bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring lncRNAs associated with human pancreatic islet cell death induced by transfer of adoptive lymphocytes in a humanized mouse model
Authors: Hossain Md Munir , Roat Regan , Christopherson Jenica , Free Colette , Ansarullah  , James Brian , Guo Zhiguang 
Published: November 2023

BackgroundLong noncoding RNA (lncRNA)-mediated posttranscriptional and epigenetic landscapes of gene regulation are associated with numerous human diseases. However, the regulatory mechanisms governing human β-cell function and survival remain unknown. Owing to technical and ethical constraints, studying the direct role of lncRNAs in β-cell function and survival in humans in vivo is difficult. Therefore, we utilized humanized mice with human islets to investigate lncRNA expression using whole transcriptome shotgun sequencing. Our study aimed to characterize lncRNAs that may be crucial for human islet cell function and survival.MethodsHuman β-cell death was induced in humanized mice engrafted with functional human islets. Using these humanized mice harboring human islets with induced β-cell death, we investigated lncRNA expression through whole transcriptome shotgun sequencing. Additionally, we systematically identified, characterized, and explored the regulatory functions of lncRNAs that are potentially important for human pancreatic islet cell function and survival.ResultsHuman islet cell death was induced in humanized mice engrafted with functional human islets. RNA sequencing analysis of isolated human islets, islet grafts from humanized mice with and without induced cell death, revealed aberrant expression of a distinct set of lncRNAs that are associated with the deregulated mRNAs important for cellular processes and molecular pathways related to β-cell function and survival. A total of 10 lncRNA isoforms (SCYL1-1:22, POLG2-1:1, CTRB1-1:1, SRPK1-1:1, GTF3C5-1:1, PPY-1:1, CTRB1-1:5, CPA5-1:1, BCAR1-2:1, and CTRB1-1:4) were identified as highly enriched and specific to human islets. These lncRNAs were deregulated in human islets from donors with different BMIs and with type 2 diabetes (T2D), as well as in cultured human islets with glucose stimulation and induced cell death induced by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the medium used to culture islets with cytokines.ConclusionIslet-enriched and specific human lncRNAs are deregulated in human islet grafts and cultured human islets with induced cell death. These lncRNAs may be crucial for human β-cell function and survival and could have an impact on identifying biomarkers for β-cell loss and discovering novel therapeutic targets to enhance β-cell function and survival.
Reclassifying variations of unknown significance in diseases affecting Saudi Arabia’s population reveal new associations
Authors: Al Eissa Mariam M. , Alotibi Raniah S. , Alhaddad Bader , Aloraini Taghrid , Samman Manar S. , AlAsiri Abdulrahman , Abouelhoda Mohamed , AlQahtani Amerh S. 
Published: November 2023

Introduction: Physicians face diagnostic dilemmas upon reports indicating disease variants of unknown significance (VUS). The most puzzling cases are patients with rare diseases, where finding another matched genotype and phenotype to associate their results is challenging. This study aims to prove the value of updating patient files with new classifications, potentially leading to better assessment and prevention.Methodology: We recruited retrospective phenotypic and genotypic data from King Saud Medical City, Riyadh, Kingdom of Saudi Arabia. Between September 2020 and December 2021, 1,080 patients’ genetic profiles were tested in a College of American Pathologists accredited laboratory. We excluded all confirmed pathogenic variants, likely pathogenic variants and copy number variations. Finally, we further reclassified 194 VUS using different local and global databases, employing in silico prediction to justify the phenotype–genotype association.Results: Of the 194 VUS, 90 remained VUS, and the other 104 were reclassified as follows: 16 pathogenic, 49 likely pathogenic, nine benign, and 30 likely benign. Moreover, most of these variants had never been observed in other local or international databases.Conclusion: Reclassifying the VUS adds value to understanding the causality of the phenotype if it has been reported in another family or population. The healthcare system should establish guidelines for re-evaluating VUS, and upgrading VUS should reflect on individual/family risks and management strategies.
Semaphorin 7a aggravates TGF-β1-induced airway EMT through the FAK/ERK1/2 signaling pathway in asthma
Authors: Peng Haiying , Sun Fei , Jiang Yunxiu , Guo Zihan , Liu Xinyi , Zuo Anli , Lu Degan 
Published: November 2023

BackgroundTGF-β1 can induce epithelial-mesenchymal transition (EMT) in primary airway epithelial cells (AECs). Semaphorin7A (Sema7a) plays a crucial role in regulating immune responses and initiating and maintaining transforming growth factor β1 TGF-β1-induced fibrosis.ObjectiveTo determine the expression of Sema7a, in serum isolated from asthmatics and non-asthmatics, the role of Sema7a in TGF-β1 induced proliferation, migration and airway EMT in human bronchial epithelial cells (HBECs) in vitro.MethodsThe concentrations of Sema7a in serum of asthmatic patients was detected by enzyme-linked immunosorbent assay (ELISA). The expressions of Sema7a and integrin-β1 were examined using conventional western blotting and real-time quantitative PCR (RT-PCR). Interaction between the Sema7a and Integrin-β1 was detected using the Integrin-β1 blocking antibody (GLPG0187). The changes in EMT indicators were performed by western blotting and immunofluorescence, as well as the expression levels of phosphorylated Focal-adhesion kinase (FAK) and Extracellular-signal-regulated kinase1/2 (ERK1/2) were analyzed by western blot and their mRNA expression was determined by RT-PCR.ResultsWe described the first differentially expressed protein of sema7a, in patients with diagnosed bronchial asthma were significantly higher than those of healthy persons (P&lt;0.05). Western blotting and RT-PCR showed that Sema7a and Integrin-β1 expression were significantly increased in lung tissue from the ovalbumin (OVA)-induced asthma model. GLPG0187 inhibited TGF-β1-mediated HBECs EMT, proliferation and migration, which was associated with Focal-adhesion kinase (FAK) and Extracellular-signal-regulated kinase1/2 (ERK1/2) phosphorylation.ConclusionSema7a may play an important role in asthma airway remodeling by inducing EMT. Therefore, new therapeutic approaches for the treatment of chronic asthma, could be aided by the development of agents that target the Sema7a.
Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience
Authors: Gutierrez Antonio , Alonso Aser , Garcia-Recio Marta , Perez Sandra , Garcia-Maño Lucia , Martinez-Serra Jordi , Ros Teresa , Garcia-Gasalla Mercedes , Ferrer Joana , Vögler Oliver , Alemany Regina , Salar Antonio , Sampol Antonia , Bento Leyre 
Published: November 2023

IntroductionThe use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens.MethodsOur objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital.ResultsIn our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines.DiscussionWe report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.
Detection of cell-free histones in the cerebrospinal fluid of pediatric central nervous system malignancies by imaging flow cytometry
Authors: Buzova Diana , Frohlich Jan , Zapletalova Danica , Raffaele Marco , Lo Re Oriana , Tsoneva Desislava K. , Sterba Jaroslav , Cerveny Jan , Vinciguerra Manlio 
Published: November 2023

Introduction: Pediatric brain tumours (PBT) are one of the most common malignancies during childhood, with variable severity according to the location and histological type. Certain types of gliomas, such a glioblastoma and diffuse intrinsic pontine glioma (DIPG), have a much higher mortality than ependymoma and medulloblastoma. Early detection of PBT is essential for diagnosis and therapeutic interventions. Liquid biopsies have been demonstrated using cerebrospinal fluid (CSF), mostly restricted to cell free DNA, which display limitations of quantity and integrity. In this pilot study, we sought to demonstrate the detectability and robustness of cell free histones in the CSF.Methods: We collected CSF samples from a pilot cohort of 8 children with brain tumours including DIPG, medulloblastoma, glioblastoma, ependymoma and others. As controls, we collected CSF samples from nine children with unrelated blood malignancies and without brain tumours. We applied a multichannel flow imaging approach on ImageStream(X) to image indiviual histone or histone complexes on different channels.Results: Single histones (H2A, macroH2A1.1, macroH2A1.2 H2B, H3, H4 and histone H3 bearing the H3K27M mutation), and histone complexes are specifically detectable in the CSF of PBT patients. H2A and its variants macroH2A1.1/macroH2A1/2 displayed the strongest signal and abundance, together with disease associated H3K27M. In contrast, mostly H4 is detectable in the CSF of pediatric patients with blood malignancies.Discussion: In conclusion, free histones and histone complexes are detectable with a strong signal in the CSF of children affected by brain tumours, using ImageStream(X) technology and may provide additive diagnostic and predictive information.
Short-term efficacy of stenting as a rescue therapy for acute atherosclerotic occlusion in anterior cerebral circulation
Authors: Wang Jianyi , Shang Suhang , Dun Wanghuan , Chen Chen , Gao Fan , Yu Jia , Han Jianfeng , Liu Fude 
Published: November 2023

PurposeThe study aimed to explore the efficacy and safety of the Neuroform EZ stent in treating acute anterior circulation large artery occlusion.MethodsThe clinical data of 42 consecutive patients with acute anterior circulation large atherosclerotic occlusion who were treated with the Neuroform EZ stent from January 2018 to August 2019 in our stroke care center, including baseline characteristics, images, therapeutic condition, and follow-up data were retrospectively analyzed.ResultsThere were 42 mechanical thrombectomy (MT) failure cases of intracranial atherosclerotic stenosis with rescue Neuroform EZ stent implantation, of which 78.6% (33/42) had a good prognosis and 88.1% (37/42) showed no re-stenosis at follow-up. The average time from puncture to recanalization is 79.50 ± 14.19 min. The successful rate of intraoperative stent release is 97.6%, while there is one case of stent displacement, three cases of thrombus escape, and six cases of hemorrhage.ConclusionRescue therapy of the Neuroform EZ stent for acute anterior circulation large atherosclerotic occlusion can archive good short-term imaging and clinical results, while long-term follow-up is still needed to verify.
Impact of different chemotherapy regimens on intestinal mucosal injury assessed with bedside ultrasound: a study in 213 AML patients
Authors: Benedetti Edoardo , Traverso Ginevra , Pucci Giulia , Morganti Riccardo , Bramanti Emilia , Lippolis Piero , Susini Maria Chiara , Mazzantini Elisa , Giubbolini Rachele , Mavilia Fabrizio , Capochiani Enrico , Neri Emanuele , Arena Chiara , Cerri Francesca , De Simone Luigi , Valentini Katia , Stella Salvatore Massimo , Ricchiuto Vittorio , Bruno Benedetto , Galimberti Sara 
Published: November 2023

IntroductionNeutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. MethodsIn our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussionOverall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening.
Review time of oncology drugs and its underlying factors: an exploration in China
Authors: Zhu Xingyue , Liu Bao 
Published: November 2023

Introduction: How the launch delay of drugs and other factors of interest can influence the length of the review period by drug agencies is still unknown, and understanding this can help better strike the trade-off related to review speed.Methods: We included all new oncology drug applications submitted to China’s National Medical Product Administration (NMPA) between 1 January 2018 and 31 December 2021, and ultimately succeeded in achieving marketing approval. For each drug, the length of the NMPA review process and other major characteristics were collected, including the registration class, approval class, priority review designation, and launch delay relative to the United States, as well as the number of patients enrolled, comparator, and primary endpoint of the pivotal trials supporting the approval. Linear regression model was employed to analyze the effects of factors of interest on the NMPA review time.Results: From 2018 to 2021, NMPA received 137 oncology applications that were ultimately approved. Half of the approvals [76 (55.5%)] were first licensed in the US, leaving a median launch delay of 2.71 years (IQR, 1.03–5.59) in China. In the pivotal studies, the median enrollment was 361 participants (IQR, 131–682), and the use of control groups [90 (65.7%)] and surrogate endpoints [101 (73.7%)] was prevalent. The median review time was 304 days (IQR, 253–376). Multivariate analysis for log-transformed review time showed that larger enrollment (> 92) was associated with a drop of 20.55% in review time (coefficient = −0.230; 95% CI, −0.404 to −0.055; p = 0.010); and a short delay (0 < delay ≤ 1.95 years) was associated with a drop of 17.63% in review time (coefficient = −0.194; 95% CI, −0.325 to −0.062; p = 0.004).Discussion: The short launch delay relative to the US was one important driver to the review speed of NMPA, which might suggest its latent regulatory reliance on the other global regulator during the post-marketing period when new information on the drug’s clinical benefit was still lacking.
Associations between COVID-19 outcomes and asthmatic patients with inhaled corticosteroid
Authors: Yong Su-Boon , Gau Shuo-Yan , Li Chia-Jung , Tseng Chih-Wei , Wang Shiow-Ing , Wei James Cheng-Chung 
Published: November 2023

Background: The impact of inhaled corticosteroid (ICS) in the interaction between asthma, COVID-19 and COVID-19 associated outcomes remain largely unknown. The objective of this study is to investigate the risk of COVID-19 and its related outcomes in patients with asthma using and not using inhaled corticosteroid (ICS).Methods: We used the TriNetX Network, a global federated network that comprises 55 healthcare organizations (HCO) in the United States, to conduct a retrospective cohort study. Patients with a diagnosis of asthma with and without ICS between January 2020 and December 2022 were included. Propensity score matching was used to match the case cohorts. Risks of COVID-19 incidence and medical utilizations were evaluated.Results: Out of 64,587 asthmatic patients with ICS and without ICS, asthmatic patients with ICS had a higher incidence of COVID-19 (Hazard ratio, HR: 1.383, 95% confidence interval, CI: 1.330–1.437). On the contrary, asthmatic patients with ICS revealed a significantly lower risk of hospitalization (HR: 0.664, 95% CI: 0.647–0.681), emergency department visits (HR: 0.774, 95% CI: 0.755–0.793), and mortality (HR:0.834, 95% CI:0.740–0.939). In addition, subgroup or sensitivity analyses were also conducted to examine the result of different vaccination status, disease severity, or COVID-19 virus variants.Conclusion: For asthmatic patients using ICS, risk of COVID-19 was significantly higher than non-users. The observed association could provide potential guidance for primary care physicians regarding the risk of COVID-19 in asthmatic patients.
Longitudinal associations between paternal mental health and child behavior and cognition in middle childhood
Authors: Jones Sherri Lee , Caccese Christina , Davis Kelsey P. , Lew Jimin , Elgbeili Guillaume , Herba Catherine M. , Barnwell Julia , Robert Cindy Hénault , Gavanski Isabella , Horsley Kristin , Fraser William D. , Da Costa Deborah , Séguin Jean R. , Nguyen Tuong-Vi , Montreuil Tina C. 
Published: November 2023

IntroductionPaternal mental health has been associated with adverse consequences on offspring psychosocial development, and family environmental factors may partly explain those associations. To clarify this, we need comprehensive prospective studies, particularly in middle-childhood when the child enters school and is expected to make use of behavioral and cognitive skills as part of their interactions and learning.MethodUsing data from a sub-sample of the prospective 3D birth cohort study comprised of mother-father-child triads, and a follow-up of the parents and the children at 6–8 years of age (n = 61; 36 boys, 25 girls), we examined whether paternal anxious and depressive symptoms measured during the pregnancy period (i.e., prenatally) or concurrently when the child was assessed at 6–8 years old were associated with children's cognition/behavior.ResultsIn contrast to our hypotheses, we found that greater prenatal paternal depressive symptoms predicted fewer child behavioral difficulties; and that greater concurrent childhood paternal depression or anxiety symptoms were associated with higher child full-scale IQ, controlling for the equivalent maternal mental health assessment and parental education. Father parenting perception did not mediate these associations, nor were they moderated by maternal mental health at the concurrent assessment, or paternal ratings of marital relationship quality.DiscussionThese findings suggest that higher symptoms of paternal mental health symptoms are associated with fewer child behavioral difficulties and higher cognitive performance in middle childhood. Potential clinical implications and future research directions are discussed.
Perceiving violence against healthcare workers in a child and adolescent emergency psychiatric ward in Hungary: a qualitative pilot study
Authors: Sófi Gyula , Törő Krisztina , Csikós Gábor , Fliegauf Gergely 
Published: November 2023

AimPsychiatry is a challenging setting that requires extraordinary effort from the staff. Healthcare workers in the field of psychiatry face substantial levels of violence, making the identification of abuse risk factors a social concern. Both the conduct of the children and their relatives can pose potential harm. Our study delved into the criminological and psychiatric factors underlying violence against healthcare workers.MethodologyWe used qualitative, semi-structured, self-developed, online questionnaire involving 21 respondents. The participants were representing the staff composition of our department. The data set was coded in two phases using a multi-stage content analysis method. The results were compared with Hungarian and international literature.FindingsAmong the participants, 52% reported no instances of physical abuse. The most prevalent form of perceived non-contact abuse was threats, accounting for 38% of reported cases. The identified risk factors for abuse included the child’s psychiatric disorder, communication issues, parental behavior, and low socio-economic status. Psychological trauma was identified as the most severe consequence. The respondents’ opinion indicated that the most common cause of violence (52%) was attributed to the child’s mental disorder. Workers primarily deal with abuse through negative emotions, with 76% of them reporting feelings of victimization. Additionally, 43% believed that abuse cannot be avoided, while 19% emphasized the significance of worker competence.ValueOur research can help to identify risk factors in child psychiatry wards and provide guidance for developing effective responses to violence against healthcare workers in Hungary, especially at our ward.