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Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones’ survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models. We developed new HDAC inhibitors (5a–p), typified by a tetrahydro-γ-carboline scaffold, characterized by high HDAC6 inhibition potency with balanced physicochemical properties for in vivo studies. Compound 5d(repistat, IC50HDAC6 = 6.32 nM) increased the levels of acetylated α-tubulin compared to histone H3 in ARPE-19 and 661W cells. 5dpromoted vision rescue in the atp6v0e1–/–zebrafish model of photoreceptor dysfunction. A single intravitreal injection of 5din the rd10mouse model of RP supported morphological and functional preservation of cone cells and maintenance of the retinal pigment epithelium array.

Human presence and activities have profoundly altered animals’ habitats, exposing them to greater risks but also providing new opportunities and resources. The animals’ capacity to effectively navigate and strike a balance between risks and benefits is crucial for their survival in the Anthropocene era. Red foxes (Vulpes vulpes), adept urban dwellers, exhibit behavioral plasticity in human-altered environments. We investigated variations in detection frequency on trail cameras and the behavioral responses (explorative, bold, and fearful) of wild red foxes living along an urbanization gradient when exposed to a metal bin initially presented clean and then filled with anthropogenic food. All fox populations displayed an increased interest and similar explorative behavioral responses toward the anthropogenic food source, irrespective of the urbanization gradient. Despite no impact on explorative behaviors, foxes in more urbanized areas initially showed heightened fear toward the empty bin, indicating increased apprehension toward novel objects. However, this fear diminished over time, and in the presence of food, urban foxes displayed slightly reduced fear compared with their less urban counterparts. Our results highlight foxes’ potential for adaptability to human landscapes, additionally underscoring the nuanced interplay of fear and explorative behavioral response of populations living along the urbanization gradient.

Distance traveled and home range size describe how animals move in space. The seasonal variations of these parameters are important to comprehensively understand animal ecology and its connection with reproductive behavior and energy costs. Researchers usually estimate the distance traveled as the sum of the straight-line displacements between sampled positions, but this approach is sensitive to the sampling frequency and does not account for the tortuosity of the animal’s movements. By means of the continuous-time movement modeling which takes into account autocorrelation and tortuosity of movement data, we estimated the distance traveled and monthly home range size of 28 wild boar Sus scrofaand modeled their inter-sexual seasonal variability. Males traveled longer distances and used larger home ranges than females, particularly during the rut in autumn-winter, consistently with the different biological cycles of males and females. Males enlarged their home ranges during the rut but traveled constant average distances along the year, whereas females traveled shorter distances in correspondence with the peak of food resources and birth periods but exhibited constant home range size across seasons. The differences between the seasonal variation patterns of distance traveled and home range size, observed in both sexes, revealed the complex relationship between these two aspects of spatial behavior and the great opportunity of including both distance traveled and home range size in behavioral ecology investigations. We provided a detailed analysis of wild boar spatial behavior and its relationships with the reproductive cycles of males and females, promoting a deeper comprehension of their behavioral ecology.

New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)-5a–v, (±)-6a–j, and (±)-7a–d) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-5d, (±)-5l, and (±)-5r. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. 5vwas identified as selective for MAGL when compared with other serine hydrolases. Solubility, in vitrometabolic stability, cytotoxicity, and absence of mutagenicity were determined for selected analogues. The most promising compounds ((±)-5c, (±)-5d, and (±)-5v) were used for in vivostudies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl-sn-glycerol levels in forebrain tissue. In particular, 5vis characterized by a high eudysmic ratio and (3R,4S)-5vis one of the most potent irreversible inhibitors of h/mMAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.

ABSTRACTThe European policy on disinformation has changed in the last years. From a self-regulatory approach, the Union has moved towards a comprehensive strategy to address disinformation. The Digital Services Act and the Strengthened Code of Practice on Disinformation are particular examples of this transformation. However, the European approach still faces important challenges in the implementation phase. This work aims to address the evolution of the European policy on disinformation, particularly looking at the Strengthened Code of Practice on Disinformation.

Arrays of single photon avalanche diodes (SPADs) fabricated in a 150 nm CMOS technology have been exposed to neutrons up to fluences of about $4.3 \times 10^{10}~1$ MeV neutron equivalent cm $^{-2}$ , with fluxes around $3 \times 10^{6}~1$ MeV neutron equivalent cm $^{-2}\text{s}^{-1}$ . Dark count rate (DCR) was monitored during irradiation and for some time, from 5 to 23 min, depending on the irradiation step, at the end of the irradiation interval to investigate the dynamics of defect formation and short-term annealing. Measurements were performed both on single- and on dual-layer devices, where SPAD arrays are face to face bonded and read out in coincidence. A range of different DCR behaviors were detected after single neutron interaction with the device substrate, including in particular partial performance recovery following a logarithmic relaxation process, but also damped oscillation phenomena, sudden step-shaped changes, and the emergence of RTS-like fluctuations, pointing to different defect reordering dynamics.

