bluuebunny/crossref_metadata_2025_split huggingface dataset:
Butyrate-producingFaecalibacterium prausnitziisuppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway
Authors: Shi Zhuangzhuang , Li Min , Zhang Chen , Li Hongwen , Zhang Yue , Zhang Lei , Li Xin , Li Ling , Wang Xinhua , Fu Xiaorui , Sun Zhenchang , Zhang Xudong , Tian Li , Zhang Mingzhi , Chen Wei-Hua , Li Zhaoming 
Published: December 2024

BackgroundNatural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes.ObjectiveTo characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL.DesignThis cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms.ResultsWe first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction inFaecalibacterium prausnitziiwhich correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties ofF. prausnitziiin NKTCL mouse models. Furthermore,F. prausnitziiculture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1.ConclusionThese findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential ofF. prausnitziito ameliorate this malignancy.
Transforming safety culture in neonatal intensive care teams
Authors: Hu Zheng Jing , Fusch Gerhard , El Gouhary Enas , Twiss Jennifer , Sidhu Amneet , Chappell Elias , Sheehan Emmeline , el Helou Zoe , Robson Robert , Anazodo Kemi Salawu , Thabane Lehana , Lachman Peter , el Helou Salhab 
Published: December 2024

BackgroundHealthcare organisations face widespread challenges in optimising their safety culture, especially amid conflicting stakeholder needs, staffing shortages and increasing acuity of patients. McMaster University Children’s Hospital Neonatal Intensive Care Unit developed a safety culture programme that prioritises the needs of patients, hospital staff and learners altogether.MethodsThe safety culture programme and activities revolve around six primary drivers: psychological safety, provider well-being, equity, diversity and inclusion, teamwork and communication, organisational learning and leadership. We describe how these drivers influence safety culture, the ongoing activities being implemented, stakeholder feedback and contextual factors. We evaluated the maturity of our safety culture using the Manchester Patient Safety Framework (MaPSaF) questionnaire.ResultsMaPSaF assessments were conducted three times over 4 years. Most domains of safety culture in MaPSaF maintained their position despite COVID-19 while some indicators declined or have been maintained.ConclusionsWe provide a framework for implementing a safety culture programme that addresses the needs of diverse stakeholders. Transformation of the safety culture takes time and the failure to improve the patient safety measures over the period may be attributed to rapidly increasing workload and worsening patient acuity. These challenges underscore the imperative of balancing transactional and transformational projects to preserve a safety culture.
Rips and regular future scenario with holographic dark energy: a comprehensive look
Authors: Brevik I. , Khlopov Maxim , Odintsov S. D. , Timoshkin Alexander V. , Trivedi Oem 
Published: December 2024

Abstract
Interest on the possible future scenarios the universe could have has grew substantially with breakthroughs on late-time acceleration. Holographic dark energy (HDE) presents a very interesting approach towards addressing late-time acceleration, presenting an intriguing interface of ideas from quantum gravity and cosmology. In this work we present an extensive discussion of possible late-time scenarios, focusing on rips and similar events, in a universe with holographic dark energy. We discuss these events in the realm of the generalized Nojiri–Odintsov cutoff and also for the more primitive holographic cutoffs like Hubble, particle and event horizon cutoffs. We also discuss the validity of the generalized second law of thermodynamics and various energy conditions in these regimes. Our work points towards the idea that it is not possible to have alternatives of the big rip consistently in the simpler HDE cutoffs, and shows the flexibility of the generalized HDE cutoff as well.
Effective metric descriptions of quantum black holes
Authors: Del Piano Manuel , Hohenegger Stefan , Sannino Francesco 
Published: December 2024

Abstract
In a recent work (Del Piano et al. in Phys Rev D 109(2):024045, 2024), we have described spherically symmetric and static quantum black holes as deformations of the classical Schwarzschild metric that depend on the physical distance to the horizon. We have developed a framework that allows us to compute the latter in a self-consistent fashion from the deformed geometry, in the vicinity of the horizon. However, in this formalism, the distance can be replaced by other physical quantities, e.g. curvature invariants such as the Ricci- or Kretschmann scalar. Here, we, therefore, define a more general framework, which we call an effective metric description (EMD), that captures the deformed geometry based on a generic physical quantity. We develop in detail the Ricci- and Kretschmann scalar EMD, in particular demonstrating how to compute the geometry in a self-consistent manner. Moreover, we provide explicit relations that allow us to express one EMD in terms of the others, thus demonstrating their equivalence.
Identifying neural network structures explained by personality traits: combining unsupervised and supervised machine learning techniques in translational validity assessment
Authors: Stoyanova Kristina , Stoyanov Drozdstoy , Khorev Vladimir , Kurkin Semen 
Published: December 2024

AbstractThere have been studies previously the neurobiological underpinnings of personality traits in various paradigms such as psychobiological theory and Eysenck’s model as well as five-factor model. However, there are limited results in terms of co-clustering of the functional connectivity as measured by functional MRI, and personality profiles. In the present study, we have analyzed resting-state connectivity networks and character type with the Lowen bioenergetic test in 66 healthy subjects. There have been identified direct correspondences between network metrics such as eigenvector centrality (EC), clustering coefficient (CC), node strength (NS) and specific personality characteristics. Specifically, N Acc L and OFCmed were associated with oral and masochistic traits in terms of EC and CC, while Insula R is associated with oral traits in terms of NS and EC. It is noteworthy that we observed significant correlations between individual items and node measures in specific regions, suggesting a more targeted relationship. However, the more relevant finding is the correlation between metrics (NS, CC, and EC) and overall traits. A hierarchical clustering algorithm (agglomerative clustering, an unsupervised machine learning technique) and principal component analysis were applied, where we identified three prominent principal components that cumulatively explain 76% of the psychometric data. Furthermore, we managed to cluster the network metrics (by unsupervised clustering) to explore whether neural connectivity patterns could be grouped based on combined average network metrics and psychometric data (global and local efficiencies, node strength, eigenvector centrality, and node strength). We identified three principal components, where the cumulative amount of explained data reaches 99%. The correspondence between network measures (CC and NS) and predictors (responses to Lowen’s items) is 62% predicted with a precision of 90%.
HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma
Authors: Turnham Rigney E. , Pitea Adriana , Jang Gwendolyn M. , Xu Zhong , Lim Huat Chye , Choi Alex L. , Von Dollen John , Levin Rebecca S. , Webber James T. , McCarthy Elizabeth , Hu Junjie , Li Xiaolei , Che Li , Singh Ananya , Yoon Alex , Chan Gary K.L. , Kelley Robin K. , Swaney Danielle L. , Zhang Wei , Bandyopadhyay Sourav , Theis Fabian J. , Eckhardt Manon , Chen Xin , Shokat Kevan M. , Ideker Trey , Krogan Nevan J. , Gordan John D. 
Published: December 2024

Abstract
Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite a primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in hepatocellular carcinoma (HCC), suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. In this study, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in HCC. A subset of the host factors targeted by HBV proteins were preferentially mutated in non–HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2, which can prevent YAP degradation. mTOR complex 2–mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, providing an alternative paradigm for the cellular effects of a tumor-promoting virus.
Significance: Integrative proteomic and genomic analysis of HBV/host interactions illuminated modifiers of hepatocellular carcinoma behavior and key signaling mechanisms in advanced disease, which suggested that HBV may have therapeutically actionable effects.
Adenosine Uptake through the Nucleoside Transporter ENT1 Suppresses Antitumor Immunity and T-cell Pyrimidine Synthesis
Authors: Allard David , Cormery Jeanne , Bricha Salma , Fuselier Camille , Abbas Aghababazadeh Farnoosh , Giraud Lucie , Skora Emma , Haibe-Kains Benjamin , Stagg John 
Published: December 2024

Abstract
Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. Although adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T-cell–dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFNγ, IL2, TNFα, and CXCL10. ENT1 deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1 deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when cocultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase in activated T cells, thereby suppressing production of uridine 5′-monophosphate and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T-cell responses.
Significance: ENT1 is a potential therapeutic target to overcome immunosuppression induced by extracellular adenosine and to increase the activity of PD-1 blockade.
Imlunestrant Is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wild-Type and Mutant Breast Cancer
Authors: Bhagwat Shripad V. , Mur Cecilia , Vandekopple Matthew , Zhao Baohui , Shen Weihua , Marugán Carlos , Capen Andrew , Kindler Lisa , Stephens Jennifer R. , Huber Lysiane , Castanares Mark A. , Garcia-Tapia David , Cohen Jeff D. , Bastian Jolie , Mattioni Brian , Yuen Eunice , Baker Thomas K. , Rodriguez Cruz Vivian , Fei Dongling , Manro Jason R. , Pulliam Nicholas , Dowless Michele S. , Ortiz Ruiz Maria Jesus , Yu Chunping , Puca Loredana , Klippel Anke , Bacchion Francesca , Ismail-Khan Roohi , Rodrik-Outmezguine Vanessa , Peng Sheng-Bin , Lallena María Jose , Gong Xueqian , de Dios Alfonso 
Published: December 2024

Abstract
Targeting of the estrogen receptor (ER) by antiestrogens is the standard of care for patients with ER+ HER2− advanced/metastatic breast cancer. Although antiestrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective ER degrader. Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared with vehicle or alternative selective ER degrader therapies. Together, these findings support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1-WT and mutant breast cancer, including brain metastatic tumors.
Significance: Imlunestrant, a next-generation, brain-penetrant oral ERα degrader, displays potent activity in ESR1 wild-type and mutant breast cancer, enhances combination activity with standard-of-care agents, and inhibits growth of ER+ intracranial tumors.
Abstract A008: Evaluation of natural and synthetic compounds on epithelial to mesenchymal transition in triple negative breast cancer
Authors: Faruk Asef , Patel Saloni , Hallak Ramez , Flaherty Patrick , Cavanaugh Jane 
Published: December 2024

Abstract
Epithelial to mesenchymal transition (EMT) is a biological process through which epithelial cells undergo cytoskeletal changes and transform into a mesenchymal phenotype. This phenotypical transformation leads to enhanced migratory capabilities and increased resistance to apoptosis and drug therapies. The EMT characterized in part by an increase in vimentin, a mesenchymal marker, and a decrease in E-cadherin, an epithelial marker, plays a significant role in cancer metastasis and progression. The MEK5/ERK5 pathway is essential in regulating cell survival, proliferation, and migration. Inhibition of the MEK5/ERK5 pathway by small molecule inhibitors decreases cellular proliferation and impedes migration of cancer cells, including triple negative breast cancer (TNBCs) cells. A type III allosteric inhibitor of MEK5 designed by our collaborators reverses the EMT and induces a mesenchymal to epithelial transition (MET). Using a TNBC cell line, MDA-MB-231, genetically engineered with RFP tagged vimentin, we established a cellular assay to evaluate analogues of our lead type III inhibitor to further investigate the role of the MEK5-ERK pathway in the EMT, design optimal compounds that induce an MET, and explore structure-activity relationships for kinase inhibition. This research will help identify targets for EMT and optimize compound modification to improve potency and efficiency.
Citation Format: Asef Faruk, Saloni Patel, Ramez Hallak, Patrick Flaherty, Jane Cavanaugh. Evaluation of natural and synthetic compounds on epithelial to mesenchymal transition in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A008.
Abstract A013: Prioritization of Eleven-Nineteen-Leukemia (ENL) inhibitors as orally available drug candidates for acute myeloid leukemia
Authors: Liu Wenshe R. , Guo Xuejiao , Alta Sandeep , Xu Shiqing 
Published: December 2024

Abstract
Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on The YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified Inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent anti-proliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, Inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.
Citation Format: Wenshe R. Liu, Xuejiao Guo, Sandeep Alta, Shiqing Xu. Prioritization of Eleven-Nineteen-Leukemia (ENL) inhibitors as orally available drug candidates for acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A013
Abstract IA006: Progress, pitfalls and promise: the journey to effective and well tolerated DNA damage response inhibitor combinations in the clinic
Authors: Yap Timothy A. 
Published: December 2024

A mounting body of evidence now indicates that poly(ADP-ribose) polymerase (PARP) inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. There are multiple promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness". Despite promising efficacy data, several of the combinations have been hampered by supra-additive toxicities, restricting the combination of full monotherapy doses and schedules of component drugs. I will discuss the progress, pitfalls and promise of different classes of DNA damage response (DDR) inhibitor combinations in the clinic, and discuss potential clinical strategies to develop effective and well tolerated combinations to target PARP inhibitor resistance and to widen the application of DDR agents beyond approved indications
Citation Format: Timothy A. Progress, pitfalls and promise: the journey to effective and well tolerated DNA damage response inhibitor combinations in the clinic. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA006
Abstract IA009: An integrative approach to nanomedicine: Leveraging new tools to advance drug delivery
Authors: Boehnke Natalie 
Published: December 2024

Abstract
In the era of personalized cancer medicine, therapeutics are becoming increasingly complex, requiring advanced delivery systems, such as nanoparticles, to ensure their safety and efficacy. While current formulation strategies focus predominantly on drug loading, stability, and enhanced circulation, the role that nanoparticle composition plays in driving interactions with the biological environment to improve cell targeting and tumor accumulation remains an underexplored concept. Successful translation of drug delivery systems is additionally hampered by an incomplete understanding of how these parameters influence delivery outcomes in the context of biological heterogeneity. We have leveraged barcoded and pooled screening approaches to comprehensively gain new and fundamental insights into the material properties and biological features, and combinations thereof, that mediate successful delivery outcomes. The development of chemical barcoding strategies and pooled pan-cancer screens will be discussed along with how findings from these screens can be utilized to design simple yet effective targeted delivery systems for next-generation therapeutics.
Citation Format: Natalie Boehnke. An integrative approach to nanomedicine: Leveraging new tools to advance drug delivery [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA009.