tbuckley/cabot-search huggingface dataset:
Leaf: an ultrafast filter for population-scale long-read SV detection
Authors: Chenxu Pan, Knut Reinert
Journal: Genome biology (2024)

Abstract Advances in sequencing technology have facilitated population-scale long-read structural variant (SV) detection. Arguably, one of the main challenges in population-scale analysis is developing effective computational pipelines. Here, we present a new filter-based pipeline for population-scale long-read SV detection. It better captures SV signals at an early stage than conventional assembly-based or alignment-based pipelines. Assessments in this work suggest that the filter-based pipeline helps better resolve intra-read rearrangements. Moreover, it is also more computationally efficient than conventional pipelines and thus may facilitate population-scale long-read applications.
Cumulative radiation dose from medical imaging in pediatric congenital heart disease patients with epicardial cardiac implantable electronic devices
Authors: Oluyemi B Aboyewa, Christina Laternser, Andrada Popescu, Nicole Murphy, Dhaivat Shah, Michael C Monge, Cynthia K Rigsby, Laleh Golestanirad, Gregory Webster, Daniel Kim
Journal:  (2024)

Abstract Aims To determine whether paediatric congenital heart disease (CHD) patients with epicardial cardiac implantable electronic devices (CIEDs) receive high cumulative effective doses (CEDs) of ionizing radiation from medical imaging tests. Methods and results We compared 28 paediatric CHD patients with epicardial CIEDs (cases) against 40 patients with no CIED matched by age at operation, sex, surgical era, and CHD diagnosis (controls). We performed a retrospective review of radiation exposure from medical imaging exams between 2006 and 2022. Radiation dose from computed tomography (CT) and X-ray radiography was calculated using the National Cancer Institute Radiation Dosimetry Tool. We performed univariate analysis to compare the CED between the two groups. In the case subgroup, we convened experts’ review to adjudicate the prevalence of CT exams that should have been performed with magnetic resonance imaging (MRI) in the absence of a CIED. Children (median age 2.5 years at implant) with CIEDs received significantly higher median CED compared with matched controls (6.90 vs. 1.72 mSv, P = 0.0018). In cases, expert adjudication showed that 80% of the CT exams would have been performed with MRI in the absence of a CIED. This resulted, on average, a five-fold increase in the effective dose (ED) from post-lead implant CTs. Conclusion Paediatric CHD patients with CIED received four times higher CED than matched controls. Improved access to medical imaging tests without ionizing radiation, such as MRI, could potentially reduce the ED in CIED patients by up to five times.
Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial
Authors: Andrea J Bullock, Benjamin L Schlechter, Marwan G Fakih, Apostolia M Tsimberidou, Joseph E Grossman, Michael S Gordon, Breelyn A Wilky, Agustin Pimentel, Daruka Mahadevan, Ani S Balmanoukian, Rachel E Sanborn, Gary K Schwartz, Ghassan K Abou-Alfa, Neil H Segal, Bruno Bockorny, Justin C Moser, Sunil Sharma, Jaymin M Patel, Wei Wu, Dhan Chand, Katherine Rosenthal, Gabriel Mednick, Chloe Delepine, Tyler J Curiel, Justin Stebbing, Heinz-Josef Lenz, Steven J O'Day, Anthony B El-Khoueiry
Journal: Nature Medicine (2024)

