bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Replication Protein A Inhibition and Post-Translational Modification on ATR Kinase Signaling
Authors: Jordan Matthew R. , Oakley Greg G. , Mayo Lindsey D. , Balakrishnan Lata , Turchi John J. 
Published: July 2024

Abstract

The ATR kinase responds to elevated levels of single-stranded DNA (ssDNA) to activate the G2/M checkpoint, regulate origin utilization, preserve fork stability, and allow DNA repair towards ensuring genome integrity. The intrinsic replication stress in cancer cells makes this pathway an attractive therapeutic target. The ssDNA that drives ATR signaling is sensed by the ssDNA-binding protein replication protein A (RPA), which acts as a platform for ATRIP recruitment and subsequent ATR activation by TopBP1. We have developed chemical RPA inhibitors (RPAi) that block RPA-ssDNA interactions, termed RPA-DBi, and RPA protein-protein interactions, termed RPA-PPIi; both activities are required for ATR activation. Here, we employ a biochemically reconstituted ATR kinase signaling pathway and demonstrate that both RPA-DBi and RPA-PPIi abrogate ATR-dependent phosphorylation of downstream target proteins. We demonstrate that RPA post-translational modifications (PTMs) impact ATR kinase activation but do not alter sensitivity to RPAi. Specifically, phosphorylation of RPA32 and TopBP1 stimulate, while RPA70 acetylation has no effect on ATR phosphorylation of target proteins. Collectively, this work reveals the RPAi mechanism of action to inhibit ATR signaling that can be regulated by RPA PTMs and offers insight into the anti-cancer activity of ATR pathway targeted cancer therapeutics.
Drug Repurposing: Therapeutic Role of Aripiprazole in the Cartilage Defect
Authors: Lee Jun-Ku , Yeo Hyunjeong , Choi Sujin , Kim Kyeong Mi , Kim Hannah , Lee Sung-Sahn , Lee Hyun Il , Jeong Younghoon , An Hyun-Ju , Lee Soonchul 
Published: July 2024

Abstract

Owing to the limited regenerative capacity of articular cartilage, damaged cartilage does not spontaneously heal over time. Various scientific efforts have been made to improve damaged articular cartilage. Nevertheless, no single approach has achieved a promising outcome for the damaged cartilage. Meanwhile, owing to the increasing cost of drug development, drug repositioning has been actively attempted. We aimed to identify the drug that can improve the cartilage defect, using chondrogenesis related microarray data recruited from the Gene Expression Omnibus (GEO) public database. Furthermore, we attempted to experiment using cellular and animal models to verify the cartilage regeneration potential for the identified drug. To screen for drugs that promote cartilage restoring, chondrogenesis related microarray data were collected from the GEO public database. The GSE69110, GSE107649, GSE111822, and GSE116173 datasets from the GEO were used to identify cartilage differentiation-related genes. Differentially expressed genes were identified using StringTie, and drug data were extracted from the Drug-Gene Interaction database. The effect of aripiprazole on cartilage was evaluated in aripiprazole-treated adipose-derived mesenchymal stem cells (ADMSCs) and chondrocyte using qRT-PCR and 3D pellet culture. The cartilage restoring efficacy was verified in vivo by mixing it with a scaffold and introducing it into the artificially damaged cartilage of Sprague-Dawley rats. Next, mRNA was sequenced for mechanistic analysis. As a result, aripiprazole significantly increased the mRNA expression of COL2A1 and SOX9, two cartilage differentiation-related genes, and chondrogenic condensation in vitro. Moreover, it effectively promoted cartilage regeneration in the cartilage defect rat model. Analysis of mRNA sequencing data from chondrocyte treated with aripiprazole, using KEGG and GOBP, indicated that aripiprazole significantly upregulates genes associated with ribosomes and cytoplasmic translation, thus promoting chondrogenesis. In conclusion, we discovered that aripiprazole can effectively improve damaged cartilage, providing a promising approach for cartilage regeneration.
Construction of an immune-related signature based on single-cell RNA-sequencing and machine learning for optimal prognosis prediction and treatment decisions in hepatocellular carcinoma
Authors: Zhang Huien , Wang Yang , Xu Zihan , Ma Guikai , Wang Xueying , Zhong Shoubin , Wang Bowen , Lun Jia , Li Zhenhua , Zhang Xuede 
Published: July 2024

