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PurposeThis study aims to investigate the feasibility of using a commercially available clinical 0.55 T MRI scanner for comprehensive structural and functional fetal cardiac imaging.MethodsBalanced steady-state free precession (bSSFP) and phase contrast (PC) sequences were optimized by in utero studies consisting of 14 subjects for bSSFP optimization and 9 subjects for PC optimization. The signal-to-noise ratio (SNR) of the optimized sequences were investigated. Flow measurements were performed in three vessels, umbilical vein (UV), descending aorta (DAo), and superior vena cava (SVC) using the PC sequences and retrospective gating. The optimized bSSFP, PC and half-Fourier single shot turbo spin-echo (HASTE) sequences were acquired in a cohort of 21 late gestation-age fetuses (>36 weeks) to demonstrate the feasibility of a fetal cardiac exam at 0.55 T. The HASTE stacks were reconstructed to create an isotropic reconstruction of the fetal thorax, followed by automatic great vessel segmentations. The intra-abdominal UV blood flow measurements acquired with MRI were compared to ultrasound UV free-loop flow measurements.ResultsUsing the parameters from 1.5 T as a starting point, the bSSFP sequences were optimized at 0.55 T, resulting in a 1.6-fold SNR increase and improved image contrast compared to starting parameters, as well as good visibility of most cardiac structures as rated by two experienced fetal cardiologists. The PC sequence resulted in increased SNR and reduced scan time, subsequent retrospective gating enabled successful blood flow measurements. The reconstructions and automatic great vessel segmentations showed good quality, with 18/21 segmentations requiring no or minor refinements. Blood flow measurements were within the expected range. A comparison of the UV measurements performed with ultrasound and MRI showed agreement between the two sets of measurements, with better correlation observed at lower flows.ConclusionWe demonstrated the feasibility of low-field (0.55 T) MRI for fetal cardiac imaging. The reduced SNR at low field strength can be effectively compensated for by strategically optimizing sequence parameters. Major fetal cardiac structures and vessels were consistently visualized, and flow measurements were successfully obtained. The late gestation study demonstrated the robustness and reproducibility at low field strength. MRI performed at 0.55 T is a viable option for fetal cardiac examination.

Facial nerve (FN) palsy, as a solitary symptom resulting from a metastatic tumor, is uncommon, and metastases to the external auditory canal (EAC) are even more infrequent. In this article, we report a unique case of the de novo stage IV invasive lobular breast carcinoma (LBC) presenting as an EAC metastasis and leading to FN palsy as the first symptom, highlighting the importance of considering a broad differential diagnosis.

Abstract Genes of the Sprouty family (Spry1-4) restrain signaling by certain receptor tyrosine kinases. Consequently, these genes participate in several developmental processes and function as tumor suppressors in adult life. Despite these important roles, the biology of this family of genes still remains obscure. Here we show that Sprouty proteins are general mediators of cellular senescence. Induction of cellular senescence by several triggers in vitro correlates with upregulation of Sprouty protein levels. More importantly, overexpression of Sprouty genes is sufficient to cause premature cellular senescence, via a conserved N-terminal tyrosine (Tyrosine 53 of Sprouty1). Accordingly, fibroblasts from knockin animals lacking that tyrosine escape replicative senescence. In vivo, heterozygous knockin mice display delayed induction of cellular senescence during cutaneous wound healing and upon chemotherapy-induced cellular senescence. Unlike other functions of this family of genes, induction of cellular senescence appears to be independent of activation of the ERK1/2 pathway. Instead, we show that Sprouty proteins induce cellular senescence upstream of the p38 pathway in these in vitro and in vivo paradigms.

Background Femoroacetabular impingement syndrome (FAIS) can cause hip pain and chondrolabral damage that may be managed non-operatively or surgically. Squatting motions require large degrees of hip flexion and underpin many daily and sporting tasks but may cause hip impingement and provoke pain. Differential effects of physiotherapist-led care and arthroscopy on biomechanics during squatting have not been examined previously. This study explored differences in 12-month changes in kinematics and moments during squatting between patients with FAIS treated with a physiotherapist-led intervention (Personalised Hip Therapy, PHT) and arthroscopy. Methods A subsample (n = 36) of participants with FAIS enrolled in a multi-centre, pragmatic, two-arm superiority randomised controlled trial underwent three-dimensional motion analysis during squatting at baseline and 12-months following random allocation to PHT (n = 17) or arthroscopy (n = 19). Changes in time-series and peak trunk, pelvis, and hip biomechanics, and squat velocity and maximum depth were explored between treatment groups. Results No significant differences in 12-month changes were detected between PHT and arthroscopy groups. Compared to baseline, the arthroscopy group squatted slower at follow-up (descent: mean difference −0.04 m∙s−1 (95%CI [−0.09 to 0.01]); ascent: −0.05 m∙s−1 [−0.11 to 0.01]%). No differences in squat depth were detected between or within groups. After adjusting for speed, trunk flexion was greater in both treatment groups at follow-up compared to baseline (descent: PHT 7.50° [−14.02 to −0.98]%; ascent: PHT 7.29° [−14.69 to 0.12]%, arthroscopy 16.32° [−32.95 to 0.30]%). Compared to baseline, both treatment groups exhibited reduced anterior pelvic tilt (descent: PHT 8.30° [0.21–16.39]%, arthroscopy −10.95° [−5.54 to 16.34]%; ascent: PHT −7.98° [−0.38 to 16.35]%, arthroscopy −10.82° [3.82–17.81]%), hip flexion (descent: PHT −11.86° [1.67–22.05]%, arthroscopy −16.78° [8.55–22.01]%; ascent: PHT −12.86° [1.30–24.42]%, arthroscopy −16.53° [6.72–26.35]%), and knee flexion (descent: PHT −6.62° [0.56– 12.67]%; ascent: PHT −8.24° [2.38–14.10]%, arthroscopy −8.00° [−0.02 to 16.03]%). Compared to baseline, the PHT group exhibited more plantarflexion during squat ascent at follow-up (−3.58° [−0.12 to 7.29]%). Compared to baseline, both groups exhibited lower external hip flexion moments at follow-up (descent: PHT −0.55 N∙m/BW∙HT[%] [0.05–1.05]%, arthroscopy −0.84 N∙m/BW∙HT[%] [0.06–1.61]%; ascent: PHT −0.464 N∙m/BW∙HT[%] [−0.002 to 0.93]%, arthroscopy −0.90 N∙m/BW∙HT[%] [0.13–1.67]%). Conclusion Exploratory data suggest at 12-months follow-up, neither PHT or hip arthroscopy are superior at eliciting changes in trunk, pelvis, or lower-limb biomechanics. Both treatments may induce changes in kinematics and moments, however the implications of these changes are unknown. Trial registration details Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549. Trial registered 2/11/2015.

Genomic prediction has mostly been used in single environment contexts, largely ignoring genotype x environment interaction, which greatly affects the performance of plants. However, in the last decade, prediction models including marker x environment (MxE) interaction have been developed. We evaluated the potential of genomic prediction in red clover (Trifolium pratense L.) using field trial data from five European locations, obtained in the Horizon 2020 EUCLEG project. Three models were compared: (1) single environment (SingleEnv), (2) across environment (AcrossEnv), (3) marker x environment interaction (MxE). Annual dry matter yield (DMY) gave the highest predictive ability (PA). Joint analyses of DMY from years 1 and 2 from each location varied from 0.87 in Britain and Switzerland in year 1, to 0.40 in Serbia in year 2. Overall, crude protein (CP) was predicted poorly. PAs for date of flowering (DOF), however ranged from 0.87 to 0.67 for Britain and Switzerland, respectively. Across the three traits, the MxE model performed best and the AcrossEnv worst, demonstrating that including marker x environment effects can improve genomic prediction in red clover. Leaving out accessions from specific regions or from specific breeders’ material in the cross validation tended to reduce PA, but the magnitude of reduction depended on trait, region and breeders’ material, indicating that population structure contributed to the high PAs observed for DMY and DOF. Testing the genomic estimated breeding values on new phenotypic data from Sweden showed that DMY training data from Britain gave high PAs in both years (0.43–0.76), while DMY training data from Switzerland gave high PAs only for year 1 (0.70–0.87). The genomic predictions we report here underline the potential benefits of incorporating MxE interaction in multi-environment trials and could have perspectives for identifying markers with effects that are stable across environments, and markers with environment-specific effects.

