bluuebunny/crossref_metadata_2025_split huggingface dataset:
AWT020: a novel fusion protein harnessing PD-1 blockade and selective IL-2 Cis-activation for enhanced anti-tumor immunity and diminished toxicity
Authors: Ye Fan , Huang Jianing , Cheng Xiaoli , Chen Shih Chieh , Huang Fang , Huang Wen-Chin , Hua Botong , Li Ella , Jiang Jenny , Lin Hanna , Siegel Matthew , Liao Eric , Wang Ji , Yue Bella , Shi Wenli , Xu Yanghua , Wang Xin , Wang Jiaming , Yan Yuyuan , He Honglin , Liu Eugene , Lu Binfeng , Zhong Ziyang 
Published: February 2025

BackgroundThe clinical success of the immune checkpoint inhibitor (ICI) targeting programmed cell death protein 1 (PD-1) has revolutionized cancer treatment. However, the full potential of PD-1 blockade therapy remains unrealized, as response rates are still low across many cancer types. Interleukin-2 (IL-2)-based immunotherapies hold promise, as they can stimulate robust T cell expansion and enhance effector function - activities that could synergize potently with PD-1 blockade. Yet, IL-2 therapies also carry a significant drawback: they can trigger severe systemic toxicities and induce immune suppression by expanding regulatory T cells.MethodsTo overcome the challenges of PD-1 blockade and IL-2 therapies while enhancing safety and efficacy, we have engineered a novel fusion protein, AWT020, combining a humanized anti-PD-1 nanobody and an engineered IL-2 mutein (IL-2c). The IL-2c component of AWT020 has been engineered to exhibit no binding to the IL-2 receptor alpha (IL-2Rα) subunit and attenuated affinity for the IL-2 receptor beta and gamma (IL-2Rβγ) complex, aiming to reduce systemic immune cell activation, thereby mitigating the severe toxicity often associated with IL-2 therapies. The anti-PD-1 antibody portion of AWT020 serves a dual purpose: it precisely delivers the IL-2c payload to tumor-infiltrating T cells while blocking the immune-inhibitory signals mediated by the PD-1 pathway.ResultsAWT020 showed significantly enhanced pSTAT5 signaling in PD-1 expressing cells and promoted the proliferation of activated T cells over natural killer (NK) cells. In preclinical studies using both anti-PD-1-sensitive and -resistant mouse tumor models, the mouse surrogate of AWT020 (mAWT020) demonstrated markedly enhanced anti-tumor efficacy compared to an anti-PD-1 antibody, IL-2, or the combination of an anti-PD-1 antibody and IL-2. In addition, the mAWT020 treatment was well-tolerated, with minimal signs of toxicity. Immune profiling revealed that mAWT020 preferentially expands CD8+ T cells within tumors, sparing peripheral T and NK cells. Notably, this selective tumoral T-cell stimulation enables potent tumor-specific T-cell responses, underscoring the molecule’s enhanced efficacy and safety.ConclusionThe AWT020 fusion protein offers a promising novel immunotherapeutic strategy by integrating PD-1 blockade and IL-2 signaling, conferring enhanced anti-tumor activity with reduced toxicity.
Claudin-2 enhances human antibody-mediated complement-dependent cytotoxicity of porcine endothelial cells by modulating antibody binding and complement activation
Authors: Li Weilong , Yang Fang , Yang Dexin , Song Zhuoheng , Xu Zigan , Wu Jinmei , Li Yanmei , Chen Zixi , Chen Peishan , Yu Yeye , Xie Ting , Yang Cuishan , Zhou Liying , Luan Shaodong , Gao Hanchao 
Published: February 2025

