Retinoic acid-induced differentiation sensitizes myeloid progenitors cells to ER stress

The clonal expansion of hematopoietic myeloid precursors blocked at different stages of differentiation characterizes the acute myeloid leukemia (AML) phenotype. A subtype of AML, acute promyelocytic leukemia (APL), characterized by the chimeric protein PML-RARα is considered a paradigm of differentiation therapy. In this leukemia subtype the all-trans-retinoic acid (RA)-based treatments are able to induce PML-RARα degradation and leukemic blast terminal differentiation [1-2]. Granulocytic differentiation of APL cells driven by RA triggers a physiological Unfolded Protein Response (UPR), a series of pathways emanating from the ER in case of ER stress, which ensues when higher protein folding activity is required as during differentiation. We show here that, although mild, the ER stress induced by RA is sufficient to render human APL cell lines and primary blasts very sensitive to low doses of Tunicamycin (Tm), an ER stress inducing drug, at doses that are not toxic in the absence of RA. Importantly only human progenitors cells derived from APL patients resulted sensitive to the combined treatment with RA and Tm whereas those obtained from healthy donors were not affected. We also show that the UPR pathway downstream of PERK plays a major protective role against ER stress in differentiating cells and, by using a specific PERK inhibitor, we potentiated the toxic effect of the combination of RA and Tm. In conclusion, our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML

Performance comparison of two commercial human whole-exome capture systems on formalin-fixed paraffin-embedded lung adenocarcinoma samples

Background: Next Generation Sequencing (NGS) has become a valuable tool for molecular landscape characterization of cancer genomes, leading to a better understanding of tumor onset and progression, and opening new avenues in translational oncology. Formalin-fixed paraffin-embedded (FFPE) tissue is the method of choice for storage of clinical samples, however low quality of FFPE genomic DNA (gDNA) can limit its use for downstream applications. Methods: To investigate the FFPE specimen suitability for NGS analysis and to establish the performance of two solution-based exome capture technologies, we compared the whole-exome sequencing (WES) data of gDNA extracted from 5 fresh frozen (FF) and 5 matched FFPE lung adenocarcinoma tissues using: SeqCap EZ Human Exome v.3.0 (Roche NimbleGen) and SureSelect XT Human All Exon v.5 (Agilent Technologies). Results: Sequencing metrics on Illumina HiSeq were optimal for both exome systems and comparable among FFPE and FF samples, with a slight increase of PCR duplicates in FFPE, mainly in Roche NimbleGen libraries. Comparison of single nucleotide variants (SNVs) between FFPE-FF pairs reached overlapping values >90 % in both systems. Both WES showed high concordance with target re-sequencing data by Ion PGM\u2122 in 22 lung-cancer genes, regardless the source of samples. Exon coverage of 623 cancer-related genes revealed high coverage efficiency of both kits, proposing WES as a valid alternative to target re-sequencing. Conclusions: High-quality and reliable data can be successfully obtained from WES of FFPE samples starting from a relatively low amount of input gDNA, suggesting the inclusion of NGS-based tests into clinical contest. In conclusion, our analysis suggests that the WES approach could be extended to a translational research context as well as to the clinic (e.g. to study rare malignancies), where the simultaneous analysis of the whole coding region of the genome may help in the detection of cancer-linked variants

Exploring the relationship between accommodation and intraocular pressure: a systematic literature review and meta-analysis

purposeto investigate the relationship between accommodation and intraocular pressure (IOP).methods systematic literature search and meta-analysis following PRISMA guidelines was conducted on studies analyzing the relationship between accommodation and intraocular pressure. after removal of duplicates, title and abstract screening, full-text analysis was performed to select relevant articles and meta-analysis was then conducted as well.ResultsOf the 1357 records identified, 17 met the selection criteria and were included. Overall, all studies showed that accommodation can influence IOP levels and meta-analysis indicated a significant IOP reduction of 1.10 mmHg (95%CI, -1.77; -0.42) following accommodative stimulus in healthy individuals, albeit with high heterogeneity among studies. differences in IOP changes between emmetropic and progressing myopic individuals were not significant. controversial results were obtained in patients with glaucoma with significantly lower IOP fluctuations being noted in eyes with previous trabeculectomy; however, the clinical heterogeneity of enrolled patients among studies made it not possible to combine results. type of accommodative task, extraocular muscle contraction, head and body position all could potentially play a role in the measured IOP changes with, interestingly, near reading on a smartphone suggesting IOP increase.conclusion accommodation has an impact on IOP measurements and, overall, determines IOP decrease in healthy individuals. while such variations might not hold clinical significance for individuals in good health, their impact in patients with glaucoma should be considered. further studies focused on specific components of such relationship are required to elucidate their individual impact and to define their potential role as non-pharmacological strategies to reduce IOP levels in selected patient categories

