tbuckley/cabot-search huggingface dataset:
Cypher/ZASP drives cardiomyocyte maturation via actin-mediated MRTFA-SRF signalling
Authors: Jialan Lyu, Zhicheng Pan, Ruobing Li, Hailong Yu, Yuesheng Zhang, Dongfei Wang, Xiang Yin, Yan He, Liding Zhao, Siyuan Chen, Shan Zhang, Hongqiang Cheng, Xiaogang Guo
Journal: Theranostics (2024)

Rationale: Cardiomyocytes (CMs) undergo dramatic structural and functional changes in postnatal maturation; however, the regulatory mechanisms remain greatly unclear.Cypher/Z-band alternatively spliced PDZ-motif protein (ZASP) is an essential sarcomere component maintaining Z-disc stability.Deletion of mouse Cypher and mutation in human ZASP result in dilated cardiomyopathy (DCM).Whether Cypher/ZASP participates in CM maturation and thereby affects cardiac function has not been answered.Methods: Immunofluorescence, transmission electron microscopy, real-time quantitative PCR, and Western blot were utilized to identify the role of Cypher in CM maturation.Subsequently, RNA sequencing and bioinformatics analysis predicted serum response factor (SRF) as the key regulator.Rescue experiments were conducted using adenovirus or adeno-associated viruses encoding SRF, both in vitro and in vivo.The molecular mechanisms were elucidated through G-actin/F-actin fractionation, nuclear-cytoplasmic extraction, actin disassembly assays, and co-sedimentation assays.Results: Cypher deletion led to impaired sarcomere isoform switch and morphological abnormalities in mitochondria, transverse-tubules, and intercalated discs.RNA-sequencing analysis revealed significant dysregulation of crucial genes related to sarcomere assembly, mitochondrial metabolism, and electrophysiology in the absence of Cypher.Furthermore, SRF was predicted as key transcription factor mediating the transcriptional differences.Subsequent rescue experiments showed that SRF re-expression during the critical postnatal period effectively rectified CM maturation defects and notably improved cardiac function in Cypher-depleted mice.Mechanistically, Cypher deficiency resulted in the destabilization of F-actin and a notable increase in G-actin levels, thereby impeding the nuclear localisation of myocardin-related transcription factor A (MRTFA) and subsequently initiating SRF transcription.Conclusion: Cypher/ZASP plays a crucial role in CM maturation through actin-mediated MRTFA-SRF signalling.The linkage between CM maturation abnormalities and the late-onset of DCM is suggested, providing further insights into the pathogenesis of DCM and potential treatment strategies.
Biomimetic nanoparticles with enhanced rapamycin delivery for autism spectrum disorder treatment via autophagy activation and oxidative stress modulation
Authors: Chenlin Miao, Yizhe Shen, Yue Lang, Hui Li, Yan Gong, Yamei Liu, Huafei Li, Byron C. Jones, Fuxue Chen, Shini Feng
Journal: Theranostics (2024)

Rationale: Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions.Given the multifaced etiology of ASD, there exist no effective treatment for ASD.Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects.Methods: To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism.Results: The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress.In vitro results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage.SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA.Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models.Conclusions: The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions.
Circular RNA ACVR2A promotes the progression of hepatocellular carcinoma through mir-511-5p targeting PI3K-Akt signaling pathway
Authors: Du Fei, Fang Wang, Yaohui Wang, Ji Chen, Shendong Chen, Lianpeng Fan, Luhan Yang, Qingyi Ren, Suwit Duangmano, Fukuan Du, Hao Liu, Jie Zhou, Jing Sheng, Yueshui Zhao, Xu Wu, Mingxing Li, Zhangang Xiao, Zhuo Zhang, Xian Jiang
Journal: Molecular Cancer (2024)

Circular RNA (circRNA) is thought to mediate the occurrence and development of human cancer and usually acts as a tiny RNA (miRNA) sponge to regulate downstream gene expression. However, it is not clear whether and how circACVR2A (hsa_circ_0001073) is involved in the progression of HCC. The purpose of this study is to clarify the potential role and molecular mechanism of circACVR2A in regulating the progression of hepatocellular carcinoma cells (HCC). The abundance of related proteins in circACVR2A, microRNA (miR511-5p) and PI3K-Akt signaling pathway was determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or Western blotting. Cell viability, invasion and apoptosis were analyzed by CCK-8, Transwell analysis and Tunel staining, respectively. The interaction between circACVR2A and microRNA was evaluated by double luciferase reporter gene assay. The results showed that circACVR2A was highly expressed in hepatocellular carcinoma cell lines. Our in vivo and in vitro data showed that circACVR2A promoted the proliferation, migration and invasion of HCC. In terms of mechanism, we found that circACVR2A can directly interact with miR511-5p and act as a miRNA sponge to regulate the expression of related proteins in PI3K-Akt signaling pathway. In HCC, circACVR2A can mediate miR-511-5p/mRNA network to activate PI3K signal pathway. This shows that the molecular regulatory network with circACVR2A as the core is a new potential target for diagnosis and treatment of hepatocellular carcinoma.
A novel assessment of whole-mount Gleason grading in prostate cancer to identify candidates for radical prostatectomy: a machine learning-based multiomics study
Authors: Jing Ning, Clemens P. Spielvogel, David Haberl, Karolina Trachtova, Stefan Stoiber, Sazan Rasul, Vojtech Bystry, Gabriel Wasinger, Pascal Baltzer, Elisabeth Gurnhofer, Gerald Timelthaler, Michaela Schlederer, Laszlo Papp, Helga Schachner, Thomas Helbich, Markus Hartenbach, Bernhard Grubmüller, Shahrokh F Shariat, Marcus Hacker, Alexander Haug, Lukas Kenner
Journal: Theranostics (2024)

Purpose: This study aims to assess whole-mount Gleason grading (GG) in prostate cancer (PCa) accurately using a multiomics machine learning (ML) model and to compare its performance with biopsy-proven GG (bxGG) assessment.Materials and Methods: A total of 146 patients with PCa recruited in a pilot study of a prospective clinical trial (NCT02659527) were retrospectively included in the side study, all of whom underwent 68 Ga-PSMA-11 integrated positron emission tomography (PET) / magnetic resonance (MR) before radical prostatectomy (RP) between May 2014 and April 2020.To establish a multiomics ML model, we quantified PET radiomics features, pathway-level genomics features from whole exome sequencing, and pathomics features derived from immunohistochemical staining of 11 biomarkers.Based on the multiomics dataset, five ML models were established and validated using 100-fold Monte Carlo cross-validation.Results: Among five ML models, the random forest (RF) model performed best in terms of the area under the curve (AUC).Compared to bxGG assessment alone, the RF model was superior in terms of AUC (0.87 vs 0.75), specificity (0.72 vs 0.61), positive predictive value (0.79 vs 0.75), and accuracy (0.78 vs 0.77) and showed slightly decreased sensitivity (0.83 vs 0.89) and negative predictive value (0.80 vs Ivyspring International Publisher 0.81).Among the feature categories, bxGG was identified as the most important feature, followed by pathomics, clinical, radiomics and genomics features.The three important individual features were bxGG, PSA staining and one intensity-related radiomics feature. Conclusion:The findings demonstrate a superior assessment of the developed multiomics-based ML model in whole-mount GG compared to the current clinical baseline of bxGG.This enables personalized patient management by identifying high-risk PCa patients for RP.
ISG15 accelerates acute kidney injury and the subsequent AKI-to-CKD transition by promoting TGFβR1 ISGylation
Authors: Na Cui, Chengyu Liu, Xiang Tang, Liangliang Song, Zixuan Xiao, Chen Wang, Yancai Wu, Yihao Zhou, Chentai Peng, Yuxia Liu, Ling Zheng, Xinran Liu, Kun Huang, Hong Chen
Journal: Theranostics (2024)

Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown.
Remote actuation and on-demand activation of biomaterials pre-incorporated with physical cues for bone repair
Authors: Xueping Kong, Tianyi Zheng, Zhaoyi Wang, Tong Zhou, Jiezhong Shi, Ying Wang, Ben Zhang
Journal: Theranostics (2024)

The high incidence of bone defect-related diseases caused by trauma, infection, and tumor resection has greatly stimulated research in the field of bone regeneration. Generally, bone healing is a long and complicated process wherein manipulating the biological activity of interventional scaffolds to support long-term bone regeneration is significant for treating bone-related diseases. It has been reported that some physical cues can act as growth factor substitutes to promote osteogenesis through continuous activation of endogenous signaling pathways. This review focuses on the latest progress in bone repair by remote actuation and on-demand activation of biomaterials pre-incorporated with physical cues (heat, electricity, and magnetism). As an alternative method to treat bone defects, physical cues show many advantages, including effectiveness, noninvasiveness, and remote manipulation. First, we introduce the impact of different physical cues on bone repair and potential internal regulatory mechanisms. Subsequently, biomaterials that mediate various physical cues in bone repair and their respective characteristics are summarized. Additionally, challenges are discussed, aiming to provide new insights and suggestions for developing intelligent biomaterials to treat bone defects and promote clinical translation.
Long‐term quality of life after hematopoietic cell transplant for sickle cell disease in childhood: A <scp>STELLAR</scp> interim analysis
Authors: Staci D. Arnold, Nitya Bakshi, Diana Ross, Crystal Smith, Cynthia Sinha, Anirudh Veludhandi, Valerie Dutreuil, Shasha Bai, Lillian R. Meacham, Greg Guilcher, Monica Bhatia, Allistair Abraham, Kimberly A. Kasow, Ann Haight, Fuad El Rassi, Elizabeth Stenger, Joseph Lipscomb, Lakshmanan Krishnamurti
Journal: American Journal of Hematology (2024)

We prospectively collected PROMIS©25 and PROMIS©29 surveys in the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR). Mobility and social participation T-scores were decreased; all other domains were within the norm.
Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease
Authors: Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, Luming Yin, E. Kathleen Carter, Marla Gearing, Alice Chen-Plotkin, Edward B. Lee, John Q. Trojanowski, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Lenora Higginbotham
Journal: Molecular Neurodegeneration (2024)

Lewy body dementia (LBD), a class of disorders comprising Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer's disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson's disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or "modules" of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.
99mTc-PYP and 68Ga-FAPI PET/CT Images of Hereditary Transthyretin Amyloidosis With Cardiac Involvement
Authors: Ali Kibar, Kubra Sahin, Baris Ikitimur, Sait Sager, Haluk Burcak Sayman
Journal: Clinical Nuclear Medicine (2024)

Amyloidosis is a protein misfolding disorder characterized by the extracellular deposition of insoluble amyloid fibrils, derived from abnormally folded proteins. These fibrils disrupt tissue structure and function, leading to organ dysfunction. The condition encompasses various subtypes, each associated with distinct precursor proteins and clinical manifestations. 99mTc-PYP scintigraphy is used widely and holds significant importance for diagnosis. 68Ga-FAPI is also a promising radiotracer for various diseases. To our knowledge, this is the first case of a patient with hereditary transthyretin amyloidosis with cardiac involvement, which FAPI PET showed diffuse increased myocardial uptake.
A Tumor‐Activatable Liposomal Nanoprobe for Selective Visualization of Metastatic Lymph Nodes
Authors: Yi Cui, Heming Xia, Qiyu Liu, Bin Ma, Meijie Pan, Chunliang Shang, Qiang Zhang, Yiguang Wang, Binlong Chen, Hongyan Guo
Journal: Advanced Healthcare Materials (2024)

