tbuckley/cabot-search huggingface dataset:
A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds
Authors: Thijs C. J. Verheul, Nynke Gillemans, Kerstin Putzker, Rezin Majied, Tingyue Li, Memnia Vasiliou, Bert Eussen, Annelies de Klein, Wilfred F. J. van IJcken, Emile van den Akker, Marieke von Lindern, Joe Lewis, Ulrike Uhrig, Yukio Nakamura, Thamar van Dijk, Sjaak Philipsen
Journal: HemaSphere (2024)

Abstract Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β‐globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal‐to‐adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ‐globin subunit to reverse this switch and ameliorate these symptoms. Despite decades of research, only one compound, hydroxyurea, found its way to the clinic as an inducer of fetal hemoglobin. Unfortunately, its efficacy varies among patients, highlighting the need for more effective treatments. Erythroid cell lines have been instrumental in the pursuit of both pharmacological and genetic ways to reverse the postnatal hemoglobin switch. Here, we describe the first endogenously tagged fetal hemoglobin reporter cell line based on the adult erythroid progenitor cell line HUDEP2. Utilizing CRISPR‐Cas9‐mediated knock‐in, a bioluminescent tag was integrated at the HBG1 gene. Subsequent extensive characterization confirmed that the resulting reporter cell line closely mirrors the HUDEP2 characteristics and that the cells report fetal hemoglobin induction with high sensitivity and specificity. This novel reporter cell line is therefore highly suitable for evaluating genetic and pharmacologic strategies to induce fetal hemoglobin. Furthermore, it provides an assay compatible with high‐throughput drug screening, exemplified by the identification of a cluster of known fetal hemoglobin inducers in a pilot study. This new tool is made available to the research community, with the aspiration that it will accelerate the search for safer and more effective strategies to reverse the hemoglobin switch.
Restrictions on Pesticides and Deliberate Self-Poisoning in Sri Lanka
Authors: Firouzeh Noghrehchi, Andrew H. Dawson, Jacques Raubenheimer, Fahim Mohamed, Indika B. Gawarammana, Michael Eddleston, Nicholas A. Buckley
Journal: JAMA Network Open (2024)

Deliberate self-poisoning using pesticides as a means of suicide is an important public health problem in low- and middle-income countries. Three highly toxic pesticides-dimethoate, fenthion, and paraquat-were removed from the market in Sri Lanka between 2008 and 2011. In 2015, less toxic pesticides (chlorpyrifos, glyphosate, carbofuran, and carbaryl) were restricted. Subsequent outcomes have not been well described.
The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function
Authors: Christopher M. Jackson, Ayush Pant, Wikum Dinalankara, John Choi, Aanchal Jain, Ryan Nitta, Eli Yazigi, Laura Saleh, Liang Zhao, Thomas R. Nirschl, Christina M. Kochel, Brandon Hwa-Lin Bergsneider, Denis Routkevitch, Kisha Patel, Kwang Bog Cho, Stephany Tzeng, Sarah Y. Neshat, Young-Hoon Kim, Barbara J. Smith, Maria Cecilia Ramello, Elena Sotillo, Xinnan Wang, Jordan J. Green, Chetan Bettegowda, Gordon Li, Henry Brem, Crystal L. Mackall, Drew M. Pardoll, Charles G. Drake, Luigi Marchionni, Michael Lim
Journal: Immunity (2024)
Diversity of ribosomes at the level of rRNA variation associated with human health and disease
Authors: Daphna Rothschild, Teodorus Theo Susanto, Xin Sui, Jeffrey P. Spence, Ramya Rangan, Naomi R. Genuth, Nasa Sinnott-Armstrong, Xiao Wang, Jonathan K. Pritchard, Maria Barna
Journal: Cell Genomics (2024)

With hundreds of copies of rDNA, it is unknown whether they possess sequence variations that form different types of ribosomes. Here, we developed an algorithm for long-read variant calling, termed RGA, which revealed that variations in human rDNA loci are predominantly insertion-deletion (indel) variants. We developed full-length rRNA sequencing (RIBO-RT) and in situ sequencing (SWITCH-seq), which showed that translating ribosomes possess variation in rRNA. Over 1,000 variants are lowly expressed. However, tens of variants are abundant and form distinct rRNA subtypes with different structures near indels as revealed by long-read rRNA structure probing coupled to dimethyl sulfate sequencing. rRNA subtypes show differential expression in endoderm/ectoderm-derived tissues, and in cancer, low-abundance rRNA variants can become highly expressed. Together, this study identifies the diversity of ribosomes at the level of rRNA variants, their chromosomal location, and unique structure as well as the association of ribosome variation with tissue-specific biology and cancer.
Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types
Authors: Laura V. Blanton, Adrianna K. San Roman, Geryl Wood, Ashley Buscetta, Nicole Banks, Helen Skaletsky, Alexander K. Godfrey, Thao T. Pham, Jennifer F. Hughes, Laura G. Brown, Paul Kruszka, Angela E. Lin, Daniel L. Kastner, Maximilian Muenke, David C. Page
Journal: Cell Genomics (2024)

