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The study investigated the effects of housing conditions and temperature-humidity index (THI) during the dry period on total bacteria counts of bedding material, animal cleanliness, and teat bacterial contamination on 212 cows from three farms. Additionally, milk yield, quality, total somatic cells, and leucocyte fractions were evaluated in the subsequent lactation on a subgroup of 119 cows. The results showed a relationship between persistent high THI, teat bacterial contamination, and pathogens on teat skin. Somatic cell count (SCC) in milk at the beginning of the next lactation was not affected by THI during the dry period. Multiple correlation analysis revealed a relationship among high milk SCC, high percentage of neutrophils, high bacterial count of bedding during the dry period, and high milk production at dry-off. The study confirms that critical environmental conditions, such as high THI and poor bedding hygiene, during the dry period, can affect teat bacterial contamination and increase the risks for high SCC in the next lactation. High milk production at dry-off may be another risk factor.

Abstract Good hygienic milking practices including the disinfection of the cow teat skin before and after milking aimed at preventing the occurrence of new intramammary infections (IMI) in dairy cows. This practice is generally performed using disinfectants, and in the current context of attention to the emergence of resistances, it is of greatest interest to evaluate alternative solutions that can expand treatment options. We assessed the efficacy of a pre-dipping and a post-dipping product based on the bacteriocin-containing culture of Lactococcus cremoris strain FT27, as compared to commercial disinfectants. FT27 was selected for the bactericidal activity in vitro against food pathogens. In the present study, it also revealed a high bactericidal activity against the main mastitis pathogens, most likely related to Nisin A production, according to genomic and proteomic analysis. The lactococcus-based preparations were applied in two commercial dairy farms in Northern Italy. Overall, 298 dairy cows were enrolled, 141 in the treated group (TR), and 157 in the control group (CTR). The cows were sampled at quarter level every two weeks for 3 months. During the trial, all cows showed a good health status. The hygiene level for udder, flanks and legs was generally good (on average

Despite the fact that rock textures depend on the 3D spatial distribution of minerals, our tectono-metamorphic reconstructions are mostly based on a 2D visualisation (i.e. thin sections). This work compares 2D and 3D investigations of petrography and microstructures, modal abundances, and local bulk rock composition and their implication for P–T estimates, showing the pros and cons and reliability of 2D analysis. For this purpose, a chloritoid–garnet-bearing mica schist from the Dora-Maira Massif in the Western Alps has been chosen. In particular, for 2D a thin section scan has been combined with chemical X-ray maps, whereas for 3D the X-ray computerised axial microtomography (µCT) has been applied. Two-dimensional investigations are readily accessible and straightforward but do not consider the entire rock volume features. Conversely, the rise of 3D techniques offers a more comprehensive and realistic representation of metamorphic features in the 3D space. However, they are computationally intensive, requiring specialised tools and expertise. The choice between these approaches should be based on the research aims, available resources, and the level of detail needed to address specific scientific questions. Nevertheless, despite differences in the modal distribution, the estimated bulk rock compositions and relative thermodynamic modelled phase fields show similarities when comparing the 2D and 3D results. Also, since different thin section cut orientations may influence the results and consequent interpretations, three different cuts from the 3D model have been extrapolated and discussed (i.e. XZ, YZ, and XY planes of the finite-strain ellipsoid). This study quantitatively corroborates the reliability of the thin section approach for tectono-metamorphic reconstructions, still emphasising that 3D visualisation can help understand rock textures.

BackgroundImmune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy.Materials and methodsThis retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed.ResultsAmong 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against “self”. In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients’ life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

The aim of the study was to evaluate the effect of the adoption of precision technologies in dairy cattle farms on environmental impact of milk production, estimated using the Life Cycle Assessment methodology. Primary data were collected from five dairy farms. Based on this information, scenarios were created to evaluate the effect of introducing an Automated Milking System (AMS) and adopting technologies for udder health monitoring and heat detection. Comparisons among scenarios showed that the application of these technologies helps to reduce the environmental impact of milk production at the farm level. The introduction of the AMS resulted in a mitigation of 1.2–5.8% of Global Warming Potential (GWP) per kg Fat and Protein Corrected Milk (FPCM). The implementation of technological systems for udder health monitoring led to a decrease in GWP per kg FPCM of 0.06–0.04% for every 5% increase in the detection of infected cows. The use of automatic systems for heat detection reduced GWP of 1 kg of FPCM by 9.4%, Acidification by more than 10% and Land use 5.65–7.69%. The effectiveness of precision technologies on environmental impact mitigation depends not only on their implementation and reliability but also on how the information provided is used by farmer.

BackgroundImmunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy.MethodsThe Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS.ResultsOverall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 – 10.1), while mPFS was 7.0 months (95% CI: 5.7 – 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59).ConclusionWe found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

Summary: The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII) have been reported as prognosticators in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and melanoma. This analysis of the INVIDIa-2 study on influenza vaccination in patients with cancer treated with immune checkpoint inhibitors (ICIs) assessed NLR and SII on overall survival (OS) by literature-reported (LR), receiver operating characteristic curve (ROC)-derived (ROC) cutoffs or as continuous variable (CV). NLR and SII with ROC cutoffs of

The routine use of intramammary antimicrobial products in all dairy cows at the beginning of the dry period is no longer allowed in European Union (EU) countries due to the new Regulation (EU) 2019/6 to reduce antimicrobial resistance. This study investigated the application of a selective dry cow therapy scheme and the risk factors of high individual milk somatic cell count (SCC) and individual neutrophil count in early lactation, as a response to the application of a selective dry cow therapy (SDCT) protocol. The study was carried out on three commercial farms, and a total of 243 lactating cows were monitored at the end of lactation and at the beginning of the next one, 91 of which were dried off without the use of antimicrobials (NoT) based on milk SCC, differential somatic cell count (DSCC), and the response of Vetscan DC-Q milk analyser, using a secret algorithm. The remaining 152 cows received antimicrobials (T). After calving, similar means were observed between the two treatment groups for SCC (4.8 vs 4.9 log10 cells/ml for T and NoT, respectively, P = 0.5) and total milk leucocyte count (TLC) (5 vs 5.1 log10 cells/ml for T and NoT, respectively, P = 0.7) in milk. However, the use of antimicrobials led to a lower DSCC (58 vs 64% for T and NoT, respectively, P = 0.01) and lower percentage of neutrophils (59 vs 64% for T and NoT, respectively, P = 0.05), although the levels of DSCC and percentage of neutrophils in cows dried off without antimicrobials remained lower than the risk threshold suggested by the international literature. A logistic regression was computed after the application of selective dry cow therapy to identify risk factors of high milk SCC (≥100 000 cells/mL) at the beginning of lactation. Increased milk SCC after calving was related to high SCC at the end of lactation and abandonment of antimicrobial therapy at dry-off. Moreover, the length of the dry period, milk protein content, and flank cleanliness in the last test day before dry-off were other factors in the logistic regression. Neutrophil counts at the beginning of the next lactation were affected by the same factors that influenced SCC, together with milk production, TLC, and macrophages on the last test day. The results obtained in these studied farms showed that selective dry cow therapy may be applied without adversely affecting the next lactation.

Background Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA11a isoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA11a downregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA11a downregulation.Methods Effects of hMENA11a downregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort.Results Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA11a induces IFN pathway activation, the production of different inflammatory mediators including IFNβ via RIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA11a, high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy.Conclusions Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA11a in modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC.

IntroductionAdvanced urothelial carcinoma remains aggressive and very hard to cure, while new treatments will pose a challenge for clinicians and healthcare funding policymakers alike. The U-CHANGE Project aimed to redesign the current model of care for advanced urothelial carcinoma patients to identify limitations (“as is” scenario) and recommend future actions (“to be” scenario).MethodsTwenty-three subject-matter experts, divided into three groups, analyzed the two scenarios as part of a multidimensional consensus process, developing statements for specific domains of the disease, and a simplified Delphi methodology was used to establish consensus among the experts.ResultsRecommended actions included increasing awareness of the disease, increased training of healthcare professionals, improvement of screening strategies and care pathways, increased support for patients and caregivers and relevant recommendations from molecular tumor boards when comprehensive genomic profiling has to be provided for appropriate patient selection to ad hoc targeted therapies.DiscussionWhile the innovative new targeted agents have the potential to significantly alter the clinical approach to this highly aggressive disease, the U-CHANGE Project experience shows that the use of these new agents will require a radical shift in the entire model of care, implementing sustainable changes which anticipate the benefits of future treatments, capable of targeting the right patient with the right agent at different stages of the disease.