Abstract

Introduction: Immune cells play a dual role inhepatocellular carcinoma (HCC) – it can both restrain and promote tumor growth, which is the significant component of the tumour immune microenvironment (TIME). This study aimed to develop a immune-related signature model to predict the prognosis and TIME of patients with HCC. Methods: Data for the TCGA-LIHC and GSE14520 cohorts were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Single-cell RNA-sequencing data for HCC samples were retrieved from the GSE140228 cohort. The Least Absolute Shrinkage and Selection Operator algorithm was employed to develop a Immune-related signature (IRSig). The predictive value of the IRSig was determined using Kaplan-Meier, Cox regression and Receiver Operating Characteristic curves. Gene set enrichment analysis (GSEA), Gene Set Variation Analysis (GSVA) and gene ontology (GO) analysis were performed to explore the functional enrichment of the IRSig. Finally, the TIMER platform, single sample Gene Set Enrichment Analysis and the Estimation of STromal and Immune cells in MAlignant Tumour tissues using Expression data algorithms were performed to determine the TIME landscape. Results: The immune-related signature demonstrated its superior ability to predict the clinical outcome of patients with HCC. TMB, immune score, stromal score, and ESTIMATE score were higher in the high-risk group compared to the low-risk group. Additionally, most immune checkpoints, including CTLA4, PD1 and PD-L1, were expressed at significantly higher levels in high-risk group. Conclusions: Our study established an immune-related signature based on single-cell RNA-sequencing and machine learning for optimal prognosis prediction and treatment decisions in hepatocellular carcinoma, and verified by TCGA and GEO databases. Besides, we found immune-related cells and pathways were significant differences in high- and low-risk group, which might be helpful for illustrating the application of immunotherapy for HCC patients.
Unraveling the Rapid Progression of Non-Target Lesions: Risk Factors and the Therapeutic Potential of PCSK9 Inhibitors in Post-PCI Patients
Authors: Mei Jiajie , Fu Xiaodan , Liu Zhenzhu , Zhang Lijiao , Geng Zhaohong , Xie Wenli , Yu Ming , Wang Yuxing , Zhao Jinglin , Zhang Xiaodong , Yin Lili , Qu Peng 
Published: July 2024

Abstract

Background
Rapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors for the rapid progression of NTLs post-PCI. Proprotein convertase subtilisin-kexin 9(PCSK9) inhibitors lower low-density lipoprotein cholesterol(LDL-c) levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI.
Methods
This retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI, and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI.
Results
There were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid ,higher hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group.LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI).
Conclusions
LDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters can predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors has a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque.
Registration number:
ChiCTR2200058529; Date of registration: 2022-04-10
Internalized and Externalized Mental Health Symptoms among Latinx Children:A Comparison between Rural Latinx Farmworker and Urban Latinx Low-Income Families Living in North Carolina
Authors: Berenson Lesley , Nugent William , Strand Elizabeth , Zottarelli Lisa , Laurienti Paul 
Published: July 2024

Abstract

This study examined mental health symptoms among 8-11-year-old children of Latinx farmworkers in rural North Carolina (N = 76) and urban children of Latinx parents (N = 65). All had household incomes of 200% below the poverty line. A Spanish version of the Child Behavioral Checklist (CBCL) for children aged 6–18 assessed internalized (anxious/depression) and externalized (aggression) mental health symptoms. CBCL scores obtained at baseline and subsequent follow-up evaluations approximately one year and two years after the first evaluation were analyzed with multi-level regression to determine if the CBCL outcomes changed over time. Children from farmworker families showed lower levels of anxious/depressive symptoms at baseline (mean = 50.59) than urban children (mean = 54.74), but these differences diminished with age. The mean depression score for the urban sample decreased by -1.17 points each year after the initial assessment. Both rural (mean = 44.15) and urban Latinx children (mean = 49.92) developed increased externalized aggressive symptoms over time, and rural children's aggression increased faster than urban children. The rural children showed a statistically significant increase with a mean linear rate of change of + 3.63 over time. This study contributes to the current research on how community settings may affect children's socio-emotional development, and suggests further examination into the impact of social, physical, and economic disadvantages on children's mental health.
Conversion of Naphthenic Hydrocarbons Over Hzm-12 Zeolites - Activity and Selectivity to Light Olefins Depending on Their Acid and Textural Properties and on the Size of the Processed Molecule
Authors: JUNIOR JOSE ROBERTO SILVA 
Published: July 2024

