Publications by Marta Lovino

A gene fusion is a chromosomal aberration from juxtaposing separate genes. Since some gene fusions are involved in tumorigenesis, proper gene fusion investigation and analysis are crucial in the literature. After DNA/RNA sample extraction, detecting gene fusions requires first gene fusion detection tools, which usually provide many false positives. Given the high experimental costs in wet lab validation of a single fusion, gene fusion prioritization tools were made available over the years to significantly narrow down candidate gene fusions for validation (e.g., Oncofuse, Pegasus, DEEPrior, ChimerDriver). Although a few reviews about gene fusion detection tools are available, a benchmark on prioritization tools is not available yet in the literature. The aim of this paper is twofold: 1. to provide a curated dataset for a fair gene fusion prioritization tool evaluation. 2. to develop a proper comparison based on time, resources, and tool confidence on selected gene fusions. Based on this benchmark, it can be stated that ChimerDriver is the most reliable tool for prioritizing oncogenic fusions.

The control of soil-borne diseases in hops, such as Verticillium wilt remains challenging due to the limited effectiveness of fungicides, the perennial nature of hop cultivation, and the long-term persistence of the pathogens in the soil. Microbial biocontrol agents (mBCAs) with plant growth-promoting (PGP) and antagonistic effects offer a sustainable ecofriendly alternative for hops protection. Two Pseudomonas spp. strains from the UniMORE microbial collection were selected for this study based on their strong antagonistic activity against Verticillium spp. and multiple plant growth-promoting (PGP) traits. Rhizospheric and endophytic colonization capacities of the strains DLS1929 and DLS2318 were evaluated in hop plants (cv. Cascade) under controlled conditions at seven- and fourteen-days post-inoculation (DPI). Both bacterial strains were rhizosphere and endorhiza competent, with slight differences in their abundances. The highest cell density was observed at 7 DPI for the strain DLS2318, reaching log10 6.39 CFU g−1 root fresh weight in the rhizosphere and log10 4.75 CFU g−1 root fresh weight in the endorhiza; at 14 DPI, colonization results were in line with the previous assessment. Confocal laser scanning microscopy visualization of both eGFP-tagged Pseudomonas spp. strains confirmed their rhizosphere competence in hop. Additionally, root colonization by these bacteria enhanced the photosynthetic capacity in hop leaves, supporting their potential as a PGP agents observed in vitro. Successful root colonization and PGP effects are key prerequisites for an effective biocontrol of soilborne pathogens. Further studies are required to assess the consistent efficacy in the field of these beneficial mBCA candidates. This research was funded by the Italian Ministry of University and Research (MUR), under the European Union funding – Next Generation EU - PRIN- 2022, (prot. 2022M3HR45) project: “IoHOP: Quality valorization of the Italian hop based on a multi-approach strategy”.

MicroRNAs (miRNAs) are small molecules that play an essential role in regulating gene expression by post-transcriptional gene silencing. Their study is crucial in revealing the fundamental processes underlying pathologies and, in particular, cancer. To date, most studies on miRNA regulation consider the effect of specific miRNAs on specific target mRNAs, providing wet-lab validation. However, few tools have been developed to explain the miRNAmediated regulation at the protein level. In this paper, the MoPC computational tool is presented, that relies on the partial correlation between mRNAs and proteins conditioned on the miRNA expression to predict miRNA-target interactions in multi-omic datasets. MoPC returns the list of significant miRNA-target interactions and plot the significant correlations on the heatmap in which the miRNAs and targets are ordered by the chromosomal location. The software was applied on three TCGA/CPTAC datasets (breast, glioblastoma, and lung cancer), returning enriched results in three independent targets databases.

Gene fusions are common in high-grade serous ovarian cancer (HGSC). Such genetic lesions may promote tumorigenesis, but the pathogenic mechanisms are currently poorly understood. Here, we investigated the role of a PIK3R1-CCDC178 fusion identified from a patient with advanced HGSC. We show that the fusion induces HGSC cell migration by regulating ERK1/2 and increases resistance to platinum treatment. Platinum resistance was associated with rod and ring-like cellular structure formation. These structures contained, in addition to the fusion protein, CIN85, a key regulator of PI3K-AKT-mTOR signaling. Our data suggest that the fusion-driven structure formation induces a previously unrecognized cell survival and resistance mechanism, which depends on ERK1/2-activation.

