Journal articles on the topic 'Carbone, Zenica'

Abstract Introduction: Multiple gene expression profile assays have successfully prognosticated the overall survival (OS) outcomes of patients with Newly Diagnosed Multiple Myeloma (NDMM) and are now available for use in clinical practice. The genes included in these profiles encompass several aspects of cancer biology broadly such as cell-cycle biology, energy metabolism, migration, adhesion, immune evasion etc. Since altered energy metabolism is one of the hallmarks of all cancer cells, our goal was to take a deep-dive into specific genes associated with intracellular central carbon energy metabolism (CCEM) pathways such as oxidative phosphorylation (OxPhos) as well as glycolysis and lactate fermentation (Glyco-Lac) in MM cells to determine their impact on the pathogenesis and prognosis of MM patients. Methods: Gene expression level data via RNA sequencing from the COMMPASS dataset (made available by the Multiple Myeloma Research Foundation (MMRF)) was utilized. The expression levels of all genes associated with the OxPhos (N = 118) and Glyco-Lac (N = 34) pathways were evaluated in CD138+ cells derived from patients with NDMM. Each gene was dichotomized into low and high expression groups -based on their expression level above and below the median fragments per kilobase of transcript per million (FPKM), respectively. The prognostic significance of dichotomizing each of the 152 genes in this NDMM cohort was evaluated by levels of their hazard ratios (HRs) for OS determined by the log-rank method. Genes from the OxPhos and Glyco-Lac pathways were selected based on their significant negative impact on OS, wide representation of their biologic activity throughout the pathway and high independence from each other. This resulted in the selection of 12 distinct genes of interest. A scoring system consisting of assigning a point for every gene where their FPKM was above the median yielded a minimum of 0 and a maximum of 12 for the set of genes in the OxPhos and Glyco-Lac pathways to create an energy metabolism score (EMS). Patients were then categorized into "low" (0-8) or "high" (9-12) EMS groups. In addition, patients were designated as having high-risk cytogenetics if they had any of the following: t(4;14), t(14;16), t(14;20), del17p, and Amp 1q. Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Finally, the distribution of the EMS score among patients within a spectrum of plasma cell disorders such as, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma and MM as well as normal plasma cells was assessed using a previously published transcriptome dataset (GSE6477). Results: A total of 766 patients were included in this study. The selected genes included in this scoring system and their biological relevance in the OxPhos and Glyco-Lac pathways are depicted in Figure A. The distribution of low and high EMS groups across ISS stage and cytogenetic risk are depicted in Figure B and C respectively. The median OS (mOS) and PFS for the high (N = 248) vs. low (N = 518) EMS groups was 55 vs. 94 months (HR: 2.41; (95%CI: 1.85-3.14); P <0.0001) (Figure D) and 24 vs. 42 months (HR: 1.74; (95%CI: 1.42-2.13); P <0.0001). Patients with ISS 2 stage disease categorized as having a high or low EMS score had a similar mOS to patients with ISS 3 and ISS 1 stage disease respectively (Figure E). Similarly, the mOS was similar among patients with standard risk and high-risk cytogenetics when categorized by low and high EMS (Figure F). Finally, the relative expression of most of the 12 select CCEM genes (Figure G) and the probability of a high EMS score increased among patients along the spectrum of plasma cell disorders (Normal plasma cell -> MGUS -> SMM -> MM) (Figure H). Conclusions: The expression levels of specific genes associated with the activity of intracellular CCEM pathways such as glycolysis, lactate fermentation and oxidative phosphorylation in plasma cells provides evidence for the impact of cellular energy metabolism on the pathogenesis and survival outcomes of MM. This provides an opportunity for developing future studies aimed at understanding the energy metabolism pathways of plasma cell malignancies in greater detail so as to exploit them for diagnostic and therapeutic purposes in MM. Figure 1 Figure 1. Disclosures Kumar: Novartis: Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Carsgen: Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dispenzieri: Alnylam: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Kapoor: AbbVie: Research Funding; Takeda: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Dingli: Apellis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; GSK: Consultancy; Novartis: Research Funding; Alexion: Consultancy. Lin: Gamida Cell: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy; Novartis: Consultancy; Legend: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Merck: Research Funding; Vineti: Consultancy. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Fonseca: Aduro: Consultancy; Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Takeda: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mayo Clinic in Arizona: Current Employment; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; GSK: Consultancy.

