tbuckley/cabot-search huggingface dataset:
CD47-SIRPα Blockade Sensitizes Head and Neck Squamous Cell Carcinoma to Cetuximab by Enhancing Macrophage Adhesion to Cancer Cells
Authors: Bolei Li, Yu Hao, Hongzhi He, Yu Fan, Biao Ren, Xian Peng, Xuedong Zhou, Lei Cheng
Journal: Cancer Research (2024)

Developing effective treatments for patients with head and neck squamous cell carcinoma (HNSCC) is a significant challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. Here, we used pooled CRISPR screening to find targets that can synergize with cetuximab and identified CD47 as the leading candidate. Rather than inhibiting cancer cell proliferation, CD47 inhibition promoted cetuximab-triggered antibody-dependent cellular phagocytosis (ADCP), thereby enhancing macrophage-mediated cancer cell removal. The combination of CD47-signal-regulatory protein α (SIRPα) blockade and cetuximab demonstrated strong anticancer activity in vivo. In addition to blocking the phagocytosis checkpoint, CD47-SIRPα inhibition upregulated CD11b/CD18 on the surface of macrophages, which accelerated intercellular adhesion between macrophages and cancer cells to enhance subsequent phagocytosis. Inhibition of the interaction between macrophage CD11b/CD18 and cancer cell intercellular adhesion molecule-1 (ICAM1) eliminated the intercellular adhesion and phagocytosis induced by CD47-SIRPα blockade. Thus, CD47-SIRPα blockade enhances ADCP through CD11b/CD18-ICAM1-mediated intercellular adhesion and sensitizes HNSCC to cetuximab. Significance: CD47-SIRPα blockade increases surface CD11b/CD18 on macrophages to enhance adhesion to cancer cells, resulting in robust synergistic phagocytosis in combination with cetuximab treatment in head and neck squamous cell carcinoma.
Asparagine Dependency is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer
Authors: Young A. Yoo, Songhua Quan, William Yang, Qianyu Guo, Yara Rodríguez, Zachary R. Chalmers, Mary F. Dufficy, Barbara Lackie, Vinay Sagar, Kenji Unno, Mihai I. Truica, Navdeep S. Chandel, Sarki A. Abdulkadir
Journal: Cancer Research (2024)

TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we have shown here that TP53-altered prostate cancer exhibits an increased dependency on asparagine (Asn) and overexpresses Asn synthetase (ASNS), the enzyme catalyzing the synthesis of Asn. Mechanistically, the loss or mutation of TP53 transcriptionally activated ASNS expression, directly and via mTORC1-mediated ATF4 induction, driving de novo Asn biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to Asn restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of Asn, respectively, and cell viability was rescued by Asn addition. Notably, pharmacological inhibition of intracellular Asn biosynthesis using a glutaminase inhibitor and depletion of extracellular Asn with L-asparaginase significantly reduced Asn production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting Asn production to treat these lethal prostate cancers. Significance: TP53-mutated castration-resistant prostate cancer is dependent on asparagine biosynthesis due to upregulation of ASNS and can be therapeutically targeted by approaches that deplete intracellular and extracellular asparagine.
Nasal tau immunotherapy clears intracellular tau pathology and improves cognitive functions in aged tauopathy mice
Authors: Sagar Gaikwad, Nicha Puangmalai, Minal Sonawane, Mauro Montalbano, Rachel Price, Malini S. Iyer, Anamika Ray, Sandra Moreno, Rakez Kayed
Journal: Science Translational Medicine (2024)

Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation–specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological tau aggregates in brain tissues from patients with AD, dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target intracellular tau aggregates and ensure rapid delivery to the brain, TTCM2 was loaded in micelles (TTCM2-ms) and administered through the intranasal route. We found that intranasally administered TTCM2-ms efficiently entered the brain in hTau-tauopathy mice, targeting pathological tau in intracellular compartments. Moreover, a single intranasal dose of TTCM2-ms effectively cleared pathological tau, elevated synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies revealed that TTCM2-ms cleared intracellular, synaptic, and seed-competent tau aggregates through tripartite motif-containing 21 (TRIM21), an intracellular antibody receptor and E3 ubiquitin ligase known to facilitate proteasomal degradation of cytosolic antibody-bound proteins. TRIM21 was found to be essential for TTCM2-ms–mediated clearance of tau pathology. Our study collectively provides evidence of the effectiveness of nasal tau immunotherapy in targeting and clearing intracellular tau pathology through TRIM21 and enhancing cognition in aged tauopathy mice. This study could be valuable in designing effective tau immunotherapies for AD and other tauopathies.
Prostate tissue ablation and drug delivery by an image-guided injectable ionic liquid in ex vivo and in vivo models
Authors: Yusuf M. Demirlenk, Hassan Albadawi, Zefu Zhang, Dila Atar, Enes Cevik, Hyeongseop Keum, Jinjoo Kim, Suliman Rehman, Seyda Gunduz, Erin Graf, Joseph L. Mayer, Pedro R. Dos Santos, Rahmi Oklu
Journal: Science Translational Medicine (2024)

Benign prostatic hyperplasia and prostate cancer are often associated with lower urinary tract symptoms, which can severely affect patient quality of life. To address this challenge, we developed and optimized an injectable compound, prostate ablation and drug delivery agent (PADA), for percutaneous prostate tissue ablation and concurrently delivered therapeutic agents. PADA is an ionic liquid composed of choline and geranic acid mixed with anticancer therapeutics and a contrast agent. The PADA formulation was optimized for mechanical properties compatible with hand injection, diffusion capability, cytotoxicity against prostate cells, and visibility of an x-ray contrast agent. PADA also exhibited antibacterial properties against highly resistant clinically isolated bacteria in vitro. Ultrasound-guided injection, dispersion of PADA in the tissue, and tissue ablation were tested ex vivo in healthy porcine, canine, and human prostates and in freshly resected human tumors. In vivo testing was conducted in a murine subcutaneous tumor model and in the canine prostate. In all models, PADA decreased the number of viable cells in the region of dispersion and supported the delivery of nivolumab throughout a portion of the tissue. In canine survival experiments, there were no adverse events and no impact on urination. The injection approach was easy to perform under ultrasound guidance and produced a localized effect with a favorable safety profile. These findings suggest that PADA is a promising therapeutic prostate ablation strategy to treat lower urinary tract symptoms.
Lupus IgA1 autoantibodies synergize with IgG to enhance plasmacytoid dendritic cell responses to RNA-containing immune complexes
Authors: Hayley R. Waterman, Matthew J. Dufort, Sylvia E. Posso, Minjian Ni, Lucy Z. Li, Chengsong Zhu, Prithvi Raj, Kelly D. Smith, Jane H. Buckner, Jessica A. Hamerman
Journal: Science Translational Medicine (2024)

Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis.
Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection
Authors: Michael J. Peluso, Dylan Ryder, Robert R. Flavell, Yingbing Wang, Jelena Levi, Brian H. LaFranchi, Tyler-Marie Deveau, Amanda M. Buck, Sadie E. Munter, Kofi A. Asare, Maya Aslam, Walter Koch, Gyula Szabo, Rebecca Hoh, Monika Deswal, Antonio E. Rodriguez, Melissa Buitrago, Viva Tai, Uttam Shrestha, Scott Lu, Sarah A. Goldberg, Thomas Dalhuisen, Joshua J. Vasquez, Matthew S. Durstenfeld, Priscilla Y. Hsue, J. Daniel Kelly, Nitasha Kumar, Jeffrey N. Martin, Aruna Gambhir, Ma Somsouk, Youngho Seo, Steven G. Deeks, Zoltan G. Laszik, Henry F. VanBrocklin, Timothy J. Henrich
Journal: Science Translational Medicine (2024)

The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [
PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections
Authors: Ryan M. Shepard, Anghesom Ghebremedhin, Isaraphorn Pratumchai, Sally R. Robinson, Courtney Betts, Jingjing Hu, Roman Sasik, Kathleen M. Fisch, Jaroslav Zak, Hui Chen, Marc Paradise, Jason Rivera, Mohammad Amjad, Satoshi Uchiyama, Hideya Seo, Alejandro D. Campos, Denise Ann Dayao, Saul Tzipori, Cesar Piedra-Mora, Soumita Das, Farnaz Hasteh, Hana Russo, Xin Sun, Le Xu, Laura Crotty E. Alexander, Jason M. Duran, Mazen Odish, Victor Pretorius, Nell C. Kirchberger, Shao-ming Chin, Tami Von Schalscha, David Cheresh, John D. Morrey, Rossitza Alargova, Brenda O’Connell, Theodore A. Martinot, Sandip P. Patel, Victor Nizet, Amanda J. Martinot, Lisa M. Coussens, John R. Teijaro, Judith A. Varner
Journal: Science Translational Medicine (2024)

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant
Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms
Authors: Haitao Sun, Kaijian Sun, Hao Tian, Xiheng Chen, Shixing Su, Yi Tu, Shilan Chen, Jiaxuan Wang, Meichang Peng, Meiqin Zeng, Xin Li, Yunhao Luo, Yugu Xie, Xin Feng, Zhuang Li, Xin Zhang, Xifeng Li, Yanchao Liu, Wei Ye, Zhengrui Chen, Zhaohua Zhu, Youxiang Li, Fangbo Xia, Hongwei Zhou, Chuanzhi Duan
Journal: Gut (2024)

Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome.
Do low skeletal muscle bulk and disturbed body fat mass impact tumor recurrence in stage I/II HCC undergoing surgery? An observational cohort study
Authors: Chao-Wei Lee, Hsin-I Tsai, Hsiao-Mei Hsu, Ming-Chin Yu, Wei-Chen Lee, Chih-Chi Wang, Yi-Chung Hsieh, Cheng-Yu Lin, Mei-Ling Cheng, Chi-Jen Lo, Ching-Ting Wang, Yu-Ching Lin
Journal: International Journal of Surgery (2024)

The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed.
The global, regional, and national patterns of change in the burden of non-malignant upper gastrointestinal diseases from 1990 to 2019 and the forecast for the next decade
Authors: Zihao Bai, Hao Wang, Chong Shen, Jia An, Zhaocong Yang, Xuming Mo
Journal: International Journal of Surgery (2024)

Background: Non-malignant upper gastrointestinal diseases, including peptic ulcer disease (PUD), gastritis and duodenitis (GD), and gastroesophageal reflux disease (GERD), significantly challenge global healthcare. These conditions not only impact patient health but also highlight socio-economic development issues and healthcare system accessibility and efficiency. Utilizing the Global Burden of Disease (GBD) database, this study aims to assess the global burden of PUD, GD, and GERD comprehensively, examining their association with the sociodemographic index (SDI). Methods: Employing data from the GBD 2019 database, this study analyzed the disability-adjusted life years (DALYs) for PUD, GD, and GERD. We integrated the SDI with the inequality slope index and concentration index for an international health inequality analysis, assessing disparities in the burden of these non-malignant upper gastrointestinal diseases. Decomposition analysis was conducted to determine the effects of population growth, aging, and epidemiological shifts on disease burden. Frontier analysis was performed to identify potential improvement areas and disparities among countries by development status. Disease time trends were depicted using a Joinpoint regression model, and the Bayesian age-period-cohort (BAPC) model projected the disease burden up to 2030. Results: Between 1990 and 2019, the age-standardized DALYs rates (ASDR) for non-malignant upper gastrointestinal diseases declined. However, global geographic heterogeneity remained evident, closely linked to the SDI. Notably, low-SDI countries experienced higher disease burdens. Population growth and aging emerged as principal contributors to the increasing disease burden. Despite development levels, many countries have considerable potential for reducing the burden of these diseases. Furthermore, significant variations in the time trends of non-malignant upper gastrointestinal diseases were observed among countries and regions with different SDI levels, a pattern expected to continue through 2030. Conclusion: Non-malignant upper gastrointestinal diseases demonstrate notable heterogeneity across age, gender, and geography, with the disparities most marked in underdeveloped regions or countries. Consequently, it is imperative to focus research on policy development and to enact prevention and treatment strategies tailored to high-risk groups. This targeted approach is essential for mitigating the disease burden effectively.
Clinical efficacy of different therapeutic strategies in patients with spontaneous rupture of the esophagus: a multicenter retrospective cohort study
Authors: Siyuan Luan, Xin Xiao, Xiaoxi Zeng, Jie Ren, Wen Liu, Jiwen Luo, Xinyu Mei, Xinpeng Zhou, Rulin Li, Yufeng Deng, Maoyong Fu, Guidong Shi, Shijian Du, Yunhua Wu, Chong Li, Yuncang Wang, Gang Li, Changjie Yang, Jianfeng Zhou, Chengyi Mao, Weipeng Hu, Longqi Chen, Yushang Yang, Yong Yuan
Journal: International Journal of Surgery (2024)

The therapeutic strategy for patients with spontaneous rupture of the esophagus includes surgical repair, endoscopic therapy, supportive care, and others. However, no evidence exists to direct clinical decision-making regarding the choice of operative and nonoperative management. The aim of this study was to determine the clinical efficacy of different therapeutic strategies in both general and stratified patients.
A mendelian randomization approach to study causal association between four types of endometriosis and immune cells: experimental studies
Authors: Wangshu Li, Xiuying Wang, Xu Zhang, Shu Sun, Jiuxiang Feng, Aziz ur Rehman Aziz
Journal: International Journal of Surgery (2024)

Li, Wangshu; Wang, Xiuying; Zhang, Xu; Sun, Shu; Feng, Jiuxiang; Aziz, Aziz ur Rehman PhD Author Information
Tissue-resident memory T cells break tolerance to renal autoantigens and orchestrate immune-mediated nephritis
Authors: Frederic Arnold, Laurence Kupferschmid, Philipp Weissenborn, Lukas Heldmann, Jonas F. Hummel, Paulina Zareba, None Sagar, Manuel Rogg, Christoph Schell, Yakup Tanriver
Journal: Cellular and Molecular Immunology (2024)

Abstract Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease. While the role of B cells and antibodies has been extensively investigated in the past, the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology. However, it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis. Here, we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen. We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation, combining hallmarks of activation and T cell dysfunction. While circulating memory T cells rapidly disappeared, tissue-resident memory T cells emerged and persisted within the kidney, orchestrating immune-mediated nephritis. Notably, T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency. This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man. Consequently, targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.
A gene for all seasons: The evolutionary consequences of HIF-1 in carcinogenesis, tumor growth and metastasis
Authors: Ranjini Bhattacharya, Joel S. Brown, Robert A. Gatenby, Arig Ibrahim-Hashim
Journal: Seminars in Cancer Biology (2024)

Oxygen played a pivotal role in the evolution of multicellularity during the Cambrian Explosion. Not surprisingly, responses to fluctuating oxygen concentrations are integral to the evolution of cancer—a disease characterized by the breakdown of multicellularity. Poorly organized tumor vasculature results in chaotic patterns of blood flow characterized by large spatial and temporal variations in intra-tumoral oxygen concentrations. Hypoxia-inducible growth factor (HIF-1) plays a pivotal role in enabling cells to adapt, metabolize, and proliferate in low oxygen conditions. HIF-1 is often constitutively activated in cancers, underscoring its importance in cancer progression. Here, we argue that the phenotypic changes mediated by HIF-1, in addition to adapting the cancer cells to their local environment, also "pre-adapt" them for proliferation at distant, metastatic sites. HIF-1-mediated adaptations include a metabolic shift towards anaerobic respiration or glycolysis, activation of cell survival mechanisms like phenotypic plasticity and epigenetic reprogramming, and formation of tumor vasculature through angiogenesis. Hypoxia induced epigenetic reprogramming can trigger epithelial to mesenchymal transition in cancer cells—the first step in the metastatic cascade. Highly glycolytic cells facilitate local invasion by acidifying the tumor microenvironment. New blood vessels, formed due to angiogenesis, provide cancer cells a conduit to the circulatory system. Moreover, survival mechanisms acquired by cancer cells in the primary site allow them to remodel tissue at the metastatic site generating tumor promoting microenvironment. Thus, hypoxia in the primary tumor promoted adaptations conducive to all stages of the metastatic cascade from the initial escape entry into a blood vessel, intravascular survival, extravasation into distant tissues, and establishment of secondary tumors.
Author Correction: IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial
Authors: Glenn M. Chertow, Anna Marie Chang, G. Michael Felker, Mark Heise, Elena Velkoska, Bengt Fellström, David M. Charytan, Regina Clementi, C. Michael Gibson, Shaun G. Goodman, Meg Jardine, Adeera Levin, Yuliya Lokhnygina, Jenny Mears, Roxana Mehran, Peter Stenvinkel, Angela Yee-Moon Wang, David C. Wheeler, Carmine Zoccali, Paul M. Ridker, Kenneth W. Mahaffey, Pierluigi Tricoci, Myles Wolf
Journal: Nature Medicine (2024)
Personalized drug screening using patient-derived organoid and its clinical relevance in gastric cancer
Authors: Yi Zhao, Shangru Li, Lefan Zhu, Mingle Huang, Yubin Xie, Xinming Song, Zhihui Chen, Harry Cheuk-Hay Lau, Joseph Jao-Yiu Sung, Lixia Xu, Jun Yu, Xiaoxing Li
Journal: Cell Reports Medicine (2024)

The efficacy of chemotherapy varies significantly among patients with gastric cancer (GC), and there is currently no effective strategy to predict chemotherapeutic outcomes. In this study, we successfully establish 57 GC patient-derived organoids (PDOs) from 73 patients with GC (78%). These organoids retain histological characteristics of their corresponding primary GC tissues. GC PDOs show varied responses to different chemotherapeutics. Through RNA sequencing, the upregulation of tumor suppression genes/pathways is identified in 5-fluorouracil (FU)- or oxaliplatin-sensitive organoids, whereas genes/pathways associated with proliferation and invasion are enriched in chemotherapy-resistant organoids. Gene expression biomarker panels, which could distinguish sensitive and resistant patients to 5-FU and oxaliplatin (area under the dose-response curve [AUC] >0.8), are identified. Moreover, the drug-response results in PDOs are validated in patient-derived organoids-based xenograft (PDOX) mice and are consistent with the actual clinical response in 91.7% (11/12) of patients with GC. Assessing chemosensitivity in PDOs can be utilized as a valuable tool for screening chemotherapeutic drugs in patients with GC.