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4
Adjuvant Everolimus in Non–Clear Cell Renal Cell Carcinoma
Authors: Shuchi Gulati, Catherine Tangen, Christopher W. Ryan, Ulka N. Vaishampayan, Brian M. Shuch, Pedro C. Barata, Deepak K. Pruthi, Cristiane D. Bergerot, Abhishek Tripathi, Seth P. Lerner, Ian M. Thompson, Primo N. Lara, Sumanta K. Pal
Journal: JAMA Network Open (2024)

Importance Clinical trial data on adjuvant therapy in patients with non–clear cell renal cell carcinoma (RCC) are scant. Objective To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC. Design, Setting, and Participants This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022. Intervention The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo. Main Outcomes and Measures The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS. Results Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high–risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high–risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non–clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo. Conclusions and Relevance In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out. Trial Registration ClinicalTrials.gov Identifier: NCT01120249
Poor Physician Adherence to Clinical Guidelines in Hypertension—Time for Physicians to Face Clinical Inertia
Authors: Michel Burnier
Journal: JAMA Network Open (2024)

Yuan Lu, ScD; Oreoluwa Arowojolu, MD; Xiaoliang Qiu, MD; Yuntian Liu, MS; Leslie A. Curry, PhD; Harlan M. Krumholz, MD, SM
Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma
Authors: Guanzhang Li, Di Wang, You Zhai, Changqing Pan, Jiazheng Zhang, Chen Wang, Ruoyu Huang, Mingchen Yu, Yiming Li, Xing Liu, Yanwei Liu, Fan Wu, Zheng Zhao, Huimin Hu, Zhongfang Shi, Ulf Dietrich Kahlert, Tao Jiang, Wei Zhang
Journal: Cell Metabolism (2024)

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.
Adjuvant Therapy for Non–Clear Cell Renal Cell Carcinoma—The Ascent Continues
Authors: Jacqueline T. Brown
Journal: JAMA Network Open (2024)

Shuchi Gulati, MD, MSc; Catherine Tangen, DrPH; Christopher W. Ryan, MD; Ulka N. Vaishampayan, MD; Brian M. Shuch, MD; Pedro C. Barata, MD, MSc; Deepak K. Pruthi, MD; Cristiane D. Bergerot, PhD; Abhishek Tripathi, MD; Seth P. Lerner, MD; Ian M. Thompson Jr, MD; Primo N. Lara Jr, MD; Sumanta K. Pal, MD
Alleviating protein-condensation-associated damage at the endoplasmic reticulum enhances plant disease tolerance
Authors: Zhijuan Tang, Shaosong Shi, Ruixia Niu, Yulu Zhou, Zhao Wang, Rongrong Fu, Rui Mou, Suming Chen, Pingtao Ding, Guoyong Xu
Journal: Cell Host & Microbe (2024)
Performance and Clinical Impact of Radiomics and 3D-CNN Models for the Diagnosis of Neurodegenerative Parkinsonian Syndromes on 18F-FDOPA PET
Authors: Thi Khuyen Le, Victor Comte, Jacques Darcourt, Micheline Razzouk-Cadet, Anne-Capucine Rollet, Fanny Orlhac, Olivier Humbert
Journal: Clinical Nuclear Medicine (2024)

The aim of this study was to compare the performance and added clinical value of a semiautomated radiomics model and an automated 3-dimensinal convolutional neural network (3D-CNN) model for diagnosing neurodegenerative parkinsonian syndromes on 18 F-FDOPA PET images.
Repurposing NAMPT inhibitors for germinal center B-cell-like diffuse large B-cell lymphoma
Authors: Claudio Scuoppo, Bowen Cai, Kenneth Ofori, Hanna Scholze, Rahul Kumar, Angelo D’Alessandro, Katia Basso, Laura Pasqualucci, Riccardo Dalla-Favera
Journal: Blood Cancer Discovery (2024)

Diffuse large B-cell lymphoma (DLBCL) includes the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, which differ in cell of origin, genetics, and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCL in vitro and in vivo. We validated three chemically distinct NAMPTis for their on-target activity based on biochemical and genetic rescue approaches and found the ratio between NAMPT and PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher antitumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacologic and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs. Significance: Targeted therapies have emerged for the ABC subtype of DLBCL, but not for the GCB subtype, despite the evidence of a significant subset of high-risk cases. We identify a drug that specifically targets a subset of GCB-DLBCL and provide preclinical evidence for BCL2 translocations as biomarkers for their identification.
68Ga-DOTA-IBA PET/CT and 18F-FDG PET/CT in Ewing Sarcoma
Authors: Feifan Xiang, Huipan Liu, Xiaoqi Tan, Wenzhe Ma, Yue Chen
Journal: Clinical Nuclear Medicine (2024)

Abstract A 29-year-old man with Ewing sarcoma in the right ankle underwent 68 Ga-DOTA-IBA PET/CT and 18 F-FDG PET/CT, both of which showed high radiotracer activity for the primary tumor. Interestingly, bone metastases were detected early using 68 Ga-DOTA-IBA PET/CT for the sixth thoracic vertebrae and with 18 F-FDG PET/CT for the bilateral humerus. Higher uptake of 68 Ga-DOTA-IBA was found in both primary and metastatic sites of Ewing sarcoma. 177 Lu-DOTA-IBA may be one of the possible therapies for metastatic or recurrent Ewing sarcoma.
Ventilation strategies in cardiogenic shock: Insights from the <scp>AltShock</scp>‐2 registry
Authors: Alice Sacco, Andrea Montisci, Giovanni Tavecchia, Simone Frea, Davide Bernasconi, Costanza N.J. Colombo, Stephanie Bertolin, Giovanna Viola, Luca Villanova, Martina Briani, Lisa Patrini, Pier Paolo Bocchino, Carlotta Sorini Dini, Nicoletta D'Ettore, Maurizio Bertaina, Mario Iannaccone, Luciano Potena, Letizia Bertoldi, Serafina Valente, Rita Camporotondo, Marco Marini, Matteo Pagnesi, Marco Metra, Gaetano De Ferrari, Fabrizio Oliva, Nuccia Morici, Federico Pappalardo, Guido Tavazzi
Journal: European Journal of Heart Failure (2024)

Aims To describe the use and the relation to outcome of different ventilation strategies in a contemporary, large, prospective registry of cardiogenic shock patients. Methods and results Among 657 patients enrolled from March 2020 to November 2023, 198 (30.1%) received oxygen therapy (OT), 96 (14.6%) underwent non‐invasive ventilation (NIV), and 363 (55.3%) underwent invasive mechanical ventilation (iMV). Patients in the iMV group were significantly younger compared to those in the NIV and OT groups (63 vs. 69 years, p &lt; 0.001). There were no significant differences between groups regarding cardiovascular risk factors. Patients with SCAI B and C were more frequently treated with OT and NIV compared to iMV (65.1% and 65.4% vs. 42.6%, respectively, p &gt; 0.001), while the opposite trend was observed in SCAI D patients (12% and 12.2% vs. 30.9%, respectively, p &lt; 0.001). All‐cause mortality at 24 h did not differ amongst the three groups. The 60‐day mortality rates were 40.2% for the iMV group, 26% for the OT group, and 29.3% for the NIV group ( p = 0.005), even after excluding patients with cardiac arrest at presentation. In the multivariate analysis including SCAI stages, NIV was not associated with worse mortality compared to iMV (hazard ratio 1.97, 95% confidence interval 0.85–4.56), even in more severe SCAI stages such as D. Conclusions Compared to previous studies, we observed a rising trend in the utilization of NIV among cardiogenic shock patients, irrespective of aetiology and SCAI stages. In this clinical scenario, NIV emerges as a safe option for appropriately selected patients.
DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants
Authors: Simon C Biddie, Giovanna Weykopf, Elizabeth F Hird, Elias T Friman, Wendy A Bickmore
Journal: Genome biology (2024)

Abstract Background Genome-wide association studies (GWAS) have revealed a multitude of candidate genetic variants affecting the risk of developing complex traits and diseases. However, the highlighted regions are typically in the non-coding genome, and uncovering the functional causative single nucleotide variants (SNVs) is challenging. Prioritization of variants is commonly based on genomic annotation with markers of active regulatory elements, but current approaches still poorly predict functional variants. To address this, we systematically analyze six markers of active regulatory elements for their ability to identify functional variants. Results We benchmark against molecular quantitative trait loci (molQTL) from assays of regulatory element activity that identify allelic effects on DNA-binding factor occupancy, reporter assay expression, and chromatin accessibility. We identify the combination of DNase footprints and divergent enhancer RNA (eRNA) as markers for functional variants. This signature provides high precision, but with a trade-off of low recall, thus substantially reducing candidate variant sets to prioritize variants for functional validation. We present this as a framework called FINDER—Functional SNV IdeNtification using DNase footprints and eRNA. Conclusions We demonstrate the utility to prioritize variants using leukocyte count trait and analyze variants in linkage disequilibrium with a lead variant to predict a functional variant in asthma. Our findings have implications for prioritizing variants from GWAS, in development of predictive scoring algorithms, and for functionally informed fine mapping approaches.
Efficient inference of large prokaryotic pangenomes with PanTA
Authors: Duc Quang Le, Tien Anh Nguyen, Son Hoang Nguyen, Tam Thi Nguyen, Canh Hao Nguyen, Huong Thanh Phung, Tho Huu Ho, Nam S. Vo, Trang Nguyen, Hoang Anh Nguyen, Minh Duc Cao
Journal: Genome biology (2024)

Pangenome inference is an indispensable step in bacterial genomics, yet its scalability poses a challenge due to the rapid growth of genomic collections. This paper presents PanTA, a software package designed for constructing pangenomes of large bacterial datasets, showing unprecedented efficiency levels multiple times higher than existing tools. PanTA introduces a novel mechanism to construct the pangenome progressively without rebuilding the accumulated collection from scratch. The progressive mode is shown to consume orders of magnitude less computational resources than existing solutions in managing growing datasets. The software is open source and is publicly available at https://github.com/amromics/panta and at 10.6084/m9.figshare.23724705 .
Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity
Authors: Kenji Ichiyama, Jia Long, Yusuke Kobayashi, Yuji Horita, Takeshi Kinoshita, Yamami Nakamura, Chizuko Kominami, Katia Georgopoulos, Shimon Sakaguchi
Journal: Immunity (2024)
SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo
Authors: Ben Vermaercke, Ryohei Iwata, Keimpe Wierda, Leïla Boubakar, Paula Rodriguez, Martyna Ditkowska, Vincent Bonin, Pierre Vanderhaeghen
Journal: Neuron (2024)

Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs.
Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials
Authors: Nicholas A. Marston, James P. Pirruccello, Giorgio E. M. Melloni, Frederick Kamanu, Marc P. Bonaca, Robert P. Giugliano, Benjamin M. Scirica, Stephen D. Wiviott, Deepak L. Bhatt, Philippe Gabriel Steg, Itamar Raz, Eugene Braunwald, Peter Libby, Patrick T. Ellinor, Alexander G. Bick, Marc S. Sabatine, Christian T. Ruff
Journal: Nature Medicine (2024)
The First Case of 99mTc-FAPI Uptake in Optic Nerve Sheath Meningioma
Authors: Pegah Sahafi, Farid Jafari Zarrin Ghabaei, Kamran Aryana, Seyed amir Aledavood, Atena Aghaee
Journal: Clinical Nuclear Medicine (2024)

This case study presents the first demonstration of FAPI ligand uptake in a patient with optic nerve sheath meningioma. The patient, a 23-year-old woman who had previously undergone surgery for refractory optic meningioma, was referred to our department for 177Lu-DOTATATE therapy. After 3 cycles of 177Lu-DOTATATE administration, her proptosis significantly decreased. Two months after her last therapeutic cycle, a 99mTc-FAPI scan was performed. The scan revealed a mass with moderately increased uptake in the left retro-orbital region. This study is believed to be the first to demonstrate FAPI ligand uptake in a patient with optic nerve sheath meningioma.
A Case of Metastatic Pulmonary Calcification Detected on 99mTc-MDP Bone Scan and 99mTc-FAPI Scan
Authors: Pegah Sahafi, Amin Sabertanha, Sajad Ataei Azimi, Kamran Aryana, Atena Aghaee
Journal: Clinical Nuclear Medicine (2024)

A 59-year-old woman with recent history of weakness, loss of appetite, and significant weight loss was referred for malignancy workup. On the first day, the patient underwent a 99mTc-MDP scan, which revealed diffuse pulmonary uptake in both lungs. Two days later, 99mTc-FAPI scan was performed and showed diffuse pulmonary uptake in the planar and SPECT/CT images. The study present an interesting case demonstrating FAPI-ligand uptake in metastatic pulmonary calcification.