bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exosomal circPOLQ promotes macrophage M2 polarization via activating IL-10/STAT3 axis in a colorectal cancer model
Authors: Sun Zhenqiang , Xu Yanxin , Shao Bo , Dang Pengyuan , Hu Shengyun , Sun Haifeng , Chen Chen , Wang Chaoguan , Liu Jinbo , Liu Yang , Hu Junhong 
Published: May 2024

BackgroundAccumulating evidence demonstrates that an increased tumor-associated macrophage abundance is often associated with poor prognosis in colorectal cancer (CRC). The mechanism underlying the effect of tumor-derived exosomes on M2 macrophage polarization remains elusive.ResultsThe novel circular RNA circPOLQ exhibited significantly higher expression in CRC tissues than in paired normal tissues. Higher circPOLQ expression was associated with poorer prognosis in patients with CRC. In vitro and in vivo experiments showed that tumor-derived exosomal circPOLQ did not directly regulate CRC cell development but promoted CRC metastatic nodule formation by enhancing M2 macrophage polarization. circPOLQ activated the interleukin-10/signal transducer and activator of transcription 3 axis by targeting miR-379–3 p to promote M2 macrophage polarization.ConclusioncircPOLQ can enter macrophages via CRC cell-derived exosomes and promote CRC metastatic nodule formation by enhancing M2 macrophage polarization. These findings reveal a tumor-derived exosome-mediated tumor–macrophage interaction potentially affecting CRC metastatic nodule formation.
Dose escalation study of a personalized peptide-based neoantigen vaccine (EVX-01) in patients with metastatic melanoma
Authors: Mørk Sofie Kirial , Skadborg Signe Koggersbøl , Albieri Benedetta , Draghi Arianna , Bol Kalijn , Kadivar Mohammad , Westergaard Marie Christine Wulff , Stoltenborg Granhøj Joachim , Borch Annie , Petersen Nadia Viborg , Thuesen Nikolas , Rasmussen Ida Svahn , Andreasen Lars Vibe , Dohn Rebecca Bach , Yde Christina Westmose , Noergaard Nis , Lorentzen Torben , Soerensen Anders Bundgaard , Kleine-Kohlbrecher Daniela , Jespersen Anders , Christensen Dennis , Kringelum Jens , Donia Marco , Hadrup Sine Reker , Marie Svane Inge 
Published: May 2024

BackgroundNeoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical studyNCT03715985showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy.MethodsPatients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study’s primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates.ResultsCompared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score.ConclusionImmunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.
Development and validation of a SCORing systEm for pre-thrombectomy diagnosis of IntraCranial Atherosclerotic Disease (Score-ICAD)
Authors: A Tarek Mohamed , Damiani Monteiro Mateus , Mohammaden Mahmoud H , Martins Pedro N , Sheth Sunil A , Dolia Jaydevsinh , Pabaney Aqueel , Grossberg Jonathan A , Nahhas Michael , A De La Garza Carlos , Salazar-Marioni Sergio , Rangaraju Srikant , Nogueira Raul G , Haussen Diogo C 
Published: May 2024

BackgroundEarly identification of intracranial atherosclerotic disease (ICAD) may impact the management of patients undergoing mechanical thrombectomy (MT). We sought to develop and validate a scoring system for pre-thrombectomy diagnosis of ICAD in anterior circulation large vessel/distal medium vessel occlusion strokes (LVOs/DMVOs).MethodsRetrospective analysis of two prospectively maintained comprehensive stroke center databases including patients with anterior circulation occlusions spanning 2010–22 (development cohort) and 2018–22 (validation cohort). ICAD cases were matched for age and sex (1:1) to non-ICAD controls.ResultsOf 2870 MTs within the study period, 348 patients were included in the development cohort: 174 anterior circulation ICAD (6% of 2870 MTs) and 174 controls. Multivariable analysis β coefficients led to a 20 point scale: absence of atrial fibrillation (5); vascular risk factor burden (1) for each of hypertension, diabetes, smoking, and hyperlipidemia; multifocal single artery stenoses on CT angiography (3); absence of territorial cortical infarct (3); presence of borderzone infarct (3); or ipsilateral carotid siphon calcification (2). The validation cohort comprised 56 ICAD patients (4.1% of 1359 MTs): 56 controls. Area under the receiver operating characteristic curve was 0.88 (0.84–0.91) and 0.82 (0.73–0.89) in the development and validation cohorts, respectively. Calibration slope and intercept showed a good fit for the development cohort although with overestimated risk for the validation cohort. After intercept adjustment, the overestimation was corrected (intercept 0, 95% CI −0.5 to –0.5; slope 0.8, 95% CI 0.5 to 1.1). In the full cohort (n=414), ≥11 points showed the best performance for distinguishing ICAD from non-ICAD, with 0.71 (95% CI 0.65 to 0.78) sensitivity and 0.82 (95% CI 0.77 to 0.87) specificity, and 3.92 (95% CI 2.92 to 5.28) positive and 0.35 (95% CI 0.28 to 0.44) negative likelihood ratio. Scores ≥12 showed 90% specificity and 63% sensitivity.ConclusionThe proposed scoring system for preprocedural diagnosis of ICAD LVOs and DMVOs presented satisfactory discrimination and calibration based on clinical and non-invasive radiological data.
Dynamic internal jugular vein venography: a descriptive study in 89 patients with suspected cerebral venous outflow disorders
Authors: Fargen Kyle M , Midtlien Jackson P , Margraf Connor , Kiritsis Nicholas R , Chang Emily , Hui Ferdinand 
Published: May 2024