BackgroundImmune pathways have been implicated in both systemic sclerosis (SSc)-related interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). Determination of blood cytokine differences in these two disorders need to be elucidated to better understand potential biological processes and common pathogenic pathways.ObjectivesThis study compared 87 circulating cytokine levels amongst healthy controls and both SSc-ILD and IPF. There was also exploration of the association between cytokine levels and disease progression based on the annualized rate of decline of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO).MethodsLevels of 87 plasma cytokines were measured using commercial panels for consecutive SSc-ILD, IPF, and healthy individuals recruited at a Canadian tertiary-care center. Pulmonary function tests were performed as clinically indicated every 3-12 months. Cytokine levels are compared using the Wilcoxon rank sum test for two samples pairwise. The association between differentially expressed cytokines with both percent predicted annualized FVC and DLCO change was assessed within each disease group using multiple linear models adjusted for age, sex, baseline FVC, and immunosuppressive or anti-fibrotic treatment at sampling. Correction for multiplicity of testing was by Holm’s method.ResultsThere were 19 healthy controls, 40 SSc-ILD, and 17 IPF participants with clinical features shown in Table 1. Eotaxin-1 and interleukin 6 (IL-6) were significantly elevated in both SSc-ILD and IPF compared to healthy controls (Figure 1). SSc-ILD had significantly lower soluble epidermal growth factor receptor (sEGFR) and higher levels of both soluble tumor necrosis factor receptor type II (sTNFRII) and soluble vascular endothelial growth factor receptor-1 (sVEGFR1) compared to healthy controls. IPF cases were distinguished from healthy controls by significantly higher monocyte chemoattractant protein-1 (MCP-1) and monokine induced by gamma interferon (MIG, also known as CXCL9) levels. No significant association was found for any of the cytokines with ILD progression based on annualized rates of either FVC or DLCO change.Table 1.Baseline patient characteristics stratified by disease groupsHealthy control(n = 19)SSc-ILD(n = 40)IPF(n = 17)Age, year51 ± 1956 ± 1273 ± 7Male, count (%)6 (32)12 (30)12 (71)Disease duration, yearNA6.41 (7.81)1.76 (2.14)Ever smoker, count (%)2 (11)19 (48)14 (82)•4 (82)oker0.4 [0, 1]11 [4, 29]19 [11, 35]Treatment presence, count (%)NA16 (40)7 (41)Baseline FVC %NA80 ± 2285 ± 21Baseline DLCO %NA51 ± 1749 ± 11Annualized FVC % changeNA-1.7 ± 8.2-6.2 ± 13.6Annualized DLCO % changeNA-0.5 ± 6.2-7.8 ± 18.6The number (%), mean ± standard deviation, and median [interquartile range] are shown. Disease duration is defined as time of ILD first seen on HRCT in IPF and time from first non-Raynaud’s phenomenon in SSc-ILD. Treatment includes presence of ILD therapies: nintedanib, pirfenidone, mycophenolate mofetil, azathioprine, rituximab. FVC = forced vital capacity, DLCO = diffusing capacity for carbon monoxideFigure 1.Notched box plots of cytokine differences between disease groups. All cytokine levels are shown on a log scale. Overlap of notches indicates lack of a statistically significant difference in medians in a pairwise comparison. P-values are for SSc-ILD or IPF compared to healthy controls using Wilcoxon rank sum two-sample test corrected for multiple testing using Holms method.ConclusionDifferences in seven circulating cytokines between healthy controls with both SSc-ILD and IPF show evidence of systemic cytokine activation. All seven cytokines have a role in immune cell extravasation and pro-fibrotic signaling, which provides further evidence of immune pathways involved in pulmonary fibrosis. Further studies will be pursued of longitudinal change of these biomarkers for halting or slowing disease progression and improving response to treatment.Disclosure of InterestsBoyang Zheng: None declared, Kevin Keen Grant/research support from: Merck Canada Inc, Marvin Fritzler Shareholder of: Abbott Laboratories; Roche Holdings; Abcellera; Moderna, Speakers bureau: For diagnostic company: Werfen, Consultant of: For diagnostic company: Werfen; Aesku, Employee of: Medical Director of Mitogen Diagnostics, Christopher Ryerson Speakers bureau: Boehringer Ingelheim, Hoffmann-La Roche, Consultant of: Boehringer Ingelheim, Hoffmann-La Roche, Veracyte, Astra Zeneca, Grant/research support from: Boehringer Ingelheim, Hoffmann-La Roche, Pearce Wilcox Speakers bureau: Vertex, Valeo, Boehringer, Beth Whalen: None declared, Basak Sahin: None declared, Haiyan Hou Employee of: Mitogen Diagnostics, Penny Latham Employee of: Eve technologies, Mei Feng Zhang Employee of: Mitogen diagnostics, Iris Yao: None declared, James Dunne: None declared

