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ABSTRACT Mannose-capped lipoarabinomannan (ManLAM) is an immunomodulatory epitope of Mycobacterium tuberculosis ( Mtb). An aptamer (ZXL1) that specifically binds to ManLAM from the virulent Mtb H37Rv strain was previously generated and it was found that ZXL1 functions as an antagonist, inhibiting the ManLAM-induced immunosuppression of DCs. In the present study, it was found that ZXL1 inhibits Mtb entry into murine macrophages and that ZXL1 enhances IL-1β and IL-12 mRNA expression and cytokine production in ManLAM-treated macrophages but decreases IL-10 production. Inducible nitric oxide synthase expression in macrophages was upregulated in the presence of ZXL1 after stimulation with ManLAM. ZXL1 was also found to inhibit expression of lipid-sensing nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ). These results suggest that ZXL1 promotes anti-tuberculosis activity through downregulation of PPAR-γ expression, which may contribute to M1 macrophage polarization and Mtb killing by macrophages. [ABSTRACT FROM AUTHOR]

In our investigation of the anti - hyperglycaemic constituents of Eugenia jambolana L. (Jamun), one new triterpenoid, 2- O - cis - p -coumaroyl maslinic acid, along with thirteen known triterpenoids were isolated from the fruit ethyl acetate extract. The structures of compounds 1 – 14 were elucidated on the basis of mass spectrometry and nuclear magnetic resonance analyses. Animal studies demonstrated that the triterpenoid-enriched Jamun fruit extract (TJFE) decreased blood glucose content in C57BL/6 mice (P < 0.05) upon sucrose loading challenge, improved the glucose tolerance in mice administrated with TJFE for 2 weeks via oral gavage (100 mg/kg body weight), and increased Akt phosphorylation levels and Glut4 protein levels in skeletal muscle. Additionally, TJFE administration inhibited hepatic gluconeogenesis through suppressing the gluconeogenic gene expression of Pgc1α, Pepck, and G6Pase. The current study advances scientific knowledge of Jamun constituents and suggests that triterpenoids may play an important role in the anti-diabetic properties attributed to this edible purple berry. [ABSTRACT FROM AUTHOR]

Background: The diagnostic value of circulating microRNAs (miRNAs) detection in prostate cancer (PC) patients is currently under debate. Thus, we performed this meta-analysis of published literature to systematically evaluate the diagnostic potential of circulating miRNAs in PC. Methods: Eligible studies were searched in PubMed, Embase and Chinese National Knowledge Infrastructure databases. Sensitivity and specificity were pooled using a random-effects model and were used to plot the summary receiver operator characteristic (SROC) curve. All analyses were performed using the Stata 13.0 software and Meta-Disc 1.4 for windows. Results: A total of ten articles were included for the meta-analysis according to the inclusion criteria. The pooled results based on all included studies showed circulating miRNAs have a relatively good diagnostic performance, with a sensitivity of 0.74, a specificity of 0.71 and an area under SROC curve (AUC) of 0.77 in indiscriminating PC from controls. Furthermore, meta-regression and subgroup analyses indicate that multiple circulating miRNAs detection displayed a better diagnostic performance than single one, with an AUC rising from 0.75 to 0.81. Additional interesting finding was that Caucasian-based circulating miRNAs assays could reach a higher accuracy compared with non-Caucasian-based one for PC with the p value of 0.0378. Conclusion: Our results confirmed the potential use of circulating miRNAs in the early diagnosis of PC, especially the combination of multiple circulating miRNAs. However, large-scale prospective studies are still needed to further validate our findings. [ABSTRACT FROM AUTHOR]

Simple Summary: No consensus has been reached regarding whether nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) ≤ 2 cm should be resected or observed. In this retrospective international multicenter study, 483 patients who underwent resection for NF-pNETs ≤ 2 cm in 18 institutions from 2000 to 2017 were enrolled and their medical records were reviewed. Tumor size > 1.5 cm, Ki-67 index ≥ 3%, and nodal metastasis were independent adverse prognostic factors for survival after multivariable analysis. NF-pNET patients with tumors ≤ 1.5 cm can be observed if the preoperative Ki-67 index is under 3%, and if nodal metastasis is not suspected in preoperative radiologic studies. These findings support the clinical use to make decisions about small NF-pNETs. Several treatment guidelines for sporadic, nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) have recommended resection, however, tumors ≤ 2 cm do not necessarily need surgery. This study aims to establish a surgical treatment plan for NF-pNETs ≤ 2 cm. From 2000 to 2017, 483 patients who underwent resection for NF-pNETs ≤ 2 cm in 18 institutions from Korea and China were enrolled and their medical records were reviewed. The median age was 56 (range 16–80) years. The 10-year overall survival rate (10Y-OS) and recurrence-free survival rate (10Y-RFS) were 89.8 and 93.1%, respectively. In multivariable analysis, tumor size (>1.5 cm; HR 4.28, 95% CI 1.80–10.18, p = 0.001) and nodal metastasis (HR 3.32, 95% CI 1.29–8.50, p = 0.013) were independent adverse prognostic factors for OS. Perineural invasion (HR 4.36, 95% CI 1.48–12.87, p = 0.008) and high Ki-67 index (≥3%; HR 9.06, 95% CI 3.01–27.30, p < 0.001) were independent prognostic factors for poor RFS. NF-pNETs ≤ 2 cm showed unfavorable prognosis after resection when the tumor was larger than 1.5 cm, Ki-67 index ≥ 3%, or nodal metastasis was present. NF-pNET patients with tumors ≤ 1.5 cm can be observed if the preoperative Ki-67 index is under 3%, and if nodal metastasis is not suspected in preoperative radiologic studies. These findings support the clinical use to make decisions about small NF-pNETs. [ABSTRACT FROM AUTHOR]

Neurogenic lower urinary tract dysfunction (NLUTD) is a frequent consequence of spinal cord injury (SCI), leading to symptoms that significantly impact quality of life. Although many life-saving techniques are available, current treatment strategies for managing NLUTD still exhibit limitations and drawbacks. Here, we introduce a new electrical neuromodulation strategy involving electrical stimulation of the major pelvic ganglion (MPG) to initiate bladder contraction, in conjunction with innovative programmable (IPG) electrical stimulation on the pudendal nerve (PN) to induce external urethral sphincter (EUS) relaxation in freely moving or anesthetized SCI mice. Furthermore, we conducted the void spot assay, and cystometry coupled with EUS electromyography (EMG) recordings to evaluate voiding function, and monitor bladder pressure and EUS activity. Our findings demonstrate that our novel electrical neuromodulation approach effectively triggers coordinated bladder muscle contraction and EUS relaxation, effectively counteracting SCI-induced NLUTD. Additionally, this electrical neuromodulation method enhances voiding efficiency, closely resembling natural reflexive urination in SCI mice. Thus, our study offers a promising electrical neurostimulation approach aimed at restoring physiological coordination and potentially offering personalized treatment for improving voiding efficiency in individuals with SCI-associated NLUTD. [ABSTRACT FROM AUTHOR]

For telecom operators, it is of great significance to employ artificial intelligence (AI) and big data technology in a software-defined network (SDN) in order to achieve intelligent network control, traffic management and optimization. This paper proposes a solution for intelligent work control and traffic optimization. This paper is mainly focused on SDN-based network traffic algorithm optimization and experimental verification. In this paper, we design a network control mechanism for network intelligent control as well as solutions for traffic optimization based on SDN and artificial intelligence. We analyze operators' network requirements (e.g., the carrying of the 5th generation mobile network (5G) service, multi-protocol label switching virtual private networks optimization, cloudification of services and the IP backbone network). Then, we propose an intelligent network control architecture based on SDN and artificial intelligence. The proposed architecture consists of three modules, including a network status collection/perception module, an AI intelligent analysis module and an SDN controller module. Moreover, this paper also analyzes the objects of traffic optimization as well as routing calculation algorithms (e.g., the greedy algorithm, the top-k-shortest paths (KSP) algorithm) and routing optimization algorithms (e.g., particle swarm optimization, simulated annealing and genetic algorithms). In addition, we also put forward three optimization algorithms for the operator's network, namely, network congestion control and prevention algorithms, resource preemption algorithms and balance of the entire network traffic algorithms. Then, we propose optimization algorithms for the above three objectives of operator network optimization, respectively. Finally, we conduct large-scale experiments to verify the effectiveness of the control mechanism and algorithms. The experimental results demonstrate that the use of SDN and artificial intelligence in operator networks can realize network intelligent control and traffic optimization more intelligently. [ABSTRACT FROM AUTHOR]

The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA. [ABSTRACT FROM AUTHOR]

Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC. [ABSTRACT FROM AUTHOR]