bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor
Authors: Fiskus Warren , Piel Jessica , Collins Mike , Hentemann Murphy , Cuglievan Branko , Mill Christopher P. , Birdwell Christine E. , Das Kaberi , Davis John A. , Hou Hanxi , Jain Antrix , Malovannaya Anna , Kadia Tapan M. , Daver Naval , Sasaki Koji , Takahashi Koichi , Hammond Danielle , Reville Patrick K. , Wang Jian , Loghavi Sanam , Sen Rwik , Ruan Xinjia , Su Xiaoping , Flores Lauren B. , DiNardo Courtney D. , Bhalla Kapil N. 
Published: March 2024

Abstract
BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286–based combinations as a promising therapy for AML with MLL1r or mtNPM1.
CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells
Authors: Mensurado Sofia , Condeço Carolina , Sánchez-Martínez Diego , Shirley Sara , Coelho Rui M. L. , Tirado Néstor , Vinyoles Meritxell , Blanco-Domínguez Rafael , Barros Leandro , Galvão Beatriz , Custódio Noélia , Gomes da Silva Maria , Menéndez Pablo , Silva-Santos Bruno 
Published: March 2024

Abstract
Relapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell–based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here, we dissected the role of natural killer (NK) cell receptor ligands in AML cell recognition by DOT cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/pulmonary vascular resistance (PVR), CD112/nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key nonredundant and synergistic contributions of PVR and B7-H6 but not nectin-2 to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT cells. These data provide new mechanistic insight into tumor targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT cell–based clinical trials.
CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy
Authors: Sam Johannes , Hofer Thomas , Kuettel Christine , Claus Christina , Thom Jenny , Herter Sylvia , Georges Guy , Korfi Koorosh , Lechmann Martin , Eigenmann Miro Julian , Marbach Daniel , Jamois Candice , Lechner Katharina , Krishnan Sreenath M. , Gaillard Brenda , Marinho Joana , Kronenberg Sven , Kunz Leo , Wilson Sabine , Briner Stefanie , Gebhardt Samuel , Varol Ahmet , Appelt Birte , Nicolini Valeria , Speziale Dario , Bez Miriam , Bommer Esther , Eckmann Jan , Hage Carina , Limani Florian , Jenni Silvia , Schoenle Anne , Le Clech Marine , Vallier Jean-Baptiste Pierre , Colombetti Sara , Bacac Marina , Gasser Stephan , Klein Christian , Umaña Pablo 
Published: March 2024

Abstract
Effective T-cell responses not only require the engagement of T-cell receptors (TCRs; “signal 1”), but also the availability of costimulatory signals (“signal 2”). T-cell bispecific antibodies (TCBs) deliver a robust signal 1 by engaging the TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells to CD20-expressing malignant B cells. Although glofitamab exhibits strong single-agent efficacy, adding costimulatory signaling may enhance the depth and durability of T-cell–mediated tumor cell killing. We developed a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, because its activity requires the simultaneous presence of a TCR signal and CD19 target binding. This is achieved through its engineered format incorporating a mutated Fc region with abolished FcγR and C1q binding, CD28 monovalency, and a moderate CD28 binding affinity. In combination with glofitamab, CD19-CD28 strongly increased T-cell effector functions in ex vivo assays using peripheral blood mononuclear cells and spleen samples derived from patients with lymphoma and enhanced glofitamab-mediated regression of aggressive lymphomas in humanized mice. Notably, the triple combination of glofitamab with CD19-CD28 with the costimulatory 4-1BB agonist, CD19–4-1BBL, offered substantially improved long-term tumor control over glofitamab monotherapy and respective duplet combinations. Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a phase 1 clinical trial in combination with glofitamab. This trial was registered at www.clinicaltrials.gov as #NCT05219513.
An across breed, diet and tissue analysis reveals the transcription factor NR1H3 as a key mediator of residual feed intake in beef cattle
Authors: Keogh Kate , Kenny D. A. , Alexandre P. A. , McGee M. , Reverter A. 
Published: March 2024

