tbuckley/cabot-search huggingface dataset:
Multicenter validation of an RNA-based assay to predict anti-PD-1 disease control in patients with recurrent or metastatic head and neck squamous cell carcinoma: the PREDAPT study
Authors: Kevin C Flanagan, Jon Earls, Jeffrey Hiken, Rachel L Wellinghoff, Michelle M Ponder, Howard L McLeod, William H Westra, Vera Vavinskaya, Leisa Sutton, Ida Deichaite, Orlan K Macdonald, Karim Welaya, James Wade, Georges Azzi, Andrew W Pippas, Jennifer Slim, Bruce Bank, Xingwei Sui, Steven E Kossman, Todd D Shenkenberg, Warren L Alexander, Katharine A Price, Jessica Ley, David N Messina, Jarret I Glasscock, A Dimitrios Colevas, Ezra E W Cohen, Douglas Adkins, Eric J Duncavage
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Despite advances in cancer care and detection, &gt;65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. Trial registration number NCT04510129 .
Reporting of late-onset immune-related adverse events with immune checkpoint inhibitors in VigiBase
Authors: Roberta Noseda, Francesca Bedussi, Valentina Giunchi, Michele Fusaroli, Emanuel Raschi, Alessandro Ceschi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background To date, evidence on late-onset immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is limited to a small number of clinical cases. This study aimed to identify drug- and patient-related characteristics potentially associated with the reporting of late-onset irAEs with ICIs in VigiBase, the WHO global database of individual case safety reports (ICSRs). Methods Observational study comparing deduplicated ICSRs with ICIs reporting late-onset irAEs (occurred &gt;90 days after ICI discontinuation) versus ICSRs with ICIs not reporting late-onset irAEs, collected in VigiBase from 2011 to December 31, 2022. Logistic regression was used to model the relationship between drug-related and patient-related characteristics of ICSRs and the reporting of late-onset irAEs. Significance was determined for variables with the lower bound of the 95% CI of the reporting OR (ROR) higher than 1 and a p value &lt;0.05. Results The study population consisted of 6006 ICSRs with ICI-related irAEs (4574, 76.2%, originated from Europe; 3900, 64.9%, involved males; median patient age was 67 years, IQR 59–74 years). Of these, 344 (5.7%) ICSRs reported a total of 388 late-onset irAEs, among which the most frequent were thyroiditis (n=45), pneumonitis (n=37), interstitial lung disease (n=25), hepatitis (n=23) and vitiligo (n=19). Median time to onset since ICI discontinuation was 167 days (IQR 115–294 days), with negligible proportion (3.2%) of co-reported antineoplastic agents during the discontinuation period. Logistic regression models showed disproportionate reporting of late-onset irAEs with ICI combination therapy (ROR 2.33, 95% CI 1.19 to 4.57), reporting of multiple irAEs (ROR 3.96, 95% CI 2.85 to 5.52), reporting of cutaneous irAEs (ROR 1.83, 95% CI 1.24 to 2.71), and melanoma (ROR 1.47, 95% CI 1.04 to 2.06). Conclusions This global pharmacovigilance study provides the largest case series of late-onset irAEs with ICIs to date and identifies characteristics of ICSRs associated with disproportionate reporting. Dedicated prospective observational studies focused on long-term sequelae, quality of life and survival of patients developing late-onset irAEs with ICIs should be planned to confirm whether these reporting characteristics are predictors of actual occurrence. Furthermore, translational research should be encouraged to clarify the molecular mechanisms underlying late-onset irAE development.
High performance P300 spellers using GPT2 word prediction with cross-subject training
Authors: Nithin Parthasarathy, James Soetedjo, Saarang Panchavati, Nitya Parthasarathy, Corey Arnold, Nader Pouratian, William Speier
Journal: Brain-Computer Interfaces (2024)

Amyotrophic lateral sclerosis (ALS) severely impairs patients' ability to communicate, often leading to a decline in their quality of life within a few years of diagnosis. The P300 speller brain–computer interface (BCI) offers an alternative communication method by interpreting a subject's EEG response to flashing characters presented on a grid interface. This paper addresses the common speed limitations encountered in training efficient P300-based multi-subject classifiers by introducing innovative 'across-subject' classifiers. We leverage a combination of the second-generation Generative Pre-Trained Transformer (GPT2) and Dijkstra's algorithm to optimize stimuli and suggest word completion choices based on subjects' typing history. Additionally, we employ a multi-layered smoothing technique to accommodate out-of-vocabulary (OOV) words. Through extensive simulations employing random sampling of EEG data from multiple subjects, we demonstrate significant speed enhancements in typing passages containing rare and OOV words. These optimizations result in approximately 10% improvement in character-level typing speed and up to 40% improvement in multi-word prediction. We demonstrate that augmenting standard row/column highlighting techniques with layered word prediction yields close-to-optimal performance. Furthermore, we explore both 'within-subject' and 'across-subject' training techniques, showing that speed improvements are consistent across both approaches.
Recommendations for Aligned Nomenclature of Peripheral Nervous System Disorders Across Rheumatology and Neurology
Authors: Ghaith Noaiseh, Anahita Deboo, Jennifer K. King, Arun Varadhachary, George Sarka, Brent P. Goodman, Katherine M. Hammitt, Julie Frantsve‐Hawley, Robert Fox, Matthew C. Baker, Stamatina Danielides, Steven Mandel, Pantelis P. Pavlakis, R. Hal Scofield, Daniel J. Wallace, Nancy Carteron, Steven Carsons
Journal: Arthritis & Rheumatology (2024)

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Minimalist Adjuvant‐Free Nano‐Vaccine Based on Antigen Self‐Assembled Amyloid‐Like Fibrils to Induce Potent Immune Response
Authors: Xiang Wang, Haiyang Xia, Tiantian Li, Qinhua Zuo, Zhen Wang, Kangjian Yan, Zejun Xu, Wei Xue, Guodong Sun, Zonghua Liu, Yi Zhang
Journal: Advanced Healthcare Materials (2024)

Abstract The development of cancer vaccines is at the forefront of cancer immunotherapy. Most existing strategies to induce an efficient anti‐tumor immune response rely on molecular adjuvants and the incorporation of complex synthetic vectors into vaccine formulations. In contrast, this study introduces a one‐step engineering technique to assemble the model antigen, Ovalbumin (OVA), into amyloid aggregates, leveraging biomimetic folding and aggregation to create non‐fibrillar OVA globular aggregates and OVA amyloid‐like fibrils as single‐component, adjuvant‐free vaccines. Notably, the OVA amyloid‐like fibrils induced stronger immune responses compared to the native form, as evidenced by robust humoral immune reactions and the establishment of immune memory. These enhanced responses can be attributed to the self‐adjuvant effect of the unique assembled structure, which preserves antigenic epitopes, improves antigen stability, facilitates antigen internalization, prolongs retention at the injection site, enhances antigen trafficking to the lymphoid organs, and promotes increased secretion of antibodies and cytokines. Furthermore, the efficacy of the vaccine was validated in a high OVA‐expressing tumor model, demonstrating the potential of OVA amyloid‐like fibrils as an effective vaccine for cancer immunoprevention. This minimalist self‐adjuvant vaccine strategy holds promising implications for cancer immunotherapy and can inform the design of other protein antigen‐based vaccines.
MBG/BSA Bone Grafts Immunomodulate Bone Regeneration by Releasing Bioactive Ions in Inflammatory Bone Defects
Authors: Yijie Yang, Wen Gu, Xue Jiang, Xiaolei Lv, Jianxu Wei, Xiaomeng Zhang, Kai Zheng, Hongchang Lai
Journal: Advanced Healthcare Materials (2024)

Abstract Since the diseases that cause bone defects are mostly inflammatory diseases, the current bone grafts are unable to effectively regulate osteoimmune activity, leading to the impaired osteogenesis and unfavorable bone regeneration. In this study, inspired by bone composition, biomimetic mesoporous bioactive glass nanoparticle (MBG)/bovine serum albumin (BSA) bone grafts are designed for inflammatory bone defects. Systematically, MBG/BSA bone grafts are evaluated for characterization, bioactivity, anti‐inflammatory, antioxidant activity, and osteogenic activity. MBG/BSA bone grafts are proved to be biocompatible and can release bioactive ions including calcium and silicon in a sustained manner. Furthermore, MBG/BSA reprograms the macrophage phenotype toward anti‐inflammation that is beneficial for bone regeneration. The antioxidative activity is also validated under inflammation and the mechanism may be via the interleukin‐4 (IL‐4)/Signal transducer and activator of transcription 6 (STAT6) pathway. The osteogenic differentiation and mineralization are also facilitated due to the improved immunoregulation of MBG/BSA. Overall, this work suggests that the MBG/BSA bone grafts with improved immunomodulatory properties are an ideal material for inflammatory bone regeneration application.
Reply to Correspondence Re: Gedde et al.: Reporting Clinical Endpoints in Studies of Minimally Invasive Glaucoma Surgery
Authors: Steven J. Gedde, Kateki Vinod, Eileen C. Bowden, Natasha N. Kolomeyer, Vikas Chopra, Pratap Challa, Donald L. Budenz, Michael X. Repka, Flora Lum
Journal: Ophthalmology (2024)
Critical role of ROCK1 in AD pathogenesis via controlling lysosomal biogenesis and acidification
Authors: Chenghuan Song, Wanying Huang, Pingao Zhang, Jiyun Shi, Ting Yu, Jing Wang, Yongbo Hu, Lanxue Zhao, Rui Zhang, Gang Wang, Yongfang Zhang, Hongzhuan Chen, Hao Wang
Journal: Translational Neurodegeneration (2024)

Abstract Background Lysosomal homeostasis and functions are essential for the survival of neural cells. Impaired lysosomal biogenesis and acidification in Alzheimer’s disease (AD) pathogenesis leads to proteolytic dysfunction and neurodegeneration. However, the key regulatory factors and mechanisms of lysosomal homeostasis in AD remain poorly understood. Methods ROCK1 expression and its co-localization with LAMP1 and SQSTM1/p62 were detected in post-mortem brains of healthy controls and AD patients. Lysosome-related fluorescence probe staining, transmission electron microscopy and immunoblotting were performed to evaluate the role of ROCK1 in lysosomal biogenesis and acidification in various neural cell types. The interaction between ROCK1 and TFEB was confirmed by surface plasmon resonance and in situ proximity ligation assay (PLA). Moreover, we performed AAV-mediated ROCK1 downregulation followed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and behavioral tests to unveil the effects of the ROCK1–TFEB axis on lysosomes in APP/PS1 transgenic mice. Results ROCK1 level was significantly increased in the brains of AD individuals, and was positively correlated with lysosomal markers and Aβ. Lysosomal proteolysis was largely impaired by the high abundance of ROCK1, while ROCK1 knockdown mitigated the lysosomal dysfunction in neurons and microglia. Moreover, we verified ROCK1 as a previously unknown upstream kinase of TFEB independent of m-TOR or GSK-3β. ROCK1 elevation resulted in abundant extracellular Aβ deposition which in turn bound to Aβ receptors and activated RhoA/ROCK1, thus forming a vicious circle of AD pathogenesis. Genetically downregulating ROCK1 lowered its interference with TFEB, promoted TFEB nuclear distribution, lysosomal biogenesis and lysosome-mediated Aβ clearance, and eventually prevented pathological traits and cognitive deficits in APP/PS1 mice. Conclusion In summary, our results provide a mechanistic insight into the critical role of ROCK1 in lysosomal regulation and Aβ clearance in AD by acting as a novel upstream serine kinase of TFEB.
Efficacy of 3D-TSE Sequence-based Radiosurgery in Prolonging Time to Distant Intracranial Failure: A Session-wise Analysis in a Histology-Diverse Patient Cohort
Authors: Eyub Y Akdemir, Selin Gurdikyan, Muni Rubens, Kevin J Abrams, Charif Sidani, Margaret C Chaneles, Matthew D Hall, Robert H Press, D Jay Wieczorek, Ranjini Tolakanahalli, Alonso N Gutierrez, Omer Gal, Alonso La Rosa, Tugce Kutuk, Michael W McDermott, Yazmin Odia, Minesh P Mehta, Rupesh Kotecha
Journal: Neuro-Oncology (2024)

Stereotactic radiosurgery (SRS) for patients with brain metastases (BM) is associated with a risk of distant intracranial failure (DIF). This study evaluates the impact of integrating dedicated 3D-TSE sequences to MPRAGE in BM detection and DIF prolongation in a histology-agnostic patient cohort.
Phase II Trial of Pathology-based Tripartite Treatment Stratification for Patients with CNS Germ Cell Tumors: A Long-term Follow-up Study
Authors: Hirokazu Takami, Masao Matsutani, Tomonari Suzuki, Kazuhiko Takabatake, Takamitsu Fujimaki, Michinari Okamoto, Shigeru Yamaguchi, Masayuki Kanamori, Kenichiro Matsuda, Yukihiko Sonoda, Manabu Natsumeda, Toshiya Ichinose, Mitsutoshi Nakada, Ai Muroi, Eiichi Ishikawa, Masamichi Takahashi, Yoshitaka Narita, Shota Tanaka, Nobuhito Saito, Fumi Higuchi, Masahiro Shin, Yohei Mineharu, Yoshiki Arakawa, Naoki Kagawa, Shinji Kawabata, Masahiko Wanibuchi, Takeshi Takayasu, Fumiyuki Yamasaki, Kentaro Fujii, Joji Ishida, Isao Date, Keisuke Miyake, Yutaka Fujioka, Daisuke Kuga, Shinji Yamashita, Hideo Takeshima, Naoki Shinojima, Akitake Mukasa, Akio Asai, Ryo Nishikawa
Journal: Neuro-Oncology (2024)

Abstract Background A previous Phase II clinical trial, conducted from 1995 to 2003, evaluated CNS germ cell tumors (GCTs) using a three-group treatment stratification based on histopathology. The primary objective of the study was to assess the long-term efficacy of standardized treatment regimens, while the secondary objective focused on identifying associated long-term complications. Methods Total 228 patients were classified into three groups for treatment: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), excluding one mature teratoma case. Treatment involved stratified chemotherapy regimens and varied radiation doses/coverage. Clinical data was retrospectively analyzed at a median follow-up of 18.5 years. Results The treatment outcomes for germinoma, with or without syncytiotrophoblastic giant cell, were similar. The 10- and 20-year event-free survival rates for the germinoma, intermediate, and poor prognosis groups were 82/76/49% and 73/66/49%, respectively. Overall survival (OS) rates were 97/87/61% at 10 years and 92/70/53% at 20 years. Germinomas in the basal ganglia, treated without whole-brain radiation therapy (WBRT), frequently relapsed but were effectively managed with subsequent WBRT. Deaths in germinoma cases had varied causes, whereas deaths in the poor prognosis group were predominantly disease-related. Nineteen treatment-related complications were identified in 16 patients, with cumulative event rates of 1.9% at 10 years and 11.3% at 20 years. OS rates at 1 and 2 years post-relapse for tumors initially classified as germinoma, intermediate, and poor prognosis were 94/88/18% and 91/50/9%, respectively. Conclusions Initial treatment intensity is crucial for managing non-germinomatous GCTs, while long-term follow-up for relapse and complications is imperative in germinomas. Irradiation extending beyond the immediate tumor site is essential for basal ganglia germinomas. Addressing relapse in non-germinomatous GCT remains a significant challenge.
Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol–Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis
Authors: Harpreet S. Bhatia, Simon Wandel, Peter Willeit, Anastasia Lesogor, Keith Bailey, Paul M. Ridker, Paul Nestel, John Simes, Andrew Tonkin, Gregory G. Schwartz, Helen Colhoun, Christoph Wanner, Sotirios Tsimikas
Journal: Circulation (2024)

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined. METHODS: A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models. RESULTS: Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level &gt;50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1–77.0 mg/dL), those with Lp(a) level &gt;50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06–1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level &gt;50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46–2.48]). CONCLUSIONS: These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.
Kindlin-2 Phase Separation in Response to Flow Controls Vascular Stability
Authors: Nina Ma, Fangfang Wu, Jiayu Liu, Ziru Wu, Lu Wang, Bochuan Li, Yuming Liu, Xue Dong, Junhao Hu, Xi Fang, Heng Zhang, Ding Ai, Jing Zhou, Xiaohong Wang
Journal: Circulation Research (2024)

BACKGROUND: Atheroprotective shear stress preserves endothelial barrier function, while atheroprone shear stress enhances endothelial permeability. Yet, the underlying mechanisms through which distinct flow patterns regulate EC integrity remain to be clarified. This study aimed to investigate the involvement of Kindlin-2, a key component of focal adhesion and endothelial adherens junctions crucial for regulating endothelial cell (EC) integrity and vascular stability. METHODS: Mouse models of atherosclerosis in EC-specific Kindlin-2 knockout mice ( Kindlin-2 iΔEC ) were used to study the role of Kindlin-2 in atherogenesis. Pulsatile shear (2±4 dynes/cm 2 ) or oscillatory shear (0.5±4 dynes/cm 2 ) were applied to culture ECs. Live-cell imaging, fluorescence recovery after photobleaching assay, and optoDroplet assay were used to study the liquid-liquid phase separation (LLPS) of Kindlin-2. Co-immunoprecipitation, mutagenesis, proximity ligation assay, and transendothelial electrical resistance assay were used to explore the underlying mechanism of flow-regulated Kindlin-2 function. RESULTS: We found that Kindlin-2 localization is altered under different flow patterns. Kindlin-2 iΔEC mice showed heightened vascular permeability. Kindlin-2 iΔEC were bred onto ApoE −/− mice to generate Kindlin-2 iΔEC ; ApoE − /− mice, which displayed a significant increase in atherosclerosis lesions. In vitro data showed that in ECs, Kindlin-2 underwent LLPS, a critical process for proper focal adhesion assembly, maturation, and junction formation. Mass spectrometry analysis revealed that oscillatory shear increased arginine methylation of Kindlin-2, catalyzed by PRMT5 (protein arginine methyltransferase 5). Functionally, arginine hypermethylation inhibits Kindlin-2 LLPS, impairing focal adhesion assembly and junction maturation. Notably, we identified R290 of Kindlin-2 as a crucial residue for LLPS and a key site for arginine methylation. Finally, pharmacologically inhibiting arginine methylation reduces EC activation and plaque formation. CONCLUSIONS: Collectively, our study elucidates that mechanical force induces arginine methylation of Kindlin-2, thereby regulating vascular stability through its impact on Kindlin-2 LLPS. Targeting Kindlin-2 arginine methylation emerges as a promising hemodynamic-based strategy for treating vascular disorders and atherosclerosis. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02783300.
Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma
Authors: Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai
Journal: Cellular and Molecular Immunology (2024)