tbuckley/cabot-search huggingface dataset:
Single-cell long-read sequencing-based mapping reveals specialized splicing patterns in developing and adult mouse and human brain
Authors: Anoushka Joglekar, Wen Hu, Bei Zhang, Oleksandr Narykov, Mark Diekhans, Jordan Marrocco, Jennifer Balacco, Lishomwa C. Ndhlovu, Teresa A. Milner, Olivier Fedrigo, Erich D. Jarvis, Gloria Sheynkman, Dmitry Korkin, M. Elizabeth Ross, Hagen U. Tilgner
Journal: Nature Neuroscience (2024)

Abstract RNA isoforms influence cell identity and function. However, a comprehensive brain isoform map was lacking. We analyze single-cell RNA isoforms across brain regions, cell subtypes, developmental time points and species. For 72% of genes, full-length isoform expression varies along one or more axes. Splicing, transcription start and polyadenylation sites vary strongly between cell types, influence protein architecture and associate with disease-linked variation. Additionally, neurotransmitter transport and synapse turnover genes harbor cell-type variability across anatomical regions. Regulation of cell-type-specific splicing is pronounced in the postnatal day 21-to-postnatal day 28 adolescent transition. Developmental isoform regulation is stronger than regional regulation for the same cell type. Cell-type-specific isoform regulation in mice is mostly maintained in the human hippocampus, allowing extrapolation to the human brain. Conversely, the human brain harbors additional cell-type specificity, suggesting gain-of-function isoforms. Together, this detailed single-cell atlas of full-length isoform regulation across development, anatomical regions and species reveals an unappreciated degree of isoform variability across multiple axes.
The algorithm journey map: a tangible approach to implementing AI solutions in healthcare
Authors: William Boag, Alifia Hasan, Jee Young Kim, Mike Revoir, Marshall Nichols, William Ratliff, Michael Gao, Shira Zilberstein, Zainab Samad, Zahra Hoodbhoy, Mushyada Ali, Nida Saddaf Khan, Manesh Patel, Suresh Balu, Mark Sendak
Journal: npj Digital Medicine (2024)

Abstract When integrating AI tools in healthcare settings, complex interactions between technologies and primary users are not always fully understood or visible. This deficient and ambiguous understanding hampers attempts by healthcare organizations to adopt AI/ML, and it also creates new challenges for researchers to identify opportunities for simplifying adoption and developing best practices for the use of AI-based solutions. Our study fills this gap by documenting the process of designing, building, and maintaining an AI solution called SepsisWatch at Duke University Health System. We conducted 20 interviews with the team of engineers and scientists that led the multi-year effort to build the tool, integrate it into practice, and maintain the solution. This “Algorithm Journey Map” enumerates all social and technical activities throughout the AI solution’s procurement, development, integration, and full lifecycle management. In addition to mapping the “who?” and “what?” of the adoption of the AI tool, we also show several ‘lessons learned’ throughout the algorithm journey maps including modeling assumptions, stakeholder inclusion, and organizational structure. In doing so, we identify generalizable insights about how to recognize and navigate barriers to AI/ML adoption in healthcare settings. We expect that this effort will further the development of best practices for operationalizing and sustaining ethical principles—in algorithmic systems.
Preclinical Development of CAR T Cells with Antigen-Inducible IL18 Enforcement to Treat GD2-Positive Solid Cancers
Authors: Lena Fischer-Riepe, Sareetha Kailayangiri, Katharina Zimmermann, Rita Pfeifer, Michael Aigner, Bianca Altvater, Sascha Kretschmann, Simon Völkl, Jordan Hartley, Celine Dreger, Katja Petry, Andreas Bosio, Angelika von Döllen, Wolfgang Hartmann, Holger Lode, Dennis Görlich, Andreas Mackensen, Melanie Jungblut, Axel Schambach, Hinrich Abken, Claudia Rossig
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Cytokine-engineering of chimeric antigen receptor-redirected T cells (CAR T cells) is a promising principle to overcome the limited activity of canonical CAR T cells against solid cancers. Experimental Design: We developed an investigational medicinal product, GD2IL18CART, consisting of CAR T cells directed against ganglioside GD2 with CAR-inducible IL18 to enhance their activation response and cytolytic effector functions in the tumor microenvironment. To allow stratification of patients according to tumor GD2 expression, we established and validated immunofluorescence detection of GD2 on paraffin-embedded tumor tissues. Results: Lentiviral all-in-one vector engineering of human T cells with the GD2-specific CAR with and without inducible IL18 resulted in cell products with comparable proportions of CAR-expressing central memory T cells. Production of IL18 strictly depends on GD2 antigen engagement. GD2IL18CART respond to interaction with GD2-positive tumor cells with higher IFNγ and TNFα cytokine release and more effective target cytolysis compared with CAR T cells without inducible IL18. GD2IL18CART further have superior in vivo antitumor activity, with eradication of GD2-positive tumor xenografts. Finally, we established GMP-compliant manufacturing of GD2IL18CART and found it to be feasible and efficient at clinical scale. Conclusions: These results pave the way for clinical investigation of GD2IL18CART in pediatric and adult patients with neuroblastoma and other GD2-positive cancers (EU CT 2022– 501725–21–00). See related commentary by Locatelli and Quintarelli, p. 3361
St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors
Authors: Gavriel Y. Matt, Edgar Sioson, Kyla Shelton, Jian Wang, Congyu Lu, Airen Zaldivar Peraza, Karishma Gangwani, Robin Paul, Colleen Reilly, Aleksandar Acić, Qi Liu, Stephanie R. Sandor, Clay McLeod, Jaimin Patel, Fan Wang, Cindy Im, Zhaoming Wang, Yadav Sapkota, Carmen L. Wilson, Nickhill Bhakta, Kirsten K. Ness, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou
Journal: Cancer Discovery (2024)

Abstract Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. More than 1,600 phenotypic variables and 400 million genetic variants from more than 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry. Significance: The St. Jude Survivorship Portal is the first data portal designed to share and explore clinical and genetic data from childhood cancer survivors. The portal provides both open- and controlled-access features and will fulfill a wide range of data sharing needs of the survivorship research community and beyond.
Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial
Authors: Hyung-Joo Oh, Suk-Chul Bae, In-Jae Oh, Cheol-Kyu Park, Kyoung-Mi Jung, Da-Mi Kim, Jung-Won Lee, Chang Kyun Kang, Il Yeong Park, Young-Chul Kim
Journal: Clinical Cancer Research (2024)

Abstract Purpose: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR–tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations. Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Results: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4–18.3], while the placebo group had a PFS of 10.9 months (9.0–13.2; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide. Conclusions: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739).
Associations of Dietary Cholesterol Consumption With Incident Diabetes and Cardiovascular Disease: The Role of Genetic Variability in Cholesterol Absorption and Disease Predisposition
Authors: Shuxiao Shi, Ying Dong, Sujing Wang, Xihao Du, Nannan Feng, Lan Xu, Victor W. Zhong
Journal: Diabetes Care (2024)

Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear.
MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer
Authors: Si Min Zheng, Yu Chen Feng, Qin Zhu, Ruo Qi Li, Qian Qian Yan, Liu Teng, Yi Meng Yue, Man Man Han, Kaihong Ye, Sheng Nan Zhang, Teng Fei Qi, Cai Xia Tang, Xiao Hong Zhao, Yuan Yuan Zhang, Liang Xu, Ran Xu, Jun Xing, Mark Baker, Tao Liu, Rick F. Thorne, Lei Jin, Thomas Preiss, Xu Dong Zhang, Shundong Cang, Jin Nan Gao
Journal: Cancer Research (2024)

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment.
CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors
Authors: Sophie Archer, Phillip M. Brailey, Minjung Song, Phillip D. Bartlett, Ines Figueiredo, Bora Gurel, Christina Guo, Verena Brucklacher-Waldert, H. Lorraine Thompson, Jude Akinwale, Samantha E. Boyle, Christine Rossant, Neil R. Birkett, Julia Pizzey, Mark Maginn, James Legg, Richard Williams, Colette M. Johnston, Philip Bland-Ward, Johann S. de Bono, Andrew J. Pierce
Journal: Clinical Cancer Research (2024)

Abstract Purpose: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. Experimental Design: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. Results: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. Conclusions: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.
Importance of experience in transoesophageal echocardiographic evaluation of vegetation size in patients with infective endocarditis: a reliability study
Authors: Louise Schmidt, Lauge Østergaard, Frederik Fasth Grund, Line Schmidt, Jesper James Linde, Lars Køber, Emil L Fosbøl
Journal:  (2024)

Abstract Aims Vegetation size assessed by transoesophageal echocardiography (TOE) is a decisive metric in guiding surgical intervention and prognosis in patients with definite infective endocarditis (IE). The aim of this study was to assess the impact of echocardiographic experience on the reliability and reproducibility of TOE measurements of vegetations in patients with IE. Methods and results Twenty-nine raters from a cardiac department at a tertiary centre were divided into three groups according to echocardiographic experience: experts, cardiologists, and novices. All raters were instructed to measure the maximum length of vegetations in 20 different TOE exams. Interrater agreement was evaluated using intraclass correlation coefficient (ICC), one-way analysis of variance, Kruskal–Wallis test, and Bland–Altmann plots. Reliability was assessed by minimal detectable change (MDC). All measurements were compared with the measured size agreed on by the multi-disciplinary IE team. There was an overall significant interrater variance between the three groups (P &amp;lt; 0.001). The variance was 10.1, 14.8, and 21.7 for the experts, cardiologists, and novices, respectively. ICC was excellent for experts (96.3%) and cardiologists (93.7%) and good for novices (84.6%). The three groups tended to measure smaller than the endocarditis team. MDC was 2.6 mm for experts, 3.3 mm for cardiologists, and 3.6 mm for novices. Conclusion The study showed good to excellent intraclass correlation but high dispersion in all groups. Variance decreased with higher experience. Our findings support current recommendations that complicated cases should be cared for by the multi-disciplinary endocarditis team and underline the importance of echocardiographic expertise when evaluating and measuring vegetations in patients with IE.
Evaluating the clinical utility of the Atopic Dermatitis Control Tool: measurement properties and agreement between patients’ responses and clinicians’ impressions of atopic dermatitis control
Authors: Eric L Simpson, Laurent Eckert, Abhijit Gadkari, T Michelle Brown, Peter A Lio, Benjamin Lockshin, Lauren Nelson, Sheri E Fehnel, Puneet Mahajan, Jingdong Chao, Michaela Nygårdas, Isabelle Guillemin
Journal: British Journal of Dermatology (2024)

Previous analyses have demonstrated the validity and reliability of the Atopic Dermatitis Control Tool (ADCT) in assessing patient-perceived control of atopic dermatitis (AD). We evaluated levels of agreement between patient and clinician assessments of AD control using the ADCT and clinician global assessment of control, respectively, providing further support to the measurement properties of the ADCT.
Antifungal-resistant <i>Trichophyton indotineae</i>: transmission is occurring outside previously identified endemic areas – are we prepared?
Authors: Alireza Abdolrasouli, Roderick J Hay
Journal: British Journal of Dermatology (2024)

This is a response to ‘Rapid emergence of recalcitrant dermatophytosis caused by a cluster of multidrug-resistant Trichophyton indotineae in China’ by Xie et al.
Myeloid C-type lectin receptors in innate immune recognition
Authors: Caetano Reis e Sousa, Sho Yamasaki, Gordon D. Brown
Journal: Immunity (2024)

C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.
The NLR family of innate immune and cell death sensors
Authors: Balamurugan Sundaram, Rebecca E. Tweedell, Sivakumar Prasanth Kumar, Thirumala-Devi Kanneganti
Journal: Immunity (2024)

Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes—multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes—PANoptosomes—driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer.
Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1–2, open-label, multicohort trial
Authors: Ana Oaknin, Kathleen Moore, Tim Meyer, José López-Picazo González, Lot A Devriese, Asim Amin, Christopher D Lao, Valentina Boni, William H Sharfman, Jong Chul Park, Makoto Tahara, Suzanne L Topalian, Manuel Magallanes, Alejandro Molina Alavez, Tariq Aziz Khan, Catherine Copigneaux, Michelle Lee, Charlie Garnett-Benson, Xuya Wang, R Wendel Naumann
Journal: The Lancet Oncology (2024)
Duodenal neuroendocrine tumor successfully removed by endoscopic submucosal dissection with adaptative traction device
Authors: Elena De Cristofaro, Jérôme Rivory, Thomas Walter, Jérémie Jacques, Timothée Wallenhorst, Pierre Lafeuille, Mathieu Pioche
Journal: Endoscopy (2024)

Duodenal neuroendocrine tumors (D-NETs) are uncommon neoplastic entities [1]. The current guidelines advocate for resection when the lesion is ≤20 mm in size, in the absence of lymph node involvement [2]. However, the utility of endoscopic resection remains unclear, especially due to the risk of incomplete resection [3]. Endoscopic submucosal dissection (ESD) is an attractive technique because it offers the potential to achieve en bloc resection with clear margins. In a previous retrospective study, ESD for D-NETs achieved a 100% en bloc resection rate; however, the R0 resection rate is far from perfect and the perforation rate is not null [4]. The use of a traction device, with double clips and rubber band traction, has been described previously to improve the exposure of the tiny submucosal space [5].
Effective hemostasis with a self-assembling peptide hemostatic gel to manage leaky hemorrhage at the ulcer closure site after gastric endoscopic submucosal dissection
Authors: Ryohei Maruoka, Mitsuru Esaki, Yosuke Minoda, Yoshihiro Otsuka, Kazuhiro Haraguchi, Haruei Ogino, Eikichi Ihara
Journal: Endoscopy (2024)

Intraoperative bleeding is a major complication of endoscopic submucosal dissection (ESD), presenting challenges in identifying the bleeding source and achieving effective hemostasis. Recently, a self-assembling peptide hemostatic gel (PuraStat; 3D Matrix, Tokyo, Japan) was developed as a hemostatic agent that reacts with blood or body fluids to form a hydrogel that coats the bleeding surface [1] [2] [3]. This process results in the occlusion of ruptured vessels, halting bleeding by inducing blood coagulation. Here, we report the successful use of a hemostatic gel in controlling leaky bleeding at a fully closed ESD site where the specific bleeding point could not be identified ([Fig. 1]; [Video 1]).
Liver transplant bile duct suture leading to acute cholangitis: endoscopic removal via cholangioscopy
Authors: Emil Thyssen, Parsia Vagefi, Arjmand Mufti, Thomas Tielleman
Journal: Endoscopy (2024)

Acute cholangitis occurs from biliary obstruction. Gallstones, strictures and neoplasia account for most cases [1]. Sutures from prior surgical interventions have previously been described as leading to obstruction [2]. We present a case of a patient who had undergone orthotopic liver transplantation with duct-to-duct anastomosis 4 years previously and developed acute cholangitis ultimately due to a retained suture at the site of the biliary anastomosis ([Video 1]). This suture was successfully removed endoscopically to prevent future recurrences.
Retrograde navigational tunnel technique in peroral endoscopic myotomy for sigmoid-type achalasia
Authors: Zhenguo Pan, Zhiying Gao, Zhongshang Sun, Feng Pan
Journal: Endoscopy (2024)

Standard peroral endoscopic myotomy (POEM) techniques are effective for typical achalasia [1] [2] [3] [4]; however, limitations are encountered when treating the sigmoid type owing to its complex anatomy. Here, we introduce a novel retrograde navigational tunnel technique in POEM that aims to address these challenges.