Clonally unrelated primary large B-cell lymphomas separated by over a decade involving the central nervous system and testicle: Possible predisposition to lymphomas of immune-privileged sites?

Primary large B-cell lymphomas of immune-privileged sites (IP-LBCLs) comprise LBCLs arising within "immune sanctuaries," including the central nervous system (CNS), vitreoretina, and testes. Although patients present with localized disease, the prognosis remains poor with high relapse rates, either at the originating site or within another immune-privileged site. Generally, in the presence of an antecedent IP-LBCL, subsequent LBCLs are expected to be clonally related. However, we present a primary CNS LBCL and later primary testicular LBCL in a middle-aged man, diagnosed over a decade apart, which proved to be clonally unrelated by targeted ultra-deep next-generation sequencing of the IgH locus.

Effect of Hydroxyurea on Morphology, Proliferation, and Protein Expression on Taenia crassiceps WFU Strain.

Flatworms are known for their remarkable regenerative ability, one which depends on totipotent cells known as germinative cells in cestodes. Depletion of germinative cells with hydroxyurea (HU) affects the regeneration of the parasite. Here, we studied the reduction and recovery of germinative cells in T. crassiceps cysticerci after HU treatment (25 mM and 40 mM of HU for 6 days) through in vitro assays. Viability and morphological changes were evaluated. The recovery of cysticerci's mobility and morphology was evaluated at 3 and 6 days, after 6 days of treatment. The number of proliferative cells was evaluated using EdU. Our results show morphological changes in the size, shape, and number of evaginated cysticerci at the 40 mM dose. The mobility of cysticerci was lower after 6 days of HU treatment at both concentrations. On days 3 and 6 of recovery after 25 mM of HU treatment, a partial recovery of the proliferative cells was observed. Proteomic and Gene Ontology analyses identified modifications in protein groups related to DNA binding, DNA damage, glycolytic enzymes, cytoskeleton, skeletal muscle, and RNA binding.

Micrococcin cysteine-to-thiazole conversion through transient interactions between the scaffolding protein TclI and the modification enzymes TclJ and TclN.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a broad group of compounds mediating microbial competition in nature. Azole/azoline heterocycle formation in the peptide backbone is a key step in the biosynthesis of many RiPPs. Heterocycle formation in RiPP precursors is often carried out by a scaffold protein, an ATP-dependent cyclodehydratase, and an FMN-dependent dehydrogenase. It has generally been assumed that the orchestration of these modifications is carried out by a stable complex including the scaffold, cyclodehydratase, and dehydrogenase. The antimicrobial RiPP micrococcin begins as a precursor peptide (TclE) with a 35-amino acid N-terminal leader and a 14-amino acid C-terminal core containing six Cys residues that are converted to thiazoles. The putative scaffold protein (TclI) presumably presents the TclE substrate to a cyclodehydratase (TclJ) and a dehydrogenase (TclN) to accomplish the two-step installation of the six thiazoles. In this study, we identify a minimal TclE leader region required for thiazole formation, demonstrate complex formation between TclI, TclJ, and TclN, and further define regions of these proteins required for complex formation. Our results point to a mechanism of thiazole installation in which TclI associates with the two enzymes in a mutually exclusive fashion, such that each enzyme competes for access to the peptide substrate in a dynamic equilibrium, thus ensuring complete modification of each Cys residue in the TclE core. IMPORTANCE: Thiopeptides are a family of antimicrobial peptides characterized for having sulfur-containing heterocycles and for being highly post-translationally modified. Numerous thiopeptides have been identified; almost all of which inhibit protein synthesis in gram-positive bacteria. These intrinsic antimicrobial properties make thiopeptides promising candidates for the development of new antibiotics. The thiopeptide micrococcin is synthesized by the ribosome and undergoes several post-translational modifications to acquire its bioactivity. In this study, we identify key interactions within the enzymatic complex that carries out cysteine to thiazole conversion in the biosynthesis of micrococcin.

