tbuckley/cabot-search huggingface dataset:
Evaluating the positive predictive value of code-based identification of cirrhosis and its complications utilizing GPT-4
Authors: Aryana T. Far, Asal Bastani, Albert Lee, Oksana Gologorskaya, Chiung-Yu Huang, Mark J. Pletcher, Jennifer C. Lai, Jin Ge
Journal: Hepatology (2024)

Background and Aims: Diagnosis code classification is a common method for cohort identification in cirrhosis research, but it is often inaccurate and augmented by labor-intensive chart review. Natural language processing using large language models (LLMs) is a potentially more accurate method. To assess LLMs’ potential for cirrhosis cohort identification, we compared code-based versus LLM-based classification with chart review as a “gold standard.” Approach and Results: We extracted and conducted a limited chart review of 3788 discharge summaries of cirrhosis admissions. We engineered zero-shot prompts using a Generative Pre-trained Transformer 4 to determine whether cirrhosis and its complications were active hospitalization problems. We calculated positive predictive values (PPVs) of LLM-based classification versus limited chart review and PPVs of code-based versus LLM-based classification as a “silver standard” in all 3788 summaries. Compared to gold standard chart review, code-based classification achieved PPVs of 82.2% for identifying cirrhosis, 41.7% for HE, 72.8% for ascites, 59.8% for gastrointestinal bleeding, and 48.8% for spontaneous bacterial peritonitis. Compared to the chart review, Generative Pre-trained Transformer 4 achieved 87.8%–98.8% accuracies for identifying cirrhosis and its complications. Using LLM as a silver standard, code-based classification achieved PPVs of 79.8% for identifying cirrhosis, 53.9% for HE, 55.3% for ascites, 67.6% for gastrointestinal bleeding, and 65.5% for spontaneous bacterial peritonitis. Conclusions: LLM-based classification was highly accurate versus manual chart review in identifying cirrhosis and its complications. This allowed us to assess the performance of code-based classification at scale using LLMs as a silver standard. These results suggest LLMs could augment or replace code-based cohort classification and raise questions regarding the necessity of chart review.
Prevalence of hepatitis C virus hypervariable region 1 insertions and their role in antibody evasion
Authors: Christina Holmboe Olesen, Laura Collignon, Rodrigo Velázquez-Moctezuma, Margherita Fanalista, Ulrik Fahnøe, Sarah Mollerup, Uffe V. Schneider, Kenn Holmbeck, Jens Bukh, Jannick Prentoe
Journal: Hepatology (2024)

Background and Aims: Chronic hepatitis C virus (HCV) infection afflicts around 50 million people globally, causing ~250,000 deaths yearly. An effective vaccine needs to overcome high viral diversity and HCV’s ability to evade neutralizing antibodies (NAbs). Rapid antigenic drift in the N-terminal motif of envelope protein E2, named hypervariable region 1 (HVR1), is critically involved in NAb evasion via an incompletely understood mechanism involving viral entry factors. The canonical length of HVR1 is 27 amino acids, but insertions of 2-4 amino acids was described in patients infected with genotype 1b. We aimed at determining whether HVR1 insertions may be underreported due to extreme HVR1 variability. Approach and Results: We observed a 0.7% HVR1 insertion prevalence in routine NGS patient contigs. Thus, we performed direct sequence analysis of E1E2 sequences from 131 HCV infected patients. Interestingly, we observed that 3% of patients harbored viruses (genotype 1a, 2b, 3a) with dominant HVR1 insertions. Insertion of longer non-canonical HVR1s into HCV cell culture recombinants frequently caused loss of fitness. However, culture-viable viruses with HVR1 insertions were fully viable in vivo . Interestingly, in adapted genotype 1b recombinants with HVR1 insertions, we found internal HVR1 deletions, that increased antibody sensitivity, which surprisingly correlated more with reduced LDLr than reduced SR-BI dependency, indicating a role of LDLr in NAb evasion. Conversely, HVR1 insertions had no effect on receptor dependency, however, they modulated epitope-specific NAb sensitivity. Conclusions: HVR1 insertion prevalence and NAb sensitivity modulation indicate they represent a mechanism by which HCV evades emerging NAbs during infection.
The penetration of therapeutics across the blood-brain barrier: Classic case studies and clinical implications
Authors: William A. Banks, Elizabeth M. Rhea, May J. Reed, Michelle A. Erickson
Journal: Cell Reports Medicine (2024)

