bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Treatment Outcomes of Prostate Cancer Patients With Lymph Node Metastasis Treated With Definitive Radiotherapy
Authors: Onal Cem , Guler Ozan Cem , Erpolat Petek , Hurmuz Pervin , Sutera Philip , Deek Matthew P. , Elmali Aysenur , Yilmaz Melek Tugce , Koken Ummu Habibe , Yavuz Melek , Ozyigit Gokhan , Tran Phuoc T. 
Published: June 2024

Purpose
We investigated the impact of prostate-specific membrane antigen (PSMA) PET/CT compared with conventional imaging on treatment outcomes for node-positive prostate cancer (PCa) patients who underwent androgen deprivation therapy (ADT) and external radiotherapy (RT).

Patients and Methods
A multicentric, retrospective study recruited patients with node-positive PCa patients who underwent conventional radiological evaluation or PSMA PET/CT and received ADT and RT at 3 hospitals from 2009 to 2021 were enrolled. Patients underwent prostate and pelvis RT, accompanied by a minimum of 6 months of ADT. The primary endpoints were progression-free survival (PFS) and PCa-specific survival (PCSS). Cox regression analyzed the association of survival with potential prognostic factors, whereas logistic regression identified the predictors of bone and lymph node metastasis.

Results
The median follow-up time was 64.0 months. The majority of patients (64.1%) underwent PSMA PET/CT for staging. The 5-year rates of PFS and PCSS were 63.7% and 83.7%, respectively. Disease progression was observed in 90 patients (36.3%). In multivariable analysis, ADT duration of less than 24 months and post-RT prostate-specific antigen (PSA) nadir were prognostic for PFS. Early clinical T stage and PSMA PET/CT predicted better PCSS. Patients staged with PSMA PET/CT had exhibited significantly higher 5-year PCSS rates than compared with those staged with conventional imaging (95.1% vs 76.9%; P = 0.01). Shorter ADT duration and higher PSA levels after RT independently predicted bone metastasis in multivariable logistic regression. Advanced T stage, shorter ADT duration, and higher PSA levels after neoadjuvant ADT predicted nonregional lymph node recurrence.

Conclusions
ADT with pelvis RT is an effective treatment option for node-positive PCa patients. The PSMA PET/CT outperformed conventional imaging in PCSS, emphasizing the importance of precise clinical staging for patients undergoing definitive RT.
Bioinformatics Study on Mechanism of Postnatal Development of Craniofacial Bone
Authors: Shang Guangling , Lei Liu , Peng Changliang 
Published: June 2024

Objective:
The postnatal development of craniofacial bone plays a crucial role in shaping the overall structure and functionality of the skull and face. Understanding the underlying mechanisms of this intricate process is essential for both clinical and research purposes. In this study, the authors conducted a bioinformatics analysis using the Gene Expression Omnibus database to investigate the molecular pathways and regulatory networks involved in the postnatal development of craniofacial bone.

Methods:
In this study, the online Gene Expression Omnibus microarray expression profiling data set GSE27976 was used to identify differentially expressed genes (DEGs) in different age groups. Protein-Protein Interaction network analyses, functional enrichment, and hub genes analysis were performed. The differences in immune infiltration and microenvironment among different types of cells were also analyzed.

Results:
In total, 523 DEGs, including 287 upregulated and 236 downregulated genes, were identified. GO and KEGG analysis showed that the DEGs were significantly enriched in multiple signaling pathways, such as skeletal system morphogenesis, osteoblast differentiation, and stem cell differentiation. Immune infiltration and microenvironment characteristics analysis showed that there were significant differences in fibroblasts, mesenchymal stem cell, osteoblast, stroma score, and microenvironment score between the two groups. Five hub genes, including IGF1, IL1B, ICAM1, MMP2, and brain-derived neurotrophic factor, were filled out.

Conclusion:
The findings of this study showed a significant shift in gene expression towards osteogenesis during the first 12 months after birth. These findings emphasize the critical role of the postnatal period in craniofacial bone development and provide valuable insights into the molecular mechanisms underlying this process.
Late Treatment With Autologous Expanded Regulatory T-cell Therapy After Alemtuzumab Induction Is Safe and Facilitates Immunosuppression Minimization in Living Donor Renal Transplantation
Authors: Brook Matthew O. , Hennessy Conor , Hester Joanna , Hammad Salim , Alzhrani Alaa , Rombach Ines , Dutton Susan , Lombardi Giovanna , Wood Kathryn J. , Friend Peter , Harden Paul N. , Issa Fadi 
Published: June 2024

Background.
The TWO Study (Transplantation Without Overimmunosuppression) aimed to investigate a novel approach to regulatory T-cell (Treg) therapy in renal transplant patients, using a delayed infusion protocol at 6 mo posttransplant to promote a Treg-skewed lymphocyte repopulation after alemtuzumab induction. We hypothesized that this would allow safe weaning of immunosuppression to tacrolimus alone. The COVID-19 pandemic led to the suspension of alemtuzumab use, and therefore, we report the unique cohort of 7 patients who underwent the original randomized controlled trial protocol. This study presents a unique insight into Treg therapy combined with alemtuzumab and is therefore an important proof of concept for studies in other diseases that are considering lymphodepletion.

Methods.
Living donor kidney transplant recipients were randomized to receive autologous polyclonal Treg at week 26 posttransplantation, coupled with weaning doses of tacrolimus, (Treg therapy arm) or standard immunosuppression alone (tacrolimus and mycophenolate mofetil). Primary outcomes were patient survival and rejection-free survival.

Results.
Successful cell manufacturing and cryopreservation until the 6-mo infusion were achieved. Patient and transplant survival was 100%. Acute rejection-free survival was 100% in the Treg-treated group at 18 mo after transplantation. Although alemtuzumab caused a profound depletion of all lymphocytes, including Treg, after cell therapy infusion, there was a transient increase in peripheral Treg numbers.

Conclusions.
The study establishes that delayed autologous Treg therapy is both feasible and safe, even 12 mo after cell production. The findings present a new treatment protocol for Treg therapy, potentially expanding its applications to other indications.
Head trauma impairs HPA-axis functions by increased R-loop structure and shortens telomeres
Authors: Şükranlı Zeynep Yılmaz , Taheri Serpil , Mehmetbeyoğlu Ecmel , Gülcihan Önal Müge , Memiş Mehmet , Er Begüm , Karaca Züleyha , Tanrıverdi Fatih , Ünlühızarcı Kürsad , Rassoulzadegan Minoo , Keleştimur Fahrettin 
Published: June 2024

ABSTRACTTraumatic brain injury (TBI) causes inflammation, one of the main causes of cellular aging. Telomere repeat-containing RNA (TERRA) hybridizes to telomere regions, forming R-loop structures and ensuring genome stabilization. Deregulation of R-loop homeostasis leads to genomic instability linked to neurodegenerative diseases and cancer. The hypothalamus-pituitary-adrenal (HPA) axis response is critical to maintaining homeostasis after TBI. We showed that the local increase in the transcription levels of theCrhandPomcgenes, in particular, suggests a defensive response through transcriptional alteration against mild TBI despite the decreased rate in the serum in the chronic phase. Additionally, changes in the transcription levels of TERRA and correlations with hormonal deficits after repetitive mTBI head trauma were observed. Telomere shortening and increased hybridized TERRA levels, especially after repeated mTBI in the chronic phase, suggest a possible disorder of genome stabilization and loss of cellular function in tissues of the hypothalamus, pituitary, and adrenal glands.
Increased motility inCampylobacter jejuniand changes in its virulence, fitness and morphology following protein expression on ribosomes with altered RsmA methylation
Authors: Sałamaszyńska-Guz Agnieszka , Murawska Małgorzata , Bącal Paweł , Ostrowska Agnieszka , Kwiecień Ewelina , Stefańska Ilona , Douthwaite Stephen 
Published: June 2024