[Diagnosis and treatment in a series of patients with cardiac corrected transposition of the great arteries (double discordance)]. / Diagnóstico y tratamiento en una serie de pacientes con transposición corregida de las grandes arterias (doble discordancia cardiaca).

Objective: The atrio-ventricular and ventricle-arterial double discordance (DD) or corrected transposition of the great arteries is a rare heart disease, it occurs in 0.02-0.07 of every 1,000 live newborns. The objective of the study is to describe the diagnosis, treatment and evolution of a series of patients with DD. Method: A retrospective and descriptive study was carried out, reviewing the records of patients diagnosed with DD in the last 22 years. Descriptive statistics were performed. Numerical variables were obtained using means and standard deviation and categorical variables using frequencies and percentages. Results: Thirty patients were studied in 22 years with a ratio of 1.5:1 for men, with a mean age of 20 months. The situs was solitus in 24/29 patients (82.7%). Ventricular septal defect was the most frequent lesion in 25/29 (86.2%) Tricuspid insufficiency in 70%. Four patients diagnosed with pulmonary atrial hypertension. With atrio-ventricular block 20%. One with Wolff-Parkinson-White syndrome. Surgical treatment was carried out in 70% of patients. Eight with Glenn procedure (26.6%) and 4 with Fontan surgery (13.3%). Follow-up ranged from 1 month to 17 years. Five died (16.6%). Of the 25 patients in follow-up, 18 patients (72%) had normal ventricular function, 5 with Grade II Ross classification (20%) and 2 in Grade III (8%). Conclusions: The quality of life of these patients is improving and there is still controversy in the literature about the ideal time to perform the most appropriate surgical procedure.

Objetivo: La doble discordancia auriculo-ventricular y ventrículo-arterial (DD) o transposición corregida de las grandes arterias, se presenta en 0.02-0.07 de cada 1,000 recién nacidos vivos. El objetivo del estudio es describir el diagnóstico, tratamiento y evolución de pacientes con DD. Método: Se realizó un estudio retrospectivo y descriptivo, revisando los registros de pacientes con DD en los últimos 22 años. Se realizó estadística descriptiva. Las variables numéricas se obtuvieron mediante medias y desviación estándar y las categóricas mediante frecuencias y porcentajes. Resultados: Se estudiaron 30 pacientes con una relación de 1.5:1 para el varón, con una edad media de 20 meses. El situs fue solitus en 24/29 pacientes (82.7%). La comunicación interventricular fue la lesión más frecuente en 25/29 pacientes (86.2%), insuficiencia tricuspídea en el 70%. Cuatro pacientes con diagnóstico de hipertensión arterial pulmonar. Con bloqueo atrio-ventricular un 20%. Uno con síndrome de Wolff-Parkinson-White. El tratamiento quirúrgico se realizó en el 70% de los pacientes. Con procedimiento de Glenn 8 (26.6%) y 4 cirugías de Fontan (13.3%). El seguimiento fue de 1 mes a 17 años. Cinco fallecieron (16.6%). De los 25 restantes, 18 pacientes (72%) con función ventricular normal, 5 con clasificación de Ross grado II (20%) y 2 en G III (8%). Conclusiones: La calidad de vida de estos pacientes está mejorando, aún existe controversia sobre el momento ideal para realizar el procedimiento más adecuado quirúrgico.

Paracrine Ovarian Cancer Cell-Derived CSF1 Signaling Regulates Macrophage Migration Dynamics in a 3D Microfluidic Model that Recapitulates In Vivo Infiltration Patterns in Patient-Derived Xenografts.

