bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of autologous bone marrow clot as a multifunctional bioscaffold for instrumental posterior lumbar fusion: a 1-year follow-up pilot study
Authors: Salamanna Francesca , Tedesco Giuseppe , Sartori Maria , Griffoni Cristiana , Spinnato Paolo , Romeo Paolo , Ghermandi Riccardo , Fini Milena , Giavaresi Gianluca , Gasbarrini Alessandro , Barbanti Brodano Giovanni 
Published: January 2024

BackgroundBone marrow aspirate (BMA), when combined with graft substitutes, has long been introduced as a promising alternative to iliac crest bone graft in spinal fusion. However, the use of BMA is limited by the absence of a standardized procedure, a structural texture, and the potential for diffusion away from the implant site. Recently, the potential use of a new formulation of BMA, named BMA clot, has been preclinically described. In this report, we present the results of a prospective pilot clinical study aimed at evaluating the safety and efficacy of autologous vertebral BMA (vBMA) clot as a three-dimensional and multifunctional bioscaffold in instrumented posterior lumbar fusion.MethodsTen consecutive patients with an indication of multilevel (≤5) posterior spinal fusion due to lumbar spine degenerative diseases were included in the study and treated with vBMA. Clinical outcomes were assessed using the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and EuroQoL-5L (EQ-5L) preoperatively and at 3 months and 12 months after spinal fusion. Bone fusion quality was evaluated at the 12-month follow-up using the Brantigan classification on radiography (XR) imaging. Bone density was measured on computed tomography (CT) scans at 6 and 12 months of follow-up visits at the intervertebral arches and intervertebral joint areas and expressed in Hounsfield unit (HU).ResultsThe results indicate a successful posterolateral fusion rate of approximately 100% (considering levels with C, D, and E grades according to the Brantigan classification) at the 12-month follow-up, along with an increase in bone density from 6 to 12 months of follow-up. An improvement in the quality of life and health status following surgery, as assessed by clinical scores (ODI, VAS, and EQ-5L), was also observed as early as 3 months postsurgery. No adverse events related to the vBMA clot were reported.ConclusionThis prospective pilot study demonstrates the effectiveness and safety profile of vBMA clot as an advanced bioscaffold capable of achieving posterior lumbar fusion in the treatment of degenerative spine diseases. This lays the groundwork for a larger randomized clinical study.
Melatonin as an anti-stress signal: effects on an acute stress model and direct actions on interrenal tissue in goldfish
Authors: Azpeleta Clara , Delgado Mª Jesús , Metz Juriaan R. , Flik Gert , de Pedro Nuria 
Published: January 2024

BackgroundMelatonin is a key hormone in regulation of circadian rhythms, and involved in many rhythmic functions, such as feeding and locomotor activity. Melatonin reportedly counteracts stress responses in many vertebrates, including fish. However, targets for this action of melatonin and underlying mechanisms remain unknown.ResultsThis study reports potential anti-stress properties of melatonin in goldfish (Carassius auratus), with a focus on its effect on plasma cortisol, food intake, and locomotor activity, all of them involved in the responses to stress exposure. Indeed, acute injection of melatonin counteracted stress-induced hypercortisolinemia and reduced food intake. The reduced locomotor activity following melatonin treatment suggests a possible sedative role in fish. To assess whether this anti-stress effects of melatonin involve direct actions on interrenal tissue, in vitro cultures of head kidney (containing the interrenal cortisol-producing tissue) were carried out in presence of ACTH, melatonin, and luzindole, an antagonist of melatonin receptors. Melatonin in vitro reduced ACTH-stimulated cortisol release, an effect attenuated by luzindole; this suggests the presence of specific melatonin receptors in interrenal tissue.ConclusionsOur data support a role for melatonin as an anti-stress signal in goldfish, and suggest that the interrenal tissue of teleosts may be a plausible target for melatonin action decreasing cortisol production.
Genetically based variation in heat tolerance covaries with climate in a globally important disease vector
Authors: Orlinick Benjamin L. , Smith Angela , Medley Kim A. , Westby Katie M. 
Published: January 2024

