tbuckley/cabot-search huggingface dataset:
Integrated analysis of gut metabolome, microbiome, and brain function reveal the role of gut-brain axis in longevity
Authors: Bin Jiao, Ziyu Ouyang, Qianqian Liu, Tianyan Xu, Meidan Wan, Guangrong Ma, Lu Zhou, Jifeng Guo, Junling Wang, Beisha Tang, Zhixiang Zhao, Lu Shen
Journal: Gut Microbes (2024)

The role of microbiota-gut-brain axis in modulating longevity remains undetermined. Here, we performed a multiomics analysis of gut metagenomics, gut metabolomics, and brain functional near-infrared spectroscopy (fNIRS) in a cohort of 164 participants, including 83 nonagenarians (NAs) and 81 non-nonagenarians (NNAs) matched with their spouses and offspring. We found that 438 metabolites were significantly different between the two groups; among them, neuroactive compounds and anti-inflammatory substances were enriched in NAs. In addition, increased levels of neuroactive metabolites in NAs were significantly associated with NA-enriched species that had three corresponding biosynthetic potentials: Enterocloster asparagiformis, Hungatella hathewayi and Oxalobacter formigenes. Further analysis showed that the altered gut microbes and metabolites were linked to the enhanced brain connectivity in NAs, including the left dorsolateral prefrontal cortex (DLPFC)-left premotor cortex (PMC), left DLPFC-right primary motor area (M1), and right inferior frontal gyrus (IFG)-right M1. Finally, we found that neuroactive metabolites, altered microbe and enhanced brain connectivity contributed to the cognitive preservation in NAs. Our findings provide a comprehensive understanding of the microbiota-gut-brain axis in a long-lived population and insights into the establishment of a microbiome and metabolite homeostasis that can benefit human longevity and cognition by enhancing functional brain connectivity.
Robustness evaluation of deep neural networks for endoscopic image analysis: Insights and strategies
Authors: Tim J.M. Jaspers, Tim G.W. Boers, Carolus H.J. Kusters, Martijn R. Jong, Jelmer B. Jukema, Albert J. de Groof, Jacques J. Bergman, Peter H.N. de With, Fons van der Sommen
Journal: Medical Image Analysis (2024)

Computer-aided detection and diagnosis systems (CADe/CADx) in endoscopy are commonly trained using high-quality imagery, which is not representative for the heterogeneous input typically encountered in clinical practice. In endoscopy, the image quality heavily relies on both the skills and experience of the endoscopist and the specifications of the system used for screening. Factors such as poor illumination, motion blur, and specific post-processing settings can significantly alter the quality and general appearance of these images. This so-called domain gap between the data used for developing the system and the data it encounters after deployment, and the impact it has on the performance of deep neural networks (DNNs) supportive endoscopic CAD systems remains largely unexplored. As many of such systems, for e.g. polyp detection, are already being rolled out in clinical practice, this poses severe patient risks in particularly community hospitals, where both the imaging equipment and experience are subject to considerable variation. Therefore, this study aims to evaluate the impact of this domain gap on the clinical performance of CADe/CADx for various endoscopic applications. For this, we leverage two publicly available data sets (KVASIR-SEG and GIANA) and two in-house data sets. We investigate the performance of commonly-used DNN architectures under synthetic, clinically calibrated image degradations and on a prospectively collected dataset including 342 endoscopic images of lower subjective quality. Additionally, we assess the influence of DNN architecture and complexity, data augmentation, and pretraining techniques for improved robustness. The results reveal a considerable decline in performance of 11.6% (±1.5) as compared to the reference, within the clinically calibrated boundaries of image degradations. Nevertheless, employing more advanced DNN architectures and self-supervised in-domain pre-training effectively mitigate this drop to 7.7% (±2.03). Additionally, these enhancements yield the highest performance on the manually collected test set including images with lower subjective quality. By comprehensively assessing the robustness of popular DNN architectures and training strategies across multiple datasets, this study provides valuable insights into their performance and limitations for endoscopic applications. The findings highlight the importance of including robustness evaluation when developing DNNs for endoscopy applications and propose strategies to mitigate performance loss.
Immune cells: potential carriers or agents for drug delivery to the central nervous system
Authors: Shan-Shan Zhang, Ruo-Qi Li, Zhong Chen, Xiao-Ying Wang, Aaron S. Dumont, Xiang Fan
Journal: Military Medical Research (2024)

Abstract Drug delivery systems (DDS) have recently emerged as a promising approach for the unique advantages of drug protection and targeted delivery. However, the access of nanoparticles/drugs to the central nervous system (CNS) remains a challenge mainly due to the obstruction from brain barriers. Immune cells infiltrating the CNS in the pathological state have inspired the development of strategies for CNS foundation drug delivery. Herein, we outline the three major brain barriers in the CNS and the mechanisms by which immune cells migrate across the blood–brain barrier. We subsequently review biomimetic strategies utilizing immune cell-based nanoparticles for the delivery of nanoparticles/drugs to the CNS, as well as recent progress in rationally engineering immune cell-based DDS for CNS diseases. Finally, we discuss the challenges and opportunities of immune cell-based DDS in CNS diseases to promote their clinical development.
Patients with hepatocellular carcinoma extrahepatic metastases can benefit from hepatic arterial infusion chemotherapy combined with lenvatinib plus programmed Death-1 inhibitors
Authors: Renguo Guan, Nan Zhang, Min Deng, Ye Lin, Guanjie Huang, Yizhen Fu, Zehao Zheng, Wei Wei, Chong Zhong, Haitao Zhao, Jie Mei, Rongping Guo
Journal: International Journal of Surgery (2024)

Background: Lenvatinib plus Programmed Death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy. Materials and Methods: This multi-center cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n=127) or LEN-P alone (n=103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Results: After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P &lt;0.001; mPFS: 8.0 months vs. 3.0 months, P =0.001). After IPTW, the mOS (hazard ratio (HR)=0.384, P &lt;0.001) and mPFS (HR=0.507, P &lt;0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group’s objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P &lt;0.001; IPTW cohort: 66.1% vs. 27.8%, P &lt;0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group ( P &gt;0.05). Conclusion: HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management.
A commentary on “Predicting recurrence and survival in patients with non-metastatic renal-cell carcinoma after nephrectomy: a prospective population-based study with multicenter validation”
Authors: Aimin Jiang, Peng Luo, Chenxin Chen, Chen Cai, Linhui Wang
Journal: International Journal of Surgery (2024)

aDepartment of Urology, Changhai Hospital, Naval Medical University, Shanghai, China bDepartment of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China cDepartment of Health Statistics, Naval Medical University, Shanghai, China dDepartment of Special Clinic, Changhai Hospital, Naval Medical University, Shanghai, China Aimin Jiang, Peng Luo, Chenxin Chen and Chen Cai: Those author contribute equally to this work. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China. E-mail address: [email protected] (L. Wang). This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/
The menace of severe adverse events and deaths associated with viral gene therapy and its potential solution
Authors: Artyom Kachanov, Anastasiya Kostyusheva, Sergey Brezgin, Ivan Karandashov, Natalia Ponomareva, Andrey Tikhonov, Alexander Lukashev, Vadim Pokrovsky, Andrey A. Zamyatnin, Alessandro Parodi, Vladimir Chulanov, Dmitry Kostyushev
Journal: Medicinal Research Reviews (2024)

Abstract Over the past decade, in vivo gene replacement therapy has significantly advanced, resulting in market approval of numerous therapeutics predominantly relying on adeno‐associated viral vectors (AAV). While viral vectors have undeniably addressed several critical healthcare challenges, their clinical application has unveiled a range of limitations and safety concerns. This review highlights the emerging challenges in the field of gene therapy. At first, we discuss both the role of biological barriers in viral gene therapy with a focus on AAVs, and review current landscape of in vivo human gene therapy. We delineate advantages and disadvantages of AAVs as gene delivery vehicles, mostly from the safety perspective (hepatotoxicity, cardiotoxicity, neurotoxicity, inflammatory responses etc.), and outline the mechanisms of adverse events in response to AAV. Contribution of every aspect of AAV vectors (genomic structure, capsid proteins) and host responses to injected AAV is considered and substantiated by basic, translational and clinical studies. The updated evaluation of recent AAV clinical trials and current medical experience clearly shows the risks of AAVs that sometimes overshadow the hopes for curing a hereditary disease. At last, a set of established and new molecular and nanotechnology tools and approaches are provided as potential solutions for mitigating or eliminating side effects. The increasing number of severe adverse reactions and, sadly deaths, demands decisive actions to resolve the issue of immune responses and extremely high doses of viral vectors used for gene therapy. In response to these challenges, various strategies are under development, including approaches aimed at augmenting characteristics of viral vectors and others focused on creating secure and efficacious non‐viral vectors. This comprehensive review offers an overarching perspective on the present state of gene therapy utilizing both viral and non‐viral vectors.
Tetrahedral DNA‐Based Functional MicroRNA‐21 Delivery System: Application to Corneal Epithelial Wound Healing
Authors: Yulin Li, Shu Wang, Yueyan Dong, Xin Jin, Jingrao Wang, Hong Zhang
Journal: Advanced Healthcare Materials (2024)

Abstract Corneal injury occurs frequently which may lead to serious visual impairment. Rapid and efficient re‐epithelialization after corneal epithelial injury is the key issue for maintaining corneal homeostasis. Among various treatment strategies, microRNA (miR)‐based therapy shows great potential. However, structural limitations of miRNAs hinder its biomedical functionality. Nucleic acid nanotechnology is an appealing candidate for gene delivery because of its flexible modification and excellent biocompatibility. Herein, modified 3D tetrahedral framework nucleic acids (tFNAs) utilized as gene carriers for miR‐21 delivery are constructed. TFNAs‐miR‐21 (T‐21) shows great enzymatic resistance in extracellular environment and payload delivery into human corneal epithelial cells (HCECs) via clathrin‐mediated endocytosis. T‐21 facilitates proliferation and migration in HCECs via activating PI3K/AKT and ERK1/2 signaling pathways in vitro. In vivo studies, T‐21 can be internalized by corneal epithelium in mice. In the mice corneal scratch model, T‐21 ophthalmic solutions used as eye drops show no apparent side effects on the ocular surface histologically and exert great potential in accelerating corneal wound healing. These findings demonstrate that modified tFNAs are promising candidates for miRNA delivery for corneal wound healing. The convenient administration and great biocompatibility of tetrahedral DNA nanoparticles highlight its potential as gene transporter in solving ocular problems.
The role of quiescent thymic progenitors in TAL/LMO2-induced T-ALL chemotolerance
Authors: Kevin W. O’Connor, Kensei Kishimoto, Irena O. Kuzma, Kelsey P. Wagner, Jonathan S. Selway, Justine E. Roderick, Keshab K. Karna, Kayleigh M. Gallagher, Kai Hu, Haibo Liu, Rui Li, Michael A. Brehm, Lihua Julie Zhu, David J. Curtis, Cedric S. Tremblay, Michelle A. Kelliher
Journal: Leukemia (2024)

Abstract Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1 / LMO mouse models, double negative-3 (DN3; CD4 − CD8 − CD25 + CD44 − ) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle–restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL / LMO patient samples revealed a similar pattern in CD7 + CD1a − thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO -induced T-ALL and its clinical implications in therapy failure.
Engineered Luminescent Oncolytic Vaccinia Virus Activation of Photodynamic‐Immune Combination Therapy for Colorectal Cancer
Authors: Lu‐Yi Ye, Yi‐Shu Li, Tong Ge, Long‐Cai Liu, Jing‐Xing Si, Xue Yang, Wei‐Jiao Fan, Xiao‐Zhen Liu, You‐Ni Zhang, Jun‐Wei Wang, Shi‐Bing Wang, Hai Zou, Yue‐Liang Zheng, Ke‐Tao Jin, Zheng‐Wei Mao, Yu Cai, Xiao‐Zhou Mou
Journal: Advanced Healthcare Materials (2024)

Abstract Oncolytic virus therapy is currently regarded as a promising approach in cancer immunotherapy. It has greater therapeutic advantages for colorectal cancer that is prone to distant metastasis. However, the therapeutic efficacy and clinical application of viral agents alone for colorectal cancer remain suboptimal. In this study, an engineered oncolytic vaccinia virus (OVV‐Luc) that expresses the firefly luciferase gene is developed and loaded Chlorin e6 (Ce6) onto the virus surface through covalent coupling, resulting in OVV‐Luc@Ce6 (OV@C). The OV@C infiltrates tumor tissue and induces endogenous luminescence through substrate catalysis, resulting in the production of reactive oxygen species. This unique system eliminates the need for an external light source, making it suitable for photodynamic therapy (PDT) in deep tissues. Moreover, this synergistic effect between PDT and viral immunotherapy enhances dendritic cell maturation, macrophage polarization, and reversal of the immunosuppressive microenvironment. This synergistic effect has the potential to convert a “cold” into a “hot” tumor, it offers valuable insights for clinical translation and application.
Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy
Authors: Darcy L. Fehlings, Mehdi Zarrei, Worrawat Engchuan, Neal Sondheimer, Bhooma Thiruvahindrapuram, Jeffrey R. MacDonald, Edward J. Higginbotham, Ritesh Thapa, Tarannum Behlim, Sabrina Aimola, Lauren Switzer, Pamela Ng, John Wei, Prakroothi S. Danthi, Giovanna Pellecchia, Sylvia Lamoureux, Karen Ho, Sergio L. Pereira, Jill de Rijke, Wilson W. L. Sung, Alireza Mowjoodi, Jennifer L. Howe, Thomas Nalpathamkalam, Roozbeh Manshaei, Siavash Ghaffari, Joseph Whitney, Rohan V. Patel, Omar Hamdan, Rulan Shaath, Brett Trost, Shannon Knights, Dawa Samdup, Anna McCormick, Carolyn Hunt, Adam Kirton, Anne Kawamura, Ronit Mesterman, Jan Willem Gorter, Nomazulu Dlamini, Daniele Merico, Murto Hilali, Kyle Hirschfeld, Kritika Grover, Nelson X. Bautista, Kara Han, Christian R. Marshall, Ryan K. C. Yuen, Padmaja Subbarao, Meghan B. Azad, Stuart E. Turvey, Piush Mandhane, Theo J. Moraes, Elinor Simons, George Maxwell, Michael Shevell, Gregory Costain, Jacques L. Michaud, Fadi F. Hamdan, Julie Gauthier, Kevin Uguen, Dimitri J. Stavropoulos, Richard F. Wintle, Maryam Oskoui, Stephen W. Scherer
Journal: Nature Genetics (2024)
A Horn Peptide‐Thermoresponsive Hydrogel for Angiogenesis and Bone Regeneration
Authors: Nannan Xue, Pei Liu, Wenjian Zhao, Ziyi Zhou, Lixiang Zhang, Rizhong Huang, Rui Liu, Ali Fathi, Jin‐Ao Duan, Jun Chen, Yiwei Wang
Journal: Advanced Healthcare Materials (2024)

Abstract The management of critical‐sized bone defects presents a formidable clinical challenge, especially given the increasing incidence of bone diseases in the aging population. Consequently, there is an increased demand for minimally invasive bone repair materials that can effectively address this challenge, particularly in outpatient settings. In this study, the goal is to develop an injectable and biodegradable biomaterial that adheres to and fills bone‐defect sites to support bone regeneration. The osteogenic and angiogenic activities of animal horn peptides are investigated by incorporating them into biologically active moieties, in combination with a novel thermosensitive hydrogel. The resulting thermosensitive hydrogel exhibited essential biological functionalities, allowing precise modulation of its physical and chemical properties. Notably, the hydrogel incorporating the horn peptide rapidly filled the bone defect site, promoting both angiogenesis and bone induction. Consequently, this approach significantly accelerates new bone regeneration. In summary, the findings of this study present a promising, minimally invasive solution for addressing critical‐sized bone defects.
Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort
Authors: Jennifer L. Guida, Geehong Hyun, Daniel W. Belsky, Gregory T. Armstrong, Matthew J. Ehrhardt, Melissa M. Hudson, Paige A. Green, Leslie L. Robison, Brennan P. Streck, Emily S. Tonorezos, Yutaka Yasui, Carmen L. Wilson, Zhaoming Wang, Kirsten K. Ness
Journal: Nature Cancer (2024)
Thioredoxin is a metabolic rheostat controlling regulatory B cells
Authors: Hannah F. Bradford, Thomas C. R. McDonnell, Alexander Stewart, Andrew Skelton, Joseph Ng, Zara Baig, Franca Fraternali, Deborah Dunn-Walters, David A. Isenberg, Adnan R. Khan, Claudio Mauro, Claudia Mauri
Journal: Nature Immunology (2024)

Abstract Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (B reg ) cell differentiation and function is unknown. Here we show that B reg cell differentiation, unlike non-B reg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN , encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by B reg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing B reg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by B reg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx + B cells. Exogenous Trx stimulation restored B reg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies B reg cell impairment in patients with SLE.
Authorship of Publications Supported by NCI-Funded Grants Involving Low- and Middle-Income Countries
Authors: Linsey Eldridge, Elise M. Garton, Kalina Duncan, Satish Gopal
Journal: JAMA Network Open (2024)

Importance Scientific publication is an important tool for knowledge dissemination and career advancement, but authors affiliated with institutions in low- and middle-income countries (LMICs) are historically underrepresented on publications. Objective To assess the country income level distribution of author affiliations for publications resulting from National Cancer Institute (NCI)–supported extramural grants between 2015 and 2019, with international collaborating institutions exclusively in 1 or more LMICs. Design and Setting This cross-sectional study assessed authorship on publications resulting from NCI-funded grants between October 1, 2015, and September 30, 2019. Grants with collaborators in LMICs were identified in the National Institutes of Health (NIH) Query/View/Report and linked to publications using Dimensions for NIH, published between 2011 and 2020. Statistical analysis was performed from May 2021 to July 2022. Main Outcomes and Measures Author institutional affiliation was used to classify author country and related income level as defined by the World Bank. Relative citation ratio and Altmetric data from Dimensions for NIH were used to compare citation impact measures using the Wilcoxon rank sum test. Results In this cross-sectional study, 159 grants were awarded to US institutions with collaborators in LMICs, and 5 grants were awarded directly to foreign institutions. These 164 grants resulted in 2428 publications, of which 1242 (51%) did not include any authors affiliated with an institution in an LMIC. In addition, 1884 (78%) and 2009 (83%) publications had a first or last author, respectively, affiliated with a high-income country (HIC). Publications with HIC-affiliated last authors also demonstrated greater citation impact compared with publications with LMIC-affiliated last authors as measured by relative citation ratios and Altmetric Attention Scores; publications with HIC-affiliated first authors also had higher Altmetric Attention Scores. Conclusions and Relevance This cross-sectional study suggests that LMIC-affiliated authors were underrepresented on publications resulting from NCI-funded grants involving LMICs. It is critical to promote equitable scientific participation by LMIC institutions in cancer research, including through current and planned programs led by the NCI.