Preparation of 2D sequences of corneal images for 3D model building

A confocal microscope provides a sequence of images, at incremental depths, of the various corneal layers and structures. From these, medical practioners can extract clinical information on the state of health of the patient's cornea. In this work we are addressing problems associated with capturing and processing these images including blurring, non-uniform illumination and noise, as well as the displacement of images laterally and in the anterior–posterior direction caused by subject movement. The latter may cause some of the captured images to be out of sequence in terms of depth. In this paper we introduce automated algorithms for classification, reordering, registration and segmentation to solve these problems. The successful implementation of these algorithms could open the door for another interesting development, which is the 3D modelling of these sequences

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Homologous recombination deficiency in pancreatic cancer: a systematic review and prevalence meta-analysis

Purpose: To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: We conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813). Results: Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD). Conclusion: Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC

Retomando a Interrupção... Getting Back to Interruption...

Este trabalho é uma continuação de outros estudos sobre interrupção que vêm sendo desenvolvidos desde 1995 pelo grupo "Organização textual interativa" no âmbito do Projeto da Gramática do Português Falado. Nosso objetivo é explicitar o estatuto da interrupção: trata-se de um mecanismo de construção do texto falado ou, apenas, de um índice de ocorrência de alguns desses mecanismos (correção, paráfrase, repetição, parênteses)? Para responder a essa questão, analisamos seis inquéritos de natureza diferente (elocuções formais - EFs - , entrevistas - DIDs - e diálogos entre dois informantes - D2s), extraídos do Projeto NURC/SP, NURC/RJ e NURC/Recife. Do ponto de vista teórico, recorremos às pesquisas desenvolvidas pelo grupo acima mencionado, cujos artigos foram publicados na coleção: Gramática do Português Falado ( volumes IV, V e VI ) .<br>This work follows other studies on interruption that we have been developping since 1995 in a group engaged in the interactive textual organization within the Grammatical Project of the Spoken Portuguese. Our aim is to uncover the status of interruption: is it a mecanism of construction of the spoken text or only of a token of the occurrence of some of these mecanisms (correction, paraphrase, repetition, parentheses)? To answer this question, we analysed six inquiries of different nature (formal elocutions - Efs; interviews - DIDs - and dialogues between two informants - D2s) extracted from the NURC/SP, NURC/RJ and NURC/Recife Project. As to the theoretical point of view, we turned our attention to assumptions which supported the arguments put forward by the researchers belonging to the above mentioned group, whose articles were published in Grammatical Project of Spoken Portuguese (IV, V, VI