Impact of the COVID-19 Pandemic on Corneal Transplantation: A Report From the Italian Association of Eye Banks

Purpose: To analyze the impact of COVID-19 on Italian corneal transplantation from March-2020 to February 2021 compared to the same timeframe of the 2 previous years, in order to identify potential consequences of a global pandemic on corneal procurement and transplantation services during this time. Methods: This national, multicentric, retrospective cohort study evaluated data collected from 12 (100%) Italian eye banks from March 2020 to February 2021 (Group A). The number of tissues collected, distributed and discarded were compared with the same time-frame of the 2 previous years: 2019 and 2018 (group B and C, respectively). The different type of transplants performed were reported. Data were analyzed using a non-parametric Friedman test. Results: Corneal procurement and the percentage of distributed tissues reduced in 2020 by more than 30 and 15%, respectively, compared to the 2 previous years. During the pandemic corneal transplant surgery showed only a modest drop: the number of the penetrating keratoplasties (PKs) and the anterior lamellar keratoplasties (ALKs) decreased by about 30 and 20% in comparison with groups B and C, respectively; between the Endothelial Keratoplasties (EKs), the Descemet membrane endothelial keratoplasty (DMEK) increased slightly from March 2020 to February 2021. Conclusions: Italy was one of the first countries most affected by the outbreak of COVID-19, and the Italian government adopted severe measures to limit viral transmission. The pandemic generated several implications in corneal transplant activity during the first lockdown. Then an efficacious reaction with constant, vigorous work led to a resumption of transplant surgery to a near-normal standard. The increase of EKs, despite the pandemic, is a sign that the advance in corneal transplantation has gone ahead and it continues to evolve

Bases moleculares da interação celular em modelos de reprodução e câncer: identificação de proteínas e mecanismos envolvidos

La interacción entre las células somáticas y entre las gametas involucra una serie de eventos moleculares que no han sido dilucidados totalmente. Nuestro grupo de investigación ha desarrollado proyectos dirigidos a profundizar el conocimiento de dichos eventos. Los estudios han comprendido el análisis de moduladores de la funcionalidad espermática (ej. efecto de la temperatura de incubación, las concentraciones del ión calcio, los anticuerpos antiespermáticos de fluidos biológicos en la motilidad, la capacitación y la exocitosis acrosomal). Asimismo, hemos caracterizado componentes del espermatozoide (ej. CaM Kinasa IV, proacrosina/acrosina) y de secreciones del tracto femenino (ej. Grp78/BiP), evaluado su rol en el desarrollo de capacidad fecundante y, en algunos casos, investigado su relación con la infertilidad. En años recientes, nuestros proyectos se han extendido al estudio de las cadherinas en eventos de adhesión celular durante la fecundación; hemos caracterizado la expresión de cadherina epitelial y neural en tejidos reproductivos y gametas y evaluado su participación en la fecundación. Dada su reconocida relevancia en el cáncer, hemos abordado estudios en diversos modelos tumorales. Nuestras investigaciones han contribuido a la comprensión de los eventos de interacción de las gametas durante la fecundación así como entre las células somáticas durante la progresión tumoral.Cell-cell interaction between somatic cells as well as gametes involves molecular events that have not been completely elucidated. Our research group has developed projects aimed at studying proteins and mechanisms participating in these interactions. Several modulators of sperm functions have been analyzed (i.e. incubation temperature, calcium ion concentration, and antisperm antibodies present in biological fluids upon sperm motility, capacitation and acrosomal exocytosis). In addition, proteins from spermatozoa (i.e. CaM Kinase IV, proacrosin/acrosin) and from secretions of the female tract (Grp78/BiP) have been characterized, and their role in the development of sperm fertilizing ability assessed. In some cases, their relationship with infertility was evaluated. In recent years, our projects have been extended to study members of the cadherin superfamily and related proteins; in particular, the expression of epithelial and neural cadherin in reproductive tissues and gametes was characterized and evidence of their participation in fertilization-related cell-cell adhesion events shown. Based on the vast evidence of the role of these proteins in tumor progression, our current research also involves studies of cancer models. Our projects have contributed to the understanding of the molecular basis of cell-cell interaction during fertilization as well as during tumor progression.A interação entre as células somáticas e entre os gametas envolve uma série de eventos moleculares que não têm sido elucidados totalmente. Nosso grupo de pesquisa tem desenvolvido projetos encaminhados a aprofundar o conhecimento de tais eventos. Os estudos têm compreendido a análise de moduladores da funcionalidade espermática (ex. efeito da temperatura de incubação, as concentrações do íon cálcio, os anticorpos antiespermáticos de fluidos biológicos na motilidade, a capacitação e a exocitose acrossomal). Do mesmo modo, caracterizamos componentes do espermatozoide (ex. CaM Kinase IV, proacrosina /acrosina) e de secreções do trato feminino (ex. Grp78/BiP), avaliamos seu papel no desenvolvimento de capacidade fecundante e, em alguns casos, investigamos sua relação com a infertilidade. Em anos recentes, nossos projetos se têm estendido ao estudo das caderinas em eventos de adesão celular durante a fecundação; temos caracterizado a expressão de caderina epitelial e neural em tecidos reprodutivos e gametas e avaliamos sua participação na fecundação. Dada sua reconhecida relevância no câncer, temos abordado estudos em diversos modelos tumorais. Nossas pesquisas têm contribuído à compreensão dos eventos de interação dos gametas durante a fecundação bem como entre as células somáticas durante a progressão tumoralFil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Furlong, Laura I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Marin Briggiler, Clara Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Veaute, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Veiga, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Matos, María L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Lapyckyj, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Gabrielli, Nieves María. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Arzondo, María M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Edelsztein, Nadia Yasmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness : Its Relationship With TGF-β1 and NF-κB Pathways