BackgroundAutologous haematopoietic stem cell transplantation (HSCT) ameliorates event-free survival, skin thickening and lung function in patients with progressive diffuse cutaneous systemic sclerosis (dcSSc). Anti-thymocyte globulin (ATG) is a key lymphoablative constituent of conditioning protocols and is administered in a body weight-based dose. Response to HSCT and occurrence of infections is still highly variable across dcSSc patients. Studies in haemato-oncological patients suggest that ATG exposure varies across subjects and impacts outcomes [1].ObjectivesTo explore the relation between rabbit derived ATG exposure, lymphocyte reconstitution and clinical outcomes in patients with dcSSc undergoing autologous HSCT.MethodsWe retrospectively analysed patients with dcSSc undergoing autologous HSCT between 2014 and 2020. ATG levels were measured in cryopreserved serum samples at four time points (day 1 and week 1, 2 and 4) after stem cell reinfusion. ATG exposure was estimated using population pharmacokinetics models [1]. Treatment response was defined as pulmonary stabilisation (with no decline more than 10% in forced vital capacity and 15% in diffusing capacity for carbon monoxide) and/or skin improvement (modified Rodnan skin score reduction of more than 30%). Differences between groups were examined with Wilcoxon rank-sum test for contentious variables and Fisher exact test for categorical variables.ResultsFifteen patients were included in this study with median age 43 years-old (IQR 37–50). During a median follow-up of 45 months (IQR 19—66), 73% (n=11) of patients had a treatment response, and 27% (n=4) were non-responders. Eight (73%) responders achieved long-term remission and three (27%) responders had progressive disease in the follow-up, at a median time of eight months (IQR 5—17) post-HSCT. Although all patients received the same weight-based ATG dosage (7.5 mg/kg), ATG exposure varied across patients. ATG exposure was higher in responders than non-responders (p = 0.026, Table 1) but was not correlated with lymphocyte reconstitution or infection rate.ConclusionIn our study, ATG exposure highly varied across dcSSc patients undergoing HSCT despite the same weight-based dosage. Responders had a higher ATG exposure than non-responders. More research into optimal ATG dosing is needed to improve HSCT outcomes.References[1]Admiraal R, Nierkens S, de Witte MA, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol 2017;4(4):e183-e91.Table 1.ATG-exposure comparison on outcomesYesNop-valueResponse to aHSCTTotal exposure163 (153—183)137 (101—149)0.026*Exposure before stem cell reinfusion30 (30—33)27 (23—30)0.226Exposure after stem cell reinfusion130 (120—153)108 (78—117)0.026*Progressive disease following initial treatment responseTotal exposure178 (164—180)153 (141—168)0.536Exposure before stem cell reinfusion30 (30—32)30 (27—32)0.840Exposure after stem cell reinfusion148 (132—150)121 (114—136)0.633The median (interquartile range) anti-thymocyte globulin (ATG) exposure was presented in the cumulative area under the concentration–time curves (AU*day/mL).AcknowledgementsThe authors want to thank all patients participating in this study and the department of Medical Microbiology UMC Utrecht, for providing the cryopreserved serum samples.Disclosure of InterestsYu-Hsiang Chiu: None declared, Anouk Drijver: None declared, Rick Admiraal: None declared, Anna van Rhenen: None declared, Stefan Nierkens: None declared, Jacob M. van Laar Grant/research support from: Grant from Boehringer, Astra Zeneca, MSD, Roche., Julia Spierings Grant/research support from: A grant from Boehringer.

