tbuckley/cabot-search huggingface dataset:
Inhibition of IL-25/IL-17RA improves immune-related adverse events of checkpoint inhibitors and reveals antitumor activity
Authors: Xizi Hu, Shoiab M Bukhari, Carly Tymm, Kieran Adam, Shalom Lerrer, Brian S Henick, Robert J Winchester, Adam Mor
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune checkpoint inhibitors (ICIs) have improved outcomes and extended patient survival in several tumor types. However, ICIs often induce immune-related adverse events (irAEs) that warrant therapy cessation, thereby limiting the overall effectiveness of this class of therapeutic agents. Currently, available therapies used to treat irAEs might also blunt the antitumor activity of the ICI themselves. Therefore, there is an urgent need to identify treatments that have the potential to be administered alongside ICI to optimize their use. Methods Using a translationally relevant murine model of anti-PD-1 and anti-CTLA-4 antibodies-induced irAEs, we compared the safety and efficacy of prednisolone, anti-IL-6, anti-TNFɑ, anti-IL-25 (IL-17E), and anti-IL-17RA (the receptor for IL-25) administration to prevent irAEs and to reduce tumor size. Results While all interventions were adequate to inhibit the onset of irAEs pneumonitis and hepatitis, treatment with anti-IL-25 or anti-IL-17RA antibodies also exerted additional antitumor activity. Mechanistically, IL-25/IL-17RA blockade reduced the number of organ-infiltrating lymphocytes. Conclusion These findings suggest that IL-25/IL-17RA may serve as an additional target when treating ICI-responsive tumors, allowing for better tumor control while suppressing immune-related toxicities.
Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1
Authors: Annelisa M. Cornel, Loutje van der Sman, Jip T van Dinter, Marta Arrabito, Ester Dunnebach, Marliek van Hoesel, Thomas A Kluiver, Ana P Lopes, Noël M M Dautzenberg, Linde Dekker, Jorik M van Rijn, Denise A M H van den Beemt, Juliane L Buhl, Aimee du Chatinier, Farnaz Barneh, Yuyan Lu, Luca Lo Nigro, Anja Krippner-Heidenreich, Zsolt Sebestyén, Jurgen Kuball, Esther Hulleman, Jarno Drost, Sebastiaan van Heesch, Olaf T Heidenreich, Weng Chuan Peng, Stefan Nierkens
Journal: Journal for ImmunoTherapy of Cancer (2024)

Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro . MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers.
Advances and challenges in cancer immunoprevention and immune interception
Authors: Sasha E Stanton, Philip E Castle, Olivera J Finn, Shizuko Sei, Leisha A Emens
Journal: Journal for ImmunoTherapy of Cancer (2024)

Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting immune interventions to prevent or intercept premalignant lesions, before significant immune dysregulation has occurred, may be a more successful strategy. The field of cancer immune interception and prevention is nascent, and the scientific community has been slow to embrace this potentially most rational approach to reducing the global burden of cancer. This may change due to recent promising advances in cancer immunoprevention including the use of vaccines for the prevention of viral cancers, the use of cancer-associated antigen vaccines in the setting of precancers, and the development of cancer-preventative vaccines for high-risk individuals who are healthy but carry cancer-associated heritable genetic mutations. Furthermore, there is increasing recognition of the importance of cancer prevention and interception by national cancer organizations. The National Cancer Institute (NCI) recently released the National Cancer Plan, which includes cancer prevention among the top priorities of the institute. The NCI's Division of Cancer Prevention has been introducing new funding opportunities for scientists with an interest in the field of cancer prevention: The Cancer Prevention-Interception Targeted Agent Discovery Program and The Cancer Immunoprevention Network. Moreover, the Human Tumor Atlas Network is spearheading the development of a precancer atlas to better understand the biology of pre-invasive changes, including the tissue microenvironment and the underlying genetics that drive carcinogenesis. These data will inform the development of novel immunoprevention/immuno-interception strategies. International cancer foundations have also started recognizing immunoprevention and immune interception with the American Association for Cancer Research, Cancer Research UK and the Society for Immunotherapy of Cancer each implementing programming focused on this area. This review will present recent advances, opportunities, and challenges in the emerging field of cancer immune prevention and immune interception.
Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling contributing to kidney fibrosis
Authors: Xiao Xiao, Wei Wang, Chunyuan Guo, Jiazhu Wu, Sheng Zhang, Huidong Shi, Sangho Kwon, Jiankang Chen, Zheng Dong
Journal: Kidney International (2024)

Epigenetic regulations, including DNA methylation, are critical to the development and progression of kidney fibrosis, but the underlying mechanisms remain elusive. Here, we show that fibrosis of the mouse kidney was associated with the induction of DNA methyltransferases and increases in global DNA methylation and was alleviated by the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza). Genome wide analysis demonstrated the hypermethylation of 94 genes in mouse unilateral ureteral obstruction kidneys, which was markedly reduced by 5-Aza. Among these genes, Hoxa5 was hypermethylated at its gene promoter and this hypermethylation was associated with reduced HOXA5 expression in fibrotic mouse kidneys after ureteral obstruction or unilateral ischemia-reperfusion injury. 5-Aza prevented Hoxa5 hypermethylation, restored HOXA5 expression, and suppressed kidney fibrosis. Down-regulation of HOXA5 was verified in human kidney biopsies from patients with chronic kidney disease and correlated with the increased kidney fibrosis and DNA methylation. Kidney fibrosis was aggravated by conditional knockout of Hoxa5 and alleviated by conditional knockin of Hoxa5 in kidney proximal tubules of mice. Mechanistically, we found that HOXA5 repressed Jag1 transcription by directly binding to its gene promoter, resulting in the suppression of JAG1-NOTCH signaling during kidney fibrosis. Thus, our results indicate that loss of HOXA5 via DNA methylation contributes to fibrogenesis in kidney diseases by inducing JAG1 and consequent activation of the NOTCH signaling pathway.
Balancing neuronal activity to fight neurodevelopmental disorders
Authors: Stephanie Le, Carmen Menacho, Alessandro Prigione
Journal: Trends in Neurosciences (2024)

In a recent study, Rylaarsdam and colleagues revealed that mutant PACS1 gene, which causes a rare neurodevelopmental syndrome, affects the firing ability of human neurons without dysregulating the cellular architecture of brain organoids. These findings suggest aberrant neuronal electrophysiology as a possible interventional target for pediatric diseases impairing brain development.
Reply to Alessandro Guercio, Antonio Franco, Elisa Mancini, et al’s Letter to the Editor re: Roxana Ramos, Ethan Ferguson, Mahmoud Abou Zeinab, et al. Single-port Transvesical Robot-assisted Simple Prostatectomy: Surgical Technique and Clinical Outcomes. Eur Urol. 2024;85:445–456
Authors: Roxana Ramos, Jihad Kaouk
Journal: European Urology (2024)
Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study
Authors: Nicholas M Fountain-Jones, Robert Vanhaeften, Jan Williamson, Janelle Maskell, I-Ly J Chua, Michael Charleston, Louise Cooley
Journal: The Lancet Microbe (2024)

IntroductionContinued SARS-CoV-2 infection among immunocompromised individuals is likely to play a role in generating genomic diversity and the emergence of novel variants. Antiviral treatments such as molnupiravir are used to mitigate severe COVID-19 outcomes, but the extended effects of these drugs on viral evolution in patients with chronic infections remain uncertain. This study investigates how molnupiravir affects SARS-CoV-2 evolution in immunocompromised patients with prolonged infections.MethodsThe study included five immunocompromised patients treated with molnupiravir and four patients not treated with molnupiravir (two immunocompromised and two non-immunocompromised). We selected patients who had been infected by similar SARS-CoV-2 variants and with high-quality genomes across timepoints to allow comparison between groups. Throat and nasopharyngeal samples were collected in patients up to 44 days post treatment and were sequenced using tiled amplicon sequencing followed by variant calling. The UShER pipeline and University of California Santa Cruz genome viewer provided insights into the global context of variants. Treated and untreated patients were compared, and mutation profiles were visualised to understand the impact of molnupiravir on viral evolution.FindingsPatients treated with molnupiravir showed a large increase in low-to-mid-frequency variants in as little as 10 days after treatment, whereas no such change was observed in untreated patients. Some of these variants became fixed in the viral population, including non-synonymous mutations in the spike protein. The variants were distributed across the genome and included unique mutations not commonly found in global omicron genomes. Notably, G-to-A and C-to-T mutations dominated the mutational profile of treated patients, persisting up to 44 days post treatment.InterpretationMolnupiravir treatment in immunocompromised patients led to the accumulation of a distinctive pattern of mutations beyond the recommended 5 days of treatment. Treated patients maintained persistent PCR positivity for the duration of monitoring, indicating clear potential for transmission and subsequent emergence of novel variants.FundingAustralian Research Council.
A legal mapping of 48 WHO member states' inclusion of public health emergency of international concern, pandemic, and health emergency terminology within national emergency legislation in responding to health emergencies
Authors: Clare Wenham, Liam Stout
Journal: The Lancet (2024)

WHO has determined a public health emergency of international concern (PHEIC) seven times, and beyond this nomenclature declared COVID-19 to be a pandemic. Under the International Health Regulations (IHR), and through their operationalisation in the joint external evaluation (JEE), governments are urged to create suitable legislation to be able to enact a response to a public health emergency. Whether the pandemic declaration had a greater effect than a PHEIC in encouraging goverments to act, however, remains conjecture, as there is no systemic analysis of what each term means in practice and whether either has meaningful legal implications at the national level. We undertook a legal scoping review to assess the utilisation of PHEIC and pandemic language within national legislation in 28 WHO member states. Data were collected from national websites, JEE reviews, COVID Analysis and Mapping of Policies Tool, Natlex, and Oxford Compendium of National Legal Responses to COVID-19. We found that only 16% of countries have any reference to the PHEIC in national legislation and 37·5% of countries reference the term pandemic. This finding paints a weakened picture of the IHR and PHEIC mechanisms. Having such legalese enshrined in legislation might enhance the interaction between WHO determining a PHEIC or declaring a pandemic and resulting action to mitigate transnational spread of disease and enhance health security. Given the ongoing negotiations at WHO in relation to the amendments to the IHR and creation of the pandemic accord, both of which deal with this declaratory power of the PHEIC and pandemic language, negotiators should understand the possible implications of any changes to these proclamations at the national level and for global health security.
Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise
Authors: Anna K Coussens, Syed M A Zaidi, Brian W Allwood, Puneet K Dewan, Glenda Gray, Mikashmi Kohli, Tamara Kredo, Ben J Marais, Guy B Marks, Leo Martinez, Morten Ruhwald, Thomas J Scriba, James A Seddon, Phumeza Tisile, Digby F Warner, Robert J Wilkinson, Hanif Esmail, Rein M G J Houben, David Alland, Marcel A Behr, Busisiwe B Beko, Erlina Burhan, Gavin Churchyard, Frank Cobelens, Justin T Denholm, Ryan Dinkele, Jerrold J Ellner, Razia Fatima, Kate A Haigh, Mark Hatherill, Katherine C Horton, Emily A Kendall, Palwasha Y Khan, Peter MacPherson, Stephanus T Malherbe, Vidya Mave, Simon C Mendelsohn, Munyaradzi Musvosvi, Elisa Nemes, Adam Penn-Nicholson, Dharanidharan Ramamurthy, Molebogeng X Rangaka, Suvanand Sahu, Alvaro Schwalb, Divya K Shah, Dylan Sheerin, Donald Simon, Adrie J C Steyn, Nguyen Thu Anh, Gerhard Walzl, Charlotte L Weller, Caroline ML Williams, Emily B Wong, Robin Wood, Yingda L Xie, Siyan Yi
Journal: The Lancet Respiratory Medicine (2024)
Targeted therapy of kidney disease with nanoparticle drug delivery materials
Authors: Shunlai Shang, Xiangmeng Li, Haoran Wang, Yena Zhou, Keying Pang, Ping Li, Xiaomin Liu, Min Zhang, Wenge Li, Qinggang Li, Xiangmei Chen
Journal: Bioactive Materials (2024)

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications.
Abstract 2615: Preclinical development of a next generation antibody drug conjugate (ADC) targeting cMET for treatment of solid tumors
Authors: Liang Xiao, Wei Lian, Shuai Song, Qigang Liu, Qing Zong, Sasha Stann, Jiaqiang Cai, Tongtong Xue
Journal: Cancer Research (2024)

Abstract cMET (mesenchymal-epithelial transition factor), which belongs to the MET family, is a type of receptor tyrosine kinase that is expressed on the surfaces of various epithelial cells. The elevation of cMET can promote the development and progression of multiple cancers. cMET- ADCs have shown promising clinical activity with highest cMET levels, indicating tumor cMET levels may be limited for efficacy. YL211, a novel cMET-ADC was developed by leveraging on MediLink’s tumor microenvironment activable linker-payload platform (TMALIN platform), which could release the payload both in the tumor cell and in the tumor microenvironment. YL211 is comprised of an anti-cMET humanized monoclonal antibody conjugated to a novel topoisomerase 1 inhibitor via a protease-cleavable linker. The novel linker-payload and site-specific conjugation of YL211 results in a homogeneous product with a DAR (Drug-to-Antibody Ratio) of 8. Furthermore, the advancement in linker-payload design has facilitated the development of more hydrophilic ADCs, which exhibit minimal impact on the antibody's characteristics while being less prone to aggregation and showcasing lower systematic clearance. Along with release of the payload in the tumor microenvironment extracellularly, upon binding to cMET on tumor cell surfaces, the antigen-ADC complexes are internalized to lysosomal vesicles and subsequently release the toxic payload. The cytotoxic features drive cell cycle arrest, apoptosis, elevation of PARP/caspase 7 expression, as well as cell death and bystander effect. These findings translated in vivo where YL211 showed superior efficacy in causing tumor regressions and good tolerability in both cell lines and patient-derived xenograft (CDX and PDX) mouse models with both low to high cMET expression levels (H358, CR5088, ect.). The in vivo pharmacokinetics in monkeys showed that YL211 is highly stable with less than 0.1% (molar ratio) payload released in circulation. GLP safety evaluations demonstrated good safety profiles and no off-target toxicity in monkeys. These non-clinical data suggest the stability of the linker in circulation as well as efficient release of the payload in tumors with improved therapeutic window. Taken together, preclinical data suggest that YL211 could be a promising treatment strategy for cMET positive cancer patients. Citation Format: Liang Xiao, Wei Lian, Shuai Song, Qigang Liu, Qing Zong, Sasha Stann, Jiaqiang Cai, Tongtong Xue. Preclinical development of a next generation antibody drug conjugate (ADC) targeting cMET for treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2615.
Abstract 4848: An analysis of black women in the Deep South with triple negative breast cancer and the social determinants of health
Authors: Lauren K. Evans, Ivan T. Jubilee, KiTani Parker Lemieux
Journal: Cancer Research (2024)

Abstract Background: Triple negative breast cancer (TNBC) has a higher incidence both of diagnosis and mortality among Black women. This research aims to identify specific social determinants of health among African American women in the Deep South with breast cancer. The biological presentation of disease accounts for approximately forty percent of the Experience with the health care providers, access to greenspace, and the quality of infrastructure, such as sidewalks and streetlights evaluate environmental trends associated with the outcomes of Black women in the Deep South who have been diagnosed with TNBC. Methods: Survey data was derived from the All of Us Research Program Database with inclusion criteria of Black women from Alabama, Georgia, Mississippi, and Louisiana who are 18 or older, born a female, and have been diagnosed with TNBC. Selected questions from the SDoH survey examined infrastructure, interactions with healthcare providers, and perceptions of community dynamics. Participants were identified via the cohort selection tool and further subdivided based on zip codes within the target states. Python was used in Jupyter Notebook to analyze the data the AoURP Workbench, responses were organized according to their corresponding survey questions. Participant responses were then extracted and quantified, facilitating the interpretation of respondents’ answers on a larger scale. Results: Three hundred and twenty women met the criteria of being born female, being black, being diagnosed with TNBC, and living in the Deep South. Of the topics examined, infrastructure was the area where participants’ feedback indicated the largest socioeconomic deficit. Forty-eight and 49%, respectively. Indicated that did not have access to greenspace nor did not live within 10-15-minute walking distance of a transit stop. Thirty percent reported that their doctor or nurse does not listen to what they are saying. Conclusion: Quality of life and interaction with members of the health care team associated with poorer health outcomes for Black women in the Deep South. These preliminary results indicate that those diagnosed with TNBC are impacted by the social determinants of health, specifically, proximity to public transportation, quality healthcare, recreational facilities, and infrastructure which suggests that basic needs are not met. Citation Format: Lauren K. Evans, Ivan T. Jubilee, KiTani Parker Lemieux. An analysis of black women in the Deep South with triple negative breast cancer and the social determinants of health [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4848.