Summary: Background: The prospective multicentre observational INVIDIa-2 study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving immune checkpoint inhibitors (ICI). In this secondary analysis of the original trial, we aimed to assess the outcomes of patients to immunotherapy based on vaccine administration. Methods: The original study enrolled patients with advanced solid tumours receiving ICI at 82 Italian Oncology Units from Oct 1, 2019, to Jan 31, 2020. The trial's primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020, the results of which were reported previously. Secondary endpoints (data cut-off Jan 31, 2022) included the outcomes of patients to immunotherapy based on vaccine administration, for which the final results are reported herein. A propensity score matching by age, sex, performance status, primary tumour site, comorbidities, and smoking habits was planned for the present analysis. Only patients with available data for these variables were included. The outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease-control rate (DCR). Findings: The original study population consisted of 1188 evaluable patients. After a propensity score matching, 1004 patients were considered (502 vaccinated and 502 unvaccinated), and 986 of them were evaluable for overall survival (OS). At the median follow-up of 20 months, the influenza vaccination demonstrated a favourable impact on the outcome receiving ICI in terms of median OS [27.0 months (CI 19.5–34.6) in vaccinated vs. 20.9 months (16.6–25.2) in unvaccinated, p = 0.003], median progression-free survival [12.5 months (CI 10.4–14.6) vs. 9.6 months (CI 7.9–11.4), p = 0.049], and disease-control rate (74.7% vs. 66.5%, p = 0.005). The multivariable analyses confirmed the favourable impact of influenza vaccination in terms of OS (HR 0.75, 95% C.I. 0.62–0.92; p = 0.005) and DCR (OR 1.47, 95% C.I. 1.11–1.96; p = 0.007). Interpretation: The INVIDIa-2 study results suggest a favourable immunological impact of influenza vaccination on the outcome of cancer patients receiving ICI immunotherapy, further encouraging the vaccine recommendation in this population and supporting translational investigations about the possible synergy between antiviral and antitumour immunity. Funding: The Federation of Italian Cooperative Oncology Groups (FICOG), Roche S.p.A., and Seqirus.

Abstract Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p

Abstract Although clinical antitumor activity of Tumor Treating Fields (TTFields) has been reported in malignant pleural mesothelioma (MPM) patients, the mechanisms behind the different selectivity displayed by the various MPM histotypes to this physical therapy has not been elucidated yet. Taking advantage of the development of well characterized human MPM cell lines derived from pleural effusion and/or lavages of patients’ thoracic cavity, we investigated the biological effects of TTFields against these cells, representative of epithelioid, biphasic, and sarcomatoid histotypes. Growth inhibition and cell cycle perturbations caused by TTFields were investigated side by side with RNA-Seq analyses at different exposure times to identify pathways involved in cell response to treatment. We observed significant differences of response to TTFields among the cell lines. Cell cycle analysis revealed that the most sensitive cells (epithelioid CD473) were blocked in G2M phase followed by formation of polyploid cells. The least sensitive cells (sarcomatoid CD60) were only slightly affected by TTFields with a general delay in all cell cycle phases. Apoptosis was present in all samples, but while epithelioid cell death was already observed during the first 24 h of treatment, sarcomatoid cells needed longer times before they engaged apoptotic pathways. RNA-Seq experiments demonstrated that TTFields induced a transcriptional response already detectable at early time points (8 h). The number of differentially expressed genes was higher in CD473 than in CD60 cells, involving several pathways, such as those pertinent to cell cycle checkpoints, DNA repair, and histone modifications. Our data provide further support to the notion that the antitumor effects of TTFields are not simply related to a non-specific reaction to a physical stimulus, but are dependent on the biological background of the cells and the particular sensitivity to TTFields observed in epithelioid MPM cells is associated with a higher transcriptional activity than that observed in sarcomatoid models.