AimsActivating somatic mutations or gene amplification of KITresult in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence of KITgenetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours.MethodsA retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs with KITalterations. A histological assessment of KIT-altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lacking KITgenetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type.ResultsWe identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affecting KIT, including activating somatic mutations (n=4) or gene amplification (n=14). All KIT-altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lacking KITgenetic alterations, no distinctive genetic features were identified. In two metastatic KIT-altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, the KITmutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers.ConclusionsKITgenetic alterations are vanishingly rare in BC. KIT-altered BCs are of high grade but lack distinctive histological features. Genetic alterations in KITmight be late events in the evolution and/or progression of BC.

Potential benefits such as agile service delivery have led many companies to deliver their business capabilities through microservices. Bad smells are however always around the corner, as witnessed by the considerable body of literature discussing architectural smells that possibly violate the design principles of microservices. In this paper, we systematically review the white and grey literature on the topic, in order to identify the most recognised architectural smells for microservices and to discuss the architectural refactorings allowing to resolve them.

Despite a wide spectrum of clinical presentations, including primary or secondary, most angiosarcomas are considered high grade. One exception is primary breast angiosarcoma, where historically, histologic grading has shown to predict outcome using the Rosen 3-tier system. However, more recent studies have challenged this concept suggesting that even in this specific clinical context angiosarcomas should be considered high grade. This study aimed to critically reevaluate the impact of histologic grade in a clinically uniform cohort managed at a single institution using a newly proposed grading system. Our study included 49 primary breast angiosarcomas diagnosed during 1994 to 2022 (median follow-up: 33 mo), classified as low grade (29%), intermediate grade (20%), and high grade (51%), based on mitotic count, extent of solid components, and necrosis. At last follow-up, 22% patients developed locoregional recurrences, 63% distant metastases, and 47% patients died of disease. As patients with low and intermediate-grade angiosarcomas had relatively similar outcomes, our cohort was further analyzed using a 2-tier system (low grade and high grade). Targeted-DNA next-generation sequencing (505 cancer gene panel) performed in 11 cases found KDRmutations in 78% and PIK3CAmutations in 44% of high-grade lesions. Histologic grade, by either 3-tier or 2-tier grading systems, had a strong impact on survival, with the 2-tier system being an independent predictor of disease-specific survival and overall survival. Based on 2-tier system, the 5-year overall survival was 38% for high-grade angiosarcoma and 74% for low-grade angiosarcoma. PIK3CAmutations alone or concurrent with KDRalterations were identified in angiosarcomas with worse prognosis.

Core needle biopsy (CNB) of breast lesions is routine for diagnosis and treatment planning. Despite refinement of diagnostic criteria, the diagnosis of breast lesions on CNB can be challenging. At many centers, including ours, confirmation of diagnoses rendered in other laboratories is required before treatment planning. We identified CNBs first diagnosed elsewhere that were reviewed in our department over the course of 1 year because the patients sought care at our center and in which a change in diagnosis had been recorded. The outside and in-house CNB diagnoses were then classified based on Breast WHO Fifth Edition diagnostic categories. The impact of the change in diagnosis was estimated based on the subsequent surgical management. Findings in follow-up surgical excisions (EXCs) were used for validation. In 2018, 4950 outside cases with CNB were reviewed at our center. A total of 403 CNBs diagnoses were discrepant. Of these, 147 had a change in the WHO diagnostic category: 80 (54%) CNBs had a more severe diagnosis and 44 (30%) a less severe diagnosis. In 23 (16%) CNBs, the change of diagnostic category had no impact on management. Intraductal proliferations (n=54), microinvasive carcinoma (n=18), and papillary lesions (n=35) were the most disputed diagnoses. The in-house CNB diagnosis was confirmed in most cases with available excisions. Following CNB reclassification, 22/147 (15%) lesions were not excised. A change affecting the surgical management at our center occurred in 2.5% of all CNBs. Our results support routine review of outside breast CNB as a clinically significant practice before definitive treatment.

Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality.

Microservice security smells denote possible symptoms of bad design decisions that may compromise the security of an application. Therefore, security smells should be carefully checked and possibly resolved by applying some refactorings. In this paper, we introduce SST (Security Smell Triager) an open-source tool that automates the triage of the possibly multiple instances of security smells affecting an existing microservice application, to support determining which instance is “more urgent” than others and should be considered first. SST also supports reasoning on whether/how to resolve a security smell instance through refactoring, by displaying the impact on quality attributes (like maintainability and performance efficiency) of both security smell instances and their refactoring. We also assess the usefulness of SST through a controlled experiment.

