tbuckley/cabot-search huggingface dataset:
Evolving insights into the improvement of adoptive T-cell immunotherapy through PD-1/PD-L1 blockade in the clinical spectrum of lung cancer
Authors: Yutao Li, Amit Sharma, Ingo G.H. Schmidt-Wolf
Journal: Molecular Cancer (2024)

Undeniably, cancer immunotherapies have expanded the spectrum of cancer treatment, however, some patients do not respond to immunotherapies. This scenario is no different for lung cancer, whose two main types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), still pose a serious clinical challenge. Adoptive T-cell therapies (ATC), which primarily include cytokine-induced killer (CIK) cell therapy, chimeric antigen receptor T-cell (CAR T-cell) therapy and γδ-T-cell therapy, strengthen the patient's immune system in combating cancer. Combining ATC with immune checkpoint inhibitors (ICI) further enhances the effectiveness of this approach to eradicate cancer. With a particular emphasis on CIK cell therapy, which recently completed 30 years, we highlight the role of the PD-1/PD-L1 axis in NSCLC and SCLC. Besides, we provide insights into the potential synergies of PD-1/PD-L1 inhibitors with adoptive T-cell immunotherapy in reshaping the treatment paradigm for lung cancer.
Condensate-Promoting ENL Mutation Drives Tumorigenesis <i>In Vivo</i> Through Dynamic Regulation of Histone Modifications and Gene Expression
Authors: Yiman Liu, Qinglan Li, Lele Song, Chujie Gong, Sylvia Tang, Krista A. Budinich, Ashley Vanderbeck, Kaeli M. Mathias, Gerald B. Wertheim, Son C. Nguyen, Riley Outen, Eric F. Joyce, Ivan Maillard, Liling Wan
Journal: Cancer Discovery (2024)

Gain-of-function mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment. Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.
Organ Neuroprosthetics: Connecting Transplanted and Artificial Organs with the Nervous System
Authors: Silvestro Micera, Arianna Menciassi, Luisella Cianferotti, Emanuele Gruppioni, Vincenzo Lionetti
Journal: Advanced Healthcare Materials (2024)

Implantable neural interfaces with the central and peripheral nervous systems are currently used to restore sensory, motor, and cognitive functions in disabled people with very promising results. They have also been used to modulate autonomic activities to treat diseases such as diabetes or hypertension. Here, this study proposes to extend the use of these technologies to (re-)establish the connection between new (transplanted or artificial) organs and the nervous system in order to increase the long-term efficacy and the effective biointegration of these solutions. In this perspective paper, some clinically relevant applications of this approach are briefly described. Then, the choices that neural engineers must implement about the type, implantation location, and closed-loop control algorithms to successfully realize this approach are highlighted. It is believed that these new "organ neuroprostheses" are going to become more and more valuable and very effective solutions in the years to come.
Teicoplanin‐Decorated Reduced Graphene Oxide Incorporated Silk Protein Hybrid Hydrogel for Accelerating Infectious Diabetic Wound Healing and Preventing Diabetic Foot Osteomyelitis
Authors: Bianza Moise Bakadia, Ruizhu Zheng, Abeer Ahmed Qaed Ahmed, Zhijun Shi, Bakamona Lyna Babidi, Tun Sun, Ying Li, Guang Yang
Journal: Advanced Healthcare Materials (2024)

