tbuckley/cabot-search huggingface dataset:
The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches
Authors: J.R. Caldera, Chih-Ming Tsai, Desmond Trieu, Cesia Gonzalez, Irshad A. Hajam, Xin Du, Brian Lin, George Y. Liu
Journal: Cell Reports Medicine (2024)

The failure of the Staphylococcus aureus (SA) IsdB vaccine trial can be explained by the recall of non-protective immune imprints from prior SA exposure. Here, we investigate natural human SA humoral imprints to understand their broader impact on SA immunizations. We show that antibody responses against SA cell-wall-associated antigens (CWAs) are non-opsonic, while antibodies against SA toxins are neutralizing. Importantly, the protective characteristics of the antibody imprints accurately predict the failure of corresponding vaccines against CWAs and support vaccination against toxins. In passive immunization platforms, natural anti-SA human antibodies reduce the efficacy of the human monoclonal antibodies suvratoxumab and tefibazumab, consistent with the results of their respective clinical trials. Strikingly, in the absence of specific humoral memory responses, active immunizations are efficacious in both naive and SA-experienced mice. Overall, our study points to a practical and predictive approach to evaluate and develop SA vaccines based on pre-existing humoral imprint characteristics.
Artificial intelligence, ChatGPT, and other large language models for social determinants of health: Current state and future directions
Authors: Jasmine Chiat Ling Ong, Benjamin Jun Jie Seng, Jeren Zheng Feng Law, Lian Leng Low, Andrea Lay Hoon Kwa, Kathleen M. Giacomini, Daniel Shu Wei Ting
Journal: Cell Reports Medicine (2024)

This perspective highlights the importance of addressing social determinants of health (SDOH) in patient health outcomes and health inequity, a global problem exacerbated by the COVID-19 pandemic. We provide a broad discussion on current developments in digital health and artificial intelligence (AI), including large language models (LLMs), as transformative tools in addressing SDOH factors, offering new capabilities for disease surveillance and patient care. Simultaneously, we bring attention to challenges, such as data standardization, infrastructure limitations, digital literacy, and algorithmic bias, that could hinder equitable access to AI benefits. For LLMs, we highlight potential unique challenges and risks including environmental impact, unfair labor practices, inadvertent disinformation or "hallucinations," proliferation of bias, and infringement of copyrights. We propose the need for a multitiered approach to digital inclusion as an SDOH and the development of ethical and responsible AI practice frameworks globally and provide suggestions on bridging the gap from development to implementation of equitable AI technologies.
Mapping the proteogenomic landscape enables prediction of drug response in acute myeloid leukemia
Authors: James C. Pino, Camilo Posso, Sunil K. Joshi, Michael Nestor, Jamie Moon, Joshua R. Hansen, Chelsea Hutchinson-Bunch, Marina A. Gritsenko, Karl K. Weitz, Kevin Watanabe-Smith, Nicola Long, Jason E. McDermott, Brian J. Druker, Tao Liu, Jeffrey W. Tyner, Anupriya Agarwal, Elie Traer, Paul D. Piehowski, Cristina E. Tognon, Karin D. Rodland, Sara J.C. Gosline
Journal: Cell Reports Medicine (2024)

Acute myeloid leukemia is a poor-prognosis cancer commonly stratified by genetic aberrations, but these mutations are often heterogeneous and fail to consistently predict therapeutic response. Here, we combine transcriptomic, proteomic, and phosphoproteomic datasets with ex vivo drug sensitivity data to help understand the underlying pathophysiology of AML beyond mutations. We measure the proteome and phosphoproteome of 210 patients and combine them with genomic and transcriptomic measurements to identify four proteogenomic subtypes that complement existing genetic subtypes. We build a predictor to classify samples into subtypes and map them to a "landscape" that identifies specific drug response patterns. We then build a drug response prediction model to identify drugs that target distinct subtypes and validate our findings on cell lines representing various stages of quizartinib resistance. Our results show how multiomics data together with drug sensitivity data can inform therapy stratification and drug combinations in AML.
Fc-fused IL-7 provides broad antiviral effects against respiratory virus infections through IL-17A-producing pulmonary innate-like T cells
Authors: Dong-il Kwon, Subin Park, Yujin L. Jeong, Young-Min Kim, Jeongyong Min, Changhyung Lee, Jung-ah Choi, Yoon Ha Choi, Hyun-Jung Kong, Youngwon Choi, Seungtae Baek, Kun-Joo Lee, Yeon-Woo Kang, Chaerim Jeong, Gihoon You, Youngsik Oh, Sun-Kyoung Im, Manki Song, Jong Kyoung Kim, Jun Chang, Donghoon Choi, Seung-Woo Lee
Journal: Cell Reports Medicine (2024)

