tbuckley/cabot-search huggingface dataset:
Ultrasensitive Detection and Monitoring of Circulating Tumor DNA using Structural Variants in Early-Stage Breast Cancer
Authors: Mitchell J. Elliott, Karen Howarth, Sasha Main, Jesús Fuentes Antrás, Philippe Echelard, Aaron Dou, Eitan Amir, Michelle B. Nadler, Elizabeth Shah, Celeste Yu, Scott Bratman, Taylor Bird, June Roh, Elza C. de Bruin, Christopher Rushton, Sofia Birkeälv, Miguel Alcaide, Lucia Oton, Girish Putcha, Samuel Woodhouse, Philippe L. Bedard, Lillian L. Siu, Hal K. Berman, David W. Cescon
Journal: Clinical Cancer Research (2025)

Abstract Purpose: The detection of circulating tumor DNA (ctDNA) after curative-intent therapy in early breast cancer (EBC) is highly prognostic of disease recurrence. Current ctDNA assays, mainly targeting single nucleotide variants (SNVs), vary in sensitivity and specificity. While increasing the number of SNVs in tumor-informed assays improves sensitivity, structural variants (SVs) may achieve similar or better sensitivity without compromising specificity. SVs occur across all cancers, linked to genomic instability and tumorigenesis, with unique tumor- and patient-specific breakpoints occurring throughout the genome. SVs in breast cancer are underexplored, and their potential for ctDNA detection and monitoring has not been fully evaluated. Experimental Design: We retrospectively analyzed a tumor-informed SV-based ctDNA assay in a cohort of EBC patients (n=100, 568 timepoints) receiving neoadjuvant systemic therapy (NAT), evaluating ctDNA dynamics and lead times to clinical recurrence in the postoperative period. Results: ctDNA was detected in 96% (91/95) of participants at baseline with a median variant allele frequency (VAF) of 0.15% (range: 0.0011–38.7%); 10% (9/91) had a VAF&amp;lt;0.01%. ctDNA detection at cycle 2 (C2) of NAT was associated with a higher likelihood of distant recurrence (Log-rank p=0.047) and enhanced residual cancer burden (RCB) prognostication (Log-rank p=0.041). ctDNA was detected prior to distant recurrence in all cases (100% sensitivity) with a median lead time of 417 days (range: 4–1931 days). Conclusion: These results demonstrate the clinical validity of ultrasensitive ctDNA detection and monitoring using SVs. Prospective trials are required to evaluate ctDNA-guided treatment strategies.
The microbiota-derived bile acid taurodeoxycholic acid improves hepatic cholesterol levels in mice with cancer cachexia
Authors: Morgane M. Thibaut, Martin Roumain, Edwige Piron, Justine Gillard, Axelle Loriot, Audrey M. Neyrinck, Julie Rodriguez, Isabelle Massart, Jean-Paul Thissen, Joshua R. Huot, Fabrizio Pin, Andrea Bonetto, Nathalie M. Delzenne, Giulio G. Muccioli, Laure B. Bindels
Journal: Gut Microbes (2025)

Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA). This reduction in hepatic TDCA occurred before the appearance of cachexia. Longitudinal analysis of the gut microbiota pinpointed an ASV, identified as Xylanibacter rodentium, as a bacterium potentially involved in the reduced production of TDCA. Coherently, stable isotope-based experiments highlighted a robust decrease in the microbial 7α-dehydroxylation (7α-DH) activity with no changes in the bile salt hydrolase (BSH) activity in cachectic mice. This approach also highlighted a reduced microbial 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 12α-hydroxysteroid dehydrogenase (12α-HSDH) activities in these mice. The contribution of the lower production of TDCA to cancer cachexia was explored in vitro and in vivo. In vitro, TDCA prevented myotube atrophy, whereas in vivo hepatic whole transcriptome analysis revealed that TDCA administration to cachectic mice improved the unfolded protein response and cholesterol homeostasis pathways. Coherently, TDCA administration reversed hepatic cholesterol accumulation in these mice. Altogether, this work highlights the contribution of the gut microbiota to bile acid dysmetabolism and the therapeutic interest of the secondary bile acid TDCA for hepatic cholesterol homeostasis in the context of cancer cachexia. Such discovery may prove instrumental in the understanding of other metabolic diseases characterized by microbial dysbiosis. More broadly, our work demonstrates the interest and relevance of microbial activity measurements using stable isotopes, an approach currently underused in the microbiome field.
Tumor Suppressor Gene Zygosity Can Predict Therapeutic Response in Cancer
Journal: Cancer Discovery (2025)

