cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.11826969.v1
title: Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of <sup>177</sup>Lu-DOTATATE PRRT

description: <b>Background:</b> Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity. <b>Material and methods:</b> Our single-center retrospective study enrolled all patients treated with <sup>177</sup>Lu-DOTATATE PRRT (1–4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (<i>N</i> = 41), or targeted agents (everolimus, sunitinib or both; <i>N</i> = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored. <b>Results:</b> Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (<i>N</i> = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events. <b>Conclusions:</b> In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of <sup>177</sup>Lu-DOTATATE PRRT.
DOI: 10.6084/m9.figshare.11955882.v1
title: Can a machine-learning model improve the prediction of nodal stage after a positive sentinel lymph node biopsy in breast cancer?

description: <b>Background:</b> The current standard for evaluating axillary nodal burden in clinically node negative breast cancer is sentinel lymph node biopsy (SLNB). However, the accuracy of SLNB to detect nodal stage N2-3 remains debatable. Nomograms can help the decision-making process between axillary treatment options. The aim of this study was to create a new model to predict the nodal stage N2-3 after a positive SLNB using machine learning methods that are rarely seen in nomogram development. <b>Material and methods:</b> Primary breast cancer patients who underwent SLNB and axillary lymph node dissection (ALND) between 2012 and 2017 formed cohorts for nomogram development (training cohort, <i>N</i> = 460) and for nomogram validation (validation cohort, <i>N</i> = 70). A machine learning method known as the gradient boosted trees model (XGBoost) was used to determine the variables associated with nodal stage N2-3 and to create a predictive model. Multivariate logistic regression analysis was used for comparison. <b>Results:</b> The best combination of variables associated with nodal stage N2-3 in XGBoost modeling included tumor size, histological type, multifocality, lymphovascular invasion, percentage of ER positive cells, number of positive sentinel lymph nodes (SLN) and number of positive SLNs multiplied by tumor size. Indicating discrimination, AUC values for the training cohort and the validation cohort were 0.80 (95%CI 0.71–0.89) and 0.80 (95%CI 0.65–0.92) in the XGBoost model and 0.85 (95%CI 0.77–0.93) and 0.75 (95%CI 0.58–0.89) in the logistic regression model, respectively. <b>Conclusions:</b> This machine learning model was able to maintain its discrimination in the validation cohort better than the logistic regression model. This indicates advantages in employing modern artificial intelligence techniques into nomogram development. The nomogram could be used to help identify nodal stage N2-3 in early breast cancer and to select appropriate treatments for patients.
DOI: 10.6084/m9.figshare.14681418.v2
title: miRNA exosomes in patientes with ICAD -5.xlsx

description: miRNA in Intracranial AtherosclerosisData Availability Access PolicyThe deidentified miRNA data is available to all investigators that provide theinvestigators with a request and have a plan for a research project in which theinformation collected could be used. Please be aware that the paper originally publishedfrom this data needs to be cited for any additional use.Please include the following information in an email to the corresponding author (Dr.<br>
DOI: 10.6084/m9.figshare.14681430
title: DATA TRIAL

description: SHARING TRIAL DATA
DOI: 10.6084/m9.figshare.11777844.v1
title: Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice

description: Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial <i>Atg5</i> caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation <i>via</i> PDE10A (phosphodiesterase 10A)–cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. <b>Abbreviations</b>: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.
DOI: 10.6084/m9.figshare.11777844
title: Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice

description: Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial <i>Atg5</i> caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation <i>via</i> PDE10A (phosphodiesterase 10A)–cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. <b>Abbreviations</b>: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.
DOI: 10.6084/m9.figshare.11760327
title: Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet

description: Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention-induced weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used <i>Pdgfra-Cre<sup>Ert2</sup> </i> transgenic mice to create conditional deletion of <i>Atg7</i> alleles in AT progenitor cells (<i>atg7</i> cKO) and examined sex-dependent, depot-specific AT remodeling in high-fat diet (HFD)-fed mice. Mice with <i>atg7</i> cKO had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous, and epicardial adipose depots compared to <i>Atg7<sup>lox/lox</sup> </i> littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors could mimic these effects. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of ATG7 inhibition confirms the requirement of autophagy for white/beige adipocyte turnover, and combined to <i>in vitro</i> experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through the paracrine remodeling of TGF-BMP factors balance. <b>Abbreviations:</b> CQ: chloroquine; ECM: extracellular matrix; EpiAT: epididymal adipose tissue; GTF2IRD1: general transcription factor II I repeat domain-containing 1; HFD: high-fat diet; KO: knockout; OvAT: ovarian adipose tissue; PDGFR: platelet derived growth factor receptor; ScAT: subcutaneous adipose tissue; TGF-BMP: transforming growth factor-bone morphogenic protein
DOI: 10.6084/m9.figshare.11760327.v1
title: Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet

description: Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention-induced weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used <i>Pdgfra-Cre<sup>Ert2</sup> </i> transgenic mice to create conditional deletion of <i>Atg7</i> alleles in AT progenitor cells (<i>atg7</i> cKO) and examined sex-dependent, depot-specific AT remodeling in high-fat diet (HFD)-fed mice. Mice with <i>atg7</i> cKO had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous, and epicardial adipose depots compared to <i>Atg7<sup>lox/lox</sup> </i> littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors could mimic these effects. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of ATG7 inhibition confirms the requirement of autophagy for white/beige adipocyte turnover, and combined to <i>in vitro</i> experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through the paracrine remodeling of TGF-BMP factors balance. <b>Abbreviations:</b> CQ: chloroquine; ECM: extracellular matrix; EpiAT: epididymal adipose tissue; GTF2IRD1: general transcription factor II I repeat domain-containing 1; HFD: high-fat diet; KO: knockout; OvAT: ovarian adipose tissue; PDGFR: platelet derived growth factor receptor; ScAT: subcutaneous adipose tissue; TGF-BMP: transforming growth factor-bone morphogenic protein
DOI: 10.6084/m9.figshare.13299169
title: A multifactorial score including autophagy for prognosis and care of COVID-19 patients

description: In less than eleven months, the world was brought to a halt by the COVID-19 outbreak. With hospitals becoming overwhelmed, one of the highest priorities concerned critical care triage to ration the scarce resources of intensive care units. Which patient should be treated first? Based on what clinical and biological criteria? A global joint effort rapidly led to sequencing the genomes of tens of thousands of COVID-19 patients to determine the patients’ genetic signature that causes them to be at risk of suddenly developing severe disease. In this commentary, we would like to consider some points concerning the use of a multifactorial risk score for COVID-19 severity. This score includes macroautophagy (hereafter referred to as autophagy), a critical host process that controls all steps harnessed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. <b>Abbreviation list:</b> ATG5: autophagy related 5; BECN1: beclin 1; COVID-19: coronavirus infectious disease-2019; EGR1: early growth response 1; ER: endoplasmic reticulum; DMVs: double-membrane vesicles; IBV: infectious bronchitis virus; MAP1LC3: microtubule associated protein 1 light chain 3; LC3-I: proteolytically processed, non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; MEFs: mouse embryonic fibroblasts; MERS-CoV: Middle East respiratory syndrome-coronavirus; MHV: mouse hepatitis virus; NSP: non-structural protein; PEDV: porcine epidemic diarrhea virus; PLP2-TM: membrane-associated papain-like protease 2; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TGEV: transmissible gastroenteritis virus.
DOI: 10.6084/m9.figshare.13299169.v1
title: A multifactorial score including autophagy for prognosis and care of COVID-19 patients

description: In less than eleven months, the world was brought to a halt by the COVID-19 outbreak. With hospitals becoming overwhelmed, one of the highest priorities concerned critical care triage to ration the scarce resources of intensive care units. Which patient should be treated first? Based on what clinical and biological criteria? A global joint effort rapidly led to sequencing the genomes of tens of thousands of COVID-19 patients to determine the patients’ genetic signature that causes them to be at risk of suddenly developing severe disease. In this commentary, we would like to consider some points concerning the use of a multifactorial risk score for COVID-19 severity. This score includes macroautophagy (hereafter referred to as autophagy), a critical host process that controls all steps harnessed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. <b>Abbreviation list:</b> ATG5: autophagy related 5; BECN1: beclin 1; COVID-19: coronavirus infectious disease-2019; EGR1: early growth response 1; ER: endoplasmic reticulum; DMVs: double-membrane vesicles; IBV: infectious bronchitis virus; MAP1LC3: microtubule associated protein 1 light chain 3; LC3-I: proteolytically processed, non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; MEFs: mouse embryonic fibroblasts; MERS-CoV: Middle East respiratory syndrome-coronavirus; MHV: mouse hepatitis virus; NSP: non-structural protein; PEDV: porcine epidemic diarrhea virus; PLP2-TM: membrane-associated papain-like protease 2; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TGEV: transmissible gastroenteritis virus.
DOI: 10.6084/m9.figshare.12852066.v1
title: A DUF4148 family protein produced inside RAW264.7 cells is a critical Burkholderia pseudomallei virulence factor

description: Burkholderia pseudomallei: is the etiological agent of the disease melioidosis and is a Tier 1 select agent. It survives and replicates inside phagocytic cells by escaping from the endocytic vacuole, replicating in the cytosol, spreading to other cells via actin polymerization and promoting the fusion of infected and uninfected host cells to form multinucleated giant cells. In this study, we utilized a proteomics approach to identify bacterial proteins produced inside RAW264.7 murine macrophages and host proteins produced in response to <i>B. pseudomallei</i> infection. Cells infected with <i>B. pseudomallei</i> strain K96243 were lysed and the lysate proteins digested and analyzed using nanoflow reversed-phase liquid chromatography and tandem mass spectrometry. Approximately 160 bacterial proteins were identified in the infected macrophages, including BimA, TssA, TssB, Hcp1 and TssM. Several previously uncharacterized <i>B. pseudomallei</i> proteins were also identified, including BPSS1996 and BPSL2748. Mutations were constructed in the genes encoding these novel proteins and their relative virulence was assessed in BALB/c mice. The 50% lethal dose for the <i>BPSS1996</i> mutant was approximately 55-fold higher than that of the wild type, suggesting that BPSS1996 is required for full virulence. Sera from <i>B. pseudomallei</i>-infected animals reacted with BPSS1996 and it was found to localize to the bacterial surface using indirect immunofluorescence. Finally, we identified 274 host proteins that were exclusively present or absent in infected RAW264.7 cells, including chemokines and cytokines involved in controlling the initial stages of infection.
DOI: 10.6084/m9.figshare.13053349.v1
title: Exploring metal availability in the natural niche of <i>Streptococcus pneumoniae</i> to discover potential vaccine antigens

