bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nrf2 Plays a Key Role in Iron-Overload Cardiomyopathy
Authors: Federti Enrica , Vinchi Francesca , Iatcenko Iana , Ghigo Alessandra , Mattè Alessandro , Cedrick Serge , Siciliano Angela , Chiabrando Deborah , Tolosano Emanuela , Vance S. Zebulon , Riccardi Veronica , Andolfo Immacolata , Iolascon Achille , de Franceschi Lucia 
Published: November 2021

Abstract
Cardiomyopathy due to iron-overload is a severe complication of patients undergoing chronic transfusion regimen such as β-thalassemia and myelodysplastic syndromes. Previous studies have shown the key role of Nrf2, a redox-related transcriptional factor, in both β-thalassemia erythropoiesis and iron homeostasis (Matte A et al. ARS 2018, 2019; Lim PJ et al Nat Metab, 2019). Here, we compared Nrf2 knockout male mice (Nrf2 -/-) and C57BL-6J as wild-type (WT) controls, with a focus on cardiac function. Nrf2 -/- mice were characterized by a mild chronic hemolytic anemia associated with ineffective erythropoiesis, similar to what observed in murineβ-thalassemia (Toya SCM et al., Blood, 2019). Aging Nrf2 -/- mice developed systolic and diastolic dysfunction, associated with increased cardiac oxidative stress, degradation of the calcium-dependent SERCA2A transporter and activation of metalloproteinase MMP9, involved in both SERCA2A degradation and heart remodeling. In Nrf2 -/- mice, we observed increased plasma NTBI, heart iron deposition and elevated expression of cardiac ferroportin when compared to WT animals. Moreover, cardiac Hamp mRNA levels were down-regulated in aging Nrf2 -/- mice when compared to WT mice. This pattern was consistent with progressive cardiac iron overload in absence of Nrf2. Interestingly, activation of TGF-b receptor and PDGF-B-related pathway as well as increased collagen deposition were observed in hearts from 12 months old Nrf2 -/- mice. Taken together our data suggest an aging-associated development of iron-overload cardiomyopathy in mice genetically lacking Nrf2. To evaluate the role of Nrf2 in iron overload cardiomyopathy, Nrf2 -/- and WT mice were exposed to dietary iron supplementation (2.5% w/w carbonyl iron for 28 days). Nrf2 -/- mice developed cardiac hypertrophy which was accompanied by a worsening in collagen deposition and persistent activation of PDGF-B pathway. This was associated with inflammatory vasculopathy. The biologic importance of Nrf2 is supported by the cardiac activation of Nrf2, degradation of SERC2A and activation of TGF-b receptor and PDGF-B pathway in a mouse model of beta thalassemia intermedia, the Hbb3th/+ mice. Collectively our data support the crucial role of Nrf2 in the protection of cardiomyocytes against iron cytotoxicity which significantly develops in aging as well as in β-thalassemia.

Disclosures
Vinchi: Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vifor Pharma: Research Funding; PharmaNutra: Research Funding; Novartis: Research Funding. Ghigo: Kither Biotech: Other: Board member and Co-Founder. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board.
The Compass-COVID19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19
Authors: Van Dreden Patrick , Fraser Douglas D , Voiriot Guillaume , Rousseau Aurélie , Elalamy Ismail , Prassas Ioannis , Terpos Evangelos , Dimopoulos Meletios A. , Grusse Matthieu , Gerotziafas Grigoris 
Published: November 2021

Abstract
Background: In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation or death is un unmet need.
Objective: To derive a prognostic score for the risk of intubation or death in patients with critical COVID-19 by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes.
Methods: We conducted a prospective, observational monocentric study enrolling 118 patients with COVID-19 admitted in the intensive care unit. At the 1st day of ICU admission all patients were assessed for the following biomarkers : protein C, protein S, antithrombin, D-Dimer, fibrin monomers, factors VIIa, V, XII, XII, VIII, von Willebrand antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing tissue factor, IL-6, complement C3a, C5a, thrombin generation, prothrombin time, activated partial thromboplastin time, hemogram, platelet count) and clinical predictors. The clinical outcomes were intubation and mortality during hospitalization in ICU.
Results: The intubation and mortality rate were 70 % and 18% respectively. Multivariate analysis led to the derivation of the COMPASS- COVID19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization. The score predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively).
Conclusions and Relevance: Critical COVID-19 is related with severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID19-ICU score is an accurate predictive model for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The assessment with the COMPASS- COVID-19-ICU score is feasible in tertiary hospitals. In this context it could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

