Comparison of the degree of exercise tolerance in children after surgical treatment of complex cardiac defects, assessed using ergospirometry and the level of brain natriuretic peptide

Children who underwent surgery for complex congenital heart defects present worse exercise capacity than their healthy peers. In adults and adolescents, heart failure is assessed on the basis of clinical symptoms using the New York Heart Association (NYHA) score, while in an infant Ross scale; heart failure can also be evaluated by other parameters. The purpose of this study was to compare the degree of exercise tolerance in children after surgery for complex heart defects, assessed by the ratio of maximum oxygen uptake (VO2max) and the brain natriuretic peptide (N-terminal fragment of the prohormone brain-type natriuretic peptide [NT-proBNP]) concentration. The study group consisted of 42 children, ages 9 to 17 years (mean 14.00 ± 2.72). Among them there were 22 children with tetralogy of Fallot (ToF) after total correction, 18 children with transposition of the great arteries (d-TGA) after the arterial switch operation, and 2 children with single ventricle (SV) after the Fontan operation. All but 1 child were in NYHA class I. The control group consisted of 20 healthy children. Outcomes of interest were the ratio of VO2max, determined during ergospirometry, and the level of NT-proBNP. The statistical analysis was performed and the groups were considered significantly different for P < 0.05. There was no statistically significant correlation between NT-proBNP and maximum oxygen uptake (VO2) kg(−1) min(−1) in the study group compared with the control group. The VO2max in the test group had a mean value less (34.6 ± 8.0) than controls (38.4 ± 7.7), and the differences were statistically significant (P = 0.041). In contrast, the average concentration of NT-proBNP in the study group was higher than controls (117.9 ± 74.3 vs 18.0 ± 24.5), and these differences were statistically significant (P < 0.001). After operations for complex heart defects (ToF, TGA, and SV), children have worse heart function parameters and exercise capacity than the healthy population. To control this, we recommend postoperative ergospirometry and determination of NT-proBNP concentrations

Reduced expression of innate immunity-related genes in lymph node metastases of luminal breast cancer patients

Immune system plays a dual role in cancer by either targeting or supporting neoplastic cells at various stages of disease, including metastasis. Yet, the exact immune-related transcriptome profiles of primary tumours (PT) and lymph node metastases (LNM) and their evolution during luminal breast cancer (BCa) dissemination remain undiscovered. In order to identify the immune-related transcriptome changes that accompany lymphatic spread, we analysed PT-LNM pairs of luminal BCa using NanoString technology. Decrease in complement C3—one of the top-downregulated genes, in LNM was validated at the protein level using immunohistochemistry. Thirty-three of 360 analysed genes were downregulated (9%), whereas only 3 (0.8%) upregulated in LNM when compared to the corresponding PT. In LNM, reduced expression was observed in genes related to innate immunity, particularly to the complement system (C1QB, C1S, C1R, C4B, CFB, C3, SERPING1 and C3AR1). In validation cohort, complement C3 protein was less frequently expressed in LNM than in PT and it was associated with worse prognosis. To conclude, local expression of the complement system components declines during lymphatic spread of non-metastatic luminal BCa, whilst further reduction of tumoral complement C3 in LNM is indicative for poor survival. This points to context-dependent role of complement C3 in BCa dissemination.publishedVersio

Utjecaj kronične istodobne izloženosti olovu, kadmiju i manganu na oksidativni stres u jetri i srcu štakora

