Miracle-dz/UniFAR-FTUs huggingface dataset:
Landscape analysis of adjacent gene rearrangements reveals BCL2L14–ETV6 gene fusions in more aggressive triple-negative breast cancer

Significance Identification of triple-negative breast cancer (TNBC)-specific genetic events that could guide the treatment decisions represents an unmet clinical need, whereas recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. In this study, analysis of whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions. Among different types of rearrangements, we found that a special class of cryptic adjacent gene rearrangements (AGRs) may occur more frequently than realized in breast cancer. The most frequent AGRs are preferentially found in more aggressive forms of breast cancers, among which BCL2L14–ETV6 is exclusively detected in TNBC. BCL2L14–ETV6 is enriched in high-grade, necrotic, mesenchymal TNBC tumors, and endows increased invasiveness and paclitaxel resistance via inducing partial epithelial mesenchymal transition. Triple-negative breast cancer (TNBC) accounts for 10 to 20% of breast cancer, with chemotherapy as its mainstay of treatment due to lack of well-defined targets, and recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. Recurrent gene fusions comprise a class of viable genetic targets in solid tumors; however, their role in breast cancer remains underappreciated due to the complexity of genomic rearrangements in this cancer. Our interrogation of the whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions, 57% of which are cryptic adjacent gene rearrangements (AGRs). The most frequent AGRs, BCL2L14–ETV6, TTC6–MIPOL1, ESR1–CCDC170, and AKAP8–BRD4, were preferentially found in the more aggressive forms of breast cancers that lack well-defined genetic targets. Among these, BCL2L14–ETV6 was exclusively detected in TNBC, and interrogation of four independent patient cohorts detected BCL2L14–ETV6 in 4.4 to 12.2% of TNBC tumors. Interestingly, these fusion-positive tumors exhibit more aggressive histopathological features, such as gross necrosis and high tumor grade. Amid TNBC subtypes, BCL2L14–ETV6 is most frequently detected in the mesenchymal entity, accounting for ∼19% of these tumors. Ectopic expression of BCL2L14–ETV6 fusions induce distinct expression changes from wild-type ETV6 and enhance cell motility and invasiveness of TNBC and benign breast epithelial cells. Furthermore, BCL2L14–ETV6 fusions prime partial epithelial–mesenchymal transition and endow resistance to paclitaxel treatment. Together, these data reveal AGRs as a class of underexplored genetic aberrations that could be pathological in breast cancer, and identify BCL2L14–ETV6 as a recurrent gene fusion in more aggressive form of TNBC tumors.
NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications

Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to a third of the world’s adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) is associated with a higher risk of all-cause mortality and that the leading causes of death among patients with NAFLD are cardiovascular diseases (CVDs), followed by extrahepatic malignancies and liver-related complications. A growing body of evidence also indicates that NAFLD is strongly associated with an increased risk of major CVD events and other cardiac complications (ie, cardiomyopathy, cardiac valvular calcification and cardiac arrhythmias), independently of traditional cardiovascular risk factors. This narrative review provides an overview of the literature on: (1) the evidence for an association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications, (2) the putative pathophysiological mechanisms linking NAFLD to CVD and other cardiac complications and (3) the current pharmacological treatments for NAFLD that might also benefit or adversely affect risk of CVD.
CaMKII inhibitor 1 (CaMK2N1) mRNA is upregulated following LTP induction in hippocampal slices.

CaMK2N1 and CaMK2N2 (also known as CaMKIINα and β) are endogenous inhibitors of calcium/calmodulin-dependent kinase II (CaMKII), an enzyme critical for memory and long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. CaMK2N1/2 mRNAs are rapidly and differentially upregulated in the hippocampus and amygdala after acquisition or retrieval of fear memory. Moreover, CaMK2N2 protein levels increase after contextual fear conditioning. Therefore, it was proposed that CaMK2N1/2 genes (Camk2n1/2) could be immediate-early genes (IEG) transcribed promptly (30-60 min) after training. As a first approach to explore a role in synaptic plasticity, we assessed a possible regulation of Camk2n1/2 during the expression phase of LTP in hippocampal CA3-CA1 connections in rat brain slices. Quantitative PCR revealed that Camk2n1, but not Camk2n2, is upregulated 60 min after LTP induction by Schaffer collaterals high-frequency stimulation. We observed a graded, significant positive correlation between the magnitude of LTP and Camk2n1 change in individual slices, suggesting a coordinated regulation of these properties. If mRNA increment actually resulted in the protein upregulation in plasticity-relevant subcellular locations, CaMK2N1 may be involved in CaMKII fine-tuning during LTP maintenance or in the regulation of subsequent plasticity events (metaplasticity).
A review of hepatic nanotoxicology – summation of recent findings and considerations for the next generation of study designs

ABSTRACT The liver is one of the most important multi-functional organs in the human body. Amongst various crucial functions, it is the main detoxification center and predominantly implicated in the clearance of xenobiotics potentially including particulates that reach this organ. It is now well established that a significant quantity of injected, ingested or inhaled nanomaterials (NMs) translocate from primary exposure sites and accumulate in liver. This review aimed to summarize and discuss the progress made in the field of hepatic nanotoxicology, and crucially highlight knowledge gaps that still exist. Key considerations include In vivo studies clearly demonstrate that low-solubility NMs predominantly accumulate in the liver macrophages the Kupffer cells (KC), rather than hepatocytes. KCs lining the liver sinusoids are the first cell type that comes in contact with NMs in vivo. Further, these macrophages govern overall inflammatory responses in a healthy liver. Therefore, interaction with of NM with KCs in vitro appears to be very important. Many acute in vivo studies demonstrated signs of toxicity induced by a variety of NMs. However, acute studies may not be that meaningful due to liver’s unique and unparalleled ability to regenerate. In almost all investigations where a recovery period was included, the healthy liver was able to recover from NM challenge. This organ’s ability to regenerate cannot be reproduced in vitro. However, recommendations and evidence is offered for the design of more physiologically relevant in vitro models. Models of hepatic disease enhance the NM-induced hepatotoxicity. The review offers a number of important suggestions for the future of hepatic nanotoxicology study design. This is of great significance as its findings are highly relevant due to the development of more advanced in vitro, and in silico models aiming to improve physiologically relevant toxicological testing strategies and bridging the gap between in vitro and in vivo experimentation.
Caractérisation fonctionnelle de deux facteurs de transcription MYB R2R3 : rôle dans la formation du bois chez les angiospermes

Le xyleme secondaire (appele bois chez les arbres), est un tissu vasculaire caracterise par la presence d'un compose phenolique caracteristique, la lignine qui confere hydrophobicite et resistance mecanique aux parois. La differenciation du xyleme est un processus complexe qui fait intervenir plusieurs centaines de genes dont l'expression doit etre strictement regulee dans l'espace et dans le temps. Cette coordination spatiotemporelle tres fine est assuree au niveau transcriptionnel par des facteurs de transcription. Certains membres de la famille MYB sont par exemple connus pour reguler l'expression des genes de la voie de biosynthese des phenylpropanoides, incluant la lignine. Le but de mes travaux etait de caracteriser fonctionnellement deux facteurs de transcription MYB, EgMYB1 et EgMYB2, isoles a partir d'une banque d'ADNc de xyleme d'Eucalyptus gunnii. La majeure partie de mes resultats concerne la caracterisation d'EgMYB1 qui phylogenetiquement, fait partie du sous-groupe 4 des MYB R2R3. Ce sous-groupe comprend plusieurs represseurs des genes du metabolisme phenolique. Des experiences de co-expression in vivo dans le tabac appuient l'hypothese qu'EgMYB1 pourrait agir en tant que regulateur negatif de l'expression des genes de la voie de biosynthese de la lignine. Ce role potentiel en accord avec l'expression preferentielle d'EgMYB1 dans le xyleme de racines et de tiges d'Eucalyptus a ete verifie in planta chez des peupliers transgeniques. En reponse a la surexpression d'EgMYB1, le contenu en lignine du xyleme secondaire des tiges est reduit. On note egalement une diminution du nombre de fibres de phloeme, et des taux de transcrits des genes de la biosynthese de la lignine. De plus, des analyses transcriptomiques realisees a partir d'ARNs de xyleme et d'ecorce de tiges de peupliers surexprimant EgMYB1 met en evidence des classes de genes sous-exprimes ou surexprimes. De nombreuses similitudes sont retrouvees avec les classes de genes deregulees chez les mutants affectes dans une des etapes de la voie de biosynthese de la lignine, renforcant le role initialement propose pour EgMYB1. Les peupliers surexprimant EgMYB1 montrent egalement d'interessants phenotypes foliaires qui ont ete etudies. La caracterisation fonctionnelle d'EgMYB2 realisee chez des tabacs transgeniques surexpresseurs, nous a amenes a proposer un role d'activateur transcriptionnel de la voie de biosynthese des lignines. Les resultats presentes dans cette these, apportent des indications claires quant aux roles opposes des facteurs de transcription EgMYB1 et EgMYB2 dans la lignification lors de la formation du bois.
The management of emergency spinal surgery during the COVID-19 pandemic in Italy

Aims The current pandemic caused by COVID-19 is the biggest challenge for national health systems for a century. While most medical resources are allocated to treat COVID-19 patients, several non-COVID-19 medical emergencies still need to be treated, including vertebral fractures and spinal cord compression. The aim of this paper is to report the early experience and an organizational protocol for emergency spinal surgery currently being used in a large metropolitan area by an integrated team of orthopaedic surgeons and neurosurgeons. Methods An organizational model is presented based on case centralization in hub hospitals and early management of surgical cases to reduce hospital stay. Data from all the patients admitted for emergency spinal surgery from the beginning of the outbreak were prospectively collected and compared to data from patients admitted for the same reason in the same time span in the previous year, and treated by the same integrated team. Results A total of 19 patients (11 males and eight females, with a mean age of 49.9 years (14 to 83)) were admitted either for vertebral fracture or spinal cord compression in a 19-day period, compared to the ten admitted in the previous year. No COVID-19 patients were treated. The mean time between admission and surgery was 1.7 days, significantly lower than 6.8 days the previous year (p < 0.001). Conclusion The structural organization and the management protocol we describe allowed us to reduce the time to surgery and ultimately hospital stay, thereby maximizing the already stretched medical resources available. We hope that our early experience can be of value to the medical communities that will soon be in the same emergency situation. Cite this article: Bone Joint J 2020;102-B(6):671–676.
Interpretation of exposure effect in competing risks setting under accelerated failure time models

Received 14.07. 2017 Revised 09.09. 2017 Accepted 08.12. 2017 Background & Aim: In survival studies, incidence of competing risks causes that the time of event of interest to be unknown. Analysis of competing risk data, often implemented using hazard-based method under proportional hazard assumption. In this study, we interpreted covariate effect under accelerated failure time model and cause-specific survival function. Methods & Materials: We considered Weibull hazard and survival function as causespecific hazard and survival function and explored the relation between these function. Estimation of parameters performed using Bayesian methods with non-informative priors that implemented in R2WinBUGS package of R software. Results: Simulation study showed that, the relation between hazard and survival parameters for Weibull distribution is also established between parameters of cause-specific hazard and cause-specific survival function. This relation also verified in PBC data set for logarithm of serum bilirubin and D-penicillamine effect. Conclusion: Although in competing risk studies, most of the analysis performed under PH assumption, analysis based on AFT models will also be applicable for these data. In these setting, coefficients can be interpreted as effects of covariate on time to each event.
Current radiotherapy techniques in NSCLC: challenges and potential solutions

ABSTRACT Introduction: Radiotherapy is an important therapeutic strategy in the management of non-small cell lung cancer (NSCLC). In recent decades, technological implementations and the introduction of image guided radiotherapy (IGRT) have significantly increased the accuracy and tolerability of radiation therapy. Area covered: In this review, we provide an overview of technological opportunities and future prospects in NSCLC management. Expert opinion: Stereotactic body radiotherapy (SBRT) is now considered the standard approach in patients ineligible for surgery, while in operable cases, it is still under debate. Additionally, in combination with systemic treatment, SBRT is an innovative option for managing oligometastatic patients and features encouraging initial results in clinical outcomes. To date, in inoperable locally advanced NSCLC, the radical dose prescription has not changed (60 Gy in 30 fractions), despite the median overall survival progressively increasing. These results arise from technological improvements in precisely hitting target treatment volumes and organ at risk sparing, which are associated with better treatment qualities. Finally, for the management of NSCLC, proton and carbon ion therapies and the recent development of MR-Linac are new, intriguing technological approaches under investigation.
The microcircuits of striatum in silico

Significance Our aim is to reconstruct a full-scale mouse striatal cellular level model to provide a framework to integrate and interpret striatal data. We represent the main striatal neuronal subtypes, the two types of projection neurons (dSPNs and iSPNs) giving rise to the direct and indirect pathways, the fast-spiking interneurons, the low threshold spiking interneurons, and the cholinergic interneurons as detailed compartmental models, with properties close to their biological counterparts. Both intrastriatal and afferent synaptic inputs (cortex, thalamus, dopamine system) are optimized against existing data, including short-term plasticity. This model platform will be used to generate new hypotheses on striatal function or network dynamic phenomena. The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, soma–dendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.
Reduced perceptual narrowing in synesthesia