AbstractThe severity of the COVID-19 pandemic has necessitated the search for drugs against SARS-CoV-2. In this study, we explored via in silicoapproaches myxobacterial secondary metabolites against various receptor-binding regions of SARS-CoV-2 spike which are responsible in recognition and attachment to host cell receptors mechanisms, namely ACE2, GRP78, and NRP1. In general, cyclic depsipeptide chondramides conferred high affinities toward the spike RBD, showing strong binding to the known viral hot spots Arg403, Gln493 and Gln498 and better selectivity compared to most host cell receptors studied. Among them, chondramide C3 (1) exhibited a binding energy which remained relatively constant when docked against most of the spike variants. Chondramide C (2) on the other hand exhibited strong affinity against spike variants identified in the United Kingdom (N501Y), South Africa (N501Y, E484K, K417N) and Brazil (N501Y, E484K, K417T). Chondramide C6 (9) showed highest BE towards GRP78 RBD. Molecular dynamics simulations were also performed for chondramides 1and 2against SARS-CoV-2 spike RBD of the Wuhan wild-type and the South African variant, respectively, where resulting complexes demonstrated dynamic stability within a 120-ns simulation time. Protein-protein binding experiments using HADDOCK illustrated weaker binding affinity for complexed chondramide ligands in the RBD against the studied host cell receptors. The chondramide derivatives in general possessed favorable pharmacokinetic properties, highlighting their potential as prototypic anti-COVID-19 drugs limiting viral attachment and possibly minimizing viral infection.Communicated by Ramaswamy H. Sarma

The terms „Socinian“ and „Arminian“ (despite their often equivocal and polyvalent use) refer primarily to the members of two small Christian communities viewed with great suspicion by the established churches: the Ecclesia minorof the Polish Brethren, on the one hand, and the Dutch Remonstrant Brotherhood, on the other. These were two numerically small and marginalized groups, but capable of influencing substantial numbers of theologians and intellectuals of different denominational backgrounds in many European countries. The Dutch Remonstrants faced frequent allegations of Socinianism: far from diminishing over time, these charges became harsher and more insistent after the destruction of the Ecclesia minorand the resulting Socinian diaspora. However, this study shows that the relationship was not one-way: Arminius’ heirs in turn influenced those of Sozzini, as evidenced by the development of the two theological traditions on the crucial issue of Christ’s redemption and atonement. At the end of the seventeenth century, on this as on other subjects, the theories of the Remonstrants established some hegemony over the doctrinal elaborations of the successors to the Socinian tradition.

ABSTRACTIntroductionIn this article, authors report an inclusive discussion about the combinatorial approach for the treatment of cardiovascular diseases (CVDs) and for counteracting the cardiovascular risk factors. The mentioned strategy was demonstrated to be useful for improving the efficacy of pharmacological treatments and in CVDs showed superior efficacy with respect to the classical monotherapeutic approach.Areas coveredAccording to this topic, authors analyzed the combinatorial treatments that are available on the market, highlighting clinical studies that demonstrated the efficacy of combinatorial drug strategies to cure CVDs and related risk factors. Furthermore, the review gives an outlook on the future perspective of this therapeutic option, highlighting novel drug targets and disease models that could help the future cardiovascular drug discoveryExpert opinionThe use of specifically designed and increasingly rational and effective drug combination therapies can therefore be considered the evolution of polypharmacy in cardiometabolic and CVDs. This approach can allow to intervene on multiple etiopathogenetic mechanisms of the disease or to act simultaneously on different pathologies/risk factors, using the combinations most suitable from a pharmacodynamic, pharmacokinetic, and toxicological perspective, thus finding the most appropriate therapeutic option.

Bull-related injury continues to contribute to an unacceptable number of serious injuries and deaths, and bullfighting continues to be a popular, deeply traditional celebration of the culture of many Iberic-American countries. Most accidents due to bull attacks are horn-related penetrating traumas. Blunt chest trauma can cause a wide range of clinical presentations and injuries, making the diagnostics and therapies extremely challenging. Consequently, it is vital to quickly identify major life-threatening chest wall and intrathoracic injuries. In this case report, we aimed to describe the complexity of the management and the treatment of a blunt trauma patient hit by a bull.

On a population level, individual plasticity in reproductive phenology can provoke either anticipations or delays in the average reproductive timing in response to environmental changes. However, a rigid reliance on photoperiodism can constraint such plastic responses in populations inhabiting temperate latitudes. The regulation of breeding season length may represent a further tool for populations facing changing environments. Nonetheless, this skill was reported only for equatorial, nonphotoperiodic populations. Our goal was to evaluate whether species living in temperate regions and relying on photoperiodism to trigger their reproduction may also be able to regulate breeding season length. During 10 years, we collected 2,500 female reproductive traits of a mammal model species (wild boar Sus scrofa) and applied a novel analytical approach to reproductive patterns in order to observe population-level variations of reproductive timing and synchrony under different weather and resources availability conditions. Under favorable conditions, breeding seasons were anticipated and population synchrony increased (i.e., shorter breeding seasons). Conversely, poor conditions induced delayed and less synchronous (i.e., longer) breeding seasons. The potential to regulate breeding season length depending on environmental conditions may entail a high resilience of the population reproductive patterns against environmental changes, as highlighted by the fact that almost all mature females were reproductive every year.