Influencia del patrón de crecimiento y la edad sobre algunas propiedades de la madera en sauces

El objetivo del trabajo fue determinar la influencia del crecimiento y la edad sobre la longitud de fibras y densidad básica de la madera de 3 sauces. Los árboles muestreados fueron obtenidos de plantaciones comerciales y estaqueros conducidos en el campo Las Carabelas, perteneciente a Papel Prensa SA, en el Delta Bonaerense ubicado1ª sección de islas, Buenos Aires (34º 30’ LS y 59 ºW). Los clones estudiados fueron: Salix matsudana x Salix alba `NZ 26992´, Salix babylonica x Salix alba `A 250-33´ y sauce americano (S. babylonica var sacramenta). Se midieron los diámetros a la altura de pecho (DAP) y se establecieron clases diamétricas. Se apearon 18 árboles por clon (6 por clase diamétrica). Las variables medidas fueron el ancho de los anillos de crecimiento, la densidad básica de la madera y la longitud de fibras. Esta dos últimas en 3 ó 4 posiciones radiales (edades). Se realizaron ANOVAS tomando como fuentes de variación a la clase diamétrica y la posición radial de muestreo. Se construyeron curvas de incrementos corrientes anuales (ICA) por clon y clase diamétrica. Los patrones de crecimiento (ICA) son diferentes según los clones. Dentro de cada clon la producción máxima de madera se produce a diferentes edades según el sitio y la clase diamétrica. El comportamiento del 26992 es similar para las 3 clases diamétricas. El sauce híbrido 250-33 se destaca por sus altos crecimientos en las edades próximas al arranque (2 y 3 años) diferenciándose según las clases diamétricas, en cambio el sauce americano produce un incremento máximo a los 4 años para todas las clases, con crecimientos igualmente importantes a los 3 y 5 años. El crecimiento, medido como clase diamétrica, tuvo influencia en la densidad del híbrido 26992 y no la tuvo para el 250-33 y el americano. Si consideramos la longitud de fibras el resultado se invierte, siendo significativa la influencia de la clase diamétrica en el 250-33 y americano, y no significativa en el 26992. La edad fue una fuente significativa de variación para ambas variables (densidad y longitud) en los tres clones. Para los 3 sauces y las 2 propiedades de la madera consideradas, la producción de árboles de mayor tasa de crecimiento produce mayor ganancia en madera de calidad, además de volumen. Los 3 sauces considerados presentaron diferencias en cuanto al tipo de crecimiento y porcentaje de ganancias de madera de calidad.Facultad de Ciencias Agrarias y Forestale

Burden of acute otitis media in primary care pediatrics in Italy: A secondary data analysis from the Pedianet database

Background: The incidence of acute otitis media (AOM) vary from country to country. Geographical variations together with differences in study designs, reporting and settings play a role. We assessed the incidence of AOM in Italian children seen by primary care paediatricians (PCPs), and described the methods used to diagnose the disease.Methods: This secondary data analysis from the Pedianet database considered children aged 0 - 6 years between 01/2003 and 12/2007. The AOM episodes were identified and validated by means of patient diaries. Incidence rates/100 person-years (PY) were calculated for total AOM and for single or recurrent AOM.Results: The 92,373 children (52.1% males) were followed up for a total of 227,361 PY: 23,039 (24.9%) presented 38,241 episodes of AOM (94.6% single episodes and 5.4% recurrent episodes). The total incidence rate of AOM in the 5-year period was 16.8 episodes per 100 PY (95% CI: 16.7-16.9), including single AOM (15.9 episodes per 100 PY; 95% CI: 15.7-16.1) and recurrent AOM (0.9 episodes per 100 PY; 95% CI: 0.9-0.9). There was a slight and continuously negative trend decrease over time (annual percent change -4.6%; 95%CI: -5.3, -3.9%). The AOM incidence rate varied with age, peaking in children aged 3 to 4 years (22.2 episodes per 100 PY; 95% CI 21.8-22.7). The vast majority of the AOM episodes (36,842/38,241, 96.3%) were diagnosed using a static otoscope; a pneumatic otoscope was used in only 3.7%.Conclusions: Our data fill a gap in our knowledge of the incidence of AOM in Italy, and indicate that AOM represents a considerable burden for the Italian PCP system. Educational programmes concerning the diagnosis of AOM are needed, as are further studies to monitor the incidence in relation to the introduction of wider pneumococcal conjugate vaccines