CO2 is one of the major contributors to the emission of greenhouse gases boosting climate change. Meanwhile, renewable energy production is fluctuating due to weather conditions, demanding for appropriate storage, e. g. by Power-to-X technology. The first step of these processes, the production of hydrogen via water electrolysis, is typically linked to a second step to obtain hydrocarbons [1]. Meanwhile, electrochemical CO2 reduction (eCO2R) is capable of generating chemical feedstocks by converting excess CO2, simultaneously using renewable energy sources during peak times. A promising pathway of eCO2R focuses on CO, as it can be produced with high selectivity at silver catalysts, concurrently generating hydrogen as the only byproduct [2]. To partly overcome the mass transport limitations resulting from the very limited solubility of CO2 in aqueous electrolytes, gas diffusion electrodes (GDEs) are typically used for eCO2R in a three-chamber setup with anolyte, catholyte and separate gas compartment [3]. However, there are still considerable overpotentials in this setup, among others caused by ohmic losses such as the electrolyte resistance. Employing membrane electrode assemblies (MEAs), either both electrodes or one of them can be combined with the membrane to form a full- or half-MEA, respectively, resulting in a significant decrease in cell voltage. Although there have already been studies on the fabrication of MEAs employing silver catalysts for eCO2R [4, 5], they are still very limited in options and mostly based on carbon gas diffusion layers (GDLs). The manufacturing approach applied in this work is based on a catalyst ink recipe for sintered silver GDEs originally developed for chlor-alkali electrolysis by Moussallem et al. [6]. Instead of using Nickel mesh as a substrate, the suspension is spray-coated on a stainless steel plate to enable the required treatment at temperatures above 300 °C. Afterwards, the catalyst layer is hot-pressed on the prepared anion exchange membrane at more moderate temperatures, forming a supportless cathodic half-MEA. Resulting from variations in the manufacturing procedure, different MEAs are electrochemically characterized, examining Faradaic efficiencies as well as cell voltages, also in comparison to measurements performed in three-chamber setup. Addressing challenges in product efficiency and membrane degradation, it is shown that this type of MEA is capable of eCO2R to CO, already reducing the cell potential at elevated current densities by nearly 50 %, see fig. 1. [1] Tom Kober et al. Report: perspectives of power-to-X technologies in Switzerland: supplementary report to the white paper. en. Technical report. 2019. doi: 10.3929/ETHZ-B-000525806. [2] Yoshio Hori et al. “Electrocatalytic process of CO selectivity in electrochemical reduction of CO2 at metal electrodes in aqueous media”. Electrochimica Acta, 39 (11-12), (1994), 1833–1839. [3] Thomas Burdyny and Wilson A. Smith. “CO2 reduction on gas-diffusion electrodes and why catalytic performance must be assessed at commercially-relevant conditions”. Energy & Environmental Science, 12 (5), (2019), 1442–1453. doi: 10.1039/C8EE03134G. [4] Zengcai Liu et al. “CO2 electrolysis to CO and O2 at high selectivity, stability and efficiency using Sustainion membranes”. Journal of The Electrochemical Society, 165 (15), (2018), J3371–J3377. doi: 10.1149/2.0501815jes. [5] Jonghyeok Lee et al. “Electrochemical CO2 reduction using alkaline membrane electrode assembly on various metal electrodes”. Journal of CO2 Utilization, 31 (2019), 244–250. doi: 10.1016/j.jcou.2019.03.022. [6] Imad Moussallem et al. “Development of high-performance silver-based gas-diffusion electrodes for chlor-alkali electrolysis with oxygen depolarized cathodes”. Chemical Engineering and Processing: Process Intensification, 52 (2012), 125–131. doi: 10.1016/j.cep.2011.11.003. Figure 1