Main Findings: Assessing selection for biallelic loss of tumor suppressor genes (TSG) reveals TSG zygosity as an important feature of cancer etiology.Approach: An allele-specific analysis of somatic TSG alterations was performed on tumors of 67 cancer types from over 48,000 patients.Impact: This study sheds light on mechanisms of TSG inactivation and proposes TSG zygosity as a predictive biomarker of response.
A phase I clinical trial of intrahepatic artery delivery of TG6002 in combination with oral 5-fluorocytosine in patients with liver-dominant metastatic colorectal cancer
Authors: Emma J. West, Alain Sadoun, Kaidre Bendjama, Philippe Erbs, Cristina Smolenschi, Philippe A. Cassier, Thierry de Baere, Sophie Sainte-Croix, Maud Brandely, Alan A. Melcher, Fay Ismail, Karen J. Scott, Angela Bennett, Emma Banks, Ewa Gasior, Sarah Kent, Marta Kurzawa, Christopher Hammond, Jai V. Patel, Fiona J. Collinson, Chris Twelves, D. Alan. Anthoney, Dan Swinson, Adel Samson
Journal: Clinical Cancer Research (2025)

Abstract Background: Effective treatment for patients with metastatic cancer is limited, particularly for colorectal cancer patients with metastatic liver lesions (mCRC), where accessibility to numerous tumours is essential for favourable clinical outcomes. Oncolytic viruses (OVs) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoural administration routes. Methods: We conducted a multi-centre, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral pro-drug 5-fluorocytosine to fifteen mCRC patients. Results: Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by virus within tumour biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumour, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially-expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer- and neo-antigens, with elevated functional activity, may be associated with improved anti-cancer activity. Despite these findings, no clinical efficacy was observed. Conclusions: In summary, these data demonstrate delivery of OV to tumour via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data supports the need for future studies using IHA administration of OVs.
KL-50: A Novel Therapeutic Agent Targeting <i>MGMT</i>-Deficient Glioblastoma
Authors: Kenan Zhang, Mehdi Touat, Mustafa Khasraw
Journal: Neuro-Oncology (2025)

Journal Article Accepted manuscript KL-50: A Novel Therapeutic Agent Targeting MGMT-Deficient Glioblastoma Get access Kenan Zhang, Kenan Zhang Duke University Medical Center, Duke University, Durham, NC, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Mehdi Touat, Mehdi Touat Neurooncology Departement, Pitié-Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France https://orcid.org/0000-0002-5910-7799 Search for other works by this author on: Oxford Academic PubMed Google Scholar Mustafa Khasraw Mustafa Khasraw Duke University Medical Center, Duke University, Durham, NC, USA Corresponding author: Mustafa Khasraw MD, Duke University Medical Center, Duke University, Box 3624, Durham, NC 27710, USA, Phone: +1 919.684.6173, Email: [email protected] https://orcid.org/0000-0003-3249-9849 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noaf001, https://doi.org/10.1093/neuonc/noaf001 Published: 08 January 2025 Article history Received: 17 December 2024 Published: 08 January 2025
Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis
Authors: Zachary Papadopoulos, Leon C.D. Smyth, Igor Smirnov, Daniel A. Gibson, Jasmin Herz, Jonathan Kipnis
Journal: The Journal of Experimental Medicine (2024)

Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping. Impaired dcLN drainage led to elevated CSF outflow resistance and delayed CSF-to-blood efflux despite the recruitment of the nasal-to-scLN pathway. Fluid regulation was better compensated after scLN obstruction. The dcLN pathway exhibited steady, consistent drainage across conditions, while the nasal-to-scLN pathway was dynamically activated to mitigate perturbances. These findings highlight the complex physiology of CSF homeostasis and lay the groundwork for future studies aimed at assessing and modulating CNS lymphatic function.
Phenotypic plasticity and increased infiltration of peripheral blood-derived TREM1+ mono-macrophages following radiotherapy in rectal cancer
Authors: Haihong Wang, Menglan Zhai, Mingjie Li, Chaoqun Han, Lichao Liu, Chuying Huang, Lei Zhao, Dandan Yu, Kaixiong Tao, Jinghua Ren, Zhenyu Lin, Tao Zhang
Journal: Cell Reports Medicine (2025)
Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth
Authors: Ohuod Hawsawi, Weinan Xue, Tingting Du, Mengqi Guo, Xiaolin Yu, Mingyi Zhang, Paul S Hoffman, Roni Bollag, Jun Li, Jia Zhou, Hongbo Wang, Junran Zhang, Zheng Fu, Xiaoguang Chen, Chunhong Yan
Journal: Cell Reports Medicine (2025)

Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis. Consequently, NTZ/TIZ induces S-phase kinase-associated protein 2 (SKP2)-mediated G1 arrest while impeding DNA synthesis, lipogenesis, and the growth of prostate cancer cells. The anti-cancer activity of TIZ correlates with its OXPHOS-uncoupling activity. NTZ/TIZ appears to inhibit ATP production, thereby activating the AMP-activated kinase (AMPK)-p38 pathway, leading to cyclin D1 degradation, Rb dephosphorylation, and subsequent E2F1 inhibition. Our results thus connect OXPHOS uncoupling to the inhibition of an essential oncogenic pathway, supporting repositioning NTZ and other mitochondrial uncouplers for prostate cancer therapy.
CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells
Authors: Linqin Wang, Yiyun Wang, Xiangjun He, Zhuomao Mo, Mengyu Zhao, Xinghua Liang, Kejia Hu, Kexin Wang, Yanan Yue, Guolong Mo, Yixuan Zhou, Ruimin Hong, Linghui Zhou, Youqin Feng, Nian Chen, Lihong Shen, Xiaobin Song, Wenxiu Zeng, Xiaofeng Jia, Yuxuan Shao, Peng Zhang, Mengqi Xu, Dongrui Wang, Yongxian Hu, Luhan Yang, He Huang
Journal: Cell Reports Medicine (2025)
Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence
Authors: Hao Yang, Tongyao Wang, Chenglang Qian, Huijing Wang, Dong Yu, Meifang Shi, Mengwei Fu, Xueguang Liu, Miaomiao Pan, Xingyu Rong, Zhenming Xiao, Xiejiu Chen, Anaguli Yeerken, Yonglin Wu, Yufan Zheng, Hui Yang, Ming Zhang, Tao Liu, Peng Qiao, Yifan Qu, Yong Lin, Yiqin Huang, Jianliang Jin, Nan Liu, Yumei Wen, Ning Sun, Chao Zhao
Journal: Nature Aging (2025)
The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes
Authors: Shauni Loopmans, Katerina Rohlenova, Thomas van Brussel, Ingrid Stockmans, Karen Moermans, Nicolas Peredo, Peter Carmeliet, Diether Lambrechts, Steve Stegen, Geert Carmeliet
Journal: Nature Metabolism (2025)

Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis. Loopmans et al. show that the pentose phosphate pathway in chondrocytes provides reducing power to ensure proteostasis necessary for bone lengthening.
Autologous macrophage therapy for liver cirrhosis: a phase 2 open-label randomized controlled trial
Authors: Paul N. Brennan, Mark MacMillan, Thomas Manship, Francesca Moroni, Alison Glover, Debbie Troland, Iain MacPherson, Catriona Graham, Rhona Aird, Scott I. K. Semple, David M. Morris, Alasdair R. Fraser, Chloe Pass, Neil W. A. McGowan, Marc L. Turner, Lynn Manson, Neil J. Lachlan, John F. Dillon, Alastair M. Kilpatrick, John D. M. Campbell, Jonathan A. Fallowfield, Stuart J. Forbes
Journal: Nature Medicine (2025)

Abstract Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis and stimulate liver regeneration. In a multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥10 and ≤17, we evaluated the efficacy of autologous monocyte-derived macrophage therapy ( n = 27) compared to standard medical care ( n = 24). The primary endpoint was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive fibrosis biomarkers and health-related quality of life (HRQoL) at 90 d, 180 d and 360 d. The ΔΔMELD between day 0 and day 90 in the treatment group compared to controls was −0.87 (95% confidence interval: −1.79, 0.0; P = 0.06); therefore, the primary endpoint was not met. During 360-d follow-up, five of 24 participants in the control group developed a total of 10 severe adverse events, four of which were liver related, and three deaths (two liver related), whereas no liver-related severe adverse events or deaths occurred in the treatment group. Although no differences were observed in biomarkers or HRQoL, exploratory analysis showed anti-inflammatory serum cytokine profiles after macrophage infusion. This study reinforces the safety and potential efficacy of macrophage therapy in cirrhosis, supporting further investigation.
Subcutaneous weekly semaglutide with automated insulin delivery in type 1 diabetes: a double-blind, randomized, crossover trial
Authors: Melissa-Rosina Pasqua, Michael A. Tsoukas, Alessandra Kobayati, Wedyan Aboznadah, Adnan Jafar, Ahmad Haidar
Journal: Nature Medicine (2025)

Efforts to improve glycemic control in type 1 diabetes are ongoing. We performed a randomized, double-blind, crossover trial to assess semaglutide as adjunct to automated insulin delivery therapy in adults with type 1 diabetes. At each intervention, participants were titrated up to 1 mg or the maximum tolerated dose of semaglutide or placebo over 11 weeks, followed by the use of an automated insulin delivery system for 4 weeks. The primary outcome was the percentage of time spent in the target glucose range of 3.9–10.0 mmol l−1 during the last 4 weeks of each intervention. Twenty-eight participants were randomized and 24 completed the trial. The primary endpoint was met. Compared to placebo, semaglutide increased time in the target range by a mean 4.8 (s.d. = 7.6) percentage points (P = 0.006), without increasing the time spent below 3.9 mmol l−1 (P = 0.19) or below 3.0 mmol l−1 (P = 0.65). While no diabetic ketoacidosis or severe hypoglycemia occurred during any of the interventions, there were two episodes of recurrent euglycemic ketosis without acidosis during semaglutide use. We conclude that semaglutide improves glycemic control with automated insulin delivery compared to placebo. ClinicalTrials.gov registration: NCT05205928 In a crossover trial evaluating semaglutide versus placebo as an add-on to automated insulin delivery therapy in adults with type 1 diabetes, the use of semaglutide was associated with an increased percentage of time spent within the target glucose range, along with reduced insulin requirements.
Orphanhood and caregiver death among children in the United States by all-cause mortality, 2000–2021
Authors: Andrés Villaveces, Yu Chen, Sydney Tucker, Alexandra Blenkinsop, Lucie Cluver, Lorraine Sherr, Jan L. Losby, Linden Graves, Rita Noonan, Francis Annor, Victor Kojey-Merle, Douhan Wang, Greta Massetti, Laura Rawlings, Charles A. Nelson, H. Juliette T. Unwin, Seth Flaxman, Susan Hillis, Oliver Ratmann
Journal: Nature Medicine (2025)

