tbuckley/cabot-search huggingface dataset:
Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT
Authors: Maria E. Bernabéu-Herrero, Dilipkumar Patel, Adrianna Bielowka, JiaYi Zhu, Kinshuk Jain, Ian S. Mackay, Patricia Chaves Guerrero, Giulia Emanuelli, Luca Jovine, Michela Noseda, Stefan J. Marciniak, Micheala A. Aldred, Claire L. Shovlin
Journal: Blood (2024)

For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.
Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer
Authors: Seema Nagpal, Michael T Milano, Veronica L Chiang, Scott G Soltys, Alexandria Brackett, Lia M Halasz, Amit K Garg, Arjun Sahgal, Manmeet S Ahluwalia, Martin C Tom, Joshua D Palmer, Jonathan P S Knisely, Samuel T Chao, Melanie Hayden Gephart, Tony J C Wang, Simon S Lo, Eric L Chang
Journal: Neuro-Oncology (2024)

Abstract The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT). The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at (1) diagnosis or (2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1–3, 4–6 and 7–9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method. Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2–4 BrM, where it was considered usually not appropriate. We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision- making in this complex clinical space.
A novel approach to evaluation of tumor response for advanced pulmonary adenocarcinoma using the intertumoral heterogeneity response score
Authors: Xinlong Zheng, Tao Lu, Shiwen Wu, Xiaoyan Lin, Jing Bai, Xiaohui Chen, Qian Miao, Jianqun Yan, Kan Jiang, Longfeng Zhang, Xiaobing Zheng, Haibo Wang, Yiquan Xu, Weijin Xiao, Cao Li, Wenying Peng, Jianming Ding, Qiaofeng Zhong, Zihua Zou, Shanshan Yang, Yujing Li, Sihui Chen, Qiuyu Zhang, Jianfeng Yan, Guofeng Tang, Yuandong Cai, Miao kang, Tony S. K. Mok, Gen Lin
Journal: MedComm (2024)

Abstract Treatment response and prognosis estimation in advanced pulmonary adenocarcinoma are challenged by the significant heterogeneity of the disease. The current Response Evaluation Criteria in Solid Tumors (RECIST) criteria, despite providing a basis for solid tumor response evaluation, do not fully encompass this heterogeneity. To better represent these nuances, we introduce the intertumoral heterogeneity response score (THRscore), a measure built upon and expanding the RECIST criteria. This retrospective study included patients with 3–10 measurable advanced lung adenocarcinoma lesions who underwent first‐line chemotherapy or targeted therapy. The THRscore, derived from the coefficient of variation in size for each measurable tumor before and 4–6 weeks posttreatment, unveiled a correlation with patient outcomes. Specifically, a high THRscore was associated with shorter progression‐free survival, lower tumor response rate, and a higher tumor mutation burden. These associations were further validated in an external cohort, confirming THRscore's effectiveness in stratifying patients based on progression risk and treatment response, and enhancing the utility of RECIST in capturing complex tumor behaviors in lung adenocarcinoma. These findings affirm the promise of THRscore as an enhanced tool for tumor response assessment in advanced lung adenocarcinoma, extending the RECIST criteria's utility.
Maresin‐1 ameliorates hypertensive vascular remodeling through its receptor LGR6
Authors: Zheng Yin, Jishou Zhang, Mengmeng Zhao, Shanshan Peng, Jing Ye, Jianfang Liu, Yao Xu, Shuwan Xu, Wei Pan, Cheng Wei, Juan‐Juan Qin, Jun Wan, Menglong Wang
Journal: MedComm (2024)

Abstract Hypertensive vascular remodeling is defined as the changes in vascular function and structure induced by persistent hypertension. Maresin‐1 (MaR1), one of metabolites from Omega‐3 fatty acids, has been reported to promote inflammation resolution in several inflammatory diseases. This study aims to investigate the effect of MaR1 on hypertensive vascular remodeling. Here, we found serum MaR1 levels were reduced in hypertensive patients and was negatively correlated with systolic blood pressure (SBP). The treatment of MaR1 reduced the elevation of blood pressure and alleviated vascular remodeling in the angiotensin II (AngII)‐infused mouse model. In addition, MaR1‐treated vascular smooth muscle cells (VSMCs) exhibited reduced excessive proliferation, migration, and phenotype switching, as well as impaired pyroptosis. However, the knockout of the receptor of MaR1, leucine‐rich repeat‐containing G protein‐coupled receptor 6 (LGR6), was seen to aggravate pathological vascular remodeling, which could not be reversed by additional MaR1 treatment. The mechanisms by which MaR1 regulates vascular remodeling through LGR6 involves the Ca 2+ /calmodulin‐dependent protein kinase II/nuclear factor erythroid 2‐related factor 2/heme oxygenase‐1 signaling pathway. Overall, supplementing MaR1 may be a novel therapeutic strategy for the prevention and treatment of hypertension.
Dendritic nanomedicine enhances chemo-immunotherapy by disturbing metabolism of cancer-associated fibroblasts for deep penetration and activating function of immune cells
Authors: Yunkun Li, Xiaoding Shen, Haitao Ding, Yuxin Zhang, Dayi Pan, Liping Su, Yahui Wu, Zaixiang Fang, Jie Zhou, Qiyong Gong, Kui Luo
Journal: Acta Pharmaceutica Sinica B (2024)

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells. Herein, we constructed a PEGylated dendritic epirubicin (Epi) prodrug (Epi-P4D) to regulate the metabolism of cancer-associated fibroblasts (CAFs), thus enhancing Epi penetration into both multicellular tumor spheroids (MTSs) and tumor tissues in mouse colon cancer (CT26), mouse breast cancer (4T1) and human breast cancer (MDA-MB-231) models. Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin, α-SMA, and collagen secretion. Besides, thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell (DC) maturation and subsequent immune activation, including elevating the CD4+ T cell population, reducing CD4+ and CD8+ T cell hyperactivation and exhaustion, and amplifying the natural killer (NK) cell proportion and effectively activating them. As a result, this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.
Bladder-cancer-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating fatty acid transporter protein 2 and down-regulating receptor-interacting protein kinase 3 in PMN-MDSCs
Authors: Xiaojun Shi, Shiyu Pang, Jiawei Zhou, Guang Yan, Ruxi Gao, Haowei Wu, Zhou Wang, Yuqing Wei, Xinyu Liu, Wanlong Tan
Journal: Molecular Cancer (2024)

Abstract Background Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is one of the causes of tumor immune tolerance and failure of cancer immunotherapy. Here, we found that bladder cancer (BCa)-derived exosomal circRNA_0013936 could enhance the immunosuppressive activity of PMN-MDSCs by regulating the expression of fatty acid transporter protein 2 (FATP2) and receptor-interacting protein kinase 3 (RIPK3). However, the underlying mechanism remains largely unknown. Methods BCa-derived exosomes was isolated and used for a series of experiments. RNA sequencing was used to identify the differentially expressed circRNAs. Western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, ELISA and Flow cytometry were performed to reveal the potential mechanism of circRNA_0013936 promoting the immunosuppressive activity of PMN-MDSC. Results CircRNA_0013936 enriched in BCa-derived exosomes could promote the expression of FATP2 and inhibit the expression of RIPK3 in PMN-MDSCs. Mechanistically, circRNA_0013936 promoted the expression of FATP2 and inhibited the expression of RIPK3 expression via sponging miR-320a and miR-301b, which directly targeted JAK2 and CREB1 respectively. Ultimately, circRNA_0013936 significantly inhibited the functions of CD8 + T cells by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway, and down-regulating RIPK3 through the circRNA_0013936/miR-301b/CREB1 pathway in PMN-MDSCs. Conclusions BCa-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway and down-regulating RIPK3 through the circRNA_0013936/miR-301b-3p/CREB1 pathway in PMN-MDSCs. These findings help to find new targets for clinical treatment of human bladder cancer.
Childbirth rates in women with myeloproliferative neoplasms
Authors: Anna Ravn Landtblom, Therese M-L Andersson, Anna L V Johansson, Frida E Lundberg, Jan Samuelsson, Magnus Björkholm, Malin Hultcrantz
Journal: Leukemia (2024)

Abstract Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify risk of miscarriage and stillbirth. Women aged 15–44 years with an MPN diagnosis 1973–2018, were identified in Swedish health care registers, and age-matched 1:4 to population controls. We identified 1141 women with MPN and 4564 controls. Women with MPN had a lower rate of childbirth (hazard ratio [HR] with 95% confidence interval was 0.78 (0.68–0.90)). Subgroup analysis showed that the rate was not significantly reduced in essential thrombocythemia, HR 1.02 (0.86–1.22) while the HR was 0.50 (0.33–0.76) in PV and 0.45 (0.28–0.74) in PMF. The risk of miscarriage was not significantly increased before MPN diagnosis, the HR during follow-up after diagnosis was 1.25 (0.89-1.76). Women with MPN were more likely to have had a previous stillbirth. Women with MPN had fewer children at diagnosis, and fewer children in total. In conclusion, the childbirth rate was lower among women with MPN than controls, but not among women with essential thrombocythemia.
AMPK‐upregulated microRNA‐708 plays as a suppressor of cellular senescence and aging via downregulating disabled‐2 and mTORC1 activation
Authors: Jian Zhang, Hui Gong, Tingting Zhao, Weitong Xu, Honghan Chen, Tiepeng Li, Yu Yang, Ming Yang, Ning Huang, Chuhui Gong, Fangfang Wang, Cuiying Zhang, Jin Liu, Hengyi Xiao
Journal: MedComm (2024)