The aim of this study was to assess the effects of chronic combined exposure to low, environmental doses of Cd, Pb, and Mn on oxidative stress in the liver and heart of rats and on their liver function parameters. Male Wistar rats were divided randomly into eight groups. For nine months controls were receiving drinking water alone, whereas the exposed groups were receiving drinking water with Pb (0.2 mg L-1), Cd (1 mg L-1), and Mn (2 mg L-1) alone or in combinations. Malondialdehyde (MDA) significantly increased in both heart and liver of the animals after combined exposure to metals. Heart MDA correlated with blood Cd, Pb, and Mn and liver MDA with blood Cd. Aspartate aminotransferase (AST) activity and bilirubin concentration also increased significantly in the animal group exposed to all three metals and correlated positively with blood Cd, Pb, and Mn. Our study has confirmed the synergistic effect of the Cd, Mn, and Pb combination on the increase in heart MDA. A similar synergy was observed for Pb+Mn in the increase of serum alanine aminotransferase (ALT) activity as an indicator of liver function.Cilj je ovog istraživanja bio ocijeniti učinke kronične izloženosti kombinaciji Cd, Pb i Mn u niskim dozama kakve su u okolišu na oksidativni stres u jetrima i srcu štakora te na pokazatelje jetrene funkcije. U tu smo svrhu mužjake Wistar štakora nasumce podijelili u osam skupina, od kojih je kontrolna pila čistu vodu, a izložene skupine vodu pomiješanu s olovom (0,2 mg L-1), kadmijem (1 mg L-1) i manganom (2 mg L-1), zasebno ili u kombinacijama. Koncentracija malondialdehida (MDA) značajno se povećala u oba organa životinja izloženih kombinacijama metala. Srčani MDA korelirao je s razinama kadmija, olova i mangana u krvi, a jetreni MDA s razinom kadmija u krvi. Aktivnost aspartat aminotransferaza (AST) i koncentracije bilirubina također su bile značajno povišene u skupini izloženoj svim trima metalima te su korelirale s razinama kadmija, olova i mangana u krvi. Rezultati istraživanja potvrdili su da zajedno ova tri metala djeluju na povećanje MDA u srcu. Slična je sinergija zamijećena i između olova i mangana s obzirom na povećanje razine alanin aminotransferaze (ALT) u serumu, koji je pokazatelj jetrene funkcije

Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial

Background: The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina.Methods: Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS II–IV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (≥ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment.Results: The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period.Conclusions: Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia

Genetically determined telomere length and multiple myeloma risk and outcome

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL.Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.Univerity of PisaHelmholtz AssociationInstituto de Salud Carlos III PI12/02688 PI17/02276Instituto de Salud Carlos IIIEuropean CommissionFEDER funds-a way to build Europe PI14-00613Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723Projekt DEA

The Pediatric Choroidal and Ciliary Body Melanoma Study A Survey by the European Ophthalmic Oncology Group

Purpose: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Design: Retrospective, multicenter observational study. Participants: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. Methods: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Main Outcome Measures: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Results: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. Conclusions: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups. (C) 2016 by the American Academy of Ophthalmology.Peer reviewe

Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization

Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data.Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte hemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP corre lated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+ IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4 ) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB).This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Analysis of ibrutinib efficacy in a subgroup of chronic lymphocytic leukemia patients with 17p deletion: observational study of the Polish Adult Leukemia Group (PALG)

BackgroundThe 17p deletion is regarded as the strongest poor prognostic factor in chronic lymphocytic leukemia (CLL). Results of recently performed clinical trials have suggested that ibrutinib significantly improves the outcome in this patient group.AimThe study aimed at analyzing the efficacy and adverse events profile of ibrutinib monotherapy in CLL patients with 17p deletion treated in routine clinical practice outside clinical trials.Materials and MethodsClinical response and adverse events profile of ibrutinib monotherapy were assessed in thirty-five CLL patients with 17p deletion treated within the ibrutinib named patients program in Poland.ResultsOverall response rate was 80% (28/35 patients) with median observation time of 24.2 months (range 0,1 – 30,9). Complete remission was observed in 5 patients (14.3%), partial remission in 11 (31.4%), partial remission with lymphocytosis in 13 (37.1%), whereas stable disease and progression was noted in 4 (11.4%) and 1 (2.9%) respectively. Response was not assessed in 1 patient. Median progression-free survival was 29.5 months, whereas median overall survival was not reached. Eleven patients died (7 because of infection, 1 of CLL progression, 1 of sudden cardiac death, 1 of disseminated breast cancer and 1 of unknown causes). In 13 patients (37.1%) at least one 3 or 4 grade adverse event occurred. In 11 patients (31.4%) the treatment was temporary withheld or the dose reduced due to adverse events.ConclusionIbrutinib is characterized by high clinical efficacy and acceptable toxicity in CLL patients with 17p deletion in daily clinical practice