bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex differences in the epidemiology of spontaneous and traumatic cervical artery dissections
Authors: Schipani Elke , Griffin Kim J , Oakley Carlee I , Keser Zafer 
Published: September 2024

BackgroundRecent studies show cervical artery dissection (CeAD) is equally common between sexes, and that the incidence of CeAD has risen at a greater rate in females than males. In this population-based study, we identify sex differences in patients diagnosed with spontaneous and traumatic CeAD.Methods144 patients with spontaneous or traumatic CeAD were studied for sex differences in medical comorbidities, presenting symptoms and outcomes.ResultsFemales were more likely to carry a diagnosis of migraine, while males were more likely to have hyperlipidaemia. Females were more likely to present with neck pain, males with stroke. Females were significantly more likely to develop recurrent dissections in the study period.ConclusionsThese findings underscore the importance of understanding CeAD through the lens of sex differences and may explain the significant rise in the diagnosis of CeAD in females. These findings support the importance of considering sex-specific risk factors and medical comorbidities with sex predilection in the diagnosis and management of CeAD. Furthermore, it emphasises the importance of female patients understanding risk factors and presenting signs that should prompt evaluation for CeAD.
Association between ASPECTS region of infarction and clinical outcome in non-acute large vessel occlusion ischaemic stroke after endovascular recanalisation
Authors: Lu Jialiang , Lu Ziwei , Li Ye , Li Fangcun , Feng Yuxuan , Dang Meijuan , Yang Yang , Tang Fan , Li Tao , Zhao Lili , Jian Yating , Wang Xiaoya , Zhang Lei , Fan Hong , Zhang Guilian 
Published: September 2024

PurposeThis study retrospectively investigated whether infarction in specific Alberta Stroke Program Early CT Score (ASPECTS) regions is associated with clinical outcome in patients with symptomatic non-acute internal carotid or middle cerebral artery occlusion who underwent endovascular recanalisation (ER).MethodsPreoperative ASPECTS and region of infarction were recorded before recanalisation. Clinical outcome was evaluated 90 days after the procedure using the modified Rankin Scale; a score>2 was defined as poor outcome. Secondary outcomes included postprocedural cerebral oedema, intracranial haemorrhage (ICH) and symptomatic ICH.ResultsAmong the 86 patients included, 90-day outcome was poor in 30 (34.9%) and 40 experienced cerebral oedema (46.5%). Multivariate logistic regression models showed that lenticular nucleus infarction (OR 19.61–26.00, p<0.05), admission diastolic blood pressure (OR 1.07–1.08, p<0.05), preprocedural National Institutes of Health Stroke Scale (OR 1.96–2.05, p<0.001) and haemorrhagic transformation (OR 14.99–18.81, p<0.05) were independent predictors of poor 90-day outcome. The area under the receiver operating characteristic curve for lenticular nucleus infarction as a predictor of poor outcome was 0.73. M2 region infarction (OR 26.07, p<0.001) and low American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral circulation grade (OR 0.16, p=0.001) were independent predictors of postprocedural cerebral oedema. The area under the receiver operating characteristic curve for M2 region infarction as a predictor of cerebral oedema was 0.64. Region of infarction did not significantly differ between patients with and without postprocedural ICH or symptomatic ICH.ConclusionsLenticular nucleus and M2 region infarction were independent predictors of poor 90-day outcome and postprocedural cerebral oedema, respectively, in patients with non-acute anterior circulation large artery occlusion who underwent ER.
Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Preleukemic Cells
Authors: Liu Xiaoyu , Liu Yu , Rao Qing , Mei Yihan , Xing Haiyan , Gu Runxia , Mou Junli , Chen Manling , Ding Fan , Xie Wanqing , Tang Kejing , Tian Zheng , Wang Min , Qiu Shaowei , Wang Jianxiang 
Published: September 2024

Abstract
Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSC) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of preleukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1–ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating preleukemic clones, in this study, we used a conditional Runx1::Runx1t1 knockin mouse model to evaluate preleukemic cell metabolism. AML1–ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these preleukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1–ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of preleukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.
Significance: Fatty acid metabolism is required for maintenance of preleukemic cells but dispensable for normal hematopoiesis, indicating that dietary lipid deprivation or inhibiting fatty acid uptake may serve as potential strategies to prevent leukemogenesis.
Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M. 
Published: September 2024

Abstract

Purpose:
The spatial variability and clinical relevance of the tumor immune microenvironment (TIME) are still poorly understood for hepatocellular carcinoma (HCC). In this study, we aim to develop a deep learning (DL)–based image analysis model for the spatial analysis of immune cell biomarkers and microscopically evaluate the distribution of immune infiltration.

Experimental Design:
Ninety-two HCC surgical liver resections and 51 matched needle biopsies were histologically classified according to their immunophenotypes: inflamed, immune-excluded, and immune-desert. To characterize the TIME on immunohistochemistry (IHC)-stained slides, we designed a multistage DL algorithm, IHC-TIME, to automatically detect immune cells and their localization in the TIME in tumor–stroma and center–border segments.

Results:
Two models were trained to detect and localize the immune cells on IHC-stained slides. The framework models (i.e., immune cell detection models and tumor–stroma segmentation) reached 98% and 91% accuracy, respectively. Patients with inflamed tumors showed better recurrence-free survival than those with immune-excluded or immune-desert tumors. Needle biopsies were found to be 75% accurate in representing the immunophenotypes of the main tumor. Finally, we developed an algorithm that defines immunophenotypes automatically based on the IHC-TIME analysis, achieving an accuracy of 80%.

Conclusions:
Our DL-based tool can accurately analyze and quantify immune cells on IHC-stained slides of HCC. Microscopic classification of the TIME can stratify HCC according to the patient prognosis. Needle biopsies can provide valuable insights for TIME-related prognostic prediction, albeit with specific constraints. The computational pathology tool provides a new way to study the HCC TIME.
TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma
Authors: Sheng Nan , Shindo Koji , Ohuchida Kenoki , Shinkawa Tomohiko , Zhang Bo , Feng Haimin , Yamamoto Takeo , Moriyama Taiki , Ikenaga Naoki , Nakata Kohei , Oda Yoshinao , Nakamura Masafumi 
Published: September 2024

Abstract

Purpose:
We aim to clarify the precise function of TGFβ1-activated kinase 1 (TAK1) in cancer-associated fibroblasts (CAF) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways.

Experimental Design:
The expression of TAK1 in pancreatic cancer was confirmed by The Cancer Genome Atlas data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect coculture with PDAC tumors to investigate TAK1 function. Additionally, organoids from [LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC)] mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1.

Results:
The Cancer Genome Atlas data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the inflammatory CAF signature and increased the myofibroblastic CAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered epithelial–mesenchymal transition and outgrowth in vitro in spheroid cocultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T-cell abundance, and reduced immunosuppressive cells present in vivo.

Conclusions:
Blocking the TAK1+ CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.
Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders
Authors: Nakano Yoshiko , Kuiper Roland P. , Nichols Kim E. , Porter Christopher C. , Lesmana Harry , Meade Julia , Kratz Christian P. , Godley Lucy A. , Maese Luke D. , Achatz Maria Isabel , Khincha Payal P. , Savage Sharon A. , Doria Andrea S. , Greer Mary-Louise C. , Chang Vivian Y. , Wang Lisa L. , Plon Sharon E. , Walsh Michael F. 
Published: September 2024

Abstract
Genomic instability disorders are characterized by DNA or chromosomal instability, resulting in various clinical manifestations, including developmental anomalies, immunodeficiency, and increased risk of developing cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop, where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article discusses childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, xeroderma pigmentosum, Bloom syndrome, and Rothmund–Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anticancer therapy.
The Epstein–Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction
Authors: Warner Benjamin E. , Patel Japan , Wang Renwei , Adams-Haduch Jennifer , Gao Yu-Tang , Koh Woon-Puay , Wong Ka Wo , Chiang Alan K.S. , Yuan Jian-Min , Shair Kathy H.Y. 
Published: September 2024

Abstract

Purpose:
Antibodies to select Epstein–Barr virus proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against Epstein–Barr virus nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years before diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay.

Experimental Design:
Mammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A, which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using prediagnostic NPC sera from two independent cohorts in Singapore and Shanghai, the People’s Republic of China.