A high density of macrophages in the ovarian cancer microenvironment is associated with disease progression and poor outcomes. Understanding cancer-macrophage interaction mechanisms that establish this pro-tumorigenic microenvironment is critical for developing macrophage-targeted therapies. Here, 3D microfluidic assays and patient-derived xenografts are utilized to define the role of cancer-derived colony stimulating factor 1 (CSF1) on macrophage infiltration dynamics toward ovarian cancer cells. It is demonstrated that multiple ovarian cancer models promote the infiltration of macrophages into a 3D extracellular matrix in vitro in a cell density-dependent manner. Macrophages exhibit directional migration and increased migration speed under both direct interactions with cancer cells embedded within the matrix and paracrine crosstalk with cancer cells seeded in an independent microchannel. It is also found that platinum-based chemotherapy increases macrophage recruitment and the levels of cancer cell-derived CSF1. Targeting CSF1 signaling under baseline or chemotherapy-treatment conditions reduces the number of infiltrated macrophages. It is further shown that results obtained with the 3D microfluidic model reflect the recruitment profiles of macrophages in patient-derived xenografts in vivo. These findings highlight the role of CSF1 signaling in establishing macrophage-rich ovarian cancer microenvironments, as well as the utility of microfluidic models in recapitulating 3D tumor ecosystems and dissecting cancer-macrophage signaling.

Dupilumab in adolescent eosinophilic esophagitis: Experience with fibrostenosis and eosinophilic gastrointestinal disease with esophageal involvement.

We evaluated patients aged 12-20 on dupilumab 300 mg weekly for treatment of eosinophilic esophagitis (EoE) who had ≥1 follow-up endoscopy at a tertiary care pediatric hospital (n = 18). Fifty percent had inflammatory EoE (n = 9), 22% had fibrostenotic EoE (n = 4), and 28% had non-EoE eosinophilic gastrointestinal disease (EGID) with esophageal involvement (n = 5). Ninety-four percent discontinued topical corticosteroids (TCS) 2-4 weeks after starting dupilumab. Eighty-nine percent of inflammatory EoE patients had histological response (<15 eosinophils/high-powered field) after an average of 19.1 weeks. One hundred percent of patients with fibrostenotic disease exhibited histological response after 16.8 weeks. Of patients with non-EoE EGID, 60% achieved esophageal histological response after an average of 40.1 weeks. In a small cohort, dupilumab was very effective for adolescent inflammatory and fibrostenotic EoE despite rapid weaning of TCS. Dupilumab was also somewhat effective for non-EoE EGID with esophageal involvement; however, a longer duration of therapy was required.

The association of TNF-alpha secretion and mtDNA copy number in CD14+ monocytes of patients with obesity and CHD.

Introduction: Mitochondrial dysfunction may be one of the causes of inflammatory activation of monocytes and macrophages, which leads to excessive secretion of inflammatory mediators and the development of chronic inflammation. Aims: The study was aimed to evaluate the secretion of inflammatory cytokine tumor necrosis factor-α (TNF-α) in the primary culture of monocytes, and to analyze its relationship with the number of mitochondrial DNA (mtDNA) copies in the blood of patients with coronary heart disease (CHD) and obesity. Materials and methods: 108 patients with obesity and concomitant CHD and a control group of 25 participants were included in the study. CD14+ monocytes were isolated by a standard method in a ficoll-urographin gradient, followed by separation using magnetic particles. The number of mtDNA copies was estimated using qPCR. Results: It was demonstrated that the number of mtDNA copies was significantly increased in groups of patients with CHD and obesity + CHD in comparison with control group. mtDNA copy number positively correlated with basal and LPS-stimulated TNF-α secretion, the most significant correlation was found in the group of patients with CHD and obesity. Conclusion: Thus, the change in mtDNA copy number in CD14+ monocytes which indicates the presence of mitochondrial dysfunction, confirm the direct involvement of mitochondria in the violation of the inflammatory response of monocytes revealed in this study as an increased secretion of inflammatory cytokine TNF-α.

Unveiling the role of hydroxyapatite and hydroxyapatite/silver composite in osteoblast-like cell mineralization: An exploration through their viscoelastic properties.