Disclosures
Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria.
Alternate-Day Dosing of Caplacizumab for Immune-Mediated Thrombotic Thrombocytopenic Purpura
Authors: Kühne Lucas , Eichenauer Dennis A. , Knöbl Paul , Völker Linus A. , Kaufeld Jessica , Wendt Ralph , Hägele Holger , Osterholt Thomas , Bieringer Marcus , Buxhofer-Ausch Veronika , Menne Jan , Schoenermarck Ulf , Brinkkoetter Paul 
Published: November 2021

Abstract
Background: The anti-VWF nanobody caplacizumab directly prevents the fatal microthrombi formation in immune-mediated thrombotic thrombocytopenic purpura, thereby adding a new therapeutic principle to the treatment of this autoimmune disorder. However, real-world treatment modalities beyond clinical trials remain heterogeneous.
Methods: Here, we describe the risks and benefits of an alternate-day dosing regimen for caplacizumab, by thoroughly analyzing the timing and outcome of this treatment approach in a retrospective cohort of 25 iTTP patients treated with caplacizumab in Austria and Germany between 2018 and 2021.
Results: Alternate-day dosing of caplacizumab appeared feasible and led to persisting normal platelet counts in the majority of patients, who were converted after a median time of 17 days daily treatment. Four patients experienced iTTP exacerbations or relapses that led to the resumption of daily caplacizumab application and/or other therapies. VWF activity was repeatedly measured in 17 out of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 hours, in line with published pharmacokinetics.
Conclusion: Extension of caplacizumab injection intervals from daily to alternate-day dosing may be safely considered in selected patients after 30 days of daily treatment. Earlier modifications may be considered in low-risk patients, but require close monitoring for clinical and laboratory features of thrombotic microangiopathy.

Disclosures
Völker: Sanofi-Genzyme: Honoraria, Other: counselling fees.
Genome-Wide CRISPR-Cas9 Screen Identifies Rationally Designed Combination Therapies Relevant for CRLF2-Rearranged Ph-like ALL
Authors: Sasaki Kensuke , Yamauchi Takuji , Semba Yuichiro , Nogami Jumpei , Imanaga Hiroshi , Terasaki Tatsuya , Nakao Fumihiko , Akahane Koshi , Inukai Takeshi , Verhoeyen Els , Akashi Koichi , Maeda Takahiro 
Published: November 2021

Abstract
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL, also known as BCR-ABL1-like ALL) is a disease entity of B-cell ALL that exhibits a gene expression profile, similar to that of Philadelphia chromosome-positive ALL. Ph-like ALL is categorized into two disease subtypes: "ABL-class"- and "CRLF2/JAK pathway"-types, both of which harbor gene alterations that constitutively activate cytokine/growth factor-related signals. Ph-like ALL with the CRLF2 rearrangement exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. Tyrosine kinase inhibitor (TKI)-based treatment regimens are effective in treating ABL-class type Ph-like ALL; however, no standard regimen has been established for the CRLF2/JAK pathway type. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. Thus, novel approaches are needed to treat CRLF2/JAK pathway type Ph-like ALL, in particular for CRLF2-rearranged (CRLF2-r) ALL.
To identify molecules/pathways relevant for CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines (MUTZ5 and KOPN49) that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which, for the first time, enabled highly efficient transduction of human B cell amenable for genome-wide CRSPR/Cas9 screens.
While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that the JAK-STAT axis is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL and FLT3 depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that reduces CRKL activity, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status.
Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

Disclosures
No relevant conflicts of interest to declare.
Conservative approach for the treatment of urethral prolapse in children: case report and literature review of 278 pediatric cases
Authors: Kacimi Salah Eddine Oussama , Aloulou Mohammad , Naoum Ranim , Moumeni Mohammed , Kaddour Abdallah , ElSheemy Mohammed Said 
Published: November 2021

Abstract
Background
Urethral prolapse (UP) is a rare, benign condition that often goes misdiagnosed and mistreated. It consists of the eversion of the distal urethral mucosa through the outer urethral meatus, leading to vascular obstruction and prolapsed tissue edema, which aggravates the prolapse. Although many review articles were reported on this condition, none of them focused on the conservative approach nor targeted the pediatric population. In this paper, we present successful medical management of UP in a 13-month-old Caucasian female and perform an extensive review of the literature to include articles that reported a conservative approach in patients under 18-years-old. We also suggested a practical algorithm for both diagnosis and management of this condition.

