bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss-of-function of the hippo transducer TAZ reduces mammary tumor growth through a myeloid-derived suppressor cell-dependent mechanism
Authors: Shen He , Zhang Yuwen , Kramer Elliot D. , Katsuta Eriko , Wan Yin , Chen Yanmin , Wang Jianmin , Zhang Yali , Matsuzaki Junko , Frangou Costa , Abrams Scott I. , Zhang Jianmin 
Published: July 2022

AbstractTAZ, one of the key effectors in the Hippo pathway, is often dysregulated in breast cancer, leading to cancer stemness, survival, and metastasis. However, the mechanistic bases of these tumor outcomes are incompletely understood and even less is known about the potential role played by the non-malignant cellular constituents of the tumor microenvironment (TME). Here, we revealed an inverse correlation between TAZ expression and survival in triple-negative breast cancer (TNBC), but not other subtypes of breast cancer. We found that TAZ knockdown in two murine TNBC tumor cell line models significantly inhibited tumor growth and metastasis in immune competent but not immune deficient hosts. RNA-seq analyses identified substantial alterations in immune components in TAZ knockdown tumors. Using mass cytometry analysis, we found that TAZ-deficiency altered the immune landscape of the TME leading to significant reductions in immune suppressive populations, namely myeloid-derived suppressor cells (MDSCs) and macrophages accompanied by elevated CD8+ T cell/myeloid cell ratios. Mechanistic studies demonstrated that TAZ-mediated tumor growth was MDSC-dependent in that MDSC depletion led to reduced tumor growth in control, but not TAZ-knockdown tumor cells. Altogether, we identified a novel non-cancer cell-autonomous mechanism by which tumor-intrinsic TAZ expression aids tumor progression. Thus, our findings advance an understanding of the crosstalk between tumor-derived TAZ expression and the immune contexture within the TME, which may lead to new therapeutic interventions for TNBC or other TAZ-driven cancers.
MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state
Authors: Zhang Wen Cai , Skiados Nicholas , Aftab Fareesa , Moreno Cerena , Silva Luis , Corbilla Paul Joshua Anthony , Asara John M. , Hata Aaron N. , Slack Frank J. 
Published: July 2022

AbstractIn EGFR-mutant lung cancer, drug-tolerant persister cells (DTPCs) show prolonged survival when receiving EGFR tyrosine kinase inhibitor (TKI) treatments. They are a likely source of drug resistance, but little is known about how these cells tolerate drugs. Ribonucleic acids (RNAs) molecules control cell growth and stress responses. Nucleic acid metabolism provides metabolites, such as purines, supporting RNA synthesis and downstream functions. Recently, noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), have received attention due to their capacity to repress gene expression via inhibitory binding to downstream messenger RNAs (mRNAs). Here, our study links miRNA expression to purine metabolism and drug tolerance. MiR-21-5p (guide strand) is a commonly upregulated miRNA in disease states, including cancer and drug resistance. However, the expression and function of miR-21-3p (passenger strand) are not well understood. We found that upregulation of miR-21-5p and miR-21-3p tune purine metabolism leading to increased drug tolerance. Metabolomics data demonstrated that purine metabolism was the top pathway in the DTPCs compared with the parental cells. The changes in purine metabolites in the DTPCs were partially rescued by targeting miR-21. Analysis of protein levels in the DTPCs showed that reduced expression of adenylosuccinate lyase (ADSL) was reversed after the miR-21 knockdown. ADSL is an essential enzyme in the de novo purine biosynthesis pathway by converting succino-5-aminoimidazole-4-carboxamide riboside (succino-AICAR or SAICAR) to AICAR (or acadesine) as well as adenylosuccinate to adenosine monophosphate (AMP). In the DTPCs, miR-21-5p and miR-21-3p repress ADSL expression. The levels of top decreased metabolite in the DTPCs, AICAR was reversed when miR-21 was blocked. AICAR induced oxidative stress, evidenced by increased reactive oxygen species (ROS) and reduced expression of nuclear factor erythroid-2-related factor 2 (NRF2). Concurrently, miR-21 knockdown induced ROS generation. Therapeutically, a combination of AICAR and osimertinib increased ROS levels and decreased osimertinib-induced NRF2 expression. In a MIR21 knockout mouse model, MIR21 loss-of-function led to increased purine metabolites but reduced ROS scavenging capacity in lung tissues in physiological conditions. Our data has established a link between ncRNAs, purine metabolism, and the redox imbalance pathway. This discovery will increase knowledge of the complexity of the regulatory RNA network and potentially enable novel therapeutic options for drug-resistant patients.
Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations
Authors: Mannarino Laura , Mirimao Federica , Panini Nicolò , Paracchini Lara , Marchini Sergio , Beltrame Luca , Amodeo Rosy , Grosso Federica , Libener Roberta , De Simone Irene , Ceresoli Giovanni L. , Zucali Paolo A. , Lupi Monica , D’Incalci Maurizio 
Published: July 2022