Developing hybrid hydrogel dressings with anti-inflammatory, antioxidant, angiogenetic, and antibiofilm activities with higher bone tissue penetrability to accelerate diabetic wound healing and prevent diabetic foot osteomyelitis (DFO) is highly desirable in managing diabetic wounds. Herein, the glycopeptide teicoplanin is used for the first time as a green reductant to chemically reduce graphene oxide (GO). The resulting teicoplanin-decorated reduced graphene oxide (rGO) is incorporated into a mixture of silk proteins (SP) and crosslinked with genipin to yield a physicochemically crosslinked rGO-SP hybrid hydrogel. This hybrid hydrogel exhibits high porosity, self-healing, shear-induced thinning, increased cell proliferation and migration, and mechanical properties suitable for tissue engineering. Moreover, the hybrid hydrogel eradicates bacterial biofilms with a high penetrability index in agar and hydroxyapatite disks covered with biofilms, mimicking bone tissue. In vivo, the hybrid hydrogel accelerates the healing of noninfected wounds in a diabetic rat and infected wounds in a diabetic mouse by upregulating anti-inflammatory cytokines and downregulating matrix metalloproteinase-9, promoting M2 macrophage polarization and angiogenesis. The implantation of hybrid hydrogel into the infected site of mouse tibia improves bone regeneration. Hence, the rGO-SP hybrid hydrogel can be a promising wound dressing for treating infectious diabetic wounds, providing a further advantage in preventing DFO.
NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD‐L1‐dependent manner
Authors: Jiwei Zhang, Fen Ma, Zhe Li, Yuan Li, Xun Sun, Mingxu Song, Fan Yang, Enjiang Wu, Xiaohui Wei, Zhengtao Wang, Li Yang
Journal: MedComm (2024)

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8
Healing with precision: A multi-functional hydrogel-bioactive glass dressing boosts infected wound recovery and enhances neurogenesis in the wound bed
Authors: Yu Kang, Kun Liu, Zhenbing Chen, Jiahe Guo, Kaituo Xiang, Xiaopei Wu, Tao Jiang, Jing Chen, Chenqi Yan, Guoyong Jiang, Yufeng Wang, Maojie Zhang, Xuejiao Xiang, Honglian Dai, Xiaofan Yang
Journal: Journal of Controlled Release (2024)
A facile and smart strategy to enhance bone regeneration with efficient vitamin D3 delivery through sterosome technology
Authors: Shuxi Ye, Jing Wen, Wen-Hao Ye, Zhen Li, Xiaomeng Huang, Sixu Chen, Jian-Chao Ma, Yaohong Wu, Rongchun Chen, Zhong-Kai Cui
Journal: Journal of Controlled Release (2024)
<i>NECTIN4</i> Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer
Authors: Niklas Klümper, Ngoc Khanh Tran, Stefanie Zschäbitz, Oliver Hahn, Thomas Büttner, Florian Roghmann, Christian Bolenz, Friedemann Zengerling, Constantin Schwab, Dora Nagy, Marieta Toma, Glen Kristiansen, Hendrik Heers, Philipp Ivanyi, Günter Niegisch, Camilla Marisa Grunewald, Christopher Darr, Arian Farid, Katrin Schlack, Mahmoud Abbas, Can Aydogdu, Jozefina Casuscelli, Theresa Mokry, Michael Mayr, Dora Niedersüß-Beke, Steffen Rausch, Dimo Dietrich, Jonas Saal, Jörg Ellinger, Manuel Ritter, Abdullah Alajati, Christoph Kuppe, Joshua Meeks, Francisco E. Vera Badillo, J. Alberto Nakauma-González, Joost Boormans, Kerstin Junker, Arndt Hartmann, Viktor Grünwald, Michael Hölzel, Markus Eckstein
Journal: Journal of Clinical Oncology (2024)

PURPOSE The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non–EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup ( P &lt; .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P &lt; .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.
Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis
Authors: Juan Rong, Chenxia Han, Yan Huang, Yiqin Wang, Qi Qiu, Manjiangcuo Wang, Shisheng Wang, Rui Wang, Juqin Yang, Xia Li, Chenggong Hu, Zhiyao Chen, Lihui Deng, Wei Huang, Qing Xia, Dan Du
Journal: Acta Pharmaceutica Sinica B (2024)

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death
Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer
Authors: Xin Jin, Wenke Jin, Linlin Tong, Jia Zhao, Lan Zhang, Na Lin
Journal: Acta Pharmaceutica Sinica B (2024)

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.
PIM1–HDAC2 axis modulates intestinal homeostasis through epigenetic modification
Authors: Jianming Yang, Yawen Xiao, Ningning Zhao, Geng Pei, Yan Sun, Xinyu Sun, Kaiyuan Yu, Chunhui Miao, Ran Liu, Junqiang Lv, Hongyu Chu, Lu Zhou, Bangmao Wang, Zhi Yao, Quan Wang
Journal: Acta Pharmaceutica Sinica B (2024)

The mucosal barrier is crucial for intestinal homeostasis, and goblet cells are essential for maintaining the mucosal barrier integrity. The proviral integration site for Moloney murine leukemia virus-1 (PIM1) kinase regulates multiple cellular functions, but its role in intestinal homeostasis during colitis is unknown. Here, we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models, in the presence of intestinal microbiota. Epithelial PIM1 leads to decreased goblet cells, thus impairing resistance to colitis and colitis-associated colorectal cancer (CAC) in mice. Mechanistically, PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways. Interestingly, PIM1 interacts with histone deacetylase 2 (HDAC2) and downregulates its level via phosphorylation, thereby altering the epigenetic profiles of Wnt signaling pathway genes. Collectively, these findings investigate the unknown function of the PIM1–HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis, which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.
Glucocorticoids-based prodrug design: Current strategies and research progress
Authors: Hongbing Liu, Muse Ji, Peifu Xiao, Jingxin Gou, Tian Yin, Haibing He, Xing Tang, Yu Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Attributing to their broad pharmacological effects encompassing anti-inflammation, antitoxin, and immunosuppression, glucocorticoids (GCs) are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus, nephritis, arthritis, ulcerative colitis, asthma, keratitis, macular edema, and leukemia. However, long-term use often causes undesirable side effects, including metabolic disorders-induced Cushing's syndrome (buffalo back, full moon face, hyperglycemia, etc.), osteoporosis, aggravated infection, psychosis, glaucoma, and cataract. These notorious side effects seriously compromise patients' quality of life, especially in patients with chronic diseases. Therefore, glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention. Among them, prodrugs have the advantages of low investment, low risk, and high success rate, making them a promising strategy. In this review, we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades, including polymer-based prodrugs, dendrimer-based prodrugs, antibody-drug conjugates, peptide-drug conjugates, carbohydrate-based prodrugs, aliphatic acid-based prodrugs and so on. Besides, we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs. This review is expected to be helpful for the research and development of novel GCs and prodrugs.
Checkpoint inhibitor-expressing lentiviral vaccine suppresses tumor growth in preclinical cancer models
Authors: Takuya Tada, Thomas D Norton, Rebecca Leibowitz, Nathaniel R Landau
Journal: Journal for ImmunoTherapy of Cancer (2024)

While immunotherapy has been highly successful for the treatment of some cancers, for others, the immune response to tumor antigens is weak leading to treatment failure. The resistance of tumors to checkpoint inhibitor therapy may be caused by T cell exhaustion resulting from checkpoint activation. In this study, lentiviral vectors that expressed T cell epitopes of an experimentally introduced tumor antigen, ovalbumin, or the endogenous tumor antigen, Trp1 were developed. The vectors coexpressed CD40 ligand (CD40L), which served to mature the dendritic cells (DCs), and a soluble programmed cell death protein 1 (PD-1) microbody to prevent checkpoint activation. Vaccination of mice bearing B16.OVA melanomas with vector-transduced DCs induced the proliferation and activation of functional, antigen-specific, cytolytic CD8 T cells. Vaccination induced the expansion of CD8 T cells that infiltrated the tumors to suppress tumor growth. Vector-encoded CD40L and PD-1 microbody increased the extent of tumor growth suppression. Adoptive transfer demonstrated that the effect was mediated by CD8 T cells. Direct injection of the vector, without the need for ex vivo transduction of DCs, was also effective. This study suggests that therapeutic vaccination that induces tumor antigen-specific CD8 T cells coupled with a vector-expressed checkpoint inhibitor can be an effective means to suppress the growth of tumors that are resistant to conventional immunotherapy.
Corrigendum to: “People living with HIV who have poor immune status are a key population for SARS-CoV-2 prevention” Journal of Infection, Volume 88, Issue 3, March 2024, 106122
Authors: Jie Zhou, Liuyan Lan, Sufang Ai, Jianyan Lin, Ningmei Liu, Yulan Xie, Ping Cui, Hao Liang, Li Ye, Jiegang Huang, Zhiman Xie
Journal: Journal of Infection (2024)
NETscape or NEThance: tailoring anti-cancer therapy
Authors: Alexandra Mousset, Lola Bellone, Cedric Gaggioli, Jean Albrengues
Journal: Trends in cancer (2024)