BackgroundImmune rejection represents a significant barrier to transplantation, especially in the context of xenotransplantation. Endothelial cells (ECs) derived from pigs serve as the initial barrier against the human immune system in xenotransplantation. Tight junction proteins are essential components of endothelial cell tight junctions; however, their role in xenotransplantation has been less thoroughly investigated. Claudin-2, a key tight junction protein, was investigated here for its role in human antibody-mediated complement-dependent cytotoxicity (CDC).MethodsUsing an in vitro model of human antibody-mediated CDC, we assessed the effect of Claudin-2 on porcine aortic endothelial cells (PAECs) and porcine iliac endothelial cells (PIECs). Claudin-2 expression was either knocked down or overexpressed in these cells. A flow cytometry assay was used to evaluate C3c, C9, and the C5b-9 deposition, as well as the extent of human IgM and IgG binding to PIECs. The mRNA levels of complement regulators (CD46, CD55, CD59, Factor H, Factor I) were quantified by real-time PCR.ResultsThe loss of Claudin-2 protected PAECs and PIECs from human antibody-mediated CDC, while the overexpression of Claudin-2 enhanced the cytotoxicity in PAECs and PIECs within the same model. Unexpectedly, the loss or overexpression of Claudin-2 did not influence the mRNA expression levels of complement regulators (CD46, CD55, CD59, Factor H, and Factor I). Importantly, the loss of Claudin-2 significantly decreased the deposition of the C5b-9 complex, commonly referred to as the membrane attack complex (MAC), whereas the overexpression of Claudin-2 enhanced the deposition of the C5b-9 complex, indicating that Claudin-2 facilitates complement activation. Furthermore, the loss of Claudin-2 resulted in a decrease in the deposition of C3c and C9 on PIECs. Moreover, Claudin-2 enhanced human antibody binding to porcine ECs, as evidenced by increased IgG and IgM binding.ConclusionOur findings indicate that Claudin-2 enhances the cytotoxicity of porcine ECs through modulating antibody binding and complement activation. The deficient of Claudin-2 in genetically modified pigs is likely to protect porcine ECs and enhance xenograft survival in pig-to-human organ or tissue xenotransplantation.
Epilepsy in the onchocerciasis endemic area of Deim Zubeir, South Sudan: a household survey
Authors: Mamur Jurel Payii , Van Cutsem Gilles , Motto Sekonjo Juliano Hamid , Jada Stephen Raimon , Gerber Tatjana , Bol Yak Yak , Siewe Fodjo Joseph Nelson , Colebunders Robert 
Published: February 2025

BackgroundHigh epilepsy prevalence and mortality has been reported in onchocerciasis-endemic areas with suboptimal elimination programs in South Sudan. In Deim Zubeir, an onchocerciasis-endemic area in Western Bahr El Ghazal state, demand for antiseizure medication is high, but epilepsy prevalence has never been investigated.MethodsA two-step household survey was conducted in four locations in Deim Zubeir over two weeks in July 2023. Trained local community volunteers screened household members for epilepsy using four screening questions, assessed blindness, and inquired about family members’ deaths in the past three years. Participants with suspected epilepsy were referred to a medical doctor for confirmation of the diagnosis.ResultsA total of 7,807 individuals in 1,803 households participated in the survey; 180 (2.3%) had epilepsy and 146 (1.9%) were blind in at least one eye. The point prevalence of active epilepsy was 23.1 (95% confidence interval [CI] 20.0-26.6) per 1,000 persons. The median age of persons with epilepsy (PWE) was 25 (interquartile range [IQR] 20-31.5) years; median age at onset of seizures was 14 (IQR 9-19) years; 36.4% of PWE had siblings with a history of seizures; 5.3% were blind in at least one eye; 40.7% had burn lesions and 24.7% had skin lesions compatible with onchocerciasis; 55% met the criteria for onchocerciasis-associated epilepsy (OAE). The mortality rate of PWE was 182.4 per 100,000 person-years (95%CI 132.8-232.0) and the epilepsy case fatality rate was 64.1 (95% CI 47.2-80.9) per 1,000 PWE per year. PWE were six times more likely to die within one year than people without epilepsy. Their median age of death was 21.5 (IQR 16-34) years compared to 41 (IQR 7-60) years for people without epilepsy.ConclusionThe prevalence of epilepsy and epilepsy-related mortality in Deim Zubeir is high, likely because of ongoing Onchocerca volvulus transmission. Strengthening the local onchocerciasis elimination program and ensuring consistent access to epilepsy care is urgently needed to prevent OAE and epilepsy-related mortality and morbidity. It is necessary to increase advocacy and funding to ensure early identification of epilepsy and uninterrupted, free access to antiseizure medication for PWE in this remote, impoverished area.
Targeting gut microbiota dysbiosis in inflammatory bowel disease: a systematic review of current evidence
Authors: Farah Asmaa , Paul Pradipta , Khan Anfal Sher , Sarkar Aparajita , Laws Sa’ad , Chaari Ali 
Published: February 2025

IntroductionThe dysbiosis of the gut microbiota has been identified as a central factor in the pathogenesis of inflammatory bowel disease (IBD), a chronic condition characterized by frequent recurrence and various adverse effects of traditional therapies. While treatments targeting the gut microbiota show promise, their efficacy in IBD management still requires extensive evaluation. Our systematic review analyzes recent studies to elucidate the advancements and challenges in treating IBD using microbial-based therapies.MethodsThrough a comprehensive systematic review spanning key scientific databases—PubMed, Embase, Cochrane, Web of Science, Scopus, and Google Scholar—we scrutinized the impact of probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) on individuals with IBD. Our detailed analysis covered study and participant demographics, along with seven key outcome measures: disease activity index, inflammatory markers, serum cytokines, microbiome composition, adverse effects, and the rates of remission and relapse.ResultsFrom 6,080 initial search hits, we included 71 studies that assessed various interventions compared to placebo or standard medical therapy. Although there was notable variation in clinical results while assessing different outcomes, overall, probiotics, prebiotics, and synbiotics enhanced the success rates in inducing remission among IBD patients. Furthermore, we noted significant reductions in levels of pro-inflammatory markers and cytokines. Additionally, the requirement for steroids, hospitalization, and poor outcomes in endoscopic and histological scores were significantly reduced in individuals undergoing FMT.ConclusionOur investigation highlights the potential of targeting gut microbiota dysbiosis with microbial-based therapies in patients with IBD. We recommend conducting larger, placebo-controlled randomized trials with extended follow-up periods to thoroughly assess these treatments’ clinical efficacy and safety before widespread recommendations for clinical application.
How to create a faculty development program that transforms medical education according to actual institutional needs: evidence-based approach and experience at the University of Rijeka, Faculty of Medicine, Croatia
Authors: Pereza Nina , Hauser Goran , Dević Pavlić Sanja , Marić Ivana , Sotošek Vlatka , Grgasović Tina , Mršić-Pelčić Jasenka 
Published: February 2025

AimAlthough previous studies demonstrated short, medium and long-term effectiveness of faculty development programs (FDP) for medical teachers, there is a lack of studies describing the methodology for creating a sustainable comprehensive FDP in medical education. We present the methodology for creating the “Modern and Practical Medical Education (MPME),” a comprehensive four-month educational FDP tailored to actual institutional needs, and the initial results of its implementation and transformation of medical education at the University of Rijeka, Faculty of Medicine, Croatia (EU).Materials and methodsWe conducted a multi-phase mixed-method cross-sectional study from July 2021 to June 2024 consisting of three steps: (1) construction of MPME FDP basic structure according to local/national priorities/specificities, literature and expertise, (2) a 360-degree current state analysis for adaptation of basic structure to actual institutional needs, and (3) analysis of the FDP education effectiveness. Step 2 included syllabi analyses and group interviews with 65 teachers’ at 8 departments (qualitative), as well as the analysis of medical students’ perspective using the “Medical students’ questionnaire” on 236 participants (quantitative), and 23 interviews with 8 participants using the “Medical students’ focus group” (qualitative). Step 3 included the quantitative analysis of 40 medical teachers’ self-assessments for 30 teachers’ competencies before and after MPME education using the “MPME questionnaire,” and qualitative analysis of measurable program outcomes.ResultsThe MPME FDP consists of three major modules with seven courses, and is based on a tripartite flipped classroom model. The results of qualitative and quantitative 360-degree analysis identified common weak spots in teachers’ competencies, which were used for program development. Program effectiveness was demonstrated through a highly significant change in the self-assessment for all 30 teachers’ competencies before and after education (p &lt; 0.001), and numerous measurable educational outcomes.ConclusionThe creation of a comprehensive and sustainable FDP in medical education should be based on a three-step quantitative and qualitative process that includes the 360-degree analysis of actual institutional needs, and the effectiveness of the program education. This methodology has a highly significant positive effect on teachers’ competencies at the individual level, and creation of educational projects that transform medical education at the institutional level.
Optic neuropathy as an early manifestation of granulomatosis with polyangiitis: a case report and literature review
Authors: Kim Yukang , Woo Tonghoon , Lee Sun-Uk , Park Euyhyun , Shin Hyun-Jin , Sim Jongmin , Kim Gerard Jounghyun , Kim Ji-Soo 
Published: February 2025

IntroductionOphthalmic involvement occurs in up to 40% of patients with granulomatosis with polyangiitis (GPA), usually confined to the anterior segment. Herein, we describe patients presenting with optic neuropathy as an early manifestation of GPA, without other signs of ocular or adnexa involvement.MethodsWe report a case of isolated optic neuropathy without other ocular or adnexal involvement and examine the reported clinical features of 17 additional patients through a literature review. We analyzed clinical characteristics and neuro-ophthalmological findings and discuss the clinical implications for the early detection of GPA-associated optic neuropathy.ResultsAmong the 17 patients, 10 had optic neuropathy confined to one eye, three exhibited simultaneous bilateral optic neuropathies at initial presentation, and four had unilateral involvement initially; however, the fellow eye was subsequently affected during follow-up. Nine patients had optic neuropathy as the first clinical presentation and no prior diagnosis of GPA (9/17, 53%). Among the 21 eyes (15 patients, excluding two without descriptions), disc edema was observed in five eyes (24%). Visual impairment was often profound; the measurements of 23 affected eyes at the initial presentation showed that the patient’s acuity was to count fingers or worse (14/23, 61%). The final visual outcome was often poor, with significant visual recovery in only eight eyes (8/23, 35%). Other constitutional symptoms or systemic involvements were found in most patients (15/16, 94%), mostly affecting the lung (n = 10), sinus (n = 9), and pachymeninges (n = 8). Furthermore, 88% of the patients (15/17) showed positive results on antineutrophil cytoplastic antibody. Elevated CRP (n = 6) or ESR (n = 5) was found in 56% of cases.DiscussionOur case and literature review indicates that optic neuropathy can present in the context of systemic inflammation of GPA, without any other signs of ocular or orbital involvement. Catching other clinical, imaging, and laboratory signs of systemic inflammation is important in cases of GPA-associated optic neuropathy with atypical presentations.
Evaluating the performance of ChatGPT in patient consultation and image-based preliminary diagnosis in thyroid eye disease
Authors: Wang Yue , Yang Shuo , Zeng Chengcheng , Xie Yingwei , Shen Ya , Li Jian , Huang Xiao , Wei Ruili , Chen Yuqing 
Published: February 2025

BackgroundThe emergence of Large Language Model (LLM) chatbots, such as ChatGPT, has great promise for enhancing healthcare practice. Online consultation, accurate pre-diagnosis, and clinical efforts are of fundamental importance for the patient-oriented management system.ObjectiveThis cross-sectional study aims to evaluate the performance of ChatGPT in inquiries across ophthalmic domains and to focus on Thyroid Eye Disease (TED) consultation and image-based preliminary diagnosis in a non-English language.MethodsWe obtained frequently consulted clinical inquiries from a published reference based on patient consultation data, titled A Comprehensive Collection of Thyroid Eye Disease Knowledge. Additionally, we collected facial and Computed Tomography (CT) images from 16 patients with a definitive diagnosis of TED. From 18 to 30 May 2024, inquiries about the TED consultation and preliminary diagnosis were posed to ChatGPT using a new chat for each question. Responses to questions from ChatGPT-4, 4o, and an experienced ocular professor were compiled into three questionnaires, which were evaluated by patients and ophthalmologists on four dimensions: accuracy, comprehensiveness, conciseness, and satisfaction. The preliminary diagnosis of TED was deemed accurate, and the differences in the accuracy rates were further calculated.ResultsFor common TED consultation questions, ChatGPT-4o delivered more accurate information with logical consistency, adhering to a structured format of disease definition, detailed sections, and summarized conclusions. Notably, the answers generated by ChatGPT-4o were rated higher than those of ChatGPT-4 and the professor, with accuracy (4.33 [0.69]), comprehensiveness (4.17 [0.75]), conciseness (4.12 [0.77]), and satisfaction (4.28 [0.70]). The characteristics of the evaluators, the response variables, and other quality scores were all correlated with overall satisfaction levels. Based on several facial images, ChatGPT-4 twice failed to make diagnoses because of lacking characteristic symptoms or a complete medical history, whereas ChatGPT-4o accurately identified the pathologic conditions in 31.25% of cases (95% confidence interval, CI: 11.02–58.66%). Furthermore, in combination with CT images, ChatGPT-4o performed comparably to the professor in terms of diagnosis accuracy (87.5, 95% CI 61.65–98.45%).ConclusionChatGPT-4o excelled in comprehensive and satisfactory patient consultation and imaging interpretation, indicating the potential to improve clinical practice efficiency. However, limitations in disinformation management and legal permissions remain major concerns, which require further investigation in clinical practice.
Associations of the Life’s Essential 8 with Parkinson’s disease: a population-based study
Authors: Zhou Chenguang , Cheng Oumei 
Published: February 2025

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disorder with increasing global prevalence. This study investigated the association between the American Heart Association’s Life’s Essential 8 (LE8) and PD prevalence using a large, nationally representative database.MethodsWe analyzed data from 18,277 participants aged 40 years and older from the National Health and Nutrition Examination Survey (NHANES) 2005–2018. LE8 scores were calculated based on diet, physical activity, nicotine exposure, sleep, body mass index, blood lipids, blood glucose, and blood pressure. PD cases were identified through self-reported anti-PD medication use. Multivariate logistic regression models were employed to examine the association between LE8 and PD prevalence, adjusting for various demographic and clinical factors. In addition, we performed restricted cubic splines (RCS), subgroup analyses, and weighted quantile sum (WQS) regression to verify the robustness of the study results.ResultsThe prevalence of PD was 1.3% in the study population. After full adjustment, individuals with moderate (50–79) and high (80–100) LE8 scores showed lower odds of PD compared to those with low (0–49) scores (OR 0.53, 95% CI 0.29–0.97 and OR 0.43, 95% CI 0.17–1.04, respectively; p for trend &lt;0.05). A dose-response relationship was observed between LE8 scores and PD prevalence. WQS regression identified dietary factors and glycemic health as the main contributors to the inverse association between LE8 and PD.ConclusionOur findings suggest a significant inverse association between Life’s Essential 8 (LE8) and PD prevalence, with dietary factors and glycemic health emerging as the most influential components.
Efficacy of vigorous physical activity as an intervention for mitigating depressive symptoms in adolescents and young adults: a comprehensive systematic review and meta-analysis
Authors: Yang Wei , Chen Huijing , Liu Wei , Qu Sheng , Ge Yao , Song Jin 
Published: February 2025

PurposeThis study aimed to evaluate the effectiveness of vigorous physical activity as an intervention for alleviating depressive symptoms among adolescents and young adults.MethodsA comprehensive search on systematically reliable databases was carried out, and studies running till August 2023 were considered in this study. The articles included in this meta-analysis assessed the impact of exercise interventions on depressive symptomatology in adolescents and young adults. Two independent investigators screened the studies, extracted data, and evaluated quality.ResultsPhysical activity produced an important reduction in depressive symptoms [SMD] = −4.23, 95% CI: −7.02, −1.44, p = 0.0001; a moderate effect size in both the adolescent population with clinical depression and adolescents who presented with subclinical depressive symptoms. Notably, vigorous physical exercise worked most favorably for adolescent depressive symptomatology, while moderate-intensity exercise was the best choice for adolescents with diagnosed clinical depression.ConclusionThis meta-analysis suggests that vigorous physical activity could reduce depressive symptoms in adolescents and young adults. However, further studies are needed to provide clearer recommendations regarding the type, duration, and intensity of exercise necessary to treat clinical depression in this population.
Dezocine modulates the reinstatement of conditioned place preference in morphine-dependent rats via the dopamine reward circuitry
Authors: He Yan , Piao Zhi-Sheng , Jia Yi , Wu Hui-Qi , Wang Xiao-Qiang , Yu Wei-Feng , Wu Fei-Xiang 
Published: February 2025

IntroductionOpioid addiction is a significant public health issue, with existing treatments such as buprenorphine and methadone exhibiting limitations, including side effects and insufficient prevention of relapse. Novel therapeutic strategies are needed to address these challenges. This study investigates the potential of dezocine in reducing addiction-related behaviors and preventing relapse.MethodsA morphine-induced conditioned place preference (CPP) model was established in rats to evaluate the effect of dezocine on addiction-related behaviors. Behavioral assessments were conducted to measure withdrawal symptoms and CPP reinstatement. To explore the underlying mechanism, Western blot (WB) and immunofluorescence (IF) were used to quantify the expression of phosphorylated DARPP32 (p-DARPP32) and DOPA decarboxylase (DDC) in reward-related brain regions, including the nucleus accumbens (NAc), ventral tegmental area (VTA), hippocampus (HP), and prefrontal cortex (PFC).ResultsDezocine significantly reduced withdrawal symptoms and prevented CPP reinstatement, indicating its potential to alleviate addiction behaviors. Western blotting and immunofluorescence analysis revealed that dezocine increased p-DARPP32 expression in the NAc, VTA, HP, and PFC, without altering DDC levels.DiscussionThese findings suggest that dezocine may exert its therapeutic effects by inhibiting kappa opioid receptor activation and enhancing dopamine signaling in reward-related brain circuitry. The increase in p-DARPP32 expression in key brain regions supports this mechanism, providing insights into the potential clinical application of dezocine for managing opioid addiction. Dezocine represents a promising candidate for opioid addiction treatment, with the ability to control withdrawal symptoms and prevent relapse.