tbuckley/cabot-search huggingface dataset:
Integrated analysis of single-cell and bulk transcriptomics develops a robust neuroendocrine cell-intrinsic signature to predict prostate cancer progression
Authors: Tingting Zhang, Faming Zhao, Yahang Lin, Mingsheng Liu, Hongqing Zhou, Fengzhen Cui, Yang Jin, Liang Chen, Xia Sheng
Journal: Theranostics (2024)

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options.The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined.Methods: Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model.Results: Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets.Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers.Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores.By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression.Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. Conclusion:The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.
Correction: Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma
Authors: Georg Lenz, Eliza Hawkes, Gregor Verhoef, Corinne Haioun, Soon Thye Lim, Dae Seog Heo, Kirit Ardeshna, Geoffrey Chong, Jacob Haaber, Wei Shi, Igor Gorbatchevsky, Susanne Lippert, Florian Hiemeyer, Paolo Piraino, Georg Beckmann, Carol Peña, Viktoriya Buvaylo, Barrett H. Childs, Gilles Salles
Journal: Leukemia (2024)
Acute cellular and vascular responses to photodynamic therapy using EGFR-targeted nanobody-photosensitizer conjugates studied with intravital optical imaging and magnetic resonance imaging: Erratum
Authors: Henriette S. de Bruijn, Vida Mashayekhi, Tom J.L. Schreurs, Pieter B.A.A. van Driel, Gustav J. Strijkers, Paul J. van Diest, Clemens W.G.M. Lowik, Ann L.B. Seynhaeve, Timo L.M. ten Hagen, Jeanine J. Prompers, Paul M.P. van Bergen en Henegouwen, Dominic J. Robinson, Sabrina Oliveira
Journal: Theranostics (2024)

[This corrects the article DOI: 10.7150/thno.37949.].
Association of Primary Open-Angle Glaucoma with Diabetic Retinopathy among Patients with Type 1 and Type 2 Diabetes
Authors: Muhammad Z. Chauhan, Abdelrahman M. Elhusseiny, Krishna S. Kishor, Carina T. Sanvicente, Arsalan A. Ali, Ahmed B. Sallam, Sanjoy K. Bhattacharya, Sami H. Uwaydat
Journal: Ophthalmology (2024)
Keratinocyte-to-macrophage communication exacerbate psoriasiform dermatitis via LRG1-enriched extracellular vesicles
Authors: Wenjuan Jiang, Tingting Zhang, Yueqi Qiu, Qianmei Liu, Xiaoyun Chen, Qiaolin Wang, Xiaoli Min, Lianlian Ouyang, Sujie Jia, Qianjin Lu, Yuan He, Ming Zhao
Journal: Theranostics (2024)

Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the progression of psoriasiform dermatitis. However, how these two types of cells communicate remains obscure.
Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study
Authors: Olaf Penack, Thomas Luft, Christophe Peczynski, Axel Benner, Simona Sica, Mutlu Arat, Maija Itäla-Remes, Lucia López Corral, Nicolaas P M Schaap, Michal Karas, Ludek Raida, Thomas Schroeder, Peter Dreger, Elisabetta Metafuni, Tulay Ozcelik, Brenda M Sandmaier, Lambros Kordelas, Ivan Moiseev, Hélène Schoemans, Christian Koenecke, Grzegorz W Basak, Zinaida Peric
Journal: Journal for ImmunoTherapy of Cancer (2024)