Abstract Introduction: Altered cellular metabolism is a hallmark of every cancer cell. Aerobic glycolysis ("The Warburg Effect") is one of the earliest recognized metabolic abnormalities in cancer cells whereby extracellular glucose is preferentially metabolized and eventually processed to generate lactate and energy in the form of ATP before the former is released extracellularly, irrespective of oxygen availability. While extracellular lactate produced and released from cancer cells has traditionally been considered a waste metabolic by-product, recent understanding of cell metabolism suggests that it can also serve as a primary metabolic fuel for cancer cells via uptake by monocarboxylate transporters (MCTs). Our goal was to evaluate this "Reverse Warburg Effect" phenomenon in multiple myeloma (MM) cells and determine if it can be exploited for therapeutic purposes. Methods: All HMCLs, MM1S, RPMI-8226 and U266, were grown in RPMI-1640 cell culture medium containing 11 mM glucose and supplemented with 10% dialyzed fetal bovine serum (FBS) and 2 mM Glutamine. Primary MM cells were extracted using magnetic bead CD138 positive selection from MM patient bone marrow aspirates. For 13C-labeling experiments, HMCLs and primary MM cells were suspended in RPMI-1640 cell culture media containing 13C-labeled isotopes. Isotopomer analysis of glycolytic and tricarboxylic acid (TCA) cycle metabolites from HMCL and primary MM cell pellets was performed using Agilent Technologies 5975C gas chromatography-mass spectrometry. Small molecule inhibitors, AZD3965 and syrosingopine, were purchased from Selleck Chemicals and Sigma respectively. Cellular viability and proliferation were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrasodium bromide (MTT) and CCK-8 assays respectively. MCT-1 and MCT-4 antibodies for western blotting were utilized to evaluate their cell membrane expression on HMCLs. Results: The HMCLs, MM1S and RPMI-8226 as well as primary CD138+ cells from MM patient bone marrow were cultured in cell culture media containing physiological levels (1 mM) of U-13C-Lactate. The incorporation of extracellular 13C into the intracellular glycolytic and TCA cycle metabolite pool was observed (Fig 1) based on the expected isotopomeric patterns, demonstrating the Reverse Warburg Effect in MM cells. The relative contribution of carbon substrate by extracellular lactate compared to extracellular glucose was assessed in the following HMCLs: MM1S, RPMI-8226 and U266 cells by culturing in cell culture media containing 3-13C-Lactate and U-13C-Glucose. Extracellular lactate (yellow bar) contribution to the formation of TCA metabolites equaled that of glucose (red bar) based on the expected isotopomer patterns, suggesting the relative importance of extracellular lactate as an essential nutrient like glucose (Fig 2). Since MCT-1 and MCT-4 are key bidirectional cell membrane transporters of lactate in and out of cells, we explored the clinical significance of their gene expression level on clinical outcomes using the COMMPASS dataset provided by the Multiple Myeloma Research Foundation (MMRF). When MM patients were dichotomized at above or below the median of the expression levels of fragments per kilobase of transcript per million (FPKM), MCT-1 and MCT-4 overexpression conferred a worse progression free survival and overall survival (Fig 3). The MCT-1/MCT-4 protein expression was detectable across the various HMCLs: MM1S, U266 and RPMI-8226 (Fig 4). Inhibition of MCT-1 by specific inhibitor AZD3965 was able to reduce proliferation but not affect viability of HMCLs at 48 hours (Fig 5). However, dual inhibition of MCT-1/MCT-4 using syrosingopine was able to significantly reduce proliferation and decrease viability of HMCLs in a dose dependent fashion (Fig 6). Finally, dual inhibition of MCT-1/MCT-4 using syrosingopine reduced the utilization of extracellular lactate into the TCA cycle pool by HMCLs in media containing 3-13C-Lactate (Fig 7). Conclusion: Utilization of extracellular lactate via Reverse Warburg Effect phenomenon appears highly active in MM cells. Disrupting the utilization of extracellular lactate by dual inhibition of both MCT-1 and MCT-4 appears therapeutic. In the future, dual inhibition of MCT-1/MCT-4 in combination with other anti-MM therapies should be evaluated to determine synergistic therapeutic potential. Figure 1 Figure 1. Disclosures Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Antengene: Consultancy, Honoraria; Beigene: Consultancy; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding.

