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"Lu, Le"
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لقاء في القرية العالمية = An encounter in the global village : قصص مختارة من المؤتمر الدولي الرابع عشر للقصة القصيرة
هذا الكتاب يحتوي على قصص مختارة من المؤتمر الدولي الرابع عشر للقصة القصيرة وهذا اللقاء الذي نظم من قبل جمعية دراسة القصص القصيرة الإنجليزية (أس أس أس أس إي) وهي جمعية عالمية أنشئت في الولايات المتحدة عام 1992 وينعقد كل عامين ويعتبر اللقاء العالمي الوحيد الذي يركز بشكل خاص على دراسات القصة القصيرة أما القصص المشاركة في اللقاء فهي مكتوبة من قبل 29 كاتبا ينتمون إلى عشرة دول هي الصين وتايوان والهند والولايات المتحدة وكندا ونيوزلندا وفرنسا وإيرلندا والنمسا وسنغافورا وجامايكا.
BOOK
Large-scale pancreatic cancer detection via non-contrast CT and deep learning
Pancreatic ductal adenocarcinoma (PDAC), the most deadly solid malignancy, is typically detected late and at an inoperable stage. Early or incidental detection is associated with prolonged survival, but screening asymptomatic individuals for PDAC using a single test remains unfeasible due to the low prevalence and potential harms of false positives. Non-contrast computed tomography (CT), routinely performed for clinical indications, offers the potential for large-scale screening, however, identification of PDAC using non-contrast CT has long been considered impossible. Here, we develop a deep learning approach, pancreatic cancer detection with artificial intelligence (PANDA), that can detect and classify pancreatic lesions with high accuracy via non-contrast CT. PANDA is trained on a dataset of 3,208 patients from a single center. PANDA achieves an area under the receiver operating characteristic curve (AUC) of 0.986–0.996 for lesion detection in a multicenter validation involving 6,239 patients across 10 centers, outperforms the mean radiologist performance by 34.1% in sensitivity and 6.3% in specificity for PDAC identification, and achieves a sensitivity of 92.9% and specificity of 99.9% for lesion detection in a real-world multi-scenario validation consisting of 20,530 consecutive patients. Notably, PANDA utilized with non-contrast CT shows non-inferiority to radiology reports (using contrast-enhanced CT) in the differentiation of common pancreatic lesion subtypes. PANDA could potentially serve as a new tool for large-scale pancreatic cancer screening.
A deep learning model provides high accuracy in detecting pancreatic lesions in multicenter data, outperforming radiology specialists.
Journal Article
Malignant peripheral nerve sheath tumor: models, biology, and translation
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8–13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
Journal Article
Estimation of axial load-carrying capacity of concrete-filled steel tubes using surrogate models
The main objective of the present work is to estimate the load-carrying capacity of concrete-filled steel tubes (CFST) under axial compression using hybrid artificial intelligence (AI) algorithms. In particular, the adaptive neuro-fuzzy inference system (ANFIS) with various metaheuristic optimization methods, such as the biogeography-based optimization (ANFIS-BBO), the particle swarm optimization (ANFIS-PSO), and the genetic algorithm (ANFIS-GA), have been employed taking into account the variability of input parameters. Commonly used statistical criteria, such as the coefficient of determination (
R
2
), the a20-index, and the root mean squared error (RMSE), were utilized to evaluate and compare the effectiveness of the proposed AI models. The Monte Carlo approach was used to propagate the variability in the input space to the predicted output. The results showed that the ANFIS system, optimized by PSO, was the most effective and robust model with respect to three considered criteria (a20-index = 0.881,
R
2
= 0.942 and RMSE = 185.631). Sensitivity analysis was performed, indicating that the minor axis length and thickness of the steel tube exhibited the highest contribution to the axial compression load-carrying capacity of the CFST.
Journal Article
Exosomal lncRNA TUG1 from cancer-associated fibroblasts promotes liver cancer cell migration, invasion, and glycolysis by regulating the miR-524-5p/SIX1 axis
Background
Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; however, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized.