Abstract Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1–confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population ( n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10–26%), and DCR was 61% (62/101; 95% CI, 51–71%). Median DOR was not reached (NR; 95% CI, 5.7 months–NR), and median PFS was 3.5 months (95% CI, 2.7–4.1 months), at a median follow-up of 10.3 months (range, 0.5–42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
Resource requirements to accelerate clinical applications of next generation sequencing and radiomics: Workshop commentary and review
Authors: Lyndsay Harris, Lalitha K Shankar, Claire Hildebrandt, Wendy S Rubinstein, Kristofor Langlais, Henry Rodriguez, Adam Berger, John Freymann, Erich P Huang, P Mickey Williams, Jean Claude Zenklusen, Robert Ochs, Zivana Tezak, Berkman Sahiner
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract The National Institutes of Health–US Food and Drug Administration Joint Leadership Council Next-Generation Sequencing and Radiomics Working Group was formed by the National Institutes of Health–Food and Drug Administration Joint Leadership Council to promote the development and validation of innovative next-generation sequencing tests, radiomic tools, and associated data analysis and interpretation enhanced by artificial intelligence and machine learning technologies. A 2-day workshop was held on September 29-30, 2021, to convene members of the scientific community to discuss how to overcome the “ground truth” gap that has frequently been acknowledged as 1 of the limiting factors impeding high-quality research, development, validation, and regulatory science in these fields. This report provides a summary of the resource gaps identified by the working group and attendees, highlights existing resources and the ways they can potentially be employed to accelerate growth in these fields, and presents opportunities to support next-generation sequencing and radiomic tool development and validation using technologies such as artificial intelligence and machine learning.
Legal aspects of privacy-enhancing technologies in genome-wide association studies and their impact on performance and feasibility
Authors: Alissa Brauneck, Louisa Schmalhorst, Stefan Weiss, Linda Baumbach, Uwe Völker, David Ellinghaus, Jan Baumbach, Gabriele Buchholtz
Journal: Genome biology (2024)

Abstract Genomic data holds huge potential for medical progress but requires strict safety measures due to its sensitive nature to comply with data protection laws. This conflict is especially pronounced in genome-wide association studies (GWAS) which rely on vast amounts of genomic data to improve medical diagnoses. To ensure both their benefits and sufficient data security, we propose a federated approach in combination with privacy-enhancing technologies utilising the findings from a systematic review on federated learning and legal regulations in general and applying these to GWAS.
Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala
Authors: Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis, Marios Abatis
Journal: Nature Neuroscience (2024)

Abstract The lateral amygdala (LA) encodes fear memories by potentiating sensory inputs associated with threats and, in the process, recruits 10–30% of its neurons per fear memory engram. However, how the local network within the LA processes this information and whether it also plays a role in storing it are still largely unknown. Here, using ex vivo 12-patch-clamp and in vivo 32-electrode electrophysiological recordings in the LA of fear-conditioned rats, in combination with activity-dependent fluorescent and optogenetic tagging and recall, we identified a sparsely connected network between principal LA neurons that is organized in clusters. Fear conditioning specifically causes potentiation of synaptic connections between learning-recruited neurons. These findings of synaptic plasticity in an autoassociative excitatory network of the LA may suggest a basic principle through which a small number of pyramidal neurons could encode a large number of memories.
The elite haplotype OsGATA8-H coordinates nitrogen uptake and productive tiller formation in rice
Authors: Wei Wu, Xiaoou Dong, Gaoming Chen, Zhixi Lin, Wenchao Chi, Weijie Tang, Jun Yu, Saisai Wang, Xingzhou Jiang, Xiaolan Liu, Yujun Wu, Chunyuan Wang, Xinran Cheng, Wei Zhang, Wei Xuan, William Terzaghi, Pamela C. Ronald, Haiyang Wang, Chunming Wang, Jianmin Wan
Journal: Nature Genetics (2024)

Abstract Excessive nitrogen promotes the formation of nonproductive tillers in rice, which decreases nitrogen use efficiency (NUE). Developing high-NUE rice cultivars through balancing nitrogen uptake and the formation of productive tillers remains a long-standing challenge, yet how these two processes are coordinated in rice remains elusive. Here we identify the transcription factor OsGATA8 as a key coordinator of nitrogen uptake and tiller formation in rice. OsGATA8 negatively regulates nitrogen uptake by repressing transcription of the ammonium transporter gene OsAMT3.2 . Meanwhile, it promotes tiller formation by repressing the transcription of OsTCP19 , a negative modulator of tillering. We identify OsGATA8 -H as a high-NUE haplotype with enhanced nitrogen uptake and a higher proportion of productive tillers. The geographical distribution of OsGATA8- H and its frequency change in historical accessions suggest its adaption to the fertile soil. Overall, this study provides molecular and evolutionary insights into the regulation of NUE and facilitates the breeding of rice cultivars with higher NUE.
Distinct developmental pathways generate functionally distinct populations of natural killer cells
Authors: Yi Ding, Marieke Lavaert, Simon Grassmann, Victor I. Band, Liang Chi, Arundhoti Das, Sumit Das, Christelle Harly, Susannah C. Shissler, Justin Malin, Dingkang Peng, Yongge Zhao, Jinfang Zhu, Yasmine Belkaid, Joseph C. Sun, Avinash Bhandoola
Journal: Nature Immunology (2024)
Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes
Authors: Hüsün S. Kizilkaya, Kimmie V. Sørensen, Jakob S. Madsen, Peter Lindquist, Jonathan D. Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A. Gerlach, Lærke S. Gasbjerg, Jacek Mokrosiński, Stephanie A. Mowery, Patrick J. Knerr, Brian Finan, Jonathan E. Campbell, David A. D’Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J. Holst, Torben Hansen, Shane C. Wright, Volker M. Lauschke, Niels Grarup, Alexander S. Hauser, Mette M. Rosenkilde
Journal: Nature Metabolism (2024)

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes
Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real‐world intention‐to‐treat analysis
Authors: Maeve A. O'Reilly, William Wilson, David Burns, Andrea Kuhnl, Frances Seymour, Ben Uttenthal, Caroline Besley, Rajesh Alajangi, Thomas Creasey, Shankara Paneesha, Johnathon Elliot, Carlos Gonzalez Arias, Sunil Iyengar, Matthew R. Wilson, Alison Delaney, Lourdes Rubio, Jonathan Lambert, Khalil Begg, Stephen Boyle, Kathleen P. L. Cheok, Graham P. Collins, Claire Roddie, Rod Johnson, Robin Sanderson
Journal: HemaSphere (2024)

Abstract Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS &gt; 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.
Multi-target measurable residual disease assessed by error-corrected sequencing in patients with acute myeloid leukemia: An ALFA study
Authors: Pierre Hirsch, Jérôme Lambert, Maxime Bucci, Caroline Deswarte, Augustin Boudry, Juliette Lambert, Laurene Fenwarth, Jean-Baptiste Micol, Christine Terré, Karine Celli-Lebras, Xavier Thomas, Hervé Dombret, Nicolas Duployez, Claude Preudhomme, Raphael Itzykson, Francois Delhommeau
Journal: Blood Cancer Journal (2024)

Abstract The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A , TET2 , and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p &lt; 0.0001), lower RFS (HR = 3.36, p &lt; 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1 -MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection ( p = 0.0059) and NGS-MRD ( p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.
Gut microbiome encoded purine and amino acid pathways present prospective biomarkers for predicting metformin therapy efficacy in newly diagnosed T2D patients
Authors: Ilze Elbere, Zigmunds Orlovskis, Laura Ansone, Ivars Silamikelis, Lauma Jagare, Liga Birzniece, Kaspars Megnis, Kristaps Leskovskis, Annija Vaska, Maris Turks, Kristaps Klavins, Valdis Pirags, Monta Briviba, Janis Klovins
Journal: Gut Microbes (2024)

Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population. Understanding the potential indirect or synergistic effects of metformin on gut microbiota composition and encoded functions could potentially offer new insights into predicting treatment efficacy and designing more personalized treatments in the future. We combined targeted metabolomics and metagenomic profiling of gut microbiomes in newly diagnosed T2D patients before and after metformin therapy to identify potential pre-treatment biomarkers and functional signatures for metformin efficacy and induced changes in metformin therapy responders. Our sequencing data were largely corroborated by our metabolic profiling and identified that pre-treatment enrichment of gut microbial functions encoding purine degradation and glutamate biosynthesis was associated with good therapy response. Furthermore, we identified changes in glutamine-associated amino acid (arginine, ornithine, putrescine) metabolism that characterize differences in metformin efficacy before and after the therapy. Moreover, metformin Responders' microbiota displayed a shifted balance between bacterial lipidA synthesis and degradation as well as alterations in glutamate-dependent metabolism of N-acetyl-galactosamine and its derivatives (e.g. CMP-pseudaminate) which suggest potential modulation of bacterial cell walls and human gut barrier, thus mediating changes in microbiome composition. Together, our data suggest that glutamine and associated amino acid metabolism as well as purine degradation products may potentially condition metformin activity via its multiple effects on microbiome functional composition and therefore serve as important biomarkers for predicting metformin efficacy.
Gene expression landscape of cutaneous squamous cell carcinoma progression
Authors: Tomas Bencomo, Carolyn S Lee
Journal: British Journal of Dermatology (2024)

