tbuckley/cabot-search huggingface dataset:
Abstract PO-019: Ubiquitin E3 ligase OSTM1 regulates the cAMP/PKA/CREB pathway and suppresses B-cell malignancies
Authors: Muhammad Usama Tariq, Julia Shen, Jaeyong Jung, Namratha Sheshadri, Junrong Yan, Rongrong Li, Kevin Lu, Tong Liu, Hong Li, Yue Lynn Wang, Ping Xie, Wei-Xing Zong
Journal: Blood Cancer Discovery (2024)

Abstract B-cell malignancies (BCM) often arise from genomic alterations introduced during different stages of B-cell development. Here, we performed a whole genome targeting CRISPR/Cas9 screen in the immortalized yet non-transformed IL-3-dependent Ba/F3 murine pro-B cell line to identify genes whose loss confers IL-3 independence, reasoning that these genes may function as tumor suppressor genes (TSGs) in BCM. One of the candidate genes is osteoporosis-associated transmembrane protein 1 (OSTM1), an E3 ubiquitin ligase whose loss-of-function causes autosomal recessive osteoporosis. Informatics analysis of patient data showed that OSTM1 is frequently deleted across BCM, which co-occurs with the deletion of a well-characterized TSG Cdkn2a. Genetic silencing of OSTM1 in Ba/F3 cells conferred IL-3-independent survival and proliferation, as well as splenomegaly, lymphadenopathy, and abnormal peripheral blood cell count, indicative of transformation in vivo. Using mass spectrometry screens, we identified phosphodiesterase 3B (PDE3B) as an interacting partner of OSTM1. OSTM1 ubiquitylates PDE3B and promotes its proteasomal degradation. The OSTM1-PDE3B interaction and PDE3B degradation are negatively regulated by OSTM1 N-glycosylation. As PDE3B catalyzes the conversion of cAMP to AMP, it negatively regulates the cAMP-dependent PKA/CREB/CREBBP tumor suppressive pathway. Indeed, overexpression of PDE3B accelerated cell proliferation while PDE3B silencing in OSTM1 KO cells reversed the transformation phenotype in cell lines and in mouse allograft tumors. Importantly, a strong correlation between OSTM1 disruption, increased PDE3B stability, and decreased PKA/CREB/CEBBP signaling was observed in cell lines and in BCM patient datasets. Finally, CD19-Cre mediated B-cell specific ablation of OSTM1 cooperated with CDKN2A deletion to drive spontaneous immature B-cell lymphomagenesis in mice. Collectively, these results indicate that OSTM1 is a novel TSG which targets PDE3B for proteasomal degradation. Loss of OSTM1 enhances PDE3B stability and abrogates the tumor-suppressive role of cAMP/CREB/CREBBP pathway which promotes BCM. Citation Format: Muhammad Usama Tariq, Julia Shen, Jaeyong Jung, Namratha Sheshadri, Junrong Yan, Rongrong Li, Kevin Lu, Tong Liu, Hong Li, Yue Lynn Wang, Ping Xie, Wei-Xing Zong. Ubiquitin E3 ligase OSTM1 regulates the cAMP/PKA/CREB pathway and suppresses B-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-019.
Abstract PR03: Immunosurveillance of precancerous germinal center B cells
Authors: Lingling Zhang, Oscar Atkins, Miu Shing Hung, Hans Christian Reinhardt, Dinis Pedro Parente Calado
Journal: Blood Cancer Discovery (2024)

Abstract Most Non-Hodgkin Lymphomas (NHLs) originate from germinal center (GC) or post-GCB cells. While the immune system actively targets precancerous cells in epithelial-derived cancers, it is uncertain if the same applies to precancerous GCB cells. Knowledge on Follicular Lymphoma (FL), the most common low-grade NHL derived from GCB cells, prompted us to develop novel mouse models to mimic the precancerous state. In FL, BCL2 translocation and CREBBP loss-of-function (LoF) mutations are characteristic of a precancerous state. These mutations can be detected years before FL diagnosis, hinting at potential immune involvement in preventing FL. Our research affirms the effectiveness of the mouse models in replicating the FL precancerous state. Mice with BCL2 overexpression (OE) alone or together with CREBBP LoF showed increased GCB cell expansion, up to 6-fold compared to control. This expansion involved reduced GCB cell death rather than increased proliferation, consistent with FL slow-growing nature. Mice harboring mutant GCB cells also exhibited a significant increase in memory B cells, up to 20-fold when compared to control. As the GC reaction progressed, the impact of CREBBP LoF emerged, profoundly altering GCB cell phenotypes, and triggering a remarkable surge in cell expansion, escalating up to 80-fold compared to mice with BCL2 OE alone or control. However, this hyperplasia was swiftly followed by a decline, indicative of immunosurveillance targeting precancerous GCB cells. Prior to the reduction of GCB cells with BCL2 OE and CREBBP LoF, we observed a notable expansion of PD1+ CD8+ T cells expressing granzyme A and perforin. These activated CD8+ T cells also expressed CXCR5, facilitating their infiltrating into the B cell follicle to specifically eliminate GCB cells with BCL2 OE and CREBBP LoF. Preemptive depletion of CD8+ T cell effectively prevented the loss of precancerous GCB cells. The examination of the GC reaction over time provided new perspectives into the immunosurveillance of precancerous GCB cells and FL development. The data supports the concept that precancerous GCB cells must overcome robust anti-tumor immunity for Lymphoma to ensue. This knowledge offers potential explanation for the infrequent and extended duration of the transition from precancerous GCB cells to full-blown FL. These models provide a foundation to explore mechanisms underlying immune evasion by precancerous GCB cells. Citation Format: Lingling Zhang, Oscar Atkins, Miu Shing Hung, Hans Christian Reinhardt, Dinis Pedro Parente Calado. Immunosurveillance of precancerous germinal center B cells [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PR03.
Surveillance of Invasive Pneumococcal Disease in Spain Exploring the Impact of the COVID-19 Pandemic (2019-2023)
Authors: Covadonga Pérez-García, Julio Sempere, Sara de Miguel, Samantha Hita, Aída Úbeda, Erick Joan Vidal, Joaquín Llorente, Aurora Limia, Angel Gil de Miguel, Juan Carlos Sanz, Federico Martinón-Torres, Carmen Ardanuy, Mirian Domenech, Jose Yuste
Journal: Journal of Infection (2024)

Dynamic trends of invasive pneumococcal disease (IPD) including the evolution of prevalent serotypes are very useful to evaluate the impact of current and future pneumococcal conjugate vaccines (PCVs) and the rise of non-vaccine serotypes. In this study, we include epidemiological patterns of S. pneumoniae before and after COVID-19 pandemic.
Abstract PO-020: ZBTB24 is a novel tumor suppressor and cooperates with CDKN2A to suppress B-cell lymphomagenesis
Authors: Rongrong Li, Namratha Sheshadri, Jianliang Shen, Junrong Yan, Jaeyong Jung, Muhammad Usama Tariq, Y Lynn Wang, Ping Xie, Wei-Xing Zong
Journal: Blood Cancer Discovery (2024)

Abstract B-cell lymphoma is the most common hematological malignancy that accounts for the sixth highest mortality among all cancers. Despite recent improvements on combined chemotherapy and immunotherapy, treatments remain challenging due to complex genetic heterogeneity and molecular pathogenesis. To explore novel mechanisms in B-cell lymphomagenesis, we performed a genome-wide CRISPR knockout screen in the murine interleukin-3 (IL-3)-dependent Ba/F3 pro-B cell line and identified Zbtb24 as a putative target whose silencing leads to elevated proliferative signaling and reduced apoptosis, conferring IL-3-independent growth in Ba/F3 cells. Silencing of ZBTB24 also accelerated growth in multiple human B-cell lymphoma cell lines. ZBTB24 is a member of the zinc-finger and BTB domain containing transcription factor that is highly expressed in spleen and bone marrow. While it has been shown that ZBTB24 may play an important role in B-cell development and activation, its involvement in B-cell lymphoma has not been described. Analysis of publicly available datasets found that ZBTB24 copy number deletion occurs in various B-cell lymphomas, which frequently co-occurs with deletion of the tumor suppressor CDKN2A. Hence, we generated B-cell specific Zbtb24 single knockout and Zbtb24/Cdkn2a double knockout mice to explore the role of Zbtb24 in vivo. While Zbtb24 and Cdkn2a single knockout mice remained tumor-free or showed low penetrance of tumorigenesis, the double knockout mice developed lymphadenopathy and splenomegaly accompanied with accelerated mortality. Flow cytometry analysis of bone marrow, spleen, and lymph nodes revealed malignant B-cells. Subsequent transplantation of the splenic cells induced identical malignant B-cell lymphomagenesis and immunophenotype in athymic nude mice, further confirming its malignant identity. These results indicate that ZBTB24 is a novel tumor suppressor in B-cell malignancy. Ongoing studies are being conducted to understand the mechanistic basis for ZBTB24 tumor suppressive function that may involve transcriptional regulation of its target gene expression. This project is supported by the NIH R01CA232246, R01CA129536, and the John Colaizzi Endowment Fund. Citation Format: Rongrong Li, Namratha Sheshadri, Jianliang Shen, Junrong Yan, Jaeyong Jung, Muhammad Usama Tariq, Y Lynn Wang, Ping Xie, Wei-Xing Zong. ZBTB24 is a novel tumor suppressor and cooperates with CDKN2A to suppress B-cell lymphomagenesis [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-020.
Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications
Authors: Dezhuang Ye, Chinwendu Chukwu, Yaoheng Yang, Zhongtao Hu, Hong Chen
Journal: Advanced Drug Delivery Reviews (2024)

