Novel Association of RAD54L Mutation with Müllerian Clear Cell Carcinoma of the Male Urethra: New Insights Regarding the Molecular Mechanisms of a Rare Tumour.

INTRODUCTION: Müllerian clear cell carcinoma of the male urethra is similar to that of the female genital tract in terms of morphology and immunohistochemical expression but is rarely observed in clinical practice. CASE PRESENTATION: Here, we report the case of a 65-year-old man diagnosed with Müllerian clear cell carcinoma who harboured a mutation in RAD54L. This patient was diagnosed by electrocautery and ultimately underwent prostatectomy. After a six-month follow-up period, no signs of recurrence or additional malignancy were found. Based on our analysis of the available literature, it appears that Müllerian clear cell carcinoma with RAD54L mutation has not been reported until now. CONCLUSION: This case enhances our knowledge of the molecular biology of Müllerian clear cell carcinoma of the male urethra, which will help clinicians select optimal treatment options for this rare cancer in patients with specific driver mutations.

Circular RNA Dipeptidyl Peptidase 4 (circDPP4) Stimulates the Expression of Glutamate Dehydrogenase 1 to Contribute to the Malignant Phenotypes of Prostate Cancer by Sponging miR-497-5p.

Circular RNA dipeptidyl peptidase 4 (circDPP4) has been confirmed as a novel oncogene in prostate cancer (PCa). In this study, we aimed to explore the underlying mechanism of circDPP4 in PCa progression. Levels of circDPP4, microRNA (miR)-497-5p, glutamate dehydrogenase 1 (GLUD1), proliferating cell nuclear antigen (PCNA), BCL2 associated X, apoptosis regulator (Bax), E-cadherin and Ki67 were gauged by a quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, or immunohistochemical method. We assessed the roles of variables in PCa cell phenotypes by measuring cell growth, apoptosis, motility and invasiveness. We performed RNA immunoprecipitation (RIP) and dual-luciferase reporter assays to confirm the interactions of circDPP4/miR-497-5p and miR-497-5p/GLUD1. A xenograft model was established to gauge the effect of circDPP4 in the tumorigenicity of PCa cells. PCa tumor tissues and cell lines revealed higher levels of circDPP4 and GLUD1 and a lower expression of miR-497-5p than controls. CircDPP4 silencing hindered the growth, motility and invasiveness of PCa cells. Conversely, silencing circDPP4 enhanced PCa cell apoptosis. Mechanistic analysis showed that circDPP4 functioned as a miR-497-5p sponge to reduce the suppressive action of miR-497-5p on GLUD1, which was validated as a direct miR-497-5p target. Furthermore, circDPP4 knockdown weakened the tumorigenicity of PCa cells. CircDPP4 facilitated PCa process by mediating the miR-497-5p/GLUD1 axis, providing a possible therapy target for PCa.

CircSCNN1A is a tumor suppressor in renal cell carcinoma via inducing the upregulation of MPP7 by the sponge effect on miR-421.

BACKGROUND: Circular RNAs (circRNAs) function as oncogenic factors or tumor repressors in variety of human malignancies. CircRNA Sodium Channel Epithelial 1 Subunit Alpha (circSCNN1A, hsa_circ_0025135) was downregulated in renal cell carcinoma (RCC). This study performed further research of circSCNN1A in RCC. METHODS: The level detection for circSCNN1A, microRNA-421 (miR-421) or Membrane Palmitoylated Protein 7 (MPP7) was conducted by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell behaviors were analyzed by Cell counting kit-8 (CCK-8) assay for cell viability, EDU assay for cell proliferation, flow cytometry for cell apoptosis, transwell assay for cell invasion and tube formation assay for angiogenesis. The protein expression was determined using western blot. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and pull-down assay were applied to validate the interaction between targets. In vivo research was performed by xenograft tumor assay. RESULTS: The level of circSCNN1A was significantly downregulated in RCC tissues and cells. RCC cell proliferation, invasion and angiogenesis were reduced but apoptosis was promoted by circSCNN1A overexpression. Interestingly, circSCNN1A could interact with miR-421. Overexpression of miR-421 has reversed the anti-tumor function of circSCNN1A in RCC cells. MPP7 served as a target of miR-421, and MPP7 inhibited the malignant phenotypes of RCC cells. In addition, miR-421 downregulation induced the inhibitory effect on the RCC development via elevating the MPP7 level. Moreover, RCC tumorigenesis was suppressed by circSCNN1A through the miR-421/MPP7 axis in vivo. CONCLUSION: The experimental data revealed that circSCNN1A upregulated the expression of MPP7 via sponging miR-421, then inhibiting the progression of RCC.

