Oxidative stress and DNA damage in agricultural workers after exposure to pesticides

Background: Recent epidemiological studies on workers describe that exposure to pesticides can induce oxidative stress by increased production of free radicals that can accumulate in the cell and damage biological macromolecules, for example, RNA, DNA, DNA repair proteins and other proteins and/or modify antioxidant defense mechanisms, as well as detoxification and scavenger enzymes. This study aimed to assess oxidative stress and DNA damage among workers exposed to pesticides. Methods: For this purpose, 52 pesticide exposed workers and 52 organic farmers were enrolled. They were assessed: the pesticide exposure, thiobarbituric acid reactive substances (TBARS), total glutathione (TG), oxidized glutathione levels (GSSG), and 8-oxo-7,8-dihydro-2\u2032-deoxyguanosine (8-oxodG), levels. Results: Correlation between pesticide exposure was positively associated with high TBARS and 8-oxodG levels (p < 0.001). A negative association was founded with TG and GSSG and pesticide exposure. Conclusions: The present investigation results seem to indicate a mild augment in oxidative stress associated with pesticide exposure, followed by an adaptive response to increase the antioxidant defenses to prevent sustained oxidative adverse effects stress

Cytosine deaminase base editing to restore COL7A1 in dystrophic epidermolysis bullosa human:murine skin model

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating blistering skin disorder caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils (AFs) at the dermal-epidermal junction (DEJ). Although conventional gene therapy approaches through viral vectors have been tested in pre-clinical and clinical trials, they are limited by transgene size constraints and only support unregulated gene expression. Genome editing could potentially overcome some of these limitations, and CRISPR/Cas9 has already been applied in research studies to restore COL7A1 expression. Delivery of suitable repair templates for repair of DNA cleaved by Cas9 is still major challenge, and alternative base editing strategies may offer corrective solutions for certain mutations. We demonstrate highly targeted and efficient cytidine deamination and molecular correction of a defined RDEB mutation (c.425A>G) leading to restoration of full-length C7 protein expression in primary human fibroblasts and iPSCs. C7 basement membrane expression and skin architecture were restored with de novo AFs identified by electron microscopy in base edited human RDEB grafts recovered from immunodeficient mice. The results demonstrate the potential and promise of emerging base editing technologies in tackling inherited disorders with well-defined single nucleotide mutations

Brief communication: Co-seismic displacement on 26 and 30 October 2016 ( M w = 5.9 and 6.5) – earthquakes in central Italy from the analysis of a local GNSS network

Abstract. On 24 August 2016 a strong earthquake (Mw = 6.0) affected central Italy and an intense seismic sequence started. Field observations, DInSAR (Differential INterferometry Synthetic-Aperture Radar) analyses and preliminary focal mechanisms, as well as the distribution of aftershocks, suggested the reactivation of the northern sector of the Laga fault, the southern part of which was already rebooted during the 2009 L'Aquila sequence, and of the southern segment of the Mt Vettore fault system (MVFS). Based on this preliminary information and following the stress-triggering concept (Stein, 1999; Steacy et al., 2005), we tentatively identified a potential fault zone that is very vulnerable to future seismic events just north of the earlier epicentral area. Accordingly, we planned a local geodetic network consisting of five new GNSS (Global Navigation Satellite System) stations located a few kilometres away from both sides of the MVFS. This network was devoted to working out, at least partially but in some detail, the possible northward propagation of the crustal network ruptures. The building of the stations and a first set of measurements were carried out during a first campaign (30 September and 2 October 2016). On 26 October 2016, immediately north of the epicentral area of the 24 August event, another earthquake (Mw = 5.9) occurred, followed 4 days later (30 October) by the main shock (Mw = 6.5) of the whole 2016 summer–autumn seismic sequence. Our local geodetic network was fully affected by the new events and therefore we performed a second campaign soon after (11–13 November 2016). In this brief note, we provide the results of our geodetic measurements that registered the co-seismic and immediately post-seismic deformation of the two major October shocks, documenting in some detail the surface deformation close to the fault trace. We also compare our results with the available surface deformation field of the broader area, obtained on the basis of the DInSAR technique, and show an overall good fit

Epidemiology and drug susceptibility of nontuberculous mycobacteria (NTM) in Italy in 2016-2020

Introduction. Nontuberculous mycobacteria (NTM) are environmental mycobacteria which may cause pulmonary and extrapulmonary diseases. These organisms are difficult to treat due to their intrinsic drug-resistance. In Italy, no major nationwide study on NTM epidemiology and drug susceptibility was performed. Methods. Data on the epidemiology of 7,469 NTM clinical isolates identified in Italy in 2016-2020 and on the minimum inhibitory concentrations (MICs) of 1,506 of these strains were analysed. Results. Overall, 63 species were identified in 42 hospital laboratories located in 16 out of 20 regions, with Mycobacterium avium complex (MAC) being the most frequently iso-lated, followed by M. gordonae, M. xenopi, M. abscessus. The MICs of 12 drugs for MAC, M. xenopi, M. kansasii, M. abscessus, M. fortuitum and M. chelonae were interpreted for clinical significance (susceptible, intermediate, resistant) based on the guidelines pub-lished by the Clinical and Laboratory Standards Institute in November 2018. Conclusions. Our data are in line with other nationwide studies and may be of value for further update of microbiological and clinical guidelines