Neutrophils, major regulators of innate immunity, have recently emerged as key components of the tumor microenvironment. The role of neutrophils in cancer has been linked to their ability to form neutrophil extracellular traps (NETs), structures composed of decondensed DNA decorated with enzymes that are released into the extracellular space. Here, we discuss the pivotal roles of NETs in influencing responses to anticancer therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Highlighting recent insights, we delve into the dual nature of NETs in the context of anticancer treatments, examining their potential to either counteract or enhance treatment outcomes. Strategic targeting of NETs may be a promising avenue for crafting combination therapies to counteract resistance or enhance anticancer treatments' efficacy.
α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury
Authors: Debasish Roy, Elliot Dion, Jesse A. Sepeda, Juan Peng, Sai Rishik Lingam, Kristy Townsend, Andrew Sas, Wenjing Sun, Andrea Tedeschi
Journal: Cell Reports Medicine (2024)

Spinal cord injury (SCI) increases the risk of cardiometabolic disorders, including hypertension, dyslipidemia, and insulin resistance. Not only does SCI lead to pathological expansion of adipose tissue, but it also leads to ectopic lipid accumulation in organs integral to glucose and insulin metabolism. The pathophysiological changes that underlie adipose tissue dysfunction after SCI are unknown. Here, we find that SCI exacerbates lipolysis in epididymal white adipose tissue (eWAT). Whereas expression of the α2δ1 subunit of voltage-gated calcium channels increases in calcitonin gene-related peptide-positive dorsal root ganglia neurons that project to eWAT, conditional deletion of the gene encoding α2δ1 in these neurons normalizes eWAT lipolysis after SCI. Furthermore, α2δ1 pharmacological blockade through systemic administration of gabapentin also normalizes eWAT lipolysis after SCI, preventing ectopic lipid accumulation in the liver. Thus, our study provides insight into molecular causes of maladaptive sensory processing in eWAT, facilitating the development of strategies to reduce metabolic and cardiovascular complications after SCI.
Antibiotics taken within the first year of life are linked to infant gut microbiome disruption and elevated atopic dermatitis risk
Authors: Courtney Hoskinson, Maria V. Medeleanu, Myrtha E. Reyna, Darlene L.Y. Dai, Biswajit Chowdhury, Theo J. Moraes, Piushkumar J. Mandhane, Elinor Simons, Anita L. Kozyrskyj, Meghan B. Azad, Charisse Petersen, Stuart E. Turvey, Padmaja Subbarao
Journal: Journal of Allergy and Clinical Immunology (2024)

Graphical abstractAbstractBackgroundAtopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD.ObjectivesThis study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD.MethodsWe used statistical modeling and differential analysis to link CHILD Cohort Study participants' history of antibiotic usage and early-life gut microbiome alterations to AD.ResultsHere we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio [aOR] = 1.81; 95% CI: 1.28-2.57; P < .001), with an increased number of antibiotic courses corresponding to a dose response–like increased risk of AD risk (1 course: aOR: 1.67; 95% CI: 1.17-2.38; 2 or more courses: aOR: 2.16; 95% CI: 1.30-3.59). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (βindirect = 0.072; P < .001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis, increased monosaccharide utilization, and parallel decreased Bifidobacterium and Eubacterium spp, and fermentative pathways.ConclusionsThese findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD.