bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the adherence of intervertebral disc degeneration clinical trial protocols to SPIRIT guidelines
Authors: Chemorion Francis , Bisotti Marc-Antonio 
Published: October 2024

AbstractIntroductionClinical trials are important for advancing medical knowledge and protocols are the core documents that facilitate their appraisal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist offers a framework for standardizing the quality and content of clinical trial protocols. Although there is a high growth in number of clinical trials investigating the efficacy and safety of various therapies, many still exhibit deficiencies in information contained in both their reports and protocols. The main objective for this study were to check the findability of intervertebral disc degeneration (IVD) clinical trial protocols and assessing their adherence to SPIRIT recommendations.MethodsWe included randomized controlled trials (RCTs) that investigated various therapeutic interventions for IVD provided they included a control group and reported at least one relevant clinical outcome. Studies were excluded if they were not recruiting, were observational, case reports, reviews, meta-analyses, editorials, or commentaries, or if they lacked complete data, such as missing results or a protocol. A search was conducted onClinicalTrials.govusing terms related to IVD, covering the period from January 2013 to the present, aligning with the post-SPIRIT recommendation publication period. Data extraction was performed using a reduced SPIRIT checklist to assess adherence to protocol guidelines, with compliance measured across 64 key items. A narrative synthesis was conducted to summarize study characteristics, adherence levels and patterns by intervention and sponsor type.ResultsAdherence rates vary from 28.13% to 98.44% with a median of 48.44%. Heatmaps revealed heterogeneity, highlighting areas of consistent adherence and regions requiring improvement. High adherence was noted in inclusion criteria and outcome measurement, while lower in research ethics and funding declarations. Industry-sponsored studies demonstrated highest adherence in ‘DRUG’ (79.69%) and ‘DEVICE’ (62.50%) categories, while non-industry sponsors were most adherent in ‘BIOLOGICAL’ (50.00%) and ‘OTHER’ intervention categories.DiscussionOur findings shows a critical need for findability of clinical trial protocols to assist in appraisal of interventions and enhanced adherence to SPIRIT guidelines among IVD clinical trials, for greater transparency and accuracy. Adherence is essential for ensuring high-quality evidence that can inform clinical practice and patient care in managing IVD.
Mental Health Promotion in Victims of Colombian Armed conflict: a Scoping Review
Authors: Ballesteros Lina María González , Mojica Luis Eduardo , Marín Jennifer Clavijo , Ortiz Andrés Felipe , Ponce Mariana Vásquez , Pérez-Lalinde Sofía , Sanabria Nicolas León , Silva Luisa María Carrera , Álvarez Andrea Clavijo 
Published: October 2024

ABSTRACTObjectiveTo explore mental health promotion interventions for victims of Colombian armed conflict.DesignScoping review.MethodsSearches were conducted using indexed and free terms regarding mental health promotion interventions for victims of Colombian armed conflict in different databases, including MEDLINE, EMBASE, Scielo, Cochrane Central Register of Controlled Trials, LiLACS, Google Scholar, and PsycArticles. We included primary and secondary research sources, including clinical trials, randomized controlled trials, qualitative research, online journals, meta-analyses, scoping reviews, and systematic reviews, as well as government reports and articles about implementing mental health promotion strategies for victims of Colombian armed conflict.ResultsOur search returned 317 identified articles through database exploration. Four more articles were included through literature research and another four records were included through gray literature and government reports. Retrieved citations were screened using Rayyan QCRI. A total of 259 records were left after duplicate removal. Members of the group then performed a paired-blind screening, which left us with 16 articles to be included in the analysis. Data analysis was conducted by authors in pairs using custom tools developed by the research team. After reviewing the articles, only six met the inclusion criteria established for this scoping review. Among these, two of the interventions addressed were randomized clinical trials that demonstrated effects on depression, anxiety, and post-traumatic stress disorder (PTSD). Additionally, one of these trials assessed impairments in functionality.ConclusionA total of six articles demonstrated the effectiveness of mental health promotion and primary prevention interventions in Colombian victims of armed conflict. However, only two of the studies were randomized clinical trials, and methodological limitations were evident, including loss in sample follow-up, challenges in comparing populations, and use of non-standardized scales across different studies. This hinders the possibility of a unified assessment of these interventions and highlights the need for bigger study samples and use of tools that facilitate access to programs and one-year follow-ups to enhance interventions government organizations employ to address these mental health needs.
The impact of health-system pharmacists on hospitalizations in heart failure: a systematic review and meta-analysis
Authors: Van der Linden Lorenz , Beavers Craig , Forsyth Paul , Vandenbriele Christophe , Tsuyuki Ross T. , Karapinar-Carkıt Fatma , Van Aelst Lucas 
Published: October 2024