Palbociclib plus fulvestrant or everolimus plus exemestane for pretreated advanced breast cancer with lobular histotype in er+/her2 12 patients: A propensity score-matched analysis of a multicenter retrospective patient series

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) show meaningful efficacy and tolerability in patients with metastatic breast cancer (MBC), but the optimal sequence of ET has not been established. It is not clear if patients with lobular breast carcinomas (LBC) derive the same benefits when receiving second line CDK4/6i. This retrospective study compared the efficacy of palbociclib plus fulvestrant (PALBO\u2013FUL) with everolimus plus exemestane (EVE\u2013EXE) as second-line ET for hormone-resistant metastatic LBC. From 2013 to 2018, patients with metastatic LBC positivity for estrogen and/or progesterone receptors and HER2/neu negativity, who had relapsed during adjuvant hormonal therapy or first-line hormonal treatment, were enrolled from six centers in Italy in this retrospective study. A total of 74 out of 376 patients (48 treated with PALBO\u2013FUL and 26 with EVE\u2013EXE) with metastatic LBC were eligible for inclusion. Progression-free survival (PFS) was longer in patients receiving EVE\u2013EXE compared with PALBO\u2013FUL (6.1 vs. 4.5 months, univariate HR 0.58, 95% CI 0.35\u20130.96; p = 0.025). On the propensity score (PS) analysis, PFS was confirmed to be significantly longer for patients treated with EVE\u2013EXE compared to PALBO\u2013FUL (6.0 vs. 4.6 months, p = 0.04). This retrospective analysis suggests that EVE\u2013EXE is more effective than PALBO\u2013FUL for second line ET of metastatic LBC, allowing us to speculate on the optimal therapeutic sequence

Breast cancer "tailored follow-up" in Italian oncology units: a web-based survey

urpose: Breast cancer follow-up procedures after primary treatment are still a controversial issue. Aim of this study was to investigate, through a web-based survey, surveillance methodologies selected by Italian oncologists in everyday clinical practice. Methods: Referents of Italian medical oncology units were invited to participate to the study via e-mail through the SurveyMonkey website. Participants were asked how, in their institution, exams of disease staging and follow-up are planned in asymptomatic women and if surveillance continues beyond the 5th year. Results: Between February and May 2013, 125 out of 233 (53.6%) invited referents of Italian medical oncology units agreed to participate in the survey. Ninety-seven (77.6%) referents state that modalities of breast cancer follow-up are planned according to the risk of disease progression at diagnosis and only 12 (9.6%) oncology units apply the minimal follow-up procedures according to international guidelines. Minimal follow-up is never applied in high risk asymptomatic women. Ninety-eight (78.4%) oncology units continue follow-up in all patients beyond 5 years. Conclusions: Our survey shows that 90.4% of participating Italian oncology units declare they do not apply the minimal breast cancer follow-up procedures after primary treatment in asymptomatic women, as suggested by national and international guidelines. Interestingly, about 80.0% of interviewed referents performs the so called "tailored follow-up", high intensity for high risk, low intensity for low risk patients. There is an urgent need of randomized clinical trials able to determine the effectiveness of risk-based follow-up modalities, their ideal frequency and persistence in time

Versican G3 Promotes Mouse Mammary Tumor Cell Growth, Migration, and Metastasis by Influencing EGF Receptor Signaling

Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells expressed low levels. We exogenously expressed a G3 construct in 66c14 cells and analyzed its effects on cell proliferation, migration, cell cycle progression, and EGFR signaling. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and systemic metastasis in vivo. Activation of pERK correlated with high levels of G3 expression. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. G3 expressing cells demonstrated increased CDK2 and GSK-3β (S9P) expression, which were related to cell growth. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling pathway. Taken together, EGFR-signaling appears to be an important pathway in versican G3-mediated breast cancer tumor invasiveness and metastasis

Influence of paleogeography on thrust system geometries: an analogue modelling approach for the Abruzzi-Molise (Italy) case history

The Abruzzi-Molise sector in the Central Apennines is a part of a fold and thrust belt that has been deforming since the Late Cretaceous as a result of collision tectonics between the European and Adriatic plates. The superposition of different deformational styles highly reworked the originally complex palaeogeography of this portion of the southern Tethyan margin. Analogue modelling has been performed on thrusting mechanisms in the Abruzzi-Molise area in order to (1) reduce the number of admissible hypotheses regarding palaeogeographic setting, and (2) define thrusting mechanics. Both of these goals are crucial for hydrocarbon exploration purposes. The sandbox apparatus used to simulate the undeformed passive margin consisted of a thin compartment juxtaposed against a thick one along a linear boundary having variable geometries and mechanical stratigraphy; a rigid but mobile backstop was used to deform the stratigraphy in a Coulomb thrust wedge. Results from six experiments show that the geometric relationships between different structural units depend on the distribution of palaeogeographic domains. These domains are defined by mechanical and/or geometrical parameters, such as the orientation between the maximum compression direction and the palaeogeographic boundary, the mechanical stratigraphy and the thickness of the successions reproduced in the models. The present-day tectonic styles and Meso-Cenozoic palaeogeography of the Abruzzi-Molise area are discussed in terms of the mechanisms and structures analysed through the models