We previously reported that the "Endothelial Activation and Stress Index" (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as continuous score. For broad clinical implementation, a prospectively validated EASIX-pre cut-off is needed that defines a high-risk cohort and is easy to use. In the current study, we first performed a retrospective cohort analysis in n=2022 alloSCT recipients and identified an optimal cut-off for predicting non-relapse mortality (NRM) as EASIX-pre=3. For cut-off validation, we conducted a multicenter prospective study with inclusion of n=317 first alloSCTs from peripheral blood stem cell in adult patients with acute leukemia, lymphoma or myelodysplastic syndrome/myeloproliferative neoplasms in the European Society for Blood and Marrow Transplantation network. Twenty-three % (n=74) of alloSCT recipients had EASIX-pre ≥3 taken before conditioning. NRM at 2 years was 31.1% in the high EASIX group versus 11.5% in the low EASIX group (p<0.001). Patients with high EASIX-pre also had worse 2 years overall survival (51.6% vs 70.9%; p=0.002). We were able to validate the cut-off and found that EASIX ≥3 was associated with more than twofold increased risk for NRM in multivariate analysis (HR=2.18, 95% CI 1.2 to 3.94; p=0.01). No statistically significant difference could be observed for the incidence of relapse. The results of this study provide a prospectively validated standard laboratory biomarker index to estimate the transplant-related mortality risk after alloSCT. EASIX ≥3 taken before conditioning identifies a population of alloSCT recipients who have a more than twofold increased risk of treatment-related mortality.
Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial
Authors: Ning Jiang, Jingyuan Zhang, Zhen Guo, Yinan Wu, Lijun Zhao, Cheng Kong, Xue Song, Lingling Gu, Yang Zhao, Si Li, Xia He, Binhui Ren, Xiangzhi Zhu, Ming Jiang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population. Methods RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m 2 ), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4–6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform. Results Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity. Conclusions Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients. Trial registration number ChiCTR2100045104.
Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study
Authors: Sabine Hoffmann, Sarah Gerhardt, Christiane Mühle, Iris Reinhard, Dominic Reichert, Patrick Bach, Rafat Boroumand-Jazi, Christine Kuehner, Alvaro Aguilera, Acelya Aslan, Nadja S. Bahr, Matthew Belanger, Friederike Deeken, Claudia Ebrahimi, Pascale C. Fischbach, Marvin Ganz, Maria Garbusow, Charlotte M. Großkopf, Marie Heigert, Angela Hentschel, Damian Karl, Shuyan Liu, Massimiliano Mazza, Patricia Pelz, Mathieu Pinger, Matthias Reichl, Carlotta Riemerschmid, Annika Rosenthal, Johannes Steffen, Jens Strehle, Friederike Wedemeyer, Franziska Weiss, Julia Wenzel, Gesine Wieder, Alfred Wieland, Judith Zaiser, Hilmar G. Zech, Sina Zimmermann, Johannes Kornhuber, Christian P. Müller, Wolfgang H. Sommer, Rainer Spanagel, Tobias Banaschewski, Lorenz Deserno, Ulrich W. Ebner-Priemer, Herta Flor, Peter Kirsch, Marcella Rietschel, Sabine Vollstädt-Klein, Henrik Walter, Andreas Meyer-Lindenberg, Michael A. Rapp, Stephanie Witt, Michael N. Smolka, Andreas Heinz, Heike Tost, Falk Kiefer, Markus Reichert, Bernd Lenz
Journal: American Journal of Psychiatry (2024)

Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD.
Mindfulness-Oriented Recovery Enhancement for Veterans and Military Personnel on Long-Term Opioid Therapy for Chronic Pain: A Randomized Clinical Trial
Authors: Eric L. Garland, Yoshio Nakamura, Craig J. Bryan, Adam W. Hanley, Anna Parisi, Brett Froeliger, William R. Marchand, Gary W. Donaldson
Journal: American Journal of Psychiatry (2024)

This randomized clinical trial evaluated the efficacy of Mindfulness-Oriented Recovery Enhancement (MORE) among past and present U.S. military personnel with prescriptions for long-term opioid therapy for chronic pain.
Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer
Authors: Junyi Li, Yuanjie Cao, Yancheng Liu, Lu Yu, Zhen Zhang, Xiaofeng Wang, Hui Bai, Yuhan Zhang, Shaochuan Liu, Miaomiao Gao, Chenglu Lu, Chen Li, Yong Guan, Zhen Tao, Zhiqiang Wu, Jie Chen, Zhiyong Yuan
Journal: Journal for ImmunoTherapy of Cancer (2024)