AbstractBackgroundProvision of feed is a major determinant of overall profitability in beef production systems, accounting for up to 75% of the variable costs. Thus, improving cattle feed efficiency, by way of determining the underlying genomic control and subsequently selecting for feed efficient cattle, provides a method through which feed input costs may be reduced. The objective of this study was to undertake gene co-expression network analysis using RNA-Sequence data generated fromLongissimus dorsiand liver tissue samples collected from steers of two contrasting breeds (Charolais and Holstein-Friesian) divergent for residual feed intake (RFI), across two consecutive distinct dietary phases (zero-grazed grass and high-concentrate). Categories including differentially expressed genes (DEGs) based on the contrasts of RFI phenotype, breed and dietary source, as well as key transcription factors and proteins secreted in plasma were utilised as nodes of the gene co-expression network.ResultsOf the 2,929 DEGs within the network analysis, 1,604 were reported to have statistically significant correlations (≥ 0.80), resulting in a total of 43,876 significant connections between genes. Pathway analysis of clusters of co-expressed genes revealed enrichment of processes related to lipid metabolism (fatty acid biosynthesis, fatty acid β-oxidation, cholesterol biosynthesis), immune function, (complement cascade, coagulation system, acute phase response signalling), and energy production (oxidative phosphorylation, mitochondrial L-carnitine shuttle pathway) based on genes related to RFI, breed and dietary source contrasts.ConclusionsAlthough similar biological processes were evident across the three factors examined, no one gene node was evident across RFI, breed and diet contrasts in both liver and muscle tissues. However within the liver tissue, theIRX4,NR1H3,HOXA13andZNF648gene nodes, which all encode transcription factors displayed significant connections across the RFI, diet and breed comparisons, indicating a role for these transcription factors towards the RFI phenotype irrespective of diet and breed. Moreover, theNR1H3gene encodes a protein secreted into plasma from the hepatocytes of the liver, highlighting the potential for this gene to be explored as a robust biomarker for the RFI trait in beef cattle.
RNA-seq analysis reveals narrow differential gene expression in MEP and MVA pathways responsible for phytochemical divergence in extreme genotypes of Thymus daenensis Celak
Authors: Ahmadi Hosein , Fatahi Reza , Zamani Zabihollah , Shokrpour Majid , Sheikh-Assadi Morteza , Poczai Peter 
Published: March 2024

Abstract
Background
Here, we investigated the underlying transcriptional-level evidence behind phytochemical differences between two metabolically extreme genotypes of Thymus daenensis. The genotypes ‘Zagheh-11’ (thymol/carvacrol type, poor in essential oil [EO] [2.9%] but rich in triterpenic acids) and ‘Malayer-21’ (thymol type and rich in EO [3.8%]) were selected from an ongoing breeding program and then clonally propagated for further experimental use.

Materials and methods
GC-MS, GC-FID, and HPLC-PDA were utilized to monitor the fluctuation of secondary metabolites at four phenological stages (vegetative, bud burst, early, and full-flowering stages). The highest phytochemical divergence was observed at early flowering stage. Both genotypes were subjected to mRNA sequencing (approximately 100 million paired reads) at the aforementioned stage. The expression patterns of four key genes involved in the biosynthesis of terpenoids were also validated using qRT-PCR.

Results
Carvacrol content in ‘Zagheh-11’ (26.13%) was approximately 23 times higher than ‘Malayer-21’ (1.12%). Reciprocally, about 10% higher thymol was found in ‘Malayer-21’ (62.15%). Moreover, the concentrations of three major triterpenic acids in ‘Zagheh-11’ were approximately as twice as those found in ‘Malayer-21’. Transcriptome analysis revealed a total of 1840 unigenes that were differentially expressed, including terpene synthases, cytochrome P450, and terpenoid backbone genes. Several differentially expressed transcription factors (such as MYB, bZIP, HB-HD-ZIP, and WRKY families) were also identified. These results suggest that an active cytosolic mevalonate (MVA) pathway may be linked to higher levels of sesquiterpenes, triterpenic acids, and carvacrol in ‘Zagheh-11’. The chloroplastic pathway of methyl erythritol phosphate (MEP) may have also contributed to a higher accumulation of thymol in Malayer-21. Indeed, ‘Zagheh-11’ showed higher expression of certain genes (HMGR, CYP71D180, β-amyrin 28-monooxygenase, and sesquiterpene synthases) in the MVA pathway, while some genes in the MEP pathway (including DXR, ispG, and γ-terpinene synthase) were distinctly expressed in Malayer-21. Future efforts in metabolic engineering of MVA/MEP pathways may benefit from these findings to produce increased levels of desired secondary metabolites at commercial scale.
Ensemble species distribution modeling and multilocus phylogeography provide insight into the spatial genetic patterns and distribution dynamics of a keystone forest species, Quercus glauca
Authors: Song Ying , Xu Gang-Biao , Long Ke-Xin , Wang Chun-Cheng , Chen Ran , Li He , Jiang Xiao-Long , Deng Min 
Published: March 2024

Abstract
Background
Forests are essential for maintaining species diversity, stabilizing local and global climate, and providing ecosystem services. Exploring the impact of paleogeographic events and climate change on the genetic structure and distribution dynamics of forest keystone species could help predict responses to future climate change. In this study, we combined an ensemble species distribution model (eSDM) and multilocus phylogeography to investigate the spatial genetic patterns and distribution change of Quercus glauca Thunb, a keystone of East Asian subtropical evergreen broad-leaved forest.