BackgroundInternal jugular vein (IJV) stenosis has recently been recognized as a plausible source of symptom etiology in patients with cerebral venous outflow disorders (CVD). Diagnosis and determining surgical candidacy remains difficult due to a poor understanding of IJV physiology and positional symptom exacerbation often reported by these patients.MethodsA retrospective single-center chart review was conducted on adult patients who underwent diagnostic cerebral venography with rotational IJ venography from 2022 to 2024. Patients were divided into three groups for further analysis based on symptoms and diagnostic criteria: presumed jugular stenosis, near-healthy venous outflow, and idiopathic intracranial hypertension.ResultsEighty-nine patients were included in the study. Most commonly, ipsilateral rotation resulted in ipsilateral IJV stenosis and gradient development at C4–6 and contralateral stenosis and gradient appearance in the contralateral IJV at C1, with stenosis and gradient development in bilateral IJVs at C1–3 bilaterally during chin flexion. In all patients, 93.3% developed at least moderate dynamic stenosis of at least one IJV, more than two-thirds (69.7%) developed either severe or occlusive stenosis during rightward and leftward rotation, and 81.8% developed severe or occlusive stenosis with head flexion. Dynamic gradients of at least 4 mmHg were seen in 68.5% of patients, with gradients of at least 8 mmHg in 31.5% and at least 10 mmHg in 12.4%.ConclusionThis study is the first to document dynamic changes in IJV caliber and gradients in different head positions, offering insights into the complex nature of venous outflow and its impact on CVD.
iTRAQ-based mass spectrometry screen to identify serum biomarkers in systemic lupus erythematosus
Authors: Vanarsa Kamala , Zhang Ting , Hutcheson Jack , Kumar Sneha Ravi , Nukala Satyavani , Inthavong Haleigh , Stanley Bruce , Wu Tianfu , Mok C C , Saxena Ramesh , Mohan Chandra 
Published: May 2024

ObjectiveSystemic lupus erythematosus (SLE) is a complex systemic autoimmune disorder with no reliable serum biomarkers currently available other than autoantibodies.MethodsIn the present study, isobaric tags for relative and absolute quantitation-based mass spectrometry was used to screen the sera of patients with SLE to uncover potential disease biomarkers.Results85 common proteins were identified, with 16 being elevated (≥1.3) and 23 being decreased (≤0.7) in SLE. Of the 16 elevated proteins, serum alpha-1-microglobulin/bikunin precursor (AMBP), zinc alpha-2 glycoprotein (AZGP) and retinol-binding protein 4 (RBP4) were validated in independent cross-sectional cohorts (Cohort I, N=52; Cohort II, N=117) using an orthogonal platform, ELISA. Serum AMBP, AZGP and RBP4 were validated to be significantly elevated in both patients with inactive SLE and patients with active SLE compared with healthy controls (HCs) (p<0.05, fold change >2.5) in Cohort I. All three proteins exhibited good discriminatory power for distinguishing active SLE and inactive SLE (area under the curve=0.82–0.96), from HCs. Serum AMBP exhibited the largest fold change in active SLE (5.96) compared with HCs and correlated with renal disease activity. The elevation in serum AMBP was validated in a second cohort of patients with SLE of different ethnic origins, correlating with serum creatinine (r=0.60, p<0.001).ConclusionSince serum AMBP is validated to be elevated in SLE and correlated with renal disease, the clinical utility of this novel biomarker warrants further analysis in longitudinal cohorts of patients with lupus and lupus nephritis.
Heart disease in pregnancy and risk of pre-eclampsia: a Swedish register-based study
Authors: Bergman Karl , Svanvik Teresia , Basic Carmen , Rosengren Annika , Zverkova Sandström Tatiana , Celind Jimmy , Sjöland Helen , Wikström Anna-Karin , Schaufelberger Maria , Thunström Erik 
Published: May 2024

Background and aimsPre-eclampsia complicates 3–5% of pregnancies worldwide and is associated with adverse outcomes for the mother and the offspring. Pre-eclampsia and heart failure have common risk factors, including hypertension, obesity and diabetes. It is not known whether heart failure increases the risk of pre-eclampsia. This study examines whether pregestational heart failure increases the risk of pre-eclampsia.MethodsIn a registry-based case–cohort study that included all pregnancies in Sweden (n=3 125 527) between 1990 and 2019, all pregnancies with pre-eclampsia (n=90 354) were identified and up to five control pregnancies (n=451 466) for each case were chosen, matched on the mother’s birth year. Multiple logistic regression analysis was used to evaluate the impact of heart failure on the risk of pre-eclampsia, with adjustment for established risk factors and other cardiovascular diseases.ResultsWomen with heart failure had no increased risk for pre-eclampsia, OR 1.02 (95% CI 0.69 to 1.50). Women with valvular heart disease had an increased OR of preterm pre-eclampsia, with an adjusted OR of 1.78 (95% CI 1.04 to 3.06). Hypertension and diabetes were independent risk factors for pre-eclampsia. Obesity, multifetal pregnancies, in vitro fertilisation, older age, Nordic origin and nulliparity were more common among women who developed pre-eclampsia compared with controls.ConclusionWomen with heart failure do not have an increased risk of pre-eclampsia. However, women with valvular heart disease prior to pregnancy have an increased risk of developing preterm pre-eclampsia independent of other known risk factors.
Role of histone deacetylases and sirtuins in the ischaemic stroke: a protocol for a systematic review and meta-analysis of animal studies
Authors: Majdi Ali , Mostafavi Hossein , Moharrami Ali , Yaraghi Shahin , Ghaffari Tabrizi Amirreza , Dojahani Morteza , Alirezapour Erfan , Mansori Kamyar 
Published: May 2024

BackgroundStroke is a major cause of global mortality and disability. Currently, the treatment of acute ischaemic stroke through reperfusion has posed several challenges, raising the need for complementary options to protect the ischaemic penumbra. Recent investigations have indicated that certain epigenetic factors, specifically, histone deacetylases (HDACs) and sirtuins, can be promising for ischaemic stroke therapy, with recent studies suggesting that inhibitors of HDACs or sirtuins may provide neuronal protection after ischaemic stroke. However, the impact of specific HDAC/sirtuin isoforms on the survival of neuronal cells following stroke is still uncertain. This study aims to provide a comprehensive overview of the function of HDACs and their modulators in the treatment of acute ischaemic stroke.MethodsThis systematic review and meta-analysis will encompass animal intervention studies that explore the efficacy of modulation of HDACs and sirtuins in the acute phase of ischaemic stroke. The review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Electronic searches will be conducted in PubMed, Web of Science and Scopus, with subsequent screening by independent reviewers based on the established eligibility criteria. Methodological quality will be evaluated using the SYRCLE risk of bias tool. The primary outcomes will be infarct volume and functional response, with the secondary outcomes established a priori. Data pertaining to infarct volume will be used for random-effects meta-analysis. Additionally, a descriptive summary will be conducted for the functional response and secondary outcomes.DiscussionNo systematic review and meta-analysis on the treatment of ischaemic stroke through HDAC modulation has been conducted to date. A comprehensive analysis of the available literature on the relevant preclinical investigations can yield invaluable insights in discerning the most effective trials and in further standardisation of preclinical studies.Systematic review registrationThis systematic review has been recorded in the International Prospective Register of Systematic Reviews (PROSPERO), with the assigned reference number: CRD42023381420
SURFACE MORPHOLOGY OF SILICON NITRIDE (Si3N4)-TITANIUM NITRIDE (TiN) COMPOSITES USING GRA-RSM STRATEGY ENCOMPASSED WITH EDMed PARAMETERS
Authors: SELVARAJAN L. , VENKATARAMANAN K. , KANNAN S. , KUMAR S. SENTHIL , PERUMAL K. P. SRINIVASA , KUMAR P. MATHAN , PARTHASARATHI N. L. , KASTHURI N. , DURAISAMY KATHERASAN , ARUN C. 
Published: May 2024

This investigation explores the application of electrical discharge machining (EDM) to ceramic composites constructed from Si3N4–TiN (Syalon 501) by testing both square and cylindrical electrodes. Various experimental methods have been employed, including design-of-experiments (DoE), Grey relational analysis (GRA), analysis of variance (ANOVA), confirmation testing, and scanning electron microscopy (SEM), in an effort to optimize machining settings and comprehend their effect on performance. While ANOVA revealed crucial parameter levels influencing overall machining conditions as measured by the grey relational grade (GRG), the sophisticated method of GRA considerably improved the machining characteristics. Significant improvements in the EDM process were shown experimentally, resulting in outstanding results for material removal rate (MRR), surface roughness (SR), and electrode wear rate (EWR). In particular, numerous benefits of the square electrode layout over the more common cylindrical arrangement stood out. All of the aforementioned resulted in an impressively high MRR (measured at 0.0281[Formula: see text]gm/min), a low EWR (at 0.0020[Formula: see text]gm/min), and a significant improvement in SR (at 0.3150[Formula: see text][Formula: see text]m). The GRG value was 0.0163 for the square electrode design, which was excellent, and 0.0025 for the cylindrical electrode, which was significantly better. The optimized parameters were successfully used, especially with the square electrode arrangement, leading to significant improvements in MRR and decreases in EWR. On the other hand, surface quality was negatively affected by larger parameter values, which increased the development of microfractures, particularly when using the square electrode design. In any case, our study provides strong proof that adjusted settings can greatly improve EDM performance, allowing for accurate machining of Si3N4–TiN composites with increased MRR, great surface texture, and reduced electrode wear. In conclusion, our study provides useful information to improve EDM procedures for Si3N4–TiN ceramic composites, as well as practical insights into increasing the efficiency and quality of EDM operations in a variety of industrial sectors.
Serum Spexin Level Is Negatively Associated With Peripheral Neuropathy and Sensory Pain in Type 2 Diabetes
Authors: Liu Ying , Wu Di , Zheng Hangping , Ni Yunzhi , Zhu Lu , Jiang Yaojing , Dai Jiarong , Sun Quanya , Zhao Ying , Zhang Qi , Yang Yehong , Liu Rui 
Published: May 2024

Background: Spexin is a novel peptide hormone and has shown antinociceptive effects in experimental mice. This study is aimed at evaluating the association of serum spexin level with diabetic peripheral neuropathy (DPN) and related pain in a Chinese population.Methods: We enrolled 167 type 2 diabetes mellitus (T2DM) including 56 patients without DPN (non‐DPN), 67 painless DPN, and 44 painful DPN. Serum spexin was measured using ELISA. Logistic regression models were performed to analyze the independent effects of spexin on prevalence of DPN and painful DPN. In streptozotocin (STZ)‐induced diabetic mice, mechanical pain threshold was measured using electronic von Frey aesthesiometer. Human peripheral blood mononuclear cells (PBMCs) were isolated and further stimulated with lipopolysaccharide without or with spexin. The gene expression was assayed by qPCR.Results: Compared with non‐DPN, serum spexin level decreased in painless DPN and further decreased in painful DPN. The odds of DPN was associated with low spexin level in T2DM, which was similar by age, sex, BMI, and diabetes duration, but attenuated in smokers. The odds of having pain was associated with decreased spexin level in DPN, which was similar by age, sex, smoking status, and diabetes duration, but attenuated in normal weight. Furthermore, we observed that mechanical pain threshold increased in spexin‐treated diabetic mice. We also found that lipopolysaccharide treatment increased the mRNA level of TNF‐α, IL‐6, and MCP‐1 in human PBMCs, while spexin treatment prevented this increase.Conclusions: These results suggested that spexin might serve as a protective factor for diabetes against neuropathology and pain‐related pathogenesis.
Crizotinib Enhances PARP Inhibitor Efficacy in Ovarian Cancer Cells and Xenograft Models by Inducing Autophagy
Authors: Santiago-O’Farrill Janice M. , Blessing Bollu Alicia , Yang Hailing , Orellana Vivian , Pina Marc , Zhang Xudong , Liu Jinsong , Bast Robert C. , Lu Zhen 
Published: May 2024

Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and clonogenic growth in two-olaparib resistant cell lines. More importantly, this effect was consistently observed in patient-derived organoids. Furthermore, combined treatment with crizotinib and olaparib led to tumor regression in human ovarian xenograft models. Mechanistically, the combination resulted in increased levels of reactive oxygen species (ROS), induced DNA damage, and decreased the phosphorylation of AKT, mTOR, and ULK-1, contributing to increased olaparib-induced autophagy and apoptosis. Notably, pharmacologic, or genetic inhibition or autophagy reduced the sensitivity of ovarian cancer cell lines to olaparib and crizotinib treatment, underscoring the role of autophagy in cell death. Blocking ROS mitigated olaparib/crizotinib-induced autophagy and cell death while restoring levels of phosphorylated AKT, mTOR and ULK-1. These findings suggest that crizotinib can improve the therapeutic efficacy of olaparib by enhancing autophagy.
Implications: The combination of crizotinib and PARPi presents a promising strategy, that could provide a novel approach to enhance outcomes for patients with ovarian cancer.