Case presentation
A 13-month-old Caucasian white female was presented with a urinary tract infection and vaginal bleeding. Genital examination showed a hyperemic donut-shaped mass covering the urinary meatus, of 0.7 cm diameter, with an actively bleeding open center. After confirming the diagnosis of UP with catheterization, a conservative approach was decided; antibiotics associated with topical corticosteroids including betamethasone 1% cream. The first-week outcome showed regression of the prolapsed tissue and the examination after four months showed normal vaginal mucosa with no evidence of relapse.

Conclusions
20 studies were retained after PubMed search with a total of 278 female patients aged between 1 month and 15 years old. The main reasons for referral were vaginal bleeding and mass, urinary symptoms followed by sexual abuse. Non-surgical treatment was tried for 162 patients. 53 of them were successfully managed, while 92 reported unsuccessful outcomes. The conservative approach was successful in 19% of all patients and raised to 32.7% in the portion of children selected for the initial conservative approach. Even though this review showed good results with medical treatment in children with UP, additional comparative studies are required to evaluate the effectiveness of conservative treatment in comparison with surgical interventions. In addition, Long-term follow-up is required as recurrence was reported up to 2 years following conservative treatment.
Benchmarking different approaches for Norovirus genome assembly in metagenome samples
Authors: Fuentes-Trillo Azahara , Monzó Carolina , Manzano Iris , Santiso-Bellón Cristina , Andrade Juliana da Silva Ribeiro de , Gozalbo-Rovira Roberto , García-García Ana-Bárbara , Rodríguez-Díaz Jesús , Chaves Felipe Javier 
Published: November 2021

Abstract
Background
Genome assembly of viruses with high mutation rates, such as Norovirus and other RNA viruses, or from metagenome samples, poses a challenge for the scientific community due to the coexistence of several viral quasispecies and strains. Furthermore, there is no standard method for obtaining whole-genome sequences in non-related patients. After polyA RNA isolation and sequencing in eight patients with acute gastroenteritis, we evaluated two de Bruijn graph assemblers (SPAdes and MEGAHIT), combined with four different and common pre-assembly strategies, and compared those yielding whole genome Norovirus contigs.

Results
Reference-genome guided strategies with both host and target virus did not present any advantages compared to the assembly of non-filtered data in the case of SPAdes, and in the case of MEGAHIT, only host genome filtering presented improvements. MEGAHIT performed better than SPAdes in most samples, reaching complete genome sequences in most of them for all the strategies employed. Read binning with CD-HIT improved assembly when paired with different analysis strategies, and more notably in the case of SPAdes.

Conclusions
Not all metagenome assemblies are equal and the choice in the workflow depends on the species studied and the prior steps to analysis. We may need different approaches even for samples treated equally due to the presence of high intra host variability. We tested and compared different workflows for the accurate assembly of Norovirus genomes and established their assembly capacities for this purpose.
Enzymatically-crosslinked gelatin hydrogels containing paenipeptin and clarithromycin against carbapenem-resistant pathogen in murine skin wound infection
Authors: Moon Sun Hee , Kaufmann Yihong , Fujiwara Ryoichi , Huang En 
Published: November 2021

Abstract
Background
The recent rise and spread of carbapenem-resistant pathogens pose an urgent threat to public health and has fueled the search for new therapies. Localized delivery of topical antibiotics is an alternative for the treatment of infected wounds caused by drug-resistant pathogens. In this study, we aimed to develop antimicrobial-loaded hydrogels for topical treatment of wound infections in a murine skin wound infection.

Results
Paenipeptin analogue 1, a linear lipopeptide, potentiated clarithromycin against multidrug-resistant Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, and Klebsiella pneumoniae. Enzymatically-crosslinked gelatin hydrogels were developed to encapsulate paenipeptin analogue 1 and clarithromycin. The encapsulated antimicrobials were gradually released from hydrogels during incubation, reaching 75.43 and 53.66% for paenipeptin and clarithromycin, respectively, at 24 h. The antimicrobial-loaded hydrogels containing paenipeptin and clarithromycin synergistically resulted in 5-log reduction in carbapenem-resistant A. baumannii within 6 h in vitro. Moreover, the antimicrobial-loaded hydrogels reduced 3.6- and 2.5-log of carbapenem-resistant A. baumannii when treated at 4 or 20 h post infection, respectively, in a murine skin wound infection.

