tbuckley/cabot-search huggingface dataset:
Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes
Authors: Thierry Facon, Philippe Moreau, Katja Weisel, Hartmut Goldschmidt, Saad Z. Usmani, Ajai Chari, Torben Plesner, Robert Z. Orlowski, Nizar Bahlis, Supratik Basu, Cyrille Hulin, Hang Quach, Michael O’Dwyer, Aurore Perrot, Caroline Jacquet, Christopher P. Venner, Noopur Raje, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, Gordon Cook, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K. Kumar
Journal: Leukemia (2025)

Abstract In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (&lt;70, ≥70 to &lt;75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45–0.67; P &lt; 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P &lt; 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, &gt;5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.
Neoadjuvant cabozantinib for locally advanced nonmetastatic clear cell renal cell carcinoma: a phase 2 trial
Authors: Mehmet A Bilen, BaoHan T Vo, Yuan Liu, Rachel Greenwald, Amir H Davarpanah, Donald McGuire, Rakesh Shiradkar, Liping Li, Adhishek Midya, Bassel Nazha, Jacqueline T Brown, Sierra Williams, Wilena Session, Greta Russler, Sarah Caulfield, Shreyas S Joshi, Vikram M Narayan, Christopher P Filson, Kenneth Ogan, Omer Kucuk, Bradley Curtis Carthon, Luke Del Balzo, Athena Cohen, Adriana Boyanton, Nataliya Prokhnevska, Maria Andrea Cardenas, Ewelina Sobierajska, Caroline S Jansen, Dattatraya H Patil, Edouard Nicaise, Adeboye O Osunkoya, Haydn T Kissick, Viraj A Master
Journal: Nature Cancer (2025)
Targeting osteoclasts for treatment of high-risk B-cell acute lymphoblastic leukemia
Authors: Rishi S. Kotecha, Sarah M. Trinder, Anastasia M. Hughes, Benjamin H. Mullin, Sarah Rashid, Jinbo Yuan, Jiake Xu, Owen Duncan, Patrycja Skut, Grace-Alyssa Chua, Sajla Singh, Joyce Oommen, Richard B. Lock, Ursula R. Kees, Sebastien Malinge, Vincent Kuek, Laurence C. Cheung
Journal: Blood Cancer Journal (2025)
Cerebrospinal fluid circulating tumor DNA profiling for risk stratification and matched treatment of central nervous system metastases
Authors: Mei-Mei Zheng, Qing Zhou, Hua-Jun Chen, Ben-Yuan Jiang, Li-Bo Tang, Guang-Ling Jie, Hai-Yan Tu, Kai Yin, Hao Sun, Si-Yang Liu, Jia-Tao Zhang, Fa-Man Xiao, Jin-Ji Yang, Xu-Chao Zhang, Wen-Zhao Zhong, Yi Pan, Bin-Chao Wang, Hong-Hong Yan, Wei-Bang Guo, Zhi-Hong Chen, Zhen Wang, Chong-Rui Xu, Su-Yun Li, Si-Yang Maggie Liu, Lu Zeng, Shang-Li Cai, Guo-Qiang Wang, Dong-Qin Zhu, Yang-Si Li, Yi-Long Wu
Journal: Nature Medicine (2025)
Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases
Authors: Somnath Tagore, Lindsay Caprio, Amit Dipak Amin, Kresimir Bestak, Karan Luthria, Edridge D'Souza, Irving Barrera, Johannes C Melms, Sharon Wu, Sinan Abuzaid, Yiping Wang, Viktoria Jakubikova, Peter Koch, D Zack Brodtman, Banpreet Bawa, Sachin K Deshmukh, Leon Ebel, Miguel A Ibarra-Arellano, Abhinav Jaiswal, Carino Gurjao, Jana Biermann, Neha Shaikh, Priyanka Ramaradj, Yohanna Georgis, Galina G Lagos, Matthew I Ehrlich, Patricia Ho, Zachary H Walsh, Meri Rogava, Michelle Garlin Politis, Devanik Biswas, Azzurra Cottarelli, Nikhil Rizvi, Catherine A Shu, Benjamin Herzberg, Niroshana Anandasabapathy, George Sledge, Emmanuel Zorn, Peter Canoll, Jeffrey N Bruce, Naiyer A Rizvi, Alison M Taylor, Anjali Saqi, Hanina Hibshoosh, Gary K Schwartz, Brian S Henick, Fei Chen, Denis Schapiro, Parin Shah, Benjamin Izar
Journal: Nature Medicine (2025)
Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10-dependent Treg–microglia crosstalk
Authors: Saef Izzy, Taha Yahya, Omar Albastaki, Hadi Abou-El-Hassan, Michael Aronchik, Tian Cao, Marilia Garcia De Oliveira, Kuan-Jung Lu, Thais G. Moreira, Patrick da Silva, Masen L. Boucher, Leah C. Beauchamp, Danielle S. LeServe, Wesley Nogueira Brandao, Ana Carolina Durão, Toby Lanser, Federico Montini, Joon-Hyuk Lee, Joshua D. Bernstock, Megha Kaul, Gabriel Pasquarelli-do-Nascimento, Kusha Chopra, Rajesh Krishnan, Rebekah Mannix, Rafael M. Rezende, Francisco J. Quintana, Oleg Butovsky, Howard L. Weiner
Journal: Nature Neuroscience (2025)

Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (Treg cells) that migrated to the brain and closely contacted microglia. Treg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing Treg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury. Nasal anti-CD3 therapy shows promise for treating traumatic brain injury by reducing neuroinflammation and aiding recovery in mice. It induces interleukin-10-producing regulatory T cells that enhance microglial phagocytic activity and reduce chronic inflammation, potentially aiding brain repair.
No evidence of positive causal effects of maternal and paternal age at first birth on children’s test scores at age 10 years
Authors: Michael Grätz, Felix C. Tropf, Fartein Ask Torvik, Ole A. Andreassen, Torkild H. Lyngstad
Journal: Nature Human Behaviour (2025)

Abstract Research has shown that higher maternal and paternal age is positively associated with children’s education. Debate continues as to whether these relationships are causal. This is of great interest given the postponement of first births in almost all developed countries during the twentieth century. Here we use an instrumental variable approach (Mendelian randomization) using maternal and paternal polygenic indices (PGIs) for age at first birth—while conditioning on the child’s PGI for age at first birth—to identify the causal effects of maternal and paternal age at first birth on children’s test scores based on data from the Norwegian Mother, Father and Child Cohort study. We do not find evidence of positive causal effects of both maternal and paternal age at first birth on children’s test scores at age 10 years once the children’s PGI and correlations among different PGIs are controlled for. We therefore conclude that our results do not provide evidence in favour of sociological theories that predict positive causal effects of parental age on children’s educational attainment.
Prediction of individual treatment allocation between electroconvulsive therapy or ketamine using the Personalized Advantage Index
Authors: Benjamin S. C. Wade, Ryan Pindale, James Luccarelli, Shuang Li, Robert C. Meisner, Stephen J. Seiner, Joan A. Camprodon, Michael E. Henry
Journal: npj Digital Medicine (2025)

Electroconvulsive therapy (ECT) and ketamine are effective treatments for depression; however, evidence-based guidelines are needed to inform individual treatment selection. We adapted the Personalized Advantage Index (PAI) using machine learning to predict optimal treatment assignment to ECT or ketamine using EHR data on 2506 ECT and 196 ketamine patients. Depressive symptoms were evaluated using the Quick Inventory of Depressive Symptomatology (QIDS) before and during acute treatment. Propensity score matching across treatments was used to address confounding by indication, yielding a sample of 392 patients (n = 196 per treatment). Models predicted differential minimum QIDS scores (min-QIDS) over acute treatment using pretreatment EHR measures and SHAP values identified prescriptive predictors. Patients with large PAI scores who received a predicted optimal had significantly lower min-QIDS compared to the non-optimal treatment group (mean difference = 1.19 [95% CI: 0.32, ∞], t = 2.25, q < 0.05, d = 0.26). Our model identified candidate pretreatment factors to provide actionable, effective antidepressant treatment selection guidelines.
Multifunctional magneto-electric and exosome-loaded hydrogel enhances neuronal differentiation and immunoregulation through remote non-invasive electrical stimulation for neurological recovery after spinal cord injury
Authors: Wubo Liu, Qiang Liu, Zeqin Li, Chunjia Zhang, Zehui Li, Han Ke, Xin Xu, Xiaoxin Wang, Huayong Du, Zuliyaer Talifu, Yunzhu Pan, Xiaoxiong Wang, Jingyun Mao, Feng Gao, Degang Yang, Yan Yu, Xinyu Liu, Jianjun Li
Journal: Bioactive Materials (2025)
Inflammation-triggered Gli1+ stem cells engage with extracellular vesicles to prime aberrant neutrophils to exacerbate periodontal immunopathology
Authors: Xin-Yue Cai, Chen-Xi Zheng, Hao Guo, Si-Yuan Fan, Xiao-Yao Huang, Ji Chen, Jie-Xi Liu, Yu-Ru Gao, An-Qi Liu, Jia-Ning Liu, Xiao-Hui Zhang, Chao Ma, Hao Wang, Fei Fu, Peng Peng, Hao-Kun Xu, Bing-Dong Sui, Kun Xuan, Yan Jin
Journal: Cellular and Molecular Immunology (2025)
A scoping review of ethical aspects of public-private partnerships in digital health
Authors: Marieke A. R. Bak, Daan Horbach, Alena Buyx, Stuart McLennan
Journal: npj Digital Medicine (2025)

Abstract Partnerships between public and private organizations in digital health can promote more accessible, affordable, and high-quality care, but they also raise ethical and governance challenges. We searched PubMed, EMBASE, and Web of Science, identifying 46 studies examining ethical aspects of digital health public-private partnerships (PPPs). Three key themes emerged: data privacy and consent, ensuring public benefit and access, and good governance and demonstrating trustworthiness. We provide recommendations for each theme. To foster responsible innovation, we conclude that early and contextual operationalisation of ethics guidelines in PPPs is necessary to balance respect for fundamental values with the pursuit of impactful innovation. If PPPs become more successful as a result, this contributes to reducing the research waste of failed collaborations. Further research should clarify the scope of PPPs and definition of ‘public benefit’, and we call for critical study on the ‘economization’ of digital health promoted by public and private sector organizations.
Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells
Authors: Linda V. Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J. Langlands, Shalini Pathak, Andrew J. M. Howden, Ian G. Ganley, Doreen A. Cantrell
Journal: Nature Immunology (2025)

Abstract Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation.
Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood–brain barrier alterations
Authors: Katarzyna A. Dudek, Sam E. J. Paton, Luisa Bandeira Binder, Adeline Collignon, Laurence Dion-Albert, Alice Cadoret, Manon Lebel, Olivier Lavoie, Jonathan Bouchard, Fernanda Neutzling Kaufmann, Valerie Clavet-Fournier, Claudia Manca, Manuel Guzmán, Matthew Campbell, Gustavo Turecki, Naguib Mechawar, Nicolas Flamand, Flavie Lavoie-Cardinal, Cristoforo Silvestri, Vincenzo Di Marzo, Caroline Menard
Journal: Nature Neuroscience (2025)

Blood–brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB. The mechanisms of neurovascular adaptations underlying stress resilience remain unclear. Here the authors show that the astrocytic endocannabinoid system modulates the blood–brain barrier changes during stress in adult mice.
Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma
Authors: Georgina V. Long, Elena Shklovskaya, Laveniya Satgunaseelan, Yizhe Mao, Inês Pires da Silva, Kristen A. Perry, Russell J. Diefenbach, Tuba N. Gide, Brindha Shivalingam, Michael E. Buckland, Maria Gonzalez, Nicole Caixeiro, Ismael A. Vergara, Xinyu Bai, Robert V. Rawson, Edward Hsiao, Umaimainthan Palendira, Tri Giang Phan, Alexander M. Menzies, Matteo S. Carlino, Camelia Quek, Sean M. Grimmond, Joseph H. A. Vissers, Dannel Yeo, John E. J. Rasko, Mustafa Khasraw, Bart Neyns, David A. Reardon, David M. Ashley, Helen Wheeler, Michael Back, Richard A. Scolyer, James Drummond, James S. Wilmott, Helen Rizos
Journal: Nature Medicine (2025)

Abstract Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH - wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).
Integrative analysis reveals the multilateral inflammatory mechanisms of CD14 monocytes in gout
Authors: Ahmed Alaswad, Georgiana Cabău, Tania O Crişan, Liang Zhou, Martijn Zoodsma, Javier Botey-Bataller, Wenchao Li, Cristina Pamfil, Mihai G Netea, Tony Merriman, Cheng-Jian Xu, Yang Li, Leo A B Joosten
Journal: Annals of the Rheumatic Diseases (2025)

Gout, prevalent inflammatory arthritis caused by urate crystal deposition, involves immune cell activation, yet the precise role of CD14 monocytes in initiating the inflammatory response is poorly understood. This study aimed to characterise the molecular and cellular landscape of CD14 monocytes in gout using single-cell transcriptomic analysis. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells from 8 gout patients and 6 age- and sex-matched healthy controls. The findings were validated using publicly available datasets. Differential gene expression and pathway enrichment analyses were conducted to identify gout's key molecular regulators and cellular subclusters. At the molecular level, we identified hypoxia-related pathways, including HIF1A, as key regulators of interleukin-1β production in CD14 monocytes in gout. We also observed significant downregulation of CLEC12A across all CD14 monocyte subclusters. At the cellular level, an S100Ahigh CD14 monocyte subcluster, characterized by high expression of S100A8/A9/A12 and linked to inflammatory and metabolic pathways, was found to drive NLRP3 and CLEC7A inflammasome activation, as well as prostaglandin secretion. In vitro stimulation with monosodium urate crystals revealed that the differentially expressed genes were enriched in S100Ahigh monocytes, highlighting the synergistic role of these pathways in driving gout inflammation. Additionally, gout genome-wide association study-prioritised genes underscored the role of fatty acid metabolism in inflammation, promoting prostaglandin secretion from S100Ahigh monocytes. These findings provide new insights into the role of CD14 monocytes in gout pathogenesis, particularly the contribution of hypoxia and fatty acid metabolism pathways, and suggest potential therapeutic targets for precision medicine in gout treatment.
Three years is the minimal effective duration of sustained clinical remission which prevents impaired kidney function and damage accrual in lupus nephritis
Authors: Mariele Gatto, Giulia Frontini, Claudia Furlan, Marta Calatroni, Claudio Cruciani, Francesco Reggiani, Elisa Bellis, Luca Iaccarino, Renato Alberto Sinico, Gabriella Moroni, Andrea Doria
Journal: Annals of the Rheumatic Diseases (2025)

To assess the minimum effective duration of remission preventing damage accrual (Systemic Lupus International Collaborating Clinics damage index [SDI]) and impaired kidney function (IKF: estimated glomerular filtration rate of <60 mL/min/1.73 m2 for at least 3 months) in active lupus nephritis (LN). Patients with biopsy-proven LN followed up at least twice yearly were enrolled; clinical variables were collected regularly. Sustained clinical remission (sCR) was defined as estimated glomerular filtration rate of >60 mL/min/1.73 m2, proteinuria of <0.5 g/24 h and clinical systemic lupus erythematosus disease activity index of 0 for at least 1 year. Log-linear regression and a time-dependent Cox proportional hazard model were used to assess the minimum duration of sCR capable of preventing SDI increase and IKF development. In total, 293 patients with LN were included (median follow-up: 15.7 [10.4-22.9] years) of whom 84.3% achieved sCR lasting 8.7 (5.4-13.1) years. At last observation, the increase in SDI was higher in patients who never achieved sCR (median: 2 [1-2.5] vs 1 [0-1.5]; P < .001). A minimum duration of 3 years of sCR prevented SDI increase (% change = -41.1%; P = .003). The analysis on IKF involved only patients with the longest follow-up; 224 patients had ≥10 years of observation. Among them, 50 (22.3%) developed IKF. A minimum duration of 3 years of sCR prevented IKF (hazard ratio = 0.10; P < .001). IKF-free survival rate at 10, 20, and 25 years was 87%, 68%, and 40% for patients who never achieved sCR and 99%, 96%, and 91% for patients with at least 3 years of sCR, respectively (P < .001). Three years is the minimum duration of sCR protecting against development of IKF and damage accrual in patients with LN.
CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis
Authors: Xue Yang, Li Cheng, Ye Xin, Jianxiang Zhang, Xinfeng Chen, Jinchao Xu, Mengli Zhang, Ruopeng Feng, Judith Hyle, Wenjie Qi, Wojciech Rosikiewicz, Beisi Xu, Chunliang Li, Peng Xu
Journal: Genome biology (2025)

Abstract Background CTCF is considered as the most essential transcription factor regulating chromatin architecture and gene expression. However, genome-wide impact of CTCF on erythropoiesis has not been extensively investigated. Results Using a state-of-the-art human erythroid progenitor cell model (HUDEP-2 and HEL cell lines), we systematically investigate the effects of acute CTCF loss by an auxin-inducible degron system on transcriptional programs, chromatin accessibility, CTCF genome occupancy, and genome architecture. By integrating multi-omics datasets, we reveal that acute CTCF loss notably disrupts genome-wide chromatin accessibility and the transcription network. We detect over thousands of decreased chromatin accessibility regions but only a few hundred increased regions after CTCF depletion in HUDEP-2 and HEL lines, suggesting the role of CTCF in maintaining proper chromatin openness in the erythroid lineage. CTCF depletion in the erythroid context notably disrupts the boundary integrity of topologically associating domains and chromatin loops but does not affect nuclear compartmentalization. We find erythroid lineage-specific genes, including some metabolism-related genes, are suppressed at immature and mature stages. Notably, we find a subset of genes whose transcriptional levels increase upon CTCF depletion, accompanied by decreased chromatin accessibility regions enriched with the GATA motif. We further decipher the molecular mechanism underlying the CTCF/GATA2 repression axis through distal non-coding chromatin regions. These results suggest a suppressive role of CTCF in gene expression during erythroid lineage specification. Conclusions Our study reveals a novel role of CTCF in regulating erythroid differentiation by maintaining its proper chromatin openness and gene expression network, which extends our understanding of CTCF biology.