tbuckley/cabot-search huggingface dataset:
Mycosis fungoides – differentiation from inflammation and detection of circulating tumor cells with the EuroClonality-NGS assay
Authors: Ulrike Wehkamp, Sophie Pietzka, Michaela Kotrová, Marion Jost, Ilske Oschlies, Agatha Schwarz, Claudia Baldus, Nikos Darzentas, Monika Brüggemann
Journal: British Journal of Dermatology (2024)

Abstract Mycosis fungoides (MF) is a rare malignancy characterized by the presence of circulating tumor cells (CTCs) in a subgroup of patients. Reliably distinguishing MF from inflammatory skin conditions (IF) is a challenging task. This study aimed to evaluate the potential benefits of next-generation sequencing (NGS)-based T-cell receptor (TR) rearrangement repertoire analysis for detecting clonal rearrangements in MF and IF. Skin biopsies and blood samples from 33 MF patients (diagnosed according to WHO-EORTC criteria) and 10 IF patients were analyzed using TRB- and TRG-NGS. 27/33 MF patients were early-stage IA (n=19), IB (n=8), and six had advanced stages (IIB, n=5; IIIA, n=1). Analysis applying the standard abundance thresholds identified at least one clonal rearrangement in the skin DNA of 32/33 MF (97%) and 9/10 IF cases (90%). To enhance specificity, an abundance- and distribution-based approach was applied, considering only rearrangements that significantly stood out from the physiological background as clonal (MF 29/33, IF 1/10), allowing for a highly sensitive (88%) and specific (90%) discrimination between MF and IF. CTCs were detected in 11/24 (46%) early-stage and 3/5 (60%) late-stage MF patients. NGS-based TR repertoire analysis is a highly sensitive and specific method for the differential diagnosis of early-stage MF compared to IF, and for the sensitive molecular detection of CTCs.
Supplemental breast cancer screening after negative mammography in U.S. women with dense breasts
Authors: Victoria M Foster, Amy Trentham-Dietz, Natasha K Stout, Christoph I Lee, Laura E Ichikawa, Joanna Eavey, Louise Henderson, Diana L Miglioretti, Anna N A Tosteson, Erin A Bowles, Karla Kerlikowske, Brian L Sprague
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract The extent and determinants of supplemental screening among women with dense breasts are unclear. We evaluated a retrospective cohort of 498 855 women aged 40-74 years with heterogeneously or extremely dense breasts who obtained 1 176 251 negative screening mammography examinations during 2011-2019 in the United States. Overall, 2.8% and 0.3% of mammograms had supplemental ultrasound or magnetic resonance imaging (MRI) within 1 year, respectively. Onsite availability was associated with ultrasound (odds ratio [OR] = 4.35, 95% confidence interval [CI] = 4.21 to 4.49) but not MRI (OR = 0.94, 95% CI = 0.85 to 1.04). Facility academic affiliation and for-profit status were inversely associated with supplemental ultrasound (OR = 0.53, 95% CI = 0.49 to 0.57, and OR = 0.83, 95% CI = 0.81 to 0.86, respectively) and positively associated with supplemental MRI (OR = 3.04, 95% CI = 2.86 to 3.46, and OR = 1.88, 95% CI = 1.66 to 2.12, respectively). Supplemental screening was more likely to occur after passage of state-specific density notification laws than before passage (OR = 3.56, 95% CI = 3.30 to 3.84, and OR = 1.79, 95% CI = 1.60 to 2.00, respectively). These results show that supplemental breast imaging utilization has been uncommon and was related to facility factors and density legislation.
Cancer chemotherapy in pregnancy and adverse pediatric outcomes: a population-based cohort study
Authors: Amy Metcalfe, Zoe F Cairncross, Carly A McMorris, Christine M Friedenreich, Gregg Nelson, Parveen Bhatti, Deshayne B Fell, Sarka Lisonkova, Khokan C Sikdar, Lorraine Shack, Joel G Ray
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Administration of chemotherapy during pregnancy is often delayed, while preterm delivery is common. If in utero exposure to chemotherapy is associated with adverse pediatric outcomes, it is unknown whether that relationship is directly attributable to the chemotherapy or is mediated by preterm birth. Methods Patients were identified from Canadian cancer registries and administrative data in Alberta, British Columbia, and Ontario, 2003-2017, with follow-up until 2018. The primary exposure was receipt of chemotherapy during pregnancy. Severe neonatal morbidity and mortality (SNM-M), neurodevelopmental disorders and disabilities (NDDs), and pediatric complex chronic conditions (PCCC) reflected short- and long-term pediatric outcomes. Modified Poisson and Cox proportional hazard regression models generated adjusted risk ratios (RR) and hazard ratios (HR), respectively. The influence of preterm birth on the association between exposure to chemotherapy in pregnancy and each study outcome was explored using mediation analysis. Results Of the 1150 incident cases of cancer during pregnancy, 142 (12.3%) received chemotherapy during pregnancy. Exposure to chemotherapy in pregnancy was associated with a higher risk of SNM-M (RR = 1.67, 95% confidence interval [CI] = 1.13 to 2.46), but not NDD (HR = 0.93, 95% CI = 0.71 to 1.22) or PCCC (HR = 0.96, 95% CI = 0.80 to 1.16). Preterm birth less than 34 and less than 37 weeks mediated 75.8% and 100% of the observed association between chemotherapy and SNM-M, respectively. Conclusions Most children born to people with cancer during pregnancy appear to have favorable long-term outcomes, even after exposure to chemotherapy in pregnancy. However, preterm birth is quite common and may contribute to increased rates of adverse neonatal outcomes.
Nanoradiosentizers with X Ray-Actuatable Supramolecular Aptamer Building Units for Programmable Immunostimulatory T Cell Engagement
Authors: Jinming He, Xijiao Ren, Qiqi Zhang, Shuang Wang, Zhongjun Li, Kaiyong Cai, Menghuan Li, Yan Hu, Qian Ran, Zhong Luo
Journal: Biomaterials (2024)
High Rates of Dientamoeba fragilis and Blastocystis species in Children’s Stool but Minor Clinical Significance
Authors: David Shasha, Orit Treygerman, Etti Levy Dahari, Efraim Bilavsky, Dror Hacham, Daniel Grupel, Yael Paran, George Prajgrod, Galia Zacay
Journal: Journal of Infection (2024)
Transcatheter Repair Versus Surgery for Atrial Versus Ventricular Functional Mitral Regurgitation – a Post-hoc Analysis of the MATTERHORN Trial
Authors: Felix Rudolph, Martin Geyer, Stephan Baldus, Valeria Maria De Luca, Torsten Doenst, Roman Pfister, Jan Gummert, Mirjam Kessler, Peter Boekstegers, Edith Lubos, Jörg Schröder, Holger Thiele, Thomas Walther, Malte Kelm, Jörg Hausleiter, Ingo Eitel, Ulrich Fischer-Rasokat, Alexander Bufe, Alexander Schmeisser, Hüseyin Ince, Philipp Lurz, Ralph Stephan von Bardeleben, Christian Hagl, Thilo Noack, Sebastian Reith, Harald Beucher, Hermann Reichenspurner, Wolfgang Rottbauer, Paul Christian Schulze, Wiebke Müller, Julia Frank, Claudia Michalik, Martin Hellmich, Thorsten Wahlers, Volker Rudolph, Christos Iliadis
Journal: Circulation (2024)
Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma
Authors: Jan Eckmann, Tanja Fauti, Marlene Biehl, Aintzane Zabaleta, Laura Blanco, Iva Lelios, Stefan Gottwald, Richard Rae, Stefanie Lechner, Christa Bayer, Quincy Dekempe, Franz Osl, Nadège Carrié, Sahar Kassem, Stefan Lorenz, Tony Christopeit, Alejandro Carpy, Alexander Bujotzek, Ann-Marie E. Bröske, Iryna Dekhtiarenko, Jan Attig, Leo Kunz, Floriana Cremasco, Roberto Adelfio, Georg Fertig, Stefan Dengl, Christian Gassner, Felix Bormann, Claudia Kirstenpfad, Thomas Emanuel Kraft, Sarah Diggelmann, Melanie Knobloch, Carina Hage, Romi Feddersen, Gordon Heidkamp, Thomas Pöschinger, Maud Lea Mayoux, Luise Bernasconi, Charles Dumontet, Felipe Prosper, Ludovic Martinet, Stephane Leclair, Wei Xu, Bruno Paiva, Christian Klein, Pablo Umaña
Journal: Blood (2024)
Pelvic Lymph Node Dissection in Prostate Cancer: Update from a Randomized Clinical Trial of Limited Versus Extended Dissection
Authors: Karim A Touijer, Emily A Vertosick, Daniel D Sjoberg, Nicole Liso, Sunny Nalavenkata, Barbara Melao, Vincent P Laudone, Behfar Ehdaie, Brett Carver, James A Eastham, Peter T Scardino, Andrew J Vickers
Journal: European Urology (2024)
H4K20me3-Mediated Repression of Inflammatory Genes is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Valentina Ramponi, Laia Richart, Marta Kovatcheva, Camille Stephan-Otto Attolini, Jordi Capellades, Alice E. Lord, Oscar Yanes, Gabriella Ficz, Manuel Serrano
Journal: Cancer Research (2024)

Abstract Anti-cancer therapies can induce cellular senescence, which is highly stable, or drug-tolerant persistence, which is efficiently reversed upon therapy termination. While approaches to target senescent cells have been extensively studied, further understanding of the processes regulating persistence is needed to develop treatment strategies to suppress persister cell survival. Here, we used mTOR/PI3K inhibition to develop and characterize a model of persistence-associated arrest in human cancer cells of various origins. Persister and senescent cancer cells shared an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells lacked other features of senescence, such as loss of lamin B1, senescence-associated β-galactosidase activity, upregulation of MHC-I, and an inflammatory and secretory phenotype (SASP). Genome-wide CRISPR/Cas9 screening for genes required for the survival of persister cells revealed that they are hypersensitive to the inhibition of one-carbon (1C) metabolism, which was validated by the pharmacological inhibition of SHMT, a key enzyme that feeds methyl groups from serine into 1C metabolism. Connecting 1C metabolism with the epigenetic regulation of transcription, the repressive heterochromatic mark H4K20me3 was enriched at the promoters of SASP and interferon response genes in persister cells, while it was absent in proliferative or senescent cells. Moreover, persister cells overexpressed the H4K20 methyltransferases KMT5B/C, and their downregulation unleashed inflammatory programs and compromised the survival of persister cells. In summary, this study defined distinctive features of persister cancer cells, identified actionable vulnerabilities, and provided mechanistic insight into their low inflammatory activity.
Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains
Authors: Biqing Zhu, Jae-Min Park, Sarah R. Coffey, Anthony Russo, I-Uen Hsu, Jiawei Wang, Chang Su, Rui Chang, TuKiet T. Lam, Pallavi P. Gopal, Stephen D. Ginsberg, Hongyu Zhao, David A. Hafler, Sreeganga S. Chandra, Le Zhang
Journal: Science Translational Medicine (2024)

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.
Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy
Authors: Veronica Jimenez, Victor Sacristan, Claudia Jambrina, Maria Luisa Jaen, Estefania Casana, Sergio Muñoz, Sara Marcó, Maria Molas, Miquel Garcia, Ignasi Grass, Xavier León, Ivet Elias, Albert Ribera, Gemma Elias, Victor Sanchez, Laia Vilà, Alba Casellas, Tura Ferre, Jordi Rodó, Ana Carretero, Marti Pumarola, Marc Navarro, Anna Andaluz, Xavier Moll, Sonia Añor, Sylvie Franckhauser, Mercedes Vergara, Assumpta Caixàs, Fatima Bosch
Journal: Molecular Therapy (2024)
Long term follow-up of the STOPAGO study
Authors: Adrien Cottu, Stéphanie Guillet, Jean-François Viallard, Etienne Riviere, Stéphane Cheze, Delphine Gobert, Antoine Neel, Julie Graveleau, Jean-Pierre Marolleau, François Lefrere, Guillaume Moulis, Jean-Christophe Lega, Aline Moignet, Ailsa Robbins, Etienne Crickx, Emmanuelle Boutin, Nicolas Noel, Marion Malphettes, Lionel Galicier, Sylvain Audia, Bernard Bonnotte, Olivier Lambotte, Olivier Fain, Mathieu Gerfaud-Valentin, Louis Terriou, Nihal Martis, Anne-Sophie Morin, Antoinette Perlat, Thomas Le Gallou, Frédérique Roy-Peaud, Matthieu Puyade, Thibault Comont, Nicolas Limal, Laetitia Languille, Marc Michel, Bertrand Godeau, Matthieu Mahevas
Journal: Blood (2024)
Genetic and Clinical Spectrum of SAMD9 and SAMD9L Syndromes: from Variant Interpretation to Patient Management
Authors: Sushree S Sahoo, Miriam Erlacher, Marcin W Wlodarski
Journal: Blood (2024)

SAMD9 and SAMD9L (SAMD9/9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germline gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure (BMF), myelodysplasia (MDS) and monosomy 7. Non-hematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, while progressive neurologic deficits characterize SAMD9L. Most patients (&amp;gt;90%) carry germline missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease (SAAD) carry frameshift truncating variants that are also GoF. Somatic genetic rescue occurs in &amp;gt;2/3 of patients and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to MDS/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission versus disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.
Protumoral lipid droplet–loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted
Authors: Valeria Governa, Kelin Gonçalves de Oliveira, Anna Bång-Rudenstam, Svenja Offer, Myriam Cerezo-Magaña, Jiaxin Li, Sarah Beyer, Maria C. Johansson, Ann-Sofie Månsson, Charlotte Edvardsson, Faris Durmo, Emma Gustafsson, Axel Boukredine, Pauline Jeannot, Katja Schmidt, Emelie Gezelius, Julien A. Menard, Raquel Garza, Johan Jakobsson, Therese de Neergaard, Pia C. Sundgren, Aliisa M. Tiihonen, Hannu Haapasalo, Kirsi J. Rautajoki, Pontus Nordenfelt, Anna Darabi, Karin Forsberg-Nilsson, Alexander Pietras, Hugo Talbot, Johan Bengzon, Mattias Belting
Journal: Science Translational Medicine (2024)

Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet–loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O -acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.
A kidney-specific fasting-mimicking diet induces podocyte reprogramming and restores renal function in glomerulopathy
Authors: Valentina Villani, Camille Nicolas Frank, Paolo Cravedi, Xiaogang Hou, Sofia Bin, Anna Kamitakahara, Cristiani Barbati, Roberta Buono, Stefano Da Sacco, Kevin V. Lemley, Roger E. De Filippo, Silvia Lai, Alessandro Laviano, Valter D. Longo, Laura Perin
Journal: Science Translational Medicine (2024)

Cycles of a fasting-mimicking diet (FMD) promote regeneration and reduce damage in the pancreases, blood, guts, and nervous systems of mice, but their effect on kidney disease is unknown. In addition, a FMD has not been tested in rats. Here, we show that cycles of a newly developed low-salt FMD (LS-FMD) restored normal proteinuria and nephron structure and function in rats with puromycin-induced nephrosis compared with that in animals with renal damage that did not receive the dietary intervention. LS-FMD induced modulation of a nephrogenic gene program, resembling renal developmental processes in multiple kidney structures. LS-FMD also activated podocyte-lineage reprogramming pathways and promoted a quiescent state in mature podocytes in the rat kidney damage model. In a pilot clinical study in patients with chronic kidney disease, FMD cycles of 5 days each month for 3 months promoted renoprotection, including reduction of proteinuria and improved endothelial function, compared with that in patients who did not receive the FMD cycles. These results show that FMD cycles, which promote the reprogramming of multiple renal cell types and lead to glomerular damage reversal in rats, should be tested further for the treatment of progressive kidney diseases.
Engineering CAR-T therapies for autoimmune disease and beyond
Authors: Emily P. English, Rachel N. Swingler, Simran Patwa, Mehmet Tosun, James F. Howard Jr., Miloš D. Miljković, Christopher M. Jewell
Journal: Science Translational Medicine (2024)

Chimeric antigen receptor–T cell (CAR-T) therapy has transformed the management of refractory hematological malignancies. Now that targeting pathogenic cells of interest with antigen-directed cytotoxic T lymphocytes is possible, the field is expanding the reach of CAR-T therapy beyond oncology. Recently, breakthrough progress has been made in the application of CAR-T technology to autoimmune diseases, exploiting the same validated targets that were used by pioneering CAR-T therapies in hematology. Here, we discuss recent advances and outcomes that are paving the way for extension to new therapeutic areas, including autoimmunity.
Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models
Authors: Marta J. Koper, Sebastiaan Moonen, Alicja Ronisz, Simona Ospitalieri, Zsuzsanna Callaerts-Vegh, Dries T’Syen, Sabine Rabe, Matthias Staufenbiel, Bart De Strooper, Sriram Balusu, Dietmar Rudolf Thal
Journal: Science Translational Medicine (2024)

Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)–Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as “GVD-necroptosis” may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.
Risk of Hepatocellular Carcinoma in Subcentimeter Liver Nodules Identified on Surveillance Ultrasound: A Systematic Review
Authors: Eden Koo, Karim Seif El Dahan, Darine Daher, Nicole E Rich, Sukul Mittal, Ju Dong Yang, Neehar D Parikh, Amit G Singal
Journal: Clinical Gastroenterology and Hepatology (2024)
Pharmacological blockade of a pioneer transcription factor
Authors: Katerina Cermakova, H. Courtney Hodges
Journal: Cancer Research (2024)

Abstract Cancers frequently co-opt lineage-specific transcription factors (TFs) utilized in normal development to sustain proliferation. However, the effects of these TFs on tumor development depend considerably on where in the genome they bind. A new paper by Taylor and colleagues expands on previously developed diamidine compounds that obstruct the DNA binding sites of the pioneer TF PU.1 (SPI1) in acute myeloid leukemia (AML). Immobilization and sequencing of genomic DNA targeted by these compounds revealed that these inhibitors alter the genomic binding patterns of PU.1. The authors report that their strategy constrains the genomic binding preferences of PU.1, leading to redistribution of PU.1 to promoters and other gene-proximal regions with elevated G/C content. Here we discuss recent developments for targeting PU.1 in hematologic malignancies. We also explore the shared functional roles of PU.1 and SWI/SNF ATP-dependent chromatin remodeling complexes, which work together to sustain the enhancer landscape needed for tumor cell proliferation but also have key roles in non-tumor settings.