IntroductionVector-borne diseases (VBDs) are an increasingly important global health concern in the face of climate change. Understanding the ecology and evolution of vector species is critical to predicting and combating VBD. Vectorial capacity models, used to forecast disease transmission, traditionally assume traits are constant among populations, and little is known about whether different vector populations vary in thermal tolerance. To test for geographic variation in upper thermal tolerance, we determined the critical thermal maximum (CTmax) of Aedes albopictus, a globally distributed mosquito and competent vector for many viruses including West Nile, chikungunya, and dengue.MethodsWe studied CTmax for eight different populations spanning four climate zones across the Eastern United States using common garden experiments to isolate genetic variation. To explore potential drivers of this variation we then tested the relationship between climatic variables measured near each population source and CTmax.ResultsWe found significant differences across populations for both adults and larvae, and these differences were more pronounced for adults. Larvae had higher CTmax values compared to adults. Several climatic variables improved models of CTmax for both adults and larvae including mean and max seasonal temperature, annual precipitation, and relative humidity. Annual precipitation appears to be particularly important and has a positive linear relationship with CTmax.DiscussionThe differences between life stages likely result from different selection pressures experienced in their terrestrial and aquatic habitats. Importantly, the assumption that mosquito populations within a species have the same upper thermal limits does not hold in this case, thus it is important to use population-specific CTmax values, among other important physiological parameters that may vary, to more accurately model and forecast VBDs.
Genetic interactions of schizophrenia using gene-based statistical epistasis exclusively identify nervous system-related pathways and key hub genes
Authors: Periyasamy Sathish , Youssef Pierre , John Sujit , Thara Rangaswamy , Mowry Bryan J. 
Published: January 2024

Background: The relationship between genotype and phenotype is governed by numerous genetic interactions (GIs), and the mapping of GI networks is of interest for two main reasons: 1) By modelling biological robustness, GIs provide a powerful opportunity to infer compensatory biological mechanisms via the identification of functional relationships between genes, which is of interest for biological discovery and translational research. Biological systems have evolved to compensate for genetic (i.e., variations and mutations) and environmental (i.e., drug efficacy) perturbations by exploiting compensatory relationships between genes, pathways and biological processes; 2) GI facilitates the identification of the direction (alleviating or aggravating interactions) and magnitude of epistatic interactions that influence the phenotypic outcome. The generation of GIs for human diseases is impossible using experimental biology approaches such as systematic deletion analysis. Moreover, the generation of disease-specific GIs has never been undertaken in humans.Methods: We used our Indian schizophrenia case-control (case-816, controls-900) genetic dataset to implement the workflow. Standard GWAS sample quality control procedure was followed. We used the imputed genetic data to increase the SNP coverage to analyse epistatic interactions across the genome comprehensively. Using the odds ratio (OR), we identified the GIs that increase or decrease the risk of a disease phenotype. The SNP-based epistatic results were transformed into gene-based epistatic results.Results: We have developed a novel approach by conducting gene-based statistical epistatic analysis using an Indian schizophrenia case-control genetic dataset and transforming these results to infer GIs that increase the risk of schizophrenia. There were ∼9.5 million GIs with a p-value ≤ 1 × 10−5. Approximately 4.8 million GIs showed an increased risk (OR &gt; 1.0), while ∼4.75 million GIs had a decreased risk (OR &lt;1.0) for schizophrenia.Conclusion: Unlike model organisms, this approach is specifically viable in humans due to the availability of abundant disease-specific genome-wide genotype datasets. The study exclusively identified brain/nervous system-related processes, affirming the findings. This computational approach fills a critical gap by generating practically non-existent heritable disease-specific human GIs from human genetic data. These novel datasets can train innovative deep-learning models, potentially surpassing the limitations of conventional GWAS.
In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS
Authors: Armstrong Christopher W. , Mensah Fane F. K. , Leandro Maria J. , Reddy Venkat , Gooley Paul R. , Berkovitz Saul , Cambridge Geraldine 
Published: January 2024

IntroductionDisturbances of energy metabolism contribute to the clinical manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Previously, we found that B cells from ME/CFS patients have an increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand was compared.MethodsCD24, the ectonucleotidases CD39 and CD73, the NAD-degrading enzyme CD38, and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor and costimulation with either T-cell-dependent or Toll-like-receptor-9-dependent agonists. The levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analyzed in relation to cell growth and immunophenotype.ResultsProliferating B cells from patients with ME/CFS showed a lower mitochondrial mass and a significantly increased usage of essential amino acids compared with those from HC, with a significantly delayed loss of CD24 and an increased expression of CD38 following stimulation.DiscussionThe immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with the increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.
Large-scale epidemiological analysis of common skin diseases to identify shared and unique comorbidities and demographic factors
Authors: Li Qinmengge , Patrick Matthew T. , Sreeskandarajan Sutharzan , Kang Jian , Kahlenberg J. Michelle , Gudjonsson Johann E. , He Zhi , Tsoi Lam C. 
Published: January 2024

IntroductionThe utilization of large-scale claims databases has greatly improved the management, accessibility, and integration of extensive medical data. However, its potential for systematically identifying comorbidities in the context of skin diseases remains unexplored.MethodsThis study aims to assess the capability of a comprehensive claims database in identifying comorbidities linked to 14 specific skin and skin-related conditions and examining temporal changes in their association patterns. This study employed a retrospective case-control cohort design utilizing 13 million skin/skin-related patients and 2 million randomly sampled controls from Optum’s de-identified Clinformatics® Data Mart Database spanning the period from 2001 to 2018. A broad spectrum of comorbidities encompassing cancer, diabetes, respiratory, mental, immunity, gastrointestinal, and cardiovascular conditions were examined for each of the 14 skin and skin-related disorders in the study.ResultsUsing the established type-2 diabetes (T2D) and psoriasis comorbidity as example, we demonstrated the association is significant (P-values&lt;1x10-15) and stable across years (OR=1.15-1.31). Analysis of the 2014-2018 data reveals that celiac disease, Crohn’s disease, and ulcerative colitis exhibit the strongest associations with the 14 skin/skin-related conditions. Systemic lupus erythematosus (SLE), leprosy, and hidradenitis suppurativa show the strongest associations with 30 different comorbidities. Particularly notable associations include Crohn’s disease with leprosy (odds ratio [OR]=6.60, 95% confidence interval [CI]: 3.09-14.08), primary biliary cirrhosis with SLE (OR=6.07, 95% CI: 4.93-7.46), and celiac disease with SLE (OR=6.06, 95% CI: 5.49-6.69). In addition, changes in associations were observed over time. For instance, the association between atopic dermatitis and lung cancer demonstrates a marked decrease over the past decade, with the odds ratio decreasing from 1.75 (95% CI: 1.47-2.07) to 1.02 (95% CI: 0.97-1.07). The identification of skin-associated comorbidities contributes to individualized healthcare and improved clinical management, while also enhancing our understanding of shared pathophysiology. Moreover, tracking these associations over time aids in evaluating the progression of clinical diagnosis and treatment.DiscussionThe findings highlight the potential of utilizing comprehensive claims databases in advancing research and improving patient care in dermatology.
Disease patterns and specific trajectories of anti-MDA5-related disease: a multicentre retrospective study of 70 adult patients
Authors: de Boysson Hubert , Cuchet Marie , Cassius Charles , Cuchet Pierre , Agard Christian , Audemard-Verger Alexandra , Marchand-Adam Sylvain , Cohen-Sors Raphaëlla , Gallay Laure , Graveleau Julie , Lesort Cécile , Ly Kim , Meyer Alain , Monseau Grégoire , Néel Antoine , Bonnotte Bernard , Pérard Laurent , Schleinitz Nicolas , Mariotte Delphine , Le Mauff Brigitte , Bourdenet Gwladys , Masmoudi Wafa , Deshayes Samuel , Dumont Anaël , Dompmartin Anne , Kottler Diane , Aouba Achille 
Published: January 2024

IntroductionThis study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies.MethodsAmong a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up.ResultsAmong the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21–22], p&lt;0.0001), the occurrence of thromboembolic events (HR: 5.22 [1.61–14.77], p=0.008) and the presence of any malignancy (HR: 19.73 [6.67–60], p&lt;0.0001) were the three factors independently associated with poor outcomes.DiscussionThis new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors.
Adjuvant immunotherapy improves recurrence-free and overall survival following surgical resection for intermediate/advanced hepatocellular carcinoma a multicenter propensity matching analysis
Authors: Xu Xiao , Wang Ming-Da , Xu Jia-Hao , Fan Zhong-Qi , Diao Yong-Kang , Chen Zhong , Jia Hang-Dong , Liu Fu-Bao , Zeng Yong-Yi , Wang Xian-Ming , Wu Han , Qiu Wei , Li Chao , Pawlik Timothy M. , Lau Wan Yee , Shen Feng , Lv Guo-Yue , Yang Tian 
Published: January 2024

Background &amp; aimsThe effectiveness of adjuvant immunotherapy to diminish recurrence and improve long-term prognosis following curative-intent surgical resection for hepatocellular carcinoma (HCC) is of increased interest, especially among individuals at high risk of recurrence. The objective of the current study was to investigate the impact of adjuvant immunotherapy on long-term recurrence and survival after curative resection among patients with intermediate/advanced HCC.MethodsUsing a prospectively-collected multicenter database, patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC were identified. Propensity score matching (PSM) analysis was used to compare recurrence-free survival (RFS) and overall survival (OS) between patients treated with and without adjuvant immune checkpoint inhibitors (ICIs). Multivariate Cox-regression analysis further identified independent factors of RFS and OS.ResultsAmong the 627 enrolled patients, 109 patients (23.3%) received adjuvant immunotherapy. Most ICI-related adverse reactions were grading I-II. PSM analysis created 99 matched pairs of patients with comparable baseline characteristics between patients treated with and without adjuvant immunotherapy. In the PSM cohort, the median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) were better among patients who received adjuvant immunotherapy versus patients who did not. After adjustment for other confounding factors on multivariable analyzes, adjuvant immunotherapy remained independently associated with favorable RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyzes identified potentially prognostic benefits of adjuvant immunotherapy among patients with intermediate-stage and advanced-stage HCC.ConclusionThis real-world observational study demonstrated that adjuvant immunotherapy was associated with improved RFS and OS following curative-intent resection of intermediate/advanced HCC. Future randomized controlled trials are warranted to establish definitive evidence for this specific population at high risks of recurrence.
A facile approach to preparing personalized cancer vaccines using iron-based metal organic framework
Authors: Li Xia , Hattori Shinya , Ebara Mitsuhiro , Shirahata Naoto , Hanagata Nobutaka 
Published: January 2024

BackgroundConsidering the diversity of tumors, it is of great significance to develop a simple, effective, and low-cost method to prepare personalized cancer vaccines.MethodsIn this study, a facile one-pot synthetic route was developed to prepare cancer vaccines using model antigen or autologous tumor antigens based on the coordination interaction between Fe3+ ions and endogenous fumarate ligands.ResultsHerein, Fe-based metal organic framework can effectively encapsulate tumor antigens with high loading efficiency more than 80%, and act as both delivery system and adjuvants for tumor antigens. By adjusting the synthesis parameters, the obtained cancer vaccines are easily tailored from microscale rod-like morphology with lengths of about 0.8 μm (OVA-ML) to nanoscale morphology with sizes of about 50~80 nm (OVA-MS). When cocultured with antigen-presenting cells, nanoscale cancer vaccines more effectively enhance antigen uptake and Th1 cytokine secretion than microscale ones. Nanoscale cancer vaccines (OVA-MS, dLLC-MS) more effectively enhance lymph node targeting and cross-presentation of tumor antigens, mount antitumor immunity, and inhibit the growth of established tumor in tumor-bearing mice, compared with microscale cancer vaccines (OVA-ML, dLLC-ML) and free tumor antigens.ConclusionsOur work paves the ways for a facile, rapid, and low-cost preparation approach for personalized cancer vaccines.
Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors
Authors: Anfray Clément , Varela Carmen Fernández , Ummarino Aldo , Maeda Akihiro , Sironi Marina , Gandoy Sara , Brea Jose , Loza María Isabel , León Sergio , Calvo Alfonso , Correa Juan , Fernandez-Megia Eduardo , Alonso María José , Allavena Paola , Crecente-Campo José , Andón Fernando Torres 
Published: January 2024

BackgroundIn the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer. Toll-like receptors (TLRs) ligands, such as poly(I:C) or resiquimod (R848) are able to reprogram TAMs towards M1-like antitumor effector cells. The objective of our work has been to develop and evaluate polymeric nanocapsules (NCs) loaded with poly(I:C)+R848, to improve drug stability and systemic toxicity, and evaluate their targeting and therapeutic activity towards TAMs in the TME of solid tumors.MethodsNCs were developed by the solvent displacement and layer-by-layer methodologies and characterized by dynamic light scattering and nanoparticle tracking analysis. Hyaluronic acid (HA) was chemically functionalized with mannose for the coating of the NCs to target TAMs. NCs loaded with TLR ligands were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry, using primary human monocyte-derived macrophages. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry and multispectral immunophenotyping.ResultsWe have developed polymeric NCs loaded with poly(I:C)+R848. Among a series of 5 lead prototypes, protamine-NCs were selected based on their physicochemical properties (size, charge, stability) and in vitro characterization, showing good biocompatibility on primary macrophages and ability to stimulate their production of T-cell attracting chemokines (CXCL10, CCL5) and to induce M1-like macrophages cytotoxicity towards tumor cells. In mouse tumor models, the intratumoral injection of poly(I:C)+R848-protamine-NCs significantly prevented tumor growth and lung metastasis. In an orthotopic murine lung cancer model, the intravenous administration of poly(I:C)+R848-prot-NCs, coated with an additional layer of HA-mannose to improve TAM-targeting, resulted in good antitumoral efficacy with no apparent systemic toxicity. While no significant alterations were observed in T cell numbers (CD8, CD4 or Treg), TAM-reprogramming in treated mice was confirmed by the relative decrease of interstitial versus alveolar macrophages, having higher CD86 expression but lower CD206 and Arg1 expression in the same cells, in treated mice.ConclusionMannose-HA-protamine-NCs loaded with poly(I:C)+R848 successfully reprogram TAMs in vivo, and reduce tumor progression and metastasis spread in mouse tumors.