Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance.

BACKGROUND: Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility. METHODS: We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway. RESULTS: Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway. CONCLUSIONS: These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues.

Impact of hyperparathyroidism on allograft histology and function after kidney transplantation: Rethinking its causal role in graft dysfunction.

INTRODUCTION: The causal relationship between hyperparathyroidism and kidney graft dysfunction remains inconclusive. Applying Bradford-Hill's temporality and consistency causation principles, we assessed the effect of parathyroid hormone (iPTH) on graft histology and eGFR trajectory on kidney transplant recipients (KTRs) with normal time-zero graft biopsies. METHODS: Retrospective cohort study evaluating the effect of hyperparathyroidism on interstitial fibrosis and tubular atrophy (IF/TA) development in 1232 graft biopsies. Pre-transplant hyperparathyroidism was categorized by KDIGO or KDOQI criteria, and post-transplant hyperparathyroidism by iPTH >1× and >2× the URL 1 year after transplantation. RESULTS: We included 325 KTRs (56% female, age 38 ± 13 years, follow-up 4.2 years [IQR: 2.7-5.8]). Based on pre-transplant iPTH levels, 26% and 66% exceeded the KDIGO and KDOQI targets, respectively. There were no significant differences in the development of >25% IF/TA between KTRs with pre-transplant iPTH levels above and within target range according to KDIGO (53% vs. 62%, P = .16, HR.94 [95% CI:.67-1.32]) and KDOQI (60% vs. 60%, P = 1.0, HR 1.19 [95% CI:.88-1.60]) criteria. Similarly, there were no differences when using 1 year post-transplant iPTH cut-offs > 88 pg/mL (58% vs. 64%, P = .33) and > 176 pg/mL (55% vs. 62%, P = .19). After adjusting for confounders, no significant differences were observed in eGFR trajectories among the iPTH strata. CONCLUSION: In young KTRs who received a healthy graft, no association was found between increased pre- and post-transplant iPTH levels and graft dysfunction, as assessed histologically and through eGFR trajectory. The concept of hyperparathyroidism as a risk factor for graft dysfunction in recipients at low risk requires reevaluation.

Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation.

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.

Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines.

Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer's disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue.

Sinus node dysfunction during transcatheter assessment and stent correction of sinus venosus atrial septal defects.

Covered stent correction of a superior sinus venosus atrial septal defect is increasingly performed as an alternative to surgical repair. While sinus node dysfunction requiring pacemaker implantation may be required after surgical repair, this has not been previously reported after covered stent implantation. We reviewed the experience in two interventional centers. Balloon inflation in the superior vena cava was used to confirm the anomalous pulmonary vein drainage would be unobstructed after stent implantation. During balloon testing in 62 consecutive patients, we assessed gradients across the pulmonary vein to left atrium while monitoring the rhythm. We observed the outcomes after covered stent correction in 51 patients. In a single patient, significant bradycardia and pauses developed on repeat balloon testing and the procedure was abandoned without stent implantation. In another patient, there was no sign of sinus node dysfunction during balloon testing but several hours after stent implantation, the patient became symptomatic from sinus bradycardia and pauses and had a pacemaker implanted 3 days later. Over a year later there are some signs of improvement in sinus node function. While sinus node dysfunction has not been described previously during balloon testing or after stent implantation, this report demonstrates for the first time that it may occur. Larger registries are therefore required to monitor for this uncommon complication.

The Best Models of Bodipy's Electronic Excited State: Comparing Predictions from Various DFT Functionals with Measurements from Femtosecond Stimulated Raman Spectroscopy.

Density functional theory (DFT) and time-dependent DFT (TD-DFT) are pivotal approaches for modeling electronically excited states of molecules. However, choosing a DFT exchange-correlation functional (XCF) among the myriad of alternatives is an overwhelming task that can affect the interpretation of results and lead to erroneous conclusions. The performance of these XCFs to describe the excited-state properties is often addressed by comparing them with high-level wave function methods or experimentally available vertical excitation energies; however, this is a limited analysis that relies on evaluation of a single point in the excited-state potential energy surface (PES). Different strategies have been proposed but are limited by the difficulty of experimentally accessing the electronic excited-state properties. In this work, we have tested the performance of 12 different XCFs and TD-DFT to describe the excited-state potential energy surface of Bodipy (2,6-diethyl-1,3,5,7-tetramethyl-8-phenyldipyrromethene difluoroborate). We compare those results with resonance Raman spectra collected by using femtosecond stimulated Raman spectroscopy (FSRS). By simultaneously fitting the absorption spectrum, fluorescence spectrum, and all of the resonance Raman excitation profiles within the independent mode displaced harmonic oscillator (IMDHO) formalism, we can describe the PES at the Franck-Condon (FC) region and determine the solvent and intramolecular reorganization energy after relaxation. This allows a direct comparison of the TD-DFT output with experimental observables. Our analysis reveals that using vertical absorption energies might not be a good criterion to determine the best XCF for a given molecular system and that FSRS opens up a new way to benchmark the excited-state performance of XCFs of fluorescent dyes.

Stimulated Resonance Raman and Excited-State Dynamics in an Excitonically Coupled Bodipy Dimer: A Test for TD-DFT and the Polarizable Continuum Model.

Bodipy is one of the most versatile and studied functional dyes due to its myriad applications and tunable spectral properties. One of the strategies to adjust their properties is the formation of Bodipy dimers and oligomers whose properties differ significantly from the corresponding monomer. Recently, we have developed a novel strategy for synthesizing α,α-ethylene-bridged Bodipy dimers; however, their excited-state dynamics was heretofore unknown. This work presents the ultrafast excited-state dynamics of a novel α,α-ethylene-bridge Bodipy dimer and its monomeric parent. The dimer's steady-state absorption and fluorescence suggest a Coulombic interaction between the monomeric units' transition dipole moments (TDMs), forming what is often termed a "J-dimer". The excited-state properties of the dimer were studied using molecular excitonic theory and time-dependent density functional theory (TD-DFT). We chose the M06 exchange-correlation functional (XCF) based on its ability to reproduce the experimental oscillator strength and resonance Raman spectra. Ultrafast laser spectroscopy reveals symmetry-breaking charge separation (SB-CS) in the dimer in polar solvents and the subsequent population of the charge-separated ion-pair state. The charge separation rate falls into the normal regime, while the charge recombination is in the inverted regime. Conversely, in nonpolar solvents, the charge separation is thermodynamically not feasible. In contrast, the monomer's excited-state dynamics shows no dependence on the solvent polarity. Furthermore, we found no evidence of significant structural rearrangement upon photoexcitation, regardless of the deactivation pathway. After an extensive analysis of the electronic transitions, we concluded that the solvent fluctuations in the local environment around the dimer create an asymmetry that drives and stabilizes the charge separation. This work sheds light on the charge-transfer process in this new set of molecular systems and how excited-state dynamics can be modeled by combining the experiment and theory.

Effect of Kidney transplantation on cyst growth in autosomal dominant polycystic kidney disease.

BACKGROUND: In patients with autosomal dominant polycystic kidney disease (ADPKD), there is limited evidence of the rate of cyst progression after kidney transplantation. AIMS: To compare the height-adjusted total kidney volume (Ht-TKV) before and after transplantation in kidney transplant recipients (KTR) with -ADPKD. MATERIALS AND METHODS: Retrospective cohort study. The estimate of Ht-TKV was calculated by the ellipsoid volume equation using measurements from CT or yearly MRI scans before and after transplantation. RESULTS: We included 30 patients with -ADPKD who underwent kidney transplantation (age 49 ± 10.1 years, 11 (37%) females, dialysis vintage 3 (1 - 6) years, and 4 (13%) underwent unilateral nephrectomy during the peritransplant period). The median follow-up time was 5 years (range 2 - 16 years). Transplantation was associated with a significant decrease in Ht-TKV after transplantation in 27 (90%) KTR. Median Ht-TKV decreased from 1,708 (IQR 1,100 - 2,350) mL/m to 710 (IQR 420 - 1,380) mL/m after 6 years of follow-up (p < 0.001), with a mean Ht-TKV change rate per year after transplantation of -1.4, -11.8, -9.7, -12.7, -7.0, and -9.4% after 1, 2, 3, 4, 5, and 6 years, respectively. Even in 2 (7%) KTR without regression, the annual growth was < 1.5% per year after transplantation. CONCLUSION: Kidney transplantation reduced Ht-TKV after the first 2 years of transplantation, and this decline was continuous for more than 6 years of follow-up.

