Potential rockfalls and analysis of slope dynamics in the palatine archaeological area (Rome, Italy)

The Palatine Hill is among the main archaeological sites of Roman antiquity. Today, this place requires continuous care for its safeguarding and conservation. Among the main problems, slope instabilities threaten the southwestern border of the hill flanked by the Velabrum Valley, as also testified by historical documents. The upper part of the investigated slope is characterized by Middle Pleistocene red-brownish tuffs known as "Tufo Lionato". The rock mass is affected by two jointing belts featuring the slope edge and its internal portion with different joint frequency and distribution. The analysis of the geometric relationship between the joint systems and the slope attitude evidenced possible planar sliding and toppling failure mechanisms on the exposed tuff cliffs. Potential rock block failures threatening the local cultural heritage were contrasted with preliminary works for site remediation. In addition, stress-strain numerical modelling verified the hypothesis of a tensile origin for the jointing belts, suggested by fracture characteristics and orientation. A first modelling was limited to the southwestern edge of the Palatine Hill and analysed the present stress-strain condition of the slope, proving the inconsistency with the observed deformation. A second modelling was extended to the Palatine-Velabrum slope-to-valley system to consider the role played by the geomorphological evolution of the area on the local slope dynamics during the late Pleistocene-Holocene. Results demonstrate how original conditions of slope instability, deformation and retreat along the Palatine western edge were determined by deep valley incision, and controlled by deformability contrasts within the slope. Slope instability influenced the site occupation and development during the Roman civilization, as also indicated by the remnants of retaining walls of different ages at the slope base

Heavy Metal Pollutions: State of the Art and Innovation in Phytoremediation

Mineral nutrition of plants greatly depends on both environmental conditions, particularly of soils, and the genetic background of the plant itself. Being sessile, plants adopted a range of strategies for sensing and responding to nutrient availability to optimize development and growth, as well as to protect their metabolisms from heavy metal toxicity. Such mechanisms, together with the soil environment, meaning the soil microorganisms and their interaction with plant roots, have been extensively studied with the goal of exploiting them to reclaim polluted lands; this approach, defined phytoremediation, will be the subject of this review. The main aspects and innovations in this field are considered, in particular with respect to the selection of efficient plant genotypes, the application of improved cultural strategies, and the symbiotic interaction with soil microorganisms, to manage heavy metal polluted soils

tumor infiltrating lymphocytes tils and pdl1 expression as prescreening enrichment biomarkers of clinical benefit to immune checkpoint inhibitors ci in early clinical trials ect

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Climate and land-use change during the late Holocene at Lake Ledro (southern Alps, Italy)

International audienceThis paper investigates the relative influences of climatic and anthropogenic factors in explaining environmental and societal changes in the southern Alps, Italy. We investigate a deep sediment core (LL081) from Lake Ledro (652 m a.s.l.). Environmental changes are reconstructed through multiproxy analysis, that is, pollen-based vegetation and climate reconstruction, magnetic susceptibility (MS), lake level, and flood frequency, and the paper focuses on the climate and land-use changes which occurred during the late Holocene. For this time interval, Lake Ledro records high mean water table, increasing amount of pollen-based precipitation, and more erosive conditions. Therefore, while a more humid late Holocene in the southern Alps has the potential to reinforce the forest presence, pollen evidence suggests that anthropogenic activities changed the impact of this regional scenario. Land-use activity (forest clearance for pastoralism, farming, and arboriculture) opened up the large vegetated slopes in the catchment of Lake Ledro, which in turn magnified the erosion related to the change in the precipitation pattern. The record of an almost continuous human occupation for the last 4100 cal. BP is divided into several land-use phases. On the one hand, forest redevelopments on abandoned or less cultivated areas appear to be climatically induced as they occurred in relation with well-known events such as the 2.8-kyr cold event and the ‘Little Ice Age’. On the other hand, climatically independent changes in land use or habitat modes are observed, such as the late-Bronze-Age lake-dwellings abandonment, the human population migration at c. 1600 cal. BP, and the period of the Black Death and famines at 600 cal. BP

Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer

Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC

Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer

Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 − 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 − 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection

Indagini Geofisiche

Nell'ambito del progetto per la Microzonazione sismica dell'area aquilana, coordinata dal DPC, il Gruppo di Lavoro ha condotto le indagini di MS nella Conca di Roio.Published336-3854T. Sismologia, geofisica e geologia per l'ingegneria sismic

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

BACKGROUND: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. PATIENTS AND METHODS: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. RESULTS: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. CONCLUSION: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors