tbuckley/cabot-search huggingface dataset:
SINEUP RNA rescues molecular phenotypes associated with CHD8 suppression in Autism Spectrum Disorder model systems.
Authors: Francesca Di Leva, Michele Arnoldi, Stefania Santarelli, Mathieu Massonot, Marianne Victoria Lemée, Carlotta Bon, Miguel Pellegrini, Maria Elena Castellini, Giulia Zarantonello, Andrea Messina, Yuri Bozzi, Raphael Bernier, Silvia Zucchelli, Simona Casarosa, Erik Dassi, Giuseppe Ronzitti, Christelle Golzio, Jasmin Morandell, Stefano Gustincich, Stefano Espinoza, Marta Biagioli
Journal: Molecular Therapy (2024)
Alphaviral genetic background of self-amplifying RNA enhances protein expression and immunogenicity against SARS-CoV-2 antigen
Authors: Irafasha C Casmil, Nuthan V Bathula, Cynthia Huang, Christopher J Wayne, Evan S Cairns, Josh J Friesen, Shekinah K Soriano, Suiyang Liao, Chia H Ho, Kristen Y S Kong, Anna K Blakney
Journal: Molecular Therapy (2024)

Self-amplifying RNA (saRNA) vectors are a next-generation RNA technology that extends the expression of heterologous genes. Clinical trials have shown the dose-sparing capacity of saRNA vectors in a vaccine context compared to conventional messenger RNA. However, saRNA vectors have historically been based on a limited number of alphaviruses, and only the Venezuelan equine encephalitis virus-based saRNA vaccines have been used clinically. Here, we designed genotypically distinct alphaviral saRNA vectors and characterized their performance in mammalian cell lines, human skin explants and mice. Five of the 12 vectors had substantial luciferase expression in mice with variable pharmacokinetics, enabling modulation of both the magnitude and duration of protein expression. Additionally, we demonstrate that the alphaviral genotype of the saRNA significantly impacts the immunogenicity of saRNA vaccines, including the humoral and cellular responses in mice. Given the differences in RNA reactogenicity and expression between mice and humans, we assessed the saRNA vectors in human skin explants obtained from patients and observed high transgene expression. saRNA bioluminescence and immunogenicity in different mice strains were highly correlative, while minimal correlation was observed when compared to human explants and mammalian cell lines. This work demonstrates that efficacious saRNA vaccines and therapies can be produced by adapting genetically diverse alphaviruses into vectors.
FDG PET/CT in a Case of Gardner Syndrome
Authors: Lili Shan, Aisheng Dong, Yan Han
Journal: Clinical Nuclear Medicine (2024)

Abstract Gardner syndrome is characterized by multiple intestinal polyps and extraintestinal lesions. We describe FDG PET/CT findings of the extraintestinal lesions in a patient with Gardner syndrome. FDG PET/CT showed 2 hypermetabolic desmoid tumors in the abdominal wall, sclerotic areas with multifocal activity in the maxilla and mandible, multiple osteomas in the bilateral parietal, left frontal, sphenoid and ethmoid bones, an impacted tooth in the right maxilla, and bone islands in the T2 and T5 vertebral bodies. Extraintestinal involvements in Gardner syndrome can precede intestinal polyposis. Therefore, familiarity with FDG PET/CT findings of extraintestinal manifestations is helpful for early diagnosis.
Comparative effectiveness and safety of single inhaler triple therapies for chronic obstructive pulmonary disease: new user cohort study
Authors: William B Feldman, Samy Suissa, Aaron S Kesselheim, Jerry Avorn, Massimiliano Russo, Sebastian Schneeweiss, Shirley V Wang
Journal: BMJ (2024)

