tbuckley/cabot-search huggingface dataset:
Abstract A101: Codon-specific KRAS mutations predict survival in advanced pancreatic cancer
Authors: Alice Boilève, Adrien Rousseau, Marc Hilmi, Anthony Tarabay, Jacques R.R. Mathieu, Negaar Goudarzi, Jérôme Cartry, Sabrina Bedja, Claudio Nicotra, Maud NgoCamus, Valérie Boige, Marine Valéry, Mohamed Amine Bani, Lambros Tselikas, Antoine Italiano, Fanny Jaulin, Cristina Smolenschi, Antoine Hollebecque, Michel Ducreux
Journal: Cancer Research (2024)

Abstract Background: How distinct KRAS alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, KRAS is now partly targetable with novel specific inhibitors targeting KRASG12 (G12C or G12D) but specific outcomes of these subgroups of patients is poorly described. We analyzed clinical/genomic characteristics, and outcomes of PDAC depending on codon-specific KRAS (G12 vs others), as well as gene expression profiles and in vitro drug sensibility using organoids (PDO). Methods: All metastatic patients with PDAC and available molecular profile from 2015-2022 were eligible and patients with KRAS mutation were included (NCT0493252) in a monocentric retrospective cohort. A cohort of PDO was used to assess the efficacy of 25 antitumor therapies (chemogram) and transcriptomic data from 69 KRAS-mutated tumors was also analyzed. Results: Overall, 263 patients were included, 238 KRASG12 (91%) and 24 (9%) KRASother. There was no difference between KRASG12 and KRASother regarding clinicopathological characteristics and potentially actionable alterations, except for BRAF that was found in 13% of KRASother (p=0.01). GNAS was found more altered in KRASother tumors (p=0.002) suggesting potential TIPMP precursors. Median overall survival from metastatic diagnosis was 16.7 months (95%CI:14.3-18.3) in KRASG12 and 24.9 months (95% CI:17.4-43.4) in KRASother (HR (ref:KRASG12)=0.56 (0.34-0.94), p=0.03 adjusted). First-line treatment-response was not different between groups (ORR and PFS), as confirmed with a similar PDO in vitro sensibility. Transcriptomic analyses showed a significant and exclusive upregulation of immune pathways in KRASG12 tumors. Conclusion: Codon-specific KRAS mutations are not equal and we report for the first time that KRASG12 patients have a worst prognosis than KRASother patients in PDAC. KRASG12 appears as a prognostic factor, as confirmed by transcriptomic analyses. These results warrant to be confirmed in larger scale studies. Citation Format: Alice Boilève, Adrien Rousseau, Marc Hilmi, Anthony Tarabay, Jacques R.R. Mathieu, Negaar Goudarzi, Jérôme Cartry, Sabrina Bedja, Claudio Nicotra, Maud NgoCamus, Valérie Boige, Marine Valéry, Mohamed Amine Bani, Lambros Tselikas, Antoine Italiano, Fanny Jaulin, Cristina Smolenschi, Antoine Hollebecque, Michel Ducreux. Codon-specific KRAS mutations predict survival in advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A101.
Abstract C093: Dysregulated spliceosomal components promote pancreatic cancer progression
Authors: Ledong Wan, Kuan-Ting Lin, Mohammad A. Rahman, Yuma Ishigami, Alexander J. Kral, Dillon Voss, Zhikai Wang, Mads A. Jensen, John E. Wilkinson, Youngkyu Park, David A. Tuveson, Adrian R. Krainer
Journal: Cancer Research (2024)

