tbuckley/cabot-search huggingface dataset:
A prognostic neural epigenetic signature in high-grade glioma
Authors: Richard Drexler, Robin Khatri, Thomas Sauvigny, Malte Mohme, Cecile L. Maire, Alice Ryba, Yahya Zghaibeh, Lasse Dührsen, Amanda Salviano-Silva, Katrin Lamszus, Manfred Westphal, Jens Gempt, Annika K. Wefers, Julia E. Neumann, Helena Bode, Fabian Hausmann, Tobias B. Huber, Stefan Bonn, Kerstin Jütten, Daniel Delev, Katharina J. Weber, Patrick N. Harter, Julia Onken, Peter Vajkoczy, David Capper, Benedikt Wiestler, Michael Weller, Berend Snijder, Alicia Buck, Tobias Weiss, Pauline C. Göller, Felix Sahm, Joelle Aline Menstel, David Niklas Zimmer, Michael B. Keough, Lijun Ni, Michelle Monje, Dana Silverbush, Volker Hovestadt, Mario L. Suvà, Saritha Krishna, Shawn L. Hervey-Jumper, Ulrich Schüller, Dieter H. Heiland, Sonja Hänzelmann, Franz L. Ricklefs
Journal: Nature Medicine (2024)

Abstract Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients’ survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients’ plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.
Inflammatory memory in psoriasis: From remission to recurrence
Authors: Luc Francis, Francesca Capon, Catherine H. Smith, Muzlifah Haniffa, Satveer K. Mahil
Journal: Journal of Allergy and Clinical Immunology (2024)

The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates up to 60% at 1 year of biologic treatment. However, psoriasis may recur following drug withdrawal, and as a result, patients tend to continue receiving costly treatment indefinitely. Here, we review research into the "inflammatory memory" in resolved psoriasis skin and the potential mechanisms leading to psoriasis recurrence following drug withdrawal. Research has implicated immune cells such as tissue resident memory T cells, Langerhans cells, and dermal dendritic cells, and there is growing interest in keratinocytes and fibroblasts. A better understanding of the interactions between these cell populations, enabled by single cell technologies, will help to elucidate the events underpinning the shift from remission to recurrence. This may inform the development of personalized strategies for sustaining remission while reducing long-term drug burden.
Methylphenidate Versus Placebo for Treating Fatigue in Patients With Advanced Cancer: Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial
Authors: Patrick Charles Stone, Ollie Minton, Alison Richardson, Peter Buckle, Zinat E. Enayat, Louise Marston, Nick Freemantle
Journal: Journal of Clinical Oncology (2024)

PURPOSE To compare effects and side effects of 6 weeks of individually dose-titrated methylphenidate or placebo on fatigue in palliative care patients with advanced cancer. METHODS This is a randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients had advanced incurable cancer and fatigue &gt;3/10. Principal exclusions were hypertension; psychiatric, cardiovascular, cerebrovascular, renal, liver, or blood disorders; substance dependency; and epilepsy. Patients were randomly assigned 1:1 methylphenidate or placebo starting at 5 mg twice daily. Dose of methylphenidate/placebo was titrated once per week, over 6 weeks, up to a maximum of 20 mg three times daily. Trial ended at 10 weeks. Primary outcome was the difference in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scores between groups at 6 ± 2 weeks. Secondary outcomes included adverse effects, quality of life, and mood. RESULTS One hundred sixty-two patients (73 men; mean, 65.8; standard deviation [SD], 10.3 years) were randomly assigned, and three were excluded from analysis. Seventy-seven were allocated placebo (baseline FACIT-F = 22 [SD, 10]); 82 were allocated methylphenidate (FACIT-F = 20 [SD, 9]). After 6 ± 2 weeks, FACIT-F scores were 1.97 points (95% CI, –0.95 to 4.90; P = .186) higher (better) on methylphenidate than placebo. Across 10 weeks of the study, FACIT-F was nominally higher in the methylphenidate group versus placebo (Diff, 2.20 [95% CI, 0.39 to 4.01]), but this did not reach the minimally clinically important difference (5-points). At 6 weeks, there were no differences between groups in quality-of-life or symptom domains except for depression scores (nominally reduced in the methylphenidate group: Diff, –1.35 [95% CI, –2.41 to –0.30]). There were no differences in mortality or serious adverse events. CONCLUSION After 6 ± 2 weeks of treatment, methylphenidate was not superior to placebo for treating fatigue in advanced cancer. Methylphenidate was safe and well-tolerated.
Robust differential expression testing for single-cell CRISPR screens at low multiplicity of infection
Authors: Timothy Barry, Kaishu Mason, Kathryn Roeder, Eugene Katsevich
Journal: Genome biology (2024)

Abstract Single-cell CRISPR screens (perturb-seq) link genetic perturbations to phenotypic changes in individual cells. The most fundamental task in perturb-seq analysis is to test for association between a perturbation and a count outcome, such as gene expression. We conduct the first-ever comprehensive benchmarking study of association testing methods for low multiplicity-of-infection (MOI) perturb-seq data, finding that existing methods produce excess false positives. We conduct an extensive empirical investigation of the data, identifying three core analysis challenges: sparsity, confounding, and model misspecification. Finally, we develop an association testing method — SCEPTRE low-MOI — that resolves these analysis challenges and demonstrates improved calibration and power.
Comparative 3D genome analysis between neural retina and retinal pigment epithelium reveals differential cis-regulatory interactions at retinal disease loci
Authors: Eva D'haene, Víctor López-Soriano, Pedro Manuel Martínez-García, Soraya Kalayanamontri, Alfredo Dueñas Rey, Ana Sousa-Ortega, Silvia Naranjo, Stijn Van de Sompele, Lies Vantomme, Quinten Mahieu, Sarah Vergult, Ana Neto, José Luis Gómez-Skarmeta, Juan Ramón Martínez-Morales, Miriam Bauwens, Juan Jesús Tena, Elfride De Baere
Journal: Genome biology (2024)

Abstract Background Vision depends on the interplay between photoreceptor cells of the neural retina and the underlying retinal pigment epithelium (RPE). Most genes involved in inherited retinal diseases display specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis -regulatory elements (CREs) in 3D nuclear space. Results To understand the role of differential chromatin architecture in establishing tissue-specific expression at inherited retinal disease loci, we mapped genome-wide chromatin interactions using in situ Hi-C and H3K4me3 HiChIP on neural retina and RPE/choroid from human adult donor eyes. We observed chromatin looping between active promoters and 32,425 and 8060 candidate CREs in the neural retina and RPE/choroid, respectively. A comparative 3D genome analysis between these two retinal tissues revealed that 56% of 290 known inherited retinal disease genes were marked by differential chromatin interactions. One of these was ABCA4 , which is implicated in the most common autosomal recessive inherited retinal disease. We zoomed in on retina- and RPE-specific cis -regulatory interactions at the ABCA4 locus using high-resolution UMI-4C. Integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish revealed tissue-specific CREs interacting with ABCA4 . Conclusions Through comparative 3D genome mapping, based on genome-wide, promoter-centric, and locus-specific assays of human neural retina and RPE, we have shown that gene regulation at key inherited retinal disease loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for non-coding genomic variation underlying unsolved inherited retinal diseases. Graphical Abstract
Abstract A027: The role of nuclear receptors as promoters of luminal tumors and suppressors of basal/squamous tumors
Authors: Cathy L. Mendelsohn, Sakina A. Plumber, Tiffany Tate
Journal: Clinical Cancer Research (2024)

Abstract Bladder cancers (BCs) can be divided into 2 major subgroups, basal/squamous (BASQ) tumors that are muscle invasive and luminal tumors which are relatively benign. Pparg, has been suggested to act as a tumor suppressor in BASQ tumors, where its expression is low or undetectable. Here we tested the effects of rosiglitazone, Pparg agonist in a mouse model of BASQ BC. We find that rosiglitazone alone, reduced proliferation but did not decrease tumor volume, while treatment with rosiglitazone plus trametinib, a MEK inhibitor induced apoptosis and reduced tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induced a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. Citation Format: Cathy L. Mendelsohn, Sakina A. Plumber, Tiffany Tate. The role of nuclear receptors as promoters of luminal tumors and suppressors of basal/squamous tumors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A027.
Abstract A006: Bladder cancer risk stratification with the Oncuria 10 plex bead-based urinalysis assay using three different Luminex xMAP instrumentation platforms
Authors: Toru Sakatani, Sunao Tanaka, Kaoru Murakami, Richard Waldron, Wayne Hogrefe, Charles Rosser, Hideki Furuya
Journal: Clinical Cancer Research (2024)