Results:
At 95% sensitivity, 487V yielded a 94.9% specificity compared with 86.1% for 487A. EBNA1 deleted for the conserved glycine–alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390–641) showed lower specificity (84.8%) than the EBNA1 GAr–deleted construct (92.4%) at 95% sensitivity.

Conclusions:
Although EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr, but with residues consistently detected in Southeast Asian NPC tumors, is optimized for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection.
Activating pyruvate kinase improves red blood cell integrity by reducing band 3 tyrosine phosphorylation
Authors: Le Kang , Wang Xunde , Chu Jonathan , Lundt Maureen , Lee Yuan Yee , Conrey Anna , Frey Ingrid , Giannini Silvia , Kosinski Penelope A. , Hausman John M. , Low Philip S. , Jeffries Neal , Desai Sanjay A. , Thein Swee Lay 
Published: September 2024

Abstract
In a phase 1 study (NCT04000165), we established proof of concept for activating pyruvate kinase (PK) in sickle cell disease (SCD) as a viable antisickling therapy. AG-348 (mitapivat), a PK activator, increased adenosine triphosphate (ATP) and decreased 2,3-diphosphoglycerate levels while patients were on treatment, in line with the mechanism of the drug. We noted that the increased hemoglobin (Hb) persisted for 4 weeks after stopping AG-348 until the end of study (EOS). Here, we investigated the pathways modulated by activating PK that may contribute to the improved red blood cell (RBC) survival after AG-348 cessation. We evaluated frozen whole blood samples taken at multiple time points from patients in the phase 1 study, from which RBC ghosts were isolated and analyzed by western blotting for tyrosine phosphorylation of band 3 (Tyr-p-bd3), ankyrin-1, and intact (active) protein tyrosine phosphatase 1B (PTP1B) levels. We observed a significant dose-dependent decrease in mean Tyr-p-bd3 from baseline in the patients, accompanied by an increase in the levels of membrane-associated ankyrin-1 and intact PTP1B, all of which returned to near baseline by EOS. Because PTP1B is cleaved (inactivated) by intracellular Ca2+-dependent calpain, we next measured the effect of AG-348 on ATP production and calpain activity and the plasma membrane Ca2+ ATPase pump–mediated efflux kinetics in HbAA and HbSS erythrocytes. AG-348 treatment increased ATP levels, decreased calpain activity, and increased Ca2+ efflux. Altogether, our data indicate that ATP increase is a key mechanism underlying the increase in hemoglobin levels upon PK activation in SCD. This trial was registered at www.clinicaltrials.gov as #NCT04000165.
Outcomes with single-agent gilteritinib for relapsed or refractory FLT3-mutant AML after contemporary induction therapy
Authors: Othman Jad , Hwang Angela , Brodermann Maximillian , Abdallah Islam , McCloskey Kayleigh , Gallipoli Paolo , Clarke Georgina , Dang Raymond , Vidler Jennifer , Krishnamurthy Pramila , Basheer Faisal , Latif Anne-Louise , Palanicawandar Renuka , Taylor Tom , Khan Asra , Campbell Victoria , Hogan Francesca , Kanellopoulos Alex , Fleming Kathryn , Collins Angela , Dalley Chris , Loke Justin , Marshall Scott , Taussig David , Munisamy Sreetharan , Loizou Eleana , Yassin Heba , Dennis Mike , Zhao Rui , Belsham Edward , Murray Duncan , Fowler Nicole , O'Nions Jenny , Khan Anjum , Sellar Rob , Dillon Richard 
Published: September 2024

Abstract
Gilteritinib is the current standard of care for relapsed or refractory fms related receptor tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or nonintensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and health care resource use is limited. Here, we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 years, and 36% had received ≥2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalization in the first cycle (median, 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21%, and CR with incomplete recovery (CRi) in a further 9%. Remission rates were lower for patients with FLT3–tyrosine kinase domain or adverse karyotype. Day-30 and day-60 mortality were 1% and 10.6%, respectively, and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement, and complex karyotype were associated with worse survival whereas RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed after first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials, but outcomes remain suboptimal, with more effective strategies needed.
Exploring the diverse applications of sol–gel synthesized CaO:MgAl2O4 nanocomposite: morphological, photocatalytic, and electrochemical perspectives
Authors: Jahnavi H. K. , Prasad S. Rajendra , Nagaswarupa H. P. , Naik Ramachandra , Basavaraju N. , Ravikumar C. R. , Goud Burragoni Sravanthi , Kim Jae Hong 
Published: September 2024

AbstractA nanocomposite of CaO:MgAl2O4 was synthesized through a straightforward and cost-effective sol–gel method. The investigation of the novel CaO:MgAl2O4 nanocomposite encompassed an examination of its morphological and structural alterations, as well as an exploration of its photocatalytic activities and electrochemical characteristics. XRD analysis revealed a nanocomposite size of 24.15 nm. The band gap, determined through UV studies, was found to be 3.83 eV, and scanning electron microscopy (SEM) illustrated flake-like morphological changes in the CaO:MgAl2O4 samples. TEM, HRTEM, and SAED studies of a CaO:MgAl2O4 nanocomposite would reveal important details about its morphology, crystallography, and nanostructure. Photocatalytic activity was quantified by studying the degradation of Acid Red-88 (AR-88) dye in a deionized solution, achieving a 70% dye degradation under UV irradiation in 120 min. Plant growth examinations were carried out using dye degraded water to test its suitability for agriculture. The electrochemical energy storage and sensing applications of the prepared nanocomposite were examined using CaO:MgAl2O4 modified carbon paste electrode through cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). In conclusion, the synthesized CaO:MgAl2O4 nanocomposite demonstrated promising morphological and structural characteristics, efficient photocatalytic activity, and potential applications in electrochemical energy storage, highlighting its versatility for various technological and environmental applications.
Graphical abstract
Mitochondrial sequence variants: testing imputation accuracy and their association with dairy cattle milk traits
Authors: Dorji Jigme , Chamberlain Amanda J. , Reich Coralie M. , VanderJagt Christy J. , Nguyen Tuan V. , Daetwyler Hans D. , MacLeod Iona M. 
Published: September 2024

Abstract
Background
Mitochondrial genomes differ from the nuclear genome and in humans it is known that mitochondrial variants contribute to genetic disorders. Prior to genomics, some livestock studies assessed the role of the mitochondrial genome but these were limited and inconclusive. Modern genome sequencing provides an opportunity to re-evaluate the potential impact of mitochondrial variation on livestock traits. This study first evaluated the empirical accuracy of mitochondrial sequence imputation and then used real and imputed mitochondrial sequence genotypes to study the role of mitochondrial variants on milk production traits of dairy cattle.

Results
The empirical accuracy of imputation from Single Nucleotide Polymorphism (SNP) panels to mitochondrial sequence genotypes was assessed in 516 test animals of Holstein, Jersey and Red breeds using Beagle software and a sequence reference of 1883 animals. The overall accuracy estimated as the Pearson’s correlation squared (R2) between all imputed and real genotypes across all animals was 0.454. The low accuracy was attributed partly to the majority of variants having low minor allele frequency (MAF < 0.005) but also due to variants in the hypervariable D-loop region showing poor imputation accuracy. Beagle software provides an internal estimate of imputation accuracy (DR2), and 10 percent of the total 1927 imputed positions showed DR2 greater than 0.9 (N = 201). There were 151 sites with empirical R2 > 0.9 (of 954 variants segregating in the test animals) and 138 of these overlapped the sites with DR2 > 0.9. This suggests that the DR2 statistic is a reasonable proxy to select sites that are imputed with higher accuracy for downstream analyses. Accordingly, in the second part of the study mitochondrial sequence variants were imputed from real mitochondrial SNP panel genotypes of 9515 Australian Holstein, Jersey and Red dairy cattle. Then, using only sites with DR2 > 0.900 and real genotypes, we undertook a genome-wide association study (GWAS) for milk, fat and protein yields. The GWAS mitochondrial SNP effects were not significant.

Conclusion
The accuracy of imputation of mitochondrial genotypes from the SNP panel to sequence was generally low. The Beagle DR2 statistic enabled selection of sites imputed with higher empirical accuracy. We recommend building larger reference populations with mitochondrial sequence to improve the accuracy of imputing less common variants and ensuring that SNP panels include common variants in the D-loop region.