Mechanical properties are becoming fundamental for advancing the comprehension of cellular processes. This study addresses the relationship between viscoelastic properties and the cellular mineralization process. Osteoblast-like cells treated with an osteogenic medium were employed for this purpose. Additionally, the study explores the impact of hydroxyapatite (HA) and hydroxyapatite/silver (HA/Ag) composite on this process. AFM relaxation experiments were conducted to extract viscoelastic parameters using the Fractional Zener (FZ) and Fractional Kelvin (FK) models. Our findings revealed that the main phases of mineralization are associated with alterations in the viscoelastic properties of osteoblast-like cells. Furthermore, HA and HA/Ag treatments significantly influenced changes in the viscoelastic properties of these cells. In particular, the HA/Ag treatment demonstrated a marked enhancement in cell fluidity, suggesting a possible role of silver in accelerating the mineralization process. Moreover, the study underscores the independence observed between fluidity and stiffness, indicating that modifications in one parameter may not necessarily correspond to changes in the other. These findings shed light on the factors involved in the cellular mineralization process and emphasize the importance of using viscoelastic properties to discern the impact of treatments on cells.

Implications in Cancer of Nuclear Micro RNAs, Long Non-Coding RNAs, and Circular RNAs Bound by PRC2 and FUS.

The eukaryotic genome is mainly transcribed into non-coding RNAs (ncRNAs), including different RNA biotypes, such as micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), among others. Although miRNAs are assumed to act primarily in the cytosol, mature miRNAs have been reported and functionally characterized in the nuclei of different cells. Further, lncRNAs are important regulators of different biological processes in the cell nucleus as part of different ribonucleoprotein complexes. CircRNAs constitute a relatively less-characterized RNA biotype that has a circular structure as result of a back-splicing process. However, circRNAs have recently attracted attention in different scientific fields due to their involvement in various biological processes and pathologies. In this review, we will summarize recent studies that link to cancer miRNAs that have been functionally characterized in the cell nucleus, as well as lncRNAs and circRNAs that are bound by core components of the polycomb repressive complex 2 (PRC2) or the protein fused in sarcoma (FUS), highlighting mechanistic aspects and their diagnostic and therapeutic potential.

Podocytes from hypertensive and obese mice acquire an inflammatory, senescent, and aged phenotype.

Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLR family pyrin domain containing 3 (NLRP3) inflammasome, protein cell death-1, and Toll-like receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased p21 and p53. Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased p16 and p19. These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice.NEW & NOTEWORTHY Hypertension and obesity can lead to glomerular dysfunction in patients, causing podocyte injury and depletion. Here, young mice given deoxycorticosterone acetate or a high-fat diet to induce hypertension or obesity, respectively. mRNA sequencing of isolated podocytes showed transcriptional changes consistent with senescence, a senescent-associated secretory phenotype, and aging, which was confirmed by immunostaining. Ongoing studies are determining the mechanistic roles of the accelerated aging podocyte phenotype in experimental hypertension and obesity.

Mechanisms of Myocardial Edema Development in CVD Pathophysiology.

Myocardial edema is the excess accumulation of fluid in the myocardial interstitium or cardiac cells that develops due to changes in capillary permeability, loss of glycocalyx charge, imbalance in lymphatic drainage, or a combination of these factors. Today it is believed that this condition is not only a complication of cardiovascular diseases, but in itself causes aggravation of the disease and increases the risks of adverse outcomes. The study of molecular, genetic, and mechanical changes in the myocardium during edema may contribute to the development of new approaches to the diagnosis and treatment of this condition. This review was conducted to describe the main mechanisms of myocardial edema development at the molecular and cellular levels and to identify promising targets for the regulation of this condition based on articles cited in Pubmed up to January 2024.

Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis.