Abstract Introduction and Objectives Oncuria® is a bead-based multiplex fluorescence immunoassay that coordinately measures 10 protein biomarkers in urine samples. The current study compared assay performance and output when urine samples were evaluated with the Oncuria assay using three different fluorescence-analyzing instruments commonly used in diagnostic laboratories worldwide. Methods We compared the performance of the clinically validated Oncuria bladder cancer (BC) multiplex immunoassay when data output was generated on three different analyzer systems. Voided urine samples from 36 subjects (18 with BC and 18 Controls) were reacted with Oncuria test reagents in three 96 well microtiter plates, and consecutively evaluated on the LED/image based MagPix, and laser/flow based Luminex 200 and FlexMap 3D (all xMAP instruments from Luminex Corp., Austin, TX). The BC assay uses magnetic bead based fluorescence technology (xMAP, Multi-analyte profiling; Luminex) to simultaneously quantify 10 protein analytes in urine specimens [i.e., angiogenin (ANG), apolipoprotein E (ApoE), carbonic anhydrase IX (CA9), CXCL8/interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-10 (MMP-10), serpin A1/alpha-1 anti-trypsin (A1AT), serpin E1/plasminogen activator inhibitor-1 (PAI-1), CD138/syndecan-1 (SDC1), and vascular endothelial growth factor-A (VEGF-A)]. Results All three platforms categorized all 10 analytes in identical samples at nearly identical concentrations, with variance across systems typically &amp;lt;5%. While the most contemporary instrument, the FlexMap 3D, output higher raw fluorescence values than the two comparator systems, standard curve slopes and analyte concentrations determined in urine samples were concordant across all three units. Forty-four percent of BC samples registered ≥1 analyte above the highest standard concentration, i.e., A1AT (n=7/18), IL-8 (n=5), and/or ANG (n=2). In Controls, A1AT was higher in one sample. Conclusions In conclusion, the Oncuria BC assay performed similarly well across three different flow analysis platforms for all 10 analytes simultaneously evaluated in urine samples. This agreement across instruments indicates that the test is amenable to standardized performance in laboratories using existing xMAP, without requiring costly outlays for new equipment. Citation Format: Toru Sakatani, Sunao Tanaka, Kaoru Murakami, Richard Waldron, Wayne Hogrefe, Charles Rosser, Hideki Furuya. Bladder cancer risk stratification with the Oncuria 10 plex bead-based urinalysis assay using three different Luminex xMAP instrumentation platforms [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A006.
Abstract IA016: The evolving role of immune-based treatment strategies in metastatic urothelial cancer
Authors: Matthew D. Galsky
Journal: Clinical Cancer Research (2024)

Abstract Immune checkpoint blockade has changed the treatment landscape for metastatic urothelial cancer. However, the role of PD-1/PD-L1 blockade in the treatment of metastatic diseaes continues to rapidly evolve since the initialy regulatory approval of these therapies in 2016. Defining biomarkers with sufficient predictive ability to establish clinical utility for selection of patients who can receive single agent PD-1/PD-L1 blockade has been challenging. However, combination regimens with either cisplatin-based chemotherapy or enfortumab vedotin has for the first time in decades improved survival compared with platinum-based chemotherapy alone. Refining the use of such combination regimens requires a better understanding of the potential immunomodulatory effects of cytotoxic therapies. Citation Format: Matthew D. Galsky. The evolving role of immune-based treatment strategies in metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA016.
Abstract IA015: Optimizing cystectomy outcomes in MIBC: What's new in 2024?
Authors: Jeremy Teoh
Journal: Clinical Cancer Research (2024)

Abstract Muscle-invasive bladder cancer often requires radical cystectomy, which is a major and complex surgery carrying significant morbidities. Optimizing the outcomes of radical cystectomy involves a multifaceted approach. There are three main aspects that we must focus on, namely the peri-operative, functional and oncological outcomes. Firstly, perioperative outcomes can be enhanced by leveraging robotic technology for the procedure, coupled with intracorporeal urinary diversion techniques. Recent evidence has shown benefits in terms of reducing blood loss, shortening hospital stay and improving quality of life. Secondly, to optimize functional outcomes, organ sparing surgery techniques can be considered when possible. Preserving organ function can improve the quality of life after surgery, especially in terms of urinary and sexual functioning. Thirdly, optimizing oncological outcomes can be achieved through the integration of neoadjuvant immunotherapy into treatment protocols. This innovative approach can potentially improve the long-term survival outcomes following radical cystectomy. By addressing these three key aspects, a more comprehensive and effective strategy can be developed to optimize the results of radical cystectomy for patients with muscle-invasive bladder cancer. Citation Format: Jeremy Teoh. Optimizing cystectomy outcomes in MIBC: What's new in 2024? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA015.
Abstract A002: Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma
Authors: Toru Sakatani, Sunao Tanaka, Kazutoshi Fujita, Jennifer Linehan, Kaoru Murakami, Riko Lee, Ian Pagano, Charles Rosser, Hideki Furuya
Journal: Clinical Cancer Research (2024)

Abstract Introduction and Objective: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with upper tract urothelial carcinoma (UTUC). The application of a robust urine-based multiplex assay, Oncuria-Detect®, to aid in the detection of UTUC has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis. Methods: To evaluate the performance of Oncuria-Detect®, a multiplex immunoassay capable of querying a voided urine sample for 10 protein biomarkers associated with urothelial carcinoma (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA). Its application to UTUC was evaluated in a multi-institutional cohort of 35 prospectively collected subjects presenting for evaluation of upper tract mass along with 46 prospective collected matched controls (i.e., non-tumor bearing). The ability of the test to identify patients harboring UTUC was assessed. UTCU status was confirmed by endoscopy and tissue biopsy or definitive surgery. Diagnostic performance was assessed using ROC curves. Results: Oncuria-Detect® provided an AUC of 0.886 (95% CI: 0.807-0.964) with an overall sensitivity of 91.4%, specificity of 73.9%, NPV 91.9% and PPV 72.7%. Sensitivity values of the diagnostic panel for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 86.7%, 90.9%, 88.9% and 94.1%, respectively. Urinary cytology or selective ureteral washing/cytology was associated with an overall sensitivity of 54.2%, specificity of 100%, NPV 63.3% and PPV 100%. Sensitivity values of cytology for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 100%, 100%, 100%, and 77.8%, respectively. Conclusions: Urinary levels of a biomarker panel enabled the accurate discrimination of UTUC and controls non-tumor bearing individuals. The multiplex Oncuria-Detect® test can achieve the efficient and accurate detection of UTUC in a non-invasive patient setting. Citation Format: Toru Sakatani, Sunao Tanaka, Kazutoshi Fujita, Jennifer Linehan, Kaoru Murakami, Riko Lee, Ian Pagano, Charles Rosser, Hideki Furuya. Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A002.
Abstract A025: Integrating genomic alterations and histopathological features for enhanced risk stratification in non-muscle invasive bladder cancer
Authors: Melinda Lillesand, Vebjørn Kvikstad, Einar Gudlaugsson, Ivar Skaland, Aida Slewa Johannessen, Almaz Nigatu Tesfahun, Sigmund Vegard Sperstad, Emiel A.M. Janssen, Marie Austdal
Journal: Clinical Cancer Research (2024)

Abstract Urothelial carcinoma is the most prevalent type of bladder cancer, where non-muscle invasive bladder cancer (NMIBC) accounts for about 75% of the initial diagnosis. Recognizing the limitations of current WHO04/16 grading and TNM staging systems, this study investigates genomic alterations, mitotic activity index (MAI) and immunohistochemical (IHC) markers CK20, p53, and CD25 to identify better prognostic biomarkers in NMIBC. In this retrospective population-based study of NMIBC patients (n=287), a targeted next-generation sequencing (NGS) panel analysis was performed using Oncomine™ Focus Assay on Ion GeneStudio S5 platform to identify genomic changes, including single nucleotide variations (SNVs) and copy number variations (CNVs) across 52 genes. The results revealed that the most frequent gene variants were identified in FGFR3 (n=183, 45%) and PIK3CA (n=98, 24%), while AKT1 (n=39, 20%), ERBB2 (n=24, 12%), MYCN (n=23, 12%) and CCND1 (n=22, 11%) were among the most amplified genes. Distinct genetic associations were observed among Ta, T1, low-grade (LG), and high-grade (HG) tumors. Ta tumors were significantly associated with FGFR3 and PIK3CA mutations, while T1 tumors were linked to ERBB2 mutations (p&amp;lt;0.001). Additionally, LG tumors were enriched with FGFR3 mutations, while HG tumors were significantly associated with FGFR1, CCND1, and ERBB2 mutations (p&amp;lt;0.001). In the analysis of tumor recurrence, patients with FGFR3 mutations had significantly shorter recurrence-free survival (RFS) (p=0.033). Analysis of stage progression revealed a significant association between FGFR3 mutations and improved PFS (p&amp;lt;0.001), while MYC, ERBB2 (p&amp;lt;0.001), and MYCN (p=0.011) were linked to shorter PFS. In gene set enrichment analysis, gene sets like PIK3CA and ERBB2 (p=0.003), and PIK3CA and MYC (p=0.005), were inversely associated with progression-free survival (PFS). In the multivariate Cox regression analysis, MAI was the strongest predictor for PFS (p&amp;lt;0.001). The study emphasizes the potential of combining genomic alterations with histopathological features for enhanced risk stratification in NMIBC patients. Citation Format: Melinda Lillesand, Vebjørn Kvikstad, Einar Gudlaugsson, Ivar Skaland, Aida Slewa Johannessen, Almaz Nigatu Tesfahun, Sigmund Vegard Sperstad, Emiel A.M. Janssen, Marie Austdal. Integrating genomic alterations and histopathological features for enhanced risk stratification in non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A025.