Mutational Profile and Potential Molecular Therapeutic Targets of Pheochromocytoma

PurposePheochromocytoma/paraganglioma (PCC/PGL; collectively known as PPGL) can be driven by germline and somatic mutations in susceptibility genes. We aimed to investigate the mutation profile and clinical features of pathogenic genes in highly genetically heterogeneous PPGL and to preliminary explore molecular therapeutic targets in PPGL.MethodsWe established a panel of 260 genes, including susceptibility genes of PPGL and other important tumorigenic genes to sequence 107 PPGL tissues.ResultsOverall, 608 genomic mutations were identified in 107 PPGL tissues. Almost 57% of PPGL tissue samples exhibited pathogenic mutations, and the most frequently mutated gene was SDHB (15/107, 14%). SDHB and HRAS were the most commonly mutated genes in germline-mutated PPGL (25/107, 23%) and nongermline-mutated PPGL (36/107, 34%), respectively. In addition, novel pathogenic mutations were detected in sporadic PPGL. PPGL with mutations in the hypoxia pathway had an earlier onset and higher norepinephrine level than those in the kinase pathway. Receptor tyrosine kinase (RTK; 22%, 24/107), mitogen-activated protein kinase (MAPK; 14%, 15/107), and tyrosine kinase (TK; 2%, 2/107) pathways were the most frequently mutated pathways in PPGL.ConclusionOur results provided the genetic mutation profile in PPGL tissues. Genetic mutations in PPGL were mainly concentrated in the RTK, TK, and MAPK pathways, suggesting potential molecular therapeutic targets for PPGL

Task-Oriented Semantic Communication with Semantic Reconstruction: An Extended Rate-Distortion Theory Based Scheme

Compressed semantic representation of source is essentially important to accomplish various artificial intelligent (AI) tasks in task-oriented semantic communication (TOSC). In this paper, by extending the rate-distortion theory to multiple tasks, we propose a TOSC scheme with semantic reconstruction (SR), named as TOSC-SR, in the joint source and channel coding (JSCC) framework. Besides extracting and compressing task semantics, our basic idea here is to reconstruct images with task semantics rather than traditionally in the pixels or features. The main purpose is to share the semantic-reconstructed images among multiple tasks with enhanced generalization ability under certain rate. We formulate the TOSC-SR scheme as a rate-distortion optimization problem, where a novel semantic distortion measurement is defined by mutual information of source, the semantic-reconstructed images, and task labels, pairwise. We derive an analytic solution for the formulated problem, where the self-consistent equations are obtained to determine the optimal mapping of source and the semantic-reconstructed images by taking task labels into account. In the TOSC-SR scheme which is feasible in practice, a relaxed version of loss function is derived based on variational approximation of mutual information. Then we adopt the classification task to train TOSC-SR, and the object detection task to validate the generalization ability. Experimental results show that the proposed TOSC-SR scheme outperforms conventional JPEG, JPEG2000 based communication schemes and deep learning based TOSC with general reconstruction schemes in terms of reconstruction quality, classification and object detection performance at the same source compression ratio and signal-to-noise (SNR) regime.Comment: 18 pages, 10 figure

Study on a Novel Gelled Foam for Conformance Control in High Temperature and High Salinity Reservoirs

A novel gelled foam for conformance control was investigated for its ability to enhance oil recovery (EOR) in high temperature and high salinity reservoirs. The formulation optimization, foaming performance, and core flooding performance of the gelled foam were systematically evaluated under harsh reservoir conditions. The gelled foam formulation was optimized with 0.4% polymer (hydrolyzed polyacrylamide; HPAM), 0.06% cross-linker (phenolic) and 0.2% foaming agent (sulphobetaine; SB). The addition of the gel improved the stability of the foam system by 3.8 times that of traditional foam. A stabilization mechanism in the gelled foam was proposed to describe the stabilization process of the foam film. The uniformly distributed three-dimensional network structure of the gel provided a thick protective layer for the foam system that maintained the stability of the foam and improved the strength and thickness of the liquid film. The gelled foam exhibited good formation adaptability, profile control, and EOR performance. The foam flowed into the high permeability layer, plugged the dominant channel, and increased the swept volume. Oil recovery was enhanced by 29.4% under harsh high -temperature and high salinity conditions

Synchronous Basal Cell Carcinoma and Squamous Cell Carcinoma of Nasal Vestibule With Novel Unique Variants Identified by Whole-exome Sequencing.

Background/aimIt is estimated that nonmelanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), affects more than 3 million Americans each year. Translation of next-generation sequencing (NGS) data into identification of new potential targets for therapeutic applications may be helpful. Whole-exome sequencing (WES) is a widely used NGS method that involves sequencing the protein-coding regions of the genome.Case reportWe report a case of a 65-year-old female smoker who was found to have two 6 mm lesions in her left nasal vestibule. Biopsies demonstrated synchronous BCC and SCC. The patient underwent surgical excision of both cancers with safe margins followed by plastic reconstruction. WES was performed on both cancers and 16 alterations including BRCA2 (p.P389S), FAM5C (S420L), KMT2A (P855L), and SMO (L412F), as unique for BCC, and 4 alterations including TP53 (p.H179Q) and CDKN2A (p.P114L), as unique for SCC, were identified.ConclusionWe report the first documented case with unique genetic alterations in two distinct and synchronous skin BCC and SCC arising from the same nasal vestibule of a patient. This adds to the growing field of data regarding genetic variants in characterizing malignancies and potentially for targeted therapies

TUMOR AND VASCULAR TARGETING OF A NOVEL ONCOLYTIC MEASLES VIRUS RETARGETED AGAINST THE UROKINASE RECEPTOR

Oncolytic measles virus (MV) induces cell fusion and cytotoxicity in a CD46 dependent manner. Development of fully retargeted oncolytic MVs would improve tumor selectivity. The urokinase receptor (uPAR) is a tumor and stromal target overexpressed in multiple malignancies. MV-H glycoproteins fully retargeted to either human or murine uPAR were engineered and their fusogenic activity was determined. Recombinant human (MV-h-uPA) and murine (MV-m-uPA) uPAR retargeted MVs expressing eGFP were rescued and characterized. Viral expression of chimeric MV-H was demonstrated by RT-PCR and Western Blot. In vitro viral replication was comparable to MV-GFP control. Receptor and species specificity of MV-uPAs were demonstrated in human and murine cells with different levels of uPAR expression. Removal of the ATF ligand from MV-uPA -by Factor Xa treatment- ablated MV-uPA’s functional activity. Cytotoxicity was demonstrated in uPAR expressing human and murine cells. MV-h-uPA efficiently infected human endothelial cells and capillary tubes in vitro. Intravenous administration of MV-h-uPA delayed tumor growth and prolonged survival in the MDA-MB-231 breast cancer xenograft model. Viral tumor targeting was confirmed by immunohistochemistry. MV-m-uPA transduced murine mammary tumors (4T1) in vivo, after intratumor administration. MV-m-uPA targeted murine tumor vasculature after systemic administration, as demonstrated by dual (CD31 and MV-N) staining of tumor capillaries in the MDA-MB-231 model. In conclusion, MV-uPA is a novel oncolytic MV associated with potent and specific antitumor effects and tumor vascular targeting. This is the first retargeted oncolytic MV able to replicate in murine cells and target tumor vasculature in an uPAR dependent manner

Synergistic effects of aerobic exercise and transcranial direct current stimulation on executive function and biomarkers in healthy young adults

Objective: This research explored the combined effects of transcranial direct current stimulation (tDCS) and aerobic exercise (AE) on executive function and specific serum biomarkers in healthy adults. Methods: Sixty healthy young adults were randomly assigned into tDCS+AE, tDCS only, or AE only groups. Interventions were carried out for 20 days. Executive functions were evaluated using tasks such as the 2,3-back task, the spatial working memory task, the Stroop test, T test, and hexagonal obstacle jump task. Serum biomarkers, including brain-derived neurotrophic factor (BDNF), malondialdehyde (MDA), superoxide dismutase (SOD), glutamate, glutathione peroxidase 4 (GPX4) and iron ion, were analyzed pre- and post-intervention. Results: The tDCS+AE group showed superior enhancements in executive function, evidenced by improved accuracy rates in 2,3-back tasks, better performance in the staircase task, and reduced reaction times in the incongruent reaction time of the Stroop task compared to other groups. Importantly, we found substantial changes in serum biomarkers: increased levels of BDNF and SOD, and decreased levels of MDA and glutamate in the tDCS+AE group. These changes were significantly different when compared with the tDCS and AE only groups. Notably, these alterations in serum biomarkers were correlated with improvements in executive function tasks, thus offering a potential physiological basis for the cognitive improvements witnessed. Conclusion: The combined tDCS and AE intervention effectively improved executive function in healthy young adults, with the improvements linked to changes in key serum biomarkers. The results emphasize the potential of combined tDCS and AE interventions in engaging multiple physiological pathways to enhance executive function