Medical diagnostics faced numerous difficulties during the COVID-19 pandemic. One of these has been the need for ongoing monitoring of SARS-CoV-2 mutations. Genomics is the technique most frequently used for precisely identifying variants. The ongoing global gathering of RNA samples of the virus has made such an approach possible. Nevertheless, variant identification techniques are frequently resource-intensive. As a result, the diagnostic capability of small medical laboratories might not be sufficient. In this work, an effective deep learning strategy for identifying SARS-CoV-2 variants is presented. This work makes two contributions: (1) a fine-tuning architecture of Bidirectional Encoder Representations from Transformers (BERT) to identify SARS-CoV-2 variants; (2) providing biological insights by exploiting BERT self-attention. Such an approach enables the analysis of the S gene of the virus to quickly recognize its variant. The selected model BERT is a transformer-based neural network first developed for natural language processing. Nonetheless, it has been effectively used in numerous applications, such as genomic sequence analysis. Thus, the fine-tuning of BERT was performed to adapt it to the RNA sequence domain, achieving a 98.59% F1-score on test data: it was successful in identifying variants circulating to date. The interpretability of the model was examined, since BERT utilizes the self-attention mechanism. In fact, it was discovered that by attending particular areas of the S gene, BERT extracts pertinent biological information on variants. Thus, the presented approach allows obtaining insights into the particular characteristics of SARS-CoV-2 RNA samples.

Whole-Slide Images (WSI) are emerging as a promising resource for studying biological tissues, demonstrating a great potential in aiding cancer diagnosis and improving patient treatment. However, the manual pixel-level annotation of WSIs is extremely time-consuming and practically unfeasible in real-world scenarios. Multi-Instance Learning (MIL) have gained attention as a weakly supervised approach able to address lack of annotation tasks. MIL models aggregate patches (e.g., cropping of a WSI) into bag-level representations (e.g., WSI label), but neglect spatial information of the WSIs, crucial for histological analysis. In the High-Grade Serous Ovarian Cancer (HGSOC) context, spatial information is essential to predict a prognosis indicator (the Platinum-Free Interval, PFI) from WSIs. Such a prediction would bring highly valuable insights both for patient treatment and prognosis of chemotherapy resistance. Indeed, NeoAdjuvant ChemoTherapy (NACT) induces changes in tumor tissue morphology and composition, making the prediction of PFI from WSIs extremely challenging. In this paper, we propose GDS-MIL, a method that integrates a state-of-the-art MIL model with a Graph ATtention layer (GAT in short) to inject a local context into each instance before MIL aggregation. Our approach achieves a significant improvement in accuracy on the ``Ome18'' PFI dataset. In summary, this paper presents a novel solution for enhancing PFI prediction in HGSOC, with the potential of significantly improving treatment decisions and patient outcomes.

Messenger RNA (mRNA) has an essential role in the protein production process. Predicting mRNA expression levels accurately is crucial for understanding gene regulation, and various models (statistical and neural network-based) have been developed for this purpose. A few models predict mRNA expression levels from the DNA sequence, exploiting the DNA sequence and gene features (e.g., number of exons/introns, gene length). Other models include information about long-range interaction molecules (i.e., enhancers/silencers) and transcriptional regulators as predictive features, such as transcription factors (TFs) and small RNAs (e.g., microRNAs - miRNAs). Recently, a convolutional neural network (CNN) model, called Xpresso, has been proposed for mRNA expression level prediction leveraging the promoter sequence and mRNAs’ half-life features (gene features). To push forward the mRNA level prediction, we present miREx, a CNN-based tool that includes information about miRNA targets and expression levels in the model. Indeed, each miRNA can target specific genes, and the model exploits this information to guide the learning process. In detail, not all miRNAs are included, only a selected subset with the highest impact on the model. MiREx has been evaluated on four cancer primary sites from the genomics data commons (GDC) database: lung, kidney, breast, and corpus uteri. Results show that mRNA level prediction benefits from selected miRNA targets and expression information. Future model developments could include other transcriptional regulators or be trained with proteomics data to infer protein levels.