Repeated pandemics caused by the influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV) have resulted in serious problems in global public health, emphasizing the need for broad-spectrum antiviral therapeutics against respiratory virus infections. Here, we show the protective effects of long-acting recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc) against major respiratory viruses, including influenza virus, SARS-CoV-2, and respiratory syncytial virus. Administration of rhIL-7-hyFc in a therapeutic or prophylactic regimen induces substantial antiviral effects. During an influenza A virus (IAV) infection, rhIL-7-hyFc treatment increases pulmonary T cells composed of blood-derived interferon γ (IFNγ)+ conventional T cells and locally expanded IL-17A+ innate-like T cells. Single-cell RNA transcriptomics reveals that rhIL-7-hyFc upregulates antiviral genes in pulmonary T cells and induces clonal expansion of type 17 innate-like T cells. rhIL-7-hyFc-mediated disease prevention is dependent on IL-17A in both IAV- and SARS-CoV-2-infected mice. Collectively, we suggest that rhIL-7-hyFc can be used as a broadly active therapeutic for future respiratory virus pandemic.
IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids
Authors: Kavitha Sasidharan, Andrea Caddeo, Oveis Jamialahmadi, Francesca Rita Noto, Melissa Tomasi, Francesco Malvestiti, Ester Ciociola, Federica Tavaglione, Rosellina M. Mancina, Alessandro Cherubini, Cristiana Bianco, Angela Mirarchi, Ville Männistö, Jussi Pihlajamäki, Vesa Kärjä, Stefania Grimaudo, Panu K. Luukkonen, Sami Qadri, Hannele Yki-Järvinen, Salvatore Petta, Silvia Manfrini, Umberto Vespasiani-Gentilucci, Vincenzo Bruni, Luca Valenti, Stefano Romeo
Journal: Cell Reports Medicine (2024)

Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.
Targeting Erbin-mitochondria axis in platelets/megakaryocytes promotes B cell-mediated antitumor immunity
Authors: Zilong Zhang, Xu Xu, Di Zhang, Songsong Zhao, Chuyi Wang, Guilin Zhang, Wenshu Chen, Jinglin Liu, Huimin Gong, Youlutuziayi Rixiati, Shi Li, Tong Shen, Jianming Li
Journal: Cell Metabolism (2024)
Targeting cell-type-specific, choroid-peripheral immune signaling to treat age-related macular degeneration
Authors: Joseph B. Lin, Andrea Santeford, Jason J. Colasanti, Yoon Lee, Aaditya V. Shah, Tzu Jui Wang, Philip A. Ruzycki, Rajendra S. Apte
Journal: Cell Reports Medicine (2024)

Age-related macular degeneration (AMD) is a leading cause of blindness featuring pathogenic neovascularization of the choroidal vasculature (CNV). Although systemic immunity plays a role in AMD, the ocular signals that recruit and activate immune cells remain poorly defined. Using single-cell RNA sequencing, we prospectively profile peripheral blood mononuclear cells from 65 individuals including AMD and controls, which we integrate with existing choroid data. We generate a network of choroid-peripheral immune interactions dysregulated in AMD, including known AMD-relevant gene vascular endothelial growth factor (VEGF) receptor 2. Additionally, we find CYR61 is upregulated in choroidal veins and may signal to circulating monocytes. In mice, we validate that CYR61 is abundant in endothelial cells within CNV lesions neighboring monocyte-derived macrophages. Mechanistically, CYR61 activates macrophage anti-angiogenic gene expression, and ocular Cyr61 knockdown increases murine CNV size, indicating CYR61 inhibits CNV. This study highlights the potential of multi-tissue human datasets to identify disease-relevant and potentially therapeutically modifiable targets.
The impact of bed rest on human skeletal muscle metabolism
Authors: Moritz Eggelbusch, Braeden T. Charlton, Alessandra Bosutti, Bergita Ganse, Ifigenia Giakoumaki, Anita E. Grootemaat, Paul W. Hendrickse, Yorrick Jaspers, Stephan Kemp, Tom J. Kerkhoff, Wendy Noort, Michel van Weeghel, Nicole N. van der Wel, Julia R. Wesseling, Petra Frings-Meuthen, Jörn Rittweger, Edwin R. Mulder, Richard T. Jaspers, Hans Degens, Rob C.I. Wüst
Journal: Cell Reports Medicine (2024)

Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle metabolism during bed rest and provide a multi-system analysis of how skeletal muscle and the circulatory system adapt to short- and long-term bed rest (German Clinical Trials: DRKS00015677). We uncover that intracellular glycogen accumulation after short-term bed rest accompanies a rapid reduction in systemic insulin sensitivity and less GLUT4 localization at the muscle cell membrane, preventing further intracellular glycogen deposition after long-term bed rest. We provide evidence of a temporal link between the accumulation of intracellular triglycerides, lipotoxic ceramides, and sphingomyelins and an altered skeletal muscle mitochondrial structure and function after long-term bed rest. An intracellular nutrient overload therefore represents a crucial determinant for rapid skeletal muscle insulin insensitivity and mitochondrial alterations after prolonged bed rest.
Integration of individualized and population-level molecular epidemiology data to model COVID-19 outcomes
Authors: Ted Ling-Hu, Lacy M. Simons, Taylor J. Dean, Estefany Rios-Guzman, Matthew T. Caputo, Arghavan Alisoltani, Chao Qi, Michael Malczynski, Timothy Blanke, Lawrence J. Jennings, Michael G. Ison, Chad J. Achenbach, Paige M. Larkin, Karen L. Kaul, Ramon Lorenzo-Redondo, Egon A. Ozer, Judd F. Hultquist
Journal: Cell Reports Medicine (2024)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with enhanced transmissibility and immune escape have emerged periodically throughout the coronavirus disease 2019 (COVID-19) pandemic, but the impact of these variants on disease severity has remained unclear. In this single-center, retrospective cohort study, we examined the association between SARS-CoV-2 clade and patient outcome over a two-year period in Chicago, Illinois. Between March 2020 and March 2022, 14,252 residual diagnostic specimens were collected from SARS-CoV-2-positive inpatients and outpatients alongside linked clinical and demographic metadata, of which 2,114 were processed for viral whole-genome sequencing. When controlling for patient demographics and vaccination status, several viral clades were associated with risk for hospitalization, but this association was negated by the inclusion of population-level confounders, including case count, sampling bias, and shifting standards of care. These data highlight the importance of integrating non-virological factors into disease severity and outcome models for the accurate assessment of patient risk.
Positioning the preventive potential of microbiome treatments for cystic fibrosis in the context of current therapies
Authors: Eline Cauwenberghs, Ilke De Boeck, Irina Spacova, Ilke Van Tente, Joke Bastiaenssen, Elise Lammertyn, Stijn Verhulst, Kim Van Hoorenbeeck, Sarah Lebeer
Journal: Cell Reports Medicine (2024)

Antibiotics and cystic fibrosis transmembrane conductance regulator (CFTR) modulators play a pivotal role in cystic fibrosis (CF) treatment, but both have limitations. Antibiotics are linked to antibiotic resistance and disruption of the airway microbiome, while CFTR modulators are not widely accessible, and structural lung damage and pathogen overgrowth still occur. Complementary strategies that can beneficially modulate the airway microbiome in a preventive way are highly needed. This could be mediated via oral probiotics, which have shown some improvement of lung function and reduction of airway infections and exacerbations, as a cost-effective approach. However, recent data suggest that specific and locally administered probiotics in the respiratory tract might be a more targeted approach to prevent pathogen outgrowth in the lower airways. This review aims to summarize the current knowledge on the CF airway microbiome and possibilities of microbiome treatments to prevent bacterial and/or viral infections and position them in the context of current CF therapies.
MRD positivity was the poor prognostic factor for adverse-risk AML patients with allogeneic hematopoietic stem cell transplantation: a multicenter TROPHY study
Authors: Yang Cao, Wenxuan Huo, Jiayu Huang, Yang Yang, Yu Wang, Yingjun Chang, Luxiang Wang, Zilu Zhang, Chuanhe Jiang, Xiaoxia Hu, Xiaodong Mo
Journal: Blood Cancer Journal (2024)