AbstractAlthough clinical antitumor activity of Tumor Treating Fields (TTFields) has been reported in malignant pleural mesothelioma (MPM) patients, the mechanisms behind the different selectivity displayed by the various MPM histotypes to this physical therapy has not been elucidated yet. Taking advantage of the development of well characterized human MPM cell lines derived from pleural effusion and/or lavages of patients’ thoracic cavity, we investigated the biological effects of TTFields against these cells, representative of epithelioid, biphasic, and sarcomatoid histotypes. Growth inhibition and cell cycle perturbations caused by TTFields were investigated side by side with RNA-Seq analyses at different exposure times to identify pathways involved in cell response to treatment. We observed significant differences of response to TTFields among the cell lines. Cell cycle analysis revealed that the most sensitive cells (epithelioid CD473) were blocked in G2M phase followed by formation of polyploid cells. The least sensitive cells (sarcomatoid CD60) were only slightly affected by TTFields with a general delay in all cell cycle phases. Apoptosis was present in all samples, but while epithelioid cell death was already observed during the first 24 h of treatment, sarcomatoid cells needed longer times before they engaged apoptotic pathways. RNA-Seq experiments demonstrated that TTFields induced a transcriptional response already detectable at early time points (8 h). The number of differentially expressed genes was higher in CD473 than in CD60 cells, involving several pathways, such as those pertinent to cell cycle checkpoints, DNA repair, and histone modifications. Our data provide further support to the notion that the antitumor effects of TTFields are not simply related to a non-specific reaction to a physical stimulus, but are dependent on the biological background of the cells and the particular sensitivity to TTFields observed in epithelioid MPM cells is associated with a higher transcriptional activity than that observed in sarcomatoid models.
Insulin-like growth factor 1 receptor mediates photoreceptor neuroprotection
Authors: Rajala Ammaji , Teel Kenneth , Bhat Mohd A. , Batushansky Albert , Griffin Timothy M. , Purcell Lindsey , Rajala Raju V. S. 
Published: July 2022

AbstractInsulin-like growth factor I (IGF-1) is a neurotrophic factor and is the ligand for insulin-like growth factor 1 receptor (IGF-1R). Reduced expression of IGF-1 has been reported to cause deafness, mental retardation, postnatal growth failure, and microcephaly. IGF-1R is expressed in the retina and photoreceptor neurons; however, its functional role is not known. Global IGF-1 KO mice have age-related vision loss. We determined that conditional deletion of IGF-1R in photoreceptors and pan-retinal cells produces age-related visual function loss and retinal degeneration. Retinal pigment epithelial cell-secreted IGF-1 may be a source for IGF-1R activation in the retina. Altered retinal, fatty acid, and phosphoinositide metabolism are observed in photoreceptor and retinal cells lacking IGF-1R. Our results suggest that the IGF-1R pathway is indispensable for photoreceptor survival, and activation of IGF-1R may be an essential element of photoreceptor and retinal neuroprotection.
Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure
Authors: Vicente Anna Luiza Silva Almeida , Novoloaca Alexei , Cahais Vincent , Awada Zainab , Cuenin Cyrille , Spitz Natália , Carvalho André Lopes , Evangelista Adriane Feijó , Crovador Camila Souza , Reis Rui Manuel , Herceg Zdenko , de Lima Vazquez Vinicius , Ghantous Akram 
Published: July 2022

AbstractUltraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival.TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.
AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer
Authors: Bardia Aditya , Chandarlapaty Sarat , Linden Hannah M. , Ulaner Gary A. , Gosselin Alice , Cartot-Cotton Sylvaine , Cohen Patrick , Doroumian Séverine , Paux Gautier , Celanovic Marina , Pelekanou Vasiliki , Ming Jeffrey E. , Ternès Nils , Bouaboula Monsif , Lee Joon Sang , Bauchet Anne-Laure , Campone Mario 
Published: July 2022

AbstractAMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2− advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.
Building programmable multicompartment artificial cells incorporating remotely activated protein channels using microfluidics and acoustic levitation
Authors: Li Jin , Jamieson William D. , Dimitriou Pantelitsa , Xu Wen , Rohde Paul , Martinac Boris , Baker Matthew , Drinkwater Bruce W. , Castell Oliver K. , Barrow David A. 
Published: July 2022