As an unconventional subpopulation of T lymphocytes, γδ T cells can recognize antigens independently of major histocompatibility complex restrictions. Recent studies have indicated that γδ T cells play contrasting roles in tumor microenvironments-promoting tumor progression in some cancers (eg, gallbladder and leukemia) while suppressing it in others (eg, lung and gastric). γδ T cells are mainly enriched in peripheral mucosal tissues. As the cervix is a mucosa-rich tissue, the role of γδ T cells in cervical cancer warrants further investigation.
Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations
Authors: Samuel Ghatan, Jeroen van Rooij, Mandy van Hoek, Cindy G. Boer, Janine F. Felix, Maryam Kavousi, Vincent W. Jaddoe, Eric J. G. Sijbrands, Carolina Medina-Gomez, Fernando Rivadeneira, Ling Oei
Journal: Genome Medicine (2024)

Abstract Background Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations. Methods We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger’s Z -test and further validated in a pediatric cohort without diabetes (aged 9–12 years old, n = 3866). Results We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta − 0.08 SD, 95% CI [− 0.10–0.07], p = 6.50 × 10 −32 ) and beta-cell dysfunction (Beta − 0.10 SD, 95% CI [− 0.12, − 0.08], p = 1.46 × 10 −47 ) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06–0.10, p = 8.0 × 10 −33 ). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02–1.62, p = 0.03). Conclusions We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.
Elevated HIV Viral Load is Associated with Higher Recombination Rate In Vivo
Authors: Elena V Romero, Alison F Feder
Journal: Molecular Biology and Evolution (2024)

Abstract HIV’s exceptionally high recombination rate drives its intrahost diversification, enabling immune escape and multidrug resistance within people living with HIV. While we know that HIV’s recombination rate varies by genomic position, we have little understanding of how recombination varies throughout infection or between individuals as a function of the rate of cellular coinfection. We hypothesize that denser intrahost populations may have higher rates of coinfection and therefore recombination. To test this hypothesis, we develop a new approach (recombination analysis via time series linkage decay or RATS-LD) to quantify recombination using autocorrelation of linkage between mutations across time points. We validate RATS-LD on simulated data under short read sequencing conditions and then apply it to longitudinal, high-throughput intrahost viral sequencing data, stratifying populations by viral load (a proxy for density). Among sampled viral populations with the lowest viral loads (&amp;lt;26,800 copies/mL), we estimate a recombination rate of 1.5×10−5 events/bp/generation (95% CI: 7×10−6 to 2.9×10−5), similar to existing estimates. However, among samples with the highest viral loads (&amp;gt;82,000 copies/mL), our median estimate is approximately 6 times higher. In addition to co-varying across individuals, we also find that recombination rate and viral load are associated within single individuals across different time points. Our findings suggest that rather than acting as a constant, uniform force, recombination can vary dynamically and drastically across intrahost viral populations and within them over time. More broadly, we hypothesize that this phenomenon may affect other facultatively asexual populations where spatial co-localization varies.
Improving the safety of CAR‐T‐cell therapy: The risk and prevention of viral infection for patients with relapsed or refractory B‐cell lymphoma undergoing CAR‐T‐cell therapy
Authors: Hu Qian, Xingcheng Yang, Tingting Zhang, Ping Zou, Yicheng Zhang, Weiwei Tian, Zekai Mao, Jia Wei
Journal: American Journal of Hematology (2024)

Abstract Chimeric antigen receptor (CAR) T‐cell therapy, an innovative immunotherapeutic against relapsed/refractory B‐cell lymphoma, faces challenges due to frequent viral infections. Despite this, a comprehensive review addressing risk assessment, surveillance, and treatment management is notably absent. This review elucidates immune response compromises during viral infections in CAR‐T recipients, collates susceptibility risk factors, and deliberates on preventive strategies. In the post‐pandemic era, marked by the Omicron variant, new and severe threats to CAR‐T therapy emerge, necessitating exploration of preventive and treatment measures for COVID‐19. Overall, the review provides recommendations for viral infection prophylaxis and management, enhancing CAR‐T product safety and recipient survival.
Public platform with 39,472 exome control samples enables association studies without genotype sharing
Authors: Mykyta Artomov, Alexander A. Loboda, Maxim N. Artyomov, Mark J. Daly
Journal: Nature Genetics (2024)