description: Nasopharyngeal colonization by <i>Streptococcus pneumoniae</i> is a prerequisite for pneumococcal transmission and disease. Current vaccines protect only against disease and colonization caused by a limited number of serotypes, consequently allowing serotype replacement and transmission. Therefore, the development of a broadly protective vaccine against colonization, transmission and disease is desired but requires a better understanding of pneumococcal adaptation to its natural niche. Hence, we measured the levels of free and protein-bound transition metals in human nasal fluid, to determine the effect of metal concentrations on the growth and proteome of <i>S. pneumoniae</i>. Pneumococci cultured in medium containing metal levels comparable to nasal fluid showed a highly distinct proteomic profile compared to standard culture conditions, including the increased abundance of nine conserved, putative surface-exposed proteins. AliA, an oligopeptide binding protein, was identified as the strongest protective antigen, demonstrated by the significantly reduced bacterial load in a murine colonization and a lethal mouse pneumonia model, highlighting its potential as vaccine antigen.
DOI: 10.6084/m9.figshare.12852045.v1
title: Transcriptional remodeling during metacyclogenesis in <i>Trypanosoma cruzi</i> I

description: Metacyclogenesis is one of the most important processes in the life cycle of <i>Trypanosoma cruzi</i>. In this stage, noninfective epimastigotes become infective metacyclic trypomastigotes. However, the transcriptomic changes that occur during this transformation remain uncertain. Illumina RNA-sequencing of epimastigotes and metacyclic trypomastigotes belonging to <i>T. cruzi</i> DTU I was undertaken. Sequencing reads were aligned and mapped against the reference genome, differentially expressed genes between the two life cycle stages were identified, and metabolic pathways were reconstructed. Gene expression differed significantly between epimastigotes and metacyclic trypomastigotes. The cellular pathways that were mostly downregulated during metacyclogenesis involved glucose energy metabolism (glycolysis, pyruvate metabolism, the Krebs cycle, and oxidative phosphorylation), amino acid metabolism, and DNA replication. By contrast, the processes where an increase in gene expression was observed included those related to autophagy (particularly Atg7 and Atg8 transcripts), corroborating its importance during metacyclogenesis, endocytosis, by an increase in the expression of the AP-2 complex subunit alpha, protein processing in the endoplasmic reticulum and meiosis. Study findings indicate that in <i>T. cruzi</i> metacyclic trypomastigotes, metabolic processes are decreased, and expression of genes involved in specific cell cycle processes is increased to facilitate transformation to this infective stage.
DOI: 10.6084/m9.figshare.12344432.v1
title: UvrY is required for the full virulence of <i>Aeromonas dhakensis</i>

description: <i>Aeromonas dhakensis</i> is an emerging human pathogen which causes fast and severe infections worldwide. Under the gradual pressure of lacking useful antibiotics, finding a new strategy against <i>A. dhakensis</i> infection is urgent. To understand its pathogenesis, we created an <i>A. dhakensis</i> AAK1 mini-Tn10 transposon library to study the mechanism of <i>A. dhakensis</i> infection. By using a <i>Caenorhabditis elegans</i> model, we established a screening platform for the purpose of identifying attenuated mutants. The <i>uvrY</i> mutant, which conferred the most attenuated toxicity toward <i>C. elegans</i>, was identified. The <i>uvrY</i> mutant was also less virulent in C2C12 fibroblast and mice models, in line with <i>in vitro</i> results. To further elucidate the mechanism of UvrY in controlling the toxicity in <i>A. dhakensis</i>, we conducted a transcriptomic analysis. The RNAseq results showed that the expression of a unique hemolysin <i>ahh1</i> and other virulence factors were regulated by UvrY. Complementation of Ahh1, one of the most important virulence factors, rescued the pore-formation phenotype of <i>uvrY</i> mutant in <i>C. elegans</i>; however, complementation of <i>ahh1</i> endogenous promoter-driven <i>ahh1</i> could not produce Ahh1 and rescue the virulence in the <i>uvrY</i> mutant. These findings suggest that UvrY is required for the expression of Ahh1 in <i>A. dhakensis</i>. Taken together, our results suggested that UvrY controls several different virulence factors and is required for the full virulence of <i>A. dhakensis</i>. The two-component regulator UvrY therefore a potential therapeutic target which is worthy of further study.