Adeno-associated virus (AAV) vectors have emerged as a promising tool in the development of gene therapies for various neurological diseases, including Alzheimer's disease and Parkinson's disease. However, the blood–brain barrier (BBB) poses a significant challenge to successfully delivering AAV vectors to the brain. Strategies that can overcome the BBB to improve the AAV delivery efficiency to the brain are essential to successful brain-targeted gene therapy. This review provides an overview of existing strategies employed for AAV delivery to the brain, including direct intraparenchymal injection, intra-cerebral spinal fluid injection, intranasal delivery, and intravenous injection of BBB-permeable AAVs. Focused ultrasound has emerged as a promising technology for the noninvasive and spatially targeted delivery of AAV administered by intravenous injection. This review also summarizes each strategy's current preclinical and clinical applications in treating neurological diseases. Moreover, this review includes a detailed discussion of the recent advances in the emerging focused ultrasound-mediated AAV delivery. Understanding the state-of-the-art of these gene delivery approaches is critical for future technology development to fulfill the great promise of AAV in neurological disease treatment.
Abstract PO-018: Commensal bacteria are required for chronic inflammation and B lymphoma development in myeloid cell-specific TRAF3-deficient mice
Authors: Jaeyong Jung, Sining Zhu, Almin I Lalani, Judith Shakarchi, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie
Journal: Blood Cancer Discovery (2024)

Abstract Myeloid cells are the major players of innate immunity and inflammation. The function of myeloid cells is critically regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/- ) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). Here we sought to identify the internal trigger of chronic inflammation and aberrant B cell activation in these mice. We first detected gut dysbiosis and transmigration of commensal bacteria to the liver in aging M-Traf3-/- mice using 16s rRNA gene sequencing of fecal bacterial DNA and bacterial culture of liver homogenates, respectively. To determine if gut dysbiosis and bacterial transmigration induce chronic inflammation and aberrant B cell activation, we treated mice with broad-spectrum antibiotics. We found that depletion of commensal bacteria with antibiotics effectively prevented chronic inflammation and BCL development in aging M-Traf3-/- mice. We next demonstrated that systemic IgG responses against commensal bacteria were induced in the mice as shown by fecal bacteria FACS analysis. Interestingly, our sequencing data of the IgH gene VDJ region revealed that many malignant B cell clones of M-Traf3-/- mice had undergone class switch recombination and contained somatic hypermutations, indicating their origination from germinal center (GC) or post-GC B cells. We also noticed that the CDR3 sequences of malignant B cell clones derived from M-Traf3-/- mice exhibit high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, aging M-Traf3-/- mice with BCL contained high titers of antibodies against commensal bacteria, but not autoantigens, in the serum. Taken together, our findings suggest that commensal bacteria dysbiosis and transmigration can promote chronic inflammation and BCL development in individuals with compromised innate immunity. Accordingly, inhibition of commensal bacteria may serve as an effective therapeutic strategy for the prevention and treatment of chronic inflammation and B-cell lymphomas in these patients. Citation Format: Jaeyong Jung, Sining Zhu, Almin I Lalani, Judith Shakarchi, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie. Commensal bacteria are required for chronic inflammation and B lymphoma development in myeloid cell-specific TRAF3-deficient mice [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-018.
Abstract PO-030: Single cell spatial analysis of large B cell lymphoma identifies biomarkers correlated with genetic subtypes and clincal outcomes
Authors: Alexander Xu, Joseph Lownik, Anton Villamejor, Simeon Mahov, Ying Li, Yidan Xu-Monette, Ken Young, Akil Merchant
Journal: Blood Cancer Discovery (2024)

