58 research outputs found
Binding of the anticancer drug BI-2536 to human serum albumin. A spectroscopic and theoretical study
BI-2536 is a potent Polo-like kinase inhibitor which induces apoptosis in diverse human cancer cell lines. The binding affinity of BI-2536 for human serum albumin (HSA) protein may define its pharmacokinetic and pharmacodynamic profile. We have studied the binding of BI-2536 to HSA by means of different spectroscopic techniques and docking calculations. We have experimentally observed that the affinity of BI-2536 for HSA is higher than that of other common HSA binding drugs. Therefore, it can be postulated that the drug dose should be increased to achieve a certain concentration of free drug in plasma, although BI-2536 could also reach tumour tissues by uptaking HSA/BI-2536 complex. Only a single binding site on HSA has been observed for BI-2536 which seems to correspond to the subdomain IIA pocket. The formation of the HSA/BI-2536 complex is a spontaneous and entropy-driven process that does not cause a significant change of the secondary structure of the protein. Its endothermic character could be related to proton release. Thermodynamic analysis showed that the main protein-drug interactions are of the van der Waals type although the presence of amide and ether groups in BI-2536 could also allow H-bonding with some residues in the subdomain IIA pocket
Shedding light on the binding mechanism of kinase inhibitors BI-2536, Volasetib and Ro-3280 with their pharmacological target PLK1
In the present work, the interactions of the novel kinase inhibitors BI-2536, Volasetib (BI-6727) and Ro-3280 with the pharmacological target PLK1 have been studied by fluorescence spectroscopy and molecular dynamics calculations. High Stern-Volmer constants were found in fluorescence experiments suggesting the formation of stable protein-ligand complexes. In addition, it was observed that the binding constant between BI-2536 and PLK1 increases about 100-fold in presence of the phosphopeptide Cdc25C-p that docks to the polo box domain of the protein and releases the kinase domain. All the determined binding constants are higher for the kinase inhibitors than for their competitor for the active center (ATP) being BI-2536 and Volasertib the inhibitors that showed more affinity for PLK1. Calculated binding free energies confirmed the higher affinity of PLK1 for BI-2536 and Volasertib than for ATP. The higher affinity of the inhibitors to PLK1 compared to ATP was mainly attributed to stronger van der Waals interactions. Results may help with the challenge of designing and developing new kinase inhibitors more effective in clinical cancer therapy
Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium
Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease.
The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2,
FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and
0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry
(P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a
gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085)
and a modest effect on IL1β levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057
and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with
a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed
that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or
macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10−7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease
in seropositive patients (PRF+ = 2.46•10−8) whereas no prediction was detected in seronegative patients
(PRF− = 0.36). Although the predictive ability of the model was substantially lower in the replication
population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive
disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid
hormone-related polymorphisms with erosive disease
Inter-Rater Variability in the Evaluation of Lung Ultrasound in Videos Acquired from COVID-19 Patients
12 páginas, 7 figuras, 1 tablaLung ultrasound (LUS) allows for the detection of a series of manifestations of COVID-19,
such as B-lines and consolidations. The objective of this work was to study the inter-rater reliability
(IRR) when detecting signs associated with COVID-19 in the LUS, as well as the performance of the
test in a longitudinal or transverse orientation. Thirty-three physicians with advanced experience in
LUS independently evaluated ultrasound videos previously acquired using the ULTRACOV system
on 20 patients with confirmed COVID-19. For each patient, 24 videos of 3 s were acquired (using
12 positions with the probe in longitudinal and transverse orientations). The physicians had no
information about the patients or other previous evaluations. The score assigned to each acquisition
followed the convention applied in previous studies. A substantial IRR was found in the cases of
normal LUS (κ = 0.74), with only a fair IRR for the presence of individual B-lines (κ = 0.36) and for
confluent B-lines occupying 50%
(κ = 0.50). No statistically significant differences between the longitudinal and transverse scans were
found. The IRR for LUS of COVID-19 patients may benefit from more standardized clinical protocols.This research was partially funded by CDTI (Spanish acronym: Centre for Industrial Tech-
nological Development), funding number COI-20201153. Partially supported by the Google Cloud
Research Credits program with the funding number GCP19980904, by the project RTI2018-099118-
A-I00 founded by MCIU/AEI/FEDER UE and by the European Commission–NextGenerationEU,
through CSIC’s Global Health Platform (PTI Salud Global)
Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)
This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer 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)
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3
ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC > 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3
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