Glucocorticoid receptors modulate dendritic spine plasticity and microglia activity in an animal model of Alzheimer's disease

Abstract Chronic exposure to high circulating levels of glucocorticoids (GCs) may be a key risk factor for Alzheimer's Disease (AD) development and progression. In addition, hyper-activation of glucocorticoid receptors (GRs) induces brain alterations comparable to those produced by AD. In transgenic mouse models of AD, GCs increase the production of the most important and typical hallmarks of this dementia such as: Aβ40, Aβ42 and tau protein (both the total tau and its hyperphosphorylated isoforms). Moreover, GCs in brain are pivotal regulators of dendritic spine turnover and microglia activity, two phenomena strongly altered in AD. Although it is well-established that GCs primes the neuroinflammatory response in the brain to some stimuli, it is unknown whether or how GRs modulates dendritic spine plasticity and microglia activity in AD. In this study, we evaluated, using combined Golgi Cox and immunofluorescence techniques, the role of GR agonists and antagonists on dendritic spine plasticity and microglia activation in hippocampus of 3xTg-AD mice. We found that dexamethasone, an agonist of GRs, was able to significantly reduce dendritic spine density and induced proliferation and activation of microglia in CA1 region of hippocampus of 3xTg-AD mice at 6 and 10 months of age. On the contrary, the treatment with mifepristone, an antagonist of GRs, strongly enhanced dendritic spine density, decreased microglia density and improved the behavioural performance of 3xTg-AD mice. Additionally, primary microglial cells in vitro were directly activated by dexamethasone. Together, these data demonstrate that stress exacerbates AD and promotes a rapid progression of the pathology acting on both neurons and glial cells, supporting an important pro-inflammatory role of GC within CNS in AD. Consequently, these results further strengthen the need to test clinical interventions that correct GCs dysregulation as promising therapeutic strategy to delay the onset and slow down the progression of AD

Columnar liquid crystalline triphenylene-bis(dithiolene)nickel complexes. Soft photothermal materials

This work reports new soft photothermal materials based on liquid crystalline nickel bis(dithiolene) complexes bearing pentakis(dodecyloxy)triphenylene units in which the triphenylene core and the metal complex are linked through –(CH2)n– (n = 2, 4, 10) connectors. The mesomorphic properties of these materials can be modulated by the length of the linker. All the complexes, except the derivative with the longest linker, show columnar mesomorphism, characterized by polarized optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray scattering studies. The structure of the mesophases contains segregated organic and inorganic columns supported respectively by π-stacking of the triphenylene discs and weak intermolecular nickel–sulfur interactions. The photothermal activity was studied on the complex with n = 2. Under laser irradiation with a power density of 0.098 W cm−2 for just over a minute an increase in temperature of ΔT = 50 °C was achieved. This produced the melting of the crystalline solid to give rise to the columnar mesophase, where, interestingly, the photothermal effect was enhanced. Quantum chemical calculations have also been performed to gain insight into the supramolecular self-assembled columnar structure at the molecular level, as well as into the photothermal behavior.This work was sponsored by the Ministerio de Ciencia e Innovación (PID2020-118547GB-I00/AEI/10.13039/501100011033). E. D. thanks MECD for a FPU grant. The authors thankfully acknowledge the computer resources at Tirant and Lusitania II and the Technical support provided by Universitat de València (FI-2022-2-005, QHS-2023-1-0010) and Cénits-COMPUTAEX (FI-2022-1-0009, FI-2022-3-0008). This research has made use of the high performance computing resources of the Castilla y León Supercomputing Center (SCAYLE, www.scayle.es), financed by the European Regional Development Fund (ERDF). This work was also supported by the Comunidad de Madrid and Universidad Autónoma de Madrid (SI3/PJI/2021-00211) and D.H.O is grateful for a Ramón y Cajal Fellowship Grant RYC2022-036732-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF investing in your future”. This work was also financially supported by the Basque Government (project IT1458-22)