Oral cancers preceded by proliferative verrucous leukoplakia exhibit distinctive molecular features.

OBJECTIVE: Proliferative verrucous leukoplakia (PVL) has high rates of malignant transformation into oral squamous cell carcinoma (OSCC), but the clinical and evolutionary pattern of OSCC from PVL (PVL-OSCC) is more favorable than that of OSCC not preceded by PVL (OSCC). Here, we aimed to explore the pathophysiologic differences between PVL-OSCC and OSCC through transcriptomic and DNA methylation analyses. MATERIALS AND METHODS: In this case-control study, oral biopsies from 8 PVL-OSCC and 10 OSCC patients were obtained for global sequencing using RNAseq and a genome-wide DNA methylation analysis via the Infinium EPIC Platform (graphical abstract). RESULTS: One hundred and thirty-three differentially expressed genes (DEGs) were detected, 94 of them upregulated in OSCC. Most of these genes were previously described in cancer and associated with prognosis. The integrative analysis revealed 26 DEGs, corresponding to 37 CpGs, whose promoters were regulated by DNA methylation. Twenty-nine of the CpGs were found as hypermethylated in PVL-OSCC. Only 5 of the genes that were aberrantly methylated and differentially expressed were upregulated in PVL-OSCC patients, whereas 21 were underexpressed. CONCLUSIONS: PVL-OSCC patients presented lower expression of cancer-related genes. Hypermethylation of the promoter region of many genes was also noticed, indicating that DNA methylation could be a regulatory mechanism.

Oral Pyogenic Granuloma: A Narrative Review.

Pyogenic granuloma (PG) is a benign vascular lesion found predominantly in the oral cavity. Characterized by rapid growth and propensity to bleed, PG presents diagnostic challenges due to its similarity and alarming proliferation. This narrative review synthesizes current knowledge on the epidemiology, etiopathogenesis, clinical manifestations, and management of oral PG, with emphasis on recent advances in diagnostic and therapeutic approaches. The epidemiology of the injury is meticulously analyzed, revealing a higher incidence in women and a wide range of ages of onset. It delves into the etiopathogenesis, highlighting the uncertainty surrounding the exact causal factors, although historical attributions suggest an infectious origin. It exhaustively analyzes the clinical and histopathological aspects of oral PG, offering information on its various presentations and the importance of an accurate diagnosis to guide effective treatment. It details treatment strategies, emphasizing the personalized approach based on individual patient characteristics. This comprehensive review consolidates current knowledge on oral PG, highlighting the need for further research to clarify its pathogenesis and optimize treatment protocols.

Computer software (SiD) assisted real-time single sperm selection associated with fertilization and blastocyst formation.

