates which included ventricular arrhythmias, acute coronary, and cerebrovascular events were observed among AHFrEF than AHFpEF. Higher proportion of patients with AHFrEF needed intensive care unit and ventilatory support during the hospitalization. The trend of incidence of AHFrEF, mortality among AHFrEF, and overall mortality worsened while AHFpEF improved over the study years 2012-2018 (p-trend < 0.05). Coronary procedures improved mortality rates among AHFpEF and AHFrEF. AHF is very common and is associated with significant mortality. The incidence of AHFrEF and mortality among AHFrEF had worsened, which calls for urgent intervention. Improved recognition of AHF is needed, and guideline-directed treatment of underlying risk factors including coronary artery disease can improve mortality. Graphic abstract of the analysis presented (created with BioRender.com).

Gut microbiota modulation by prednisolone in a rat kindling model of pentylenetetrazol (PTZ)-induced seizure.

The gut microbiota is a complex community composed by several microorganisms that interact in the maintenance of homeostasis and contribute to physiological processes, including brain function. The relationship of the taxonomic composition of the gut microbiota with neurological diseases such as autism, Parkinson's, Alzheimer's, anxiety, and depression is widely recognized. The immune system is an important intermediary between the gut microbiota and the central nervous system, being one of the communication routes of the gut-brain axis. Although the complexity of the relationship between inflammation and epilepsy has not yet been elucidated, inflammatory processes are similar in many ways to the consequences of dysbiosis and contribute to disease progression. This study aimed to analyze the taxonomic composition of the gut microbiota of rats treated with prednisolone in a kindling model of epilepsy. Male Wistar rats (90 days, n = 24) divided into four experimental groups: sodium chloride solution 0.9 g%, diazepam 2 mg/kg, prednisolone 1 mg/kg, and prednisolone 5 mg/kg administered intraperitoneally (i.p.) for 14 days. The kindling model was induced by pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. The taxonomic profile was established by applying metagenomic DNA sequencing. There was no change in alpha diversity, and the composition of the gut microbiota between prednisolone and diazepam was similar. The significant increase in Verrucomicrobia, Saccharibacteria, and Actinobacteria may be related to the protective activity against seizures and inflammatory processes that cause some cases of epilepsy. Further studies are needed to investigate the functional influence that these species have on epilepsy and the inflammatory processes that trigger it.

Clustering of adenosine A2B receptors with ectonucleotidases in caveolin-rich lipid rafts underlies immunomodulation by Leishmania amazonensis.

Extracellular adenosine plays important roles in modulating the immune responses. We have previously demonstrated that infection of dendritic cells (DC) by Leishmania amazonensis leads to increased expression of CD39 and CD73 and to the selective activation of the low affinity A2B receptors (A2B R), which contributes to DC inhibition, without involvement of the high affinity A2A R. To understand this apparent paradox, we now characterized the alterations of both adenosine receptors in infected cells. With this aim, bone marrow-derived DC from C57BL/6J mice were infected with metacyclic promastigotes of L. amazonensis. Fluorescence microscopy revealed that L. amazonensis infection stimulates the recruitment of A2B R, but not of A2A R, to the surface of infected DC, without altering the amount of mRNA or the total A2B R density, an effect dependent on lipophosphoglycan (LPG). Log-phase promastigotes or axenic amastigotes of L. amazonensis do not stimulate A2B R recruitment. A2B R clusters are localized in caveolin-rich lipid rafts and the disruption of these membrane domains impairs A2B R recruitment and activation. More importantly, our results show that A2B R co-localize with CD39 and CD73 forming a "purinergic cluster" that allows for the production of extracellular adenosine in close proximity with these receptors. We conclude that A2B R activation by locally produced adenosine constitutes an elegant and powerful evasion mechanism used by L. amazonensis to down-modulate the DC activation.

ST-Elevation Myocardial Infarction Outcomes: A United States Nationwide Emergency Departments Cohort Study.