BackgroundShort disease duration is a predictor for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD), but studies assessing ILD progression in later disease stages are lacking. To individually tailor management of ILD in SSc patients in clinical practice it is, however, of high importance to understand disease behaviour also in patients with late disease.ObjectivesAnalyse ILD progression in SSc-ILD patients from the EUSTAR cohort segregated by subgroups of disease duration.MethodsWe segregated SSc-ILD patients into four categories of disease duration (≤3 years, >3- ≤7 years, >7- ≤15 years and >15 years after onset of Raynaud’s phenomenon). We assessed progressive ILD, defined as forced vital capacity (FVC) decline >10% or FVC decline ≥10% and FVC decline 5–10% and diffusing capacity of the lungs for carbon monoxide (DLCO) decline ≥15% (composite decline) over the first and second 12+/-3 months period after first registration (baseline) into EUSTAR. Clinical characteristics, pulmonary involvement, treatment at first registration and ILD progression were evaluated by descriptive statistics.ResultsIn total, 2258 SSc-ILD patients were included, with 469 (20.8%) having a disease duration ≤3 years, 550 (24.4%) between >3- ≤7 years, 752 (33.3%) between >7- ≤15 years and 488 (21.6%) of >15 years (Table 1). Baseline characteristics and treatment patterns differed between the four subgroups, with more younger male patients with diffuse cutaneous SSc, anti-topoisomerase I antibody and higher Rodnan skin score having ≤3 years disease duration. Lung function with FVC and DLCO were similar between the four groups (Table 1). Notably, in the first and second 12+/-3 months periods after first registration in the EUSTAR database, there were no significant difference in FVC decline >10% or composite FVC and DLCO decline within the four subgroups. For example, patients with disease duration >7- ≤15 years and >15 years frequently showed disease progression of FVC >10%: 41/347 (11.8%) and 32/228 (14%) compared to 38/244 (15.6%) and 33/273 (15.6%) for disease duration ≤3 years and >3- ≤7 years (P=0.529), respectively (Figure 1).Table 1.Demographics and baseline clinical characteristics of EUSTAR patientsDisease duration≤ years(n=460)>3- ≤7 years(n=550)>7- ≤15 years(n=752)>15 years(n=488)p-valueAge, years (SD)55 (13.5)55 (14.1)57 (13.1)61 (11.5)<0.001Male, n (%)123 (26.2)115 (20.9)112 (14.9)38 (7.8)<0.001DcSSc, n (%)228 (56.4)262 (45.8)311 (45.4)163 (31.2)<0.001ATA, n (%)236 (53.4)293 (55.9)374 (52.8)218 (48.0)0.099mRSS, mean (SD)12.3(10.1)10.4 (8.3)9.4 (8.1)8.7 (7.7)<0.001GERD, n/N (%)273 (58.7)353 (64.4)482 (64.4)344 (71.2)0.001ESR, mean (SD)26.9(21.7)24.2 (19.5)26.2 (19.9)28.3 (21.2)0.022MMF, n/N (%)33 (16.6)43 (25.2)37 (20.4)14 (9.3)0.002MTX, n/N (%)19 (10)17 (10.1)19 (10.6)8 (5.2)0.296Any IS, n/N (%)81 (38.6)89 (47.1)82 (40.8)46 (28.7)0.006FVC % pred, mean (SD)86 (20.9)87 (21.6)86 (21.4)87 (22.8)0.770DLCO % pred, mean (SD)58 (19.3)59 (19.3)59 (19.9)58 (19.7)0.405NYHA class 3&4, n (%)84 (18.6)78 (14.6)125 (17.5)22.6 (7.0)0.090Figure 1.FVC decline >10% and composite FVC and DLCO decline in the first and second 12+/-3 months within the four subgroups segregated by disease durationConclusionIt was long believed that ILD burned out in late disease stages. In our analysis of ILD progression by four disease duration categories, we showed that ILD frequently progressed also in late disease stages. This has important implications for clinical practise, as SSc patients need to be regularly monitored for ILD progression independent of disease duration.Disclosure of InterestsAnna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Paolo Airò Speakers bureau: Bristol-Myers-Squibb, Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Grant/research support from: Bristol-Myers-Squibb, Roche, Jannsen, CSL Behring, Lidia P. Ananyeva Speakers bureau: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, László Czirják Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Roche, Lilly, Grant/research support from: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Serena Guiducci: None declared, Eric Hachulla Speakers bureau: GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Consultant of: CSL Behring, GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Grant/research support from: CSL Behring, Boehringer Ingelheim, GSK, Roche-Chugai, Sanofi Genzyme, Mengtao Li: None declared, Carina Mihai Speakers bureau: MEDtalks Switzerland, Mepha, Grant/research support from: Roche, Boehringer Ingelheim, Janssen, Gabriela Riemekasten Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Petros Sfikakis Consultant of: Boehringer Ingelheim, Gabriele Valentini Consultant of: Boehringer Ingelheim, Grant/research support from: Sanofi/BMS, Otylia Kowal-Bielecka Speakers bureau: Boehringer Ingelheim, Novartis, Pfizer, Gilead Sciences, Janssen-Cilag, MEDAC, MSD, Abbvie, Sandoz, Consultant of: Boehringer Ingelheim, Health Care system Navigator, CSL Behring, MSD, Novartis, Grant/research support from: CSL Behring, Boehringer Ingelheim, Abbvie, Roche, MEDAC, Yannick Allanore Speakers bureau: Boehringer, Abbvie, Consultant of: Boehringer, Bayer, Astra-Zeneca, Prometheus, Sanofi, Genentech/Roche, Boehringer, Grant/research support from: Alpine Immunosciences, OSE Immunotherapeutics, Medsenic, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim

According to the World Health Organization (WHO), air pollution is the largest single environmental risk to public health. According to the latest estimate of this organization, 9 out of 10 people on the planet breathe polluted air. The development of industry in the relatively small Zenica valley reflected on air quality in the city of Zenica. The problem of high air pollution due to emissions of pollutants from industrial sources, traffic, and individual furnaces, burning of environmentally unsuitable fuels containing high sulfur and ash content has been present in the City of Zenica for a long time. In addition, the low wind speed during the year, which ranges up to 1.5 m/s, with unfavorable temperature inversions, causes the concentrations of pollutants in the air to reach alarmingly high values in a short period. In the wider area of the City of Zenica, air quality has been monitored since 1978 in the network of stationary stations. The paper presents results of air quality monitoring which are analyzed at the Institute Kemal Kapetanovic in Zenica for the sampling period from 01.01.2019. to 31.12.2020. years. Air quality monitoring included sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and particulate matter (PM₁₀) at three locations in the wider area of the city of Zenica. In the wider area of the City of Zenica, air quality has been monitored since 1978 in the network of stationary stations. The paper presents the processed results of air quality monitoring which are analyzed at the Institute Kemal Kapetanovic in Zenica for the sampling period from 01.01.2019 to 31.12.2020. The measured concentrations of pollutants in the ambient air indicate that during the heating season, i.e. the winter months, the air quality in the urban and suburban areas of the city of Zenica is very poor. The data show that the highest hourly concentration of sulfur dioxide was recorded in December at the measuring station AMS Tetovo in the amount of 1100.59 µg/m³, which is located in the settlement next to the metallurgical facilities of the industrial zone Zenica.  

