The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Polθ) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Polθ is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Polθ as a potential therapeutic target in BRCA1/2-associated tumors. This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Polθ inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Polθ, paving the way for the development of unexplored synthetic lethality strategies.

Homologous recombination (HR) and mismatch repair (MMR) defects are driver mutational imprints and actionable biomarkers in DNA repair-defective tumors. Although usually thought as mutually exclusive pathways, recent preclinical and clinical research provide preliminary evidence of a functional crosslink and crosstalk between HRR and MMR. Shared core proteins are identified as key players in both pathways, broadening the concept of DNA repair mechanism exclusivity in specific tumor types. These observations may result in unexplored forms of synthetic lethality or hypermutable tumor phenotypes, potentially impacting the cancer risk management, and considerably expanding in the future the therapeutic window for DNA repair-defective tumors.

The transformative role of artificial intelligence (AI) and multiomics could enhance the diagnostic and prognostic capabilities of liquid biopsy (LB) for lung cancer (LC). Despite advances, the transition from tissue biopsies to more sophisticated, non-invasive methods like LB has been impeded by challenges such as the heterogeneity of biomarkers and the low concentration of tumour-related analytes. The advent of multiomics - enabled by deep learning algorithms - offers a solution by allowing the simultaneous analysis of various analytes across multiple biological fluids, presenting a paradigm shift in cancer diagnostics. Through multi-marker, multi-analyte and multi-source approaches, this review showcases how AI and multiomics are identifying clinically valuable biomarker combinations that correlate with patients' health statuses. However, the path towards clinical implementation is fraught with challenges, including study reproducibility and lack of methodological standardization, thus necessitating urgent solutions to solve these common issues.

The northern coast of Sicily and its offshore area represent a hinge zone between a sector of the Tyrrhenian Basin, characterized by the strongest crustal thinning, and the sector of the Sicilian belt which has emerged. This hinge zone is part of a wider W-E trending right-lateral shear zone, which has been affecting the Maghrebian Chain units since the Pliocene. Seismological and structural data have been used to evaluate the seismotectonic behavior of the area investigated here. Seismological analysis was performed on a data set of about 2100 seismic events which occurred between January 1988 and October 2002 in the Southern Tyrrhenian Sea. This paper focuses in particular on a set of data relating to the period from 6th September 2002, including both the main shock and about 540 aftershocks of the Palermo seismic sequence. The distribution of the hypocenters revealed the presence of two main seismogenic zones. The events of the easternmost zone may be related to the Ionian lithospheric slab diving beneath the Calabrian Arc. The seismicity associated with the westernmost zone is closely clustered around a sub-horizontal regression plane contained within the thinned Southern Tyrrhenian crust, hence suggesting that this seismogenic zone is strictly connected to the deformation field active within the hinge zone. On the basis of both structural and seismological data, the brittle deformation pattern is characterized by high-angle faults, mainly represented by transcurrent synthetic right-lateral and antithetic left-lateral systems, producing both restraining/uplifting and releasing/subsiding zones which accommodate strains developing in response to the current stress field (characterized by a maximum axis trending NW-SE) which has been active in the area since the Pliocene. The cluster of the seismic sequence which started with the 6th September 2002's main shock is located within the hinge zone. The distribution of the hypocenters relative to this sequence emphasizes the presence of a high-angle NE-SW-oriented deformation belt within which several shear surfaces are considered to be found sub-parallel to that established for the main shock. The kinematics of all these structures is consistent with a compressive right-lateral focal mechanism.

A report is given of the activity of the Sea Land Group(a) concerning the CROP MARE II seismic project. In this experiment, jointly with near-vertical seismic data acquisition (NVR), the Sea Land Group acquired high-density wide-angle reflection/refraction data (WARR) in some offshore/on-shore configurations along the Italian coast. A concise and complete overview is given of the acquisition scheme, the processing techniques used and the problems connected with the acquisition and management of this kind of data. Our experience led us to get over the standard processing techniques commonly adopted in WARR and NVR seismics, setting up innovative Matlab procedures for data processing. Such a development was directed at an integrated use of smalland great-offset seismic signals for the optimisation of imaging and modelling of lithospheric structures.

A new de-noising algorithm was implemented to perform a signal enhancement on high-density wide-angle reflection/refraction seismic sections (WARR). The algorithm was designed such as to attenuate more intensely the signal components that turn out less coherent within given offset intervals. A component is assumed here to be a portion in a short time interval of a single detail of the multi-resolution analysis of a trace. The filtered details are finally synthesised. The algorithm was given the name CDF, which stands for Coherence Detail Filter. The effectiveness of this filter was evaluated through a quantitative comparison between the results achieved from its application to noisy synthetic sections and those obtained with other filters widely used in seismic processing.

