tbuckley/cabot-search huggingface dataset:
Single-cell Transcriptional Atlas of Human Hematopoiesis Reveals Genetic and Hierarchy-Based Determinants of Aberrant AML Differentiation
Authors: Andy G.X. Zeng, Ilaria Iacobucci, Sayyam Shah, Amanda Mitchell, Gordon Wong, Suraj Bansal, David Chen, Qingsong Gao, Hyerin Kim, James A. Kennedy, Andrea Arruda, Mark D. Minden, Torsten Haferlach, Charles G. Mullighan, John E. Dick
Journal: Blood Cancer Discovery (2025)

Abstract Therapeutic targeting of acute myeloid leukemia (AML) is hampered by intra- and inter-tumoral cell state heterogeneity. To develop a more precise understanding of AML cell states, we constructed a reference atlas of human hematopoiesis from 263,159 single-cell transcriptomes spanning 55 cellular states. Using this atlas, we mapped more than 1.2 million cells spanning 318 leukemia samples, revealing 12 recurrent patterns of aberrant differentiation in AML. Notably, this uncovered unexpected AML cell states resembling lymphoid and erythroid progenitors that were prognostic within the clinically heterogeneous context of normal karyotype AML, independent of genomic classifications. Systematic mapping of genotype-to-phenotype associations revealed specific differentiation landscapes associated with more than 45 genetic drivers. Importantly, distinct cellular hierarchies can arise from samples sharing the same genetic driver, potentially reflecting distinct cellular origins for disease-sustaining leukemia stem cells. Thus, precise mapping of malignant cell states provides insights into leukemogenesis and refines disease classification in acute leukemia. Significance: We present a single-cell reference atlas of human hematopoiesis and a computational tool for rapid mapping and classification of healthy and leukemic cells. Applied to AML, this has enabled single-cell analysis at the scale of hundreds of patient samples, revealing the full breadth of derailment of differentiation in AML. See related commentary by Berger and Penter, p. XX
Putting AML Differentiation States on the BoneMarrowMap
Authors: Jonas Berger, Livius Penter
Journal: Blood Cancer Discovery (2025)

Summary: This article presents a novel computational tool, “BoneMarrowMap,” that enables the mapping of leukemic single-cell RNA sequencing datasets to hematopoietic differentiation states. By utilizing BoneMarrowMap for a large-scale single-cell RNA sequencing reanalysis, the authors discover 12 recurrent acute myeloid leukemia differentiation patterns linked to prognosis and treatment and dissect leukemic clonal architectures within individual patients. See related article by Zeng and colleagues, p. XX
Hematopoietic Stem Cell Transplantation Outcomes for High-Risk AML: A Report From the Children's Oncology Group
Authors: Benjamin J. Huang, Lauren K. Meyer, Todd A. Alonzo, Yi-Cheng Wang, Adam J. Lamble, Rhonda E. Ries, Weijie Wang, Betsy Hirsch, Gordana Raca, Xiaotu Ma, Alan S. Gamis, Richard Aplenc, E. Anders Kolb, Todd M. Cooper, Katherine Tarlock, Michael R. Loken, Soheil Meshinchi, Joseph H. Chewning, William G. Woods, John T. Horan
Journal: Journal of Clinical Oncology (2025)

PURPOSE Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML. METHODS We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic cytogenetic/molecular (CM) alterations, which were applied to reclassify patients in the current COG phase III clinical trial, AAML1831. We compared the outcomes after HSCT in CR1 with those after chemotherapy alone in CR1 in the redefined high-risk group. RESULTS Our study cohort comprised 463 patients with high-risk CM alterations and 72 patients with standard-risk (SR) CM results with positive MRD at end of induction I. In all, 33.9% and 45.8% of these groups underwent HSCT in CR1, respectively. HSCT was associated with decreased relapse and improved disease-free survival (DFS) in both groups. In the high-risk CM group, 5-year DFS was 26.0% (95% CI, 20.6 to 31.6) and 49.8% (95% CI, 41.7 to 57.4; P &lt; .001) in patients receiving chemotherapy alone and HSCT, respectively. In the SR CM and MRD+ groups, DFS was 16.9% (95% CI, 4.3 to 36.7) compared with 50.9% (95% CI, 32.7 to 66.5; P = .032). HSCT was also associated with improvement in outcomes based on multivariable analysis and across subgroups defined by clinical trial and by high-risk CM subtype, with the exception of chromosome 7 or 5 loss. CONCLUSION HSCT was associated with improved outcomes in pediatric patients with contemporarily defined high-risk AML.
Second-Line Endocrine Therapy With or Without Palbociclib Rechallenge in Patients With Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: PALMIRA Trial
Authors: Antonio Llombart-Cussac, Catherine Harper-Wynne, Antonia Perelló, Audrey Hennequin, Adela Fernández-Ortega, Marco Colleoni, Sara Marín, Vanesa Quiroga, Jacques Medioni, Vega Iranzo, Duncan Wheatley, Sonia del Barco Berrón, Antonio Antón, Erion Dobi, Manuel Ruiz-Borrego, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Gabriele Antonarelli, Miguel Sampayo-Cordero, José Manuel Pérez-García, Javier Cortés
Journal: Journal of Clinical Oncology (2025)

PURPOSE Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy (ET) represents the standard first-line treatment for patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2-negative) advanced breast cancer (ABC). However, there is no definitive consensus on the preferred second-line treatment option. The PALMIRA trial investigated whether palbociclib rechallenge with an alternative ET would improve the antitumor activity in patients progressing after a first-line palbociclib-containing regimen. METHODS This international, randomized, open-label, phase II study enrolled 198 patients with hormone receptor–positive/HER2-negative ABC with disease progression after first-line palbociclib plus ET (aromatase inhibitor or fulvestrant). Patients were eligible if they showed clinical benefit to the previous regimen (response or stable disease ≥24 weeks) or had progressed on a palbociclib-based therapy in the adjuvant setting. Patients were randomly assigned (2:1 ratio) to either palbociclib rechallenge plus second-line ET (fulvestrant or letrozole) or second-line ET alone. Stratification factors were previous ET and visceral involvement. The primary end point was investigator-assessed progression-free survival (PFS). RESULTS Between April 2019 and October 2022, 136 and 62 patients were randomly assigned to palbociclib plus ET or ET alone, respectively. Median investigator-assessed PFS was 4.9 months (95% CI, 3.6 to 6.1) with palbociclib plus ET versus 3.6 months (95% CI, 2.5 to 4.2) with ET alone (hazard ratio, 0.84 [95% CI, 0.66 to 1.07]; P = .149). Grade ≥3 treatment-emergent adverse events were higher with palbociclib plus ET (47.4% v 10.0%), without new safety signals. CONCLUSION Palbociclib rechallenge plus an alternative ET did not significantly improve PFS compared with ET alone in patients with hormone receptor–positive/HER2-negative ABC progressing on a first-line palbociclib-based ET regimen.
Harnessing traits to predict economic impacts from biological invasions
Authors: Ross N Cuthbert, Thomas W Bodey, Elizabeta Briski, Isabella Capellini, Jaimie T A Dick, Melina Kourantidou, Anthony Ricciardi, Daniel Pincheira-Donoso
Journal: Trends in Ecology & Evolution (2025)

Biological invasions stand among the main anthropogenic threats to ecosystems globally while causing multitrillion-dollar impacts. Surprisingly, while trait-based frameworks have been designed to predict invasion success and invader ecological impacts, no such approaches exist to understand and predict economic impacts. We propose the first such framework by bridging the evolutionary biology of traits and the escalation of invasion costs. Previously acquired traits can benefit performance, and their rapid change could exacerbate impacts through adaptive and non-adaptive processes during invasion, such as natural selection, genetic drift, or phenotypic plasticity. Emerging evidence suggests that some organismal traits can determine economic impact magnitudes. We discuss new transdisciplinary avenues that can inform cost forecasting and management responses for current and future biological invasions.
Repurposing trifluoperazine for glioblastoma treatment
Authors: Manam Inushi De Silva, Hui K Gan, Cedric Bardy
Journal: Trends in Pharmacological Sciences (2025)

Glioblastoma (GBM) remains a therapeutic challenge due to its heterogeneity and plasticity, which drive treatment resistance, especially when compounded by interactions with the brain microenvironment. Recent preclinical evidence indicates that trifluoperazine (TFP) inhibits treatment-induced malignant reprogramming of tumour cells, potentially helping to reduce tumour plasticity. TFP targets calmodulin, dopamine receptors, and stress-responsive proteins (nuclear protein 1, NUPR1). Through these mechanisms, TFP has been shown to reduce tumour growth, sensitise tumours to chemoradiotherapy, and prolong survival in xenograft animal models. The clinical safety profile of TFP is well known from its use as an antipsychotic, and recent preclinical evidence further indicates that TFP has low toxicity to healthy neurons and glia despite transient functional effects on dopamine receptors. This Opinion explores TFP mechanisms of action and clinical activity to assess its suitability as a repurposed therapeutic option for GBM.
SPIRIT 2025 statement: updated guideline for protocols of randomized trials
Authors: An-Wen Chan, Isabelle Boutron, Sally Hopewell, David Moher, Kenneth F Schulz, Gary S Collins, Ruth Tunn, Rakesh Aggarwal, Michael Berkwits, Jesse A Berlin, Nita Bhandari, Nancy J Butcher, Marion K Campbell, Runcie C W Chidebe, Diana R Elbourne, Andrew J Farmer, Dean A Fergusson, Robert M Golub, Steven N Goodman, Tammy C Hoffmann, John P A Ioannidis, Brennan C Kahan, Rachel L Knowles, Sarah E Lamb, Steff Lewis, Elizabeth Loder, Martin Offringa, Philippe Ravaud, Dawn P Richards, Frank W Rockhold, David L Schriger, Nandi L Siegfried, Sophie Staniszewska, Rod S Taylor, Lehana Thabane, David J Torgerson, Sunita Vohra, Ian R White, Asbjørn Hróbjartsson
Journal: Nature Medicine (2025)
Improving transparency in clinical trial reporting
Authors: Alison Farrell
Journal: PLoS Medicine (2025)

The power to interpret the results of randomised clinical trial results relies on transparent reporting of the study design, protocol, methods and analyses. Without such clarity, the benefits of the findings, to both healthcare, policy and research, cannot be realized in full. The publication of the updated CONSORT 2025 and SPIRIT 2025 statements for reporting of randomised clinical trials and protocols, respectively, offers the opportunity to reflect on the power that transparent reporting of clinical trial design and data offers to improve the quality of trials and outcomes.
SPIRIT 2025 statement: updated guideline for protocols of randomised trials
Authors: An-Wen Chan, Isabelle Boutron, Sally Hopewell, David Moher, Kenneth F Schulz, Gary S Collins, Ruth Tunn, Rakesh Aggarwal, Michael Berkwits, Jesse A Berlin, Nita Bhandari, Nancy J Butcher, Marion K Campbell, Runcie C W Chidebe, Diana R Elbourne, Andrew J Farmer, Dean A Fergusson, Robert M Golub, Steven N Goodman, Tammy C Hoffmann, John P A Ioannidis, Brennan C Kahan, Rachel L Knowles, Sarah E Lamb, Steff Lewis, Elizabeth Loder, Martin Offringa, Philippe Ravaud, Dawn P Richards, Frank W Rockhold, David L Schriger, Nandi L Siegfried, Sophie Staniszewska, Rod S Taylor, Lehana Thabane, David J Torgerson, Sunita Vohra, Ian R White, Asbjørn Hróbjartsson
Journal: The Lancet (2025)
Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation
Authors: Aitana Alonso-González, David Jáspez, José M Lorenzo-Salazar, Shwu-Fan Ma, Emma Strickland, Josyf Mychaleckyj, John S Kim, Yong Huang, Ayodeji Adegunsoye, Justin M Oldham, Iain Stewart, Philip L Molyneaux, Toby M Maher, Louise V Wain, Richard J Allen, R Gisli Jenkins, Jonathan A Kropski, Brian Yaspan, Timothy S Blackwell, David Zhang, Christine Kim Garcia, Fernando J Martinez, Imre Noth, Carlos Flores
Journal: The Lancet Respiratory Medicine (2025)
Molecular monitoring versus standard clinical care in younger adults with acute myeloid leukaemia: results from the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials
Authors: Nicola Potter, Jelena Jovanovic, Adam Ivey, Jad Othman, Abin Thomas, Amanda Gilkes, Manohursingh Runglall, Anju Kanda, Ian Thomas, Sean Johnson, Joanna Canham, William Villiers, Steven Knapper, Asim Khwaja, Mary Frances McMullin, Jamie Cavenagh, Ulrik Malthe Overgaard, Richard E Clark, Ellen Solomon, Sylvie D Freeman, Robert Hills, Alan Burnett, Nigel Russell, Richard Dillon
Journal: The Lancet Haematology (2025)
Updated recommendations for the management of hepatitis B, C, and E virus infections in patients with haematological malignancies and those undergoing haematopoietic cell transplantation: recommendations from the 9th European Conference on Infections in Leukaemia (ECIL-9)
Authors: Malgorzata Mikulska, Florian van Bömmel, Charlotte Mouliade, Giuseppe Indolfi, Helenie Kefalakes, Marie von Lilienfeld-Toal, Sven Pischke, Olivier Hermine, Darius Moradpour, Heiner Wedemeyer, Thomas Berg, Per Ljungman, Vincent Mallet
Journal: The Lancet Haematology (2025)
Long-term effects and effect heterogeneity of lifestyle and metformin interventions on type 2 diabetes incidence over 21 years in the US Diabetes Prevention Program randomised clinical trial
Authors: William C Knowler, Lindsay Doherty, Sharon L Edelstein, Peter H Bennett, Dana Dabelea, Mary Hoskin, Steven E Kahn, Rita R Kalyani, Catherine Kim, F Xavier Pi-Sunyer, Sridharan Raghavan, Vallabh O Shah, Marinella Temprosa, Elizabeth M Venditti, David M Nathan
Journal: The Lancet Diabetes & Endocrinology (2025)
Urgent need: evidence-based use of donor lymphocyte infusions – Authors' reply
Authors: Simona Pagliuca, Christoph Schmid, Nicole Santoro, Federico Simonetta, Giorgia Battipaglia, Thierry Guillaume, Raffaella Greco, Francesco Onida, Isabel Sánchez-Ortega, Ibrahim Yakoub-Agha, Florent Malard, Jurgen Kuball, Mette D Hazenberg, Annalisa Ruggeri
Journal: The Lancet Haematology (2025)
CD4 cell counts at HIV diagnosis in the Eastern Mediterranean Region
Authors: Mohammad Sharifi, Seyed Aria Nejadghaderi, Maliheh Sadat Bazrafshani, Elahe Amiri, Fatemeh Tavakoli, Soheil Mehmandoost, Ahmed S Alaama, Meraj Sharifi, Mohammad Karamouzian, Hamid Sharifi
Journal: The Lancet HIV (2025)
Early rituximab monotherapy versus watchful waiting for advanced stage, asymptomatic, low tumour burden follicular lymphoma: long-term results of a randomised, phase 3 trial
Authors: Michael Northend, William Wilson, Kushani Ediriwickrema, Laura Clifton-Hadley, Wendi Qian, Zaynab Rana, Tanya-Louise Martin, William Townsend, Moya Young, Fiona Miall, David Cunningham, Jan Walewski, Burhan Ferhanoglu, Kim Linton, Amanda Johnston, John F Seymour, David C Linch, Kirit M Ardeshna
Journal: The Lancet Haematology (2025)
Management of iron deficiency in children, adults, and pregnant individuals: evidence-based and expert consensus recommendations
Authors: Ashley E Benson, Jamie O Lo, Maureen O Achebe, Jorgeane S Aslan, Michael Auerbach, Bethany T Samuelson Bannow, Marie J Boller, Thomas G Deloughery, Jacquelin Dingman, Layla Van Doren, Geolani W Dy, Patricia A Ford, Jason A Freed, Michael K Georgieff, Kristina M Haley, Chloe I Han, Adam K Lewkowitz, Kylee L Martens, Robert T Means, Elizabeta Nemeth, Sven R Olson, Jacquelyn M Powers, Kristin C Prewitt, Toby Richards, Don C Rockey, Eric J Roeland, Kimberly S Ryan, Hanny Al-Samkari, Michelle Sholzberg, Methodius G Tuuli, Angela C Weyand, Michelle P Zeller, Annette M Totten, Ilya Ivlev, Joseph J Shatzel
Journal: The Lancet Haematology (2025)
DNA methylation profiling of pituitary neuroendocrine tumors identifies distinct clinical and pathological subtypes based on epigenetic differentiation
Authors: Sarra Belakhoua, Varshini Vasudevaraja, Chanel Schroff, Kristyn Galbraith, Misha Movahed-Ezazi, Jonathan Serrano, Yiying Yang, Daniel Orringer, John G Golfinos, Chandra Sen, Donato Pacione, Nidhi Agrawal, Matija Snuderl
Journal: Neuro-Oncology (2025)

Abstract Background Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. Methods In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. Results CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. Conclusion Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease
Authors: Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván Del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, Marja Niiranen, Sami V Heikkinen, Mitja I Kurki, Jarkko Marttila, Petri I Mäkinen, Hannah Rostalski, Tomi Hietanen, Tiia Ngandu, Jenni Lehtisalo, Céline Bellenguez, Jean-Charles Lambert, Christian Haass, Juha Rinne, Juhana Hakumäki, Tuomas Rauramaa, Johanna Krüger, Hilkka Soininen, Annakaisa Haapasalo, Stefan F Lichtenthaler, Ville Leinonen, Eino Solje, Mikko Hiltunen
Journal: Molecular Neurodegeneration (2025)

Abstract Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1–4 of TYROBP and causing NHD in homozygous carriers . We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP ) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP . Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.
Formulation of siRNA nanoparticles, transfection and enhanced adhesion -penetration in nasal mucosal tissue
Authors: Leslie Vanessa Sanchez-Castillo, Fabiola Guareschi, Eleni Tsekoura, Virginia Patterlini, Andrea Delledonne, Ilaria Ferraboschi, Cristina Sissa, Julie Suman, Fabio Sonvico, Ravin Narain
Journal: Journal of Controlled Release (2025)
Go to the scene: T<sub>H</sub>9 cells superior migration ability to the lungs explains their exceptional anticancer efficacy
Authors: Jiazhi Xu, Lionel Apetoh
Journal: Journal for ImmunoTherapy of Cancer (2025)

Antibodies against immune checkpoints are now routinely administered as a first line of treatment against metastatic lung cancer. Resistance to immune checkpoint inhibitors is, however, frequent, underscoring the need to find alternative treatments. Adoptive T-cell therapy has recently proven effective in treating patient’s refractory to immune checkpoint inhibitors. This provides impetus to characterize the T-cell subsets best able to tackle tumors. The anticancer activities of IL-9-producing CD4 T helper cells (T H 9 cells) were identified in melanoma in 2012. T H 9 cells feature strong antimelanoma effects thanks to their production of interleukin (IL)-9 and the activation of innate and adaptive immune effectors. The ability of T H 9 cells to prevent the growth of triple-negative breast cancer (TNBC) and osteosarcoma (OS), which commonly metastasize to the lungs, is elusive. In this commentary, we discuss the findings of Chen et al reported in the JITC demonstrating that T H 9 cells are lung-tropic and eliminate TNBC and OS cells developing in the lungs. We also highlight how these investigations are in line with recent studies indicating that the adoptive transfer of IL-9-producing T cells eliminate aggressive cancers, including hematological tumors like leukemia and solid tumors such as glioblastoma. Altogether, these findings over the past 13 years support the clinical evaluation of T H 9 cells in the adoptive therapy of cancer.