bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation regulator-based molecular subtyping and tumor microenvironment characterization in hepatocellular carcinoma
Authors: Zhao Junsheng , Liu Zhengtao , Yang Keda , Shen Sijia , Peng Jing 
Published: April 2024

BackgroudAlthough recent studies have reported the regulation of the immune response in hepatocellular carcinoma (HCC) through DNA methylation, the comprehensive impact methylation modifications on tumor microenvironment characteristics and immunotherapy efficacy has not been fully elucidated.MethodsIn this research, we conducted a comprehensive assessment of the patterns of DNA methylation regulators and the profiles of the tumor microenvironment (TME) in HCC, focusing on 21 specific DNA methylation regulators. We subsequently developed a unique scoring system, a DNA methylation score (DMscore), to assess the individual DNA methylation modifications among the three distinct methylation patterns for differentially expressed genes (DEGs).ResultsThree distinct methylation modification patterns were identified with distinct TME infiltration characteristics. We demonstrated that the DMscore could predict patient subtype, TME infiltration, and patient prognosis. A low DMscore, characterized by an elevated tumor mutation burden (TMB), hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, and immune activation, indicates an inflamed tumor microenvironment phenotype with a 5-year survival rate of 7.8%. Moreover, a low DMscore appeared to increase the efficacy of immunotherapy in the anti-CTLA-4/PD-1/PD-L1 cohort.ConclusionsIn brief, this research has enhanced our understanding of the correlation between modifications in DNA methylation patterns and the profile of the tumor microenvironment in individuals diagnosed with HCC. The DMscore may serve as an alternative biomarker for survival and efficacy of immunotherapy in patients with HCC.
Triglyceride-inflammation score established on account of random survival forest for predicting survival in patients with nasopharyngeal carcinoma: a retrospective study
Authors: Li Jun , Ye Yinxin , Cai Yonglin , Ji Huojin , Qin Weiling , Luo Yonglin , Zhou Xiaoying , Zhang Zhe , Xiao Xue , Zhang Bin 
Published: April 2024

ObjectiveThis study aimed to establish an effective prognostic model based on triglyceride and inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), to predict overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Additionally, we aimed to explore the interaction and mediation between these biomarkers in their association with OS.MethodsA retrospective review was conducted on 259 NPC patients who had blood lipid markers, including triglyceride and total cholesterol, as well as parameters of peripheral blood cells measured before treatment. These patients were followed up for over 5 years, and randomly divided into a training set (n=155) and a validation set (n=104). The triglyceride-inflammation (TI) score was developed using the random survival forest (RSF) algorithm. Subsequently, a nomogram was created. The performance of the prognostic model was measured by the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). The interaction and mediation between the biomarkers were further analyzed. Bioinformatics analysis based on the GEO dataset was used to investigate the association between triglyceride metabolism and immune cell infiltration.ResultsThe C-index of the TI score was 0.806 in the training set, 0.759 in the validation set, and 0.808 in the entire set. The area under the curve of time-dependent ROC of TI score in predicting survival at 1, 3, and 5 years were 0.741, 0.847, and 0.871 respectively in the training set, and 0.811, 0.837, and 0.758 in the validation set, then 0.771, 0.848, and 0.862 in the entire set, suggesting that TI score had excellent performance in predicting OS in NPC patients. Patients with stage T1-T2 or M0 had significantly lower TI scores, NLR, and PLR, and higher LMR compared to those with stage T3-T3 or M1, respectively. The nomogram, which integrated age, sex, clinical stage, and TI score, demonstrated good clinical usefulness and predictive ability, as evaluated by the DCA. Significant interactions were found between triglyceride and NLR and platelet, but triglyceride did not exhibit any medicating effects in the inflammatory markers. Additionally, NPC tissues with active triglyceride synthesis exhibited high immune cell infiltration.ConclusionThe TI score based on RSF represents a potential prognostic factor for NPC patients, offering convenience and economic advantages. The interaction between triglyceride and NLR may be attributed to the effect of triglyceride metabolism on immune response.
Transition to a mesenchymal state in neuroblastoma may be characterized by a high expression of GD2 and by the acquisition of immune escape from NK cells
Authors: Di Matteo Sabina , Bilotta Maria Teresa , Pelosi Andrea , Haas Dorothee , Theinert Tobias , Weber Gerrit , Schlegel Paul-Gerhardt , Berg Matthias , Moretta Lorenzo , Maggi Enrico , Azzarone Bruno , Vacca Paola , Tumino Nicola , Caruana Ignazio 
Published: April 2024

BackgroundNeuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid (GD2) is widely overexpressed on tumors of neuroectodermal origin promoting malignant phenotypes. MES cells are greatly enriched in post-therapy and relapsing tumors and are characterized by decreased expression of GD2. This event may cause failure of GD2-based immunotherapy. NK cells represent a key innate cell subset able to efficiently kill tumors. However, the tumor microenvironment (TME) that includes tumor cells and tumor-associated (TA) cells could inhibit their effector function.MethodsWe studied eight NB primary cultures that, in comparison with commercial cell lines, more faithfully reflect the tumor cell characteristics. We studied four primary NB-MES cell cultures and two pairs of MES/ADRN (691 and 717) primary cultures, derived from the same patient. In particular, in the six human NB primary cultures, we assessed their phenotype, the expression of GD2, and the enzymes that control its expression, as well as their interactions with NK cells, using flow cytometry, RT-qPCR, and cytotoxicity assays.ResultsWe identified mature (CD105+/CD133−) and undifferentiated (CD133+/CD105−) NB subsets that express high levels of the MES transcripts WWTR1 and SIX4. In addition, undifferentiated MES cells display a strong resistance to NK-mediated killing. On the contrary, mature NB-MES cells display an intermediate resistance to NK-mediated killing and exhibit some immunomodulatory capacities on NK cells but do not inhibit their cytolytic activity. Notably, independent from their undifferentiated or mature phenotype, NB-MES cells express GD2 that can be further upregulated in undifferentiated NB-MES cells upon co-culture with NK cells, leading to the generation of mature mesenchymal GD2bright neuroblasts. Concerning 691 and 717, they show high levels of GD2 and resistance to NK cell-mediated killing that can be overcome by the administration of dinutuximab beta, the anti-GD2 monoclonal antibody applied in the clinic.ConclusionsNB is a heterogeneous tumor representing a further hurdle in NB immunotherapy. However, different from what was reported with NB commercial cells and independent of their MES/ADRN phenotype, the expression of GD2 and its displayed sensitivity to anti-GD2 mAb ADCC indicated the possible effectiveness of anti-GD2 immunotherapy.
Neonatal and maternal upregulation of antileukoproteinase in horses
Authors: Holmes Camille M. , Babasyan Susanna , Wagner Bettina 
Published: April 2024

IntroductionThe end of gestation, ensuing parturition, and the neonatal period represent highly dynamic phases for immunological changes in both mother and offspring. The regulation of innate immune cells at the maternal-fetal interface during late term pregnancy, after birth, and during microbial colonization of the neonatal gut and other mucosal surfaces, is crucial for controlling inflammation and maintaining homeostasis. Innate immune cells and mucosal epithelial cells express antileukoproteinase (SLPI), which has anti-inflammatory and anti-protease activity that can regulate cellular activation.MethodsHere, we developed and validated new monoclonal antibodies (mAbs) to characterize SLPI for the first time in horses. Peripheral blood and mucosal samples were collected from healthy adults horses and a cohort of mares and their foals directly following parturition to assess this crucial stage.ResultsFirst, we defined the cell types producing SLPI in peripheral blood by flow cytometry, highlighting the neutrophils and a subset of the CD14+ monocytes as SLPI secreting immune cells. A fluorescent bead-based assay was developed with the new SLPI mAbs and used to establish baseline concentrations for secreted SLPI in serum and secretion samples from mucosal surfaces, including saliva, nasal secretion, colostrum, and milk. This demonstrated constitutive secretion of SLPI in a variety of equine tissues, including high colostrum concentrations. Using immunofluorescence, we identified production of SLPI in mucosal tissue. Finally, longitudinal sampling of clinically healthy mares and foals allowed monitoring of serum SLPI concentrations. In neonates and postpartum mares, SLPI peaked on the day of parturition, with mares returning to the adult normal within a week and foals maintaining significantly higher SLPI secretion until three months of age.ConclusionThis demonstrated a physiological systemic change in SLPI in both mares and their foals, particularly at the time around birth, likely contributing to the regulation of innate immune responses during this critical period.
Osteomyelitis is associated with increased anti-inflammatory response and immune exhaustion
Authors: Surendar Jayagopi , Hackenberg Roslind K. , Schmitt-Sánchez Fabio , Ossendorff Robert , Welle Kristian , Stoffel-Wagner Birgit , Sage Peter T. , Burger Christof , Wirtz Dieter C. , Strauss Andreas C. , Schildberg Frank A. 
Published: April 2024

IntroductionOsteomyelitis (OMS) is a bone infection causing bone pain and severe complications. A balanced immune response is critical to eradicate infection without harming the host, yet pathogens manipulate immunity to establish a chronic infection. Understanding OMS-driven inflammation is essential for disease management, but comprehensive data on immune profiles and immune cell activation during OMS are lacking.MethodsUsing high-dimensional flow cytometry, we investigated the detailed innate and adaptive systemic immune cell populations in OMS and age- and sex-matched controls.ResultsOur study revealed that OMS is associated with increased levels of immune regulatory cells, namely T regulatory cells, B regulatory cells, and T follicular regulatory cells. In addition, the expression of immune activation markers HLA-DR and CD86 was decreased in OMS, while the expression of immune exhaustion markers TIM-3, PD-1, PD-L1, and VISTA was increased. Members of the T follicular helper (Tfh) cell family as well as classical and typical memory B cells were significantly increased in OMS individuals. We also found a strong correlation between memory B cells and Tfh cells.DiscussionWe conclude that OMS skews the host immune system towards the immunomodulatory arm and that the Tfh memory B cell axis is evident in OMS. Therefore, immune-directed therapies may be a promising alternative for eradication and recurrence of infection in OMS, particularly in individuals and areas where antibiotic resistance is a major concern.
Durable cellular immune response against inactivated ZIKV and envelope proteins in ZIKV-infected women during pregnancy
Authors: Apostolico Juliana de Souza , Lunardelli Victória Alves Santos , Boscardin Silvia Beatriz , Botosso Viviane Fongaro , Astray Renato Mancini , Kalil Jorge , de Almeida Roque Pacheco , Cunha-Neto Edecio , Rosa Daniela Santoro 
Published: April 2024

IntroductionZika virus (ZIKV) infection has been associated to Guillain-Barré syndrome in adults and congenital malformations during pregnancy, leading to the manifestation of congenital Zika syndrome (CZS). The ZIKV envelope protein (EZIKV), prominently displayed on the virus surface, is a primary target for the humoral immune response. However, limited information exists regarding its capacity to induce cellular immunity, particularly in pregnant women with a history of ZIKV infection. The EZIKV protein comprises three domains: the central domain (EDI), a dimerization domain (EDII), and a domain responsible for binding to the cell surface receptor (EDIII). To examine the regions of EZIKV targeted by cellular immunity, we examined cellular immune responses in a cohort of mothers infected with ZIKV, whose infants exhibited microcephaly.MethodsTo assess the ZIKV-specific response, we used inactivated virus and different recombinant viral envelope proteins (EZIKV, EDI/IIZIKV and EDIIIZIKV). All women in the study contracted the infection during pregnancy, with 72% experiencing symptoms such as fever, rash, joint pain, and retro-orbital pain. Peripheral blood mononuclear cells (PMBC) were collected post- ZIKV diagnosis confirmation, with a median time of 18 months (IQR 13.5-19) after parturition. Using the ELISpot assay, we quantified specific interferon-gamma (IFNγ) producing cells by stimulating PBMC with either inactivated ZIKV particles or equimolar amounts of recombinant EZIKV, EDI/IIZIKV and EDIIIZIKV.Results and discussionOur findings demonstrate the induction of IFN-γ producing cells in PBMC from ZIKV-convalescent mothers, whose infants manifested microcephaly, upon stimulation with both inactivated ZIKV particles and recombinant proteins. The identification of immunodominant regions within ZIKV can contribute for the development of targeted treatments and vaccine candidates tailored for pregnant women.
Association between sleep duration during pregnancy and gestational diabetes mellitus: a systematic review and meta-analysis
Authors: Li Yuandong , Liang Chao , Wu Cui , Nan Zheng 
Published: April 2024

ObjectiveTo systematically review studies on the correlation between sleep duration during pregnancy and gestational diabetes mellitus (GDM) and use meta-analysis to explore the correlation between the two to provide a basis for preventing GDM during pregnancy.MethodsThe search databases were China Knowledge Network (CNKI), Weipu, Wanfang, China Biomedical Literature Service System (SinoMed), Cochrane Library, Web of Science, Embase, and PubMed, and the search time was from the establishment of the above databases to July 2023. The data were statistically analyzed using STATA/MP17 and RevMan 5.3 software. Publication bias could be accurately assessed using funnel plots and Egger’s test.ResultsA total of 5,197 papers were searched, and 13 studies were finally included, which included 80,259 individuals, including 3,461 patients with GDM. The comprehensive analysis showed that. Based on pooled data from prospective, cross-sectional, and case–control studies, extreme sleep duration during pregnancy was strongly associated with GDM compared with average sleep duration. The results of the prospective studies showed that both short (OR = 1.50, 95% CI: 1.07–2.10, I2 = 60.9%, p = 0.02) and long (OR = 1.28, 95% CI: 1.13–1.46, I2 = 0.0%, p &lt; 0.0001) sleep duration increased the risk of gestational diabetes mellitus, but the harms were more pronounced with short sleep. In analyzing the association between extreme sleep duration and GDM, publication bias was found in prospective, cross-sectional, and case–control studies with moderate heterogeneity and prospective-only studies with low heterogeneity.ConclusionBoth too short and too long sleep duration during pregnancy are strongly associated with GDM. Either too short or too long sleep duration predicts the risk of developing GDM, but the harms are more pronounced with short sleep. These findings remind us of the importance of controlling sleep duration during pregnancy and help to optimize early strategies to prevent GDM.Systematic review registration: http://www.crd.york.ac.uk/prospero, identifier [CRD42023470925].
Low-frequency repetitive transcranial magnetic stimulation in patients with motor deficits after brain tumor resection: a randomized, double-blind, sham-controlled trial
Authors: Engelhardt Melina , Schneider Heike , Reuther Jan , Grittner Ulrike , Vajkoczy Peter , Picht Thomas , Rosenstock Tizian 
Published: April 2024

ObjectiveSurgical resection of motor eloquent tumors poses the risk of causing postoperative motor deficits which leads to reduced quality of life in these patients. Currently, rehabilitative procedures are limited with physical therapy being the main treatment option. This study investigated the efficacy of repetitive navigated transcranial magnetic stimulation (rTMS) for treatment of motor deficits after supratentorial tumor resection.MethodsThis randomized, double-blind, sham-controlled trial (DRKS00010043) recruited patients with a postoperatively worsened upper extremity motor function immediately postoperatively. They were randomly assigned to receive rTMS (1Hz, 110% RMT, 15 minutes, 7 days) or sham stimulation to the motor cortex contralateral to the injury followed by physical therapy. Motor and neurological function as well as quality of life were assessed directly after the intervention, one month and three months postoperatively.ResultsThirty patients were recruited for this study. There was no significant difference between both groups in the primary outcome, the Fugl Meyer score three months postoperatively [Group difference (95%-CI): 5.05 (-16.0; 26.1); p=0.631]. Patients in the rTMS group presented with better hand motor function one month postoperatively. Additionally, a subgroup of patients with motor eloquent ischemia showed lower NIHSS scores at all timepoints.ConclusionsLow-frequency rTMS facilitated the recovery process in stimulated hand muscles, but with limited generalization to other functional deficits. Long-term motor deficits were not impacted by rTMS. Given the reduced life expectancy in these patients a shortened recovery duration of deficits can still be of high significance.Clinical Trial Registrationhttps://drks.de/DRKS00010043.
Ascorbic acid-induced warfarin resistance after breast cancer surgery: a case report and literature review
Authors: Gao Pingfa , Shen Yang , Wu Ping , Lv Wenjie 
Published: April 2024

Warfarin is an anticoagulant that requires INR-based dosage adjustment. Ascorbic acid may impair warfarin effectiveness according to limited literature. We report a rare case of a 63-year-old woman with an aortic valve replacement history who developed warfarin resistance after taking ascorbic acid for anemia following breast cancer surgery. Despite increasing the warfarin dose from 6 mg to 10 mg daily, her INR remained below the therapeutic range. After ruling out other causes of warfarin resistance, we discontinued ascorbic acid and observed a rapid increase in INR to target values. The temporal relationship and the absence of other confounding factors confirmed the causality of ascorbic acid in this case. We recommend that patients concomitantly taking vitamin C and warfarin should monitor their INR values closely and discontinue ascorbic acid as soon as possible if they exhibit signs of warfarin resistance.
Cell-type specific effects of mineralocorticoid receptor gene expression suggest intercellular communication regulating fibrosis in skeletal muscle disease
Authors: Gomatam Chetan K. , Ingale Pratham , Rodriguez Gabriel , Munger Sarah , Pomeranets Rachel , Krishna Swathy , Lowe Jeovanna , Howard Zachary M. , Rafael-Fortney Jill A. 
Published: April 2024

Introduction: Duchenne muscular dystrophy (DMD) is a fatal striated muscle degenerative disease. DMD is caused by loss of dystrophin protein, which results in sarcolemmal instability and cycles of myofiber degeneration and regeneration. Pathology is exacerbated by overactivation of infiltrating immune cells and fibroblasts, which leads to chronic inflammation and fibrosis. Mineralocorticoid receptors (MR), a type of nuclear steroid hormone receptors, are potential therapeutic targets for DMD. MR antagonists show clinical efficacy on DMD cardiomyopathy and preclinical efficacy on skeletal muscle in DMD models.Methods: We have previously generated myofiber and myeloid MR knockout mouse models to dissect cell-specific functions of MR within dystrophic muscles. Here, we compared skeletal muscle gene expression from both knockouts to further define cell-type specific signaling downstream from MR.Results: Myeloid MR knockout increased proinflammatory and profibrotic signaling, including numerous myofibroblast signature genes. Tenascin C was the most highly upregulated fibrotic gene in myeloid MR-knockout skeletal muscle and is a component of fibrosis in dystrophic skeletal muscle. Surprisingly, lysyl oxidase (Lox), canonically a collagen crosslinker, was increased in both MR knockouts, but did not localize to fibrotic regions of skeletal muscle. Lox localized within myofibers, including only a region of quadriceps muscles. Lysyl oxidase like 1 (Loxl1), another Lox family member, was increased only in myeloid MR knockout muscle and localized specifically to fibrotic regions.Discussion: This study suggests that MR signaling in the dystrophic muscle microenvironment involves communication between contributing cell types and modulates inflammatory and fibrotic pathways in muscle disease.
Effect of applying nursing-based cognitive defusion techniques on mindful awareness, cognitive fusion, and believability of delusions among clients with schizophrenia: a randomized control trial
Authors: El-Ashry Ayman Mohamed , Abd Elhay Eman Sameh , Taha Samah Mohamed , Khedr Mahmoud Abdelwahab , Attalla Mansour Feby Saad , Alabdullah Amany Anwar Saeed , Farghaly Abdelaliem Sally Mohammed , El-Sayed Mona Metwally 
Published: April 2024

BackgroundApplying cognitive defusion techniques to enduring psychotic symptoms, such as delusions, presents both a challenge and a promising opportunity for psychiatric nurses to manage delusions among schizophrenia clients.ObjectiveThis study aimed to examine the impact of cognitive defusion techniques on psychological flexibility, mindful awareness, cognitive fusion, and the believability of delusions in schizophrenia clients.MethodologyThis study used a single-blind, parallel-arm Randomized Controlled Trial design. Over five weeks, 70 clients with schizophrenia were randomized to either the cognitive defusion intervention group (n = 35) or the control group (n = 35).FindingsThe participants showed significant reductions in the believability of delusions, cognitive fusion, and psychological inflexibility immediately after the intervention and at follow-up. Notable enhancements were observed in cognitive defusion and mindfulness awareness abilities.ConclusionCognitive defusion techniques positively affect schizophrenia clients who struggle with persistent delusional beliefs. This underscores the importance of further investigating this approach to decrease the intensity of delusions as part of a comprehensive therapeutic intervention. Psychiatric nurses must receive training in “cognitive defusion skills” to aid schizophrenia clients in becoming more aware of their emotions and modifying their coping strategies for delusional beliefs. On August 3, 2023, the research was retrospectively registered under the reference number NCT05759091 as a randomized clinical trial.Clinical trial registrationhttps://classic.clinicaltrials.gov/ct2/show/NCT05759091, identifier NCT05759091.