AbstractBackgroundPrevious evidence has established the role of pharmacists in heart failure (HF) care. However, the specific role of health-system pharmacists within in- and outpatient settings for HF patients has been left unexplored. This systematic review and meta-analysis aimed to evaluate the impact of health-system pharmacy interventions on all-cause and HF hospitalizations.MethodsA systematic literature search was performed using PUBMED and EMBASE, following PRISMA guidelines. Randomized controlled trials (RCTs) published up to May 2024 that evaluated the effects of health-system pharmacy interventions on hospitalizations in HF patients were included. The quality of the included RCTs was assessed using Cochrane’s risk-of-bias tool. Meta-analyses were performed using random-effects models, with odds ratios (OR) as summary measure. Heterogeneity was assessed using the I2statistic and Cochrane’s Q test.ResultsIn total, 11 RCTs involving 3576 patients were included in our review. The meta-analysis of 9 RCTs assessing all-cause hospitalizations (3472 patients, 927 events) demonstrated a significant reduction with pharmacist care (OR 0.67, 95% CI: 0.49–0.92, p=0.0119). The second meta-analysis of also 9 RCTs, focusing on HF hospitalizations (3442 patients, 504 events), showed similar results (OR 0.64, 95% CI: 0.48–0.87, p=0.0038). Heterogeneity was moderate for both meta-analyses. Sensitivity analyses confirmed the robustness of the results. Subgroup analyses indicated greater effectiveness in outpatient settings and for extended interventions.ConclusionsHealth-system pharmacist interventions significantly reduce both all-cause and HF-specific hospitalizations in HF patients. Our findings highlight the importance of integrating pharmacists into multidisciplinary teams to improve HF management for in- and outpatients (PROSPERO: CRD42024593583).
TamL is a key player of the outer membrane homeostasis in Bacteroidetes
Authors: Giovannercole Fabio , de Smet Tom , Vences-Guzmán Miguel Angel , Lauber Frédéric , Dugauquier Rémy , Dieu Marc , Lizen Laura , Dehairs Jonas , Lima-Mendez Gipsi , Guan Ziqiang , Sohlenkamp Christian , Renzi Francesco 
Published: October 2024

AbstractIn Proteobacteria, the outer membrane protein TamA and the inner membrane-anchored protein TamB form the Translocation and Assembly Module (TAM) complex, which facilitates the transport of autotransporters, virulence factors, and likely lipids across the two membranes.In Bacteroidetes TamA is replaced by TamL, a TamA-like lipoprotein with a lipid modification at its N-terminus that likely anchors it to the outer membrane. This structural difference suggests that TamL may have a distinct function compared to TamA. However, the role of TAM in bacterial phyla other than Proteobacteria remains unexplored.Our study aimed to elucidate the functional importance of TamL inFlavobacterium johnsoniae, an environmental Bacteroidetes. Unlike its homologues in Proteobacteria, we found that TamL and TamB are essential inF. johnsoniae. Through genetic, phenotypic, proteomic, and lipidomic analyses, we discovered that TamL depletion severely compromises outer membrane integrity, as evidenced by reduced cell viability, altered cell shape, increased susceptibility to membrane-disrupting agents, and elevated levels of outer membrane lipoproteins. Notably, we did not observe any impact on outer membrane lipid composition.Via pull-down protein assays, we confirmed that TamL interacts with TamB inF. johnsoniae, likely forming the TAM complex. Furthermore, ourin silicoanalysis revealed that the presence of TamL and TamB monocistronic genes is a shared genetic feature among Bacteroidetes members, including the human pathogenCapnocytophaga canimorsuswhere we also confirmed the essentiality of the TamL and TamB homologs.To our knowledge, this study is the first to provide functional insights into a TAM subunit beyond Proteobacteria.SignificanceIn Proteobacteria, the outer membrane (OM) protein TamA forms with the inner membrane (IM)-anchored protein TamB the Translocation and Assembly Module Complex (TAM). which contributes to efficient biogenesis of the OM. In Bacteroidetes TamA is replaced by TamL, a TamA-like lipoprotein of unknown role. In this work, we studied TamL in the BacteroidetesFlavobacterium johnsoniae. We found that TamL and TamB are essential for cell viability, and that TamL depletion disrupts outer membrane stability, increases outer membrane vesicle size, and lead to higher sensitivity to OM stressors. These findings highlight TamL critical role in maintaining OM structure in Bacteroidetes. To our surprise, we also identified multiple TamL, TamB and TamA homologs in Bacteroidetes. Altogether, our findings extend the current knowledge on TAM and provide novel insights into a field of research barely investigated outside Proteobacteria.
Fluorescent anionic cyanine plasma membrane probes for live cell andin vivoimaging
Authors: Danylchuk Dmytro I. , Khalin Igor , Suseela Yelisetty V. , Filser Severin , Plesnila Nikolaus , Klymchenko Andrey S. 
Published: October 2024