Spotted fever group rickettsiae are tick-borne obligate intracellular bacteria that infect microvascular endothelial cells. Humans and mammalian infection results in endothelial cell barrier dysfunction and increased vascular permeability. We previously demonstrated that treatment of Rickettsia parkeri-infected cells with the calcium channel blocker benidipine significantly delayed vascular barrier permeability. Thus, we hypothesized that benidipine, known to be safe and effective for other clinical processes, could reduce rickettsia-induced vascular permeability in vivo in an animal model of spotted fever rickettsiosis. Based on liver, lung and brain vascular FITC-dextran extravasation studies, benidipine did not reliably impact vascular permeability. However, it precipitated a deleterious effect on responses to control sublethal R. parkeri infection. Animals treated with benidipine alone had no clinical signs or changes in histopathology and splenic immune cell distributions. Benidipine-treated infected animals had marked increases in tissue and blood bacterial loads, more extensive inflammatory histopathologic injury, and changes in splenic architecture and immune cell distributions potentially reflecting diminished Ca2+ signaling, reduced innate immune cell activation, and loss of rickettsial propagation control. Impaired T cell activation by R. parkeri antigen in the presence of benidipine was confirmed in vitro with the use of NKT cell hybridomas. The unexpected findings stand in stark contrast to recent discussions of the benefits of calcium channel blockers for viral infections and chronic infectious or inflammatory diseases. A role for calcium channel blockers in exacerbation of human rickettsiosis and acute inflammatory infections should be evaluated by a retrospective review of patient's outcomes and medications.

Biobased Interpenetrating Polymer Network Membranes for Sustainable Molecular Sieving.

There is an urgent need for sustainable alternatives to fossil-based polymer materials. Through nanodomain engineering, we developed, without using toxic cross-linking agents, interpenetrating biopolymer network membranes from natural compounds that have opposing polarity in water. Agarose and natural rubber latex were consecutively self-assembled and self-cross-linked to form patchlike nanodomains. Both nano-Fourier transform infrared (nano-FTIR) spectroscopy and computational methods revealed the biopolymers' molecular-level entanglement. The membranes exhibited excellent solvent resistance and offered tunable molecular sieving. We demonstrated control over separation performance in the range of 227-623 g mol-1 via two methodologies: adjusting the molecular composition of the membranes and activating them in water. A carcinogenic impurity at a concentration of 5 ppm, which corresponds to the threshold of toxicological concern, was successfully purged at a negligible 0.56% pharmaceutical loss. The biodegradable nature of the membranes enables an environmentally friendly end-of-life phase; therefore, the membranes have a sustainable lifecycle from cradle to grave.

Endoscopist experience with pediatric recurrent and intentional foreign body ingestion (RIFBI): Management considerations and future directions.

OBJECTIVES AND STUDY: Accidental foreign body ingestion (FBI) is a common pediatric referral concern. In contrast, recurrent and intentional FBI (RIFBI) is infrequent and associated with greater endoscopic and surgical intervention in adults. Although pediatric guidelines exist for FBI, the risk and therapeutic implications of RIFBI are not addressed. An anonymous international survey on pediatric gastroenterologist experience with RIFBI was distributed. METHODS: A 33-item REDCap© survey was distributed via email to pediatric gastroenterologists identified through mailing and email lists obtained from pediatric gastroenterology professional organizations. RESULTS: During 9-12/2021 we accrued 202 completed surveys. Respondents were from 27 countries and across the career span. Eighty percent reported experience with RIFBI; 74% reported seeing ≤ 3 patients with RIFBI within the past 24 months and 4% reported seeing ≥ 6. Of those who treated RIFBI, 38% reported an average number of annual ingestions per patient was ≥5. Frequent morbidity but not mortality was reported. Half reported adherence to FBI guidelines. Later-career endoscopists treated RIFBI more aggressively than accidental ingestion. Ninety-six percent noted that patients with RIFBI had psychiatric comorbidities. Providers at academic medical centers reported referring to behavioral health more than those in other settings. CONCLUSION: Most gastroenterologists surveyed reported encountering RFBI several times a year and in patients with psychiatric comorbidities. Greater likelihood of adverse outcomes associated with endoscopy was reported. Most reported referral to behavioral health and few had RIFBI management protocols. A broader spectrum of psychologic comorbidities in the pediatric population with RIFBI, notably depression and autism spectrum disorder, were reported.

Podocyte injury at young age causes premature senescence and worsens glomerular aging.

As life expectancy continues to rise, age-related diseases are becoming more prevalent. For example, proteinuric glomerular diseases typified by podocyte injury have worse outcomes in the elderly compared with young patients. However, the reasons are not well understood. We hypothesized that injury to nonaged podocytes induces senescence, which in turn augments their aging processes. In primary cultured human podocytes, injury induced by a cytopathic antipodocyte antibody, adriamycin, or puromycin aminonucleoside increased the senescence-related genes CDKN2A (p16INK4a/p14ARF), CDKN2D (p19INK4d), and CDKN1A (p21). Podocyte injury in human kidney organoids was accompanied by increased expression of CDKN2A, CDKN2D, and CDKN1A. In young mice, experimental focal segmental glomerulosclerosis (FSGS) induced by adriamycin and antipodocyte antibody increased the glomerular expression of p16, p21, and senescence-associated ß-galactosidase (SA-ß-gal). To assess the long-term effects of early podocyte injury-induced senescence, we temporally followed young mice with experimental FSGS through adulthood (12 m of age) and middle age (18 m of age). p16 and Sudan black staining were higher at middle age in mice with earlier FSGS compared with age-matched mice that did not get FSGS when young. This was accompanied by lower podocyte density, reduced canonical podocyte protein expression, and increased glomerular scarring. These results are consistent with injury-induced senescence in young podocytes, leading to increased senescence of podocytes by middle age accompanied by lower podocyte lifespan and health span.NEW & NOTEWORTHY Glomerular function is decreased by aging. However, little is known about the molecular mechanisms involved in age-related glomerular changes and which factors could contribute to a worse glomerular aging process. Here, we reported that podocyte injury in young mice and culture podocytes induced senescence, a marker of aging, and accelerates glomerular aging when compared with healthy aging mice.

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study.

OBJECTIVES: To determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000-2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour to be monitored. DESIGN: Population-based, observational study using congenital anomaly (CA) registration data for England curated by the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). SETTING: Regions of England with active registration in the time period. PARTICIPANTS: Babies that were liveborn or stillborn and pregnancies that resulted in a termination of pregnancy or a late miscarriage (20-23 weeks' gestation) with an NTD. MAIN OUTCOME MEASURES: Total birth prevalence of anencephaly, spina bifida and all NTDs in England. Poisson regression analysis was used to evaluate time trends with regional register as a random effect. The progress of national registration across England was assessed. RESULTS: There were 4541 NTD pregnancies out of 3 637 842 births in England; 1982 anencephaly and 2127 spina bifida. NTD prevalence was 12.5 (95% CI 12.1 to 12.9) per 10 000 total births. NTD prevalence per 10 000 total births was significantly higher in 2015-2019 (13.6, 95% CI 12.9 to 14.4) compared with 2010-2014 (12.1, 95% CI 11.7 to 12.5). An increasing trend in NTDs overall was detected (incidence rate ratio (IRR) 1.01, 1.00 to 1.02), although further analysis determined this effect was confined to 2015-2019 (compared against 2000-2004, IRR 1.14, 1.04 to 1.24). The birth prevalence of anencephaly reflected this pattern. The prevalence of spina bifida remained relatively stable over time. CONCLUSIONS: Baseline NTD prevalence for England has been established. National and standardised CA registration is in place, facilitating the systematic and consistent monitoring of pre-fortification and post-fortification NTD trends and evaluating the impact of fortification on NTD prevalence.

Association between Nfr2, HO-1, NF-kB Expression, Plasma ADMA, and Oxidative Stress in Metabolic Syndrome.

Endothelial dysfunction is one of the major factors in the pathogenesis of metabolic syndrome (MetS), and its molecular mechanisms are not completely understood. The present study aimed to examine the connection between nuclear factor2-related factor2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heme oxygenase 1 (HO-1), and plasma asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) in people with MetS. Participants in the study were as follows: with MetS (n = 30) and without MetS (Control) (n = 14). Expression of Nrf2, NF-kB, and HO-1 was measured in peripheral blood mononuclear cells (PBMCs). Plasma ADMA was determined using the ELISA technique and MDA via the thiobarbituric acid method. Our study showed that mRNA of NF-kB, Nrf2, and HO-1 levels in PBMCs in the MetS group were significantly higher than in the controls by 53%, 130%, and 185% (p < 0.05), respectively. Similarly, elevated levels of MDA (by 78%, p < 0.001) and ADMA (by 18.7%, p < 0.001) were established in the MetS group. Our findings show the importance of transcription factor Nrf2, playing an integral role in the protection of the endothelium, and of NF-κB, a transcription factor mediating the inflammatory response in MetS. Knowledge of complex cellular-molecular mechanisms would allow the use of biomarkers such as Nrf2, NF-kB, HO-1, and ADMA for the assessment of endothelial dysfunction in clinical practice.

TGF-ß/SMAD canonical pathway induces the expression of transcriptional cofactor TAZ in liver cancer cells.

The TGF-ß and Hippo pathways are critical for liver size control, regeneration, and cancer progression. The transcriptional cofactor TAZ, also named WWTR1, is a downstream effector of Hippo pathway and plays a key role in the maintenance of liver physiological functions. However, the up-regulation of TAZ expression has been associated with liver cancer progression. Recent evidence shows crosstalk of TGF-ß and Hippo pathways, since TGF-ß modulates TAZ expression through different mechanisms in a cellular context-dependent manner but supposedly independent of SMADs. Here, we evaluate the molecular interplay between TGF-ß pathway and TAZ expression and observe that TGF-ß induces TAZ expression through SMAD canonical pathway in liver cancer HepG2 cells. Therefore, TAZ cofactor is a primary target of TGF-ß/SMAD-signaling, one of the pathways altered in liver cancer.

Global longitudinal strain for prediction of mortality in ST-segment elevation myocardial infarction and aortic stenosis patients: two sides of the same coin.

OBJECTIVE: Global longitudinal strain (GLS) predicts major adverse events in ST-segment elevation myocardial infarction (STEMI) and aortic stenosis (AS). Different cut-off values and different end-points have been proposed for prognostic stratification. We aimed to verify whether a single GLS cut-off value can be used to identify increased risk of all-cause death in STEMI and AS. PATIENTS AND METHODS: One-hundred- seventeen successfully treated first STEMI (age 63.8±12.5 yrs, 70% men) and 64 AS (age 80.3±6.9 yrs, 44% men) patients, undergoing echocardiography before discharge and before AS treatment, respectively, were retrospectively analyzed. GLS was analyzed, together with pulmonary artery systolic pressure (PASP), Killip class and Genereux stage. End-point was all-cause death at 6-month follow-up. RESULTS: All-cause death occurred in 4 (3.4%) STEMI and 5 (7.8%) AS patients (p=ns). AS patients who died had GLS similar to died STEMI patients (9.7±2.1 vs. 11.3±1.7, p=ns). GLS cut-off ≤12% predicted death with 89% sensitivity and 70% specificity (AUC 0.84, p=0.001): STEMI and AS patients with GLS ≤12% had worse survival than STEMI and AS patients with GLS >12% (log-rank p=0.001). At multivariate Cox regression analysis, lower GLS values independently predicted death (HR 0.667, 95% CI 0.451-0.986, p=0.042), and the prediction model was improved when GLS was added to old age, significant comorbidities, PASP and Killip/Genereux stage (χ2 6.691 vs. 1.364, p=0.010). CONCLUSIONS: Died patients with STEMI and AS show similar values of GLS. A unique cut-off value of GLS can reliably be used to stratify the risk of all-cause death at 6-month follow-up in both two clinical settings.