Detoxifying antitumoral drugs via nanoconjugation: the case of gold nanoparticles and cisplatin

Nanoparticles (NPs) have emerged as a potential tool to improve cancer treatment. Among the proposed uses in imaging and therapy, their use as a drug delivery scaffold has been extensively highlighted. However, there are still some controversial points which need a deeper understanding before clinical application can occur. Here the use of gold nanoparticles (AuNPs) to detoxify the antitumoral agent cisplatin, linked to a nanoparticle via a pH-sensitive coordination bond for endosomal release, is presented. The NP conjugate design has important effects on pharmacokinetics, conjugate evolution and biodistribution and results in an absence of observed toxicity. Besides, AuNPs present unique opportunities as drug delivery scaffolds due to their size and surface tunability. Here we show that cisplatin-induced toxicity is clearly reduced without affecting the therapeutic benefits in mice models. The NPs not only act as carriers, but also protect the drug from deactivation by plasma proteins until conjugates are internalized in cells and cisplatin is released. Additionally, the possibility to track the drug (Pt) and vehicle (Au) separately as a function of organ and time enables a better understanding of how nanocarriers are processed by the organism.The authors acknowledge financial support from the grants “Plan Nacional” (MAT2009-14734-C02-01 and MAT2009-14734-C02-02) and NANOBIOMED-CONSOLIDER (CSD2006-00012) from the Spanish Government. Also grants VALTEC09-2-0085, VALTEC09-2-0089, and 2009-SGR-776 from the Catalan GovernmentS

SEOM-GEINO clinical guidelines for high-grade gliomas of adulthood (2022)

High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5-10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life

In silico validation of RNA-Seq results can identify gene fusions with oncogenic potential in glioblastoma

RNA-Sequencing (RNA-Seq) can identify gene fusions in tumors, but not all these fusions have functional consequences. Using multiple data bases, we have performed an in silico analysis of fusions detected by RNA-Seq in tumor samples from 139 newly diagnosed glioblastoma patients to identify in-frame fusions with predictable oncogenic potential. Among 61 samples with fusions, there were 103 different fusions, involving 167 different genes, including 20 known oncogenes or tumor suppressor genes (TSGs), 16 associated with cancer but not oncogenes or TSGs, and 32 not associated with cancer but previously shown to be involved in fusions in gliomas. After selecting in-frame fusions able to produce a protein product and running Oncofuse, we identified 30 fusions with predictable oncogenic potential and classified them into four non-overlapping categories: six previously described in cancer; six involving an oncogene or TSG; four predicted by Oncofuse to have oncogenic potential; and 14 other in-frame fusions. Only 24 patients harbored one or more of these 30 fusions, and only two fusions were present in more than one patient: FGFR3::TACC3 and EGFR::SEPTIN14. This in silico study provides a good starting point for the identification of gene fusions with functional consequences in the pathogenesis or treatment of glioblastoma

Lineamientos para una metodología de identificación de estilos de aprendizaje aplicables al sector agropecuario colombiano

In Colombia, one of the deficiencies of technology transfer processes has been the lack of strategies that allow identifying the way producers learn, which, in turn, is reflected in the low implementation of the practices suggested in training processes. For this reason, the aim of this study was to analyze the research carried out on the identification of learning styles to generate a methodological proposal suitable to be implemented in the agricultural sector, which contributes to improving the effectiveness of the transfer processes. Models that have been studied at a global level were identified and used as input to build a methodology with four dimensions (motivational, perceptive, strategic, and social) that respond to the characteristics of the rural context and the training processes of producers. These results highlight the importance of identifying learning styles before carrying out a training process to achieve the implementation of new technologies by agricultural producers.En Colombia, una de las deficiencias en los procedimientos de transferencia de tecnología ha sido la falta de estrategias que permitan identificar la forma en que aprenden los productores, lo que se ha reflejado en la baja implementación de prácticas sugeridas en los procesos de capacitación. El objetivo de este estudio fue analizar la literatura existente sobre identificación de estilos de aprendizaje para generar una propuesta metodológica aplicable al sector agropecuario que contribuya a mejorar la efectividad de los procesos de transferencia. Se identificaron modelos estudiados a nivel global, los cuales se usaron como insumo para construir una metodología con cuatro dimensiones (motivacional, perceptiva, estratégica y social) que responden a las características del contexto rural y los procesos de capacitación de productores. Los resultados permiten resaltar la importancia de identificar estilos de aprendizaje antes de llevar a cabo un proceso de formación para aumentar la implementación de nuevas tecnologías por parte de productores agropecuarios

First Colombian Multicentric Newborn Screening for Congenital Toxoplasmosis

Congenital toxoplasmosis can result in permanent sequel as blindness or neurological damage in children and it seems to be more severe in South America than in other continents. There is a lack of information about this frequency in Colombia, where no control program is established, although it is a recognized cause of potentially preventable congenital blindness. We propose the first Colombian multicentric study to determine the frequency and impact of congenital toxoplasmosis. More than 15,000 newborns in seven cities were studied. Newborns were tested at birth by doing a cord blood test for toxoplasmosis. Additionally, children from mothers with history of toxoplasmosis acquired during pregnancy were recalled for a follow-up. The program identified fifteen children otherwise undiagnosed; three of these children died as consequence of congenital toxoplasmosis. The frequency of the congenital infection varied significantly between cities, being higher in Armenia and Florencia, intermediate in Bogota, Bucaramanga and Barranquilla and very low in western cities such as Cucuta and Riohacha. For the first time a significant correlation was found between mean rainfall at the city and the incidence of this congenital infection

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 +/- 19.2 years) recruited from 29 international centers. RESULTS At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% +/- 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of <= 35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

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

El Tratamiento médico de la recidiva del glioblastoma: experiencia del hospital de Sant Pau 2005-2014

La terapia del glioblastoma combinando tres tratamientos (cirugía, radioterapia y quimioterapia) ha logrado encontrar un beneficio aunque limitado en la supervivencia de pacientes con glioblastoma multiforme, alcanzando una mediana de supervivencia de alrededor de 12 meses cuando se logra aplicar a todos los pacientes. La realidad asistencial es que en los hospitales se trata gran variedad de pacientes (la tendencia es ver pacientes más mayores y con gran número de comorbilidades). Este estudio tiene como objetivo reportar los resultados asistenciales en una serie, sin ningún sesgo de selección,de 139 pacientes afectos de glioblastoma atendidos en el Hospital de Sant Pau entre el año 2005 y 2014 Los resultados que reportamos incrementan la supervivencia global casi 5 meses respecto a otra serie del mismo hospital de los 5 años precedentes. Se aplican diferentes tipos de fármacos asistencialmente a los pacientes afectos de glioblastoma recidivado sin que haya estudios concluyentes que delimiten un tratamiento claramente estándar en segunda línea (como si lo hay para los pacientes en primera línea). Los tratamientos cuando el glioblastoma recurre aportan un beneficio clínico modesto (aumento de pocos meses de supervivencia) a costa de una posible afectación de la calidad de vida secundaria a la toxicidad. En este estudio se describen las líneas aplicadas en la recidiva y su posible beneficio clínico.Concluimos que la aplicación de segundas líneas de tratamiento puede incrementar la supervivencia en enfermos seleccionados. Un objetivo complementario del anterior es cuantificar los costes globales del tratamiento en euros delimitando los gastos que ha supuesto el tratamiento tras la primera línea. El coste global por enfermo (incluyendo cirugía, radioterapia y quimioterapia) es de 17985 euros. El gasto medio en quimioterapia total de todos los casos tratados fue de 7929 euros. El coste extra por enfermo tratado en segunda línea o líneas posteriores fue de 5630 euros. Otro de los objetivos de la tesis es delimitar en un estudio fase II realizado de forma prospectiva con pacientes recurrentes la eficacia de un fármaco inhibidor de EGFR (erlotinib).Los pacientes fueron seleccionados tras evidenciar que expresaban en inmunohistioquímica EGFRvIII y PTEN conservado .Se alcanzó una supervivencia global de 7,1 meses y una supervivencia libre de progresión de 3,9 meses. La toxicidad fue mínima (diarrea y toxicidad cutánea, ninguna grado3/4) .El estudio fue negativo y no reprodujo los resultados previos publicados por lo que concluimos que no puede considerarse el uso asistencial de los inhibidores de EGFR en este subgrupo de glioblastomas en la recurrencia dado el alto precio y limitada eficacia.Therapy for glioblastoma combining three treatments (surgery, radiotherapy and chemotherapy) has achieved a limited survival in patients with glioblastoma multiform, reaching a median of about 12 months when applied in all patients. The health care reality is that hospitals treat patients with a wide range of disease, many of whom are older patients with several comorbidites. The aim of this study was to determine the results in a series of 139 patients with glioblastoma, without any selection bias, attended at the Hospital de la Santa Creu I Sant Pau from 2005 to 2014. We found an increase in global survival of almost 5 months in comparison with another series at the same hospital from the previous five years. Patients with recurrent glioblastoma in the study group received a range of treatments and the results are not sufficiently conclusive to delimit a clear standard treatment, as in the case of patients receiving first-line therapy. Treatment for recurrent glioblastoma yields a modest clinical benefit by increasing survival by a few months but it has a minimal negative effect on the quality of life due to toxicity. In this study we describe the therapeutic approaches used and discuss their possible clinical benefit. We conclude that the application of second lines of treatment can increase survival in selected patients. A complementary aim of the study was to quantify the global costs of treatment in Euros. The global cost per patient (including surgery, radiotherapy and chemotherapy) was 17985 Euros. The average expense for total chemotherapy for the whole group was 7929 Euros. The extra cost for second- or third-line therapy was 5630 Euros. Another aim of this thesis, was to delimit the efficiency of EGFR -targeted treatment (erlotinib) in a phase II study in patients with recurrence. Patients were selected when immunohistochemistry showed EGFRvIII and preserved PTEN. We observed a global survival of 7,1 months and progression-free survival of 3,9 months. Toxicity was minimal (no grade 3-4 diarrhea or skin toxicity reported). The poor results of this study do not support the use of EGFRs in this subgroup of glioblastomas in view of their high price and limited efficiency

Pseudoprogression as an adverse event of glioblastoma therapy

We explored predictive factors of pseudoprogression (PsP) and its impact on prognosis in a retrospective series of uniformly treated glioblastoma patients. Patients were classified as having PsP, early progression (eP) or neither (nP). We examined potential associations with clinical, molecular, and basal imaging characteristics and compared overall survival (OS), progression-free survival (PFS), post-progression survival (PPS) as well as the relationship between PFS and PPS in the three groups. Of the 256 patients studied, 56 (21.9%) were classified as PsP, 70 (27.3%) as eP, and 130 (50.8%) as nP. Only MGMT methylation status was associated to PsP. MGMT methylated patients had a 3.5-fold greater possibility of having PsP than eP (OR: 3.48; 95% CI: 1.606-7.564; P = 0.002). OS was longer for PsP than eP patients (18.9 vs. 12.3 months; P = 0.0001) but was similar for PsP and nP patients (P = 0.91). OS was shorter-though not significantly so-for PsP than nP patients (OS: 19.5 vs. 27.9 months; P = 0.63) in methylated patients. PPS was similar for patients having PsP, eP or nP (PPS: 7.2 vs. 5.4 vs. 6.7; P = 0.43). Neurological deterioration occurred in 64.3% of cases at the time they were classified as PsP and in 72.8% of cases of eP (P = 0.14). PsP confounds the evaluation of disease and does not confer a survival advantage in glioblastoma