Abstract

The activity and selectivity to light olefins during conversion of naphthenic hydrocarbons over HZSM-12 zeolites depending on the textural and acid properties and the size of the processed molecule were studied. In Two ZSM-12 zeolites were synthesized under hydrothermal conditions with similar Si/Al ratio. To generate intracrystalline mesoporosity, the synthesized ZSM-12 zeolites, identified as HZ12 and MZ12, were subsequently desilicated by alkaline treatment (AT) generating the hierarchical HZ12-AT and MZ12-AT zeolites. After to obtain their protonic form, the samples were characterized by XRD, SEM, EDS, N2 physisorption, 27Al MAS NMR and NH3-TPD. XRD and N2 sorption measurements confirmed, respectively, that the MTW structure of the ZSM-12 zeolite was preserved and that after the AT occurred an increase in the mesoporous volume, consequently increasing the specific external surface area, besides with an increase in the concentration of weak acid sites in the alkaline treated sample under more severe conditions. The catalytic evaluation shows an increase in the conversion of cyclohexane, methylcyclohexane and ethylcyclohexane over the more mesoporous MZ12-AT zeolite with the yield to light olefins increasing with the increase of the length of the substitutive alkyl group in the naphthenic molecule, being this behavior more pronounced over the MZ12-AT sample.
Pharmacokinetic and pharmacodynamic evaluation of various vasopressin doses and routes in a neonatal piglet model
Authors: BSc Ramsie M , Cheung P-Y , M O’Reilly , TF Lee , Schmölzer Georg M. 
Published: July 2024

Abstract

Epinephrine is the only recommended vasopressor during neonatal cardiopulmonary resuscitation. However, there are concerns about the potential adverse effects of epinephrine, which might hamper efficacy during cardiopulmonary resuscitation. An alternative might be vasopressin, which has a preferable adverse effect profile, however, its optimal dose and route of administration is unknown. We aimed to compare the pharmacodynamics and pharmacokinetics of various vasopressin doses administered via intravenous (IV), intraosseous (IO), endotracheal (ETT), and intranasal (IN) routes in healthy neonatal piglets. Forty-four post-transitional piglets (1–3 days of age) were anesthetized, intubated via a tracheostomy, and randomized to receive vasopressin via intravenous (control), IO, ETT, or IN route. Heart rate (HR), arterial blood pressure, carotid blood flow, and cardiac function (e.g., stroke volume, ejection fraction) were continuously recorded throughout the experiment. Blood was collected prior to drug administration and throughout the observation period for pharmacodynamics and pharmacokinetic analysis. Significant changes in hemodynamic parameters were observed following IO administration of vasopressin while pharmacokinetic parameters were not different between IV and IO vasopressin. Administration of vasopressin via ETT or IN did not change hemodynamic parameters and had significantly lower maximum plasma concentrations and systemic absorption compared to piglets administered IV vasopressin (p < 0.05). The IV and IO routes appear the most effective route for vasopressin administration in neonatal piglets, while ETT and IN routes appear not suitable for vasopressin administration.
Bilateral Endobronchial Prostatic Metastases: A Rare Clinical Entity with Diagnostic and Therapeutic Challenges: A Case Report and Literature Review
Authors: Mittal Kriti , Panthi Sagar , VanBacker Justin 
Published: July 2024