Abstract Acquiring a sufficiently powered cohort of control samples matched to a case sample can be time-consuming or, in some cases, impossible. Accordingly, an ability to leverage genetic data from control samples that were already collected elsewhere could dramatically improve power in genetic association studies. Sharing of control samples can pose significant challenges, since most human genetic data are subject to strict sharing regulations. Here, using the properties of singular value decomposition and subsampling algorithm, we developed a method allowing selection of the best-matching controls in an external pool of samples compliant with personal data protection and eliminating the need for genotype sharing. We provide access to a library of 39,472 exome sequencing controls at http://dnascore.net enabling association studies for case cohorts lacking control subjects. Using this approach, control sets can be selected from this online library with a prespecified matching accuracy, ensuring well-calibrated association analysis for both rare and common variants.
The need and benefit of the Harmonising Outcome Measures for Eczema user’s guide
Authors: Wils Nielsen, Aaron M Drucker
Journal: British Journal of Dermatology (2024)

Journal Article The need and benefit of the Harmonising Outcome Measures for Eczema user's guide Get access Wils Nielsen, Wils Nielsen Conceptualization, Writing - original draft, Writing - review & editing Institute for Medical Science, University of Toronto, Toronto, ON, Canada Search for other works by this author on: Oxford Academic Google Scholar Aaron M Drucker Aaron M Drucker Conceptualization, Writing - review & editing Department of Medicine and Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, CanadaDepartment of Medicine and Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada Correspondence: Aaron Drucker. Email: Aaron.Drucker@wchospital.ca https://orcid.org/0000-0002-7388-9475 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 190, Issue 4, April 2024, Pages 462–463, https://doi.org/10.1093/bjd/ljae012 Published: 10 January 2024 Article history Accepted: 30 November 2023 Received: 05 January 2024 Published: 10 January 2024 Corrected and typeset: 06 February 2024
A single-cell atlas of the aging mouse ovary
Authors: José V. V. Isola, Sarah R. Ocañas, Chase R. Hubbart, Sunghwan Ko, Samim Ali Mondal, Jessica D. Hense, Hannah N. C. Carter, Augusto Schneider, Susan Kovats, José Alberola-Ila, Willard M. Freeman, Michael B. Stout
Journal: Nature Aging (2024)

Abstract Ovarian aging leads to diminished fertility, dysregulated endocrine signaling and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Female humans experience a sharp decline in fertility around 35 years of age, which corresponds to declines in oocyte quality. Despite a growing body of work, the field lacks a comprehensive cellular map of the transcriptomic changes in the aging mouse ovary to identify early drivers of ovarian decline. To fill this gap we performed single-cell RNA sequencing on ovarian tissue from young (3-month-old) and reproductively aged (9-month-old) mice. Our analysis revealed a doubling of immune cells in the aged ovary, with lymphocyte proportions increasing the most, which was confirmed by flow cytometry. We also found an age-related downregulation of collagenase pathways in stromal fibroblasts, which corresponds to rises in ovarian fibrosis. Follicular cells displayed stress-response, immunogenic and fibrotic signaling pathway inductions with aging. This report provides critical insights into mechanisms responsible for ovarian aging phenotypes. The data can be explored interactively via a Shiny-based web application.
The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression
Authors: Steve Stegen, Karen Moermans, Ingrid Stockmans, Bernard Thienpont, Geert Carmeliet
Journal: Nature Metabolism (2024)

Bone-resorbing osteoclasts are vital for postnatal bone health, as increased differentiation or activity results in skeletal pathologies such as osteoporosis. The metabolism of mature osteoclasts differs from their progenitor cells, but whether the observed metabolic changes are secondary to the altered cell state or actively drive the process of cell differentiation is unknown. Here, we show that transient activation of the serine synthesis pathway (SSP) is essential for osteoclastogenesis, as deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase in osteoclast progenitors impairs their differentiation and results in increased bone mass. In addition, pharmacological phosphoglycerate dehydrogenase inhibition abrogated bone loss in a mouse model of postmenopausal osteoporosis by blocking bone resorption. Mechanistically, SSP-derived α-ketoglutarate is necessary for histone demethylases that remove repressive histone methylation marks at the nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) gene locus, thereby inducing NFATc1 expression and consequent osteoclast maturation. Taken together, this study reveals a metabolic-epigenetic coupling mechanism that directs osteoclast differentiation and suggests that the SSP can be therapeutically targeted to prevent osteoporotic bone loss.