To compare the effectiveness and safety of budesonide-glycopyrrolate-formoterol, a twice daily metered dose inhaler, and fluticasone-umeclidinium-vilanterol, a once daily dry powder inhaler, in patients with chronic obstructive pulmonary disease (COPD) treated in routine clinical practice. New user cohort study. Longitudinal commercial US claims data. New initiators of budesonide-glycopyrrolate-formoterol or fluticasone-umeclidinium-vilanterol between 1 January 2021 and 30 September 2023 who had a diagnosis of COPD and were aged 40 years or older. In this 1:1 propensity score matched study, the main outcome measures were first moderate or severe COPD exacerbation (effectiveness) and first admission to hospital with pneumonia (safety) while on treatment. Potential confounders were measured in the 365 days before cohort entry and included in propensity scores. Hazard ratios and 95% confidence intervals (CIs) were estimated using a Cox proportional hazards regression model. The study cohort included 20 388 propensity score matched pairs of new users initiating single inhaler triple therapy. Patients who received budesonide-glycopyrrolate-formoterol had a 9% higher incidence of first moderate or severe COPD exacerbation (hazard ratio 1.09 (95% CI 1.04 to 1.14); number needed to harm 38) compared with patients receiving fluticasone-umeclidinium-vilanterol and an identical incidence of first admission to hospital with pneumonia (1.00 (0.91 to 1.10)). The hazard of first moderate COPD exacerbation was 7% higher (1.07 (1.02 to 1.12); number needed to harm 54) and the hazard of first severe COPD exacerbation 29% higher (1.29 (1.12 to 1.48); number needed to harm 97) among those receiving budesonide-glycopyrrolate-formoterol compared to fluticasone-umeclidinium-vilanterol. Prespecified sensitivity analyses yielded similar findings to the primary analysis. Budesonide-glycopyrrolate-formoterol was not associated with improved clinical outcomes compared with fluticasone-umeclidinium-vilanterol. Given the added climate impact of metered dose inhalers, health systems seeking to decrease use of these products may consider steps to promote further prescribing of fluticasone-umeclidinium-vilanterol compared with budesonide-glycopyrrolate-formoterol in people with COPD. Center for Open Science Real World Evidence Registry (https://osf.io/6gdyp/).
ST6GAL1-Mediated Sialylation of PECAM-1 Promotes a Transcellular Diapedesis-Like Process that Directs Lung Tropism of Metastatic Breast Cancer
Authors: Shih-Yin Chen, Pei-Lin He, Li-Yu Lu, Meng-Chieh Lin, Shih-Hsuan Chan, Jia-Shiuan Tsai, Wen-Ting Luo, Lu-Hai Wang, Hua-Jung Li
Journal: Cancer Research (2024)

Abstract Metastasis is the leading cause of mortality in breast cancer, with lung metastasis being particularly detrimental. Identification of the processes determining metastatic organotropism could enable the development of approaches to prevent and treat breast cancer metastasis. Here, we found that lung-tropic and non-lung-tropic breast cancer cells differ in their response to sialic acids, affecting the sialylation of surface proteins. Lung-tropic cells showed higher levels of ST6GAL1, while non-lung-tropic cells had more ST3GAL1. ST6GAL1-mediated α-2,6-sialylation, unlike ST3GAL1-mediated α-2,3-sialylation, increased lung metastasis by promoting cancer cell migration through pulmonary endothelial layers and reducing junction protein levels. α-2,6-sialylated PECAM-1 on breast cancer cells facilitated extravasation through the pulmonary endothelium, a critical step in lung metastasis. Knockdown of ST6GAL1 or PECAM-1 significantly reduced lung metastasis. Human pulmonary endothelium displayed high PECAM-1 levels. Through transhomophilic interaction with pulmonary PECAM-1, α-2,6-sialylated PECAM-1 on ST6GAL1-positive cancer cells increased pulmonary extravasation in a diapedesis-like, cell-autonomous manner. Additionally, lung-tropic cells and their exosomes increased the permeability of pulmonary endothelial cells, promoting metastasis in a non-cell-autonomous manner. Analysis of human breast cancer samples showed a correlation between elevated ST6GAL1/PECAM-1 expression and lung metastasis. These results suggest that targeting ST6GAL1-mediated α-2,6-sialylation could be a potential therapeutic strategy to prevent lung metastasis in breast cancer patients.
Switching Drivers: Epigenetic Rewiring to Genetic Progression in Glioma
Authors: Kristen L. Drucker, Robert B. Jenkins, Daniel Schramek
Journal: Cancer Research (2024)

Abstract IDH-mutant low-grade gliomas (LGGs) are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: in early stages, tumors are primarily driven by oligodendrocyte precursor-like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA. As the disease advances, the tumors become sustained by more proliferative neural precursor-like cells, where genetic alterations, including PDGFRA, MYCN, and CDK4 amplifications and CDKN2A/B deletion, drive tumor progression. The study further highlights a dynamic regulation of interferon (IFN) signaling during progression. In low-grade IDH-mutant gliomas, IFN responses are suppressed through epigenetic hypermethylation, which can be reversed with DNMT1 inhibitors or IDH inhibitors, leading to reactivation of the IFN pathway. In contrast, higher-grade gliomas evade IFN signaling through genetic deletions of IFN gene clusters. These findings emphasize a broader epigenetic-to-genetic shift in oncogenic regulation that drives glioma progression, provides a valuable framework for understanding the transition from indolent tumors to lethal malignancies, and has implications for therapy and clinical management.
Transcriptional landscape and predictive potential of long noncoding RNAs in peritoneal recurrence of gastric cancer
Authors: Xiao-Xia Cai, Guo-Ming Chen, Zi-Qi Zheng, Yi-Xin Yin, Shuang Wang, Li Qiao, Xiao-Jiang Chen, Bai-Wei Zhao, Jin-Ling Duan, Cheng-Cai Liang, Ruo-Peng Zhang, Cheng-Zhi Wei, Fei-Yang Zhang, Bo-Wen Huang, Ze-Xian Liu, Zhi-Wei Zhou, Dan Xie, Mu-Yan Cai, Shu-Qiang Yuan, Yuan-Fang Li, Run-Cong Nie
Journal: Molecular Cancer (2024)

Long noncoding RNAs (lncRNAs) play a critical role in gastric cancer (GC) progression and metastasis. However, research comprehensively exploring tissue-derived lncRNAs for predicting peritoneal recurrence in patients with GC remains limited. This study aims to investigate the transcriptional landscape of lncRNAs in GC with peritoneal metastasis (PM) and to develop an integrated lncRNA-based score to predict peritoneal recurrence in patients with GC after radical gastrectomy. We analyzed the transcriptome profile of lncRNAs in paired peritoneal, primary gastric tumor, and normal tissue specimens from 12 patients with GC in the Sun Yat-sen University Cancer Center (SYSUCC) discovery cohort. Key lncRNAs were identified via interactive analysis with the TCGA database and SYSUCC validation cohort. A score model was constructed using the LASSO regression model and nomogram COX regression and evaluated using receiver operating characteristic curves. The role of lncRNAs in the PM of GC was then examined through wound healing, Transwell, 3D multicellular tumor spheroid invasion, and peritoneal cavity xenograft tumorigenicity assays in mice. Five essential lncRNAs were screened and incorporated into the PM risk score to predict peritoneal recurrence-free survival (pRFS). We developed a comprehensive, integrated nomogram score, including the PM risk score, pT, pN, and tumor size, which could effectively predict the 5-year pRFS with an Area under the curve of 0.79 (95% CI: 0.71-0.88). Subsequently, we demonstrated that one of these lncRNAs, CASC15, promoted the invasion and migration of GC cells in vitro and facilitated the PM of GC cells in vivo, initially verifying that lncRNAs contribute to the PM of GC. Mechanistic analysis demonstrated that CASC15 promoted EMT and metastasis by activating the JNK and p38 pathways. A lncRNA-based integrated score was constructed in this study to predict peritoneal recurrence in patients clinically.
Incorporating Economic Evidence in Clinical Guidelines: A Framework From the Clinical Guidelines Committee of the American College of Physicians
Authors: Amir Qaseem, Tatyana Shamliyan, Douglas K. Owens, Jeffrey A. Tice, Carolyn J. Crandall, Lauri A. Hicks, Timothy J. Wilt, Ethan M. Balk, Thomas G. Cooney, J. Thomas Cross, Nick Fitterman, Johanna Lewis, Jennifer S. Lin, Amy Linsky, Michael Maroto, Matthew C. Miller, Adam J. Obley, Paul Shekelle, Janice E. Tufte, Itziar Etxeandia-Ikobaltzeta, Curtis S. Harrod, Jennifer Yost, Amir Qaseem, Tatyana Shamliyan, Carolyn J. Crandall, Douglas K. Owens, Jeffrey A. Tice
Journal: Annals of Internal Medicine (2024)

In recognition of accelerating health care spending and alignment with the American College of Physicians (ACP) principles of promoting high-value care, the ACP Clinical Guidelines Committee (CGC) developed a framework to standardize its approach to identifying, appraising, and considering economic evidence in the development of ACP clinical guidelines. This article presents the CGC's process for incorporating economic evidence, which encompasses cost-effectiveness analyses, economic outcomes in randomized controlled trials, and resource utilization (intervention cost) data. Economic evidence is one component of ACP recommendations. The CGC first and foremost assesses the certainty of evidence for clinical net benefit of interventions; it then considers patient values and preferences, and only then considers economic evidence to develop recommendations.
Medical Reference Tools and Pharmaceutical Promotion: A History of Entanglement
Authors: Andrew S. Lea, Jai Krishan Khurana
Journal: Annals of Internal Medicine (2024)

Reference tools are often uncritically accepted as balanced, objective, definitive, and evidence-based guides to medical knowledge. Yet for centuries textbooks and manuals have been entangled in various ways with industry interests. This essay shows how reference tools have served as sites of pharmaceutical promotion. Focusing on 2 reference tools,
Implementation of Billing for Patient Portal Messages as E-Visits in a Large Integrated Health System
Authors: Shannon M. Dunlay, Lindsey R. Sangaralingham, Michelle A. Lampman, Lorelle L. Ziegelbauer, Jamie L. Smith, Mikaela M. Kall, Jami A. Kinnucan, Keavy J. Farris, Josh L. Mattson, Colleen B. Storino, Conor G. Loftus
Journal: Annals of Internal Medicine (2024)

Patient-provider communication through the patient portal has markedly increased in recent years. Some health care facilities implemented programs to enable providers to bill for responding to patient-initiated messages that require substantive medical decision making through an e-visit.
The Nuances of Performance Measurement and Clinical Guidelines
Authors: Amir Qaseem, Caroline L. Goldzweig, Karen Campos, Brook Watts, Elisa I. Choi, Samantha Tierney, Nick Fitterman, Rebecca A. Andrews, Rebecca A. Andrews, Caroline L. Goldzweig, Nick Fitterman, Peter Basch, Elisa I. Choi, Roger Chou, Roger S. Khetan, Scott T. MacDonald, Nancy L. Miller, Cristin A. Mount, Rhea E. Powell, Nicole J. Van Groningen, Brook Watts
Journal: Annals of Internal Medicine (2024)
Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma
Authors: Weifeng Zeng, Furong Liu, Yachong Liu, Ze Zhang, Haofan Hu, Shangwu Ning, Hongwei Zhang, Xiaoping Chen, Zhibin Liao, Zhanguo Zhang
Journal: Clinical and Molecular Hepatology (2024)

Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed in and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated.
Prediction of primary biliary cholangitis among health check-up population with anti-mitochondrial M2 antibody positive
Authors: Haolong Li, Song Liu, Xu Wang, Xinxin Feng, Siyu Wang, Yanli Zhang, Fengchun Zhang, Li Wang, Tengda Xu, Yongzhe Li
Journal: Clinical and Molecular Hepatology (2024)