Abstract Senescence‐associated microRNAs (SA‐miRNAs) are important molecules for aging regulation. While many aging‐promoting SA‐miRNAs have been identified, confirmed aging‐suppressive SA‐miRNAs are rare, that impeded our full understanding on aging regulation. In this study, we verified that miR‐708 expression is decreased in senescent cells and aged tissues and revealed that miR‐708 overexpression can alleviate cellular senescence and aging performance. About the molecular cascade carrying the aging suppressive action of miR‐708, we unraveled that miR‐708 directly targets the 3′UTR of the disabled 2 ( Dab2 ) gene and inhibits the expression of DAB2. Interestingly, miR‐708‐caused DAB2 downregulation blocks the aberrant mammalian target of rapamycin complex 1 (mTORC1) activation, a driving metabolic event for senescence progression, and restores the impaired autophagy, a downstream event of aberrant mTORC1 activation. We also found that AMP‐activated protein kinase (AMPK) activation can upregulate miR‐708 via the elevation of DICER expression, and miR‐708 inhibitor is able to blunt the antiaging effect of AMPK. In summary, this study characterized miR‐708 as an aging‐suppressive SA‐miRNA for the first time and uncovered a new signaling cascade, in which miR‐708 links the DAB2/mTOR axis and AMPK/DICER axis together. These findings not only demonstrate the potential role of miR‐708 in aging regulation, but also expand the signaling network connecting AMPK and mTORC1.
Drug-Coated Balloons for In-Stent Restenosis—Finally Leaving Nothing Behind for US Patients
Authors: Amartya Kundu, David J. Moliterno
Journal: JAMA (2024)

Robert W. Yeh, MD, MSc; Richard Shlofmitz, MD; Jeffrey Moses, MD; William Bachinsky, MD; Suhail Dohad, MD; Steven Rudick, MD; Robert Stoler, MD; Brian K. Jefferson, MD; William Nicholson, MD; John Altman, MD; Cinthia Bateman, MD; Amar Krishnaswamy, MD; J. Aaron Grantham, MD; Frank J. Zidar, MD; Steven P. Marso, MD; Jennifer A. Tremmel, MD, MS; Cindy Grines, MD; Mustafa I. Ahmed, MD; Azeem Latib, MD; Behnam Tehrani, MD; J. Dawn Abbott, MD; Wayne Batchelor, MD; Paul Underwood, MD; Dominic J. Allocco, MD; Ajay J. Kirtane, MD, SM; AGENT IDE Investigators; Richard Shlofmitz; Jeffrey Moses; William Bachinsky; Suhail Dohad; Steven Rudick; Robert Stoler; Brian Jefferson; William Nicholson; John Altman; Robert Yeh; Cinthia Tjan Bateman; Amar Krishnaswamy; J. Aaron Grantham; Francis Zidar; Rajendran Sabapathy; Jennifer Tremmel; Cindy Grines; Mustafa Ahmed; Azeem Latib; Behnam Tehrani; Khaldoon Alaswad; Carey Kimmelstiel; William Dixon; Arthur Reitman; Lawrence Ang; Justin Levisay; Jinnette Abbott; Kathleen Kearney; Farouc Jaffer; Saroj Neupane; Kevin Croce; Kendrick Shunk; Angela Taylor; Matthew Saybolt; Claro Diaz; Alpesh Shah; Kapil Lotun; Johannes Brechtken; Himanshu Agarwal; Rajan Patel
Genome‐scale CRISPR–Cas9 screen identifies <i>PAICS</i> as a therapeutic target for <i>EGFR</i> wild‐type non‐small cell lung cancer
Authors: Yufeng Li, Lingyun Zhu, Jiaqi Mao, Hongrui Zheng, Ziyi Hu, Suisui Yang, Tianyu Mao, Tingting Zhou, Pingping Cao, Hongshuai Wu, Xuerong Wang, Jing Wang, Fan Lin, Hua Shen
Journal: MedComm (2024)

Abstract Epidermal growth factor receptor‐targeted ( EGFR ‐targeted) therapies show promise for non‐small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild‐type NSCLC. A genome‐wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase ( PAICS ), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild‐type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells. Additionally, PAICS silencing led to cell‐cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild‐type NSCLC. PAICS silencing also caused DNA damage and cell‐cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K–AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild‐type NSCLC and represents a potential therapeutic target for this disease.
Accumulation of TOX high mobility group box family member 3 promotes the oncogenesis and development of hepatocellular carcinoma through the MAPK signaling pathway
Authors: Yufu Peng, Jing Yu, Fei Liu, Leyi Tang, Bo Li, Wei Zhang, Kefei Chen, Haili Zhang, Yonggang Wei, Xuelei Ma, Hubing Shi
Journal: MedComm (2024)

Abstract Microvascular invasion (MVI) has been widely valued in the field of liver surgery because MVI positivity indicates poor prognosis in hepatocellular carcinoma (HCC) patients. However, the potential molecular mechanism underlying the poor prognosis of MVI‐positive HCC patients is unclear. Therefore, this study focused on identifying the key genes leading to poor prognosis in patients with a high degree of malignancy of HCC by examining the molecular signaling pathways in MVI‐positive HCC patients. Through RNA sequencing, TOX high mobility group box family member 3 (TOX3) was demonstrated to be significantly highly expressed in MVI‐positive HCC tissues, which was associated with poor prognosis. The results of in vivo and in vitro showed that TOX3 can promote the oncogenesis and development of HCC by targeting key molecules of the MAPK and EMT signaling pathways. The IP‐MS results indicated that proteasome degradation of TOX3 in HCC cells is potentially mediated by a tripartite motif containing 56 (TRIM56, an E3 ligase) in HCC cells. Inhibiting TRIM56 enhances TOX3 protein levels. Overall, our study identified TOX3 as a key gene in the MAPK and EMT signaling pathways in HCC, and its overexpression confers significant proliferation and invasiveness to tumor cells.
Current clinical findings of acute neurological syndromes after SARS‐CoV‐2 infection
Authors: Minjin Wang, Jierui Wang, Yan Ren, Lu Lu, Weixi Xiong, Lifeng Li, Songtao Xu, Meng Tang, Yushang Yuan, Yi Xie, Weimin Li, Lei Chen, Dong Zhou, Binwu Ying, Jinmei Li
Journal: MedComm (2024)

Abstract Neuro‐COVID, a condition marked by persistent symptoms post‐COVID‐19 infection, notably affects various organs, with a particular focus on the central nervous system (CNS). Despite scant evidence of SARS‐CoV‐2 invasion in the CNS, the increasing incidence of Neuro‐COVID cases indicates the onset of acute neurological symptoms early in infection. The Omicron variant, distinguished by heightened neurotropism, penetrates the CNS via the olfactory bulb. This direct invasion induces inflammation and neuronal damage, emphasizing the need for vigilance regarding potential neurological complications. Our multicenter study represents a groundbreaking revelation, documenting the definite presence of SARS‐CoV‐2 in the cerebrospinal fluid (CSF) of a significant proportion of Neuro‐COVID patients. Furthermore, notable differences emerged between RNA‐CSF‐positive and negative patients, encompassing aspects such as blood–brain barrier integrity, extent of neuronal damage, and the activation status of inflammation. Despite inherent limitations, this research provides pivotal insights into the intricate interplay between SARS‐CoV‐2 and the CNS, underscoring the necessity for ongoing research to fully comprehend the virus's enduring effects on the CNS. The findings underscore the urgency of continuous investigation Neuro‐COVID to unravel the complexities of this relationship, and pivotal in addressing the long‐term consequences of COVID‐19 on neurological health.
Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine
Authors: Anmi Jose, Pallavi Kulkarni, Jaya Thilakan, Murali Munisamy, Anvita Gupta Malhotra, Jitendra Singh, Ashok Kumar, Vivek M. Rangnekar, Neha Arya, Mahadev Rao
Journal: Molecular Cancer (2024)

Abstract Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer. Graphical Abstract
Enhancing Osteosacoma Killing and CT Imaging Using Ultra High Drug Loading and NIR‐Responsive Bismuth Sulfide @Mesoporous Silica Nanoparticles
Authors: Yao Lu, Lihua Li, Zefeng Lin, Mei Li, Xiaoming Hu, Yu Zhang, Mingying Peng, Hong Xia, Gang Han
Journal: Advanced Healthcare Materials (2024)

In the original version of this article, there was a mistake in Figure 7c due to errors during the compilation of the images. The correct figure is shown below. This mistake does not affect the results, discussions and conclusions published in this work. We really apologize for this mistake.