Ultra-hot Jupiters (UHJs) are among the best targets for atmospheric characterization at high spectral resolution. Resolving their transmission spectra as a function of orbital phase offers a unique window into the 3D nature of these objects. In this work, we present three transits of the UHJ WASP-121b observed with Gemini-S/IGRINS. For the first time, we measure the phase-dependent absorption signals of CO and H2O in the atmosphere of an exoplanet, and we find that they are different. While the blueshift of CO increases during the transit, the absorption lines of H2O become less blueshifted with phase, and even show a redshift in the second half of the transit. These measurements reveal the distinct spatial distributions of both molecules across the atmospheres of UHJs. Also, we find that the H2O signal is absent in the first quarter of the transit, potentially hinting at cloud formation on the evening terminator of WASP-121b. To further interpret the absorption trails of CO and H2O, as well as the Doppler shifts of Fe previously measured with VLT/ESPRESSO, we compare the data to simulated transits of WASP-121b. To this end, we post-process the outputs of the global circulation models with a 3D Monte-Carlo radiative transfer code. Our analysis shows that the atmosphere of WASP-121b is subject to atmospheric drag, as previously suggested by small hotspot offsets inferred from phase-curve observations. Our study highlights the importance of phase-resolved spectroscopy in unravelling the complex atmospheric structure of UHJs and sets the stage for further investigations into their chemistry and dynamics.

Irrigation strongly influences land‐atmosphere processes from regional to global scale. Therefore, an accurate representation of irrigation is crucial to understand these interactions and address water resources issues. While irrigation schemes are increasingly integrated into land surface models, their evaluation and further development remains challenging due to data limitations. This study assessed the representation of field‐scale irrigation using the Community Land Model version 5 (CLM5) through comparison of observed and simulated soil moisture, transpiration and crop yield. Irrigation was simulated by (a) adjusting the current irrigation routine and (b) by implementing a novel irrigation data stream that allows to directly use observed irrigation amounts and schedules. In a following step, the effect of different irrigation scenarios at the regional scale was simulated by using this novel data stream. At the plot scale, the novel irrigation data stream performed better in representing observed SM dynamics compared to the current irrigation routine. Nonetheless, simplifications in crop and irrigation representation and uncertainty in the relation between water stress and yield currently limit the ability of CLM5 for field‐scale irrigation scheduling. Still, the simulations revealed valuable insights into model performance that can inform and improve the modeling beyond the field scale. At regional scale, the simulations identified irrigation priorities and potential water savings. Furthermore, application of LSMs such as CLM5 can help to study the effects of irrigation beyond water availability, for example, on energy fluxes and climate, thus providing a powerful tool to assess the broader implications of irrigation at larger scale. Irrigation impacts how land and atmosphere interact, both locally and globally. Therefore, it is important to understand the effects of irrigation practices and improve how water resources are managed. Advanced models such as land surface models now include irrigation. However, developing these models is difficult due to limited data. This study used the Community Land Model version 5 (CLM5) to compare observed and simulated soil moisture, plant water use, and crop yield. Two methods were used: an updated irrigation routine and a new data stream that uses actual irrigation amounts and schedules. The new data stream more accurately represented soil moisture. Simplifications in how the model handles crops and irrigation, and uncertainty about the link between water stress and yield, limit CLM5's effectiveness for precise irrigation planning. Still, the simulations provided valuable insights into the model's performance. At a regional level, the simulations highlighted key areas for irrigation and potential water savings. Models like CLM5 can help study the effects of irrigation on water availability, energy fluxes, and climate, making them useful tools for improving water management and allocation. The CLM5 irrigation routine is tested at different scales and enhanced with the option to prescribe irrigation amounts and schedulesSoil moisture dynamics were simulated well but model simplifications limit the ability of CLM5 for field‐scale irrigation schedulingRegional simulations using different irrigation scenarios identified priorities and water savings for improved irrigation management The CLM5 irrigation routine is tested at different scales and enhanced with the option to prescribe irrigation amounts and schedules Soil moisture dynamics were simulated well but model simplifications limit the ability of CLM5 for field‐scale irrigation scheduling Regional simulations using different irrigation scenarios identified priorities and water savings for improved irrigation management

Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N= 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P< 0.00001). Notably, AR-V7 was detected in 2 primary BC and 7 metastatic/recurrent BC patients with no prior endocrine therapy. We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.

Classic adenoid cystic carcinomas (C-AdCCs) of the breast are rare, relatively indolent forms of triple negative cancers, characterized by recurrent MYBor MYBL1genetic alterations. Solid and basaloid adenoid cystic carcinoma (SB-AdCC) is considered a rare variant of AdCC yet to be fully characterized. Here, we sought to determine the clinical behavior and repertoire of genetic alterations of SB-AdCCs. Clinicopathologic data were collected on a cohort of 104 breast AdCCs (75 C-AdCCs and 29 SB-AdCCs). MYB expression was assessed by immunohistochemistry and MYB-NFIBand MYBL1gene rearrangements were investigated by fluorescent in-situ hybridization. AdCCs lacking MYB/MYBL1rearrangements were subjected to RNA-sequencing. Targeted sequencing data were available for 9 cases. The invasive disease-free survival (IDFS) and overall survival (OS) were assessed in C-AdCC and SB-AdCC. SB-AdCCs have higher histologic grade, and more frequent nodal and distant metastases than C-AdCCs. MYB/MYBL1rearrangements were significantly less frequent in SB-AdCC than C-AdCC (3/14, 21% vs 17/20, 85% P< 0.05), despite the frequent MYB expression (9/14, 64%). In SB-AdCCs lacking MYB rearrangements, CREBBP, KMT2C, and NOTCH1alterations were observed in 2 of 4 cases. SB-AdCCs displayed a shorter IDFS than C-AdCCs (46.5 vs 151.8 months, respectively, P< 0.001), independent of stage. In summary, SB-AdCCs are a molecularly heterogeneous but clinically aggressive group of tumors. Less than 25% of SB-AdCCs display the genomic features of C-AdCC. Defining whether these tumors represent a single entity or a collection of different cancer types with a similar basaloid histologic appearance is warranted.

