tbuckley/cabot-search huggingface dataset:
Integrated single-cell analysis reveals distinct epigenetic-regulated cancer cell states and a heterogeneity-guided core signature in tamoxifen-resistant breast cancer
Authors: Kun Fang, Aigbe G. Ohihoin, Tianxiang Liu, Lavanya Choppavarapu, Bakhtiyor Nosirov, Qianben Wang, Xue-Zhong Yu, Sailaja Kamaraju, Gustavo Leone, Victor X. Jin
Journal: Genome Medicine (2024)

Inter- and intra-tumor heterogeneity is considered a significant factor contributing to the development of endocrine resistance in breast cancer. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) allow us to explore inter- and intra-tumor heterogeneity at single-cell resolution. However, such integrated single-cell analysis has not yet been demonstrated to characterize the transcriptome and chromatin accessibility in breast cancer endocrine resistance. In this study, we conducted an integrated analysis combining scRNA-seq and scATAC-seq on more than 80,000 breast tissue cells from two normal tissues (NTs), three primary tumors (PTs), and three tamoxifen-treated recurrent tumors (RTs). A variety of cell types among breast tumor tissues were identified, PT- and RT-specific cancer cell states (CSs) were defined, and a heterogeneity-guided core signature (HCS) was derived through such integrated analysis. Functional experiments were performed to validate the oncogenic role of BMP7, a key gene within the core signature. We observed a striking level of cell-to-cell heterogeneity among six tumor tissues and delineated the primary to recurrent tumor progression, underscoring the significance of these single-cell level tumor cell clusters classified from scRNA-seq data. We defined nine CSs, including five PT-specific, three RT-specific, and one PT-RT-shared CSs, and identified distinct open chromatin regions of CSs, as well as a HCS of 137 genes. In addition, we predicted specific transcription factors (TFs) associated with the core signature and novel biological/metabolism pathways that mediate the communications between CSs and the tumor microenvironment (TME). We finally demonstrated that BMP7 plays an oncogenic role in tamoxifen-resistant breast cancer cells through modulating MAPK signaling pathways. Our integrated single-cell analysis provides a comprehensive understanding of the tumor heterogeneity in tamoxifen resistance. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and the tumor microenvironment govern the development of tumor heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.
The pharmacodynamic and pharmacological mechanisms underlying nanovesicles of natural products: Developments and challenges
Authors: Junzhe Zhang, Huanhuan Pang, Huan Tang, Qingchao Tu, Fei Xia, Hao Zhang, Yuqing Meng, Guang Han, Jigang Wang, Chong Qiu
Journal: Pharmacology & Therapeutics (2024)
Cocrystal pleomorphism-inspired drug nanoassembly for pulmonary-endothelium targeting and pulmonary hypertension treatment
Authors: Makhloufi Zoulikha, Jiahui Zou, Pei Yang, Jun Wu, Wei Wu, Kun Hao, Wei He
Journal: Acta Pharmaceutica Sinica B (2024)

Endothelial dysfunction is one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly via an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-κB/ICAM-1/TNF-α/IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.
J. Claude Bennett, <scp>MD</scp>, 1933–2024
Authors: S. Louis Bridges, Kenneth G. Saag, William J. Koopman
Journal: Arthritis & Rheumatology (2024)

Disclosure form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Safety and Efficacy of Ianalumab in Patients With Sjögren's Disease: 52‐Week Results From a Randomized, Placebo‐Controlled, Phase 2b Dose‐Ranging Study
Authors: Thomas Dörner, Simon J. Bowman, Robert Fox, Xavier Mariette, Athena Papas, Thomas Grader‐Beck, Benjamin A. Fisher, Filipe Barcelos, Salvatore De Vita, Hendrik Schulze‐Koops, Robert J. Moots, Guido Junge, Janice Woznicki, Monika Sopala, Alexandre Avrameas, Wen‐Lin Luo, Wolfgang Hueber
Journal: Arthritis & Rheumatology (2024)