BackgroundMalignant Pleural Mesothelioma (MPM) is an aggressive cancer of the mesothelial lining associated with exposure to airborne non-degradable asbestos fibers. Its poor response to currently available treatments prompted us to explore the biological mechanisms involved in its progression. MPM is characterized by chronic non-resolving inflammation; in this study we investigated which inflammatory mediators are mostly expressed in biological tumor samples from MPM patients, with a focus on inflammatory cytokines, chemokines and matrix components.MethodsExpression and quantification of Osteopontin (OPN) was detected in tumor and plasma samples of MPM patients by mRNA, immunohistochemistry and ELISA. The functional role of OPN was investigated in mouse MPM cell lines in vivo using an orthotopic syngeneic mouse model.ResultsIn patients with MPM, the protein OPN was significantly more expressed in tumors than in normal pleural tissues and predominantly produced by mesothelioma cells; plasma levels were elevated in patients and associated with poor prognosis. However, modulation of OPN levels was not significantly different in a series of 18 MPM patients receiving immunotherapy with durvalumab alone or with pembrolizumab in combination with chemotherapy, some of whom achieved a partial clinical response. Two established murine mesothelioma cell lines: AB1 and AB22 of sarcomatoid and epithelioid histology, respectively, spontaneously produced high levels of OPN. Silencing of the OPN gene (Spp1) dramatically inhibited tumor growth in vivo in an orthotopic model, indicating that OPN has an important promoting role in the proliferation of MPM cells. Treatment of mice with anti-CD44 mAb, blocking a major OPN receptor, significantly reduced tumor growth in vivo.ConclusionThese results demonstrate that OPN is an endogenous growth factor for mesothelial cells and inhibition of its signaling may be helpful to restrain tumor progression in vivo. These findings have translational potential to improve the therapeutic response of human MPM.

Metastatic hormone-sensitive prostate cancer (mHSPC) is usually categorized as high- or low-volume disease. This is relevant because low- and high-volume metastatic disease are associated with different outcomes, and thus management of the two forms should differ. Although some definitions have been reported, the concept of oligometastatic disease is not so clearly defined, giving rise to further variability in the choice of treatment, mainly between systemic agents and radiotherapy, especially in the era of metastasis-directed therapy. With the aim of providing clinicians with guidance on best practice, a group of medical and radiation oncologists, experts in prostate cancer, used the round robin method to generate a series of consensus statements on management of low-volume mHSPC. Consensus was obtained on three major areas of controversy: (1) with regard to clinical definitions of mHSPC, it was held that oligometastatic and low-volume disease refer to different concepts and should not be used interchangeably; (2) regarding therapy of de novo low-volume metastatic disease, androgen deprivation therapy alone can be considered undertreatment, and all patients should be evaluated for systemic treatment combinations; local therapy should not be denied in patients with mHSPC, regardless of the intensity of systemic therapy, and metastasis-directed therapy can be proposed in selected cases; (3) with regard to treatment of metachronous metastatic disease, patients should be evaluated for systemic treatment combinations. Metastasis-directed therapy can be proposed to delay systemic treatment in selected cases, especially if prostate-specific membrane antigen positron emission tomography staging has been performed and when indolent disease occurs. It is hoped that clinicians treating patients with mHSPC in daily practice will find this expert opinion of value.

Lithospheric slices preserving pre-Alpine metamorphic imprints are widely described in the Alps. The Variscan parageneses recorded in continental, oceanic, and mantle rocks suggest a heterogeneous metamorphic evolution across the Alpine domains. In this contribution, we collect quantitative metamorphic imprints and ages of samples that document Variscan tectonometamorphic evolution from 420 to 290 Ma. Based on age distribution and metamorphic imprint, three main stages can be identified for the Variscan evolution of the Alpine region: Devonian (early Variscan), late Devonian–late Carboniferous (middle Variscan), and late Carboniferous–early Permian (late Variscan). The dominant metamorphic imprint during Devonian times was recorded under eclogite and HP granulite facies conditions in the Helvetic–Dauphinois–Provençal, Penninic, and eastern Austroalpine domains and under Ep-amphibolite facies conditions in the Southalpine domain. These metamorphic conditions correspond to a mean Franciscan-type metamorphic field gradient. During the late Devonian–late Carboniferous period, in the Helvetic–Dauphinois–Provençal and central Austroalpine domains, the dominant metamorphic imprint developed under eclogite and HP granulite facies conditions with a Franciscan field gradient. Amphibolite facies conditions dominated in the Penninic and Southalpine domains and corresponded to a Barrovian-type metamorphic field gradient. At the Carboniferous–Permian transition, the metamorphic imprints mainly developed under amphibolite-LP granulite facies conditions in all domains of the Alps, corresponding to a mean metamorphic field gradient at the transition between Barrovian and Abukuma (Buchan) types. This distribution of the metamorphic imprints suggests a pre-Alpine burial of oceanic and continental crust underneath a continental upper plate, in a scenario of single or multiple oceanic subductions preceding the continental collision. Both scenarios are discussed and revised considering the consistency of collected data and a comparison with numerical models. Finally, the distribution of Devonian to Triassic geothermal gradients agrees with a sequence of events that starts with subduction, continues with continental collision, and ends with the continental thinning announcing the Jurassic oceanization.

