Biology subjects

Giordano, J.

Publications and source records attributed to Giordano, J..

3 recordsLinked to original sources

bioRxiv2024

Roles for RERE in lymphatic endothelial cell proliferation and survival, and human cystic lymphatic malformations

Human congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development. During a genetic study of fetuses with LAs, we identified a heterozygous pathogenic truncating variant in RERE in a fetus with a cystic lymphatic malformation (CLM). RERE is a transcriptional regulator which interacts with several key lymphangiogenic factors, including Notch and Coup-TFII. RERE also modulates retinoic acid signaling, which is essential for lymphatic vascular development. Thus, we hypothesized that RERE functions in lymphatic endothelial cells (LECs) and its loss contributes to LEC dysfunction and CLM pathogenesis. RERE was found to be expressed in the lymphatic endothelium during human development. RERE knockdown in human LECs reduced proliferation and induced apoptosis, increased expression of key lymphangiogenic genes, PROX1, COUP-TFII and VEGFR3, and altered expression of Notch target genes. RERE expression was elevated in LECs isolated from CLMs with pathogenic PIK3CA variants. These findings support a novel role for RERE in LECs, where RERE regulates LEC proliferation, LEC survival, lymphangiogenic gene expression and Notch signaling, which in turn suggests its loss contributes to CLM pathogenesis.

cell biology↗

bioRxiv2022

Decoding trans-saccadic prediction error

We are constantly sampling our environment by moving our eyes, but our subjective experience of the world is stable and constant. Stimulus displacement during or shortly after a saccade often goes unnoticed, a phenomenon called the saccadic suppression of displacement. Although we fail to notice such displacements, our oculomotor system computes the prediction errors and adequately adjusts the gaze and future saccadic execution, a phenomenon known as saccadic adaptation. In the present study, we aimed to find a brain signature of the trans-saccadic prediction error that informs the motor system but not explicit perception. We asked participants (either sex) to report whether a visual target was displaced during a saccade while recording electroencephalography (EEG). Using multivariate pattern analysis, we were able to differentiate displacements from no displacements, even when participants failed to report the displacement. In other words, we found that trans-saccadic prediction error is represented in the EEG signal 100 ms after the displacement presentation, mainly in occipital and parieto-occipital channels, even in the absence of explicit perception of the displacement. Significance StatementStability in vision occurs even while performing saccades. One suggested mechanism for this counterintuitive visual phenomenon is that external displacement is suppressed during the retinal remapping caused by a saccade. Here, we shed light on the mechanisms of trans-saccadic stability by showing that displacement information is not entirely suppressed and specifically present in the early stages of visual processing. Such a signal is relevant and computed for oculomotor adjustment despite being neglected for perception.

neuroscience↗

bioRxiv2019

Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multi-region samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

cancer biology↗