AbstractIntracellular compartments are functional units that support the metabolism within living cells, through spatiotemporal regulation of chemical reactions and biological processes. Consequently, as a step forward in the bottom-up creation of artificial cells, building analogous intracellular architectures is essential for the expansion of cell-mimicking functionality. Herein, we report the development of a droplet laboratory platform to engineer complex emulsion-based, multicompartment artificial cells, using microfluidics and acoustic levitation. Such levitated models provide free-standing, dynamic, definable droplet networks for the compartmentalisation of chemical species. Equally, they can be remotely operated with pneumatic, heating, and magnetic elements for post-processing, including the incorporation of membrane proteins; alpha-hemolysin; and mechanosensitive channel of large-conductance. The assembly of droplet networks is three-dimensionally patterned with fluidic input configurations determining droplet contents and connectivity, whilst acoustic manipulation can be harnessed to reconfigure the droplet network in situ. The mechanosensitive channel can be repeatedly activated and deactivated in the levitated artificial cell by the application of acoustic and magnetic fields to modulate membrane tension on demand. This offers possibilities beyond one-time chemically mediated activation to provide repeated, non-contact, control of membrane protein function. Collectively, this expands our growing capability to program and operate increasingly sophisticated artificial cells as life-like materials.
Making marine image data FAIR
Authors: Schoening Timm , Durden Jennifer M. , Faber Claas , Felden Janine , Heger Karl , Hoving Henk-Jan T. , Kiko Rainer , Köser Kevin , Krämmer Christopher , Kwasnitschka Tom , Möller Klas Ove , Nakath David , Naß Andrea , Nattkemper Tim W. , Purser Autun , Zurowietz Martin 
Published: July 2022

AbstractUnderwater images are used to explore and monitor ocean habitats, generating huge datasets with unusual data characteristics that preclude traditional data management strategies. Due to the lack of universally adopted data standards, image data collected from the marine environment are increasing in heterogeneity, preventing objective comparison. The extraction of actionable information thus remains challenging, particularly for researchers not directly involved with the image data collection. Standardized formats and procedures are needed to enable sustainable image analysis and processing tools, as are solutions for image publication in long-term repositories to ascertain reuse of data. The FAIR principles (Findable, Accessible, Interoperable, Reusable) provide a framework for such data management goals. We propose the use of image FAIR Digital Objects (iFDOs) and present an infrastructure environment to create and exploit such FAIR digital objects. We show how these iFDOs can be created, validated, managed and stored, and which data associated with imagery should be curated. The goal is to reduce image management overheads while simultaneously creating visibility for image acquisition and publication efforts.
Light-induced asymmetries in embryonic retinal gene expression are mediated by the vascular system and extracellular matrix
Authors: Versace Elisabetta , Sgadò Paola , George Julia , Loveland Jasmine L. , Ward Joseph , Thorpe Peter , Jensen Lars Juhl , Spencer Karen A. , Paracchini Silvia , Vallortigara Giorgio 
Published: July 2022

AbstractLeft–right asymmetries in the nervous system (lateralisation) influence a broad range of behaviours, from social responses to navigation and language. The role and pathways of endogenous and environmental mechanisms in the ontogeny of lateralisation remains to be established. The domestic chick is a model of both endogenous and experience-induced lateralisation driven by light exposure. Following the endogenous rightward rotation of the embryo, the asymmetrical position in the egg results in a greater exposure of the right eye to environmental light. To identify the genetic pathways activated by asymmetric light stimulation, and their time course, we exposed embryos to different light regimes: darkness, 6 h of light and 24 h of light. We used RNA-seq to compare gene expression in the right and left retinas and telencephalon. We detected differential gene expression in right vs left retina after 6 h of light exposure. This difference was absent in the darkness condition and had already disappeared by 24 h of light exposure, suggesting that light-induced activation is a self-terminating phenomenon. This transient effect of light exposure was associated with a downregulation of the sensitive-period mediator geneDIO2(iodothyronine deiodinase 2) in the right retina. No differences between genes expressed in the right vs. left telencephalon were detected. Gene networks associated with lateralisation were connected to vascularisation, cell motility, and the extracellular matrix. Interestingly, we know that the extracellular matrix—including the differentially expressedPDGFRBgene—is involved in morphogenesis, sensitive periods, and in the endogenous chiral mechanism of primary cilia, that drives lateralisation. Our data show a similarity between endogenous and experience-driven lateralisation, identifying functional gene networks that affect lateralisation in a specific time window.
Impairing proliferation of glioblastoma multiforme with CD44+ selective conjugated polymer nanoparticles
Authors: Lubanska Dorota , Alrashed Sami , Mason Gage T. , Nadeem Fatima , Awada Angela , DiPasquale Mitchell , Sorge Alexandra , Malik Aleena , Kojic Monika , Soliman Mohamed A. R. , deCarvalho Ana C. , Shamisa Abdalla , Kulkarni Swati , Marquardt Drew , Porter Lisa A. , Rondeau-Gagné Simon 
Published: July 2022

AbstractGlioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood–brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood–brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone regulated the levels and signaling activity of the CD44 receptor, decreasing stemness, invasive properties and proliferation of the CD44-TIC populations in vitro and in a patient-derived xenograft zebrafish model. This work proposes a novel, CPN- based, and surface moiety-driven selective way of targeting of TIC populations in brain cancer.
Statistical evaluation of proxies for estimating the rainfall erosivity factor
Authors: Ma Xiaoqing , Zheng Mingguo 
Published: July 2022

AbstractConsidering the high-temporal-resolution rainfall data requirements for calculating the Rainfall Erosivity factor (that is, the R-factor), studies have developed a large number of proxies for the R-factor (PR). This study aims to evaluate 15 widely used proxies, which were developed in various countries using daily, monthly, or yearly rainfall data, in terms of correlation and statistical equality with the R-factor by using the 6-min pluviographic data from 28 stations in Australia. Meng’s test was applied to rank the correlations. Although the Meng’s test indicated that the correlation between Rainfall Erosivity (R) and Rainfall Erosivity calculated by the proxy model (PR) generally increased with a finer time resolution of the rainfall data (in the order of year, month, and day), the 15 PRs under examination were all highly correlated with R (r > 0.62, p < 0.004), implying that all of them can be reasonably used as an R predictor. A direct estimation of the R-factor using PRs produced a mean relative error (MRE), root mean square error (RMSE), and Nash–Sutcliffe efficiency coefficient (NSE) with a mean of 50.0%, 1392 MJ mm ha−1 h−1 a−1, and 0.17, respectively. The linear calibrations improved the accuracy of the estimation and produced an MRE, RMSE, and NSE with a mean of 36.0%, 887 MJ mm ha−1 h−1 a−1, and 0.70, respectively. Finally, suitable proxies for instances where only daily, monthly, or yearly rainfall data are available were recommended.
Plasmonic hot spots reveal local conformational transitions induced by DNA double-strand breaks
Authors: Seweryn Sara , Skirlińska-Nosek Katarzyna , Wilkosz Natalia , Sofińska Kamila , Perez-Guaita David , Oćwieja Magdalena , Barbasz Jakub , Szymoński Marek , Lipiec Ewelina 
Published: July 2022

AbstractDNA double-strand breaks (DSBs) are typical DNA lesions that can lead to cell death, translocations, and cancer-driving mutations. The repair process of DSBs is crucial to the maintenance of genomic integrity in all forms of life. However, the limitations of sensitivity and special resolution of analytical techniques make it difficult to investigate the local effects of chemotherapeutic drugs on DNA molecular structure. In this work, we exposed DNA to the anticancer antibiotic bleomycin (BLM), a damaging factor known to induce DSBs. We applied a multimodal approach combining (i) atomic force microscopy (AFM) for direct visualization of DSBs, (ii) surface-enhanced Raman spectroscopy (SERS) to monitor local conformational transitions induced by DSBs, and (iii) multivariate statistical analysis to correlate the AFM and SERS results. On the basis of SERS results, we identified that bands at 1050 cm−1 and 730 cm−1 associated with backbone and nucleobase vibrations shifted and changed their intensities, indicating conformational modifications and strand ruptures. Based on averaged SERS spectra, the PLS regressions for the number of DSBs caused by corresponding molar concentrations of bleomycin were calculated. The strong correlation (R2 = 0.92 for LV = 2) between the predicted and observed number of DSBs indicates, that the model can not only predict the number of DSBs from the spectra but also detect the spectroscopic markers of DNA damage and the associated conformational changes.
Time resolved in-situ multi-contrast X-ray imaging of melting in metals
Authors: Massimi Lorenzo , Clark Samuel J. , Marussi Sebastian , Doherty Adam , Shah Saurabh M. , Schulz Joachim , Marathe Shashidhara , Rau Christoph , Endrizzi Marco , Lee Peter D. , Olivo Alessandro 
Published: July 2022

AbstractIn this work, the application of a time resolved multi-contrast beam tracking technique to the investigation of the melting and solidification process in metals is presented. The use of such a technique allows retrieval of three contrast channels, transmission, refraction and dark-field, with millisecond time resolution. We investigated different melting conditions to characterize, at a proof-of-concept level, the features visible in each of the contrast channels. We found that the phase contrast channel provides a superior visibility of the density variations, allowing the liquid metal pool to be clearly distinguished. Refraction and dark-field were found to highlight surface roughness formed during solidification. This work demonstrates that the availability of the additional contrast channels provided by multi-contrast X-ray imaging delivers additional information, also when imaging high atomic number specimens with a significant absorption.