Methods
The expression levels of TUG1, miR-524-5p, and sine oculis homeobox homolog 1 (SIX1) were determined using quantitative real-time PCR. The regulatory relationships were confirmed by dual-luciferase reporter assay. Cell proliferation and invasion were assessed using Cell Counting Kit 8 and transwell assays. Glucose uptake, cellular levels of lactate, lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) were detected using commercially available kits. Silencing of TUG1 or SIX1 was performed by lentivirus transduction. Protein levels were measured by immunoblotting.
Results
Cancer-associated fibroblasts (CAFs)-secreted exosomes promoted migration, invasion, and glycolysis in HepG2 cells by releasing TUG1. The promotive effects of CAFs-secreted exosomes were attenuated by silencing of TUG1. TUG1 and SIX1 are targets of miR-524-5p. SIX1 knockdown inhibited the promotive effects of miR-524-5p inhibitor. Silencing of TUG1 suppressed tumor growth and lung metastasis and therefore increased survival of xenograft model mice. We also found that TUG1 and SIX1 were increased in HCC patients with metastasis while miR-524-5p was decreased in HCC patients with metastasis.
Conclusions
CAFs-derived exosomal TUG1 promoted migration, invasion, and glycolysis in HCC cells via the miR-524-5p/SIX1 axis. These findings may help establish the foundation for the development of therapeutics strategies and clinical management for HCC in future.
Journal Article
Neurofibromin and suppression of tumorigenesis: beyond the GAP
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease and one of the most common inherited tumor predisposition syndromes, affecting 1 in 3000 individuals worldwide. The
NF1
gene encodes neurofibromin, a large protein with RAS GTP-ase activating (RAS-GAP) activity, and loss of
NF1
results in increased RAS signaling. Neurofibromin contains many other domains, and there is considerable evidence that these domains play a role in some manifestations of NF1. Investigating the role of these domains as well as the various signaling pathways that neurofibromin regulates and interacts with will provide a better understanding of how neurofibromin acts to suppress tumor development and potentially open new therapeutic avenues. In this review, we discuss what is known about the structure of neurofibromin, its interactions with other proteins and signaling pathways, its role in development and differentiation, and its function as a tumor suppressor. Finally, we discuss the latest research on potential therapeutics for neurofibromin-deficient neoplasms.
Journal Article
Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis
Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.
Journal Article
Hepatic β-Oxidation and Regulation of Carnitine Palmitoyltransferase (CPT) I in Blunt Snout Bream Megalobrama amblycephala Fed a High Fat Diet
High-fat diets may promote growth, partly through their protein-sparing effects. However, high-fat diets often lead to excessive fat deposition, which may have a negative impact on fish such as poor growth and suppressive immune. Therefore, this study investigated the effects of a fat-rich diet on the mechanisms of fat deposition in the liver. Three-hundred blunt snout bream (Megalobrama amblycephala) juveniles (initial mass 18.00 ± 0.05 g) were fed with one of two diets (5% or 15% fat) for 8 weeks. β-Oxidation capacity and regulation of rate-limiting enzymes were assessed. Large fat droplets were present in hepatocytes of fish fed the high-fat diet. This observation is thought to be largely owing to the reduced capacity for mitochondrial and peroxisomal β-oxidation in the livers of fish fed the high-fat diet, as well as the decreased activities of carnitine palmitoyltransferase (CPT) I and acyl-CoA oxidase (ACO), which are enzymes involved in fatty-acid metabolism. Study of CPT I kinetics showed that CPT I had a low affinity for its substrates and a low catalytic efficiency in fish fed the high-fat diet. Expression of both CPT I and ACO was significantly down-regulated in fish fed the high-fat diet. Moreover, the fatty-acid composition of the mitochondrial membrane varied between the two groups. In conclusion, the attenuated β-oxidation capacity observed in fish fed a high-fat diet is proposed to be owing to decreased activity and/or catalytic efficiency of the rate-limiting enzymes CPT I and ACO, via both genetic and non-genetic mechanisms.
Journal Article
Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.
Journal Article
Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1
Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing
Nf1
gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases
NF1
-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys
Nf1
mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone
Nf1
-mutant neurons results from reduced
NF1
-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that
NF1
mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.
Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that
Nf1
mutations differentially drive both central and peripheral nervous system tumor growth in mice through reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function.
Journal Article