ABSTRACTA new filtering technique for single‐fold wide‐angle reflection/refraction seismic data is presented. The technique is based on the wavelet decomposition of a set of adjacent traces followed by coherence analysis. The filtering procedure consists of three steps. In the first, a wavelet decomposition of traces into different detail levels is performed. In the second, the coherence attributes for each level are evaluated by calculating cross‐correlation functions of detail portions contained in a space–time moving window. Finally, the filtered traces are obtained as a weighted reconstruction of the trace details. Each weight is obtained from the coherence‐attributes distribution estimated in a proper interval. A sequence of tests is then conducted in order to select possible optimum or unsuitable wavelet bases. The efficiency of the filter proposed was assessed by calculating some properly designed parameters in order to compare it with other standard de‐noising techniques. The proposed method produced a clear signal enhancement in high‐density wide‐angle seismic data, thus proving that it is a useful processing tool for a reliable correlation of seismic phases.

A maximum-likelihood (ML) estimator of the correlation dimension d(2) of fractal sets of points not affected by the left-hand truncation of their inter-distances is defined. Such truncation might produce significant biases of the M L estimates of d(2) when the observed scale range of the phenomenon is very narrow, as often occurs in seismological studies. A second very simple algorithm based on the determination of the first two moments of the inter-distances distribution (SOM) is also proposed, itself not biased by the left-hand truncation effect. The asymptotic variance of the ML estimates is given. Statistical tests carried out on data samples with different sizes extracted from populations of interdistances following a power law, suggested that the sample variance of the estimates obtained by the proposed methods are not significantly different, and are well estimated by the asymptotic variance also for samples containing a few hundred inter-distances. To examine the effects of different sources of systematic errors, the two estimators were also applied to sets of inter-distances between points belonging to statistical fractal distributions, baker's maps and experimental distributions of earthquake epicentres. For a full evaluation of the results achieved by the methods proposed here, these were compared with those obtained by the ML estimator for untruncated samples or by the least-squares algorithm.

Estimates of the fractal dimension of hypocentral distributions require evaluating the range of independent variables in which fractal parameters exhibit a power law. Systematic and accidental errors are produced mainly by the subjective selection of this range, the insufficiency of data sets as well as by hypocenter mislocations. Therefore it is very important to determine the confidence intervals which are associated with fractal dimension estimates. The effects of various sources of errors are studied using different geometric clusters of epicenters, which have been synthetically generated using a multicluster algorithm with different hierarchical levels, so as to reproduce some characteristics of the patterns typical of real epicenter distributions. Subsequently, groups of differently sized subsets of synthetic epicenters were obtained by randomly sampling each distribution. Confidence intervals of fractal dimensions were thus calculated using all the estimates obtained for the various subsets. This procedure was also tested on real seismic data, consisting of epicentral distributions in three Sicilian areas and five clusters of mining-induced seismic events (Wujek coal mine, Poland). In that analysis both correlation dimensions and their confidence intervals were taken into account.

INTRODUCTION – Transmissible Spongiform Encephalopathies (TSE) are fatal transmissible neurodegenerative diseases occurring in a number of mammalian species such as CreutzfeldtJakob disease affecting humans, BSE affecting bovines, FSE affecting felines (cats) and Scrapie affecting moufflons, sheep and goats. TSE are characterised by the accumulation of an abnormal form of a host-encoded prion protein (PrP) in the central nervous system and lymphoid tissues of the affected individuals, eventually leading to death. Susceptibility to TSE diseases is partly genetically controlled and mainly depending on the inherited alleles of the PrP gene encoding the PrP. If it would be found that BSE could be transmitted from cattle to sheep then the effects would be huge due to the known effect of BSE causing Creutzfeldt-Jakob disease in humans. To avoid human health risks the EU is implementing policies for selection against certain alleles of the PrP gene, which make sheep susceptible to Scrapie. An initial step is the investigation of the allele frequencies in various breeds. At least 15 allelic variants of the PrP gene are known in sheep. But generally (e.g. Goldmann et al., 1990; Belt et al., 1995), the PrP genotypes are described for the three codons (136, 154 and 171) which represent a polymorphism known to be linked to Scrapie susceptibility. At these codons, named after the amino acids they encode, the following alleles are distinguished: ARR, AHQ, ARH, ARQ and VRQ in order of increasing susceptibility. The aim of this paper is to present the initial results of an investigation of the PrP allele frequencies in Sicilian Valle del Belice dairy sheep and to compare these to cross-bred animals in Sicilian flocks with Scrapie outbreaks. Furthermore the genotyping for PrP offers opportunities for pedigree verification and reconstruction. This work is part of a broader project aimed at pedigree reconstruction and genotype errors in dairy sheep.