tbuckley/cabot-search huggingface dataset:
Human 3D Ovarian Cancer Models Reveal Malignant Cell–Intrinsic and –Extrinsic Factors That Influence CAR T-cell Activity
Authors: Joash D. Joy, Beatrice Malacrida, Florian Laforêts, Panoraia Kotantaki, Eleni Maniati, Ranjit Manchanda, Alessandro Annibaldi, Sarah Hopkins, Ianire Garrobo-Calleja, Julien Gautrot, Frances R. Balkwill
Journal: Cancer Research (2024)

Abstract In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment. Here, we describe the modulation of CAR T-cell activity by malignant cells and fibroblasts in human three-dimensional (3D) in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer cell spheroids, malignant cell–intrinsic resistance to CAR T-cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T-cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell–cell and cell–matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors. Significance: Three-dimensional in vitro models of increasing complexity uncover mechanisms of resistance to CAR T cells in solid tumors, which could help accelerate development of improved CAR T-cell constructs.
New Therapies for Type 1 and Type 2 Hereditary Angioedema
Authors: Rohan Ameratunga, Hilary J Longhurst
Journal: New England Journal of Medicine (2024)

Hereditary angioedema is a rare disorder characterized by recurrent episodes of mucosal swelling. The disease is usually caused by autosomal dominant mutations in SERPING1, which encodes C1 inhibitor. Type 1 hereditary angioedema is caused by deficiency of C1 inhibitor, whereas type 2 hereditary angioedema is due to dysfunction of C1 inhibitor. As shown in Figure 1, the absence or dysfunction of C1 inhibitor leads to elevated levels of bradykinin, which acts through bradykinin B2 receptors and triggers increased vascular permeability, resulting in angioedema. Episodes of angioedema can be precipitated by surgery, accidental trauma, stress, and menstruation. The most feared complication . . .
Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia
Authors: Alena Malyukova, Mari Lahnalampi, Ton Falqués-Costa, Petri Pölönen, Mikko Sipola, Juha Mehtonen, Susanna Teppo, Karen Akopyan, Johanna Viiliainen, Olli Lohi, Anna K. Hagström-Andersson, Merja Heinäniemi, Olle Sangfelt
Journal: Genome biology (2024)

Abstract Background Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence. Results Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell state characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers. Conclusions Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.
Dual‐Responsive and Aggregation‐Induced‐Emission Probe for Selective Imaging of Infectious Urolithiasis
Authors: Xiangyu Li, Qi Wang, Shanshan Hu, Cuiyun Zhang, Zhirong Zhu, Liyang Wang, Ruoyang Chen, Zhiyin Song, Hongze Liao, Qiang Liu, Wei‐Hong Zhu
Journal: Advanced Healthcare Materials (2024)

Identifying infected stones is crucial due to their rapid growth and high recurrence rate. Here, the calcium-magnesium dual-responsive aggregation-induced emission (AIE)-active probe TCM-5COOH (Tricyano-methlene-pyridine-5COOH), distinctively engineered to distinguish high-threat infection calculi from metabolic stones, is presented. Upon incorporation of flexible alkyl carboxyl group, TCM-5COOH featuring five carboxyl moieties demonstrates excellent water solubility and enhanced penetration into porous infectious stones. The robust chelation of TCM-5COOH with stone surface-abundant Ca
Efficacy and Safety of Donidalorsen for Hereditary Angioedema
Authors: Marc A Riedl, Raffi Tachdjian, William R Lumry, Timothy Craig, Gül Karakaya, Asli Gelincik, Marcin Stobiecki, Joshua S Jacobs, Nihal M Gokmen, Avner Reshef, Mark M Gompels, Michael E Manning, Laura Bordone, Kenneth B Newman, Sabrina Treadwell, Sophie Wang, Aaron Yarlas, Danny M Cohn
Journal: New England Journal of Medicine (2024)

Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression.
Cases of Meningococcal Disease Associated with Travel to Saudi Arabia for Umrah Pilgrimage — United States, United Kingdom, and France, 2024
Authors: Madhura S. Vachon, Anne-Sophie Barret, Jay Lucidarme, John Neatherlin, Amy B. Rubis, Rebecca L. Howie, Shalabh Sharma, Daya Marasini, Basanta Wagle, Page Keating, Mike Antwi, Judy Chen, Tingting Gu-Templin, Pamala Gahr, Jennifer Zipprich, Franny Dorr, Karen Kuguru, Sarah Lee, Umme-Aiman Halai, Brittany Martin, Jeremy Budd, Ziad Memish, Abdullah M. Assiri, Noha H. Farag, Muhamed-Kheir Taha, Ala-Eddine Deghmane, Laura Zanetti, Rémi Lefrançois, Stephen A. Clark, Ray Borrow, Shamez N. Ladhani, Helen Campbell, Mary Ramsay, LeAnne Fox, Lucy A. McNamara
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Invasive meningococcal disease (IMD), caused by infection with the bacterium Neisseria meningitidis, usually manifests as meningitis or septicemia and can be severe and life-threatening (1). Six serogroups (A, B, C, W, X, and Y) account for most cases (2). N. meningitidis is transmitted person-to-person via respiratory droplets and oropharyngeal secretions. Asymptomatic persons can carry N. meningitidis and transmit the bacteria to others, potentially causing illness among susceptible persons. Outbreaks can occur in conjunction with large gatherings (3,4). Vaccines are available to prevent meningococcal disease. Antibiotic prophylaxis for close contacts of infected persons is critical to preventing secondary cases (2).
Metabolic reprogramming in liver fibrosis
Authors: Paul Horn, Frank Tacke
Journal: Cell Metabolism (2024)