Objective The objective of this study was to report 52‐week safety and efficacy of ianalumab from phase 2b dose‐finding study in patients with Sjögren's disease (SjD). Methods Patients randomly received (1:1:1:1) ianalumab (5, 50, or 300 mg) or placebo subcutaneously every 4 weeks until week 24 (treatment period [TP]1). At week 24, patients on 300 mg were rerandomized to continue 300 mg or receive placebo until week 52 (TP2), patients on placebo were switched to ianalumab 150 mg, and patients on 5 and 50 mg directly entered posttreatment safety follow‐up. Patients who discontinued treatment early or completed treatment entered safety follow‐up (≥20 weeks). Results During TP1, 190 patients were randomized (placebo = 49, 5 mg = 47, 50 mg = 47, 300 mg = 47). Of these 190 patients, 90 (47.4 %; 43 continued 300 mg and 47 received placebo) entered TP2, and 81 of 90 (90.0%) completed the study treatment. By week 52, efficacy was sustained in patients who continued 300 mg in TP2 (EULAR Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index, patient global assessment, and physician global assessment change from week 24: −1.45, −0.46, −4.69, and −6.86, respectively). Stimulated salivary flow rates and autoantibody levels numerically improved in the 300 mg group. Treatment‐emergent adverse events were not dose‐dependent, except for injection‐site reactions. Cases of decreased neutrophil counts (Common Terminology Criteria for Adverse Events v4.03 grade 3 according to laboratory listings) were observed in three patients during the posttreatment follow‐up, occurring at 3.5, 5.5, and 3 months, after the last ianalumab administration. None were associated with infection except one incidental finding of asymptomatic cytomegalovirus infection (IgM‐positive). Conclusion In patients with SjD, ianalumab 300 mg demonstrated sustained efficacy through week 52 and a favorable safety profile up to two years of follow‐up.
Stool and blood biomarkers for colorectal cancer management: an update on screening and disease monitoring
Authors: Alessandro Mannucci, Ajay Goel
Journal: Molecular Cancer (2024)

Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications. Main body. We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis. Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing.
The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease
Authors: Steven T. Bird, Kate Gelperin, Elizabeth R. Smith, Tae Hyun Jung, Hai Lyu, Aliza Thompson, Olivia Easley, Kushal B. Naik, Yueqin Zhao, Rekha Kambhampati, Michael Wernecke, Ali Niak, Marina Zemskova, Yoganand Chillarige, Jeffrey A. Kelman, David J. Graham
Journal: Annals of Internal Medicine (2024)

There is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD).
Information Disclosure, Medical Device Regulation, and Device Safety: The Case of Cook Celect IVC Filters
Authors: Kushal T. Kadakia, Behnood Bikdeli, Aakriti Gupta, Sanket S. Dhruva, Joseph S. Ross, Harlan M. Krumholz
Journal: Annals of Internal Medicine (2024)

Although medical devices are widely used in clinical practice, clinicians and the public have limited access to information on how devices are tested, regulated, and used, posing challenges to patient safety. This article uses Cook Medical's Celect inferior vena cava (IVC) filter, a medical device used for prevention of pulmonary embolism, as a case study of the transparency gap in medical device regulation. Recently unsealed court documents from litigation related to Celect reveal that the device's clinical study protocol did not follow U.S. Food and Drug Administration (FDA) guidance for IVC filter testing and that study outcome definitions for IVC perforation had lower sensitivity for detecting adverse events than those recommended by professional societies. Furthermore, a comparison of court documents and the public record indicates that adverse events and patient deaths were misreported to FDA reviewers and were inaccurately reported in the published literature and on the device label, providing patients and clinicians with inaccurate information about the device's safety. The Celect IVC filter case demonstrates the need for regulatory reforms to ensure that critical safety data are accessible to the FDA, clinicians, and patients to inform decision making.
Measurable disease as baseline criterion for response assessment in glioblastoma: A comparison of PET -based (PET RANO 1.0) and MRI-based (RANO) assessments
Authors: Katharina J Müller, Robert Forbrig, Jonas Reis, Lilian Wiegand, Enio Barci, Sophie C Kunte, Lena Kaiser, Stephan Schönecker, Christian Schichor, Patrick N Harter, Niklas Thon, Louisa von Baumgarten, Matthias Preusser, Nathalie L Albert
Journal: Neuro-Oncology (2024)

Abstract Background Recently, criteria based on amino acid positron emission tomography (PET) have been proposed for response assessment in diffuse gliomas (PET RANO 1.0). In this study, we compare the prevalence of measurable disease according to PET RANO 1.0 with magnetic resonance imaging (MRI)-based Response Assessment in Neuro-Oncology (RANO) criteria in glioblastoma. Methods We retrospectively identified patients with newly diagnosed IDH-wild-type glioblastoma who underwent [18F] Fluoroethyltyrosine (FET) PET and MRI after resection or biopsy and before radio-/radiochemotherapy. Two independent investigators analyzed measurable disease according to PET RANO 1.0 or MRI-RANO criteria. Additionally, lesion size, congruency patterns, and uptake intensity on [18F]FET PET images were assessed. Results We evaluated 125 patients including 49 cases after primary resection and 76 cases after biopsy. Using PET criteria, 113 out of 125 patients (90.4%) had measurable disease, with a median PET-positive volume of 15.34 cm3 (8.83–38.03). With MRI, a significantly lower proportion of patients had measurable disease (57/125, 45.6%; P &amp;lt; .001) with a median sum of maximum cross-sectional diameters of 35.65 mm (26.18–45.98). None of the 12 patients without measurable disease on PET had measurable disease on MRI. Contrariwise, 56/68 patients (82.4%) without measurable disease on MRI exhibited measurable disease on PET. Clinical performance status correlated significantly with PET-positive volume and MRI-based sum of diameters (P &amp;lt; .0059, P &amp;lt; .0087, respectively). Conclusions [18F]FET PET identifies a higher number of patients with measurable disease compared to conventional MRI in newly diagnosed glioblastoma. PET-based assessment may serve as a novel baseline parameter for evaluating residual tumor burden and improving patient stratification in glioblastoma studies. Further validation in prospective trials is warranted.
The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA–CAR‐T cell therapy: A retrospective study based on LEGEND‐2
Authors: Rui Liu, Gongzhizi Gao, Hongli Chen, Ruijun Dong, Wanggang Zhang, Wanhong Zhao, Jie Liu, Jianli Wang, Bo Lei, Baiyan Wang, Jiali Liu, Xuezhu Xu, Zujie Lin, Ruoyu Yang, Yiwen Wang, Aili He, Fangxia Wang, Ju Bai
Journal: HemaSphere (2024)

Abstract The emergence of abnormal protein bands (APBs), also known as oligoclonal protein bands, has been documented in patients with multiple myeloma (MM) post hematopoietic stem cell transplantation. However, the incidence rate and clinical significance of APBs remain contentious. Few studies have explored the occurrence and prognostic implications of APBs in patients with MM treated with B‐cell maturation antigen (BCMA)–specific chimeric antigen receptor (CAR)‐T therapy. In this retrospective study, we examined the frequency, isotypes, and duration of APBs, as well as their correlation with MM disease characteristics, treatment response, clinical outcomes, and immune signature in patients with relapsed/refractory MM who had received LCAR‐B38M therapy at the Xi'an site of the phase 1 LEGEND‐2 trial. Among 47 patients assessed, 23 (48.9%) developed APBs following CAR‐T therapy, with IgG being the most common isotype. The median onset and duration of APBs post‐CAR‐T infusion were 3.6 and 5.8 months, respectively. Patients with APBs demonstrated significantly improved response to LCAR‐B38M therapy, along with longer overall and progression‐free survival. Furthermore, those with APBs exhibited enhanced recovery rates of immunoglobulins and higher absolute counts of white blood cells, neutrophils, and lymphocytes post‐CAR‐T treatment compared to those without APBs. However, no significant differences were observed between the two groups in the percentages of various T‐cell subsets and natural killer cells. Overall, the presence of APBs in patients with MM following CAR‐T treatment was associated with deeper remission and a more favorable prognosis, suggesting a robust humoral response and subsequent immune reconstitution.
A single‐chain variable fragment‐based bispecific T‐cell activating antibody against CD117 enables T‐cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells
Authors: Laura Volta, Renier Myburgh, Mara Hofstetter, Christian Koch, Jonathan D. Kiefer, Celeste Gobbi, Francesco Manfredi, Kathrin Zimmermann, Philipp Kaufmann, Serena Fazio, Christian Pellegrino, Norman F. Russkamp, Danielle Villars, Mattia Matasci, Monique Maurer, Jan Mueller, Florin Schneiter, Paul Büschl, Niclas Harrer, Jacqueline Mock, Stefan Balabanov, César Nombela‐Arrieta, Timm Schroeder, Dario Neri, Markus G. Manz
Journal: HemaSphere (2024)

Abstract Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML‐exclusive, non‐HSPC‐expressed cell‐surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface‐directed immunotherapy in this disease setting, time‐limited combined immune‐targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single‐chain variable fragment‐based bispecific T‐cell engaging and activating antibody directed against CD3 on T‐cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117‐positive healthy human HSPCs, AML cell lines and patient‐derived AML blasts in the presence of T‐cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117‐expressing leukemia cells and human T‐cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117‐positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117‐expressing leukemia cells and HSPCs prior to HSCT.
Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population‐based screening study
Authors: Sæmundur Rögnvaldsson, Jón Þ. Óskarsson, Sigrun Thorsteinsdóttir, Malin Hultcrantz, Robert Palmason, Ingigerdur S. Sverrisdottir, Elias Eythorsson, Thorir E. Long, Isleifur Olafsson, Ingunn Thorsteinsdottir, Brynjar Vidarsson, Pall T. Onundarson, Bjarni A. Agnarsson, Margret Sigurdardottir, Asbjorn Jonsson, Brian G. M. Durie, Stephen Harding, Ola Landgren, Thorvardur J. Love, Sigurdur Y. Kristinsson
Journal: HemaSphere (2024)

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is characterized by asymptomatic paraproteinemia. In some cases, multiple paraproteins can be identified but the clinical implications of this phenomenon are poorly understood. In this study, we aim to inform the approach to this challenging MGUS subgroup by utilizing data from iStopMM, a population‐based screening study and randomized trial of follow‐up strategies. In total, 75,422 Icelanders over the age of 40 were screened for MGUS with 3389 (4.4%) having at least one paraprotein of whom 303 (9%) had multiple paraproteins. IgM paraproteins were more common in those with multiple paraproteins (49% vs. 27% of paraproteins, p &lt; 0.001), and IgM and non‐IgM paraproteins frequently co‐occurred (60% of cases). Two‐thirds of these participants were randomized to active follow‐up where only 31% of multiple paraproteins were persistent. Paraprotein concentrations were mostly independent, and although progression events were few, the progression rate was similar between those with multiple paraproteins and a single paraprotein. In a next‐generation flow cytometry (NGF) sub‐study, two phenotypically distinct aberrant plasma cell populations could be identified in some with multiple paraproteins. The findings suggest that multiple paraproteins often reflect independent ongoing disease processes that should be monitored independently but otherwise treated similarly to other MGUS cases. Specifically, the findings highlight the need for independent monitoring of IgM and non‐IgM paraproteins in these individuals. The study provides novel insights into the management of this understudied MGUS subset.
Phase 2 Trial of Veliparib, Local Irradiation and Temozolomide in Patients with Newly Diagnosed High-Grade Glioma: A Children's Oncology Group Study
Authors: Matthias A Karajannis, Arzu Onar-Thomas, Tong Lin, Patricia A Baxter, Daniel R Boué, Bonnie L Cole, Christine Fuller, Sofia Haque, Nada Jabado, John T Lucas, Shannon M MacDonald, Celeste Matsushima, Namrata Patel, Christopher R Pierson, Mark M Souweidane, Diana L Thomas, Michael F Walsh, Wafik Zaky, Sarah E S Leary, Amar Gajjar, Maryam Fouladi, Kenneth J Cohen
Journal: Neuro-Oncology (2024)

Abstract Background The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Methods We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations, compared to patient-level data from historical cohorts with closely matching clinical and molecular features. Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Results Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year event-free survival (EFS) was 23% (standard error, SE = 9%) and the 1-year overall survival (OS) was 64% (SE = 10%). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year EFS was 57% (SE = 13%) and 1-year OS was 93% (SE = 0.7%). Conclusions Rapid central pathology review and molecular testing for eligibility were feasible. The protocol therapy including radiation, veliparib, and temozolomide was well tolerated but failed to improve outcomes compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy. ClinicalTrials.gov Identifier NCT03581292 (first posted: July 10, 2018).
Lung function trajectories in Common Variable Immunodeficiencies: an observational retrospective multicenter study
Authors: Helena Buso, Davide Firinu, Renato Finco Gambier, Riccardo Scarpa, Giulia Garzi, Valentina Soccodato, Giulia Costanzo, Andrea G Ledda, Nicolò Rashidy, Ilaria Bertozzi, Stefania Nicola, Giulio Tessarin, Mauro Ramigni, Cinzia Piovesan, Fabrizio Vianello, Andrea Vianello, Stefano Del Giacco, Vassilios Lougaris, Luisa Brussino, Mark G Jones, Isabella Quinti, Carlo Agostini, Marcello Rattazzi, Cinzia Milito, Francesco Cinetto
Journal: Journal of Allergy and Clinical Immunology (2024)

Respiratory disease is a frequent cause of morbidity and mortality in Common Variable Immunodeficiencies (CVIDs), however lung function trajectories are poorly understood.