Results
A total of 781 samples were collected from 77 populations, largely covering the natural distribution of Q. glauca. The eSDM showed that the suitable habitat experienced a significant expansion after the last glacial maximum (LGM) but will recede in the future under a general climate warming scenario. The distribution centroid will migrate toward the northeast as the climate warms. Using nuclear SSR data, two distinct lineages split between east and west were detected. Within-group genetic differentiation was higher in the West than in the East. Based on the identified 58 haplotypes, no clear phylogeographic structure was found. Populations in the Nanling Mountains, Wuyi Mountains, and the southwest region were found to have high genetic diversity.

Conclusions
A significant negative correlation between habitat stability and heterozygosity might be explained by the mixing of different lineages in the expansion region after LGM and/or hybridization between Q. glauca and closely related species. The Nanling Mountains may be important for organisms as a dispersal corridor in the west-east direction and as a refugium during the glacial period. This study provided new insights into spatial genetic patterns and distribution dynamics of Q. glauca.
Associations between social networks, cognitive function, and quality of life among older adults in long-term care
Authors: Dodds Laura , Brayne Carol , Siette Joyce 
Published: March 2024

Abstract
Background
Having rich social networks is associated with better physical and cognitive health, however older adults entering long-term care may experience an increased risk of social isolation and consequent negative impacts on cognitive function. Our study aimed to identify if there is an association between accessing specific types of services or activities within long-term care on social networks and cognition.

Methods
A cross-sectional study of 96 residents from 2 aged care providers in New South Wales, Australia. Residents were given a battery of assessments measuring social network structure (Lubben Social Network Scale, LSNS-12), quality of life (EuroQol 5D, Eq. 5D5L) and cognitive function (Montreal Cognitive Assessment, MoCA). Demographic factors and service use factors were also collected from aged care providers’ electronic records. Independent sample t-test, ANOVA and linear regression analyses were used to explore associated factors for cognition.

Results
Residents had a mean age of 82.7 ± 9.4 years (median = 81) and 64.6% were women. Most residents had cognitive impairment (70.8%) and reported moderate sized social networks (26.7/60) (Lubben Social Network Scale, LSNS-12). Residents who had larger social networks of both family and friends had significantly better cognitive performance. Service type and frequency of attendance were not associated with cognitive function.

Conclusions
Among individuals most at risk of social isolation, having supportive and fulfilling social networks was associated with preserved cognitive function. The relationship between service provision and social interactions that offer psychosocial support within long-term facilities and its impact over time on cognitive function requires further exploration.
Persistent high sepsis-induced coagulopathy and sequential organ failure assessment scores can predict the 28-day mortality of patients with sepsis: A prospective study
Authors: Li Junyu , Liu Huizhen , Wang Na , Wang Fengrong , Shang Na , Guo Shubin , Wang Guodong 
Published: March 2024

Abstract
Background
The performance of the sepsis-induced coagulopathy (SIC) and sequential organ failure assessment (SOFA) scores in predicting the prognoses of patients with sepsis has been validated. This study aimed to investigate the time course of SIC and SOFA scores and their association with outcomes in patients with sepsis.

Methods
This prospective study enrolled 209 patients with sepsis admitted to the emergency department. The SIC and SOFA scores of the patients were assessed on days 1, 2, and 4. Patients were categorized into survivor or non-survivor groups based on their 28-day survival. We conducted a generalized estimating equation analysis to evaluate the time course of SIC and SOFA scores and the corresponding differences between the two groups. The predictive value of SIC and SOFA scores at different time points for sepsis prognosis was evaluated.

Results
In the non-survivor group, SIC and SOFA scores gradually increased during the first 4 days (P < 0.05). In the survivor group, the SIC and SOFA scores on day 2 were significantly higher than those on day 1 (P < 0.05); however, they decreased on day 4, dropping below the levels observed on day 1 (P < 0.05). The non-survivors showed higher SIC scores on days 2 (P < 0.05) and 4 (P < 0.001) than the survivors, whereas no significant differences were found between the two groups on day 1 (P > 0.05). The performance of SIC scores on day 4 for predicting mortality was more accurate than that on day 2, with areas under the curve of 0.749 (95% confidence interval [CI]: 0.674–0.823), and 0.601 (95% CI: 0.524–0.679), respectively. The SIC scores demonstrated comparable predictive accuracy for 28-day mortality to the SOFA scores on days 2 and 4. Cox proportional hazards models indicated that SIC on day 4 (hazard ratio [HR] = 3.736; 95% CI: 2.025–6.891) was an independent risk factor for 28-day mortality.