AbstractProper staining of cell plasma membrane is indispensable for fluorescence imaging. Herein, we present an array of five anionic cyanine-based turn-on plasma membrane probes with emission spanning from green to near infrared. They are analogous of commonly used MemBright probes family, where two zwitterionic anchor groups are replaced with anionic sulfonates with dodecyl chains. The developed probes provide selective wash-free staining of plasma membranes of live cells in vitro, featuring improved brightness and slower internalization inside the cells. In comparison to protein-based (wheat germ agglutinin) membrane markers, new membrane probes provide better staining in poorly assessable cell-cell contacts. A key challenge is to stain cell plasma membranes directly in vivo. Duringin vivobrain tissue imaging in living mice by two-photon microscopy, the anionic cyanine probes allowed us to visualize in detail the pyramidal neurons with high image quality, clearly resolving neuron soma, dendrites with dendritic spines and axons with axonal boutons. The developed anionic cyanine-based plasma membrane probes constitute an important extension of the toolbox of fluorescent probes for plasma membrane research.
Agent-Based Simulation of Cortical Microtubule Band Movement in theArabidopsisZygote
Authors: Nonoyama Tomonobu , Kang Zichen , Matsumoto Hikari , Nakagawa Sakumi , Ueda Minako , Tsugawa Satoru 
Published: October 2024

AbstractArabidopsis thalianazygotes form a circumferential cortical microtubule (CMT) band that stays at a constant position from the growing tip. CMT bands support zygote anisotropic growth that is essential to determine the apical-basal axis of the plant body, but how stable CMT bands are maintained remains unclear. We hypothesized that cell surface tension induces CMT reorientation of which the strength was defined as the directional cue (DC). We constructed an agent-based simulation model using the DC and its spatial distribution (DC zone) to determine the range of molecular parameters and the width and movement speed of the DC zone required to form the CMT band. We then developed a data–model correspondence method to determine the range of the parameters which are difficult to observe experimentally. We determined that the DC zone must move with an appropriate speed of mechanical change may exist to form a moving CMT band.
Nanomaterials trigger functional responses in primary human immune cells
Authors: Mittelheisser Vincent , Lefebvre Olivier , Banerjee Mainak , Ghosh Shayamita , Dupas Amandine , Diringer Marie-Charlotte , Blumberger Juliette , Bochler Louis , Harlepp Sébastien , Larnicol Annabel , Pichot Angélique , Stemmelen Tristan , Molitor Anne , Moritz Chloé , Carapito Christine , Carapito Raphaël , Charbonnière Loïc J. , Lux François , Tillement Olivier , Goetz Jacky G. , Detappe Alexandre 
Published: October 2024

AbstractTargeting the immune system with nanoparticles (NPs) to deliver immunomodulatory molecules emerged as a solution to address intra-tumoral immunosuppression and enhance therapeutic response. While the potential of nanoimmunotherapies in reactivating immune cells has been evaluated in several preclinical studies, the impact of drug-free nanomaterials on the immune system remains unknown. Here, we characterize the molecular and functional response of human NK cells and pan T cells to a selection of five NPs that are commonly used in biomedical applications. After a pre-screen to evaluate the toxicity of these nanomaterials on immune cells, we selected ultrasmall silica-based gadolinium (Si-Gd) NPs and poly(lactic-co-glycolic acid) (PLGA) NPs for further investigation. Bulk RNA-sequencing and flow cytometry analysis showcase that PLGA NPs trigger a transcriptional priming towards activation in NK and pan T cells. While PLGA NPs improved NK cells anti-tumoral functions in cytokines-deprived environment, Si-Gd NPs significantly impaired T cells activation as well as functional responses to a polyclonal antigenic stimulation. Altogether, we identified PLGAs NPs as suitable and promising candidates for further targeting approaches aiming to reactivate the immune system of cancer patients.
Expression study of Krabbe DiseaseGALCmissense variants – Insights from quantification profiles of residual enzyme activity, secretion and psychosine levels
Authors: Peng Hui , Lam Ying-Wai , Zhou Zitao , Herdt Aimee R. , Gelb Michael H. , Lee Chris W. 
Published: October 2024

AbstractKrabbe disease (KD) is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in theGALCgene, which encodes for the enzyme galactosylceramidase (GALC). GALC is crucial for myelin metabolism. Functional deficiency of GALC leads to toxic accumulation of psychosine, dysfunction and death of oligodendrocytes, and eventual brain demyelination. To date, 46 clinically-relevant, pathogenic GALC missense mutations (MMs) have been identified in KD patients. These MMs are present in ∼70% of KD cases reported over 8 published studies between 1996 – 2019. However, the mechanisms by which these MMs lead to GALC functional deficiency and their correlations with clinical phenotype remain poorly understood.To address this, we generated aGALC-knockout human oligodendrocytic cell line (MO3.13/GALC-KO) using CRISPR-Cas9 method to assess GALC function and GALC secretion. We evaluated 5 polymorphic and 31 clinically-relevant MM variants (MMVs) using transient expression assays. Our results showed that 26 MMVs, including 10 co-variants with p.I562T, reduced GALC activity by 92% - 100% compared to wild-type GALC (WT-GALC). MMVs from infantile-onset KD patients produced < 2% of WT activity, whereas those associated with juvenile- and adult-onset cases retained up to 7% of WT activity. Residual GALC activity was correlated with mature, lysosomal GALC protein levels (Pearson r = 0.93, P<0.0001). Many low-activity MMVs did not correspondingly impair GALC secretion. Twenty-one of the 26 low-activity MMVs showed a 21% - 100% reduction in sec-GALC levels, indicating varying degrees of GALC mis-trafficking among these variants.Importantly, GALC activity among MMVs strongly correlates with clinical disease severity, based on the age of symptom onset in patients with either homozygous MM (Pearson r = 0.98, P<0.0001, n = 7) or compound heterozygous (Pearson r = 0.94, P<0.0001, n = 12) MM-null mutation genotypes. Thus, our data suggests that GALC activity could serve as a prognostic disease indicator under specific experimental conditions. We further investigated the impact of pathogenic MMVs on psychosine accumulation, a key biomarker for KD. Psychosine levels were 21-fold higher in mock control cells compared to WT-GALC transfected cells (mock = 0.349 pmol/mg, WT-GALC = 0.016 pmol/mg), but negatively correlated with GALC activity among pathogenic MMVs (Pearson r = −0.63, P < 0.01, n = 15). Although psychosine levels were higher in most MMVs associated with infantile-onset KD, no significant correlations with clinical onset were detected.Overall, our study provides a comprehensive quantitative analysis of the functional deficits and mis-trafficking associated with clinically-relevant GALC MMVs, enhancing our understanding of the molecular genetics and genotype-phenotype correlations of theGALCgene in Krabbe disease.
Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer
Authors: Smalley Tracess B , Nicolaci Angelo , Tran Kim C. , Lokhandwala Jameela , Obertopp Nina , Matlack Jenet K , Miner Robert E , Teng Michael N. , Pilon-Thomas Shari , Binning Jennifer M 
Published: October 2024

AbstractHuman Papilloma Virus (HPV)-related cancers are a global health burden, yet there are no targeted therapies available for chronically infected patients. The HPV protein E6 is essential for HPV-mediated tumorigenesis and immune evasion, making it an attractive target for antiviral drug development. In this study, we developed an E6-targeting Proteolysis Targeting Chimera (PROTAC) that inhibits the growth of HPV(+) tumors. To develop E6 antagonists, we generated a panel of nanobodies targeting E6 proteins derived from the oncogenic HPV16 subtype. The highest affinity E6 nanobody, A5, was fused to Von Hippel Lindau protein (VHL) to generate a PROTAC that degrades E6 (PROTACE6). Mutational rescue experiments validated specific degradation via the CRL2VHLE3 ligase. Intralesional administration of the PROTACE6using a clinically viable DNA vaccine reduced tumor burden in an immunocompetent mouse model of HPV(+) cancer. The inhibitory effect of the PROTACE6was abrogated by CD4+and CD8+T-cell depletion, indicating that the antitumor function of the PROTACE6relies in part on a host immune response. Overall, these results suggest that the targeted degradation of E6 inhibits its oncogenic function and stimulates a robust immune response against HPV(+) tumors, opening new opportunities for virus-specific therapies in the treatment of HPV-related cancers.
Early spatiotemporal evolution of the immune response elicited by adenovirus serotype 26 vector vaccination in mice
Authors: Blass Eryn , Colarusso Alessandro , Aid Malika , Larocca Rafael A. , Reeves R. Keith , Barouch Dan H. 
Published: October 2024