Anti-mitochondrial M2 antibody (AMA-M2) is a specific marker for primary biliary cholangitis (PBC) and it could be also presented in non-PBC individuals. A total of 72173 Chinese health check-up individuals tested AMA-M2, of which non-PBC AMA-M2 positive individuals were performed follow-up. Baseline data of both clinical characteristics and laboratory examinations were collected in all AMA-M2-positive individuals. Least absolute shrinkage and selection operator (LASSO) regression was performed to investigate the potential variables for developing PBC. A total of 2333 individuals were positive with AMA-M2. Eighty-two individuals had a medical history of PBC or fulfilled the diagnostic criteria of PBC at baseline, and 2076 individuals were non-PBC. After a median follow-up of 6.6 years, 0.6% developed PBC, with an accumulative 5-year incidence rate of 0.5%. LASSO regression showed that levels of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), immunoglobulin M (IgM), eosinophilia proportion (EOS%), gamma globulin percentage, and hemoglobin (HGB) were potential variables for developing PBC. Multivariate Cox regression is used to construct a predictive model based on 7 selected variables, and time-dependent receiver operating characteristic analysis showed that the area under the curve of the prediction model at 3, 5, and 10 years were, respectively, 1.000, 0.875, and 0.917. This study offers insights into the onset of PBC among individuals who tested positive for AMA-M2 during routine health check-ups.. The prediction model based on ALP, GGT, IgM, EOS%, gamma globulin percentage, HGB, and sex has a certain predictive ability for the occurrence of PBC in this population.
Bimetallic nanoreactor mediates cascade amplification of oxidative stress for complementary chemodynamic-immunotherapy of tumor
Authors: Hao Zhou, Peng Bao, Yan-Tong Lin, Ran Meng, Xiao Yan, Xin-Chen Deng, Qian-Xiao Huang, Wei-Hai Chen, Xian-Zheng Zhang
Journal: Biomaterials (2024)
The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer
Authors: Hao Luo, Bin Hu, Xiang-Rong Gu, Jing Chen, Xiao-Qing Fan, Wei Zhang, Ren-Tao Wang, Xian-Dong He, Wei Guo, Nan Dai, Dan Jian, Qing Li, Cheng-Xiong Xu, Hua Jin
Journal: Molecular Cancer (2024)

Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex I (MHC-I) are key molecules related to tumor immune evasion and resistance to programmed cell death protein 1 (PD-1)/PD-L1 blockade. Here, we demonstrated that the upregulation of all miRNAs in the miR-23a/27a/24 - 2 cluster was correlated with poor survival, immune evasion and PD-1/PD-L1 blockade resistance in patients with non-small cell lung cancer (NSCLC). The overexpression of all miRNAs in the miR-23a/27a/24 - 2 cluster upregulated PD-L1 expression by targeting Cbl proto-oncogene B (CBLB) and downregulated MHC-I expression by increasing the level of eukaryotic initiation factor 3B (eIF3B) via the targeting of microphthalmia-associated transcription factor (MITF). In addition, we demonstrated that the expression of the miR-23a/27a/24 - 2 cluster of miRNAs is maintained in NSCLC through increased Wnt/β-catenin signaling-regulated interaction of transcription factor 4 (TCF4) and the miR-23a/27a/24 - 2 cluster promoter. Notably, pharmacologic targeting of the eIF3B pathway dramatically increased sensitivity to PD-1/PD-L1 blockade in patients with high expression of the miR-23a/27a/24 - 2 cluster in NSCLC. This effect was achieved by increasing MHC-I expression while maintaining high expression of PD-L1 induced by the miR-23a/27a/24 - 2 cluster. In summary, we elucidate the mechanism by which the miR-23a/27a/24 - 2 cluster miRNAs maintain their own expression and the molecular mechanism by which the miR-23a/27a/24 - 2 cluster miRNAs promote tumor immune evasion and PD-1/PD-L1 blockade resistance. In addition, we provide a novel strategy for the treatment of NSCLC expressing high levels of the miR-23a/27a/24 - 2 cluster.
Dual inhibition of LAG-3 and PD-1 with IBI110 and sintilimab in advanced solid tumors: the first-in-human phase Ia/Ib study
Authors: Chenyu Mao, Anwen Xiong, Jiong Qian, Wenxiang Wang, Ying Liu, Tao Zhang, Zhihai Wu, Haiqing Ni, Jia Lu, Sixiang Long, Li Zhao, Yuling Chen, Caicun Zhou, Nong Xu
Journal: Journal of Hematology & Oncology (2024)

Co-inhibition of immune checkpoints lymphocyte-activation gene 3 (LAG-3) and PD-1 is believed to enhance cancer immunotherapy through synergistic effects. Herein, we evaluate the safety and efficacy of IBI110 (anti-LAG-3 antibody) with sintilimab (an anti-PD-1 antibody) in Chinese patients with advanced solid tumors.
Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons
Authors: Amir T. Marvian, Tabea Strauss, Qilin Tang, Benjamin J. Tuck, Sophie Keeling, Daniel Rüdiger, Negar Mirzazadeh Dizaji, Hossein Mohammad-Beigi, Brigitte Nuscher, Pijush Chakraborty, Duncan S. Sutherland, William A. McEwan, Thomas Köglsperger, Stefan Zahler, Markus Zweckstetter, Stefan F. Lichtenthaler, Wolfgang Wurst, Sigrid Schwarz, Günter Höglinger
Journal: Molecular Neurodegeneration (2024)

The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates. However, similarities or differences in neuronal transport mechanisms between Tau species remain elusive.
A deep learning based smartphone application for early detection of nasopharyngeal carcinoma using endoscopic images
Authors: Yubiao Yue, Xinyu Zeng, Huanjie Lin, Jialong Xu, Fan Zhang, KeLin Zhou, Li Li, Zhenzhang Li
Journal: npj Digital Medicine (2024)

Nasal endoscopy is crucial for the early detection of nasopharyngeal carcinoma (NPC), but its accuracy relies heavily on the clinician's expertise, posing challenges for primary healthcare providers. Here, we retrospectively analysed 39,340 nasal endoscopic white-light images from three high-incidence NPC centres, utilising eight advanced deep learning models to develop an Internet-enabled smartphone application, "Nose-Keeper", that can be used for early detection of NPC and five prevalent nasal diseases and assessment of healthy individuals. Our app demonstrated a remarkable overall accuracy of 92.27% (95% Confidence Interval (CI): 90.66%-93.61%). Notably, its sensitivity and specificity in NPC detection achieved 96.39% and 99.91%, respectively, outperforming nine experienced otolaryngologists. Explainable artificial intelligence was employed to highlight key lesion areas, improving Nose-Keeper's decision-making accuracy and safety. Nose-Keeper can assist primary healthcare providers in diagnosing NPC and common nasal diseases efficiently, offering a valuable resource for people in high-incidence NPC regions to manage nasal cavity health effectively.
In situ detection of PD1–PD-L1 interactions as a functional predictor for response to immune checkpoint inhibition in NSCLC.
Authors: Amanda Lindberg, Lars Muhl, Hui Yu, Louise Hellberg, Rebecca Artursson, Jakob Friedrich, Max Backman, Neda Hekmati, Johanna Mattsson, Cecilia Lindskog, Hans Brunnström, Johan Botling, Artur Mezheyeuski, Erika Broström, Miklos Gulyas, Klas Kärre, Johan Isaksson, Patrick Micke, Carina Strell
Journal: Journal of Thoracic Oncology (2024)
In vivo tracking of ex vivo generated 89Zr-oxine labeled plasma cells by PET in a non-human primate model
Authors: David J Young, Abigail J Edwards, Kevin G Quiroz Caceda, Ella Liberzon, Johana Barrientos, Sogun Hong, Jacob Turner, Peter L Choyke, Sean Arlauckas, Adam S Lazorchak, Richard A Morgan, Noriko Sato, Cynthia E Dunbar
Journal: Molecular Therapy (2024)