Significance The perceptual validity of synesthesia has been established by behavioral and neuroimaging evidence; however, its developmental origins remain unclear. Here we tested the hypothesis that synesthesia arises when there is less experience-dependent pruning during development. We did so by comparing adults with and without synesthesia on another phenomenon that results from experience-dependent pruning: perceptual narrowing of discrimination to native categories (native phonemes and upright human faces) to the detriment of non-native categories (non-native phonemes, chimp faces, and inverted human faces). Synesthetes were better than controls at all of the non-native discriminations, with no difference for the native categories. The results support the hypothesis that in synesthesia, there is decreased experience-dependent modification of the cortical hyperconnectivity present in early development. Synesthesia is a neurologic trait in which specific inducers, such as sounds, automatically elicit additional idiosyncratic percepts, such as color (thus “colored hearing”). One explanation for this trait—and the one tested here—is that synesthesia results from unusually weak pruning of cortical synaptic hyperconnectivity during early perceptual development. We tested the prediction from this hypothesis that synesthetes would be superior at making discriminations from nonnative categories that are normally weakened by experience-dependent pruning during a critical period early in development—namely, discrimination among nonnative phonemes (Hindi retroflex /d̪a/ and dental /ɖa/), among chimpanzee faces, and among inverted human faces. Like the superiority of 6-mo-old infants over older infants, the synesthetic groups were significantly better than control groups at making all the nonnative discriminations across five samples and three testing sites. The consistent superiority of the synesthetic groups in making discriminations that are normally eliminated during infancy suggests that residual cortical connectivity in synesthesia supports changes in perception that extend beyond the specific synesthetic percepts, consistent with the incomplete pruning hypothesis.
Cell-type-specific mechanical response and myosin dynamics during retinal lens development in Drosophila

During organogenesis, different cell types need to work together to generate functional multicellular structures. To study this process, we made use of the genetically tractable fly retina, with a focus on the mechanisms that coordinate morphogenesis between the different epithelial cell types that make up the optical lens. Our work shows that these epithelial cells present contractile apical-medial MyosinII meshworks, which control the apical area and junctional geometry of these cells during lens development. Our study also suggests that these MyosinII meshworks drive cell shape changes in response to external forces, and thus they mediate part of the biomechanical coupling that takes place between these cells. Importantly, our work, including mathematical modeling of forces and material stiffness during lens development, raises the possibility that increased cell stiffness acts as a mechanism for limiting this mechanical coupling. We propose this might be required in complex tissues, where different cell types undergo concurrent morphogenesis and where averaging out of forces across cells could compromise individual cell apical geometry and thereby organ function.
Creation of a Contractile Biomaterial From a Decellularized Spinach Leaf Without ECM Protein Coating: An in vitro study.

Myocardial infarction (MI) results in the death of cardiac tissue, decreases regional contraction, and can lead to heart failure. Tissue engineered cardiac patches containing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) can restore contractile function. However, cells within thick patches require vasculature for blood flow. Recently, we demonstrated fibronectin coated decellularized leaves provide a suitable scaffold for hiPS-CMs. Yet, the necessity of this additional coating step is unclear. Therefore, we compared hiPS-CM behavior on decellularized leaves coated with collagen IV or fibronectin extracellular matrix (ECM) proteins to non-coated leaves for up to 21 days. Successful coating was verified by immunofluorescence. Similar numbers of hiPS-CMs adhered to coated and non-coated decellularized leaves for 21 days. At day 14, collagen IV coated leaves contracted more than non-coated leaves (3.25+/-0.39% vs. 1.54+/-0.60%; p<0.05). However, no differences in contraction were found between coated leaves, coated tissue culture plastic (TCP), non-coated leaves, or non-coated TCP at other time points. No significant differences were observed in hiPS-CM spreading or sarcomere lengths on leaves with or without coating. This study demonstrates that cardiac scaffolds can be created from decellularized leaves without ECM coatings. Non-coated decellularized leaf surfaces facilitate robust cell attachment for an engineered tissue patch.
Systematic age‐, organ‐, and diet‐associated ionome remodeling and the development of ionomic aging clocks

Aging involves coordinated yet distinct changes in organs and systems throughout life, including changes in essential trace elements. However, how aging affects tissue element composition (ionome) and how these changes lead to dysfunction and disease remain unclear. Here, we quantified changes in the ionome across eight organs and 16 age groups of mice. This global profiling revealed novel interactions between elements at the level of tissue, age, and diet, and allowed us to achieve a broader, organismal view of the aging process. We found that while the entire ionome steadily transitions along the young‐to‐old trajectory, individual organs are characterized by distinct element changes. The ionome of mice on calorie restriction (CR) moved along a similar but shifted trajectory, pointing that at the organismal level this dietary regimen changes metabolism in order to slow down aging. However, in some tissues CR mimicked a younger state of control mice. Even though some elements changed with age differently in different tissues, in general aging was characterized by the reduced levels of elements as well as their increased variance. The dataset we prepared also allowed to develop organ‐specific, ionome‐based markers of aging that could help monitor the rate of aging. In some tissues, these markers reported the lifespan‐extending effect of CR. These aging biomarkers have the potential to become an accessible tool to test the age‐modulating effects of interventions.