Natural compounds for pediatric cancer treatment

There is a tremendous need in clinics to impair cancer progression through noninvasive therapeutic approaches. The use of natural compounds to achieve this is of importance to improve the quality of life of young patients during their treatments. This review will address the "status of the art" related to the potential of natural compounds that are undergoing investigation in combination with standard therapeutic protocols in preclinical and clinical studies and their importance for pediatric cancer treatment. The early studies of drug discovery of these natural compounds discussed here include the main targets, the cellular signaling pathways involved, and the potential modes of action. We also focus on some promising natural compounds that have shown excellent results in vitro and in vivo: Chebulagic acid, Apigenin, Norcantharidin, Saffron/Crocin, Parthenolide, Longikaurin E, Lupeol, Spongistatin 1, and Deoxy-variolin B. Additionally, we introduce the effects of several compounds from nutraceutical and functional foods, to underline their potential use as adjuvant therapies to improve therapeutic benefits. For this purpose, we have selected several compounds: Agaritine, Ganoderma and GL6 peptide, Diallyl trisulfide and Ajoene from garlic, Epigallocatechin gallate from green tea, Curcumin, Resveratrol, and Quercetin

On using pretext tasks to learn representations from network logs

Learning meaningful representations from network data is critical to ease the adoption of AI as a cornerstone to process network logs. Since a large portion of such data is textual, Natural Language Processing (NLP) appears as an obvious candidate to learn their representations. Indeed, the literature proposes impressive applications of NLP applied to textual network data. However, in the absence of labels, objectively evaluating the goodness of the learned representations is still an open problem. We call for a systematic adoption of domain-specific pretext tasks to select the best representation from network data. Relying on such tasks enables us to evaluate different representations on side machine learning problems and, ultimately, unveiling the best candidate representations for the more interesting downstream tasks for which labels are scarce or unavailable. We apply pretext tasks in the analysis of logs collected from SSH honeypots. Here, a cumbersome downstream task is to cluster events that exhibit a similar attack pattern. We propose the following pipeline: first, we represent the input data using a classic NLP-based approach. Then, we design pretext tasks to objectively evaluate the representation goodness and to select the best one. Finally, we use the best representation to solve the unsupervised task, which uncovers interesting behaviours and attack patterns. All in all, our proposal can be generalized to other text-based network logs beyond honeypots

Ultrasonografía musculo-esquelética con doppler de poder asociado al modo B en el equino

Ultrasonography, in equine medicine, is a fundamental technique for the diagnosis of lameness and in the evaluation of the decrease in sporting performance. In spite of the great development of B Mode, there is little use of Color Doppler and specifically of Power Doppler or Power Angio in the evaluation of musculoskeletal conditions in the equine. The objective of this work was to analyze the scope, advantages and limitations of the ultrasonographic study with Power Doppler associated to B Mode in the evaluation of 122 musculoskeletal disorders in sport equines, between 2 and 15 years old, of both sexes and different breeds. A Sonoscape E2 portable ultrasound scanner with a 7-11 Mhz linear probe and a 2.5-5 Mhz convex probe was used. Of all the musculoskeletal lesions evaluated (n:122), the presence of Power Doppler signal was observed in 46/122 being grade I (29/46), followed by grade II (13/46) and finally grade III (4/46). Although this is a preliminary study and more results are needed to be able to apply statistical analysis, according to the authors’ experience, Power Doppler complementing B-mode ultra sonographic studies has proven to be a very useful tool for diagnosis, follow-up of the evolution of lesions, evaluation of therapeutic response and as a predictive value of possible future lesions.La ultrasonografía, en medicina equina, es una técnica fundamental para el diagnóstico de las claudicaciones y en la evaluación de la disminución del rendimiento deportivo. A pesar del gran desarrollo del Modo B es escasa la utilización del Doppler Color y específicamente del Doppler de Poder o power angio en la evaluación de las afecciones músculo-esqueléticas en el equino. El objetivo de este trabajo fue analizar los alcances, ventajas y limitaciones del estudio ultrasonográfico con Doppler de Poder asociado al Modo B en la evaluación de 122 afecciones músculo-esqueléticas en equinos deportivos, de entre 2 y 15 años, de ambos sexos y distintas razas Se utilizó un ecógrafo portátil Sonoscape E2 con sonda lineal de 7-11 Mhz y convexa de 2,5-5 Mhz. De la totalidad de las lesiones músculo-esqueléticas evaluadas (n:122) se observó presencia de señal con el Doppler de Poder en 46/122 siendo la más observada la de grado I (29/46), seguida del grado II (13/46) y por último de grado III (4/46). Si bien este es un estudio preliminar y faltan más resultados para poder aplicar análisis estadísticos, según la experiencia de los autores, el Doppler de Poder complementando los estudios ultra-sonográficos en Modo B, ha demostrado ser una herramienta de gran utilidad para el diagnóstico, seguimiento de la evolución de las lesiones, evaluación de la respuesta terapéutica y con valor predictivo de posibles lesiones futuras