Abstract Single cell and multiplex imaging modalities have opened new insights into the organization and architecture of the immune microenvironment of cancer. Our group was one of the first to demonstrate these methods in the analysis of Hodgkin [1,2] and non-Hodgkin lymphoma [3]. Most recently, we demonstrated that spatial biomarkers outperform gene-expression biomarkers in predicting relapse after autologous transplant [4]. Here we present previously unpublished data demonstrating single cell multiplexed spatial analysis, using the imaging mass cytometry platform, in a cohort of 426 patients with large cell lymphoma. Gene expression and mutational analysis are available for a majority of cases allowing us to correlate spatial signature with genetic classes such as LymphGen [5], and deconvolution methods such as EcoTyper [6]. Using this cohort, we identify spatial biomarkers that improve prediction of clinical outcomes beyond cell of origin or genetic subgroup and identify novel targets for clinical development. Finally, we will present our approaches to move our discovery level spatial profiling into clinical diagnostic space through application of automated multiplex immunofluorescence imaging and a machine learning based image analysis pipeline. [1] Aoki T, et al. Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma. Cancer Discov. 2020 doi: 10.1158/2159-8290.CD-19-0680. [2] Xu, A. et al. Single cell spatial analysis and biomarker discovery in Hodgkin lymphoma. Biorxiv, 2023. https://doi.org/10.1101/2023.05.24.542195. [3] Colombo AR, et al. Single-cell spatial analysis of tumor immune architecture in diffuse large B-cell lymphoma. Blood Adv. 2022 doi: 10.1182/bloodadvances.2022007493. [4] Aoki T, et al. Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma. J Clin Oncol. 2024 doi: 10.1200/JCO.23.01115. [5] Wright GW, et al. A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications. Cancer Cell. 2020 doi: 10.1016/j.ccell.2020.03.015. [6] Steen CB, et al. The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Cancer Cell. 2021 doi: 10.1016/j.ccell.2021.08.011. Citation Format: Alexander Xu, Joseph Lownik, Anton Villamejor, Simeon Mahov, Ying Li, Yidan Xu-Monette, Ken Young, Akil Merchant. Single cell spatial analysis of large B cell lymphoma identifies biomarkers correlated with genetic subtypes and clincal outcomes [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-030.
Abstract PO-001: GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance
Authors: Jayadev Mavuluri
Journal: Blood Cancer Discovery (2024)

Abstract Chimeric antigen receptor (CAR)-T cell therapies can be curative for CD19+ hematological malignancies, though are limited by frequent patient relapse and response failures. Here, we identify GPR65 as a tumor-specific determinant of responsiveness to CAR-T cell therapy. In patients and an immune competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) response to CAR-T cell therapy, high GPR65 is associated with a complete tumor response. In mice, GPR65 knockout (GPR65 KO) tumors are resistant to CAR-T cell therapy in vivo, without antigen loss. Single-cell network analyses reveal that GPR65 deficiency remodels tumor interactions with host macrophages, partially through increasing tumor VEGFA. This leads to increased macrophage numbers and preferential M2 macrophage polarization. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restores responsiveness to CAR-T cell treatment. Anti-VEGFA therapy in combination with CAR-T cell administration also prolongs the survival of GPR65 KO tumor-bearing mice. Our results indicate that tumor GPR65 expression is important for B-ALL responses to CAR-T cell therapy through its impact on the tumor microenvironment and supports new approaches to identify and overcome CAR-T cell resistance. Citation Format: Jayadev Mavuluri. GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-001.
Diabetic myocardial disorder. A clinical consensus statement of the Heart Failure Association of the <scp>ESC</scp> and the <scp>ESC</scp> Working Group on Myocardial &amp; Pericardial Diseases
Authors: Petar M. Seferović, Walter J. Paulus, Giuseppe Rosano, Marija Polovina, Mark C. Petrie, Pardeep S. Jhund, Carsten Tschöpe, Naveed Sattar, Massimo Piepoli, Zoltán Papp, Eberhard Standl, Mamas A. Mamas, Paul Valensi, Ales Linhart, Nebojša Lalić, Antonio Ceriello, Wolfram Döhner, Arsen Ristić, Ivan Milinković, Jelena Seferović, Francesco Cosentino, Marco Metra, Andrew J.S. Coats
Journal: European Journal of Heart Failure (2024)
Aqueous‐Aqueous Triboelectric Nanogenerators Empowered Multifunctional Wound Healing System with Intensified Current Output for Accelerating Infected Wound Repair
Authors: Weijiang Wang, Chongyang Fu, Yanfeng Du, Huiyuan Zheng, Yage Zhang, Yang Song, Wentao Sun, Xiaoxiong Wang, Qingming Ma
Journal: Advanced Healthcare Materials (2024)