AbstractInfection withCampylobacter jejuniis the major cause of human gastroenteritis in the United States and Europe, leading in many cases to debilitating autoimmune sequelae. While considerable progress has been made in detailing the infectious cycle ofC. jejuni, a full understanding of the molecular mechanisms responsible for virulence remains to be elucidated. Here, we apply a novel approach by modulating protein expression on the pathogen’s ribosomes by inactivating a highly conserved rRNA methyltransferase. Loss of the RsmA methyltransferase results in a more motile strain with greater adhesive and cell invasive properties. These phenotypical effects correlate with enhanced expression of specific proteins related to flagellar formation and function, together with enzymes involved in cell wall/membrane and amino acid synthesis. Despite the enhancement of certain virulent traits, the null-strain grows poorly on minimal media and is rapidly out-competed by the wild-type strain. Complementation with an active copy of thersmAgene rescues most of the traits changed in the mutant. However, the complemented strain overexpressesrsmAand displays new flaws including loss of the spiral cell shape that is distinctive forC. jejuni. Proteins linked with altered virulence and morphology are identified here by mass spectrometry proteomic analyses of the strains.Author summaryInfections withCampylobacter, and particularly with the most prevalent species of this genus,Campylobacter jejuni, are the leading cause of human bacterial gastroenteritis. Sadly, illnesses caused byC. jejunioften do not end with the infection itself, but continue with serious post-infectious autoimmune sequelae including the peripheral neuropathies Guillain–Barré syndrome, Miller Fisher syndrome and irritable bowel syndrome. Despite decades of research into theC. jejuniinfection cycle, the molecular mechanisms by which pathogenicity progresses are not yet fully understood. Here, we described a novel approach whereby we modulate protein synthesis on the pathogen’s ribosomes to interfere with specific virulence traits. This is followed up with proteome analyses of the engineered strains using state-of-the-art mass spectrometry techniques, enabling us to link specific proteins with steps in the infection cycle. Specifically, we disabled the ribosomal RNA modification enzyme RsmA, and this causes unexpectedly large changes inC. jejunimotility and its ability to attach to and invade human epithelial cells. We then identified specific flagellar, transpeptidase and peptidoglycan peptidase proteins involved in these processes. We propose that this approach of modulating protein synthesis via changes in rRNA methylation can be applied to study the infection cycles of other bacterial pathogens.
Multi-step engineered adeno-associated virus enables whole-brain mRNA delivery
Authors: Bai Weiya , Yang Dong , Zhao Yaqing , Li Guoling , Liu Zhen , Xiong Panzhi , Quan Haifeng , Wu Xiaoqing , Chen Peng , Kong Xiangfeng , Wang Xuchen , Zhang Hainan , Zhou Yingsi , Li Tong , Yuan Yuan , Yao Xuan , Shi Linyu , Yang Hui 
Published: June 2024

AbstractAdeno-associated viruses (AAVs) are commonly used vectors for DNA delivery in gene therapy. Here we developed a system that enables the AAV shell to package mRNAs by multi-step introduction of RNA-packaging components and modification of AAV Rep proteins. The resultant mRNA-carrying AAVs (RAAVs) retained most properties of conventional AAVs, including capsid composition, virus morphology, and tissue tropism. These RAAVs could mediate mRNA transfer into target cells and tissues, leading to transient expression of the functional protein. Importantly, intravenously injected RAAVs efficiently crossed the blood-brain barrier (BBB) and infected the whole mouse brain. Thus, the DNA viral vector could be modified for RNA delivery, and our RAAV represents the first highly efficient BBB-crossing mRNA delivery system that could be used for therapeutic purposes via whole-brain infection.
The Fem Cell-surface Signaling System is Regulated by ExsA inPseudomonas aeruginosaand Affects Pathogenicity
Authors: Li Yanqi , Badr Sara , Zhang Pansong , Chen Lin , Bhagirath Anjali Y. , Dadashi Maryam , Surette Michael G. , Duan Kangmin 
Published: June 2024

ABSTRACTBacterial interspecies interactions shape the function and the structural dynamics of microbial communities and affect the progression of polymicrobial infections. The FemA-FemR-FemI (Fem) cell surface signaling system inPseudomonas aeruginosais known to be involved in the uptake of iron-chelating mycobactin produced by theMycobacteriumspecies. In this report, we present the data that indicates thefemA-PA1909 operon was positively regulated by ExsA, a master regulator for the type three secretion system (T3SS), connecting the Fem system with T3SS. Intriguingly, the Fem system also influenced virulence factors inP. aeruginosa,including the quorum sensing systems, pyocyanin production, biofilm formation and the type six secretion systems (T6SSs). Using aGalleria mellonellainfection model we observed that anfemAdeletion in PAO1 significantly increased the host survival rate whilefemIover-expression decreased it, suggesting a role for the Fem system in bacterial pathogenicityin vivo. Our data indicate the Fem system is a target of the T3SS master activator ExsA, and it affectsP. aeruginosapathogenicity.
The Dual Roles of the CXCL10-CXCR3 Axis and Its Therapeutic Potential in Osteosarcoma
Authors: Gyau Benjamin B. , Wang Junyan , Chen Xiang , Clement Margaret , Man Zoe D. , Major Angela , Weiser Mathew , Xu Jun , Hicks John , Man Tsz-Kwong 
Published: June 2024

ABSTRACTThe CXCL10-CXCR3 axis is recognized for its dual role in tumor biology, promoting tumor growth and metastasis via autocrine signaling while also eliciting anti-tumor responses through paracrine signaling. However, its specific functions in osteosarcoma (OS), the most prevalent malignant bone tumor in children, remain poorly understood. Our previous research has demonstrated that elevated circulating CXCL10 levels correlate with poor prognosis in OS patients. Analysis of the TARGET OS RNAseq dataset revealed that high expression levels of CXCL10 or its receptor CXCR3 are associated with improved prognosis. Given the known role of CXCL10 in recruiting CXCR3+ immune cells to combat cancer, we further analyzed single-cell RNAseq data and found that CXCR3 is predominantly expressed in CD3+ T cell populations. These findings suggest that CXCL10 may also play a protective role in OS by recruiting anti-tumor immune cells. To elucidate the causal role of the CXCL10-CXCR3 axis in OS, we conductedin vitrophenotypic assays on three OS cell lines with and without CXCL10. The chemokine was found to enhance tumor cell migration and AKT phosphorylation. Utilizing a CRISPR-mediated CXCR3 deletion mutant, we demonstrated that the absence of CXCR3 significantly inhibited OS tumor growth and pulmonary metastasis in an orthotopic xenograft mouse model. Transfection with the CXCR3A isoform, but not the CXCR3B isoform, restored the migratory phenotype of the CXCR3 deletion mutant to levels comparable to the parental cell line. Additionally, pharmacological inhibition of CXCR3 with AMG487 markedly reduced OS cell migrationin vitroand metastasis development in the orthotopic xenograft mouse model. Our research highlights the complex interplay of the CXCL10-CXCR3 axis in both tumor and immune cells. We propose a working model for the roles of the CXCL10-CXCR3 axis in OS, suggesting that targeting CXCR3 may be an effective strategy to inhibit OS metastasis, particularly in immune-cold OS subtypes.
Evaluating the Diagnostic Performance of Large Language Models in Identifying Complex Multisystemic Syndromes: A Comparative Study with Radiology Residents
Authors: Olshaker Hagar , Brin Dana , Kalderon Elinor , Kraus Matan , Konen Eliahu , Klang Eyal 
Published: June 2024

AbstractAimThis study evaluates the diagnostic capabilities of large language models (LLMs) in interpreting imaging patterns, focusing on their utility as a resource for radiology residents. We compare the diagnostic performance of OpenAI’s GPT-3.5, GPT-4, and Google’s Gemini Pro against radiology residents in identifying complex, multisystemic syndromes with an increased risk of cancer.MethodsWe assessed diagnostic accuracy using textual descriptions of radiological findings from 60 diseases selected from The Familial Cancer Database. Participants included three LLMs and three radiology residents. Diagnostic responses were scored on accuracy and first choice correctness. Experiments with AI models were conducted using default API settings.ResultsGPT-4 achieved the highest diagnostic accuracy (63%) and first choice accuracy (40%), significantly outperforming the radiology residents whose accuracy ranged from 22% to 43%. The overall average accuracy for AI models was 49.3%, compared to 29.0% for residents. Error analysis revealed that while some diseases were universally recognized, others highlighted diagnostic challenges across both human and AI participants.ConclusionGPT-4 outperforms radiology residents in diagnosing complex, infrequent multisystemic diseases. These findings suggest potential benefits of integrating AI tools to improve diagnostic accuracy for rare conditions and imply a need for revisions in medical training to incorporate AI competencies, enhancing diagnostic processes and resident education in radiology.
Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction
Authors: Guevara Amanda , Smith Charlotte E.R. , Wang Lianguo , Caldwell Jessica L. , Tapa Srinivas , Stuart Samantha D. Francis , Ma Betty W. , Ng G. Andre , Habecker Beth A. , Wang Zhen , Ripplinger Crystal M. 
Published: June 2024

ABSTRACTChondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is associated with supersensitivity of β-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypo-innervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca2+-sensitive dyes. SNS was performed with electrical stimulation of the spinal cord and β-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct and border zone of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct vs. remote region. Action potential duration (APD) dispersion and susceptibility to ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI hearts but not in sham. SNS decreased APD80in MI but not sham hearts, while isoproterenol decreased APD80in both groups. Isoproterenol also shortened Ca2+transient duration (CaTD80) in both groups but to a greater extent in MI hearts. Our data suggest sympathetic remodeling post-MI is similar between species, with CSPGs associated with sympathetic hypo-innervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated β-adrenergic responsiveness, which may underly increased APD dispersion and susceptibility for VT/VF.NEW & NOTEWORTHYHere we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypo-innervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between species, with hypo-innervation likely associated with enhanced β-adrenergic sensitivity.
Replay of procedural experience is independent of the hippocampus
Authors: Thompson Emmett J. , Rollik Lars , Waked Benjamin , Mills Georgina , Kaur Jasvin , Geva Ben , Carrasco-Davis Rodrigo , George Tom , Domine Clementine , Dorrell William , Stephenson-Jones Marcus 
Published: June 2024

AbstractSleep is critical for consolidating all forms of memory1-3, from episodic experience to the development of motor skills4-6. A core feature of the consolidation process is offline replay of neuronal firing patterns that occur during experience7,8. This replay is thought to originate in the hippocampus and trigger the reactivation of ensembles of cortical and subcortical neurons1,3,9-18. However, non-declarative memories do not require the hippocampus for learning or for sleep-dependent consolidation19-26meaning what drives their consolidation is unknown. Here we show, using an unsupervised method, that replay occurs in the dorsal striatum of mice during offline consolidation of a non-declarative, procedural, memory and that this replay is generated independently of the hippocampus. Replay occurred at both real-world and time-compressed speeds and was also prioritised both at the level of the individual neurons and the type of neural sequence. Complete bilateral lesions of the hippocampus had no effect on any feature of this replay. Our results demonstrate that procedural replay during consolidation of a non-declarative memory is independent of the hippocampus. These results support the view that replay drives active consolidation of all types of memory during sleep but challenges the idea that the hippocampus is the source of this replay.
Data mining redefines the timeline and geographic spread of cotton leafroll dwarf virus
Authors: Olmedo-Velarde Alejandro , Shakhzadyan Hayk , Rethwisch Michael , West-Ortiz Michael , Waisen Philip , Heck Michelle 
Published: June 2024

ABSTRACTCotton leafroll dwarf virus (CLRDV), a threat to the cotton industry, was first reported in the United States (US) as an emergent pathogen in 2017. Phylogenetic analysis supports the hypothesis that US CLRDV strains are genetically distinct from strains in South America and elsewhere, which is not consistent with the hypothesis that the virus is newly introduced into the country. Therefore, using database mining, we evaluated the timeline and geographic distribution of CLRDV in the country. We uncovered evidence that shows that CLRDV had been in the US for over a decade before its official first report. CLRDV sequences were detected in datasets derived from Mississippi in 2006, Louisiana in 2015, and California in 2018. Additionally, through field surveys of upland cotton in 2023, we confirmed that CLRDV is present in California, which had no prior reports of the virus. Viral sequences from these old and new datasets exhibited high nucleotide identities (>98%) with recently characterized US isolates, and phylogenetic analyses with their homologs placed these sequences within a US-specific clade, further supporting the earlier presence of CLRDV in the country. Moreover, potential new hosts, including another fiber crop, flax, were determined through data mining. Retrospective analysis suggests CLRDV presence in the US since at least 2006 (Mississippi). These findings necessitate a reevaluation of spread patterns, inoculum sources, symptomology variations, and control strategies. Our findings challenge the current understanding of the arrival and spread of CLRDV in the US, highlight the power of data mining for virus discovery, and underscore the need for further investigation into CLRDV’s impact on US cotton.