RESEARCH QUESTION: Is it possible to explore an association between individual sperm kinematics evaluated in real time and spermatozoa selected by an embryologist for intracytoplasmic sperm injection (ICSI), with subsequent normal fertilization and blastocyst formation using a novel artificial vision-based software (SiD V1.0; IVF 2.0, UK)? DESIGN: ICSI procedures were randomly video recorded and subjected to analysis using SiD V1.0, proprietary software developed by our group. In total, 383 individual spermatozoa were retrospectively analysed from a dataset of 78 ICSI-assisted reproductive technology cycles. SiD software computes the progressive motility parameters, straight-line velocity (VSL) and linearity of the curvilinear path (LIN), of each sperm trajectory, along with a quantitative value, head movement pattern (HMP), which is an indicator of the characteristics of the sperm head movement patterns. The mean VSL, LIN and HMP measurements for each set of spermatozoa were compared based on different outcome measures. RESULTS: Statistically significant differences were found in VSL, LIN and HMP among those spermatozoa selected for injection (P < 0.001). Additionally, LIN and HMP were found to be significantly different between successful and unsuccessful fertilization (P = 0.038 and P = 0.029, respectively). Additionally, significantly higher SiD scores were found for those spermatozoa that achieved both successful fertilization (P = 0.004) and blastocyst formation (P = 0.013). CONCLUSION: The possibility of carrying out real-time analyses of individual spermatozoa using an automatic tool such as SiD creates the opportunity to assist the embryologist in selecting the better spermatozoon for injection in an ICSI procedure.

Comparison between the Right and Left Distal Radial Access for Patients Undergoing Coronary Procedures: A Propensity Score Matching Analysis.

Introduction: Distal radial access for coronary procedures decreases hemostasis time, prevents radial occlusion, and improves patient comfort compared to conventional transradial access. Initially described for left distal radial access (lDRA), the right distal radial access (rDRA) is feasible. However, there are no comparative studies to date. This study aimed to evaluate the impact of the access site on vascular access and procedural performance. Methods: From August 2020 to October 2021, coronary procedures performed through distal radial access were prospectively recorded. After propensity score matching, the rDRA and lDRA were compared. The primary endpoint was the proportion of approach success. The secondary endpoints included access time, coronary procedural success, radial spasm, exposition to ionizing radiation, patient comfort, and vascular access-related complications. Results: From a total of 385 procedures in 382 patients, after a propensity score matching, 182 procedures were compared between the rDRA and lDRA. There were no differences in the baseline characteristics between the groups. Compared to the lDRA, the rDRA presented similar approach success (96.7% vs. 96.7%, p=1.0), less access time (39 (25-60) sec vs. 50 (29-90) sec, p=0.018), comparable coronary procedural success after sheath placement (100% vs. 100%, p=1.000), and not statistically significant radial spasm (2.19% vs. 6.59%, p=0.148). No differences in dose-area product (32 (20-56.2) Gy.m2 vs. 32.3 (19.4-46.3) Gy.m2; p=0.472) and fluoroscopy time (4.4 (2.5-9.1) min vs. 4.3 (2.4-7.5) min, p=0.251) were detected between the groups. No vascular access-related complications were observed in any group. Conclusions: The rDRA, compared to the lDRA, had the same proportion of approach success and procedural performance, with a slight reduction in access time for patients undergoing coronary procedures.

Methods for analysis of specific DNA methylation status.

Methylation of CpG dinucleotides plays a crucial role in the regulation of gene expression and therefore in the development of different pathologies. Aberrant methylation has been associated to the majority of the diseases, including cancer, neurodegenerative, cardiovascular and autoimmune disorders. Analysis of DNA methylation patterns is crucial to understand the underlying molecular mechanism of these diseases. Moreover, DNA methylation patterns could be used as biomarker for clinical management, such as diagnosis, prognosis and treatment response. Nowadays, a variety of high throughput methods for DNA methylation have been developed to analyze the methylation status of a high number of CpGs at once or even the whole genome. However, identification of specific methylation patterns at specific loci is essential for validation and also as a tool for diagnosis. In this review, we describe the most commonly used approaches to evaluate specific DNA methylation. There are three main groups of techniques that allow the identification of specific regions that are differentially methylated: bisulfite conversion-based methods, restriction enzyme-based approaches, and affinity enrichment-based assays. In the first group, specific restriction enzymes recognize and cleave unmethylated DNA, leaving methylated sequences intact. Bisulfite conversion methods are the most popular approach to distinguish methylated and unmethylated DNA. Unmethylated cytosines are deaminated to uracil by sodium bisulfite treatment, while the methyl cytosines remain unconverted. In the last group, proteins with methylation binding domains or antibodies against methyl cytosines are used to recognize methylated DNA. In this review, we provide the theoretical basis and the framework of each technique as well as the analysis of their strength and the weaknesses.