Classic adenoid cystic carcinomas (C-AdCCs) of the breast are rare, relatively indolent forms of triple negative cancers, characterized by recurrent MYBor MYBL1genetic alterations. Solid and basaloid adenoid cystic carcinoma (SB-AdCC) is considered a rare variant of AdCC yet to be fully characterized. Here, we sought to determine the clinical behavior and repertoire of genetic alterations of SB-AdCCs. Clinicopathologic data were collected on a cohort of 104 breast AdCCs (75 C-AdCCs and 29 SB-AdCCs). MYB expression was assessed by immunohistochemistry and MYB-NFIBand MYBL1gene rearrangements were investigated by fluorescent in-situ hybridization. AdCCs lacking MYB/MYBL1rearrangements were subjected to RNA-sequencing. Targeted sequencing data were available for 9 cases. The invasive disease-free survival (IDFS) and overall survival (OS) were assessed in C-AdCC and SB-AdCC. SB-AdCCs have higher histologic grade, and more frequent nodal and distant metastases than C-AdCCs. MYB/MYBL1rearrangements were significantly less frequent in SB-AdCC than C-AdCC (3/14, 21% vs 17/20, 85% P< 0.05), despite the frequent MYB expression (9/14, 64%). In SB-AdCCs lacking MYB rearrangements, CREBBP, KMT2C, and NOTCH1alterations were observed in 2 of 4 cases. SB-AdCCs displayed a shorter IDFS than C-AdCCs (46.5 vs 151.8 months, respectively, P< 0.001), independent of stage. In summary, SB-AdCCs are a molecularly heterogeneous but clinically aggressive group of tumors. Less than 25% of SB-AdCCs display the genomic features of C-AdCC. Defining whether these tumors represent a single entity or a collection of different cancer types with a similar basaloid histologic appearance is warranted.

Progression in digital pathology has yielded new opportunities for a remote work environment. We evaluated the utility of digital review of breast cancer immunohistochemical prognostic markers (IHC) using whole slide images (WSI) from formalin fixed paraffin embedded (FFPE) cytology cell block specimens (CB) using three different scanners.

AimsBreast neuroendocrine tumours (NETs) constitute a rare histologic subtype of oestrogen receptor (ER)-positive breast cancer, and their definition according to the WHO classification was revised in 2019. Breast NETs display histologic and transcriptomic similarities with mucinous breast carcinomas (MuBCs). Here, we sought to compare the repertoire of genetic alterations in breast NETs with MuBCs and NETs from other anatomic origins.MethodsOn histologic review applying the new WHO criteria, 18 breast tumours with neuroendocrine differentiation were reclassified as breast NETs (n=10) or other breast cancers with neuroendocrine differentiation (n=8). We reanalysed targeted sequencing or whole-exome sequencing data of breast NETs (n=10), MuBCs type A (n=12) and type B (n=11).ResultsBreast NETs and MuBCs were found to be genetically similar, harbouring a lower frequency of PIK3CAmutations, 1q gains and 16q losses than ER-positive/HER2-negative breast cancers. 3/10 breast NETs harboured the hallmark features of ER-positive disease (ie, PIK3CAmutations and concurrent 1q gains/16q losses). Breast NETs showed an enrichment of oncogenic/likely oncogenic mutations affecting transcription factors compared with common forms of ER-positive breast cancer and with pancreatic and pulmonary NETs.ConclusionsBreast NETs are heterogeneous and are characterised by an enrichment of mutations in transcription factors and likely constitute a spectrum of entities histologically and genomically related to MuBCs. While most breast NETs are distinct from ER-positive/HER2-negative IDC-NSTs, a subset of breast NETs appears to be genetically similar to common forms of ER-positive breast cancer, suggesting that some breast cancers may acquire neuroendocrine differentiation later in tumour evolution.