Hyperspectral imaging is a key tool in numerous remote sensing applications. Images with tens or even hundreds of spectral bands contain a wealth of information to retrieve multiple geophysical parameters, to perform target detection, or land classification with unbeatable high accuracies. In addition, hyperspectral sensors are becoming smaller, and today they even fit in CubeSats. However, the amount of data they generate is so large that satellite communication systems have severe limitations to download it, especially in SmallSats. It is therefore becoming urgent to develop efficient automated algorithms that can be executed in the limited capabilities of the onboard computers of these satellites, so as to reduce the amount of data to be stored and downloaded, while keeping as much information as possible for a given scene. In this work, a band selection algorithm has been designed to deal with this problem. The proposed algorithm consists of the sequential selection of the spectral bands ranked using the amount of information provided by each band, and also the correlation of these bands with the previously selected ones. The algorithm performance is assessed by means of a suite of classification tests with hyperspectral datasets from different sensors. Results show comparable or even better performance than other existing band selection algorithms, while outperforming in terms of computational complexity, which makes it more suitable for SmallSats with limited computing resources.

The relationships between the circuits of the urban economy and retail desertification are analysed based on two retail strips in Barcelona: Passeig de Gràcia, a central hub with global reach, and the Sants-Creu Coberta strip, which responds to the demand for consumption on a local, everyday scale. The hypothesis is that the relationships between these circuits and retail desertification behave differently depending on their relative position in the city with respect to consumption flows. This is tested with a one-to-one analysis of the uses of ground floor premises in both strips for 2016 and 2021, using data from the Commercial Censuses of the Barcelona City Council and Barcelona Provincial Council, respectively. Each ground floor premises is classified as superior, lower or vacant, which allows the process to be mapped from 2016 to 2021 for each of the premises. The article provides, first and foremost, an original systematisation of the behaviour, relationships, and observed forms between the circuits and desertification, and secondly, it demonstrates the differential behaviour of these relationships and forms through case studies, indicating that retail desertification is the main cause of economic and landscape change.

IntroductionLynch syndrome patients have an inherited predisposition to cancer due to a deficiency in DNA mismatch repair (MMR) genes which could lead to a higher risk of developing cancer if exposed to ionizing radiation. This pilot study aims to reveal the association between MMR deficiency and radiosensitivity at both a CT relevant low dose (20 mGy) and a therapeutic higher dose (2 Gy).MethodsHuman colorectal cancer cell lines with (dMMR) or without MMR deficiency (pMMR) were analyzed before and after exposure to radiation using cellular and cytogenetic analyses i.e., clonogenic assay to determine cell reproductive death; sister chromatid exchange (SCE) assay to detect the exchange of DNA between sister chromatids; γH2AX assay to analyze DNA damage repair; and apoptosis analysis to compare cell death response. The advantages and limitations of these assays were assessed in vitro, and their applicability and feasibility investigated for their potential to be used for further studies using clinical samples.ResultsResults from the clonogenic assay indicated that the pMMR cell line (HT29) was significantly more radio-resistant than the dMMR cell lines (HCT116, SW48, and LoVo) after 2 Gy X-irradiation. Both cell type and radiation dose had a significant effect on the yield of SCEs/chromosome. When the yield of SCEs/chromosome for the irradiated samples (2 Gy) was normalized against the controls, no significant difference was observed between the cell lines. For the γH2AX assay, 0, 20 mGy and 2 Gy were examined at post-exposure time points of 30 min (min), 4 and 24 h (h). Statistical analysis revealed that HT29 was only significantly more radio-resistant than the MLH1-deficient cells lines, but not the MSH2-deficient cell line. Apoptosis analysis (4 Gy) revealed that HT29 was significantly more radio-resistant than HCT116 albeit with very few apoptotic cells observed.DiscussionOverall, this study showed radio-resistance of the MMR proficient cell line in some assays, but not in the others. All methods used within this study have been validated; however, due to the limitations associated with cancer cell lines, the next step will be to use these assays in clinical samples in an effort to understand the biological and mechanistic effects of radiation in Lynch patients as well as the health implications.

Yield is the most complex trait to improve crop production, and identifying the genetic determinants for high yield is a major issue in breeding new varieties. In faba bean (Vicia faba L.), quantitative trait loci (QTLs) have previously been detected in studies of biparental mapping populations, but the genes controlling the main trait components remain largely unknown. In this study, we investigated for the first time the genetic control of six faba bean yield-related traits: shattering (SH), pods per plant (PP), seeds per pod (SP), seeds per plant (SPL), 100-seed weight (HSW), and plot yield (PY), using a genome-wide association study (GWAS) on a worldwide collection of 352 homozygous faba bean accessions with the aim of identifying markers associated with them. Phenotyping was carried out in field trials at three locations (Spain, United Kingdom, and Serbia) over 2 years. The faba bean panel was genotyped with the Affymetrix faba bean SNP-chip yielding 22,867 SNP markers. The GWAS analysis identified 112 marker–trait associations (MTAs) in 97 candidate genes, distributed over the six faba bean chromosomes. Eight MTAs were detected in at least two environments, and five were associated with multiple traits. The next step will be to validate these candidates in different genetic backgrounds to provide resources for marker-assisted breeding of faba bean yield.

The moderation of user-generated content on online platforms remains a key solution to protecting people online, but also remains a perpetual challenge as the appropriateness of content moderation guidelines depends on the online community that they aim to govern. This challenge affects marginalized groups in particular, as they more frequently experience online abuse but also end up falsely being the target of content-moderation guidelines. While there have been calls for democratic, community-moderation, there has so far been little research into how to implement such approaches. Here, we present the co-creation of content moderation strategies with the users of an online platform to address some of these challenges. Within the context of AutSPACEs—an online citizen science platform that aims to allow autistic people to share their own sensory processing experiences publicly—we used a community-based and participatory approach to co-design a content moderation solution that would fit the preferences, priorities, and needs of its autistic user community. We outline how this approach helped us discover context-specific moderation dilemmas around participant safety and well-being and how we addressed those. These trade-offs have resulted in a moderation design that differs from more general social networks in aspects such as how to contribute, when to moderate, and what to moderate. While these dilemmas, processes, and solutions are specific to the context of AutSPACEs, we highlight how the co-design approach itself could be applied and useful for other communities to uncover challenges and help other online spaces to embed safety and empowerment.

Abstract Metal halide perovskites (MHPs, CsPbX3: X = Cl, Br, I) have advanced the field of optoelectronic devices due to their remarkable light‐emitting capabilities, stemming from the large overlap between their emission and absorption spectra, offering the possibility to reabsorb their own emitted photons. Herein, a straightforward method is reported to confine CsPbBr3 into mesoporous silica films with a chiral nematic structure, allowing the amplification of the photoluminescence (PL). The simple room temperature ligand‐free synthesis allows facile growth of CsPbBr3 in silica photonic films, in which the Bragg peak position can be tuned from the UV to the visible range. The perovskite/silica films demonstrate a remarkable improvement in PL intensity and lifetime compared to the as‐synthesized non‐confined perovskite nanocrystals (NCs) due to the overlap of the Bragg peak position of the chiral nematic photonic films and CsPbBr3 absorption band. Such a PL enhancement stems from the slow photon effect induced at blue and red Bragg peak edges that facilitates the photon recycling of the emitted photons. This innovative approach offers a new way to fabricate highly emissive and long‐lived photoluminescent films at ambient conditions, potentially advancing perovskite utilization in light‐emitting devices.

Abstract Smart water enables utilities, regulators, and customers to make more timely and informed decisions about how they use and regard their water resources. It has been developed to assist demand management by influencing customer behavior and reducing network leakage, lowering energy consumption, and avoiding deploying assets that are not actually needed. Smart water has seen an evolution toward monitoring wastewater applications. Challenges include the need for common operating standards and more cohesive national policy frameworks. As a result, smart water adoption occurs on a utility‐by‐utility basis.

Indoor-grown Cannabis sativa is commonly transitioned to a 12 h daily photoperiod to promote flowering. However, our previous research has shown that some indoor-grown cannabis cultivars can initiate strong flowering responses under daily photoperiods longer than 12 h. Since longer photoperiods inherently provide higher daily light integrals (DLIs), they may also increase growth and yield. To test this hypothesis, two THC-dominant cannabis cultivars, ‘Incredible Milk’ (IM) and ‘Gorilla Glue’ (GG), were grown to commercial maturity at a canopy level PPFD of 540 µmol·m−2·s−1 from white LEDS under 12 h or 13 h daily photoperiods, resulting in DLIs of 23.8 and 25.7 mol·m−2·d−1, respectively. Both treatments were harvested when the plants in the 12 h treatment reached maturity according to established commercial protocols. There was no delay in flowering initiation time in GG, but flowering initiation in IM was delayed by about 1.5 d under 13 h. Stigma browning and trichome ambering also occurred earlier and progressed faster in the 12 h treatment in both cultivars. The vegetative growth of IM plants in the 13 h treatment was greater and more robust. The inflorescence yields were strikingly higher in the 13 h vs. 12 h treatment, i.e., 1.35 times and 1.50 times higher in IM and GG, respectively, which is 4 to 6 times higher than the relative increase in DLIs. The inflorescence concentrations of major cannabinoids in the 13 h treatment were either higher or not different from the 12 h treatment in both cultivars. These results suggest that there may be substantial commercial benefits for using photoperiods longer than 12 h for increasing inflorescence yields without decreasing cannabinoid concentrations in some cannabis cultivars grown in indoor environments.

Objective Hypokalaemia and hyperkalaemia (‘dyskalaemia’) are commonly seen in patients requiring emergency hospital admission. The adverse effect of dyskalaemia on mortality is well described but there are few data for the effect on hospital length of stay. We sought to determine the association of serum potassium concentration with in-hospital length of stay.Design Systematic review and meta-analysis.Data sources A structured search of MEDLINE, PubMed and SCOPUS databases to 19 March 2021.Eligibility criteria Observational cohort studies defining exposure of interest as serum potassium levels (at admission or within the first 72 hours) and with outcome of interest as length of hospital stay. Studies had to provide estimates of length of stay as a comparison between normokalaemia and defined ranges of hyperkalaemia or hypokalaemia.Data extraction and synthesis We identified 39 articles published to March 2021 that met the inclusion and exclusion criteria. Study selection, data extraction and quality assessment were carried out by two reviewers working independently and in duplicate, to assessed eligibility and risk of bias, and extract data from eligible studies. Random effects models were used to pool estimates across the included studies. Meta-analyses were performed using Cochrane-RevMan.Results Five studies were included in the meta-analysis. Compared with the reference group (3.5–5.0 mmol/L), the pooled raw differences of medians were 4.45 (95% CI 2.71 to 6.91), 1.99 (95% CI 0.03 to 3.94), 0.98 (95% CI 0.91 to 1.05), 1.51 (95% CI 1.03 to 2.0), 1 (95% CI 0.75 to 1.25) and 2.76 (95% CI 1.24 to 4.29) for patients with potassium levels of 6.0 mmol/L, respectively.Conclusion Hospital length of stay follows a U-shaped distribution, with duration of admission being twofold greater at the extremes of the potassium range.

Until recently, most clonal cannabis (Cannabis sativa) has been propagated using fluorescent lights. Transitioning to light-emitting diodes (LEDs) may be a viable alternative to fluorescent lighting, enabling cultivators to provide specific spectrum treatments to enhance rooting while also saving energy. Vegetative stem cuttings of ‘Gelato-27’, ‘Grace’, and ‘Meridian’ were rooted for 15 days under various combinations of blue (B), red (R), ultraviolet-A (UVA) LEDs, phosphor-converted white (W) LEDs, and a fluorescent (F) control treatment, each with a canopy-level photosynthetic photon flux density (PPFD) of 200 µmol·m−2·s−1 and 16-hour photoperiod. The photon flux ratios of blue (B; 400–500 nm) and red (R; 600–700 nm) narrowband LED treatment combinations were (1) BR, fixed spectrum of B15:R85; (2) B, B75:R25 on day 0–2 followed by B15:R85 on day 2–14; (3) B+UVA, B75:R25 on day 0–2 followed by B15:R85 on day 2–14 plus 15 µmol·m−2·s−1 of UVA on day 7–14; (4) B50, B15:R85 on day 0–7 followed by B50:R50 on day 7–14. The W and F treatments both had static spectra. After the propagation period (i.e., plug stage), a portion of the cuttings under each treatment × cultivar combination were destructively harvested and the remainder were transplanted and grown vegetatively for an additional 21 days (i.e., transplant stage) under a PPFD of ≈275 µmol·m−2·s−1 from ceramic metal halide fixtures and then destructively harvested. Although there were no spectrum treatment effects on the percentage of cuttings that rooted, root index values were higher in cuttings grown under B+UVA vs. F. Further, relative root dry weights of plugs from the B, B+UVA, B50, and F treatments were higher than the W treatment. At the end of the plug stage, there were no spectrum treatment effects on the chlorophyll content index, cuttings grown under the B treatment had thicker stems compared with BR and W treatments, and cuttings grown under the F treatment exhibited the lowest percentage of new aboveground growth. None of the aforementioned spectrum treatment effects from the propagation stage persisted post-transplant. The use of LEDs is a promising, energy-efficient alternative to fluorescent lighting for cannabis propagation and B-enhanced spectrum treatments appear to enhance the rooting performance of clonal cannabis cuttings.

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide‐based tyrosine‐kinase‐activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF‐573228 and defactinib (VS‐6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS‐FAK‐PAX signaling in cell migration. Both defactinib and ROS scavenger N‐acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer‐tissue‐originated spheroids (CTOS) and a patient‐derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro‐tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS‐mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.

Abstract Background Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Methods Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. Results GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Conclusion Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome.

Abstract Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.

Review of: Justinian: Empire and Society in the Sixth Century. Debates and Documents in Ancient History Series. By F.K. Haarer. Edinburgh University Press, 2022. ISBN 978-0-7486-3979-2 (web-ready PDF). vi + 257 pp. £95.

AT‐rich interactive domain‐containing protein 1A (ARID1A) loss‐of‐function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas. However, the molecular mechanisms linking these genetic changes to the altered pathways regulating tumour initiation, maintenance and/or progression remain poorly understood. Thus, the main aim of this study was to analyse the role of ARID1A loss of function in endometrial tumorigenesis. Here, using different endometrial in vitro and in vivo models, such as tumoral cell lines, 3D primary cultures and metastatic or genetically modified mouse models, we show that altered expression of ARID1A is not enough to initiate endometrial tumorigenesis. However, in an established endometrial cancer context, ARID1A loss of function accelerates tumoral progression and metastasis through the disruption of the G2/M cell cycle checkpoint and ATM/ATR‐mediated DNA damage checkpoints, increases epithelial cell proliferation rates and induces epithelial mesenchymal transition through the activation of histone deacetylase 6 (HDAC6). Next, we demonstrated that the inhibition of HDAC6 function, using the HDAC6‐specific inhibitor ACY1215 or by transfection with HDAC6 short hairpin RNA (shRNA), can reverse the migratory and invasive phenotype of ARID1A‐knockdown cells. Further, we also show that inhibition of HDAC6 activity causes an apoptotic vulnerability to etoposide treatments in ARID1A‐deficient cells. In summary, the findings exposed in this work indicate that the inhibition of HDAC6 activity is a potential therapeutic strategy for patients suffering from ARID1A‐mutant endometrial cancer diagnosed in advanced stages.