Surgical outcomes among children with bicuspid aortic valve: 17 years of experience in a single center. First report in Mexico.

PURPOSE: To evaluate the clinical and surgical outcomes among children with bicuspid aortic valve who underwent cardiac surgery. METHODS: This observational and retrospective study included patients with a diagnosis of bicuspid aortic valve who underwent cardiac surgery between January 1, 2003, and March 31, 2020. Demographic characteristics and perioperative conditions were described. RESULTS: One hundred and sixteen patients were included, with a mean age of 12.4 ± 4.2 years; 63.2% were male. The most frequent diagnosis was congenital aortic stenosis (23.5%), followed by connective tissue disorders (16%). Mechanical aortic prostheses were used in 87.7% of cases, with a mean size of 21 ± 2.6 mm. The main factors associated with mortality were valve prosthesis dysfunction (odds ratio [OR]: 12.44; 95% confidence interval [CI]: 1.05-147.48; p = .04) and reoperation (OR: 24.29; 95% CI: 1.03-570.08; p = .04). The overall survival was 87.9%, with better outcomes among those who did not undergo reoperation (Log Rank, p = .01). CONCLUSIONS: Outcomes after aortic valve replacement in children with bicuspid aortic valve are excellent in the short and long term, regardless of using mechanical or biological prostheses.

Enjuagues antisépticos bucales como medida de control frente a la trasmisión de SARS-CoV-2 en la atención odontológica.

No disponible.

Submucosal resection via a transanal approach for treatment of epithelial rectal tumors - a multicenter study.

OBJECTIVE: To report complications and long-term outcomes after submucosal resections of benign and malignant epithelial rectal masses. STUDY DESIGN: Retrospective multicentric study. SAMPLE POPULATION: Medical records of 93 dogs at 7 referral hospitals. METHODS: Records were reviewed for surgical time, diagnosis, margins, complications, and recurrences. Survival of dogs was evaluated based on tumor types, categorized as benign, carcinoma in situ, and carcinoma. The Kaplan-Meier survival curve and Cox proportional hazards analysis were used to determine the association of a range of variables with recurrence and survival time. RESULTS: Duration of follow up was 708 days (range, 25-4383). Twenty-seven dogs (29%) developed complications. Recurrence was identified in 20/93 (21%), with 12/20 recurrent masses treated with repeat submucosal resection. Median survival was not reached in any group. The 1-,2-, 5-year survival rates for carcinomas were 95%, 89%, and 73% respectively. However, overall survival was longer for benign tumors than carcinomas (P = .001). Recurrence was more likely when complications (P = .032) or incomplete margins (P = .023) were present. Recurrence was associated with an increased risk of death (P = .046). CONCLUSION: Submucosal resection of both benign and malignant rectal masses was associated with a low rate of severe complications and prolonged survival in the 93 dogs described here. CLINICAL SIGNIFICANCE: Submucosal resection is a suitable technique for resection of selected rectal masses.

What did we learn about coronavirus disease-19-associated acute kidney injury during the pandemic?

Initial reports suggested that kidney involvement after coronavirus disease 19 (COVID-19) infection was uncommon, but this premise appears to be incorrect. Acute kidney injury can occur through various mechanisms and complicate the course of up to 25% of patients with COVID-19 hospitalized in our Institution, and of over 50% of those on invasive mechanical ventilation. Mechanisms of injury include direct kidney injury and predominantly tubular, although glomerular injury has been reported, and resulting from severe hypoxic respiratory failure, secondary infection, and exposure to nephrotoxic drugs. The mainstay of treatment remains the prevention of progressive kidney damage and, in some cases, the use of renal replacement therapy. Although the use of blood purification techniques has been proposed as a potential treatment, results to date have not been conclusive. In this manuscript, the mechanisms of kidney injury by COVID-19, risk factors, and the mainstays of treatment are reviewed.

Functionalized microchannels as xylem-mimicking environment: Quantifying X. fastidiosa cell adhesion.