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.
Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models
Authors: Sheryl M. Gough, John J. Flanagan, Jessica Teh, Monica Andreoli, Emma Rousseau, Melissa Pannone, Mark Bookbinder, Ryan Willard, Kim Davenport, Elizabeth Bortolon, Gregory Cadelina, Debbie Gordon, Jennifer Pizzano, Jennifer Macaluso, Leofal Soto, John Corradi, Katherine Digianantonio, Ieva Drulyte, Alicia Morgan, Connor Quinn, Miklós Békés, Caterina Ferraro, Xin Chen, Gan Wang, Hanqing Dong, Jing Wang, David R. Langley, John Houston, Richard Gedrich, Ian C. Taylor
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed. Experimental Design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI). Results: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%–123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%–80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib. Conclusions: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2− breast cancer.
NCCN Policy Summit: Cancer Across Geography
Authors: Sean T. McCarson, Alyssa Schatz, Victoria Hood, Ashley Orr, Aaron Bailey, Jesse Plascak, Ursa Brown-Glaberman, Elisa M. Rodriguez, Taneal Carter, Crystal Denlinger
Journal: Journal of the National Comprehensive Cancer Network (2024)

Geographic location of a patient directly impacts access to care, including preventive screenings and early detection. Although there is a higher prevalence of the most common cancers in urban areas, mortality rates are higher in rural communities. Notably, indigenous communities residing on tribal lands often experience heightened access issues and environmental exposure to known and probable human carcinogens. The burdens associated with a cancer diagnosis can be exacerbated by various barriers to accessing quality care; however, there are emerging best practices to overcome these barriers. Understanding the interplay between geography and a patient's access to cancer care services is crucial for addressing existing disparities and ensuring equitable health care provision across regions. By leveraging innovative policy and practice solutions, communities can begin to close care gaps and establish bidirectional trust between patients and providers across the care continuum, which is necessary to enact meaningful reforms. To advance the conversation on geographic disparities and strategies that mitigate associated barriers to care, NCCN hosted the Policy Summit "Cancer Across Geography" on June 15, 2023, at the National Press Club in Washington, DC. Through keynote addresses and multistakeholder panel discussions, this hybrid event explored care imbalances across geography, recent policy and technology advancements, and current challenges associated with cancer care. This created a forum for a diverse group of attendees to thoughtfully discuss policies and practices to advance high-quality, effective, efficient, equitable, and accessible cancer care for all. Speakers and attendees featured multidisciplinary clinicians, epidemiologists, community oncologists, researchers, payers, patient advocates, industry, providers, policymakers, and leaders representing underserved communities, among others.
Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface
Authors: Rachael M. Wolters, James A. Ferguson, Ivette A. Nuñez, Elaine E. Chen, Ty Sornberger, Luke Myers, Svearike Oeverdieck, Sai Sundar Rajan Raghavan, Chandrahaas Kona, Laura S. Handal, Trevor E. Esilu, Edgar Davidson, Benjamin J. Doranz, Taylor B. Engdahl, Nurgun Kose, Lauren E. Williamson, C. Buddy Creech, Katherine N. Gibson-Corley, Andrew B. Ward, James E. Crowe
Journal: Immunity (2024)
Intraperitoneal Nivolumab After Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort
Authors: Pauline Corbaux, Gilles Freyer, Olivier Glehen, Benoît You, Naoual Bakrin, Audrey Gelot, David Dayde, Christophe Sajous, Max Piffoux, Julien Péron, Gaelle Lescuyer, Lea Payen, Vahan Kepenekian
Journal: Clinical Cancer Research (2024)

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761).
TRIM33 plays a critical role in regulating dendritic cell differentiation and homeostasis by modulating Irf8 and Bcl2l11 transcription
Authors: Xiangyi Shen, Xiaoguang Li, Tao Wu, Tingting Guo, Jiaoyan Lv, Zhimin He, Maocai Luo, Xinyi Zhu, Yujie Tian, Wenlong Lai, Chen Dong, Xiaoyu Hu, Li Wu
Journal: Cellular and Molecular Immunology (2024)

The development of distinct dendritic cell (DC) subsets, namely, plasmacytoid DCs (pDCs) and conventional DC subsets (cDC1s and cDC2s), is controlled by specific transcription factors. IRF8 is essential for the fate specification of cDC1s. However, how the expression of Irf8 is regulated is not fully understood. In this study, we identified TRIM33 as a critical regulator of DC differentiation and maintenance. TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages. TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors. TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II (S2 Pol II) levels at Irf8 gene sites. Moreover, TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11, thereby maintaining DC homeostasis. Taken together, our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression. The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.
Legacy of the discovery of the T-cell receptor: 40 years of shaping basic immunology and translational work to develop novel therapies
Authors: Yufang Shi, Andreas Strasser, Douglas R. Green, Eicke Latz, Alberto Mantovani, Gerry Melino
Journal: Cellular and Molecular Immunology (2024)

Forty years have passed since the groundbreaking achievement of cloning T-cell receptor genes [1,2].The rich narrative that sets the stage for this significant event is incredibly striking, and its profound legacy in contemporary immunology and medical science is truly remarkable.
SIMS: A deep-learning label transfer tool for single-cell RNA sequencing analysis
Authors: Jesus Gonzalez-Ferrer, Julian Lehrer, Ash O’Farrell, Benedict Paten, Mircea Teodorescu, David Haussler, Vanessa D. Jonsson, Mohammed A. Mostajo-Radji
Journal: Cell Genomics (2024)

Cell atlases serve as vital references for automating cell labeling in new samples, yet existing classification algorithms struggle with accuracy. Here we introduce SIMS (scalable, interpretable machine learning for single cell), a low-code data-efficient pipeline for single-cell RNA classification. We benchmark SIMS against datasets from different tissues and species. We demonstrate SIMS's efficacy in classifying cells in the brain, achieving high accuracy even with small training sets (<3,500 cells) and across different samples. SIMS accurately predicts neuronal subtypes in the developing brain, shedding light on genetic changes during neuronal differentiation and postmitotic fate refinement. Finally, we apply SIMS to single-cell RNA datasets of cortical organoids to predict cell identities and uncover genetic variations between cell lines. SIMS identifies cell-line differences and misannotated cell lineages in human cortical organoids derived from different pluripotent stem cell lines. Altogether, we show that SIMS is a versatile and robust tool for cell-type classification from single-cell datasets.
CHIPing Away at Proteomics to Find Correlations with Myeloid Neoplasms
Authors: Avni M. Bhalgat, Justin Taylor
Journal: Clinical Cancer Research (2024)

Plasma proteomic profiling to identify associations with myeloid neoplasm (MN) risk highlights the potential of integrating proteins and genetic biomarkers for the detection of individuals at high risk of developing MN. These proteins also offer valuable insights into biological pathways and inflammatory mechanisms involved in the progression of clonal hematopoiesis to MN. See related article by Tran et al., p. 3220.
CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify <i>KDM3B</i> as a Genotype-specific Vulnerability in <i>IDH2</i>- and <i>TET2</i>-mutant Cells
Authors: Michael R. Waarts, Shoron Mowla, Meaghan Boileau, Anthony R. Martinez Benitez, Junya Sango, Maya Bagish, Inés Fernández-Maestre, Yufan Shan, Shira E. Eisman, Young C. Park, Matthew Wereski, Isabelle Csete, Kavi O’Connor, Angelica C. Romero-Vega, Linde A. Miles, Wenbin Xiao, Xiaodi Wu, Richard P. Koche, Scott A. Armstrong, Alan H. Shih, Eirini P. Papapetrou, Jason M. Butler, Sheng F. Cai, Robert L. Bowman, Ross L. Levine
Journal: Cancer Discovery (2024)

Abstract Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs. Significance: Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need to identify therapeutic targets. We develop an ex vivo platform to perform CRISPR/Cas9 screens in primary HSPCs. We identify KDM3B and downstream signaling components as genotype-specific dependencies in CH and myeloid malignancies. See related commentary by Khabusheva and Goodell, p. 1768
Th17-to-Tfh plasticity during periodontitis limits disease pathology
Authors: Flora A. McClure, Kelly Wemyss, Joshua R. Cox, Hayley M. Bridgeman, Ian E. Prise, James I. King, Shafqat Jaigirdar, Annie Whelan, Gareth W. Jones, John R. Grainger, Matthew R. Hepworth, Joanne E. Konkel
Journal: The Journal of Experimental Medicine (2024)

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.
γδ T cells: The first line of defense for neonates
Authors: Joshua I. Gray, Donna L. Farber
Journal: The Journal of Experimental Medicine (2024)

A distinct CD83-expressing subset of γδ T cells are enriched in preterm infants with sepsis, providing insights into their functional maturation dynamics in settings of homeostasis and disease (León-Lara et al. https://doi.org/10.1084/jem.20231987).