Objective: Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Methods: FXYD5/Dys messenger RNA (mRNA) levels were determined in EC tissue and UA biopsies. FXYD5/Dys expression was evaluated in EC RNAseq data from The Cancer Genome Atlas (TCGA) and GENEVESTIGATOR tools. FXYD5/Dys impact on E-cadherin expression and cell behavior was assessed in EC Hec1a cells treated with transforming growth factor (TGF)-β1, stably transfected with ETV5, and transiently transfected with FXYD5/Dys small interfering RNA (siRNA) or pcDNA3-FXYD5/Dys plasmid. Results: FXYD5/Dys was associated with EC aggressiveness, finding high mRNA levels in tumors depicting MI > 50%, Grade 3, and intermediate/high risk of recurrence. FXYD5/Dys was highly expressed at the tumor invasive front compared to the superficial area. Most results were recapitulated in UA biopsies. FXYD5/Dys modulation in Hec1a cells altered cell migration/adhesion and E-cadherin expression. TGF-β1 treatment of Hec1a cells induced FXYD5/Dys expression. TCGA-UCEC RNAseq analysis revealed a positive correlation between FXYD5/Dys, TGF-β1, and plasminogen activator inhibitor (PAI)-1 mRNA levels. FXYD5/Dys induced nuclear factor (NF)-κB pathway activation in Hec1a cells. FXYD5/Dys mRNA levels positively correlated with transcriptional activation of NF-κB p65-regulated genes. Survival analysis revealed patient segregation into low- and high-risk groups, the latter depicting the highest FXYD5/Dys, PAI-1, tumor necrosis factor (TNF)-α, and TGF-β1 mRNA levels and shorter survival rates. Conclusion: FXYD5/Dys is a novel biomarker of EC progression related to TGF-β1 and NF-κB pathways that collectively promote tumor dissemination and result in poor patient prognosis

FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness : Its Relationship With TGF-β1 and NF-κB Pathways

Objective: Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Methods: FXYD5/Dys messenger RNA (mRNA) levels were determined in EC tissue and UA biopsies. FXYD5/Dys expression was evaluated in EC RNAseq data from The Cancer Genome Atlas (TCGA) and GENEVESTIGATOR tools. FXYD5/Dys impact on E-cadherin expression and cell behavior was assessed in EC Hec1a cells treated with transforming growth factor (TGF)-β1, stably transfected with ETV5, and transiently transfected with FXYD5/Dys small interfering RNA (siRNA) or pcDNA3-FXYD5/Dys plasmid. Results: FXYD5/Dys was associated with EC aggressiveness, finding high mRNA levels in tumors depicting MI > 50%, Grade 3, and intermediate/high risk of recurrence. FXYD5/Dys was highly expressed at the tumor invasive front compared to the superficial area. Most results were recapitulated in UA biopsies. FXYD5/Dys modulation in Hec1a cells altered cell migration/adhesion and E-cadherin expression. TGF-β1 treatment of Hec1a cells induced FXYD5/Dys expression. TCGA-UCEC RNAseq analysis revealed a positive correlation between FXYD5/Dys, TGF-β1, and plasminogen activator inhibitor (PAI)-1 mRNA levels. FXYD5/Dys induced nuclear factor (NF)-κB pathway activation in Hec1a cells. FXYD5/Dys mRNA levels positively correlated with transcriptional activation of NF-κB p65-regulated genes. Survival analysis revealed patient segregation into low- and high-risk groups, the latter depicting the highest FXYD5/Dys, PAI-1, tumor necrosis factor (TNF)-α, and TGF-β1 mRNA levels and shorter survival rates. Conclusion: FXYD5/Dys is a novel biomarker of EC progression related to TGF-β1 and NF-κB pathways that collectively promote tumor dissemination and result in poor patient prognosis

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial

<div><p>Background</p><p>Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.</p><p>Methods and findings</p><p>To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow.</p><p>Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; <i>p <</i> 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study’s main limitations were the relatively small sample size and stable, well-compensated population.</p><p>Conclusions</p><p>Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01640964" target="_blank">NCT01640964</a></p></div