Microchannels can be used to simulate xylem vessels and investigate phytopathogen colonization under controlled conditions. In this work, we explore surface functionalization strategies for polydimethylsiloxane and glass microchannels to study microenvironment colonization by Xylella fastidiosa subsp. pauca cells. We closely monitored cell initial adhesion, growth, and motility inside microfluidic channels as a function of chemical environments that mimic those found in xylem vessels. Carboxymethylcellulose (CMC), a synthetic cellulose, and an adhesin that is overexpressed during early stages of X. fastidiosa biofilm formation, XadA1 protein, were immobilized on the device's internal surfaces. This latter protocol increased bacterial density as compared with CMC. We quantitatively evaluated the different X. fastidiosa attachment affinities to each type of microchannel surface using a mathematical model and experimental observations acquired under constant flow of culture medium. We thus estimate that bacterial cells present ∼4 and 82% better adhesion rates in CMC- and XadA1-functionalized channels, respectively. Furthermore, variable flow experiments show that bacterial adhesion forces against shear stresses approximately doubled in value for the XadA1-functionalized microchannel as compared with the polydimethylsiloxane and glass pristine channels. These results show the viability of functionalized microchannels to mimic xylem vessels and corroborate the important role of chemical environments, and particularly XadA1 adhesin, for early stages of X. fastidiosa biofilm formation, as well as adhesivity modulation along the pathogen life cycle.

Sorafenib as a second-line treatment in metastatic renal cell carcinoma in Mexico: a prospective cohort study.

BACKGROUND: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). METHODS: A prospective observational cohort in Mexico (2012-2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12-16 weeks. RESULTS: The mean age of the cohort was 59 years (interquartile range [IQR] 50-72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7-10.5) and 40 months (95% CI: 34.5-45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2-83.8). On multivariable analyses, age > 65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31-0.86; p = 0.018). The median PFS in subjects aged > 65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2-18.8] vs. 7.2 months [95% CI: 5.3-9.1]; p = 0.012). Adverse events grade ≥ 3 associated with sorafenib occurred in 38 (29%) patients. CONCLUSION: Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 years old.

Usefulness of the Hybrid RFR-FFR Approach: Results of a Prospective and Multicenter Analysis of Diagnostic Agreement between RFR and FFR-The RECOPA (REsting Full-Cycle Ratio Comparation versus Fractional Flow Reserve (A Prospective Validation)) Study.

BACKGROUND: The resting full-cycle ratio (RFR) is a novel resting index which in contrast to the gold standard (fractional flow reserve (FFR)) does not require maximum hyperemia induction. The objectives of this study were to evaluate the agreement between RFR and FFR with the currently recommended thresholds and to design a hybrid RFR-FFR ischemia detection strategy, allowing a reduction of coronary vasodilator use. MATERIALS AND METHODS: Patients subjected to invasive physiological study in 9 Spanish centers were prospectively recruited between April 2019 and March 2020. Sensitivity and specificity studies were made to assess diagnostic accuracy between the recommended levels of RFR ≤0.89 and FFR ≤0.80 (primary objective) and to determine the RFR "grey zone" in order to define a hybrid strategy with FFR affording 95% global agreement compared with FFR alone (secondary objective). RESULTS: A total of 380 lesions were evaluated in 311 patients. Significant correlation was observed (R 2 = 0.81; P < 0.001) between the two techniques, with 79% agreement between RFR ≤ 0.89 and FFR ≤ 0.80 (positive predictive value, 68%, and negative predictive value, 80%). The hybrid RFR-FFR strategy, administering only adenosine in the "grey zone" (RFR: 0.86 to 0.92), exhibited an agreement of over 95% with FFR, with high predictive values (positive predictive value, 91%, and negative predictive value, 92%), reducing the need for vasodilators by 58%. CONCLUSIONS: Dichotomous agreement between RFR and FFR with the recommended thresholds is significant but limited. The adoption of a hybrid RFR-FFR strategy affords very high agreement, with minimization of vasodilator use.