BACKGROUND: Literature regarding trends in incidence and mortality of ST-elevation myocardial infarction (STEMI) in emergency departments (EDs) is limited. OBJECTIVE: To study the trends of incidence and mortality of STEMI. METHODS: Using the National Emergency Department Sample database in the United States, we identified all ED encounters for patients presenting with STEMI using International Classification of Diseases codes. A linear p-trend was used to assess the trends. RESULTS: Out of the 973 million ED encounters represented, 641,762 (65/100,000; mean age 69 [59-81] years, 35.8% female) adult patients were recorded with STEMI. Among the major complications associated with STEMI, a total of 49,401 (7.7%) had cardiac complications, which included acute heart failure (n = 9361, 1.6%), ventricular tachycardia or fibrillation (n = 12,267, 1.91%), conduction block (n = 20,165, 3.1%), and cardiogenic shock (n = 7608, 1.2%). There were 5675 (0.9%) patients recorded with cerebrovascular events, which included acute ischemic stroke among 5205 (0.8%) patients and 470 (0.1%) with transient ischemic attack. Acute kidney injury was recorded for 10,082 (1.6%) patients. The trend for incidence of STEMI in the ED had decreased from 7.76/10,000 in 2011 to 4.07/10,000 in 2018 (linear p-trend 0.0006). However, the yearly mortality of STEMI related to ED encounters had remained relatively steady: 7.56% in 2011 to 7.50% in 2018 (linear p-trend 0.2364). CONCLUSION: Despite the fact that the number of patients presenting to the ED with STEMI has been decreasing, the mortality trends have remained steady. Further research of in-hospital STEMI may yield opportunities to reduce the risk of complications, improve patient outcomes and decrease health care burden.

Pooling of samples to optimize SARS-CoV-2 diagnosis by RT-qPCR: comparative analysis of two protocols.

This study has aimed to evaluate the use pool of samples as a strategy to optimize the diagnostic of SARS-CoV-2 by RT-qPCR. A total of 220 naso/orofaryngeal swab samples were collected and tested using two different protocols of sample pooling. Results from protocol A were identical with the individual results. However, for results from protocol B, reduced agreement (91%) was observed in relation to individual testing. Inconsistencies observed were related to RT-qPCR results with higher cycle thresholds. These results suggest that pooling of samples before RNA extraction is preferable in terms of diagnostic for SARS-CoV-2.

Temporal trends and outcomes in utilisation of transcatheter and surgical aortic valve therapies in aortic valve stenosis patients with heart failure.

INTRODUCTIONS & AIMS: Heart failure (HF) is a common comorbidity in patients undergoing surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). We sought to access the temporal trends and outcomes of TAVR or SAVR in HF patients. METHOD: The NIS database from 2011-2014 was queried for patients that underwent TAVR or SAVR and were subsequently diagnosed with HF. Temporal trends in the utilisation of TAVR or SAVR in HF patients were analysed. RESULTS: Among 27 982 patients who were diagnosed with HF of whom 17 681 (63.2%) had heart failure with reduced ejection fraction (HFrEF) while 10 301 (36.8%) had heart failure with preserved ejection fraction (HFpEF), 9049 (32.3%) underwent TAVR and 16 933 (76.7%) underwent SAVR. Patients with HFrEF and HFpEF had higher utilisation of TAVR compared with SAVR over the course of the study period (P trend < .001). TAVR was associated with lower mortality [2.8% in 2012 and 1.8% in 2014 (P .013)] compared with SAVR. Similarly, multiple logistic regression showed a statistically significant lower in-hospital mortality in the TAVR group compared with SAVR (aOR 0.634; CI 0.504, 0.798, P < .001). CONCLUSION: For patients with severe aortic valve stenosis and heart failure who undergo aortic valve intervention, TAVR is associated with less odds of in-hospital mortality compared with SAVR.

A case of variant parachute mitral valve associated with mitral annular disjunction arrhythmic syndrome.

Parachute mitral valve (PMV) is a rare congenital cardiac valvular anomaly often associated with other congenital cardiac defects, particularly Shone's complex, but may infrequently occur in isolation. PMV and its variants are predominantly associated with mitral stenosis (MS) or rarely mitral regurgitation (MR). We present the case of a middle-aged female who was evaluated for a syncopal episode and found to have an atypical variant PMV with disproportionately long anterior mitral leaflet, bileaflet mitral valve prolapse, and mitral annular disjunction, without associated MS or MR. This is the first case report to highlight this particular constellation of findings.

Detection of SARS-CoV-2 lineage P.1 in patients from a region with exponentially increasing hospitalisation rate, February 2021, Rio Grande do Sul, Southern Brazil.

The emergence of SARS-CoV-2 P.1 lineage coincided with a surge in hospitalisations in the North region of Brazil. In the South region's Rio Grande do Sul state, severe COVID-19 case numbers rose 3.8 fold in February 2021. During that month, at a COVID-19 referral hospital in this state, whole-genome sequencing of a subset of cases' specimens (n = 27) revealed P.1 lineage SARS-CoV-2 in most (n = 24). Findings raise concerns regarding a possible association between lineage P.1 and rapid case and hospitalisation increases.