AimsHere we explore the presence of mediator complex subunit 12 (MED12) exon 2 and telomerase reverse transcriptase (TERT) promoter hotspot mutations in complex fibroadenomas (CFAs) of the breast.MethodsThe stromal components from 18 CFAs were subjected to Sanger sequencing of MED12exon 2 and the TERTpromoter hotspot loci. The epithelial and stromal components of two MED12mutated CFAs were subjected to laser capture microdissection, and Sanger sequencing of MED12exon 2, TERTpromoter and PIK3CAexons 9 and 20, separately.ResultsMED12exon 2 mutations were identified in the stroma of 17% of CFAs. The analyses of epithelial and stromal components, microdissected separately, revealed that MED12mutations were restricted to the stroma. No TERTpromoter or PIK3CAmutations in exons 9 and 20 were detected in analysed CFAs.ConclusionsLike conventional fibroadenomas, MED12exon 2 mutations appear to be restricted to the stromal component of CFAs, supporting the notion that CFAs are stromal neoplasms.

Purpose: Hyponatremia is the most frequent electrolytic disorder in clinical practice. In addition to neurological symptoms, hyponatremia, even when mild/moderate and chronic, has been related to other manifestations, such as bone demineralization and increased risk of fractures. To better elucidate tissue alterations associated with reduced serum sodium concentration [Na+], we developed an in vivo model of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. Methods and results: Hyponatremia was induced in Foxn1nu/numice by subcutaneous infusion of the vasopressin analog 1-deamino [8-D-arginine] vasopressin (dDAVP) for 14 days via osmotic mini-pumps. Mice in the control group were infused with isotonic saline solution. Serum [Na+] progressively decreased, with a nadir of 123.4 ± 2.3 mEq/L (mean ± SD, dDAVP 0.3 ng/h) and 111.6 ± 4.7 mEq/L (mean ± SD, dDAVP 0.5 ng/h). Evident signs of liver steatofibrosis were observed at histology in hyponatremic mice. Accordingly, the expression of proteins involved in lipid metabolism (SREBP-1, PPARα and PPARγ) and in myofibroblast formation (αSMA and CTGF) significantly increased. Furthermore, heme oxygenase 1 expression was up-regulated in Kupffer and hepatic stellate cells in the liver of hyponatremic mice. Testis alterations were also observed. In particular, the thickness of the seminiferous epithelium appeared reduced. The expression levels of PCNA and PTMA, which are involved in DNA replication and germ cells maturation, were markedly reduced in the testis of hyponatremic mice. Conclusion: Overall, these findings shed new light on the possible consequences of chronic hyponatremia and prompt a more thorough evaluation of hyponatremic patients.

This work focuses on the so called 'first wave' of COVID-19 epidemic (21 February-10 April 2020) and aims at outlining a viable strategy to contain the COVID-19 spread and efficiently plan an exit from lockdown measures. It offers a model to estimate the total number of actual infected among the population at national and regional level inferring from the lethality rate, to fill the proven gap with the number of officially reported cases. The result is the reference population used to develop a forecasting exercise of new daily cases, compared to the reported ones. The eventual discrepancy is analysed in terms of compliance with the restrictive measures or to an insufficient number of tests performed. This simulation indicates that an efficient testing policy is the main actionable measure. Furthermore, the paper estimates the optimal number of tests to be performed at national and regional level, in order to be able to release an increasing number of individuals from restrictive measures.

Progression in digital pathology has yielded new opportunities for a remote work environment. We evaluated the utility of digital review of breast cancer immunohistochemical prognostic markers (IHC) using whole slide images (WSI) from formalin fixed paraffin embedded (FFPE) cytology cell block specimens (CB) using three different scanners.

Measurements of the atmospheric carbon (C) and oxygen (O) relative to hydrogen (H) in hot Jupiters (relative to their host stars) provide insight into their formation location and subsequent orbital migration1,2. Hot Jupiters that form beyond the major volatile (H2O/CO/CO2) ice lines and subsequently migrate post disk-dissipation are predicted have atmospheric carbon-to-oxygen ratios (C/O) near 1 and subsolar metallicities2, whereas planets that migrate through the disk before dissipation are predicted to be heavily polluted by infalling O-rich icy planetesimals, resulting in C/O < 0.5 and super-solar metallicities1,2. Previous observations of hot Jupiters have been able to provide bounded constraints on either H2O (refs. 3–5) or CO (refs. 6,7), but not both for the same planet, leaving uncertain4the true elemental C and O inventory and subsequent C/O and metallicity determinations. Here we report spectroscopic observations of a typical transiting hot Jupiter, WASP-77Ab. From these, we determine the atmospheric gas volume mixing ratio constraints on both H2O and CO (9.5 × 10−5–1.5 × 10−4and 1.2 × 10−4–2.6 × 10−4, respectively). From these bounded constraints, we are able to derive the atmospheric C/H (0.35−0.10+0.17× solar) and O/H (0.32−0.08+0.12× solar) abundances and the corresponding atmospheric carbon-to-oxygen ratio (C/O = 0.59 ± 0.08; the solar value is 0.55). The sub-solar (C+O)/H (0.33−0.09+0.13× solar) is suggestive of a metal-depleted atmosphere relative to what is expected for Jovian-like planets1while the near solar value of C/O rules out the disk-free migration/C-rich2atmosphere scenario.

The SWI/SNF family of proteins is a multisubunit ATPase complex frequently altered in human cancer. Inactivating mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCs) underpin a subset of tumors such as the malignant rhabdoid tumor and small cell carcinoma of the ovary, hypercalcemic type. Here, we investigated the genotypic and phenotypic characteristics of breast cancers harboring somatic genetic alterations affecting genes of the SMARC family. We analyzed a series of 6026 primary and metastatic breast cancers subjected to targeted-capture sequencing. SMARC core subunit (SMARCA4, SMARCB1, and SMARCA2) alterations were identified in <1% of all breast cancers, consisting of 27 primary and 30 recurrent/metastatic tumors. The majority of SMARCalterations were monoallelic mutations (47/57, 82%) and thus categorized into two groups: Class 1 alterations consisting of potentially pathogenic mutations and rearrangements and Class 2 alterations consisting of missense mutations and small in-frame deletions of unknown significance. Biallelic events in a SMARC gene were present in a minority of cases (10/57, 18%). Histologic patterns in the form of rhabdoid, composite rhabdoid, sarcomatoid or anaplastic features were observed in a subset of Class 1 primary and metastatic tumors (7/57, 12%). SMARC protein was preserved in nearly all tumors analyzed with immunohistochemistry (26/30, 87%). Four Class 1 tumors demonstrated altered SMARC protein expression in the form of loss (1/30, 3%) or mosaic pattern (3/30, 10%). Complete loss of SMARCA2 (BRM) was observed in a sole tumor with composite rhabdoid morphology, and biallelic hits in the SMARCA2gene. The genomic landscape of both primary Class 1 and 2 breast cancers did not reveal any characteristic findings. In summary, SMARC alterations likely contribute to the biology of a rare subset of breast cancers in the form of biallelic or pathogenic alterations in SMARC, as evidenced by SMARC-deficient phenotype or altered expression of SMARC protein.

Lobular carcinoma in situ (LCIS) is currently classified as classic (CLCIS), florid (FLCIS), and pleomorphic (PLCIS). Given the rarity of FLCIS and PLCIS, information on their clinico-pathologic features and biologic potential remains limited. We evaluated the upgrade rates at excision of FLCIS and PLCIS diagnosed on inhouse core needle biopsy (CNB) and their clinical presentation and follow-up. Over a period of 11 and a half years, there were a total of 36 inhouse CNBs with pure PLCIS (n= 8), FLCIS (n= 24), or LCIS with pleomorphic features (LCIS-PF) (n= 4). The upgrade rates to invasive carcinoma or ductal carcinoma in situ (DCIS) were 25% for PLCIS (2/8), 17% for FLCIS (4/24), and 0% for LCIS-PF (0/4). The overall upgrade rate of PLCIS and FLCIS combined was 19% (6/32). All but one case (not upgraded at excision) were radiologic–pathologic concordant. Apocrine features, previously reported only in PLCIS, were also noted in FLCIS. HER2 overexpression was seen in 13% of cases. This study highlights the more aggressive biologic features of PLCIS and FLCIS compared to CLCIS and supports surgical management for these lesions.

Lobular carcinoma in situ (LCIS) is currently classified as classic (CLCIS), florid (FLCIS), and pleomorphic (PLCIS). Given the rarity of FLCIS and PLCIS, information on their clinico-pathologic features and biologic potential remains limited. We evaluated the upgrade rates at excision of FLCIS and PLCIS diagnosed on inhouse core needle biopsy (CNB) and their clinical presentation and follow-up. Over a period of 11 and a half years, there were a total of 36 inhouse CNBs with pure PLCIS (n= 8), FLCIS (n= 24), or LCIS with pleomorphic features (LCIS-PF) (n= 4). The upgrade rates to invasive carcinoma or ductal carcinoma in situ (DCIS) were 25% for PLCIS (2/8), 17% for FLCIS (4/24), and 0% for LCIS-PF (0/4). The overall upgrade rate of PLCIS and FLCIS combined was 19% (6/32). All but one case (not upgraded at excision) were radiologic–pathologic concordant. Apocrine features, previously reported only in PLCIS, were also noted in FLCIS. HER2 overexpression was seen in 13% of cases. This study highlights the more aggressive biologic features of PLCIS and FLCIS compared to CLCIS and supports surgical management for these lesions.

Microglandular adenosis (MGA)-related lesions, including atypical MGA (AMGA) and carcinoma involving MGA (C-MGA), are characterized by epithelial atypia, negative hormone receptors, and HER2 status, and can mimic invasive triple negative breast cancer (TNBC) in core needle biopsies (CNB) resulting in selection for treatment with neoadjuvant chemotherapy (NAC). We identified 12 cases of AMGA and/or C-MGA in post-NAC excision specimens (EXC) and analyzed their morphologic and immunohistochemical (IHC) features. All CNBs were initially diagnosed as containing TNBC. Upon re-review, TNBC was confirmed in nine cases. In three CNBs AMGA and/or C-MGA had been interpreted as TNBC. AMGA was initially recognized in only one case but AMGA and/or C-MGA were present in an additional nine CNBs. At EXC, no residual TNBC was present in 5 of 9 EXCs and all 12 cases showed residual AMGA and/or C-MGA. Similar to conventional MGA, AMGA, and C-MGA were positive for S-100, laminin and collagen IV and negative for calponin and p63. Following NAC, these lesions retained their typical staining pattern despite acquiring treatment-related morphologic alterations, most notably of which were areas of single cell growth pattern seen in eight EXCs. This study is the first to report the effects of NAC on AMGA and C-MGA. Our data showed no response of the AMGA and/or C-MGA following NAC in contrast to the high response rate of conventional TNBC. In particular, the infiltrative single cell pattern of post-NAC MGA-related lesions closely mimicked residual TNBC. The persistence of AMGA and C-MGA following NAC supports the notion that these lesions are distinct from conventional TNBC. Our findings also highlight the challenges in recognizing AMGA and C-MGA in CNBs which may lead to unwarranted treatment with NAC in the absence of conventional TNBC.

Microglandular adenosis (MGA)-related lesions, including atypical MGA (AMGA) and carcinoma involving MGA (C-MGA), are characterized by epithelial atypia, negative hormone receptors, and HER2 status, and can mimic invasive triple negative breast cancer (TNBC) in core needle biopsies (CNB) resulting in selection for treatment with neoadjuvant chemotherapy (NAC). We identified 12 cases of AMGA and/or C-MGA in post-NAC excision specimens (EXC) and analyzed their morphologic and immunohistochemical (IHC) features. All CNBs were initially diagnosed as containing TNBC. Upon re-review, TNBC was confirmed in nine cases. In three CNBs AMGA and/or C-MGA had been interpreted as TNBC. AMGA was initially recognized in only one case but AMGA and/or C-MGA were present in an additional nine CNBs. At EXC, no residual TNBC was present in 5 of 9 EXCs and all 12 cases showed residual AMGA and/or C-MGA. Similar to conventional MGA, AMGA, and C-MGA were positive for S-100, laminin and collagen IV and negative for calponin and p63. Following NAC, these lesions retained their typical staining pattern despite acquiring treatment-related morphologic alterations, most notably of which were areas of single cell growth pattern seen in eight EXCs. This study is the first to report the effects of NAC on AMGA and C-MGA. Our data showed no response of the AMGA and/or C-MGA following NAC in contrast to the high response rate of conventional TNBC. In particular, the infiltrative single cell pattern of post-NAC MGA-related lesions closely mimicked residual TNBC. The persistence of AMGA and C-MGA following NAC supports the notion that these lesions are distinct from conventional TNBC. Our findings also highlight the challenges in recognizing AMGA and C-MGA in CNBs which may lead to unwarranted treatment with NAC in the absence of conventional TNBC.

Soil moisture is an essential climate variable of the Earth system. Understanding its spatiotemporal dynamics is essential for predicting weather patterns and climate variability, monitoring and mitigating the effects and occurrence of droughts and floods, improving irrigation in agricultural areas, and sustainably managing water resources. Here we review in depth how soils can remember information on soil moisture anomalies over time, as embedded in the concept of soil moisture memory (SMM). We explain the mechanisms underlying SMM and explore its external and internal drivers; we also discuss the impacts of SMM on different land surface processes, focusing on soil‐plant‐atmosphere coupling. We explore the spatiotemporal variability, seasonality, locality, and depth‐dependence of SMM and provide insights into both improving its characterization in land surface models and using satellite observations to quantify it. Finally, we offer guidance for further research on SMM. Our review paper takes an in‐depth look at soil moisture memory, which is how soil records its moisture history over time and space. Analogous to human psychology, which seeks to understand how a person's/society's memory influences his/her present and future behavior, understanding soil moisture memory encourages consideration of how such memory determines present state and might determine future behavior of soils exposed to environmental disturbances. Soil moisture memory can be affected by a variety of factors, both external (e.g., weather extremes) and internal (soil's unique properties). It affects everything from the air to the way our landscapes respond to disasters like droughts, wildfires, and floods. We also studied how this phenomenon affects the balance of water and energy in our environment, the health of our plants, and even how it communicates with the atmosphere. We show how it can change depending on where you are on the planet, the time of year, and how deep you dig into the soil. We offer scientists insights into how weather and land surface models can become more accurate by accounting for soil moisture memory. Its understanding not only helps us predict and manage our environment, but also provides opportunities for exciting scientific discoveries. Atmospheric forcings, land use and management, and soil processes and mechanisms explain how and why soil moisture memory emerges in ecosystemsNonlocality of moisture memory, its spread across different regions, and its interaction with large‐scale climate phenomena are underexploredFurther advances in land surface models and closer integration of model simulations and observations are needed to better characterize moisture memory Atmospheric forcings, land use and management, and soil processes and mechanisms explain how and why soil moisture memory emerges in ecosystems Nonlocality of moisture memory, its spread across different regions, and its interaction with large‐scale climate phenomena are underexplored Further advances in land surface models and closer integration of model simulations and observations are needed to better characterize moisture memory

Recently, a flow cytometric (FC) based test has been developed for detection of circulating fetal cells to replace the less accurate and reproducible Kleihauer-Betke test.