Abstract Background and Aims Over the past decade, there has been a growing interest in classifying foods based on the extent and purpose of industrial processing according to the NOVA system, which outlines four main food categories: unprocessed and minimally processed foods, processed culinary ingredients, processed foods, and ultra-processed foods (UPFs). The latter is characterized by industrial formulations with an elevated content of additives, sugar, unhealthy fat, and sodium. Increased consumption of UPFs can worsen metabolic derangements that develop as kidney function decreases in patients with chronic kidney disease (CKD). We evaluated food intake according to the NOVA food classification system before and after a medically tailored meal intervention with plant-based food baskets for patients with CKD who had hyperkalemia at inclusion and received sodium zirconium cyclosilicate (SZC) to normalize plasma potassium. Additionally, we aimed to assess the diets’ environmental impact by evaluating the greenhouse gas emissions (GHGE) associated with these dietary changes. Method Data were based on a six-week feasibility one-arm clinical study, the HELPFUL trial (identifier: NCT04207203), that enrolled 26 adult patients with CKD stages 4 and 5, not on dialysis and with plasma potassium 5.1-6.5 mmol/L at inclusion. In the first 3 weeks, patients were guided to adhere to a low-protein and low-potassium diet with concomitant use of SZC. The following 3 weeks, patients received food baskets containing fruits, vegetables, legumes, nuts, and either white meat, fish or egg to provide a healthy low-protein high-potassium diet. To assess dietary changes, 24-hour food recalls were collected at weeks 0, 3 and 6 and subsequently classified according to the NOVA classification. The mean adequacy ratio to the dietary recommended intake (DRI) of 11 nutrients (MAR-11 score) was calculated to assess dietary quality. Furthermore, the 24-hour food recalls were linked to GHGE estimations for analysis of environmental impact using the RISE food climate database which is representative of Swedish food consumption. Statistical analyses using Friedman's test or ANOVA for repeated measures were employed to identify significant differences before and after the plant-based food basket intervention. This study was funded by Astra Zeneca. Results The plasma potassium (mmol/L) normalized after the use of SZC (week 0: 5.52 ± 0.3; week 3: 4.72 ± 0.4; week 6: 4.8 ± 0.4; P < 0.01). Figure 1 shows changes in energy intake according to the NOVA classification. A significant reduction in UPF consumption (P = 0.024) was observed. In the post-hoc analysis, the change between week 3 and 6 was borderline significant (P = 0.052) while that between week 0 and 6 was statistically significant (P = 0.008). The healthy food basket diet led to a significant increase in dietary fibers (P = 0.002) and servings of fruits (P < 0.01), vegetables (P = 0.04), nuts (P < 0.01), poultry (P = 0.02), and fish (P < 0.001) and reduced servings of red meat (P = 0.03). As a result, the MAR-11 score increased significantly (P = 0.021). The GHGE analysis of carbon dioxide equivalents revealed no differences between emissions (median and interquartile range) in week 0 [1.79 (1.24; 3.13)], week 3 [1.79 (1.47; 2.74)] and week 6 [1.87 (1.51; 2.61)]. Conclusion Delivering medically tailored healthy food baskets to patients with CKD with concomitant use of SZC led to increased dietary quality and decreased UPF intake. However, these beneficial changes were not aligned with a decrease in GHGE, highlighting the complex relationship between dietary choices and environmental impact.

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