The precise identification of sentinel lymph nodes (SLNs) during surgery and assessment of their benign status is crucial for accurate tumor staging and optimal treatment strategizing. Currently, a deficiency exists in non-invasive in vivo diagnostic techniques that can accurately pinpoint SLNs during surgery while simultaneously evaluating their benign status. Here, a tumor-activatable liposomal nanoprobe (nTAL) is developed, remotely loaded with clinically approved photosensitizer, methyl aminolevulinate (MAL), to noninvasively visualize the tumor metastasis lymph nodes (LNs) with precision. Benefited from the highly efficient LNs draining of nanosized liposome and tumor cell-specific transformation of the non-fluorescent MAL to fluorescent protoporphyrin IX (PPIX), nTAL succeeded in targeting the SLNs and differentiated the metastatic from the benign ones with a positive correlation between PPIX generation and tumor cell infiltration in LNs. Moreover, the nTAL technology is capable of probing the early metastatic stage with a primary tumor size of 50 mm
Precision medicine and nucleotide-based therapeutics to treat MASH
Authors: Andrea Caddeo, Stefano Romeo
Journal: Clinical and Molecular Hepatology (2024)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.
Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion
Authors: Troy C. Lund, Paul J. Orchard, David R. Nascene, Carina J. King, Jennifer Braun, Stuti Thakkar, Willa Durose, Ilya Shestopalov, Himal Thakar, Ashish O. Gupta
Journal: Molecular Therapy (2024)
Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency
Authors: Jitka Rybova, Teresa Sundararajan, Ladislav Kuchar, Theresa A. Dlugi, Petr Ruzicka, William M. McKillop, Jeffrey A. Medin
Journal: Molecular Therapy (2024)

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.
Reliable Fabrication of Mineral‐Graded Scaffolds by Spin‐Coating and Laser Machining for Use in Tendon‐to‐Bone Insertion Repair
Authors: Yidan Chen, Min Hao, Ismael Bousso, Stavros Thomopoulos, Younan Xia
Journal: Advanced Healthcare Materials (2024)

A reliable method for fabricating biomimetic scaffolds with a controllable mineral gradient to facilitate the surgical repair of tendon-to-bone injuries and the regeneration of the enthesis is reported. The gradient in mineral content is created by sequentially spin-coating with hydroxyapatite/poly(ε-caprolactone) suspensions containing hydroxyapatite nanoparticles in decreasing concentrations. To produce pores and facilitate cell infiltration, the spin-coated film is released and patterned with an array of funnel-shaped microchannels by laser machining. The unique design provided both mechanical (i.e., substrate stiffness) and biochemical (e.g., hydroxyapatite content) cues to spatially control the graded differentiation of mesenchymal stem cells. Immunocytochemical analysis of human mesenchymal stem cell-seeded scaffolds after 14 days of culture demonstrated the formation of a spatial phenotypic cell gradient from osteoblasts to mineralized chondrocytes based on the level of mineralization in the scaffold. By successfully recreating compositional and cellular features of the native tendon enthesis, the biomimetic scaffolds offer a promising avenue for improved tendon-to-bone repair.
Development and validation of a stromal-immune signature to predict prognosis in intrahepatic cholangiocarcinoma
Authors: Yu-Hang Ye, Hao-Yang Xin, Jia-Li Li, Ning Li, Si-Yuan Pan, Long Chen, Jing-Yue Pan, Zhi-Qiang Hu, Peng-Cheng Wang, Chu-Bin Luo, Rong-Qi Sun, Jia Fan, Jian Zhou, Zheng-Jun Zhou, Shao-Lai Zhou
Journal: Clinical and Molecular Hepatology (2024)

Backgrounds/Aims: Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC.Methods: We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time.Results: We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort.Conclusions: We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.
An integrative framework of conflict and control
Authors: Daniela Becker, Erik Bijleveld, Senne Braem, Kerstin Fröber, Felix J. Götz, Tali Kleiman, Anita Körner, Roland Pfister, Andrea M.F. Reiter, Blair Saunders, Iris K. Schneider, Alexander Soutschek, Henk van Steenbergen, David Dignath
Journal: Trends in Cognitive Sciences (2024)