tbuckley/cabot-search huggingface dataset:
Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion
Authors: Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, William H Tomaszewski, Lucas P Wachsmuth, Selena J Lorrey, Daniel S Wilkinson, Emily Lerner, Karolina Woroniecka, John B Finlay, Katayoun Ayasoufi, Peter E Fecci
Journal: Immunity (2024)

Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)-not tumor cells-were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.
Treatment of Complicated Gram-Positive Bacteremia and Infective Endocarditis
Authors: Paul Schellong, Oana Joean, Mathias W. Pletz, Stefan Hagel, Sebastian Weis
Journal: Drugs (2024)

The Gram-positive cocci Staphylococcus aureus, Streptococcus spp., and Enterococcus spp. are the most frequent causative organisms of bloodstream infections and infective endocarditis. "Complicated bacteremia" is a term used in S. aureus bloodstream infections and originally implied the presence of metastatic infectious foci (i.e. complications of S. aureus bacteremia). These complications demand longer antimicrobial treatment durations and, frequently, interventional source control. Several risk factors for the incidence of bacteremia complications have been identified and are often used for the definition of complicated bacteremia. Here, we discuss management and diagnostic approaches and treatment options for patients with complicated bacteremia, with particular focus on infective endocarditis. We also summarize the available evidence regarding imaging modalities and the choice of antimicrobial mono- or combination therapy according to resistance patterns for these pathogens as well as treatment durations and optimized application routes. Finally, we synopsize current and future areas of research in complicated bacteremia and infective endocarditis.
A self-hygroscopic, rapidly self-gelling polysaccharide-based sponge with robust wet adhesion for non-compressible hemorrhage control and infected wounds healing
Authors: Xiong-Xin Lei, Meng-Long Liu, Chao-Feng Lu, Li-Li Han, Jie-Zhi Jia, Zheng Li, Na Xu, Jiang-Feng Li, Xuan-Jian Fu, Ya-Bin Jin, Ri-Kuan Tong, Yun-Long Yu, Gao-Xing Luo, Yang Chen
Journal: Bioactive Materials (2024)
Cryogenic, but not hypothermic, preservation disrupts the extracellular matrix of cell sheets
Authors: Sara Freitas-Ribeiro, Andreia F Carvalho, Daniel B Rodrigues, Luís Martins, Ricardo A Pires, Vera M Mendes, Bruno Manadas, Mariana Jarnalo, Ricardo Horta, Rui L Reis, Rogério P Pirraco
Journal: Bioactive Materials (2024)
Organoids, tissue slices and organotypic cultures: advancing our understanding of pancreatic ductal adenocarcinoma through in vitro and ex vivo models
Authors: Secil Ak Aksoy, Julie Earl, Jelena Grahovac, Didem Karakas, Giulia Lencioni, Sıla Sığırlı, Maarten F Bijlsma
Journal: Seminars in Cancer Biology (2024)

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all common solid cancers. For the large majority of PDAC patients, only systemic therapies with very limited efficacy are indicated. In addition, immunotherapies have not brought the advances seen in other cancer types. Several key characteristics of PDAC contribute to poor treatment outcomes, and in this review, we will discuss how these characteristics are best captured in currently available ex vivo or in vitro model systems. For instance, PDAC is hallmarked by a highly desmoplastic and immune-suppressed tumor microenvironment that impacts disease progression and therapy resistance. Also, large differences in tumor biology exist between and within tumors, complicating treatment decisions. Furthermore, PDAC has a very high propensity for locally invasive and metastatic growth. The use of animal models is often not desirable or feasible and several in vitro and ex vivo model systems have been developed, such as organotypic cocultures and tissue slices, among others. However, the absence of a full host organism impacts the ability of these models to accurately capture the characteristics that contribute to poor outcomes in PDAC. We will discuss the caveats and advantages of these model systems in the context of PDAC's key characteristics and provide recommendations on model choice and the possibilities for optimization. These considerations should be of use to researchers aiming to study PDAC in the in vitro setting.
CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer
Authors: Yuncheng Bei, Sijie Wang, Rui Wang, Owais Ahmad, Meng Jia, Pengju Yao, Jianguo Ji, Pingping Shen
Journal: Acta Pharmaceutica Sinica B (2024)