Abstract

Background Endobronchial metastases from prostate cancer are uncommon, representing a diagnostic and therapeutic challenge due to their rarity and variable clinical presentation. Here, we present a case of bilateral endobronchial metastases secondary to adenocarcinoma of the prostate in a 73-year-old male with castration-resistant prostate cancer highlighting the importance of recognizing this rare entity for optimal patient management.
Case PresentationThe patient is a 73-year-old male with past medical history of atrial fibrillation on anticoagulation alongside a diagnosis of Gleason 3+4 prostate cancer resistant to castration. He presented with shortness of breath and a hemothorax secondary to a CT-guided lung biopsy several days prior, which prompted a pigtail catheter placement. A minimally invasive chest washout was eventually required due to incomplete drainage leading to an incidental discovery of bilateral endobronchial metastases synchronous with lung parenchymal metastasis. Treatment involved endobronchial tumor ablation given chemotherapy ineffectiveness.
Discussion and Literature ReviewEndobronchial metastases from prostate cancer is rare, but must be considered in patients with respiratory symptoms and a history of prostate cancer with pulmonary metastasis. Our literature review reveals a diverse clinical presentation with cough, dyspnea, and hemoptysis being most common. Diagnostic modalities such as bronchoscopy are crucial for accurate diagnosis, allowing for tailored treatment strategies. Hormonal therapy remains the mainstay of treatment, although other modalities such as chemotherapy and bronchoscopic interventions may be considered based on individual patient factors.
Conclusions Early recognition of endobronchial metastases secondary to prostate cancer with thorough evaluation, including bronchoscopy, is essential for timely diagnosis and appropriate management.
Longitudinal evaluation of circulating tumor cells in operable locally advanced esophageal squamous cell carcinoma
Authors: Wang Jin , Chen Shuang , Zhang Weidi , Li Yang , Han Lu 
Published: July 2024

Abstract

Objective: The detection of circulating tumor cells (CTCs) at a single time point offers restricted insights into prognostic assessment. This study aims to longitudinally investigate alterations in CTCs status throughout the neoadjuvant chemotherapy, surgical, and postoperative chemotherapy phases within a homogeneous cohort. Further more, an assessment of the interrelation between patients' treatment response, survival prognosis, and CTCs status was conducted.
Materials and methods: Thirty-one patients diagnosed with operable locally advanced esophageal squamous cell carcinoma were randomly allocated to either the surgical or neoadjuvant group. CTCs detection was systematically conducted at various time points throughout the treatment on individual patients. Associations between the presence of CTCs/CTM and therapeutic efficacy, as well as clinical outcomes, were subject to rigorous analysis.
Results: We performed a total of 136 CTCs detections at the time points of pre-neoadjuvant chemotherapy, preoperative, postoperative day 2, post-operative 1 week, post-operative 3 months. The CTCs were detected in 6/12(50％), 14/31(45.16％), 22/31(70.97％), 16/31(51.6％) and 5/31(16.1％) of patients before neoadjuvant treatment, prior to surgery, on postoperative day 2, one week after surgery, and three months post-surgery, respectively. The CTC count exhibited an increase before and after surgery, whereas a decrease was observed before and after neoadjuvant chemotherapy. Among patients initially identified with CTCs+, those in the neoadjuvant group experienced extended progression-free survival (PFS) (p=0.05) and overall survival (OS) (p=0.04) compared to those in the surgical group. On postoperative day 2, 17 patients had CTCs＜4, while 14 patients had CTCs≥4. Individuals with CTCs＜4 demonstrated significantly prolonged PFS (p＜0.01, HR=6.26, 95% CI 1.96-19.96) and OS (p＜0.01, HR=6.63, 95% CI 2.08-21.13) compared to those with CTCs≥4. CTM was detected in 45.16% of patients at any given time. Survival analysis indicated that CTM- patients exhibited longer PFS (p=0.029, HR=2.92, 95% CI 1.05-8.07) and OS (p=0.03, HR=2.92, 95% CI 1.06-8.09) than CTM+ patients.
Conclusions: Single-time detection offers limited information for prognostic evaluation, a dynamic fluctuation in the quantity of CTCs/CTM throughout the course of treatment, exhibiting a robust predictive impact on patient prognosis.
High-Fidelity Pose Estimation for Real-Time Extended Reality (XR) Visualization for Cardiac Catheterization
Authors: Mosadegh Bobak , Annabestani Mohsen , Sri Sandhya , Caprio Alexandre , Janghorbani Sepehr , Wong S. Chiu , Sigaras Alexandros 
Published: July 2024

Abstract

Extended reality (XR) technologies are emerging as promising platforms for medical training and procedural guidance, particularly in complex cardiac interventions. This paper presents a high-fidelity methodology to perform real-time 3D catheter tracking and visualization during simulated cardiac interventions. A custom 3D-printed setup with mounted cameras enables biplane video capture of a catheter. A computer vision algorithm processes the biplane images in real-time to reconstruct the 3D catheter trajectory represented by any designated number of points along its length. This method accurately localizes the catheter tip within 1 mm and can reconstruct any arbitrary catheter configuration. The tracked catheter data is integrated into an interactive Unity-based scene rendered on the Meta Quest 3 headset. The visualization seamlessly combines a reconstructed 3D patient-specific heart model with the dynamically tracked catheter, creating an immersive extended reality training environment. Our experimental study, involving six participants, demonstrated that the 3D visualization provided by the proposed XR system significantly outperformed 2D visualization in terms of speed and user experience. This suggests that the XR system has the potential to enhance catheterization training by improving spatial comprehension and procedural skills. The proposed system demonstrates the potential of XR technologies to transform percutaneous cardiac interventions through improved visualization and interactivity.
Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation successfully treated with colchicine
Authors: Handa Hideo , Sugiyama Atsuhiko , Kubosawa Hitoshi , Nakagawa Yuki , Kishida Dai , Uzawa Akiyuki , Aotsuka Akiyo , Kuwabara Satoshi 
Published: July 2024

Abstract

Background: This case report aims to present a case of Mollaret meningitis caused by Kikuchi disease, an uncommon benign inflammatory disorder, thereby highlighting a novel etiology for Mollaret meningitis. Additionally, it discusses colchicine as a new potential treatment option for Kikuchi disease.
Case presentation: A 41-year-old Japanese woman presented with fever and headache. She had nuchal rigidity and bilateral cervical lymphadenopathies. Her past medical history included multiple episodes of aseptic meningitis and cervical lymphadenopathy for more than twenty years. Lumbar puncture showed increased lymphocytes and IL-6 level and pathognomonic Mollaret cells. Excisional lymph node biopsy revealed histiocytic necrotizing lymphadenitis, confirming the diagnosis of Kikuchi disease. Subsequently, her recurrent Kikuchi disease was successfully treated with colchicine. Furthermore, genetic analysis of the MEFV gene revealed heterozygous P369S/R408Q mutation in exon 3.
Conclusion: Mollaret meningitis can be caused by Kikuchi disease, and recurrence of both may be suppressed by colchicine.
Long-term culture of skin biopsies: Maintenance of fibroblast production and competency of reprogramming
Authors: Rathan-Kumar Sudiksha , Ripperger Michael A , Westlake Grant M , Ess Kevin C 
Published: July 2024

Abstract

Primary fibroblasts are a commonly used cell type used in a variety of experimental and therapeutic studies. Patient-derived skin biopsies are an accessible way to generate fibroblasts for use in various assays as well as reprogramming to iPSCs. To understand the potential of long-term skin biopsy culture, we cultured biopsy samples for 6 to 16 months and analyzed subsequent generation of fibroblasts. We found maintenance of morphology and physiology over time. Proliferation assays showed that older generations remained proliferative but at a decreased rate. mRNA analyses revealed transcriptional changes with long-term skin culture. Deep DNA sequencing did not reveal any large deletions or amplifications. Spontaneous DNA mutations seemed to be random and not enriched for any specific signaling pathways. Older fibroblasts generated after 16 months in culture retained competency for reprogramming into iPSCs. Our results support long term culture of skin to generate very large numbers of primary fibroblasts. These cells maintain their identity and integrity enabling the study of human disorders, particularly rare ones.