Permeability of self-affine rough fractures

The permeability of two-dimensional fractures with self-affine fractal roughness is studied via analytic arguments and numerical simulations. The limit where the roughness amplitude is small compared with average fracture aperture is analyzed by a perturbation method, while in the opposite case of narrow aperture, we use heuristic arguments based on lubrication theory. Numerical simulations, using the lattice Boltzmann method, are used to examine the complete range of aperture sizes, and confirm the analytic arguments.Comment: 11 pages, 9 figure

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma

Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB

Early targets of miR-34a in neuroblastoma

Several genes encoding for proteins involved in proliferation, invasion, and apoptosis are known to be direct miR-34a targets. Here, we used proteomics to screen for targets of miR-34a in neuroblastoma (NBL), a childhood cancer that originates from precursor cells of the sympathetic nervous system. We examined the effect of miR-34a overexpression using a tetracycline inducible system in two NBL cell lines (SHEP and SH-SY5Y) at early time points of expression (6, 12, and 24 h). Proteome analysis using post-metabolic labeling led to the identification of 2,082 proteins, and among these 186 were regulated (112 proteins down-regulated and 74 up-regulated). Prediction of miR-34a targets via bioinformatics showed that 32 transcripts held miR-34a seed sequences in their 3′-UTR. By combining the proteomics data with Kaplan Meier geneexpression studies, we identified seven new gene products (ALG13, TIMM13, TGM2, ABCF2, CTCF, Ki67, and LYAR) that were correlated with worse clinical outcomes. These were further validated in vitro by 3′-UTR seed sequence regulation. In addition, Michigan Molecular Interactions searches indicated that together these proteins affect signaling pathways that regulate cell cycle and proliferation, focal adhesions, and other cellular properties that overall enhance tumor progression (including signaling pathways such as TGF-β, WNT, MAPK, and FAK). In conclusion, proteome analysis has here identified early targets of miR-34a with relevance to NBL tumorigenesis. Along with the results of previous studies, our data strongly suggest miR-34a as a useful tool for improving the chance of therapeutic success with NBL

Hybrid materials for molecular sieves

Hybrid microporous organosilica membranes for molecular separations made by acid-catalyzed solgel synthesis from bridged silsesquioxane precursors have demonstrated good performance in terms of flux and selectivity and remarkable hydrothermal stability in various pervaporation and gas separation processes. The availability of wide range of α,ω-bis(trialkoxysilyl)alkane and 1,4-bis (triethoxysilyl)benzene precursors allows tuning of membrane properties such as pore size and chemistry. This chapter presents an overview of the synthesis and application of hybrid organosilica microporous membranes in liquid and gas separation processes. After a concise discussion of the history of solgel-derived microporous ceramic membranes for molecular separations, the solgel chemistry of bridged silsesquioxanes and all relevant processing steps needed to obtain a supported microporous films suitable for molecular separations are discussed. The performance of these membranes is correlated with the membrane compositional properties, such as nature, stiffness and length of the bridging group, and details of the solgel process

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3

Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice

<p>Abstract</p> <p>Background</p> <p>Histone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines.</p> <p>Objective</p> <p>To investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.</p> <p>Methods</p> <p>ALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-κB p65 in cytoplasm and nucleus was determined by Western blot analysis respectively.</p> <p>Results</p> <p>Pretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-α, IL-1β and NO. Furthermore, the expression of NF-κB p65 in nucleus was markedly suppressed by butyrate pretreatment.</p> <p>Conclusions</p> <p>Butyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-κB activation.</p