Spectral behavior of the linear polarization degree at right-angle scattering configuration for nanoparticle systems

We present a numerical study of the spectral evolution of the linear polarization degree at right-angle scattering configuration (PL(90º)) for two different particle systems: an isolated nanosphere and a nanodimer composed of two finite size spherical particles separated by a gap distance d. We shall focus on the influence of charge oscillation modes other than the dipolar on the linear polarization degree of the scattered light. The possibility of using this alternative parameter for characterizing nanoparticle systems and particle interaction is analyzed.We acknowledge financial support from USAITCA (US Army International Technology Center—Atlantic) under the project R&D1390-PH-01 and from the Ministry of Education of Spain under the project FIS2007-60158

Validación de un algoritmo para el cálculo automático de la distancia inter lesión en la ablación por catéter de radiofrecuencia de fibrilación auricular

La Fibrilación Auricular (FA) es un trastorno del ritmo cardíaco caracterizado por contracciones auriculares rápidas e irregulares, que puede aumentar el riesgo de accidente cerebrovascular (ACV) y disminuir la calidad de vida de los pacientes. Una de las técnicas principales para tratar la FA es la ablación con catéter de RF, que implica aislar eléctricamente las venas pulmonares del resto de la aurícula, a base de lesiones puntuales rodeando las venas. Todavía existe discusión en la comunidad sobre cuál es la distancia entre lesiones óptima para mejorar los resultados a largo plazo de la ablación de FA. Se ha desarrollado una herramienta en Python que, partiendo de los datos del procedimiento de ablación de FA, encuentra la secuencia óptima de ablaciones que rodea a las venas pulmonares y de esta forma puede calcular la distancia entre toda la secuencia de lesiones. El algoritmo automatizado demostró ser efectivo en la mayoría de los casos y en casi la totalidad de los casos de forma semiautomática. El trabajo deja disponible una herramienta para la comunidad que puede ayudar a la hora de optimizar la ablación de FA. En el futuro se podría mejorar el algoritmo para que fuera 100% automático, aunque ahora mismo ya es de utilidad y existen varios estudios clínicos que están en marcha utilizando esta herramienta.Este Trabajo ha sido parcialmente financiado por el proyecto del Plan Nacional de I+D+i “Cribado diagnóstico de microorganismos mediante microscopia avanzada e inteligencia artificial en patologías humana” (PID2021- 127691OB-I00), del Ministerio de Ciencia e Innovación, cofinanciado con fondos FEDER

Shell Technology, Rock Art, and the Role of Marine Resources during the Upper Paleolithic

During the Upper Paleolithic, marine resources have traditionally been considered to be low-efficiency resources. However, in recent years, new data have emerged to demonstrate that their importance for human utilization was probably greater than previously thought. The assessment of their value has generally been from the perspective of their nutritional or ornamental value, not from the technological potential that these resources might have. A use-wear analysis of shells from the Gravettian levels of Fuente del Salín, a cave in northern Spain, has documented their use for a diverse range of production activities, most notably the processing of the red pigments used in artistic representations on the cave walls, as well as for tanning hide. This technological use of shells demonstrates that marine resources were of greater importance to the hunters and gatherers of the Upper Paleolithic and that their utility was more diverse than previously understood.This research was funded by the University of Cantabria through pre- and postdoctoral contract to David Cuenca-Solana and Alejandro Garcı´a-Moreno. Igor Gutierrez-Zugasti is currently funded by the Newton International Fellowships scheme. Parts of the analyses that support this research have been carried out as part of the project Human Response to Global Climate Change in a Littoral Zone: the Case of the Transition to the Holocene on the Cantabrian Coast (10,000–5,000 cal B.C.) (HAR2010-22115-C02-01), funded by the Spanish Ministry of Science and Innovation

Circular RNA CpG island hypermethylation-associated silencing in human cancer

Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5′-3′ ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors. To tackle this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in conjuction with circRNA expression microarrays. We have found that the loss of DNA methylation provokes a release of circRNA silencing. In particular, we have identified that promoter CpG island hypermethylation of the genes TUSC3 (tumor suppressor candidate 3), POMT1 (protein O-mannosyltransferase 1), ATRNL1 (attractin-like 1) and SAMD4A (sterile alpha motif domain containing 4A) is linked to the transcriptional downregulation of both linear mRNA and the hosted circRNA. Although some circRNAs regulate the linear transcript, we did not observe changes in TUSC3 mRNA levels upon TUSC3 circ104557 overexpression. Interestingly, we found circRNA-mediated regulation of target miRNAs and an in vivo growth inhibitory effect upon TUSC3 circ104557 transduction. Data mining for 5′-end CpG island methylation of TUSC3, ATRNL1, POMT1 and SAMD4A in cancer cell lines and primary tumors showed that the epigenetic defect was commonly observed among different tumor types in association with the diminished expression of the corresponding transcript. Our findings support a role for circRNA DNA methylation-associated loss in human cancer

The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer

BRG1, a member of the SWI/SNF complex, is mutated in cancer, but it is unclear how it promotes tumourigenesis. We report that re-expression of BRG1 in lung cancer cells up-regulates lung-specific transcripts, restoring the gene expression signature of normal lung. Using cell lines from several cancer types we found that those lacking BRG1 do not respond to retinoic acid (RA) or glucocorticoids (GC), while restoration of BRG1 restores sensitivity. Conversely, in SH-SY5Y cells, a paradigm of RA-dependent differentiation, abrogation of BRG1 prevented the response to RA. Further, our data suggest an antagonistic functional connection between BRG1 and MYC, whereby, refractoriness to RA and GC by BRG1 inactivation involves deregulation of MYC activity. Mechanistically, some of these effects are mediated by BRG1 binding to MYC and MYC-target promoters. The BRG1-MYC antagonism was also evident in primary tumours. Finally, BRG1 restoration significantly dampened invasion and progression and decreased MYC in lung cancer cells orthotopically implanted in nude mice. Thus, BRG1 inactivation enables cancer cells to sustain undifferentiated gene expression programs and prevent its response to environmental stimuli

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Background: acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: we performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients

Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNA5 (mRNA5). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in -1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology

Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer

The alteration of RNA modification patterns is emerging as a common feature of human malignancies. If these changes affect key RNA molecules for mRNA translation, such as transfer RNA, they can have important consequences for cell transformation. TRIT1 is the enzyme responsible for the hypermodification of adenosine 37 in the anticodon region of human tRNAs containing serine and selenocysteine. Herein, we show that TRIT1 undergoes gene amplification-associated overexpression in cancer cell lines and primary samples of small-cell lung cancer. From growth and functional standpoints, the induced depletion of TRIT1 expression in amplified cells reduces their tumorigenic potential and downregulates the selenoprotein transcripts. We observed that TRIT1-amplified cells are sensitive to arsenic trioxide, a compound that regulates selenoproteins, whereas reduction of TRIT1 levels confers loss of sensitivity to the drug. Overall, our results indicate a role for TRIT1 as a small-cell lung cancer-relevant gene that, when undergoing gene amplification-associated activation, can be targeted with the differentiation agent arsenic trioxide

In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma

Cancer origin and development is associated not only with genetic alterations, but also with the disturbance of epigenetic profiles.1 In this regard, the tumoral epigenome is characterized by both specific and general shifts in the DNA methylation and histone-modification landscapes.1 However, in contrast to genetic disruption, the effect of epigenetic modifications or marks may potentially be reversed by the use of drugs that target enzymes involved in adding, removing or signaling DNA methylation and histone modifications.1 This basic knowledge has been adopted into clinical practice, and inhibitors of histone deacetylases and DNA demethylating agents have been approved for use in the therapy of hematologic malignancies, such as cutaneous T-cell lymphoma and myelodysplastic syndrome, respectively.2 Other promising epigenetic drugs include inhibitors of histone methyltransferases,2 histone demethylases,2 histone kinases,3 and bromodomain proteins that interfere with the 'reading' of acetylated histone residues