Glucose-6-phosphate dehydrogenase (G6PD), the first rate-limiting enzyme of the pentose phosphate pathway (PPP), is aberrantly activated in multiple types of human cancers, governing the progression of tumor cells as well as the efficacy of anticancer therapy. Here, we discovered that cyclin-dependent kinase 5 (CDK5) rewired glucose metabolism from glycolysis to PPP in breast cancer (BC) cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress. Mechanistically, CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers. More importantly, CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens. Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation, attenuated tumor growth and metastasis, and synergistically sensitized BC cells to poly-ADP-ribose polymerase (PARP) inhibitor Olaparib, in xenograft mouse models. Collectively, our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.
Microbial Landscape in Cerebrospinal Fluid of Suspected Intracranial Infections Based on Clinical Metagenomics, a Multicentre Retrospective Study
Authors: Huili Zhou, Xindie Ren, Yujing Li, Caihong Ji, Xin Wei, Xiaohan Huang, Qianqian Wang, Xuan Zhang, Yongpo Jiang, Mingqiang Wang, Hongyu Wang, Nan Wang, Kang Wang, Chao Jiang, Lingtong Huang, Qi Xia
Journal: Journal of Infection (2024)
Risk for exertional heat illness among US army enlistees: climate indexes, intrinsic factors and their interactions
Authors: Josh B Kazman, D Alan Nelson, Anwar E Ahmed, Patricia A Deuster, Francis G O'Connor, James D Mancuso, Stephen A Lewandowski
Journal: British Journal of Sports Medicine (2024)

Objectives To characterise intrinsic and extrinsic (climatic) risks for mild and severe exertional heat illness (EHI) among first-year army enlistees. Methods We examined 337 786 soldiers who enlisted between 2012 and 2019. Survival models were used to predict incident EHI from intrinsic factors (demographics, healthcare utilisation, chronic conditions, body mass index (BMI), Army Physical Fitness Test (APFT), upper/lower respiratory tract infections (URTI and LRTI), skin and soft-tissue infections (SSTI), extrinsic factors (geographical region, daily mean Universal Thermal Climate Index (UTCI), wet bulb globe temperature (WBGT)) and interactions. Results There were 1390 cases of mild and 359 cases of severe EHI. Females had a higher risk for mild (adjusted OR (aOR) 1.78; 95% CI 1.57 to 2.02) but a lower risk for severe (aOR 0.61; 95% CI 0.38 to 0.87) EHI. Obesity was associated with severe EHI (aOR: 1.76; 95% CI 1.09 to 2.84) but not mild EHI (aOR: 1.03; 95% CI 0.76 to 1.39). URTI was associated with severe (aOR: 2.44; 95% CI 1.12 to 5.30) and mild (aOR 3.72, 95% CI 2.84 to 4.87) EHI, as were LRTI (severe, aOR: 11.40; 95% CI 6.09 to 21.32; mild, aOR 2.06; 95% CI 1.22 to 3.46), but not SSTI. UTCI outperformed WBGT in predicting EHI. Outside the Southern USA, EHI risk was elevated at lower UTCI. Associations varied over climate conditions and generally did not increase with climatic heat stress. Conclusions Respiratory infections were associated with the highest risk for EHI in soldiers. Risk mitigation strategies may include monitoring prevention and recovery from respiratory infections. Female sex and obesity may have different associated risks over climate conditions.
Mechanically robust surface-degradable implant from fiber silk composites demonstrates regenerative potential
Authors: Wenhan Tian, Yuzeng Liu, Bo Han, Fengqi Cheng, Kang Yang, Weiyuan Hu, Dongdong Ye, Sujun Wu, Jiping Yang, Qi Chen, Yong Hai, Robert O Ritchie, Guanping He, Juan Guan
Journal: Bioactive Materials (2024)
NIR-II photo-accelerated polymer nanoparticles boost tumor immunotherapy via PD-L1 silencing and immunogenic cell death
Authors: Tian Zhang, Dongsheng Tang, Pengfei Wu, Shaoping Jiang, Yuquan Zhang, Abid Naeem, Yong Li, Chunhui Li, Bo Hu, Shuai Guo, Caixia Sun, Haihua Xiao, Ran Yan, Yuhua Weng, Yuanyu Huang
Journal: Bioactive Materials (2024)
Current and future immunotherapy for breast cancer
Authors: Natalie K. Heater, Surbhi Warrior, Janice Lu
Journal: Journal of Hematology & Oncology (2024)

Abstract Substantial therapeutic advancement has been made in the field of immunotherapy in breast cancer. The immune checkpoint inhibitor pembrolizumab in combination with chemotherapy received FDA approval for both PD-L1 positive metastatic and early-stage triple-negative breast cancer, while ongoing clinical trials seek to expand the current treatment landscape for immune checkpoint inhibitors in hormone receptor positive and HER2 positive breast cancer. Antibody drug conjugates are FDA approved for triple negative and HER2+ disease, and are being studied in combination with immune checkpoint inhibitors. Vaccines and bispecific antibodies are areas of active research. Studies of cellular therapies such as tumor infiltrating lymphocytes, chimeric antigen receptor-T cells and T cell receptor engineered cells are promising and ongoing. This review provides an update of recent major clinical trials of immunotherapy in breast cancer and discusses future directions in the treatment of breast cancer.
Absence of Functional Autoantibodies Targeting Angiotensin <scp>II</scp> Type 1 Receptor (<scp>AT<sub>1</sub>R</scp>) and Endothelin‐1 Type A Receptor (<scp>ET<sub>A</sub>R</scp>) in Circulation and Purified <scp>IgG</scp> from Patients with Systemic Sclerosis
Authors: Wieke M. van Oostveen, Eva M. Hoekstra, E.W. Nivine Levarht, Ilana B. Kotliar, Thomas P. Sakmar, René E.M. Toes, Jeska K. de Vries‐Bouwstra, Laura H. Heitman, Cynthia M. Fehres
Journal: Arthritis & Rheumatology (2024)

Objective Systemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. While previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II type 1 receptor (AT 1 R) and endothelin‐1 type A receptor (ET A R), leading to autoantibody‐mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of SSc patient‐derived IgG (SSc IgG) on AT 1 R‐ and ET A R signaling, the downstream EC response, as well as presence of AT 1 R‐binding autoantibodies in circulation. Methods Quantitative PCR (qPCR) and cytokine ELISA, alongside a real‐time cell analyzer, were utilized to assess receptor‐specific functional characteristics of purified IgG from SSc patients (n=18). Additionally, a novel protein capture assay using solubilized epitope‐tagged AT 1 R was developed to detect AT 1 R‐binding autoantibodies in plasma samples from SSc patients (n=28) and healthy donors (n=14). Results No evidence for EC activation in an AT 1 R‐ or ET A R‐dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation nor alter GPCR signaling upon agonist stimulation in a model with receptor overexpression. Lastly, no AT 1 R‐binding autoantibodies were detected in plasma from SSc patients when using epitope‐tagged solubilized AT 1 R. Conclusion Overall, our study did not provide evidence to support the presence of AT 1 R‐ or ET A R‐activating autoantibodies in purified SSc IgG, nor AT 1 R‐binding autoantibodies in circulation of SSc patients.
High peripheral T cell diversity is associated with lower risk of toxicity and superior response to dual immune checkpoint inhibitor therapy in patients with metastatic NSCLC
Authors: Mehmet Altan, Ruoxing Li, Ziyi Li, Runzhe Chen, Ajay Sheshadri, Hai T Tran, Latasha Little, Joshua Baguley, Jefferson Sinson, Natalie Vokes, Saumil Gandhi, Mara B Antonoff, Stephen G Swisher, Greg Lizee, Alexandre Reuben, John V Heymach, Jianjun Zhang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Introduction Despite significant successes, immune checkpoint blockade fails to achieve clinical responses in a significant proportion of patients, predictive markers for responses are imperfect and immune-related adverse events (irAEs) are unpredictable. We used T-cell receptor (TCR) sequencing to systematically analyze prospectively collected patient blood samples from a randomized clinical trial of dual immune checkpoint inhibitor therapy to evaluate changes in the T-cell repertoire and their association with response and irAEs. Methods Patients with immunotherapy-naïve metastatic non-small cell lung cancer (NSCLC) were treated with ipilimumab and nivolumab according to trial protocol (LONESTAR, NCT03391869 ). Blood samples were systematically obtained at baseline (n=107), after 12 weeks of ipilimumab and nivolumab (n=91), and at the time of grade ≥2 irAEs (n=77). For analysis of T-cell repertoire, we performed immunoSEQ to assess the complementary determining region 3β region of the TCR involved in antigen binding. Results A total of 250 samples from 119 patients were analyzed. Patients who had a response to therapy exhibited greater T-cell diversity at baseline. Interestingly, patients with irAEs demonstrated lower T-cell richness at the time of toxicity compared with those without irAEs. Conclusion Our study highlights the potential impact of peripheral blood T-cell repertoire on clinical response and toxicities from the combination of ipilimumab and nivolumab in patients with metastatic NSCLC. These findings suggest that analysis of peripheral blood T-cell repertoire may help to guide patient selection for treatment with ipilimumab and nivolumab. Trial registration number NCT03391869 .
Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion
Authors: Qianqian Xue, Wenbei Peng, Siyu Zhang, Xiaoshan Wei, Linlin Ye, Zihao Wang, Xuan Xiang, Yao Liu, Haolei Wang, Qiong Zhou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood. Methods Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2 + Treg cells and TNFR2 − Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression. Results Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE. Conclusions The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.
Atherosclerotic plaque progression and incident cardiovascular events in a 10‐year prospective study of patients with Systemic Lupus Erythematosus: the impact of persistent cardiovascular risk factor target attainment and sustained <scp>DORIS</scp> remission
Authors: Nikolaos Papazoglou, Petros P. Sfikakis, Maria G. Tektonidou
Journal: Arthritis & Rheumatology (2024)

Objective Cardiovascular disease is a leading cause of mortality in Systemic Lupus Erythematosus (SLE). We assessed atherosclerotic plaque progression and incident cardiovascular events in SLE patients over a 10‐year follow‐up. Methods We prospectively analyzed 738 carotid ultrasound measurements (413 in SLE patients and 325 in age/sex‐matched healthy controls [HC]) to assess new plaque development from baseline to 3‐, 7‐, and 10‐year follow‐up. Multivariate mixed Poisson regression models examined potential predictors of plaque progression, including patient characteristics, Systemic Coronary Risk Evaluation (SCORE), traditional cardiovascular risk factor (CVRF) target attainment, Definition of Remission in SLE (DORIS), medications, and persistent triple antiphospholipid antibody (aPL) positivity during follow‐up. Ten‐year incident cardiovascular events were recorded, and univariate Cox regression analysis assessed potential associations. Results SLE patients had a 2.3‐fold higher risk of carotid plaque progression than HC (Incidence Rate Ratio [IRR]: 2.26; p=0.002). Plaque progression risk in SLE was reduced by 32% (IRR: 0.68, p=0.004) per each sustainedly attained CVRF target during follow‐up, including blood pressure, lipids, smoking, body weight, and physical activity. DORIS achievement ≥75% of follow‐up was associated with a 43% decrease in atherosclerosis progression risk (IRR: 0.57; p=0.033). Ten‐year risk of incident cardiovascular events was higher in SLE than HC individuals (eight versus one event, permutation‐based log‐rank p=0.036) and was associated with persistent triple aPL positivity. Conclusion Patients with SLE experience a 2.3‐fold higher 10‐year atherosclerosis progression risk than HC, mitigated by sustained CVRF control and prolonged clinical remission. Persistent triple aPL positivity is associated with increased incidence of CVD events.
Children as agents of cultural adaptation
Authors: Sheina Lew-Levy, Dorsa Amir
Journal: Behavioral and Brain Sciences (2024)

Abstract The human capacity for culture is a key determinant of our success as a species. While much work has examined adults’ abilities to create and transmit cultural knowledge, relatively less work has focused on the role of children (approx. 3-17 years) in this important process. In the cases where children are acknowledged, they are largely portrayed as acquirers of cultural knowledge from adults, rather than cultural producers in their own right. In this paper, we bring attention to the important role that children play in cultural adaptation by highlighting the structure, function, and ubiquity of the large body of knowledge produced and transmitted by children, known as peer culture . Supported by evidence from diverse disciplines, we argue that children are independent producers and maintainers of these autonomous cultures, which exist with regularity across diverse societies, and persist despite compounding threats. Critically, we argue peer cultures are a source of community knowledge diversity, encompassing both material and immaterial knowledge related to geography, ecology, subsistence, norms, and language. Through a number of case studies, we further argue that peer culture products and associated practices — including exploration, learning, and the retention of abandoned adult cultural traits — may help populations adapt to changing ecological and social conditions, contribute to community resilience, and even produce new cultural communities. We end by highlighting the pressing need for research to more carefully investigate children's roles as active agents in cultural adaptation.
Romantic Relationships Matter More to Men than to Women
Authors: Iris V. Wahring, Jeffry A. Simpson, Paul A. M. Van Lange
Journal: Behavioral and Brain Sciences (2024)

Abstract Women are often viewed as more romantic than men, and romantic relationships are assumed to be more central to the lives of women than to those of men. Despite the prevalence of these beliefs, some recent research paints a different picture. Using principles and insights based on the interdisciplinary literature on mixed-gender relationships, we advance a set of four propositions relevant to differences between men and women and their romantic relationships. We propose that relative to women: (a) men expect to obtain greater benefits from relationship formation and thus strive more strongly for a romantic partner, (b) men benefit more from romantic relationship involvement in terms of their mental and physical health, (c) men are less likely to initiate breakups, and (d) men suffer more from relationship dissolution. We offer theoretical explanations based on differences between men and women in the availability of social networks that provide intimacy and emotional support. We discuss implications for friendships in general and friendships between men and women in particular.