Triboelectric nanogenerators (TENGs) have emerged as promising devices for generating self-powered therapeutic electrical stimulation over multiple aspects of wound healing. However, the challenge of achieving full 100% contact in conventional TENGs presents a substantial hurdle in the quest for higher current output, which is crucial for further improving healing efficacy. Here, a novel multifunctional wound healing system is presented by integrating the aqueous-aqueous triboelectric nanogenerators (A-A TENGs) with a functionalized conductive hydrogel, aimed at advancing infected wound therapy. The A-A TENGs are founded on a principle of 100% contact interface and efficient post-contact separation of the immiscible interface within the aqueous two-phase system (ATPS), enhancing charge transfer and subsequently increasing current performance. Leveraging this intensified current output, this system demonstrates efficient therapeutic efficacies over infected wounds both in vitro and in vivo, including stimulating fibroblast migration and proliferation, boosting angiogenesis, enhancing collagen deposition, eradicating bacteria, and reducing inflammatory cells. Moreover, the conductive hydrogel ensures the uniformity and integrity of the electric field covering the wound site, and exhibits multiple synergistic therapeutic effects. With the capability to realize accelerated wound healing, the developed "A-A TENGs empowered multifunctional wound healing system" presenting an excellent prospect in clinical wound therapy.
John Launer: Faces or candlesticks? Why we need continuity in teams
Authors: John Launer
Journal: BMJ (2024)

Sometimes a remark stays in your mind for a very long time because of what it symbolises.One such remark has remained with me for many years.At the time, I was a GP partner during what now seems a golden age.We had a wonderful primary care team, including a practice nurse, three district nurses, a midwife, a community mental health nurse, and other colleagues including two full time health visitors.We didn't need to employ locums or salaried doctors.We all met once a week to discuss cases that were complex or causing concern.Sometimes a local social worker would join us.
David Oliver: Will the actions pledged in Labour’s election manifesto save health and social care?
Authors: David Oliver
Journal: BMJ (2024)

Last week the main UK parties published their manifestos ahead of the coming general election.I was most interested in Labour's manifesto, launched on 14 June. 1 More than 20 points ahead in the opinion polls, 2 Labour is a near certainty to be the next party of government or at least the dominant partner in any coalition.Manifesto promises are often broken-so buyer beware!Looking back to the Conservatives' 2019 manifesto, they've delivered on none of the key pledges on health and social care. 3Some were quietly shelved.But what has Labour said it will do on health and social care, three weeks from the 4 July poll?On the dire state of elective care waiting times and list size, Labour reiterates its public pledge to create 40 000 more appointments a week for operations, procedures, outpatient appointments, and investigations.The prominence of this commitment is no surprise: it's seen as an area where improvement can be demonstrated quickly.How? "By incentivising staff to carry out additional appointments out of hours," by "pooling resources across neighbouring hospitals to create shared waiting lists," and by using "space capacity in the independent sector."Whether those staff have the time or energy, and how much money will be required, is another matter.And that pledge equates to an extra two million appointments a year, when the NHS has 145 million-so, only a 2% increase overall.