Conclusions
The time course of SIC and SOFA scores differed between surviving and non-surviving patients with sepsis, and persistent high SIC and SOFA scores can predict 28-day mortality.
Radiogenomic analysis of ultrasound phenotypic features coupled to proteomes predicts metastatic risk in primary prostate cancer
Authors: Fu Qihuan , Luo Li , Hong Ruixia , Zhou Hang , Xu Xinzhi , Feng Yujie , Huang Kaifeng , Wan Yujie , Li Ying , Gong Jiaqi , Le Xingyan , Liu Xiu , Wang Na , Yuan Jiangbei , Li Fang 
Published: March 2024

Abstract
Background
Primary prostate cancer with metastasis has a poor prognosis, so assessing its risk of metastasis is essential.

Methods
This study combined comprehensive ultrasound features with tissue proteomic analysis to obtain biomarkers and practical diagnostic image features that signify prostate cancer metastasis.

Results
In this study, 17 ultrasound image features of benign prostatic hyperplasia (BPH), primary prostate cancer without metastasis (PPCWOM), and primary prostate cancer with metastasis (PPCWM) were comprehensively analyzed and combined with the corresponding tissue proteome data to perform weighted gene co-expression network analysis (WGCNA), which resulted in two modules highly correlated with the ultrasound phenotype. We screened proteins with temporal expression trends based on the progression of the disease from BPH to PPCWOM and ultimately to PPCWM from two modules and obtained a protein that can promote prostate cancer metastasis. Subsequently, four ultrasound image features significantly associated with the metastatic biomarker HNRNPC (Heterogeneous nuclear ribonucleoprotein C) were identified by analyzing the correlation between the protein and ultrasound image features. The biomarker HNRNPC showed a significant difference in the five-year survival rate of prostate cancer patients (p < 0.0053). On the other hand, we validated the diagnostic efficiency of the four ultrasound image features in clinical data from 112 patients with PPCWOM and 150 patients with PPCWM, obtaining a combined diagnostic AUC of 0.904. In summary, using ultrasound imaging features for predicting whether prostate cancer is metastatic has many applications.

Conclusion
The above study reveals noninvasive ultrasound image biomarkers and their underlying biological significance, which provide a basis for early diagnosis, treatment, and prognosis of primary prostate cancer with metastasis.
Development and validation of a novel preoperative clinical model for predicting lymph node metastasis in perihilar cholangiocarcinoma
Authors: Mao Shuqi , Shan Yuying , Yu Xi , Yang Yong , Wu Shengdong , Lu Caide 
Published: March 2024

Abstract
Backgroud
We aimed to develop a novel preoperative nomogram to predict lymph node metastasis (LNM) in perihilar cholangiocarcinoma (pCCA) patients.

Methods
160 pCCA patients were enrolled at Lihuili Hospital from July 2006 to May 2022. A novel nomogram model was established to predict LNM in pCCA patients based on the independent predictive factors selected by the multivariate logistic regression model. The precision of the nomogram model was evaluated through internal and external validation with calibration curve statistics and the concordance index (C-index). Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate and determine the clinical utility of the nomogram.

Results
Multivariate logistic regression demonstrated that age (OR = 0.963, 95% CI: 0.930–0.996, P = 0.030), CA19-9 level (> 559.8 U/mL vs. ≤559.8 U/mL: OR = 3.162, 95% CI: 1.519–6.582, P = 0.002) and tumour diameter (OR = 1.388, 95% CI: 1.083–1.778, P = 0.010) were independent predictive factors of LNM in pCCA patients. The C-index was 0.763 (95% CI: 0.667–0.860) and 0.677 (95% CI: 0.580–0.773) in training cohort and validation cohort, respectively. ROC curve analysis indicated the comparative stability and adequate discriminative ability of nomogram. The sensitivity and specificity were 0.820 and 0.652 in training cohort and 0.704 and 0.649 in validation cohort, respectively. DCA revealed that the nomogram model could augment net benefits in the prediction of LNM in pCCA patients.

Conclusions
The novel prediction model is useful for predicting LNM in pCCA patients and showed adequate discriminative ability and high predictive accuracy.