tbuckley/cabot-search huggingface dataset:
One for All and All for One: New Insights into Enhancers Driving <i>MYC</i> Dysregulation
Authors: Roger Mulet-Lazaro, Ruud Delwel
Journal: Blood Cancer Discovery (2025)

Summary: The role of the proto-oncogene MYC as a driver of lymphoma has been known since the 1980s, but the mechanisms underlying its dysregulation are not completely understood. In this issue of Blood Cancer Discovery, Iyer and colleagues employ a CRISPR interference screen targeted at open chromatin regions to unveil enhancers critical for MYC overexpression in lymphoma, including a novel regulatory element in the MYC locus that controls germinal center reentry and is recurrently amplified in diffuse large B-cell lymphomas (germinal center B-cell diffuse large B-cell lymphoma). See related article by Iyer et al., p. XX
Author Correction: The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial
Authors: Lindsay B Kilburn, Dong-Anh Khuong-Quang, Jordan R Hansford, Daniel Landi, Jasper van der Lugt, Sarah E S Leary, Pablo Hernáiz Driever, Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J Waanders, David S Ziegler, Olaf Witt, Patricia A Baxter, Hyoung Jin Kang, Timothy E Hassall, Jung Woo Han, Darren Hargrave, Andrea T Franson, Michal Yalon Oren, Helen Toledano, Valérie Larouche, Cassie Kline, Mohamed S Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicolas U Gerber, Nicholas S Whipple, Devorah Segal, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley Walter, Daniel Da Costa, Peter Manley, Samuel C Blackman, Roger J Packer, Karsten Nysom
Journal: Nature Medicine (2025)
<i>FOXR2</i> activation is not exclusive of CNS neuroblastoma
Authors: Alexa N Siskar, Emily Hanzlik, Maria F Cardenas, Mohammad K Eldomery, Soniya Pinto, Christopher L Tinkle, Qunyu Zhang, Xiaoyu Li, Tong Lin, Sandeep K Dhanda, Gerald Reis, Daphne Li, Ravi Raghavan, Alexander Vortmeyer, Matthias A Karajannis, Giles W Robinson, Arzu Onar-Thomas, Patrick R Blackburn, David A Wheeler, Jason Chiang
Journal: Neuro-Oncology (2025)

Abstract Background FOXR2 activation is regarded as pathognomonic for CNS neuroblastoma (NB). However, a comprehensive understanding of the landscape for CNS tumors exhibiting FOXR2 activation is lacking. Methods Histopathologic, molecular, imaging, and clinical data of 42 CNS tumors with FOXR2 overexpression identified through screening institutional datasets and published institutional cases were analyzed. Results Among the 42 tumors, 21 (50.0%) were high-grade gliomas (HGGs), and 18 (42.9%) were embryonal tumors. The HGGs included ten H3 K27M-mutant diffuse midline gliomas (DMGs) and eight radiation-associated tumors. The embryonal tumors included 11 CNS NBs and six pineoblastomas (PBs). FOXR2 expression was similar between CNS NB and other tumor types (P = 0.82). HGGs with FOXR2 overexpression, unlike NBs and PBs, displayed diverse concomitant genetic alterations. The most common mechanisms of FOXR2 activation involved structural alterations causing promoter donation and enhancer hijacking from active genes essential for brain development, followed by alternative promoter activation or truncated LINE-1 retrotransposition. The preferential activation mechanism varied by tumor type. All but two aberrant FOXR2 transcripts incorporated non-canonical, non-coding exons. Gene set enrichment analysis demonstrated shared downstream effects of FOXR2 activation at the epigenome and transcriptome levels across tumor types. DMGs and PBs with FOXR2 overexpression were aggressive, with 0% 2-year overall survival, whereas CNS NBs responded well to combined chemotherapy and radiation. Conclusions CNS tumors with FOXR2 overexpression manifest significant histological, molecular, imaging, and clinical diversity. While HGGs and PBs with FOXR2 overexpression demonstrated inferior prognosis, CNS NBs showed favorable outcomes. Integrating histologic and molecular diagnostic approaches is imperative for accurate prognostication and optimal therapeutic decision-making.
Author Correction: Odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma: primary efficacy and safety analysis in phase 2 ELM-2 trial
Authors: Won Seog Kim, Tae Min Kim, Seok-Goo Cho, Isidro Jarque, Elżbieta Iskierka-Jażdżewska, Li Mei Poon, H Miles Prince, Huilai Zhang, Junning Cao, Mingzhi Zhang, Benoît Tessoulin, Sung Yong Oh, Francesca Lim, Cecilia Carpio, Tran-Der Tan, Sabarish Ayyappan, Antonio Gutierrez, Jingxian Cai, Melanie Ufkin, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Jan Walewski
Journal: Nature Cancer (2025)
Exclusive breastfeeding is associated with the gut microbiome maturation in infants according to delivery mode
Authors: Nathalia F. Naspolini, Paulo A. Schüroff, Pedro A. R. Vanzele, Davi Pereira-Santos, Tamires Amabili Valim, Kevin S. Bonham, André Fujita, Maria Rita Passos-Bueno, Patricia C. B. Beltrão-Braga, André C. P. L. F. Carvalho, Vanja Klepac-Ceraj, Guilherme V. Polanczyk, Alline C. Campos, Carla R. Taddei
Journal: Gut Microbes (2025)

