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Ground deformations in urban areas can be the result of a combination of multiple factors and pose several hazards to infrastructures and human lives. In order to monitor these phenomena, Interferometric Synthetic Aperture Radar (InSAR) techniques are applied. The obtained signals record the overlapping of the phenomena, and their separation is a relevant issue. In this framework, we explored a new multi-method approach based on the combination of Principal Component Analysis (PCA), Independent Component Analysis (ICA) and Hierarchal Clustering (HC) on the standardized results to distinguish the main trends and seasonal signals embedded in the time series of ground displacements, to understand spatial-temporal patterns, to correlate ground deformation phenomena with geological and anthropogenic factors, and to recognize the specific footprints of different ground deformation phenomena. This method allows us to classify the ground deformations at the site scale in the metropolitan area of Naples, which is affected by uplift cycles, subsidence, cavity instabilities and sinkholes. At the local scale, the results allow a kinematic classification using the extracted components and considering the effect of the radius of influence generated by each cavity, as it is performed from a theoretical point of view when the draw angle is considered. According to the results, among the classified cavities, 2% were assigned to subsidence and 11% to uplift kinematics, while the remaining were found to be stable. Furthermore, our results show that the centering of the Spatial-PCA (S-PCA) is representative of the region’s main trend, whereas Temporal-PCA (T-PCA) gives information about the displacement rates identified by each component.

The paper focuses on the geomorphological processes and potential geo-hazards affecting the cultural heritage rock-cut sites of AlUla region. Its best-known site is Hegra, with more than 110 monumental tombs with elaborated façades carved directly into the sandstone rock. In addition, AlUla hosts a number of fascinating historical and archaeological sites such as its Old Town, surrounded by an ancient oasis, and Dadan, the capital of the Dadan and Lihyan kingdoms. The study is mainly aimed at investigating the local rock material, evaluating characteristics of rock masses, understanding rock degradation processes and characterizing the potential impact of slope instabilities on the conservation of cultural heritage.

Background: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. Interpretation: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Funding: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazion

Background: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. Interpretation: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Funding: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazion

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up-and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up-and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.

Cornelia de Lange syndrome (CdLS), which is reported to affect-1/41 in 10 000 to 30 000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. CdLS can result from mutations in at least five genes: nipped-B-like protein, structural maintenance of chromosomes 1A, structural maintenance of chromosomes 3, RAD21 cohesin complex component and histone deacetylase 8 (HDAC8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development. Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells (NSCs) and in vertebrate (Danio rerio) brain development by knockdown and chemical inhibition experiments. Underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs or in zebrafish embryos

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.

The aim of this study was to find an intramuscularly (IM) injectable anaesthetic combination for 8 to 14-days old piglets, that guarantees a calm induction and sufficient quality of anaesthesia without excitations with a maximum of two hours long lasting recovery. In preliminary dose finding trials, different combinations of ­ketamine, azaperone and romifidine were compared. A constant dose of 0.2 mg/kg of butorphanol was added to each combination and all piglets received 0.4 mg/kg meloxicam. Subsequently a dosage algorithm for the main trial was developed. In case of insufficient analgesia, lidocaine 2% (0.25 ml) was injected intratesticular. If two piglets showed an insufficient anaesthetic induction phase, depth of anaesthesia or recovery, the next dosage in the algorithm was tried. With the combination of 3 mg/kg azaperone, 0.2 mg/kg romifidine, 15 mg/kg ketamine and 0.2 mg/kg butorphanol the requirement of a smooth anaesthesia induction, sufficient anaesthesia and a recovery without excitation was fulfilled but the recovery lasted more than 120 minutes.

Background: Cornelia de Lange syndrome (CdLS) is a rare genetic disorder affecting the neurodevelopment, gastrointestinal, musculoskeletal systems. CdLS is caused by mutations within NIPBL, SMC1A, SMC3, RAD21, and HDAC8 genes. These genes codify for the “cohesin complex” playing a role in chromatid adhesion, DNA repair and gene expression regulation. The aim of this study was to investigate retinoic acid (RA) signaling pathway, a master developmental regulator, in CdLS cells. Methods: Skin biopsies from CdLS patients and healthy controls were cultured and derived primary fibroblast cells were treated with RA or dimethyl sulfoxide (vehicle). After RA treatment, cells were harvested and RNA was isolated for quantitative real-time polymerase chain reaction experiments. Results: We analyzed several components of RA metabolism in a human cell line of kidney fibroblasts (293T), in addition to fibroblasts collected from both NIPBL-mutated patients and healthy donors, with or without RA treatment. In all cases, ADH and RALDH1 gene expression was not affected by RA treatment, while CRABP1 was induced. CRABP2 was dramatically upregulated upon RA treatment in healthy donors but not in CdLS patients cells. Conclusion: We investigated if CdLS alterations are associated to perturbation of RA signaling. Cells derived from CdLS patients do not respond to RA signaling as efficiently as healthy controls. RA pathway alterations suggest a possible underlying mechanism for several cellular and developmental abnormalities associated with cohesin function. Birth Defects Research 109:1268–1276, 2017. © 2017 Wiley Periodicals, Inc.

Infrared spectroscopy is demonstrated to sensitively detect electronic excitations in 1-nm-wide wires made of indium. The polarization-dependent spectra measured at room temperature show a strong broadband plasmonic absorption feature in the direction parallel to the wires, while in the perpendicular direction the wires stay nearly transparent in the same spectral range. At 88 K the wires do not show this broadband absorption anymore, but instead, several interband-transition features arise for both polarizations, in agreement to the gap opening of the metal-to-insulator transition as known for this one-dimensional structure.