Conclusions
Enzymatically-crosslinked gelatin hydrogels loaded with paenipeptin analogue 1 and clarithromycin exhibited potent therapeutic efficacy against carbapenem-resistant A. baumannii in murine skin wound infection.
Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats
Authors: Chu Zheng , Han Wei , Liu Peng , Liu Fei , Lei Gang , Deng Lisha , Yang Liu , Dang Yonghui 
Published: November 2021

Abstract
Background
Previous studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation.

Results
Data showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What’s more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats.

Conclusions
These results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.
Survival-associated N6-adenosine methyltransferase signatures in lung squamous cell carcinoma and clinical verification
Authors: Qu Jialin , Wang Li , Jiang Man , Wei Zhimin , Fu Guangming , Zhang Xiaochun 
Published: November 2021

Abstract
Background
N6-methyladenine (m6A) is the most common modification of mRNA and IncRNA in higher organisms. m6A has been confirmed to be related to the formation and progression of tumors and m6A-related genes can be used as prognostic biomarkers in a variety of tumors. However, there have been no similar studies on lung squamous cell carcinoma. The main purpose of this study was aimed to explore the differential expression of m6A-related genes in lung squamous cell carcinoma tissues and its relationship with patient clinical prognosis.

Methods
We integrated three m6A writers that catalyze the methylation of adenine on mRNA molecules. The training set including 501 patients with LUSC was collected from The Cancer Genome Atlas (TCGA) database and the test set including 181 patients with LUSC was collected from the Gene Expression Omnibus (GEO) database. Based on the expression level of the m6A methylase gene, we established a tumor subgroup and risk-prognosis model to quantify the risk index and long-term patient prognosis, which were confirmed by principal component analysis (PCA) and receiver operating characteristic (ROC) curve analysis. After lung squamous cell carcinoma tissue specimens were obtained during surgery, immunohistochemistry (IHC) was used to verify the results in vitro.

Results
The results of the study showed that the expression of the three m6A methylases in tumor tissues and normal tissues was significantly different (P < 0.05). The survival-prognostic model based on METTL3 gene expression showed better predictive performance (AUC: 0.706). Patients in the high-risk and low-risk groups exhibited significant differences in terms of survival time and 5-year and 10-year survival rates. Immunohistochemistry revealed that patients with high METTL3 expression exhibited a longer survival time than those with low METTL3 expression.

Conclusions
Our study showed that the molecular phenotype based on the expression of METTL3 may be an independent risk factor affecting the prognosis of lung squamous cell carcinoma. These findings not only prove the important role of m6A methylase in lung squamous cell carcinoma, but are also expected to provide more accurate prognostic assessment and individualized treatment for patients with lung squamous cell carcinoma.
Funding patterns for biomedical research and infectious diseases burden in Gabon
Authors: Adegnika Olouyomi Scherif , Honkpehedji Yabo Josiane , Mougeni Lotola Fabrice , Agnandji Selidji Todagbe , Adegnika Ayola Akim , Lell Bertrand , Sicuri Elisa 
Published: November 2021

Abstract
Background
Biomedical research plays an important role in improving health. There seems to exist a negative correlation between the amount of biomedical research funding and disease burden from all Sub-Saharan African countries. In this study, we describe funding patterns for biomedical research, explore the correlation between funding and burden of diseases, and quantify inequalities in funds distribution across diseases in Gabon over the period 2005–2015.

Methods
Data on medical research funds from 2005 to 2015 were retrieved through a structured questionnaire distributed to Gabonese biomedical research institutions and by consulting online databases. Data on the burden of diseases were gathered from the World Health Organization and the Institute for Health Metrics and Evaluation. We used Kendall rank correlation coefficient to explore the correlation between cumulative funds over time and the burden of disease. The inequality distribution of funding across diseases was assessed through Gini coefficient and Lorenz curve.

Results
Biomedical research funding was characterized by a remarkable growth from 2005 to 2010 and a decline from 2010 to 2014. Funds were mostly from external sources and from partnerships. There was inequality in research funds allocation across diseases and malaria was far the most funded disease. There was a significant negative correlation between cumulative funding and the burden of HIV, tuberculosis, and of Helminthiasis (from 2006 to 2010) suggesting that research may be contributing to the management of such diseases. A positive, although not significant, correlation was found between cumulative funds and malaria burden.

Conclusions
The negative correlation between HIV and tuberculosis cumulative funding and burden suggests that research may be contributing to the management of such diseases but further research is needed to assess the causal direction of such as relationship. As the burden of non-communicable diseases is increasing, more research funds should be focused on those. While research partnerships have been and will remain fundamental, Gabon should increase the amount of national funds to overcome periods of reduced research funding flows from abroad.