Exclusive breastfeeding (EBF) plays a crucial role in infant gut microbiome assembly and development. However, few studies have investigated the effects of EBF in restoring a perturbed microbiome. In this study, we applied whole metagenomic sequencing to assess the gut microbiome assembly in 525 Brazilian infants from 3 to 9 months of age of the Germina Cohort, demonstrating the early determinants of microbial taxonomy and function modulation. Our analysis shows that EBF alters the relative abundance of genes related to the microbiome taxonomy and function, with effects varying by delivery mode. EBF alters the pattern of carbohydrates, lipid metabolism, and cell structure pathways depending on the delivery mode. The microbiome age is closer to chronological infant age in EBF than in non-EBF infants, meaning a lower microbiome maturation index (MMI). Using a complementary machine learning approach, we show that Escherichia coli, Ruminococcus gnavus, and Clostridium neonatale, as well as vitamin K and o-antigen pathways contribute strongly to EBF prediction. Moreover, EBF influences the microbiome maturation in early life, toward a microbiome age more similar to the chronological infant's age.
Response to the correspondence by Wendling et al on ‘ASAS consensus-based expert definition of difficult-to-manage, including treatment-refractory, axial spondyloarthritis’
Authors: Denis Poddubnyy, Xenofon Baraliakos, Victoria Navarro-Compán, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2025)
Organoid‐Like Neurovascular Spheroids Promote the Recovery of Hypoxic‐Ischemic Skin Flaps Through the Activation of Autophagy
Authors: Junjin Jie, Jingyi Ju, Zhenxing Wang, Jun Chen, Lin‐Ping Wu, Jiaming Sun
Journal: Advanced Healthcare Materials (2025)

Abstract Crosstalk between nerves and blood vessels plays a crucial role in flap development, injury repair, and homeostasis maintenance. However, in most flap transplantation strategies, the interactions between nerves and blood vessels have been ignored, leading to unsatisfactory repair effects. In this study, highly sprouting organoid‐like neurovascular spheroids (NVUs) with P34HB porous microsphere cores embedding in a supportive microenvironment of Gelatin Methacryloyl hydrogel are developed. Cell‐laden porous microspheres successfully recapitulated neurovascular coupling by providing a biomimetic extracellular microenvironment for neural and vascular cells at an in vivo cell density. The results demonstrated that neurovascular spheres formed complex vascular plexuses and secreted extracellular matrix, improving in vivo regeneration of skin flap. Autophagy activation regulated by nerves is detected along with the assembly of vascular networks, suggesting its role in neovascularization. By incorporating fibroblasts, highly biomimetic organoid‐like models composed of dermis, vasculature, and innervation are facilely developed to mimic dermal tissues. This stable and highly reproducible in vitro model can be utilized for organ repair and mechanistic exploration.
Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer
Authors: Rafael Blanco-Domínguez, Leandro Barros, Mariana Carreira, Manon van der Ploeg, Carolina Condeço, Gabriel Marsères, Cristina Ferreira, Carla Costa, Carlos M Ferreira, Julie Déchanet-Merville, Noel F C C de Miranda, Sofia Mensurado, Bruno Silva-Santos
Journal: Nature Cancer (2025)
Pan-genome analysis reveals the evolution and diversity of Malus
Authors: Wei Li, Chong Chu, Taikui Zhang, Haochen Sun, Shiyao Wang, Zeyuan Liu, Zijun Wang, Hui Li, Yuqi Li, Xingtan Zhang, Zhiqiang Geng, Youqing Wang, Yi Li, Hengtao Zhang, Weishu Fan, Yi Wang, Xuefeng Xu, Lailiang Cheng, Dehui Zhang, Yao Xiong, Huixia Li, Bowen Zhou, Qingmei Guan, Cecilia H Deng, Yongming Han, Hong Ma, Zhenhai Han
Journal: Nature Genetics (2025)
Bayesian multi-study non-negative matrix factorization for mutational signatures
Authors: Isabella N Grabski, Lorenzo Trippa, Giovanni Parmigiani
Journal: Genome biology (2025)

Mutational signatures are typically identified from tumor genome sequencing data using non-negative matrix factorization (NMF). However, existing NMF techniques only decompose a single dataset, limiting rigorous comparisons of signatures across conditions. We propose a Bayesian NMF method that jointly decomposes multiple datasets to identify signatures and their sharing pattern across conditions. We propose a fully unsupervised "discovery-only" model and a semi-supervised "recovery-discovery" model that simultaneously estimates known and novel signatures, and extend both to estimate covariate effects. We demonstrate our approach on extensive simulations, and apply our method to answer questions related to colorectal cancer and early-onset breast cancer.
Prevalence and Clinical Impact of BRAF p.V600E Mutation in Papillary Thyroid Carcinoma
Authors: Alexandria Brumfield, Sara Abou Azar, Rachel Nordgren, Ronald N Cohen, David Sarne, Xavier M Keutgen, Megan Applewhite, Peter Angelos, Nicole A Cipriani
Journal: Endocrine Pathology (2025)
GABA<sub>B</sub> Receptor: Structure, Biological Functions, and Therapy for Diseases
Authors: Weijie Xie, Yuan Li, Xinyue Wang, Elena Blokhina, Evgeny Krupitsky, Marina Vetrova, Ji Hu, Ti‐Fei Yuan, Jue Chen, Hua Wang, Xiangfang Chen
Journal: MedComm (2025)

ABSTRACT Gamma‐aminobutyric acid (GABA) B receptors (GABA B Rs) that acts slowly and maintains the inhibitory tone are versatile regulators in the complex nervous behaviors and their involvement in various neuropsychiatric disorders, such as anxiety, epilepsy, pain, drug addiction, and Alzheimer's disease. Additional study advances have implied the crucial roles of GABA B Rs in regulating feeding‐related behaviors, yet their therapeutic potential in addressing the neuropsychiatric disorders, binge eating, and feeding‐related disorders remains underutilized. This general review summarized the physiological structure and functions of GABA B R, explored the regulation in various psychiatric disorders, feeding behaviors, binge eating, and metabolism disorders, and fully discussed the potential of targeting GABA B Rs and its regulator‐binding sites for the treatment of different psychiatric disorders, binge eating and even obesity. While agonists that directly bind to GABA B R1 have some negative side effects, positive allosteric modulators (PAMs) that bind to GABA B R2 demonstrate excellent therapeutic efficacy and tolerability and have better safety and therapeutic indexes. Moreover, phosphorylation sites of downstream GABA B Rs regulators may be novel therapeutic targets for psychiatric disorders, binge eating, and obesity. Further studies, clinical trials in particular, will be essential for confirming the therapeutic value of PAMs and other agents targeting the GABA B R pathways in a clinical setting.
Sex-biased admixture followed by isolation and adaptive evolution shaped the genomic and blood pressure diversity of the LopNur people
Authors: Jia Wen, Hao Chen, Yuwen Pan, Yuhan Yang, Dolikun Mamatyusupu, Dilinuer Maimaitiyiming, Shuhua Xu
Journal: Molecular Biology and Evolution (2025)