Abstract Background Cutaneous squamous cell carcinomas (cSCCs) are the second most common human cancer and have been characterized by RNA sequencing (RNA-Seq); however, the transferability of findings from individual studies may be limited by small sample sizes and diverse analysis protocols. Objectives To define the transcriptome landscape at different stages in the progression of normal skin to cSCC via a meta-analysis of publicly available RNA-Seq samples. Methods Whole-transcriptome data from 73 clinically normal skin samples, 46 actinic keratoses (AK) samples, 16 in situ SCC samples, 13 keratoacanthoma (KA) samples and 147 cSCC samples [including 30 samples from immunocompromised patients and 8 from individuals with recessive dystrophic epidermolysis bullosa (RDEB)] were uniformly processed to harmonize gene expression. Differential expression, fusion detection and cell-type deconvolution analyses were performed. Results Individual RNA-Seq studies of cSCC demonstrated study-specific clustering and varied widely in their differential gene expression detection. Following batch correction, we defined a consensus set of differentially expressed genes (DEGs), including those altered in the preinvasive stages of cSCC development, and used single-cell RNA-Seq data to demonstrate that DEGs are often – but not always – expressed by tumour-specific keratinocytes (TSKs). Analysis of the cellular composition of cSCC, KA and RDEB-cSCC identified an increase in differentiated keratinocytes in KA, while RDEB-cSCC contained the most TSKs. Compared with cSCC arising in immunocompetent individuals, cSCC samples from immunosuppressed patients demonstrated fewer memory B cells and CD8+ T cells. A comprehensive and unbiased search for fusion transcripts in cSCC and intermediate disease stages identified few candidates that recurred in &amp;gt;1% of all specimens, suggesting that most cSCC are not driven by oncogenic gene fusions. Finally, using Genotype-Tissue Expression (GTEx) data, we distilled a novel 300-gene signature of chronic sun exposure that affirms greater cumulative ultraviolet (UV) exposure in later stages of cSCC development. Conclusions Our results define the gene expression landscape of cSCC progression, characterize cell subpopulation heterogeneity in cSCC subtypes that contribute to their distinct clinical phenotypes, demonstrate that gene fusions are not a common cause of cSCC and identify UV-responsive genes associated with cSCC development.
From Short Circuit to Completed Circuit: Conductive Hydrogel Facilitating Oral Wound Healing (Adv. Healthcare Mater. 15/2024)
Authors: Qiangqiang Zhou, Hanqing Dai, Yukun Yan, Zhiming Qin, Mengqi Zhou, Wanlu Zhang, Guoqi Zhang, Ruiqian Guo, Xiaoling Wei
Journal: Advanced Healthcare Materials (2024)
Supramolecular Heterodimer Peptides Assembly for Nanoparticles Functionalization (Adv. Healthcare Mater. 15/2024)
Authors: Clélia Mathieu, Shayamita Ghosh, Julien Draussin, Adeline Gasser, Guillaume Jacquot, Mainak Banerjee, Tanushree Gupta, Marc Schmutz, Céline Mirjolet, Olivier Tillement, François Lux, Andrey S. Klymchenko, Mariel Donzeau, Xavier Pivot, Sébastien Harlepp, Alexandre Detappe
Journal: Advanced Healthcare Materials (2024)
Skin‐Attached Arrayed Piezoelectric Sensors for Continuous and Safe Monitoring of Oculomotor Movements (Adv. Healthcare Mater. 15/2024)
Authors: Nam‐In Kim, Jie Chen, Weijie Wang, Ja‐Yeon Kim, Min‐Ki Kwon, Mina Moradnia, Sara Pouladi, Jae‐Hyun Ryou
Journal: Advanced Healthcare Materials (2024)
Acute lymphoblastic leukaemia
Journal: Nature Reviews Disease Primers (2024)

Blood or bone marrow T cells, B cells, lymphoblasts, red blood cells, neutrophils, basophils, eosinophils, monocytes and platelets DiagnosisBone marrow trephine biopsy and aspiration are required to confirm and complete diagnosis.Tests may include flow cytometry, immunophenotyping and high-accuracy molecular assays.