Abstract Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatic ductal adenocarcinoma (PDAC) is not well understood. We found that two proteins involved in different stages of spliceosome assembly contribute to PDAC tumorigenesis by regulating alternative splicing, either through direct or indirect interaction with RNA. First, we showed that the splicing factor SRSF1—an RNA-binding protein involved in early spliceosome assembly—can induce pancreatitis and accelerate KRASG12D-mediated PDAC by activating the MAPK pathway. Moreover, the expression of SRSF1 decreased in morphologically normal pancreatic cells expressing KRASG12D to maintain cellular homeostasis. Second, we found that breast cancer amplified sequence 2 (BCAS2, also known as SPF27)—a spliceosome scaffold protein associated with conformational changes—also contributes to PDAC progression. Although BCAS2 does not bind RNA directly, it can regulate alternative splicing events in a sequence-specific manner by promoting the usage of specific 5’ splice sites. BCAS2 promotes the inclusion of exon 21, which has a weak 5' splice site, in the SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 (SOS1) pre-mRNA, resulting in a more oncogenic isoform. These studies not only improve our understanding of the oncogenic role of aberrant alternative splicing, but also provide insights into the mechanisms of alternative-splicing regulation at different stages of spliceosome assembly. Citation Format: Ledong Wan, Kuan-Ting Lin, Mohammad A. Rahman, Yuma Ishigami, Alexander J. Kral, Dillon Voss, Zhikai Wang, Mads A. Jensen, John E. Wilkinson, Youngkyu Park, David A. Tuveson, Adrian R. Krainer. Dysregulated spliceosomal components promote pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C093.
Abstract A010: Evaluation of the Avantect Pancreatic Cancer Test for identifying high-risk pancreatic cysts
Authors: Anna Bergamaschi, David Haan, Verena Friedl, Gulfem Guler, Michael Kesling, Micah Collins, Kyle Hazen, Vanessa Lopez, Roger Malta, Maryam Nabiyouni, Michael Riviere, Anna Leighton, Melissa Peters, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy
Journal: Cancer Research (2024)

Abstract Background: Pancreatic cystic lesions are common incidental findings on imaging, but up to half may be precursors of pancreatic cancer. Current diagnostic methods cannot robustly identify cysts that have the highest probability to progress to cancer and require treatment. To address this gap, we evaluated the performance of a non-invasive epigenomic based test employing cell-free DNA, the Avantect Pancreatic Cancer test, in a cohort of patients with pancreatic cysts to identify those at higher risk of malignancy. Methods: In this study, we investigated the use of Avantect in a cohort of patients with pancreatic cysts. Whole blood was collected from 44 patients with cysts: 18 patients with high/moderate and 26 patients with low grade dysplasia/benign cysts. In parallel, demographic information, imaging results, surgical reports, and histological findings were collected for analysis and clinical annotation of patients. Results: Avantect was successfully run on all 44 pancreatic cysts. 16 out of the 18 (89%) patients with cysts of moderate/high grade dysplasia were detected having an abnormal pancreatic signal associated with pancreatic cancer. Of the 26 patients with cysts with low grade/benign features 8 (31%) were detected by Avantect as abnormal. This nearly three-fold higher detection rate for abnormal pancreatic signals in patients with cysts with medium/high grade dysplasia suggests the detection of epigenomic changes as precursors to pancreatic cancer. Conclusions: The Avantect Pancreatic Cancer test shows initial promise in distinguishing between low grade/benign and moderate/high grade dysplasia cysts. Larger studies have been commenced to enable prospective evaluation of Avantect for the management and surveillance of individuals with pancreatic cysts. Citation Format: Anna Bergamaschi, David Haan, Verena Friedl, Gulfem Guler, Michael Kesling, Micah Collins, Kyle Hazen, Vanessa Lopez, Roger Malta, Maryam Nabiyouni, Michael Riviere, Anna Leighton, Melissa Peters, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy. Evaluation of the Avantect Pancreatic Cancer Test for identifying high-risk pancreatic cysts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A010.
Abstract B115: Single-cell transcriptomic analysis reveals both shared and separate functions for <i>GATA6</i> and <i>KRT17</i> in pancreatic cancer
Authors: Brian J. Nelson, Natalie Marchenko, Luisa F. Escobar-Hoyos, Kenneth Shroyer, Scott Powers, Thomas MacCarthy
Journal: Cancer Research (2024)

Abstract Human pancreatic ductal carcinomas (PDACs) are transcriptionally heterogeneous and can be grouped into two classes, the classical subtype associated with GATA6 expression and the basal subtype associated with KRT17 expression. Accordingly, GATA6 and KRT17 are generally thought to have opposing functions in PDAC. However, through our analysis of single cell RNA sequencing data, we have found that many of the genes that are the highly correlated with KRT17 expression are also highly correlated with GATA6 expression, including KLF5, which encodes a transcription factor that promotes PDAC development, and several genes that encode components of intercellular junctions (e.g. CDH1, CLDN4, CLDN18, JUP, and SHROOM3). These results suggest that KRT17 and GATA6 share certain biological functions including the maintenance or modulation of intercellular junctions. We also found evidence for separate functions. Genes with expression that correlated specifically with GATA6 included transcription factor genes involved in normal pancreatic differentiation along with genes encoding components of the Hippo signaling pathway. On the other hand, genes with expression that correlated specifically with KRT17 included several components of PIK3-Akt signaling. Further analysis of scRNA-seq data should reveal more about the mechanisms by which these genes are involved in influencing PDAC progression and maintenance. Citation Format: Brian J. Nelson, Natalie Marchenko, Luisa F. Escobar-Hoyos, Kenneth Shroyer, Scott Powers, Thomas MacCarthy. Single-cell transcriptomic analysis reveals both shared and separate functions for GATA6 and KRT17 in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B115.
Improved modeling of RNA-binding protein motifs in an interpretable neural model of RNA splicing
Authors: Kavi Gupta, Chenxi Yang, Kayla McCue, Osbert Bastani, Phillip A. Sharp, Christopher B. Burge, Armando Solar-Lezama
Journal: Genome biology (2024)

Abstract Sequence-specific RNA-binding proteins (RBPs) play central roles in splicing decisions. Here, we describe a modular splicing architecture that leverages in vitro-derived RNA affinity models for 79 human RBPs and the annotated human genome to produce improved models of RBP binding and activity. Binding and activity are modeled by separate Motif and Aggregator components that can be mixed and matched, enforcing sparsity to improve interpretability. Training a new Adjusted Motif (AM) architecture on the splicing task not only yields better splicing predictions but also improves prediction of RBP-binding sites in vivo and of splicing activity, assessed using independent data.
The role of Toll‐like receptors in neuropsychiatric disorders: Immunopathology, treatment, and management
Authors: Kiarash Saleki, Parsa Alijanizadeh, Nima Javanmehr, Nima Rezaei
Journal: Medicinal Research Reviews (2024)

Neuropsychiatric disorders denote a broad range of illnesses involving neurology and psychiatry. These disorders include depressive disorders, anxiety, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorders, headaches, and epilepsy. In addition to their main neuropathology that lies in the central nervous system (CNS), lately, studies have highlighted the role of immunity and neuroinflammation in neuropsychiatric disorders. Toll-like receptors (TLRs) are innate receptors that act as a bridge between the innate and adaptive immune systems via adaptor proteins (e.g., MYD88) and downstream elements; TLRs are classified into 13 families that are involved in normal function and illnesses of the CNS. TLRs expression affects the course of neuropsychiatric disorders, and is influenced during their pharmacotherapy; For example, the expression of multiple TLRs is normalized during the major depressive disorder pharmacotherapy. Here, the role of TLRs in neuroimmunology, treatment, and management of neuropsychiatric disorders is discussed. We recommend longitudinal studies to comparatively assess the cell-type-specific expression of TLRs during treatment, illness progression, and remission. Also, further research should explore molecular insights into TLRs regulation and related pathways.
Implications of stress-induced gene expression for hematopoietic stem cell aging studies
Authors: Anna Konturek-Ciesla, Rasmus Olofzon, Shabnam Kharazi, David Bryder
Journal: Nature Aging (2024)

Abstract A decline in hematopoietic stem cell (HSC) function is believed to underlie hematological shortcomings with age; however, a comprehensive molecular understanding of these changes is currently lacking. Here we provide evidence that a transcriptional signature reported in several previous studies on HSC aging is linked to stress-induced changes in gene expression rather than aging. Our findings have strong implications for the design and interpretation of HSC aging studies.
A systematic review and meta-analysis of transdiagnostic cognitive behavioural therapies for emotional disorders
Authors: Carmen Schaeuffele, Laura E. Meine, Ava Schulz, Maxi C. Weber, Angela Moser, Christina Paersch, Dominique Recher, Johanna Boettcher, Babette Renneberg, Christoph Flückiger, Birgit Kleim
Journal: Nature Human Behaviour (2024)

Abstract Transdiagnostic cognitive behavioural psychotherapy (TD-CBT) may facilitate the treatment of emotional disorders. Here we investigate short- and long-term efficacy of TD-CBT for emotional disorders in individual, group and internet-based settings in randomized controlled trials (PROSPERO CRD42019141512). Two independent reviewers screened results from PubMed, MEDLINE, PsycINFO, Google Scholar, medRxiv and OSF Preprints published between January 2000 and June 2023, selected studies for inclusion, extracted data and evaluated risk of bias (Cochrane risk-of-bias tool 2.0). Absolute efficacy from pre- to posttreatment and relative efficacy between TD-CBT and control treatments were investigated with random-effects models. Of 56 identified studies, 53 (6,705 participants) were included in the meta-analysis. TD-CBT had larger effects on depression ( g = 0.74 , 95% CI = 0.57–0.92, P &lt; 0.001) and anxiety ( g = 0.77, 95% CI = 0.56–0.97, P &lt; 0.001) than did controls. Across treatment formats, TD-CBT was superior to waitlist and treatment-as-usual. TD-CBT showed comparable effects to disorder-specific CBT and was superior to other active treatments for depression but not for anxiety. Different treatment formats showed comparable effects. TD-CBT was superior to controls at 3, 6 and 12 months but not at 24 months follow-up. Studies were heterogeneous in design and methodological quality. This review and meta-analysis strengthens the evidence for TD-CBT as an efficacious treatment for emotional disorders in different settings.
Intra-tumoral T cells in pediatric brain tumors display clonal expansion and effector properties
Authors: Aditi Upadhye, Kevin E. Meza Landeros, Ciro Ramírez-Suástegui, Benjamin J. Schmiedel, Edwin Woo, Serena J. Chee, Denise Malicki, Nicole G. Coufal, David Gonda, Michael L. Levy, Jason A. Greenbaum, Grégory Seumois, John Crawford, William D. Roberts, Stephen P. Schoenberger, Hilde Cheroutre, Christian H. Ottensmeier, Pandurangan Vijayanand, Anusha-Preethi Ganesan
Journal: Nature Cancer (2024)
Exergame and cognitive training for preventing falls in community-dwelling older people: a randomized controlled trial
Authors: Daina L. Sturnieks, Cameron Hicks, Natassia Smith, Mayna Ratanapongleka, Jasmine Menant, Jessica Turner, Joanne Lo, Carly Chaplin, Jaime Garcia, Michael J. Valenzuela, Kim Delbaere, Robert D. Herbert, Catherine Sherrington, Barbara Toson, Stephen R. Lord
Journal: Nature Medicine (2024)
SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset
Authors: Michele Tomasicchio, Shameem Jaumdally, Lindsay Wilson, Andrea Kotze, Lynn Semple, Stuart Meier, Anil Pooran, Aliasgar Esmail, Komala Pillay, Riyaadh Roberts, Raymond Kriel, Richard Meldau, Suzette Oelofse, Carley Mandviwala, Jessica Burns, Rolanda Londt, Malika Davids, Charnay van der Merwe, Aqeedah Roomaney, Louié Kühn, Tahlia Perumal, Alex J. Scott, Martin J. Hale, Vicky Baillie, Sana Mahtab, Carolyn Williamson, Rageema Joseph, Alex Sigal, Ivan Joubert, Jenna Piercy, David Thomson, David L. Fredericks, Malcolm G. A. Miller, Marta C. Nunes, Shabir A. Madhi, Keertan Dheda
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for ~ 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38% (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p<0.05). Nasopharyngeal culture was negative in 23.1% (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Rosary
Authors: Marshall Robert Moyer
Journal: JAMA (2024)

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MOG-IgA as a Potential Marker of Germinal Center Activity
Authors: Adam E. Handel, Sarosh R. Irani, M. Isabel Leite
Journal: JAMA Neurology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal