RESUMEN

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Asunto(s)

Secuenciación de Inmunoprecipitación de Cromatina/métodos , Cromatina , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Núcleo Celular , Factor Nuclear 1-beta del Hepatocito/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Neoplasias Pancreáticas/metabolismo , Pronóstico , Factores de Transcripción , Transcriptoma , Neoplasias Pancreáticas

RESUMEN

A modulated structure has been fabricated from high transition temperature superconductors where the individual CuO(2) planes are composed of alternating superconducting and insulating strips. This structure is made by growing a-axis-oriented YBa(2)Cu(3)O(7)/PrBa(2)Cu(3)O(7) superlattices by 90 degrees off-axis sputtering on (100)SrTiO(3) and (100)LaAlO(3) substrates. Superlattice modulation is observed to a modulation wavelength of 24 angstroms (12 angstroms-YBa(2)Cu(3)O(7)/12 angstroms-PrBa(2)Cu(3)O(7)), both by x-ray diffraction and by cross-sectional transmission electron microscopy. Rutherford backscattering spectroscopy indicates a high degree of crystalline perfection with a channeling minimum yield of 3 percent. Quasi-one-dimensional conductivity should be obtainable in these structures.

RESUMEN

YBa(2)Cu(3)O(7) films have been grown epitaxially on SrTiO(3) (100) and LaAlO(3) (100) substrates with nearly pure a-axis orientation and with transition temperature T(c) (R = 0) of 85 K. A unique feature of these films is their smooth surface. These smooth surfaces enable the growth of short-period superlattices with well-defined modulations. The films are untwinned and the grains grow with their c-axis along one of two perpendicular directions on the substrate ([100] or [010]). The fabrication of sandwich-type Josephson junctions with good characteristics may now be possible because unlike c-axis-oriented films, the superconducting coherence length of these smooth films is appreciably large perpendicular to their surfaces.