Abstract Deaths of parents and grandparent caregivers threaten child well-being owing to losses of care, financial support, safety and family stability, but are relatively unrecognized as a public health crisis. Here we used cause-specific vital statistics death registrations in a modeling approach to estimate the full magnitude of orphanhood incidence and prevalence among US children aged 0–17 years between 2000 and 2021 by cause, child age, race and ethnicity, sex of deceased parent and state, and also accounted for grandparent caregiver loss using population survey data. In 2021, we estimate that 2.91 million children (4.2% of children) had in their lifetime experienced prevalent orphanhood and caregiver death combined, with incidence increasing by 49.5% and prevalence by 7.9% since 2000. Populations disproportionately affected by orphanhood included 5.2% of all adolescents; 6.4% and 4.7%, respectively, of non-Hispanic American Indian or Alaska Native, and non-Hispanic Black children; and children in southern and eastern states. In 2021, drug overdose was the leading cause of orphanhood among non-Hispanic white children, but not among minoritized subgroups. Effective policies and programs to support nearly three million bereaved children are needed to reduce the acute and long-term negative effects of orphanhood.
Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes
Authors: Alexander Haglund, Verena Zuber, Maya Abouzeid, Yifei Yang, Jeong Hun Ko, Liv Wiemann, Maria Otero-Jimenez, Louwai Muhammed, Rahel Feleke, Alexi Nott, James D. Mills, Liisi Laaniste, Djordje O. Gveric, Daniel Clode, Ann C. Babtie, Susanna Pagni, Ravishankara Bellampalli, Alyma Somani, Karina McDade, Jasper J. Anink, Lucia Mesarosova, Nurun Fancy, Nanet Willumsen, Amy Smith, Johanna Jackson, Javier Alegre-Abarrategui, Eleonora Aronica, Paul M. Matthews, Maria Thom, Sanjay M. Sisodiya, Prashant K. Srivastava, Dheeraj Malhotra, Julien Bryois, Leonardo Bottolo, Michael R. Johnson
Journal: Nature Genetics (2025)

Abstract Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case and control brains, we report 13,939 genes whose expression correlated with genetic variation, of which 16.7–40.8% (depending on cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a disease dependency, even after adjusting for disease status. To estimate the unconfounded effect of genes on outcomes, we repeated the analysis using nondiseased brains ( n = 183) and reported an additional 91 colocalizations not present in the larger mixed disease and control dataset, demonstrating enhanced interpretation of disease-associated variants. Principled implementation of single-cell Mendelian randomization in control-only brains identified 140 putatively causal gene–trait associations, of which 11 were replicated in the UK Biobank, prioritizing candidate peripheral biomarkers predictive of CNS outcomes.
Individual patient and donor seroprofiles in convalescent plasma treatment of COVID-19 in REMAP-CAP clinical trial
Authors: Visa Nurmi, Richard Mayne, Chanice Knight, Hannia L Almonacid-Mendoza, Shannah Secret, Lise Estcourt, Jussi Hepojoki, Tonći Šuštić, Abigail A Lamikanra, Hoi Pat Tsang, David K Menon, Manu Shankar-Hari, C Ellen van der Schoot, Gestur Vidarsson, David J Roberts, Peter Simmonds, Klaus Hedman, Heli Harvala
Journal: Journal of Infection (2025)
Canadian Medical Assistance in Dying: Provider Concentration, Policy Capture, and Need for Reform
Authors: Christopher Lyon, Trudo Lemmens, Scott Y. H. Kim
Journal: The American Journal of Bioethics (2025)

Canada's rapid rise in deaths from euthanasia and physician assisted suicide, termed Medical Assistance in Dying (MAID) in the country, now ranks it second only to the Netherlands in terms of MAiD deaths as percentage of overall deaths, with one province already hosting the highest rate of all jurisdictions in the world. Analyzing Health Canada's annual MAID reports, which show that up to 336 out of 1837 providers are likely responsible for the majority of MAID deaths in a given year, we discuss how the rapid increase likely reflects not a broad Canadian consensus but the capture of a policy-making and implementation process by a small group of activists and clinicians colonizing medicine to become an ideologically driven vehicle for expanding MAID access and delivery. As a remedy and to reprioritize patient safety and protection against premature death, a more transparent, relevant, and safeguarded compliance regime based on evidence-based, multi-perspective policy-making is needed.