Exploring novel indazole derivatives as ASK1 inhibitors: Design, synthesis, biological evaluation and docking studies.

Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c, which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH.

Discovery of a quinoline-containing compound JT21-25 as a potent and selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1).

ASK1 kinase inhibition has become a promising strategy for treating inflammatory diseases, such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we reported the discovery of a promising compound 9h (JT21-25) containing quinoline structures as a potent small molecule inhibitor of ASK1. The compound JT21-25 was selective against MAP3K kinases TAK1 (>1960.8-fold), and much higher than the selectivity of GS-4997 for TAK1 (312.3-fold). In addition, different concentrations of JT21-25 did not show significant toxicity in normal LO2 liver cells, and the cell survival rate was greater than 80 %. The Oil Red O staining experiment showed that at the 4 µM and 8 µM concentrations of JT21-25, only slight cytoplasmic fat droplets were observed in LO2 cells, and there was no significant fusion between fat droplets. In the biochemical analysis experiment, JT21-25 significantly reduced the content of CHOL, LDL, TG, ALT, and AST. In summary, these findings suggested that compound JT21-25 might be valuable for further investigation as a potential candidate in the treatment of associated diseases.

Pericyte Control of Gene Expression in the Blood-Brain Barrier Endothelium: Implications for Alzheimer's Disease.

Background: A strong body of evidence suggests that cerebrovascular pathologies augment the onset and progression of Alzheimer's disease (AD). One distinctive aspect of this cerebrovascular dysfunction is the degeneration of brain pericytes-often overlooked supporting cells of blood-brain barrier endothelium. Objective: The current study investigates the influence of pericytes on gene and protein expressions in the blood-brain barrier endothelium, which is expected to facilitate the identification of pathophysiological pathways that are triggered by pericyte loss and lead to blood-brain barrier dysfunction in AD. Methods: Bioinformatics analysis was conducted on the RNA-Seq expression counts matrix (GSE144474), which compared solo-cultured human blood-brain barrier endothelial cells against endothelial cells co-cultured with human brain pericytes in a non-contact model. We constructed a similar cell culture model to verify protein expression using western blots. Results: The insulin resistance and ferroptosis pathways were found to be enriched. Western blots of the insulin receptor and heme oxygenase expressions were consistent with those observed in RNA-Seq data. Additionally, we observed more than 5-fold upregulation of several genes associated with neuroprotection, including insulin-like growth factor 2 and brain-derived neurotrophic factor. Conclusions: Results suggest that pericyte influence on blood-brain barrier endothelial gene expression confers protection from insulin resistance, iron accumulation, oxidative stress, and amyloid deposition. Since these are conditions associated with AD pathophysiology, they imply mechanisms by which pericyte degeneration could contribute to disease progression.

Perforating cutaneous vessels: A key feature of acupoints - Anatomical evidence from five-Shu acupoints in the upper limbs.

Acupuncture has been proven an effective clinical treatment for numerous pathological conditions and malfunctions. However, substantial anatomical evidence for acupuncture points (APs) and meridians is still lacking, so the location of APs is relatively subjective and understanding of the biological mechanisms of acupuncture is limited. All these problems hinder the clinical applications and worldwide acceptance of acupuncture. Our long-term microsurgery experience has indicated that Perforating Cutaneous Vessels (PCVs) are highly relevant to APs but the anatomical evidence is insufficient. To address this lack, two specimens of fresh adult human upper limbs were dissected using an advanced vascular perfusion-fixation method and then examined. The results show that all 30 five-Shu APs in the upper limbs have corresponding PCVs. Both specimens showed a 100% coincidence rate between APs and PCVs, indicating that PCVs could be critical anatomical features of APs. This study also provides an anatomical basis for locating APs objectively via preliminary detection of PCVs. The findings could lead to a better theoretical understanding of mechanisms of acupuncture and the essence of meridians.

Small-molecule inhibitors targeting apoptosis signal-regulated kinase 1.

Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase kinase kinase (MAP3K) family. Since its first isolation from a human macrophage library in 1996, its research has been ongoing for over 25 years. A large number of reports have revealed that ASK1, as a key activator of the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) signaling cascade, responds to various stressors, and its inhibitors have important potential value in the treatment of diseases such as inflammation, cancer, and the nervous system and so on. This review summarizes the recent development in this field, including the structure and signaling pathways of ASK1, with a particular focus on the structure-activity relationships, and the hit-to-lead optimization strategies.

Amyloid-Beta Peptides 40 and 42 Employ Distinct Molecular Pathways for Cell Entry and Intracellular Transit at the Blood-Brain Barrier Endothelium.

The blood-brain barrier (BBB) plays a critical role in maintaining the equilibrium between amyloid beta (Aß) levels in blood and the brain by regulating Aß transport. Our previous publications demonstrated that BBB trafficking of Aß42 and Aß40 is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle Aß40 and Aß42 have not been clearly elucidated. In this study, we identified mechanisms of Aß endocytosis in polarized human cerebral microvascular endothelial cell monolayers. Our studies demonstrated that Aß peptides with fluorescent label (F-Aß) were internalized by BBB endothelial cells via energy, dynamin, and actin-dependent endocytosis. Interestingly, endocytosis of F-Aß40 but not F-Aß42 was substantially reduced by clathrin inhibition, whereas F-Aß42 but not F-Aß40 endocytosis was reduced by half after inhibiting the caveolae-mediated pathway. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. Although Aß42 was shown to accumulate more in the lysosomes, which could lead to its higher degradation and/or aggregation at lower lysosomal pH, Aß40 demonstrated robust accumulation in recycling endosomes, which may facilitate its exocytosis by the endothelial cells. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport Aß40 versus Aß42. This knowledge contributes to the understanding of molecular pathways underlying Aß accumulation in the BBB endothelium and associated BBB dysfunction. Moreover, it allows us to establish mechanistic rationale for altered Aß40:Aß42 ratios and anomalous amyloid deposition in the cerebral vasculature as well as brain parenchyma during Alzheimer's disease progression. SIGNIFICANCE STATEMENT: Differential interaction of Aß40 and Aß42 isoforms with the blood-brain barrier (BBB) endothelium may contribute to perturbation in Aß42:Aß40 ratio, which is associated with Alzheimer's disease (AD) progression and severity. The current study identified distinct molecular pathways by which Aß40 and Aß42 are trafficked at the BBB, which regulates equilibrium between blood and brain Aß levels. These findings provide molecular insights into mechanisms that engender BBB dysfunction and promote Aß accumulation in AD brain.

Deconvolution of Plasma Pharmacokinetics from Dynamic Heart Imaging Data Obtained by Single Positron Emission Computed Tomography/Computed Tomography Imaging.

Plasma pharmacokinetic (PK) data are required as an input function for graphical analysis of single positron emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/CT (PET/CT) data to evaluate tissue influx rate of radiotracers. Dynamic heart imaging data are often used as a surrogate of plasma PK. However, accumulation of radiolabel in the heart tissue may cause overprediction of plasma PK. Therefore, we developed a compartmental model, which involves forcing functions to describe intact and degraded radiolabeled proteins in plasma and their accumulation in heart tissue, to deconvolve plasma PK of 125I-amyloid beta 40 (125I-Aß 40) and 125I-insulin from their dynamic heart imaging data. The three-compartment model was shown to adequately describe the plasma concentration-time profile of intact/degraded proteins and the heart radioactivity time data obtained from SPECT/CT imaging for both tracers. The model was successfully applied to deconvolve the plasma PK of both tracers from their naïve datasets of dynamic heart imaging. In agreement with our previous observations made by conventional serial plasma sampling, the deconvolved plasma PK of 125I-Aß 40 and 125I-insulin in young mice exhibited lower area under the curve than aged mice. Further, Patlak plot parameters extracted using deconvolved plasma PK as input function successfully recapitulated age-dependent plasma-to-brain influx kinetics changes. Therefore, the compartment model developed in this study provides a novel approach to deconvolve plasma PK of radiotracers from their noninvasive dynamic heart imaging. This method facilitates the application of preclinical SPECT/PET imaging data to characterize distribution kinetics of tracers where simultaneous plasma sampling is not feasible. SIGNIFICANCE STATEMENT: Knowledge of plasma pharmacokinetics (PK) of a radiotracer is necessary to accurately estimate its plasma-to-brain influx. However, simultaneous plasma sampling during dynamic imaging procedures is not always feasible. In the current study, we developed approaches to deconvolve plasma PK from dynamic heart imaging data of two model radiotracers, 125I-amyloid beta 40 (125I-Aß 40) and 125I-insulin. This novel method is expected to minimize the need for conducting additional plasma PK studies and allow for accurate estimation of the brain influx rate.

Soluble ST2 predicts continuous renal replacement therapy in patients receiving venoarterial extracorporeal membrane oxygenation.

OBJECTIVE: This study aimed to evaluate the relationship between plasma soluble ST2 (sST2) levels 24 h after extracorporeal membrane oxygenation (ECMO) initiation and continuous renal replacement therapy (CRRT) in patients receiving venoarterial ECMO (V-A ECMO) support. METHODS AND RESULTS: Data of patients who received ECMO support for postcardiotomy cardiogenic shock between January 2017 and July 2019 were retrospectively collected from Beijing Anzhen Hospital, Capital Medical University. Ultimately, 116 patients were included in the present study for analysis. The concentration of sST2 was determined by enzyme-linked immunosorbent assay (ELISA). The log10 sST2 levels were higher in patients undergoing CRRT than those who did not (6.06 vs. 6.22, p = 0.019). Patients undergoing CRRT had a lower survival rate than those who did not (32.8% vs. 67.3%, p < 0.001). In the univariate logistic regression analysis, sST2, HCO3-, lactate, and creatinine levels 24 h after ECMO initiation were related to CRRT (p < 0.05). In the multivariate logistic regression analysis, HCO3- and sST2 were identified as independent risk factors for CRRT use in patients undergoing ECMO (p < 0.05). The area under receiver operator characteristic curve (AUC) for sST2 and HCO3- together was 0.72 (95% confidence interval (CI), 0.79-0.91), which was better than those of sST2 or HCO3- alone (0.63 vs. 0.67). CONCLUSIONS: sST2 and HCO3-levels at 24 h after ECMO initiation were associated with CRRT and could predict CRRT use in postcardiotomy cardiogenic shock patients undergoing ECMO.

The role of ultrasonography in diagnosis of neuralgic amyotrophy.

OBJECTIVE: To investigate the value of high frequency ultrasound in diagnosis of neuralgic amyotrophy. MATERIALS AND METHODS: From January 2010 to December 2020, the ultrasonographic images of 117 patients with neuralgic amyotrophy diagnosed by the Department of Neurology and hand & foot surgery of Shandong Provincial Hospital Affiliated to Shandong First Medical University were retrospectively analyzed. The ultrasonographic features were summarized. RESULTS: High frequency ultrasound could clearly show the degree of the affected nerves: No ultrasonic findings were found in 12 cases (10%). The affected nerves were thickening and hypoechogenicity with loss of normal fascicular definition in 28 cases (24%). The affected nerves showed hourglass-like changes, including constriction and torsion in 77 cases (66%). In addition, ultrasound can determine the extent of the lesion, and microvascular imaging can display small blood flow signal within the nerve. There was a significant statistical difference between the diameter of the thickened nerve fascicle and the diameter of the nerve fascicle at the corresponding site of the contralateral normal limb. CONCLUSIONS: High frequency ultrasound is a valuable imaging method for diagnosis of neuralgic amyotrophy.

Phenotypic and functional alterations of monocyte subsets with aging.

BACKGROUND: It has been widely accepted that monocytes are one of the central mediators contributing to inflammaging. However, it remains unclear whether aged monocytes, similar to aged T cells, have characteristics of hyperactivation and increased expression of co-inhibitory molecules. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from young (21-40 years old), middle-aged (41-60 years old), and older human subjects (> 60 years old). Flow cytometry was used to monitor changes in the expression of surface molecules of monocyte subsets and cytokine-producing capacity. RESULTS: We observed increased tumor necrosis factor-α: TNF-α and decreased interleukin-6 (IL-6) production in monocytes from older adults compared with young and middle-aged adults. Older adults had a greater percentage of intermediate and non-classical monocyte subsets, along with increased levels of the immune activation markers human leukocyte antigen-DR (HLA-DR), and adhesion molecules cluster of differentiation molecule 11b (CD11b) and L-selectin (CD62L). Furthermore, we observed increased C-C motif chemokine receptor 2 (CCR2) expression on classical monocytes and decreased C-X3-C motif chemokine receptor 1 (CX3CR1) expression on non-classical monocytes in older adult subjects. The expression of co-inhibitory receptors was reduced on monocyte subsets in older adults. CONCLUSIONS: Circulating monocytes in older adults exhibit increased expression of activation, adhesion, and migration markers, but decreased expression of co-inhibitory molecules.

Mapping the dynamics of insulin-responsive pathways in the blood-brain barrier endothelium using time-series transcriptomics data.

Critical functions of the blood-brain barrier (BBB), including cerebral blood flow, energy metabolism, and immunomodulation, are regulated by insulin signaling pathways. Therefore, endothelial insulin resistance could lead to BBB dysfunction, which is associated with neurodegenerative diseases such as Alzheimer's disease (AD). The current study aims to map the dynamics of insulin-responsive pathways in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. RNA-Sequencing was performed on hCMEC/D3 monolayers with and without insulin treatment at various time points. The Short Time-series Expression Miner (STEM) method was used to identify gene clusters with distinct and representative expression patterns. Functional annotation and pathway analysis of genes from selected clusters were conducted using Webgestalt and Ingenuity Pathway Analysis (IPA) software. Quantitative expression differences of 16,570 genes between insulin-treated and control monolayers were determined at five-time points. The STEM software identified 12 significant clusters with 6880 genes that displayed distinct temporal patterns upon insulin exposure, and the clusters were further divided into three groups. Gene ontology (GO) enrichment analysis demonstrated that biological processes protecting BBB functions such as regulation of vascular development and actin cytoskeleton reorganization were upregulated after insulin treatment (Group 1 and 2). In contrast, GO pathways related to inflammation, such as response to interferon-gamma, were downregulated (Group 3). The IPA analyses further identified insulin-responsive cellular and molecular pathways that are associated with AD pathology. These findings unravel the dynamics of insulin action on the BBB endothelium and inform about downstream signaling cascades that are potentially disrupted due to brain insulin resistance prevalent in AD.

Design, Synthesis and In Vivo Fluorescence Imaging Study of a Cytochrome P450 1B1 Targeted NIR Probe Containing a Chelator Moiety.

Cytochrome P450 (CYP) 1B1 has been found to be overexpressed specifically in tumor tissues at an early stage, which makes it a potential cancer biomarker for molecular imaging. Multimodal imaging combines different imaging modalities and offers more comprehensive information. Thus, imaging probes bearing more than one kind of signal fragment have been extensively explored and display great promise. Herein, we developed a near infrared (NIR) probe with a chelator moiety targeting CYP1B1 by conjugating α-naphthoflavone (ANF) derivatives with both an NIR dye and a chelator for potential application in bimodal imaging. Enzymatic inhibitory studies demonstrated inhibitory activity against CYP1B1 and selectivity among CYP1 were successfully retained after chemical modification. Cell-based saturation studies indicated nanomolar range binding affinity between the probe and CYP1B1 overexpressed cancer cells. In vitro competitive binding assays monitored by confocal microscopy revealed that the probe could specifically accumulate in tumor cells. In vivo and ex vivo imaging studies demonstrated that the probe could effectively light-up the tumor tissues as early as 2 hours post-injection. In addition, the fluorescence was significantly blocked by co-injection of CYP1B1 inhibitor, which indicated the probe accumulation in tumor sites was due to specific binding to CYP1B1.

Design, Synthesis, and Preliminary Evaluation of [68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer's Disease Mouse Model.

Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer's disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [68Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [68Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [68Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [68Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [68Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [68Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [68Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [18F]AV1451 and [11C]PIB to noninvasively study the role of insulin in AD pathophysiology.

Full color 3D printing of anatomical models.

We propose an effective method for manufacturing human anatomical specimens in response to the shortage of cadaver specimens and the poor simulation results of anatomical specimen substitutes. Digital human data with high precision were used to create digital models and corresponding mapped textures. Different materials were chosen to print the digital models with full-color and multimaterial 3D-printing technology based on the histological characteristics of the anatomical structures. Anatomy experts and surgeons were then invited to compare the 3D printed models with authentic anatomical specimens in terms of morphological appearance, anatomical detail, and textural properties. The skull, brain, hand muscles, blood vessels and nerves of the hand, and the deep structure of the head and face were printed. The skull model used hard material, and the brain and hand muscles models used flexible and hard materials combined. The blood vessels, nerves of the hand, and the superficial and deep structure of the head and face used transparent materials, revealing the small vessels and nerves in the interior. In all the models, there were no significant differences from anatomical specimens in morphological appearance and anatomical detail. They also affected vision and touch in the same way as authentic specimens in the textural properties of color, roughness, smoothness, and fineness. Full-color and multi-material 3D printed anatomical models have the same visual and tactile properties as anatomical specimens and could serve to complement or supplement them in anatomy teaching to compensate for the shortage of cadavers.

Design, Synthesis, and Evaluation of Novel Benzo[d]isoxazole Derivatives as Anticonvulsants by Selectively Blocking the Voltage-Gated Sodium Channel NaV1.1.

Sodium channel blockers are important antiseizure drugs. Since the launch of phenobarbital in 1912, it has a development history of nearly 100 years. However, because of the confounding symptoms, complications, and complex intrinsic pathogenesis of epilepsy, the design and development of blockers specifically targeting sodium channels as antiseizure drugs are difficult and rarely reported. In this study, we designed and synthesized a series of novel benzo[d]isoxazole derivatives as anticonvulsants. Among them, the most potent Z-6b displayed high protection against the MES-induced seizures with an ED50 value of 20.5 mg/kg and a high protective index (TD50/ED50) of 10.3. In addition, Z-6b significantly inhibited NaV1.1 channels in patch-clamp experiments but almost did not inhibit NaV1.2, NaV1.3, and NaV1.6 channels. These findings strongly support the hypothesis that new benzo[d]isoxazole derivatives display anticonvulsant activity by selectively blocking voltage-gated sodium channel NaV1.1, which provides good alternatives for developing selective NaV1.1 channel blockers as antiseizure drugs in the future.

Protective effects of 5(S)-5-carboxystrictosidine on myocardial ischemia-reperfusion injury through activation of mitochondrial KATP channels.

5(S)-5-carboxystrictosidine (5-CS) is a compound found in Mappianthus iodoides Hand.-Mazz., root, a traditional Chinese medicine used for the treatment of coronary artery disease. In this study, we investigated whether 5-CS protects heart against I/R injury. Sprague-Dawley rats were treated with 5-CS intraperitoneally for 7 days before the experiment. Hearts were perfused for 20 min global ischemia and 180 min reperfusion. 5-CS significantly inhibited an increase in the post-ischemic left ventricular end-diastolic pressure (LVEDP) and improved the post-ischemic left ventricular developed pressure (LVDP), dP/dt maximum and dP/dt minimum rates of pressure change, and coronary flow as compared with sham group. Pretreatment with 5-hydroxydecanoic acid (5-HD), an inhibitor of mitochondrial KATP channel, for 10 min before ischemia attenuated the improvement of LVEDP, LVDP, dP/dt maximum and dP/dt minimum rates of pressure change, and coronary flow induced by 5-CS. 5-CS markedly decreased the infarct size and attenuated the increased lactate dehydrogenase (LDH) level in effluent during reperfusion. Pretreatment with 5-HD also blocked these protective effects of 5-CS. 5-CS increased Mn-SOD, catalase, and HO-1 levels decreased by I/R injury and pretreatment of 5-HD blocked the 5-CS effects. Increases in Bax, cleaved caspase-3 and cytochrome c levels, caspase-3 and caspase-9 activity, and decrease in Bcl-2 level by I/R injury were attenuated by 5-CS treatment and pretreatment of 5-HD blocked its effects. These results suggest that the protective effects of 5-CS against myocardial I/R injury may be partly related to activating antioxidant enzymes and suppressing apoptosis through opening mitochondrial KATP channels.

Design, Synthesis and Binding Affinity Evaluation of Cytochrome P450 1B1 Targeted Chelators.

BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is specifically expressed in a variety of tumors which makes it a promising imaging target of tumor. OBJECTIVE: We aimed to design and synthesize CYP1B1 targeted chelators for the potential application in positron emission tomography (PET) imaging of tumor. METHODS: 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA) was connected to the CYP1B1 selective inhibitor we developed before through polyethylene glycol (PEG) linkers with different lengths. The inhibitory activities of chelators 6a-c against CYP1 family were evaluated by 7-ethoxyresorufin o-deethylation (EROD) assay. The manual docking between the chelators and the CYP1B1 was conducted subsequently. To determine the binding affinities of 6a-c to CYP1B1 in cells, we further performed a competition study at the cellular level. RESULTS: Among three chelators, 6a with the shortest linker showed the best inhibitory activity against CYP1B1. In the following molecular simulation study, protein-inhibitor complex of 6a showed the nearest F-heme distance which is consistent with the results of enzymatic assay. Finally, the cell based competitive assay proved the binding affinity of 6a-c to CYP1B1 enzyme. CONCLUSION: We designed and synthesized a series of chelators which can bind to CYP1B1 enzyme in cancer cells.To our knowledge, this work is the first attempt to construct CYP1B1 targeted chelators for radiolabeling and we hope it will prompt the application of CYP1B1 imaging in tumor detection.

The role of ultrasonography in diagnosing hourglass-like fascicular constriction(s) of the anterior interosseous nerve.

BACKGROUND: In the past, the diagnosis of hourglass-like fascicular constriction(s) of the anterior interosseous nerve mostly depended on electrophysiological examination, by which the location could not be diagnosed. There are few studies on the evaluation of hourglass-like fascicular constriction(s) by ultrasonography. PURPOSE: To evaluate the role of ultrasonography in the diagnosis of hourglass-like fascicular constriction(s) of the anterior interosseous nerve. MATERIAL AND METHODS: A retrospective analysis of 12 patients with hourglass-like fascicular constriction(s) of the anterior interosseous nerve was carried out, and the characteristics of the high-frequency ultrasonographic images were summarized and compared with surgical exploration. RESULTS: The 12 cases of hourglass-like fascicular constriction(s) of the anterior interosseous nerve were all located in the median nerve of the distal upper arm, including nine cases of single hourglass-like fascicular constriction and three cases of multiple hourglass-like fascicular constrictions. High-frequency ultrasonography can accurately locate the hourglass-like fascicular constriction(s) of the anterior interosseous nerve and the extent of neuropathy. The ultrasonographic images of hourglass-like fascicular constriction(s) of the anterior interosseous nerve showed single or multiple hourglass-like change(s) in the median nerve of the distal upper arm. The nerve fascicles on both sides of the affected nerve with hourglass-like change thickened. CONCLUSIONS: High-frequency ultrasonography could be a reliable, convenient, and non-invasive diagnostic imaging method for hourglass-like fascicular constriction(s) of the anterior interosseous nerve.

A four-lncRNA risk signature for prognostic prediction of osteosarcoma.

Aim: Osteosarcoma is the most common primary malignant tumor of bone. However, our understanding of the prognostic indicators and the genetic mechanisms of the disease progression are still incomplete. The aim of this study was to identify a long noncoding RNA (lncRNA) risk signature for osteosarcoma survival prediction. Methods: RNA sequencing data and relevant clinical information of osteosarcoma patients were downloaded from the database of Therapeutically Applicable Research to Generate Effective Treatments (TARGET). We analyzed the differentially expressed lncRNAs between deceased and living patients by univariate and multivariate Cox regression analysis to identify a risk signature. We calculated a prognostic risk score for each sample according to this prognosis signature, and divided patients into high-risk and low-risk groups according to the median value of the risk score (0.975). Kaplan-Meier analysis and receiver operating characteristic (ROC) curve statistics were used to evaluate the performance of the signature. Next, we analyzed the signature's potential function through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene-set enrichment analysis (GSEA). Lastly, qRT-PCR was used to validate the expression levels of the four lncRNAs in clinical samples. Results: Twenty-six differentially expressed lncRNAs were identified between deceased and living patients. Four of these lncRNAs (CTB-4E7.1, RP11-553A10.1, RP11-24N18.1, and PVRL3-AS1) were identified as independent prognostic factors, and a risk signature of these four lncRNAs for osteosarcoma survival prediction was constructed. Kaplan-Meier analysis showed that the five-year survival time in high-risk and low-risk groups was 33.1% and 82.5%, and the area under the curve (AUC) of the ROC was 0.784, which demonstrated that the prognostic signature was reliable and had the potential to predict the survival of patients with osteosarcoma. The expression level of the four lncRNAs in osteosarcoma tissues and cells was determined by qRT-PCR. Functional enrichment analysis suggested that the signature might be related to osteosarcoma through regulation of the MAPK signaling pathway, the PI3K-Akt signaling pathway, and the extracellular matrix and also provided new insights into the study of osteosarcoma, including the role of papillomavirus infection, olfactory receptor activity, and olfactory transduction in osteosarcoma. Conclusion: We constructed a novel lncRNA risk signature that served as an independent biomarker for predicting the prognosis of osteosarcoma patients.