Abstract Seismic anisotropy is controlled by aligned rock‐forming minerals, which most studies attribute to solid‐state shear with less consideration for magmatic fabric in plutonic rocks (rigid‐body rotation of crystals in the presence of melt). Our study counters this traditional solid‐state bias by evaluating contributions from fossil magmatic fabric. We collected samples from various tectonic settings, identified mineral orientations with electron backscatter diffraction and neutron diffraction, and calculated their bulk rock elastic properties. Results indicate that magmatic fabric may lead to moderate to strong anisotropy (3%–9%), comparable to solid‐state deformation. Also, magmatically aligned feldspar may cause foliation‐perpendicular fast velocity, a unique orientation that contrasts with a fast foliation typical of solid‐state deformation. Therefore, magmatic fabric may be more relevant to seismic anisotropy than previously recognized. Accordingly, increased considerations of magmatic fabric in arcs, batholiths, and other tectonic settings can change and potentially improve the prediction, observation, and interpretation of crustal seismic anisotropy.

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate

The rising global demand for animal products and the growing public concerns about the environment and animal welfare require dairy farms to improve their efficiency and apply more sustainable farming systems. Precision Livestock Farming (PLF) could represent a valuable support in addressing these challenges. In recent years, dairy farms have been modernising and introducing new sensors and automatic systems for managing the herd. However, the diffusion of new technologies in Italian dairy farms is still limited and farmers are reluctant to invest in precision systems. The aim of the study was to investigate the presence of PLF tools in Italian dairy farms, the motivations, benefits and limits of technological investments from the farmers’ point of view and the factors affecting the diffusion of technology. From November 2020 to June 2021, an online questionnaire was distributed and 52 responses were obtained. About 79% of the farms were located in Lombardy. The more represented milking system was the conventional milking parlour (73%), followed by automatic milking (19%). The average age of respondents was quite low: 35% of them was less than 40 years old and more than 50% was between 40 and 60. Statistical analyses were performed to evaluate the effects of different factors on the presence of technology at farm. The age of the farmer, the milk production level and the presence of an automatic milking system influenced the technological level of the farm. Precision systems that provide information on animal activity for the management of reproduction and on milk yield and flow are the most popular and are considered among the most useful. Management of reproduction and milk production are the areas where farmers appear to show interest for future investments as well. Younger farmers appear to have implemented more PLF systems than older ones, and they show a propensity to invest in latest generation precision tools. Farmers seem to have a growing interest in PLF, but some limits have been identified: the investment costs, followed by the lack of time to check information from sensor systems and the difficulty in data interpretation. As PLF technologies can play an important role in the development of sustainable, animal-friendly and efficient livestock production, further improvements and efforts are necessary to increase the propensity to PLF of dairy farmers. Results can be useful in the Italian context but also in other countries where dairy farming is rapidly intensifying but PLF is encountering resistance.

Hippocrates (Kos, c.460–c.370 BC) reminds us that “It is more important to know what sort of person has a disease than to know what sort of disease a person has”. This is still true today and reflects the emerging role of personalized medicine for patient-specific risk stratification and treatment programs. This report documents my personal experience as a patient with aggressive prostate cancer, who, as a scientist, had the privilege to access cutting-edge medical care and molecular profiling.

BackgroundTreatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors.MethodsBy a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs.ResultsThe analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction

Abstract Background Significant efforts have been made to investigate the molecular pathways involved in thymic carcinogenesis. However, genetic findings have still not impacted clinical practice. The aim of this exploratory trial was to evaluate the immunoscore and molecular profile of a series of thymic carcinomas (TCs), correlating this data with clinical outcome. Methods Formalin‐fixed, paraffin‐embedded (FFPE) TC tissues were retrieved from our center archive. The immunoscore was evaluated according to Angell and Gallon. DNA was extracted from FFPE tumor samples and, when available, from adjacent histologically normal tissues. Next‐generation sequencing (NGS) was performed targeting hotspot regions of 50 oncogenes and tumor suppressor genes. Results A series of 15 TCs were analyzed. After a median follow‐up of 82.4 months, the median overall survival was 104.7 months. The immunoscore was >2 in 5/15 patients (33%). Among the investigated genes, absence of mutations was observed in 5/15 patients (33%), whereas three variants in 1/15 (6%) patient, two variants in 4/15 (26%) patients, and one variant in 5/15 patients (33%) were found. The most recurrently mutated genes were FGFR3 (five mutations) and CDKN2A (three mutations, two of which were nonsense). Patients with CDKN2A loss showed a statistically significantly worse survival (P = 0.0013), whereas patients with FGFR3 mutations showed a statistically significantly better survival (P = 0.048). Conclusions This study adds data to the few existing reports on the mutational landscape of TCs, providing the first comprehensive analysis to date. Here, we confirm the low rate of mutations in TCs and suggest FGFR3 and CDKN2A mutations as intriguing potential therapeutic targets.

Abstract The Rocca Canavese Thrust Sheets Unit (RCTU) is a subduction-related mélange that represents the eastern-most complex of the Sesia–Lanzo Zone (SLZ), bounded by the Periadriatic (Canavese) Lineament that separates the Alpine subduction complex from the Southalpine domain. The RCTU is limited to the south by the Lanzo Massif (LM) and to the east by the Eclogitic Micaschists Complex (EMC). Particularly the tectonic contact area of the RCTU, adjacent to the neighbouring SLZ and the LM is characterised by a 100–200-m-thick mylonitic to ultra-mylonitic zone (MZ) that was active under blueschist-to greenschist-facies conditions. Despite the dominant mylonitic structure, some rocks (garnet-bearing gneiss, garnet-free gneiss and orthogneiss) still preserve pre-mylonitic parageneses in meter-sized domains. The scarcity of superposed structures and the small size of relicts impose a detailed microstructural analysis supported by chemical investigation to reconstruct the tectono-metamorphic history of the MZ. Therefore, we integrated the classical meso- and microstructural analysis approach with a novel quantitative technique based on the Quantitative X-Ray Map Analyzer (Q-XRMA), used to classify rock-forming minerals starting from an array of X-ray elemental maps, both at whole thin section and micro-domain scale, as well as to calibrate the maps for pixel-based chemical analysis and end-member component maps, relevant for a more robust conventional geothermobarometer application as well for calculating reliable PT pseudosections. Pre-Alpine relicts are garnet and white mica porphyroclasts in the garnet-bearing gneiss and biotite and K-feldspar porphyroclasts in garnet-free gneiss and orthogneiss, respectively, providing no PT constraints. The Alpine evolution of the MZ rocks, has been subdivided in three deformation and metamorphic stages. The first Alpine structural and metamorphic equilibration stage (D1 event) occurred at a pressure of ca. 1.25–1.4 GPa and at a temperature of ca. 420–510 °C, i.e. under blueschist-facies conditions. The D2 event, characterised by a mylonitic foliation that is pervasive in the MZ, occurred at ca. 0.95–1.1 GPa and ca. 380–500 °C, i.e. under epidote-blueschist-facies conditions. The D2 PT conditions in the MZ rocks are similar to those predicted for the blocks that constitute the RCTU mélange, and they overlap with the exhumation paths of the EMC and LM units. Therefore, the RCTU, EMC and LM rocks became coupled together during the D2 event. This coupling occurred during the exhumation of the different tectono-metamorphic units belonging to both continental and oceanic lithosphere and under a relatively cold thermal regime, typical for an active oceanic subduction zone, pre-dating Alpine continental collision.

The present study aims to understand the influence of a reduced amount of straw litter on goats’ lying comfort and hygienic characteristics of milk and straw. Lying behaviour (frequency, lying posture, location and social context) of 24 Alpine goats subjected to two different straw treatments (Regular: 2 kg/straw/head + 1 kg straw/head/day, n = 12; Scarce: 1 kg straw/head + 0.5 kg straw/head/day, n = 12) was observed from video recordings using a scan sampling method at 15-min scan intervals in March 2017. Moreover, straw and milk samples were submitted to microbiological analysis for the detection of total bacteria (SPC) and Enterobacteriaceae count. No significant differences in the duration of lying were observed between treatments, except at the beginning of the experimental period (Day 1: Regular: 26.0%; Scarce: 20.3% of scans; p

Because a human observer is typically not present during milking process when automatic milking systems (AMS) are used, human observation is replaced by mastitis detection systems consisting of sensors and algorithms that create alerts. Several authors suggest that sensing systems to detect clinical mastitis (CM) are in need of improvement. The aim of this retrospective study was to observe trends over time of potential indicators of CM, thus identifying promising CM indicators and analysis methods. Data from a Northeastern USA commercial dairy farm with 1280 Holstein Friesian cows using 20 AMS units were used for the analysis. Over a one-year time period, there were 117 confirmed cases of CM in this herd. Thirty milking sessions prior to CM confirmation were used for this analysis (n = 3134). Of the 117 confirmed CM cases, 12% were in primiparous cows (L1), 24% in second lactation cows (L2) and 64% in third or greater lactation cows (L3+). Differences between group average CM-confirmed and non-CM quarters were observed prior to CM confirmation for quarter-level electrical conductivity (ECq), milk production rate (MPRq), average milk flow rate (AMFq) and peak milk flow rate (PMFq). Positive indications of CM were apparent well before confirmation of visual signs of CM for ECq and MPRq; however, positive indications for AMFq occurred only one day before CM confirmation. The combination of ECq, MPRq and AMFq is potentially useful for differentiating between an early (before visual signs of CM are manifested) detection and a false positive detection.Highlights Data from 1280 Holstein Friesian cows using 20 AMS units were used for the analysis The progression over time of changes in milk and milking characteristics was investigated in the period prior to clinical mastitis Changes in quarter electrical conductivity indicate it is possible to detect developing mastitis before clinical signs are manifested

Background and Objective: Prediction of fractures in cancer survivors exposed to hormone-deprivation therapies (HDTs) is a challenge since bone loss is rapid and severe, and determinants of fractures in this setting are still largely unknown. In this study we investigated reliability of the WHO Fracture Risk Assessment Tool (FRAX) and bone mineral density (BMD) to identify subjects developing vertebral fractures during HDTs. Design: Five-hundred-twenty-seven consecutive subjects (429 females with breast cancer, 98 males with prostate cancer; median age 61 years), under HDTs for at least 6 months, were evaluated for vertebral fractures by a radiological and morphometric approach, in relationship with FRAX score, body mass index (BMI), BMD, age and duration of HDTs. Results: Vertebral fractures were found in 140 subjects (26.6%) and spine deformity index was significantly associated with duration of HDTs (rho 0.38; p

Optimal milking management leads to an increase in production efficiency while respecting animal welfare and health. Not all farms can equip themselves with high level technological systems for economic, generational and structural reasons. The aim of the study was to assess milking performances, cow behaviour and microclimatic condition in farm areas using an integrated data collection system based on surveys and low-cost sensors. The use of video recordings and mobile electronic flowmeters highlighted significant differences between farms that milked two and three times a day. Milking efficiency parameters (cow/hour; cows/stall per hour; milk/hour; milk/stall per hour) were calculated. In particular, the milk/stall per hour parameter emerged as the most interesting. Animal stay time, defined as the time running from when cows are moved from the housing to the beginning of the milking, was calculated and the highest value (76.3 minutes) was observed in farms with more than 10 stalls/row. Hobo pendant sensors were used in order to evaluate cows lying behaviour: no differences were observed between farms that milked two and three times a day (11.3 vs 11.0 h/d of lying). Microclimatic conditions were influenced by both the season (p

The aim of this study was to examine the time budgets of 20 lactating primiparous Italian Holstein cows and to determine the relationships between lying and standing behaviour, milk production and Body Condition Score in the first stage of lactation. Parturition period ranged from 15 September to 31 March and in the first seven lactation days all cows were equipped with individual 3-axes acceleration and angular displacement loggers, throughout 150 days for lying and standing behaviour measuring. Body Condition Scores (BCS) were estimated weekly, while milk production (in both morning and evening milking) and humidity and temperature air data were collected daily. Average individual milk yield was 27.3 ± 6.24 kg/d and milking time was 4.95 ± 1.94 min. Individual BCS was on average 3.46 ± 0.30 and standing daily time was 13.5 ± 2.26 h/d. Primiparous cows with BCS at parturition

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design, setting, and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.