2,389 research outputs found
UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival
International audienc
Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study
Standard treatment for osteosarcoma patients consists of a
combination of cisplatin, adriamycin, and methotrexate before surgical resection
of the primary tumour, followed by postoperative chemotherapy including
vincristine and cyclophosphamide. Unfortunately, many patients still relapse or
suffer adverse events. We examined whether common germline polymorphisms in
chemotherapeutic transporter and metabolic pathway genes of the drugs used in
standard osteosarcoma treatment may predict treatment response.
METHODOLOGY/PRINCIPAL FINDINGS: In this study we screened 102 osteosarcoma
patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number
Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin,
adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the
association of the genotypes with tumour response and overall survival. We found
that four SNPs in two ATP-binding cassette genes were significantly associated
with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI =
2.73-20.2, p-value = 5.1x10(-)(5)), and three SNPs in ABCB1, rs4148737
(per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9x10(-)(5)), rs1128503 and
rs10276036 (r(2) = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value =
7.9x10(-)(5)). Associations with these SNPs remained statistically significant
after correction for multiple testing (all corrected p-values [permutation test]
</= 0.03). CONCLUSIONS: Our findings suggest that these polymorphisms may affect
osteosarcoma treatment efficacy. If these associations are independently
validated, these variants could be used as genetic predictors of clinical outcome
in the treatment of osteosarcoma, helping in the design of individualized
therapy
Deciphering the enzymatic target of a new family of antischistosomal agents bearing a quinazoline scaffold using complementary computational tools.
A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed
The Apache Point Observatory Galactic Evolution Experiment: First Detection of High Velocity Milky Way Bar Stars
Commissioning observations with the Apache Point Observatory Galactic
Evolution Experiment (APOGEE), part of the Sloan Digital Sky Survey III, have
produced radial velocities (RVs) for ~4700 K/M-giant stars in the Milky Way
bulge. These high-resolution (R \sim 22,500), high-S/N (>100 per resolution
element), near-infrared (1.51-1.70 um; NIR) spectra provide accurate RVs
(epsilon_v~0.2 km/s) for the sample of stars in 18 Galactic bulge fields
spanning -1-32 deg. This represents the largest
NIR high-resolution spectroscopic sample of giant stars ever assembled in this
region of the Galaxy. A cold (sigma_v~30 km/s), high-velocity peak (V_GSR \sim
+200 km/s) is found to comprise a significant fraction (~10%) of stars in many
of these fields. These high RVs have not been detected in previous MW surveys
and are not expected for a simple, circularly rotating disk. Preliminary
distance estimates rule out an origin from the background Sagittarius tidal
stream or a new stream in the MW disk. Comparison to various Galactic models
suggests that these high RVs are best explained by stars in orbits of the
Galactic bar potential, although some observational features remain
unexplained.Comment: 7 pages, 4 figures, accepted for publication in ApJ Letter
Inmunoterapia con células CAR-T en hematooncologÃa pediátrica
Resumen A pesar de ser una enfermedad rara, el cáncer es la primera causa de mortalidad
por enfermedad durante la edad pediátrica en los paÃses desarrollados. En este momento, la
irrupción de nuevos tratamientos como la inmunoterapia constituye un nuevo paradigma clÃnico
y regulatorio. Uno de estos tipos de inmunoterapia es la inmunoterapia celular. En particular,
los medicamentos de terapia avanzada con receptores antigénicos quiméricos en los linfocitos T
(CAR-T), y en concreto las células CAR-T19, han supuesto un nuevo escenario en el abordaje de los tumores hematológicos, como la leucemia aguda linfoblástica y los linfomas de células tipo
B. La aprobación por las autoridades regulatorias de tisagenlecleucel y axicabtagene ciloleucel,
ha impulsado la puesta en marcha del Plan Nacional de Terapias Avanzadas-Medicamentos CART en Espana, ˜ evidenciándose no solo la conveniencia de identificar los centros más adecuados
para su administración, sino la necesidad de que estos sufran una profunda transformación para
que su actividad asistencial se extienda en algunos casos a la capacidad de fabricación propia de
este tipo de terapias. Los hospitales especializados en hematooncologÃa pediátrica tienen por
tanto el reto de evolucionar hacia un modelo asistencial que integre la inmunoterapia celular,
dotándose de capacidad propia para gestionar todos los aspectos relativos al uso, fabricación y
administración de estos nuevos tratamientos.Abstract Despite being a rare disease, cancer is the first cause of mortality due to disease
during the paediatric age in the developed countries. The current, great increase in new treatments, such as immunotherapy, constitutes a new clinical and regulatory paradigm. Cellular
immunotherapy is one of these types of immunotherapy. In particular, the advanced therapy
drugs with chimeric antigen receptors in the T-lymphocytes (CAR-T), and particularly the CART19 cells, has opened up a new scenario in the approach to haematology tumours like acute
lymphoblastic leukaemia and the B-Cell lymphomas. The approval of tisagenlecleucel and axicabtagene ciloleucel by the regulatory authorities has led to the setting up of the National Plan
for Advanced Therapies-CAR-T drugs in Spain. There is evidence of, not only the advantage of
identifying the centres most suitable for their administration, but also the need for these to
undergo a profound change in order that their healthcare activity is extended, in some cases, to
the ability for the in-house manufacture of these types of therapies. The hospitals specialised in
paediatric haematology-oncology thus have the challenge of progressing towards a healthcare
model that integrates cellular immunotherapy, having the appropriate capacity to manage all
aspects relative to their use, manufacture, and administration of these new treatments
Dynamic Edematous Response of the Human Heart to Myocardial Infarction Implications for Assessing Myocardial Area at Risk and Salvage
BACKGROUND: Clinical protocols aimed to characterize the post-myocardial
infarction (MI) heart by cardiac magnetic resonance (CMR) need to be
standardized to take account of dynamic biological phenomena evolving
early after the index ischemic event. Here, we evaluated the time course
of edema reaction in patients with ST-segment-elevation MI by CMR and
assessed its implications for myocardium-at-risk (MaR) quantification
both in patients and in a large-animal model.
METHODS: A total of 16 patients with anterior ST-segment-elevation MI
successfully treated by primary angioplasty and 16 matched controls were
prospectively recruited. In total, 94 clinical CMR examinations were
performed: patients with ST-segment-elevation MI were serially scanned
(within the first 3 hours after reperfusion and at 1, 4, 7, and 40
days), and controls were scanned only once. T2 relaxation time in the
myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau
triple inversion-recovery (ie, CMR-MaR) were evaluated at all time
points. In the experimental study, 20 pigs underwent 40-minute
ischemia/reperfusion followed by serial CMR examinations at 120 minutes
and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by
contrast-multidetector computed tomography during the index coronary
occlusion. Generalized linear mixed models were used to take account of
repeated measurements.
RESULTS: In humans, T2 relaxation time in the ischemic myocardium
declines significantly from early after reperfusion to 24 hours, and
then increases up to day 4, reaching a plateau from which it decreases
from day 7. Consequently, edema extent measured by T2-weighted short-tau
triple inversion-recovery (CMR-MaR) varied with the timing of the CMR
examination. These findings were confirmed in the experimental model by
showing that only CMR-MaR values for day 4 and day 7 postreperfusion,
coinciding with the deferred edema wave, were similar to values measured
by reference contrast-multidetector computed tomography.
CONCLUSIONS: Post-MI edema in patients follows a bimodal pattern that
affects CMR estimates of MaR. Dynamic changes in
post-ST-segment-elevation MI edema highlight the need for
standardization of CMR timing to retrospectively delineate MaR and
quantify myocardial salvage. According to the present clinical and
experimental data, a time window between days 4 and 7 post-MI seems a
good compromise solution for standardization. Further studies are needed
to study the effect of other factors on these variables.This study was partially supported by a competitive grant from the
Spanish Society of Cardiology (Proyectos de Investigacion Traslacional
en Cardiologia de la Sociedad Espanola de Cardiologia 2015, for the
project Caracterizacion tiSUlar miocaRdica con resonancia magnetica en
pacientes tras inFarto agudo de mioCardio con elevacioN de ST sometidos
a angloplastia Coronaria primaria. Estudio SURF-CNIC), by a competitive
grant from the Carlos III Institute of Health-Fondo de Investigacion
Sanitaria- and the European Regional Development Fund (ERDF/FEDER)
(PI10/02268 and PI13/01979), the Spanish Ministry of economy, industry,
and competitiveness (MEIC) and ERDF/FEDER SAF2013-49663-EXP. Dr
Fernandez-Jimenez holds a FICNIC fellowship from the Fundacio Jesus
Serra, the Fundacion Interhospitalaria de Investigacion Cardiovascular,
and the Centro Nacional de Investigaciones Cardiovasculares Carlos III
(CNIC), and Dr Aguero is a FP7-PEOPLE-2013-ITN-Cardionext fellow. This
study forms part of a Master Research Agreement between the CNIC and
Philips Healthcare, and is part of a bilateral research program between
Hospital de Salamanca Cardiology Department and the CNIC. This research
program is part of an institutional agreement between FIIS-Fundacion
Jimenez Diaz and CNIC. The CNIC is supported by the MEIC and the Pro
CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award
SEV-2015-0505).S
Lethal Interpersonal Violence in the Middle Pleistocene
Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin
Surgical treatment for colorectal cancer: Analysis of the influence of an enhanced recovery programme on long-term oncological outcomes-a study protocol for a prospective, multicentre, observational cohort study
Introduction The evidence currently available from enhanced recovery after surgery (ERAS) programmes concerns their benefits in the immediate postoperative period, but there is still very little evidence as to whether their correct implementation benefits patients in the long term. The working hypothesis here is that, due to the lower response to surgical aggression and lower rates of postoperative complications, ERAS protocols can reduce colorectal cancer-related mortality. The main objective of this study is to analyse the impact of an ERAS programme for colorectal cancer on 5-year survival. As secondary objectives, we propose to analyse the weight of each of the predefined items in the oncological results as well as the quality of life. Methods and analysis A multicentre prospective cohort study was conducted in patients older than 18 years of age who are scheduled to undergo surgery for colorectal cancer. The study involved 12 hospitals with an implemented enhanced recovery protocol according to the guidelines published by the Spanish National Health Service. The intervention group includes patients with a minimum implementation level of 70%, and the control group includes those who fail to reach this level. Compliance will be studied using 18 key performance indicators, and the results will be analysed using cancer survival indicators, including overall survival, cancer-specific survival and relapse-free survival. The time to recurrence, perioperative morbidity and mortality, hospital stay and quality of life will also be studied, the latter using the validated EuroQol Five questionnaire. The propensity index method will be used to create comparable treatment and control groups, and a multivariate regression will be used to study each variable. The Kaplan-Meier estimator will be used to estimate survival and the log-rank test to make comparisons. A p value of less than 0.05 (two-tailed) will be considered to be significant. Ethics and dissemination Ethical approval for this study was obtained from the Aragon Ethical Committee (C.P.-C.I. PI20/086) on 4 March 2020. The findings of this study will be submitted to peer-reviewed journals (BMJ Open, JAMA Surgery, Annals of Surgery, British Journal of Surgery). Abstracts will be submitted to relevant national and international meetings.The present research study was awarded a Ministerio de Ciencia e
Innovación health research project grant (PI19/00291) from the Carlos III Institute
of the Spanish National Health Service as part of the 2019 call for Strategic Action
in Health
Carcinoma-derived interleukin-8 disorients dendritic cell migration without impairing T-cell stimulation
BACKGROUND:
Interleukin-8 (IL-8, CXCL8) is readily produced by human malignant cells. Dendritic cells (DC) both produce IL-8 and express the IL-8 functional receptors CXCR1 and CXCR2. Most human colon carcinomas produce IL-8. IL-8 importance in malignancies has been ascribed to angiogenesis promotion.
PRINCIPAL FINDINGS:
IL-8 effects on human monocyte-derived DC biology were explored upon DC exposure to recombinant IL-8 and with the help of an IL-8 neutralizing mAb. In vivo experiments were performed in immunodeficient mice xenografted with IL-8-producing human colon carcinomas and comparatively with cell lines that do not produce IL-8. Allogenic T lymphocyte stimulation by DC was explored under the influence of IL-8. DC and neutrophil chemotaxis were measured by transwell-migration assays. Sera from tumor-xenografted mice contained increasing concentrations of IL-8 as the tumors progress. IL-8 production by carcinoma cells can be modulated by low doses of cyclophosphamide at the transcription level. If human DC are injected into HT29 or CaCo2 xenografted tumors, DC are retained intratumorally in an IL-8-dependent fashion. However, IL-8 did not modify the ability of DC to stimulate T cells. Interestingly, pre-exposure of DC to IL-8 desensitizes such cells for IL-8-mediated in vitro or in vivo chemoattraction. Thereby DC become disoriented to subsequently follow IL-8 chemotactic gradients towards malignant or inflamed tissue.
CONCLUSIONS:
IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation
Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.
The potential impact of targeting different components of an adverse lipid profile in populations with multiple cardiovascular risk factors is not completely clear. This study aims to assess the association between different components of the standard lipid profile with all-cause mortality and hospitalization due to cardiovascular events in a high-risk population.
This prospective registry included high risk adults over 30 years old free of cardiovascular disease (2008-2012). Diagnosis of hypertension, dyslipidemia or diabetes mellitus was inclusion criterion. Lipid biomarkers were evaluated. Primary endpoints were all-cause mortality and hospital admission due to coronary heart disease or stroke. We estimated adjusted rate ratios (aRR), absolute risk differences and population attributable risk associated with adverse lipid profiles.
51,462 subjects were included with a mean age of 62.6 years (47.6% men). During an average follow-up of 3.2 years, 919 deaths, 1666 hospitalizations for coronary heart disease and 1510 hospitalizations for stroke were recorded. The parameters that showed an increased rate for total mortality, coronary heart disease and stroke hospitalization were, respectively, low HDL-Cholesterol: aRR 1.25, 1.29 and 1.23; high Total/HDL-Cholesterol: aRR 1.22, 1.38 and 1.25; and high Triglycerides/HDL-Cholesterol: aRR 1.21, 1.30, 1.09. The parameters that showed highest population attributable risk (%) were, respectively, low HDL-Cholesterol: 7.70, 11.42, 8.40; high Total/HDL-Cholesterol: 6.55, 12.47, 8.73; and high Triglycerides/HDL-Cholesterol: 8.94, 15.09, 6.92.
In a population with cardiovascular risk factors, HDL-cholesterol, Total/HDL-cholesterol and triglycerides/HDL-cholesterol ratios were associated with a higher population attributable risk for cardiovascular disease compared to other common biomarkers.S
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