Measurement of the forward Z boson production cross-section in pp collisions at s=13\sqrt{s} = 13 TeV

A measurement of the production cross-section of Z bosons in pp collisions at $\sqrt{s} = 13$ TeV is presented using dimuon and dielectron final states in LHCb data. The cross-section is measured for leptons with pseudorapidities in the range $2.0 \eta 4.5$, transverse momenta $p_\text{T} 20$ GeV and dilepton invariant mass in the range $60 m(\ell\ell) 120$ GeV. The integrated cross-section from averaging the two final states is \begin{equation*}\sigma_{\text{Z}}^{\ell\ell} = 194.3 \pm 0.9 \pm 3.3 \pm 7.6\text{ pb,}\end{equation*} where the first uncertainty is statistical, the second is due to systematic effects, and the third is due to the luminosity determination. In addition, differential cross-sections are measured as functions of the Z boson rapidity, transverse momentum and the angular variable $\phi^*_\eta$

Performance Assessment in Fingerprinting and Multi Component Quantitative NMR Analyses

An interlaboratory comparison (ILC) was organized with the aim to set up quality control indicators suitable for multicomponent quantitative analysis by nuclear magnetic resonance (NMR) spectroscopy. A total of 36 NMR data sets (corresponding to 1260 NMR spectra) were produced by 30 participants using 34 NMR spectrometers. The calibration line method was chosen for the quantification of a five-component model mixture. Results show that quantitative NMR is a robust quantification tool and that 26 out of 36 data sets resulted in statistically equivalent calibration lines for all considered NMR signals. The performance of each laboratory was assessed by means of a new performance index (named Qp-score) which is related to the difference between the experimental and the consensus values of the slope of the calibration lines. Laboratories endowed with a Qp-score falling within the suitable acceptability range are qualified to produce NMR spectra that can be considered statistically equivalent in terms of relative intensities of the signals. In addition, the specific response of nuclei to the experimental excitation/relaxation conditions was addressed by means of the parameter named NR. NR is related to the difference between the theoretical and the consensus slopes of the calibration lines and is specific for each signal produced by a well-defined set of acquisition parameters

Retinoic acid sensitizes acute myeloid leukemia cells to ER stress

Acute myeloid leukemia (AML) is caused by the blockade of hematopoietic myeloid precursors at different stages of differentiation. A subtype of AML, acute promyelocytic leukemia (APL), is a paradigm of differentiation therapy since retinoic acid (RA) is able to induce leukemic blast terminal differentiation leading to cure rates exceeding 80% when administered in combination with chemotherapy. Although APL patients refractory to RA or who relapsed are very effectively treated with arsenic trioxide (ATO) in combination with RA, the elevated costs limit its use in developing countries and in first line therapy so that RA plus chemotherapy currently remain the standard of care (1, 2). Most importantly non-APL acute myeloid leukemia do not respond to RA indicating the need for novel strategies to sensitize AML cells to RA. Here we show that RA-triggered differentiation of APL cells induces endoplasmic reticulum (ER) stress slightly activating the unfolded protein response (UPR). This is sufficient to render leukemic cell lines and human primary blasts very sensitive to doses of ER stress inducing drugs, like tunicamycin (Tm), that are not toxic for the same cells in the absence of RA or for most cell types. Furthermore we observed that low doses of Tm, even in the absence of RA, are sufficient to strongly increase ATO toxicity. Indeed both RA-sensitive and RA-resistant APL cell lines resulted sensitive to Tm-ATO combined treatment at low doses of ATO that are ineffective in the absence of ER stress. The use of inhibitors targeting specific UPR branches indicate that the Protein Kinase RNA-like Endoplasmic Reticulum kinase (PERK) pathway protects differentiating APL cells from ER stress rendering it an interesting therapeutic molecular target. Finally, we extended our observations in a non-APL model, assessing that RA sensitize the non-APL cell line HL60 to ER stress. Altogether our data indicate ER stress as a possible target for designing novel combination therapeutic strategies in AML. Contribution of AIRC (StG 4841) and FILAS-RU-2014-1020 to FF was greatly appreciated