A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable

Background Neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) provides a small but significant survival benefit. Nevertheless, controversies on applying NAC remain because the limited benefit must be weight against chemotherapy-related toxicity and the delay of definitive local treatment. Therefore, there is a clear clinical need for tools to guide treatment decisions on NAC in MIBC. Here, we aimed to validate a previously reported 20-gene expression signature that predicted lymph node-positive disease at radical cystectomy in clinically node-negative MIBC patients, which would be a justification for upfront chemotherapy. Methods We studied diagnostic transurethral resection of bladder tumors (dTURBT) of 150 MIBC patients (urothelial carcinoma) who were subsequently treated by radical cystectomy and pelvic lymph node dissection. RNA was isolated and the expression level of the 20 genes was determined on a qRT-PCR platform. Normalized Ct values were used to calculate a risk score to predict the presence of node-positive disease. The Cancer Genome Atlas (TCGA) RNA expression data was analyzed to subsequently validate the results. Results In a univariate regression analysis, none of the 20 genes significantly correlated with nodepositive disease. The area under the curve of the risk score calculated by the 20-gene expression signature was 0.54 (95% Confidence Interval: 0.44-0.65) versus 0.67 for the model published by Smith et al. Node-negative patients had a significantly lower tumor grade at TURBT (p = 0.03), a lower pT stage (p<0.01) and less frequent lymphovascular invasion (13% versus 38%, p<0.01) at radical cystectomy than node-positive patients. In addition, in the TCGA data, none of the 20 genes was differentially expressed in node-negative versus node-positive patients. Conclusions We conclude that a 20-gene expression signature developed for nodal staging of MIBC at radical cystectomy could not be validated on a qRT-PCR platform in a large cohort of dTURBT specimens

Influence of Preparation Design and Restorative Material on Fatigue and Fracture Strength of Restored Maxillary Premolars

Statement of Problem: Extensive carious lesions and/or large preexisting restorations possibly contribute to crack formation, ultimately resulting in a fracture that may lead to the loss of a tooth cusp. Hence, preparation design strategy in conjunction with the restorative material selected could be influential in the occurrence of a cuspal fracture. Purpose: The purpose of this in vitro study was to evaluate the fatigue behavior and fracture strength of maxillary premolars restored with direct composite and indirect ceramic inlays and overlays, with different preparation depths in the presence or absence of cuspal coverage, and analyze their failure types. Methods and Materials: Sound maxillary premolars (N=90; n=10) were divided into nine groups: group C: control; group DCI3: direct composite inlay 3 mm; group DCI5: direct composite inlay 5 mm; group ICI3: indirect ceramic inlay 3 mm; group ICI5: indirect ceramic inlay 5 mm; group DCO3: direct composite overlay 3 mm; group DCO5: direct composite overlay 5 mm; group ICO3: indirect ceramic overlay 3 mm; group ICO5: indirect ceramic overlay 5 mm. In indirect ceramic, lithium disilicate restoration groups, immediate dentin sealing was applied. After restoration, all specimens were tested in fatigue (1,200,000 cycles, 50 N, 1.7 Hz). Samples were critically appraised, and the specimens without failure were subjected to a load to failure test. Failure types were classified and the data analyzed. Results: Zero failures were observed in the fatigue testing. The following mean load to failure strengths (N) were recorded: group ICO5: 858 N; group DCI3: 829 N; group ICO3: 816 N; group C: 804 N; group ICI3: 681 N; group DCO5: 635 N; group DCI5: 528 N; group DCO3: 507 N; group ICI5: 482 N. Zero interaction was found between design-depth-material (p=0.468). However, significant interactions were found for the design-depth (p=0.012) and design-material (p=0.006). Within restorations at preparation depth of 3 mm, direct composite overlays obtained a significantly lower fracture strength in comparison to indirect ceramic onlays (p=0.013) and direct composite inlays (p=0.028). In restorations at depth 5 mm, significantly higher fracture load values were observed in indirect ceramic overlays compared with the inlays (p=0.018). Indirect ceramic overlays on 3 mm were significantly stronger than the deep inlays in ceramic (p=0.002) and tended to be stronger than the deep direct composite inlays. Severe, nonreparable fractures were observed with preparation depth of 5 mm within ceramic groups. Conclusions: The preparation depth significantly affected the fracture strength of tooth when restored with either composite or ceramic materials. Upon deep cavity preparations, cuspal coverage proved to be beneficial when a glass ceramic was used as the restorative material. Upon shallow cavity preparations, a minimally invasive approach regarding preparation design used in conjunction with a direct composite material was favorable

Conservation of Maculinea butterflies at landscape level

To enhance the establishment of new populations of reintroduced Maculinea species and increase dispersal between sites, a regional action plan has been started. Public communities, nature conservation organizations, amateurs and farmers participate in the agreements on management of sites. The study describes the changes in the ant fauna in the Action Plan Area after changes in the management of canal borders, road verges and ditch sides

Fauna y bioestratigrafía del yacimiento Aragoniense de Montejo de la Vega de la Serrezuela (Segovia)

The macro and micromammals fossils of Montejo de la Vega de la Serrezuela (Segovia, Spain) are studied. The identified taxons allow to place the new locality in the Middle Aragonian, unit MN5 of Mein (1977, 1979, 1990). The Montejo de la Vega deposit can be correlated with the Arroyo del Olivar in the Madrid basin and the Las Planas 4A, 4B, Y4C in the Calatayud-Teruel basin.Se estudian los macro y micromamíferos fósiles de Montejo de la Vega de la Serrezuela (Segovia). Los taxones identificados permiten situar esta localidad en el Aragoniense medio, unidad MN5 de Mein (1977, 1979, 1990). El yacimiento de Montejo de la Vega puede correlacionarse con el de Arroyo del Olivar en la cuenca de Madrid y con los de Las Planas 4A, 4B y 4C en la cuenca de Calatayud-Teruel

Chronic anemia and unexplained inflammation:think of VEXAS syndrome

AchtergrondHet VEXAS-syndroom is een auto-inflammatoire ziekte die ontstaat door een verworven of somatische mutatie in het UBA1-gen. Deze X-gebonden aandoening komt vrijwel alleen voor bij mannen en openbaart zich pas op oudere leeftijd.CasusWij beschrijven een patiënt met het VEXAS-syndroom bij wie in eerste instantie niet de juiste diagnose werd gesteld. Nadat de diagnose was gesteld op basis van genetisch onderzoek, behandelden wij de patiënt met prednisolon en de IL-6-remmer tocilizumab.ConclusieBij mannen vanaf de middelbare leeftijd die een multisystemisch inflammatoir ziektebeeld laten zien zonder infectie, moet de diagnose ‘VEXAS-syndroom’ worden overwogen, zeker wanneer er sprake is van een bijkomende macrocytaire anemie. De diagnose kan eenvoudig worden gesteld op basis van gericht onderzoek naar mutaties in UBA1. De behandeling bestaat vooral uit toediening van immunosuppressiva. De mortaliteit is hoog.BACKGROUND: VEXAS-syndrome is an X-linked acquired multisystemic autoinflammatory disease caused by a somatic mutation in UBA1.CASE DESCRIPTION: In this manuscript we describe a 79-year-old male suffering from skin lesions, macrocytic anemia and lab results showing inflammation in which, based on finding a mutation in UBA1, VEXAS was diagnosed. He was treated with a combination of high dose corticosteroids and anti-IL-6 with good response.CONCLUSION: In middle aged males presenting with multisystemic inflammation without evidence of infection a diagnosis of VEXAS should be considered, especially if there is evidence of a macrocytic anemia. Early testing for UBA1 mutations helps in making the diagnosis. Despite treatment with intensive immunosuppression mortality remains high.</p

Chronic anemia and unexplained inflammation:think of VEXAS syndrome

AchtergrondHet VEXAS-syndroom is een auto-inflammatoire ziekte die ontstaat door een verworven of somatische mutatie in het UBA1-gen. Deze X-gebonden aandoening komt vrijwel alleen voor bij mannen en openbaart zich pas op oudere leeftijd.CasusWij beschrijven een patiënt met het VEXAS-syndroom bij wie in eerste instantie niet de juiste diagnose werd gesteld. Nadat de diagnose was gesteld op basis van genetisch onderzoek, behandelden wij de patiënt met prednisolon en de IL-6-remmer tocilizumab.ConclusieBij mannen vanaf de middelbare leeftijd die een multisystemisch inflammatoir ziektebeeld laten zien zonder infectie, moet de diagnose ‘VEXAS-syndroom’ worden overwogen, zeker wanneer er sprake is van een bijkomende macrocytaire anemie. De diagnose kan eenvoudig worden gesteld op basis van gericht onderzoek naar mutaties in UBA1. De behandeling bestaat vooral uit toediening van immunosuppressiva. De mortaliteit is hoog.BACKGROUND: VEXAS-syndrome is an X-linked acquired multisystemic autoinflammatory disease caused by a somatic mutation in UBA1.CASE DESCRIPTION: In this manuscript we describe a 79-year-old male suffering from skin lesions, macrocytic anemia and lab results showing inflammation in which, based on finding a mutation in UBA1, VEXAS was diagnosed. He was treated with a combination of high dose corticosteroids and anti-IL-6 with good response.CONCLUSION: In middle aged males presenting with multisystemic inflammation without evidence of infection a diagnosis of VEXAS should be considered, especially if there is evidence of a macrocytic anemia. Early testing for UBA1 mutations helps in making the diagnosis. Despite treatment with intensive immunosuppression mortality remains high.</p

Chronic anemia and unexplained inflammation:think of VEXAS syndrome

AchtergrondHet VEXAS-syndroom is een auto-inflammatoire ziekte die ontstaat door een verworven of somatische mutatie in het UBA1-gen. Deze X-gebonden aandoening komt vrijwel alleen voor bij mannen en openbaart zich pas op oudere leeftijd.CasusWij beschrijven een patiënt met het VEXAS-syndroom bij wie in eerste instantie niet de juiste diagnose werd gesteld. Nadat de diagnose was gesteld op basis van genetisch onderzoek, behandelden wij de patiënt met prednisolon en de IL-6-remmer tocilizumab.ConclusieBij mannen vanaf de middelbare leeftijd die een multisystemisch inflammatoir ziektebeeld laten zien zonder infectie, moet de diagnose ‘VEXAS-syndroom’ worden overwogen, zeker wanneer er sprake is van een bijkomende macrocytaire anemie. De diagnose kan eenvoudig worden gesteld op basis van gericht onderzoek naar mutaties in UBA1. De behandeling bestaat vooral uit toediening van immunosuppressiva. De mortaliteit is hoog.BACKGROUND: VEXAS-syndrome is an X-linked acquired multisystemic autoinflammatory disease caused by a somatic mutation in UBA1.CASE DESCRIPTION: In this manuscript we describe a 79-year-old male suffering from skin lesions, macrocytic anemia and lab results showing inflammation in which, based on finding a mutation in UBA1, VEXAS was diagnosed. He was treated with a combination of high dose corticosteroids and anti-IL-6 with good response.CONCLUSION: In middle aged males presenting with multisystemic inflammation without evidence of infection a diagnosis of VEXAS should be considered, especially if there is evidence of a macrocytic anemia. Early testing for UBA1 mutations helps in making the diagnosis. Despite treatment with intensive immunosuppression mortality remains high.</p

Retrieval Contexts and the Concreteness Effect: Dissociations in Memory of Concrete and Abstract Words

Decades of research on the concreteness effect, namely better memory for concrete as compared with abstract words, suggest it is a fairly robust phenomenon. Nevertheless, little attention has been given to limiting retrieval contexts. Two experiments evaluated intentional memory for concrete and abstract word lists in three retrieval contexts: free recall, explicit word-stem completion, and implicit word-stem completion. Concreteness effects were observed in free recall and in explicit word-stem completion, but not in implicit word-stem completion. These findings are consistent with both a bidirectional version of the relational-distinctiveness processing framework (Ruiz-Vargas, Cuevas, & Marschark, 1996) and a second framework combining insights from dual coding theory (Paivio, 1971, 1986) and the transfer appropriate processing framework (Roediger, Weldon, & Challis, 1989). Also, consistent with the relational-distinctiveness framework, the second experiment suggested that concreteness effects might depend on relational processing at encoding: Concreteness effects were observed in explicit memory for related word lists but not for unrelated word lists. © 2005 Psychology Press Ltd

Dexamethasone attenuates interferon-related cytokine hyperresponsiveness in COVID-19 patients

Background: Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.Objective: We combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.Methods: Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.Results: Dexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.Conclusion: We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.</p

Dexamethasone attenuates interferon-related cytokine hyperresponsiveness in COVID-19 patients

Background: Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.Objective: We combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.Methods: Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.Results: Dexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.Conclusion: We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.</p