Acute myeloid leukemia (AML) is a highly heterogeneous disease distinguished by different cytogenetic and genetic characteristics [1,2].Currently, the risk classification based on the cytogenetics and molecular markers (e.g., the European LeukemiaNet [ELN] risk stratification) is the mainstay criterion that direct the treatments of adult AML patients, and those with adverse-risk AML are recommended to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in their first complete remission (CR1) [1,3].Several studies have reported that the efficacy of allo-HSCT is superior to that of those receiving consolidation chemotherapy alone in adverse-risk AML patients and the benefit of allo-HSCT is observed across ages and donor type [4].Measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) is the commonly used approach to predict post-transplant relapse in AML [5][6][7][8][9].Many studies reported that the risk of post-transplant relapse significantly increased in patients who were MFC positivity before allo-HSCT [10-12]; however, some authors suggested that pre-transplant MFC MRD was less important in predicting relapse than variables reflecting the biology of the disease (e.g., cytogenetics) [13].Thus far, the prognostic value of pre-HSCT MFC MRD positivity is still controversial in AML patients.In addition, no study had compared the clinical outcomes between patients who were MRD positivity and MRD negativity in the adverse-risk AML group.In the present study, we aimed to identify the prognostic value of pre-HSCT MFC MRD positivity in patients with adverse-risk AML, which may further optimize the timing of allo-HSCT.This multicenter, retrospective study based on the transplant database of Wuhan Tongji Hospital, Shanghai Ruijin Hospital, and Peking University Institute of Hematology (PUIH) (i.e., TROPHY group).Consecutive AML patients receiving allo-HSCT from January 2017 to June 2022 were screened, and the eligibility criteria were as follows: (1) aged ≥ 16 years; (2) adverse-risk AML based on ELN 2022 criteria; (3) achieving CR1 before allo-HSCT.The last follow-up was June 30, 2023.The study was approved by the institutional review board of each participated hospital and was conducted in accordance with the Declaration of Helsinki.The protocols for preconditioning regimen, graft-versus-host disease prophylaxis, and infection prophylaxis were reported previously [14,15].MRD status was monitored after consolidation chemotherapy, before allo-HSCT and at 1, 2, 3, 4, 5, 6, 9, and 12 months after allo-HSCT and at 6-month intervals thereafter.
Mode of progression in smoldering multiple myeloma: a study of 406 patients
Authors: Nadine H. Abdallah, Arjun Lakshman, Shaji K. Kumar, Joselle Cook, Moritz Binder, Prashant Kapoor, Angela Dispenzieri, Morie A. Gertz, Martha Q. Lacy, Suzanne R. Hayman, Francis K. Buadi, David Dingli, Yi Lin, Taxiarchis Kourelis, Rahma Warsame, Leif Bergsagel, S. Vincent Rajkumar
Journal: Blood Cancer Journal (2024)

Abstract The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013–2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase ( n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (&gt;100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.
Abstract C024: Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer
Authors: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer related deaths in the US. This mortality is strongly linked to the complex PDA tumor microenvironment that drives resistance to chemotherapy and immune suppression. Most patients succumb to metastatic disease, with liver being the most frequently colonized organ. Despite this, most pre-clinical studies have focused on primary PDA models to study the disease. Accordingly, the extent that the liver metastatic niche promotes immune evasion and resistance to treatment remains unclear. To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. To define the similarities and differences between cell types present in these tumors, we employed a single-cell transcriptomics approach. Our analysis has identified shared populations of malignant epithelial, stromal, and immune cells between lesions, allowing for a direct comparison of programming. Here, we have observed that the dominant populations of PDA cells in pancreas vs. liver tumors engage in distinct metabolic programs that suggest different actionable vulnerabilities. Beyond these, we also observed fibroblasts and myeloid sub-populations that are exclusive to liver tumors. These data further support our hypothesis that alternative mechanisms of metabolic, immune, and stromal interactions take place in the metastatic tumor microenvironment. To define these crosstalk networks, we employed the interactome tool CellChat, which has uncovered unique signaling interactions between the CAF and cancer cell populations in pancreatic and liver tumors. Overall, these data have the potential to lead to new avenues to directly target cancer cells or engage an effective immune response that can be designed to treat metastatic pancreatic cancer- an urgent clinical need. Citation Format: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook. Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C024.