ABSTRACTAs the first responder to immunological challenges, the innate immune system shapes and regulates the ensuing adaptive immune response. Many clinical studies evaluating the role of innate immunity in initiating vaccine-elicited adaptive immune responses have largely been confined to blood due to inherent difficulty in acquiring tissue samples. However, the absence of vaccine-site and draining lymph node information limits understanding of early events induced by vaccination that could potentially shape vaccine-elicited immunity. We therefore utilized a mouse model to investigate the spatiotemporal evolution of the immune response within the first 24 hours following intramuscular adenovirus serotype 26 (Ad26) vector vaccination in tissues. We show that the Ad26 vaccine-elicited innate immune response commences by one hour and rapidly evolves in tissues and blood within the first 24 hours as reflected by the detection of cytokines, chemokines, cellular responses, and transcriptomic pathways. Furthermore, serum levels of IL-6, MIG, MIP-1α, and MIP-1β at 6 hours post-vaccination correlated with the frequency of vaccine-elicited memory CD8+T cell responses evaluated at 60 days post-vaccination in blood and tissues. Taken together, our data suggests that the immune response to Ad26 vector vaccination commences quickly in tissues by one hour and that events by as early as 6 hours post-vaccination can shape vaccine-elicited CD8+T cell responses at later memory time points.IMPORTANCEPrior studies have largely concentrated on innate immune activation in peripheral blood following vaccination. In this study, we report the detailed spatial and temporal innate immune activation in tissues following Ad26 vaccination in mice. We observed rapid innate activation rapidly not only in peripheral blood but also in draining lymph nodes and at the site of inoculation. Our findings provide a more detailed picture of host response to vaccination than previously reported.
The Role of ISG15 in Cancer Biology: Systematic Evaluation of ISG15 Expression and Its Molecular Interactions in a Pan-Cancer Context
Authors: Chatterjee Shrabonti , Mahata Joydeep 
Published: October 2024

AbstractISG15’s dual role in cancer biology still remains unclear. One major area requiring further investigation is the molecular mechanisms underlying ISG15’s pro- and anti-tumorigenic roles in different cancer types. In this study, we try to find the probable pathways that could be influenced by ISG15 in different cancers. ISG15, a ubiquitin-like protein is essential in the post-translational modification ISGylation, which involves a series of E1, E2, and E3 enzymes. During viral infections, ISG15 stimulates Type I interferon production and affects key proteins such as STAT1, JAK-1, MDA-5, Mx1, and RIG-1, thus impacting both host immunity and viral evasion strategies. Furthermore, ISG15 exhibits a complex role in cancer, acting as either a tumor suppressor or an oncogene depending on its state—free or conjugated. Intracellular free ISG15 affects protein stability, while extracellular ISG15 has immunomodulatory effects. Despite its significant role in immune regulation and cancer biology, the exact mechanisms through which ISG15 influences cancer progression remain to be fully elucidated. In this study, we examined ISG15’s role in tumor development and progression across 22 cancer types by integrating data from high-throughput databases including TCGA, GTEx, and CPTAC. We evaluated ISG15 expression at both mRNA and protein levels, noting increased mRNA expression in all cancer types except Kidney Chromophobe (KICH) and elevated protein levels in nine out of ten analyzed cancer types, with the exception of liver carcinoma. Analysis of TP53 mutations showed reduced ISG15 mRNA levels in KICH regardless of mutation status. Correlation analyses identified seven highly correlated genes—IFI35, IFI44, OASL, MX1, RSAD2, OAS2, and IRF7 involved in ISG15 downstream signaling. Protein-protein interaction networks revealed hub genes including STAT1, IFIT1, IFIT2, and OASL, which are crucial in cancer pathogenesis and warrant in-depth studies for therapeutic targets and drug repurposing.