SummaryThe blood-brain barrier (BBB) plays central roles in the maintenance and health of the brain. Its mechanisms to safeguard the brain against xenobiotics and endogenous toxins also make the BBB the primary obstacle to the development of drugs for the central nervous system (CNS). Here, we review classic examples of the intersection of clinical medicine, drug delivery, and the BBB. We highlight the role of lipid solubility (heroin), saturable brain-to-blood (efflux: opiates) and blood-to-brain (influx: nutrients, vitamins, and minerals) transport systems, and adsorptive transcytosis (viruses and incretin receptor agonists). We examine how the disruption of the BBB that occurs in certain diseases (tumors) can also be modulated (osmotic agents and microbubbles) and used to deliver treatments, and the role of extracellular pathways in gaining access to the CNS (albumin and antibodies). In summary, this review provides a historical perspective of the key role of the BBB in delivery of drugs to the brain in health and disease.Graphical abstract
Advances and challenges in neuroimaging-based pain biomarkers
Authors: Li-Bo Zhang, Yu-Xin Chen, Zhen-Jiang Li, Xin-Yi Geng, Xiang-Yue Zhao, Feng-Rui Zhang, Yan-Zhi Bi, Xue-Jing Lu, Li Hu
Journal: Cell Reports Medicine (2024)

SummaryIdentifying neural biomarkers of pain has long been a central theme in pain neuroscience. Here, we review the state-of-the-art candidates for neural biomarkers of acute and chronic pain. We classify these potential neural biomarkers into five categories based on the nature of their target variables, including neural biomarkers of (1) within-individual perception, (2) between-individual sensitivity, and (3) discriminability for acute pain, as well as (4) assessment and (5) prospective neural biomarkers for chronic pain. For each category, we provide a synthesized review of candidate biomarkers developed using neuroimaging techniques including functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (sMRI), and electroencephalography (EEG). We also discuss the conceptual and practical challenges in developing neural biomarkers of pain. Addressing these challenges, optimal biomarkers of pain can be developed to deepen our understanding of how the brain represents pain and ultimately help alleviate patients' suffering and improve their well-being.Graphical abstract
Prediction of brain metastasis development with DNA methylation signatures
Authors: Jeffrey A. Zuccato, Yasin Mamatjan, Farshad Nassiri, Andrew Ajisebutu, Jeffrey C. Liu, Ammara Muazzam, Olivia Singh, Wen Zhang, Mathew Voisin, Shideh Mirhadi, Suganth Suppiah, Leanne Wybenga-Groot, Alireza Tajik, Craig Simpson, Olli Saarela, Ming S. Tsao, Thomas Kislinger, Kenneth D. Aldape, Michael F. Moran, Vikas Patil, Gelareh Zadeh
Journal: Nature Medicine (2024)

Brain metastases (BMs) are the most common and among the deadliest brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, which limits early intervention. Lung adenocarcinoma (LUAD) is the most common BM source and here we obtained 402 tumor and plasma samples from a large cohort of patients with LUAD with or without BM (n = 346). LUAD DNA methylation signatures were evaluated to build and validate an accurate model predicting BM development from LUAD, which was integrated with clinical factors to provide comprehensive patient-specific BM risk probabilities in a nomogram. Additionally, immune and cell interaction gene sets were differentially methylated at promoters in BM versus paired primary LUAD and had aligning dysregulation in the proteome. Immune cells were differentially abundant in BM versus LUAD. Finally, liquid biomarkers identified from methylated cell-free DNA sequenced in plasma were used to generate and validate accurate classifiers for early BM detection. Overall, LUAD methylomes can be leveraged to predict and noninvasively identify BM, moving toward improved patient outcomes with personalized treatment. Using data from a cohort of patients (n = 346) with lung adenocarcinoma and from multiple independent cohorts, DNA methylation signatures were evaluated to build and validate an accurate model predicting the development of brain metastasis.
GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
Authors: Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, Walter A. Kukull, Andrew J. Saykin, David A. Bennett, Erin L. Abner, Subhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, David A. Bennett, Julie A. Schneider, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo
Journal: Nature Genetics (2024)

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk. Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer's disease and related dementias.
Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial
Authors: Gennaro Pagano, Annabelle Monnet, Adriana Reyes, Benjamin Ribba, Hanno Svoboda, Thomas Kustermann, Tanya Simuni, Ronald B. Postuma, Nicola Pavese, Fabrizio Stocchi, Kathrin Brockmann, Krzysztof Smigorski, Valentina Gerbaldo, Paulo Fontoura, Rachelle Doody, Geoffrey A. Kerchner, Patrik Brundin, Kenneth Marek, Azad Bonni, Tania Nikolcheva
Journal: Nature Medicine (2024)

Abstract The Phase II trial of Anti-alpha-Synuclein Antibody in Early Parkinson’s Disease (PASADENA) is an ongoing double-blind, placebo-controlled trial evaluating the safety and efficacy of prasinezumab in early-stage Parkinson’s disease (PD). During the double-blind period, prasinezumab-treated individuals showed less progression of motor signs (Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS–UPDRS) Part III) than placebo-treated individuals. We evaluated whether the effect of prasinezumab on motor progression, assessed as a change in MDS–UPDRS Part III score in the OFF and ON states, and MDS–UPDRS Part II score, was sustained for 4 years from the start of the trial. We compared participants enrolled in the PASADENA open-label extension study with those enrolled in an external comparator arm derived from the Parkinson’s Progression Markers Initiative observational study. The PASADENA delayed-start ( n = 94) and early-start ( n = 177) groups showed a slower decline (a smaller increase in score) in MDS–UPDRS Part III scores in the OFF state (delayed start, −51%; early start, −65%), ON state (delayed start, −94%; early start, −118%) and MDS–UPDRS Part II (delayed start, −48%; early start, −40%) than did the Parkinson’s Progression Markers Initiative external comparator ( n = 303). This exploratory analysis, which requires confirmation in future studies, suggested that the effect of prasinezumab in slowing motor progression in PD may be sustained long term. PASADENA ClinicalTrials.gov no. NCT03100149 .
Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines
Authors: Armin Bayati, Riham Ayoubi, Adriana Aguila, Cornelia E. Zorca, Ghislaine Deyab, Chanshuai Han, Sherilyn Junelle Recinto, Emmanuelle Nguyen-Renou, Cecilia Rocha, Gilles Maussion, Wen Luo, Irina Shlaifer, Emily Banks, Ian McDowell, Esther Del Cid Pellitero, Xue Er Ding, Behrang Sharif, Philippe Séguéla, Moein Yaqubi, Carol X.-Q. Chen, Zhipeng You, Narges Abdian, Heidi M. McBride, Edward A. Fon, Jo Anne Stratton, Thomas M. Durcan, Patrick C. Nahirney, Peter S. McPherson
Journal: Nature Neuroscience (2024)
Silencing of SIRPα enhances the antitumor efficacy of CAR-M in solid tumors
Authors: Han Zhang, Yi Huo, Wenjing Zheng, Peng Li, Hui Li, Lingling Zhang, Longqi Sa, Yang He, Zihao Zhao, Changhong Shi, Lequn Shan, Angang Yang, Tao Wang
Journal: Cellular and Molecular Immunology (2024)

The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47-SIRPα interaction with a CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα, thereby disrupting the CD47-SIRPα signaling pathway. These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, and the ability to eliminate patient-derived organoids. In vivo, CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. Notably, CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors, thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice. Mechanistically, SIRPα inhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells, leading to increased production of proinflammatory cytokines, reactive oxygen species, and nitric oxide, thereby enhancing their antitumor effects. These findings underscore the potential of SIRPα inhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy, particularly against solid tumors.
Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells 
Authors: Daiya Ohara, Yusuke Takeuchi, Keiji Hirota
Journal: Cellular and Molecular Immunology (2024)

The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.
Author Correction: Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling
Authors: Takahiro Nakajima, Toshio Kanno, Yuki Ueda, Keisuke Miyako, Takeru Endo, Souta Yoshida, Satoru Yokoyama, Hikari K. Asou, Kazuko Yamada, Kazutaka Ikeda, Yosuke Togashi, Yusuke Endo
Journal: Cellular and Molecular Immunology (2024)
The TET3 inflammasome senses unique long HSV-1 proteins for virus particle budding from the nucleus
Authors: Qiannv Liu, Weitao Li, Yan Qian, Chunlei Wang, Chun Kong, Mengqian Li, Liangliang Sun, Lang Sun, Yanli Pang, Changtao Jiang, Shuo Wang, Pengyan Xia
Journal: Cellular and Molecular Immunology (2024)
Impact of Gene Expression Classifier Testing on Adjuvant Treatment Following Radical Prostatectomy: The G-MINOR Prospective Randomized Cluster-crossover Trial
Authors: Todd M Morgan, Stephanie Daignault-Newton, Daniel E Spratt, Rod L Dunn, Udit Singhal, Linda A Okoth, Felix Y Feng, Anna M Johnson, Brian R Lane, Susan Linsell, Khurshid R Ghani, James E Montie, Rohit Mehra, Brent K Hollenbeck, Thomas Maatman, Kirk Wojno, Frank N Burks, Daniel Bekong, Jon Curry, Paul Rodriguez, Eduardo Kleer, Richard Sarle, David C Miller, Michael L Cher
Journal: European Urology (2024)
Impact of lesion location and pattern on the prognosis of genital extramammary Paget disease: a retrospective study
Authors: Yukiko Yasui, Hiroshi Kato, Shinji Kano, Maki Yoshimitsu, Yua Nakagawa, Motoki Nakamura, Akimichi Morita
Journal: British Journal of Dermatology (2024)

Lesion location and pattern associated with prognosis in EMPD. Nodular and erosive lesions, as well as lesion areas larger than approximately 70-100 cm2 (about palm-sized), predicted a poor prognosis.
Engineering of Kidney‐Targeting Fluorophores with Tunable Emission from NIR‐I to NIR‐II for Early Diagnosis of Kidney Disease
Authors: Yulan Jiang, Liping Wang, Bangping Hu, Chengkun Nong, Xing‐Can Shen, Hua Chen
Journal: Advanced Healthcare Materials (2024)

Abstract The development of rapidly distributed and retained probes within the kidneys is important for accurately diagnosing kidney diseases. Although molecular imaging shows the potential for non‐intrusively interrogating kidney disease‐related biomarkers, the limited kidney contrast of many fluorophores, owing to their relatively low distribution in the kidney, hinders their effectiveness for kidney disease detection. Herein, for the first time, an amino‐functionalization strategy is proposed to construct a library of kidney‐targeting fluorophores NHcy with tunable emissions from NIR‐I to NIR‐II. Among these, NHcy‐8 is the first small‐molecule NIR‐II dye without a renal clearance moiety, designed specifically for kidney‐targeting imaging. Building on this class of NIR‐II fluorophore, the first NIR‐II small‐molecule kidney‐targeting pH probe NIR‐II‐pH is developed, which exhibits a desirable kidney distribution after intravenous injection and is fluorescent only after activation by acidosis. NIR‐II in vivo fluorescence/photoacoustic imaging of kidney disease models induced by cisplatin and renal I/R injury using NIR‐II‐pH reveals increasingly severe metabolic acidosis as the disease progressed, enabling sensitive detection of the onset of acidosis 36 h (cisplatin group) earlier than clinical methods. Thus, this study introduces a practical NIR‐II kidney‐targeting probe and provides a useful molecular blueprint for guiding kidney‐targeting NIR‐II fluorophores as diagnostic aids for kidney diseases.
Design and Improvement of Bone Adhesive in response to Clinical Needs
Authors: Chenyu Liu, Dongyong Sha, Lingfei Zhao, Chuanwei Zhou, Lili Sun, Changsheng Liu, Yuan Yuan
Journal: Advanced Healthcare Materials (2024)

Abstract Fracture represents one of the most common diagnoses in contemporary medical practice, with the majority of cases traditionally addressed through metallic device fixation. However, this approach is marred by several drawbacks, including prolonged operative durations, considerable expenses, suboptimal applicability to comminuted fractures, increased infection risks, and the inevitable requirement for secondary surgery. The inherent advantages of bone adhesives in these fields have garnered the attention of orthopedic surgeons, who have commenced utilizing biocompatible and biodegradable bone adhesives to bond and stabilize bone fragments. Regrettably, the current bone adhesives generally exhibit insufficient adhesive strength in vivo environments, and it is desirable for them to possess effective osteogenesis to facilitate fracture healing. Consequently, aligning bone adhesives with practical clinical demands remains a significant hurdle, which has catalyzed a surge in research endeavors. Within this review, the conceptual framework, characteristics, and design ideas of bone adhesives based on clinical needs are delineated. Recent advancements in this domain, specifically focusing on the enhancement of two pivotal characteristics—adhesive strength and osteogenic potential are also reviewed. Finally, a prospective analysis of the future advancements in bone adhesives, offering new insights into solutions for diverse clinical problems is presented.
Polymorphic Supramolecular Therapeutic Platforms with Precise Dye/Drug Ratio to Perform Synergistic Chemo‐Photo Anti‐Tumor Therapy and Long‐Term Immune Protection
Authors: Jinhao Yan, Haoqi Wang, Xueqin Zhao, Longxiang Tao, Xuefu Wang, Jun Yin
Journal: Advanced Healthcare Materials (2024)

Abstract Malignant tumor has become one of the hellish killers threatening the health of people around the world, its diagnosis and treatment has become the concerns of public. However, the optimal therapeutic dose, undesired side‐effect, and long‐term immune activation were key and bottleneck problems in tumor treatment. Herein, different batches of supramolecular therapeutic platforms, including vesicles, spherical nanoparticles, and cylindrical nanorods, with precise ratios of dye to drug (1:2) and multiple stimulus responsiveness were constructed by host‐guest complexation between cyanine‐camptothecin conjugates (IR780‐CPT2) and β‐cyclodextrin (β‐CD) pendent hydrophilic copolymers. The reduction responsiveness, near‐infrared photothermal conversion and singlet oxygen ( 1 O 2 ) generation performances endowed these platforms excellent cancer cells killing effect in both of in vitro cellular experiments and in vivo mice models. More importantly, without affecting the weight of mice, the maturation of dendritic cells, proliferation of T cells, up‐regulation of high mobility group protein B1, and reduction of immunosuppressive regulatory T cells were detected after employing a synergistic chemo‐photo therapy, demonstrating the body's immune effect was successfully activated. Thus, during the treatment of primary tumor, the distal tumor was also inhibited. We believe this work could provide a distinctive way to fabricate supramolecular theranostic platforms with different morphologies and improve antitumor and antimetastasis capabilities.