Abstract The LopNur people are an ethnic group living on the edge of the Taklamakan Desert, and they are believed to demonstrate a unique genetic makeup due to their isolation and limited contact with neighboring populations. However, a lack of genetic studies on the LopNur people has resulted in limited knowledge about their ancestral origins and demographic history. Here, we conducted the first whole-genome sequencing study of 164 LopNur individuals (LOP) to gain insight into their genetic history and adaptive evolution in an isolated desert area. Our analysis revealed that the present-day LOP have experienced a complex history of admixture followed by long-term isolation, with their ancestry derived from East Asia (∼41.46%), West Eurasia (∼26.43%), Siberia (∼24.27%), and South Asia (∼7.82%). Notably, a remarkable sex-biased admixture occurred between Western males and Eastern females. In addition to complex admixture followed by long-term geographic isolation and further recent migrations, adaptive evolution jointly formed the gene pool and phenotypic diversity of the present-day LOP. Intriguingly, our analysis suggests that the USP35-GAB2 region may be correlated with blood pressure in LOP, based on a joint analysis of genomics and blood pressure data. Moreover, we identified two variants, rs7387065, and rs2229437, located on CSMD1 and PRCP, respectively. These variants exhibited frequency differences between Asian and European populations and were reported to be associated with antihypertensive drug absorption. Our results provide new insight into the complex history of the LOP, an admixed and isolated ethnic group residing at the crossroads of East and West, a case with ancient admixture, long-term isolation, adaptive evolution, and sex-biased gene flow.
Pan-genome analysis reveals local adaptation to climate driven by introgression in oak species
Authors: Yi-Ye Liang, Hui Liu, Qiong-Qiong Lin, Yong Shi, Biao-Feng Zhou, Jing-Shu Wang, Xue-Yan Chen, Zhao Shen, Liang-Jing Qiao, Jing-Wei Niu, Shao-Jun Ling, Wen-Ji Luo, Wei Zhao, Jian-Feng Liu, Yuan-Wen Kuang, Pär K Ingvarsson, Ya-Long Guo, Baosheng Wang
Journal: Molecular Biology and Evolution (2025)

Abstract The genetic base of local adaptation has been extensively studied in natural populations. However, a comprehensive genome-wide perspective on the contribution of structural variants (SVs) and adaptive introgression to local adaptation remains limited. In this study, we performed de novo assembly and annotation of 22 representative accessions of Quercus variabilis, identifying a total of 543,372 SVs. These SVs play crucial roles in shaping genomic structure and influencing gene expression. By analysing range-wide genomic data, we identified both SNPs and SVs associated with local adaptation in Q. variabilis and Q. acutissima. Notably, SV-outliers exhibit selection signals that did not overlap with SNP-outliers, indicating that SNP-based analyses may not detect the same candidate genes associated with SV-outliers. Remarkably, 29−37% of candidate SNPs were located in a 250 kb region on chromosome 9, referred to as Chr9-ERF. This region contains eight duplicated ethylene-responsive factor (ERF) genes, which may have contributed to local adaptation of Q. variabilis and Q. acutissima. We also found that a considerable number of candidate SNPs were shared between Q. variabilis and Q. acutissima in the Chr9-ERF region, suggesting a pattern of repeated selection. We further demonstrated that advantageous variants in this region were introgressed from western populations of Q. acutissima into Q. variabilis, providing compelling evidence that introgression facilitates local adaptation. This study offers a valuable genomic resource for future studies on oak species and highlights the importance of pan-genome analysis in understating mechanism driving adaptation and evolution.
Endothelial cell supplementation promotes xenograft revascularization during short-term ovarian tissue transplantation
Authors: Mariagiulia Spazzapan, Silvia Pegoraro, Roman Vuerich, Gabriella Zito, Andrea Balduit, Elena Longo, Lorella Pascolo, Miriam Toffoli, Giorgia Meshini, Alessandro Mangogna, Gloria Ros, Francesca Buonomo, Federico Romano, Letizia Lombardelli, Giovanni Papa, Marie-Pierre Piccinni, Serena Zacchigna, Chiara Agostinis, Roberta Bulla, Giuseppe Ricci
Journal: Bioactive Materials (2025)
ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer
Authors: Hibiki Umeda, Kunitoshi Shigeyasu, Toshiaki Takahashi, Kazuya Moriwake, Yoshitaka Kondo, Kazuhiro Yoshida, Sho Takeda, Shuya Yano, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Hideki Yamamoto, Kosei Takagi, Masashi Kayano, Hiroyuki Michiue, Keiichiro Nakamura, Yoshiko Mori, Fuminori Teraishi, Hiroshi Tazawa, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara
Journal: Molecular Cancer (2025)

Colorectal cancer (CRC) is considered the third most common type of cancer worldwide. Tumor-associated macrophages (TAMs) have been shown to promote drug resistance. Adenosine-to-inosine RNA-editing, as regulated by adenosine deaminase acting on RNA (ADAR), is a process that induces the posttranscriptional modification of critical oncogenes. The aim of this study is to determine whether the signals from cancer cells would induce RNA-editing in macrophages. The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models. The intensity of the RNA-editing enzyme ADAR1 (Adenosine deaminase acting on RNA 1) in cancer and mononuclear cells indicated a strong positive correlation between the nucleus and cytoplasm. The ADAR1-positive mononuclear cells were positive for CD68 and CD163, a marker for M2 macrophages. Cancer cells transport pro-inflammatory cytokines or ADAR1 protein directly to macrophages via the exosomes, promoting RNA-editing in AZIN1 (Antizyme Inhibitor 1) and GLI1 (Glioma-Associated Oncogene Homolog 1) and resulting in M2 macrophage polarization. GLI1 RNA-editing in the macrophages induced by cancer cells promotes the secretion of SPP1, which is supplied to the cancer cells. This activates the NFκB pathway in cancer cells, promoting oxaliplatin resistance. When the JAK inhibitors were administered, oncogenic RNA-editing in the macrophages was suppressed. This altered the macrophage polarization from M2 to M1 and decreased oxaliplatin resistance in cancer cells. This study revealed that ADAR1-high TAMs are crucial in regulating drug resistance in CRC and that targeting ADAR1 in TAMs could be a promising treatment approach for overcoming drug resistance in CRC.
Precision risk stratification of primary gastric cancer after eradication of<i>H. pylori</i>by a DNA methylation marker: a multicentre prospective study
Authors: Harumi Yamada, Seiichiro Abe, Hadrien Charvat, Takayuki Ando, Masahiro Maeda, Kazunari Murakami, Shiro Oka, Takao Maekita, Mitsushige Sugimoto, Takahisa Furuta, Mitsuru Kaise, Nobutake Yamamichi, Hiroyuki Takamaru, Akiko Sasaki, Ichiro Oda, Sohachi Nanjo, Nobuhiro Suzuki, Toshiro Sugiyama, Masaaki Kodama, Kazuhiro Mizukami, Masanori Ito, Takahiro Kotachi, Taichi Shimazu, Seiichiro Yamamoto, Toshikazu Ushijima
Journal: Gut (2025)

Background Precision cancer risk stratification for gastric cancer is urgently needed for the growing number of healthy people after Helicobacter pylori eradication. The epimutation burden in non-malignant tissues has been associated with cancer risk in multiple cross-sectional studies. Objective To confirm the clinical usefulness of a DNA methylation marker for epimutation burden, and to identify a cut-off methylation level for a super-high-risk population. Design Healthy people after H. pylori eradication with open-type atrophy were prospectively recruited. DNA methylation levels of a marker gene, RIMS1 , were measured in biopsy specimens from gastric antrum and body. The primary endpoint was the incidence rate of gastric cancer in quartiles of the methylation levels. Results 1624 participants had at least one endoscopic follow-up with a median follow-up of 4.05 years, and a primary gastric cancer developed in 27 participants. The highest quartile of RIMS1 methylation levels had a higher incidence rate (972.8 per 100 000 person-years) than the lowest quartile (127.1). Cox regression analysis revealed a univariate HR of 7.7 (95% CI 1.8–33.7) and an age- and sex-adjusted HR of 5.7 (95% CI 1.3–25.5). As a secondary objective, a cut-off methylation level of 25.7% (95% CI 1.7–7.7) was obtained to identify a population with a super-high risk based on the number needed to screen of 1000. Conclusion A DNA methylation marker can risk-stratify healthy people after H. pylori eradication even though all of them have clinically high risk. Individuals with super-high risk will need more frequent gastric cancer screening than currently recommended. Trial registration number UMIN-CTR000016894.
Integrative Multiomics Profiling of Mouse Hippocampus Reveals Transcriptional Upregulation of Interferon‐Stimulated Genes Through PU.1 Regulator in Microglial Activation Induced by Chronic Cerebral Hypoperfusion
Authors: Zengyu Zhang, Dewen Ru, Zhuohang Liu, Zimin Guo, Lei Zhu, Yuan Zhang, Min Chu, Yong Wang, Jing Zhao
Journal: MedComm (2025)

ABSTRACT Chronic cerebral hypoperfusion (CCH) is a significant factor that accelerates cognitive deterioration, yet the mechanisms of hippocampal microglial activation in this context remain unclear. Using an integrative multiomics approach, we investigated the transcriptional and epigenomic landscape of microglial activation in a mouse model of CCH induced by bilateral common carotid artery stenosis. Behavioral assessments revealed cognitive impairments, while neuropathological analysis confirmed hippocampal damage. Proteomic and transcriptomic profiling uncovered significant upregulation of stress and inflammatory pathways, particularly the interferon (IFN) signaling cascade. Epigenomic analysis identified regions of open chromatin, suggesting active transcriptional regulation driven by the transcription factor (TF) PU.1. ChIP‐nexus analysis further confirmed that PU.1 directly modulates the expression of IFN‐stimulated genes (ISGs), which are pivotal in regulating microglial activation. Our findings demonstrate that PU.1 serves as a key regulator of the IFN‐driven microglial response during CCH, mediated by enhanced chromatin accessibility and transcriptional activation of ISGs. This study highlights the critical role of PU.1 in microglial‐mediated neuroinflammation and offers potential therapeutic targets for mitigating hippocampal damage associated with chronic cerebral ischemia.
Correction: Targeting SOST using a small‑molecule compound retards breast cancer bone metastasis
Authors: Lisha Sun, Yixiao Zhang, Guanglei Chen, Yaoting Ji, Qingtian Ma, Xinbo Qiao, Sijin Wu, Lin Zhou, Jiawen Bu, Xudong Zhu, Xiaoying Zhang, Xiaofan Jiang, Chao Liu, Xinnan Li, Yang Liu, Yongliang Yang, Caigang Liu
Journal: Molecular Cancer (2025)