Identification of Prostate Cancer Risk Genetics Biomarkers Based on Intergraded Bioinformatics Analysis.

Background: Prostate cancer (PCa) is one of the most popular cancer types in men. Nevertheless, the pathogenic mechanisms of PCa are poorly understood. Hence, we aimed to identify the potential genetic biomarker of PCa in the present study. Methods: High-throughput data set GSE46602 was obtained from the comprehensive gene expression database (GEO) for screening differentially expressed genes (DEGs). The common DEGs were further screened out using The Cancer Genome Atlas (TCGA) dataset. Functional enrichment analysis includes Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to study related mechanisms. The Cox and Lasso regression analyses were carried out to compress the target genes and construct the high-risk and low-risk gene model. Survival analyses were performed based on the gene risk signature model. The CIBERSORT algorithm was performed to clarify the correlation of the high- and low-risk gene model in risk and infiltration of immune cells in PCa. Results: A total of 385 common DEGs were obtained. The results of functional enrichment analysis show that common DEGs play an important role in PCa. A three-gene signature model (KCNK3, AK5, and ARHGEF38) was established, and the model was significantly associated with cancer-related pathways, overall survival (OS), and tumor microenvironment (TME)-related immune cells in PCa. Conclusion: This new risk model may contribute to further investigation in the immune-related pathogenesis in progression of PCa.

Clinical characteristics of 2,459 severe or critically ill COVID-19 patients: A meta-analysis.

ABSTRACT: Our study aims to summarize the clinical characteristics of patients with severe or critically ill coronavirus disease 2019 (COVID-19).Five databases were electronically searched to collect studies describing clinical characteristics of severe or critically ill COVID-19 patients and published between January 1, 2020 and April 12, 2020. Three reviewers independently collected the literature, extracted the required data, and assessed the risk of publication bias of the included studies before including the studies in the meta-analysis.A total of 40 studies involving 2459 patients with severe or critically ill COVID-19 patients were included. Meta-analysis showed that a greater proportion of severe or critically COVID-19 patients were male (62.3%), and the 2 main clinical symptoms were fever (87.4%) and cough (66.3%). Other common clinical symptoms included dyspnea (45.3%), chest tightness (37.4%), fatigue (36.6%), and expectoration (31.9%). Minor symptoms included myalgia (19.5%), dizziness (11.5%), headache (11.4%), diarrhea (11.2%), pharyngalgia (11.0%), nausea, and vomiting (5.9%). Most patients showed elevated levels of C-reactive protein (83.5%) and D-dimer (73.3%), lymphopenia (70.3%), and normal leukocyte counts (56.9%). Other findings included abnormal levels of liver function (39.8%), elevated procalcitonin (36.6%), leukocytosis (21.7%), thrombocytopenia (19.0%), and leucopenia (18.2%). Most patients showed acute respiratory distress syndrome (60.8%). Other complications included acute cardiac injury (37.1%), shock (32.0%), and acute kidney injury (22.0%).The most common symptoms of severe or critically ill COVID-19 patients were fever and cough. Most patients showed lymphopenia, elevated levels of C-reactive protein and D-dimer. A large percentage of patients progress to ARDS, acute cardiac injury, acute kidney injury and shock were also common.

Down-regulation of Aquaporin1 (AQP1) by peptidoglycan via p38 MAPK pathways in primary rat pleural mesothelial cells.

BACKGROUND AND OBJECTIVE: This study was designed to investigate the p38 mitogen-activated protein kinase (MAPK) signaling pathway involved in Aquaporin1 (AQP1) expression caused by staphylococcal peptidoglycan (PGN) in cultured rat pleural mesothelial cells (rPMCs) in vitro. METHODS: RT-PCR and immunoblot analysis were used to determine the relative mRNA and protein levels of AQP1 by PGN in rPMCs. P38 kinase inhibitor SB203580, JNK inhibitor SP600125, and ERK1/2 inhibitor PD98059 were used to determine the effects of PGN-induced AQP1 expression by immunoblot. Activation of p38 by PGN was reflected by detecting the phosphorylation constituent of p38, using immunoblot. The shift of localization after activation of p38 by PGN was investigated by immunofluorescence assay. RESULTS: AQP1 transcription and protein expression were decreased by PGN in dose-dependent and time-dependent manners in rPMCs. Down-regulation of AQP1 by PGN was blocked only by SB203580, neither by SP600125 nor by PD98059. Furthermore, rPMCs exposed to PGN showed activation of p38 MAPK. Phospho-p38 protein production was increased by PGN stimulation in rPMCs. The localization of phospho-p38 was both in the cytosol and nuclei after PGN treatment, while its normal distribution is mainly in the cytosol in rPMCs. CONCLUSION: AQP1 expression was decreased by PGN in both dose-dependent and time-dependent manners in rPMCs. This down-regulation by PGN-induced AQP1 in rPMCs may be mediated by the activation of p38 MARK pathway.

In-fiber production of polymeric particles for biosensing and encapsulation.

Polymeric micro- and nanoparticles are becoming a mainstay in biomedicine, medical diagnostics, and therapeutics, where they are used in implementing sensing mechanisms, as imaging contrast agents, and in drug delivery. Current approaches to the fabrication of such particles are typically finely tuned to specific monomer or polymer species, size ranges, and structures. We present a general scalable methodology for fabricating uniformly sized spherical polymeric particles from a wide range of polymers produced with complex internal architectures and continuously tunable diameters extending from the millimeter scale down to 50 nm. Controllable access to such a wide range of sizes enables broad applications in cancer treatment, immunology, and vaccines. Our approach harnesses thermally induced, predictable fluid instabilities in composite core/cladding polymer fibers drawn from a macroscopic scaled-up model called a "preform." Through a stack-and-draw process, we produce fibers containing a multiplicity of identical cylindrical cores made of the polymers of choice embedded in a polymer cladding. The instability leads to the breakup of the initially intact cores, independent of the polymer chemistry, into necklaces of spherical particles held in isolation within the cladding matrix along the entire fiber length. We demonstrate here surface functionalization of the extracted particles for biodetection through specific protein-protein interactions, volumetric encapsulation of a biomaterial in spherical polymeric shells, and the combination of both surface and volumetric functionalities in the same particle. These particles used in distinct modalities may be produced from the desired biocompatible polymer by changing only the geometry of the macroscopic preform from which the fiber is drawn.

Enabling enhanced emission and low-threshold lasing of organic molecules using special Fano resonances of macroscopic photonic crystals.

The nature of light interaction with matter can be dramatically altered in optical cavities, often inducing nonclassical behavior. In solid-state systems, excitons need to be spatially incorporated within nanostructured cavities to achieve such behavior. Although fascinating phenomena have been observed with inorganic nanostructures, the incorporation of organic molecules into the typically inorganic cavity is more challenging. Here, we present a unique optofluidic platform comprising organic molecules in solution suspended on a photonic crystal surface, which supports macroscopic Fano resonances and allows strong and tunable interactions with the molecules anywhere along the surface. We develop a theoretical framework of this system and present a rigorous comparison with experimental measurements, showing dramatic spectral and angular enhancement of emission. We then demonstrate that these enhancement mechanisms enable lasing of only a 100-nm thin layer of diluted solution of organic molecules with substantially reduced threshold intensity, which has important implications for organic light-emitting devices and molecular sensing.

Silicon-in-silica spheres via axial thermal gradient in-fibre capillary instabilities.

The ability to produce small scale, crystalline silicon spheres is of significant technological and scientific importance, yet scalable methods for doing so have remained elusive. Here we demonstrate a silicon nanosphere fabrication process based on an optical fibre drawing technique. A silica-cladded silicon-core fibre with diameters down to 340 nm is continuously fed into a flame defining an axial thermal gradient and the continuous formation of spheres whose size is controlled by the feed speed is demonstrated. In particular, spheres of diameter <500 nm smaller than those produced under isothermal heating conditions are shown and analysed. A fibre with dual cores, p-type and n-type silicon, is drawn and processed into spheres. Spatially coherent break-up leads to the joining of the spheres into a bispherical silicon 'p-n molecule'. The resulting device is measured to reveal a rectifying I-V curve consistent with the formation of a p-n junction.

Formulation for scalable optimization of microcavities via the frequency-averaged local density of states.

We present a technique for large-scale optimization of optical microcavities based on the frequency-averaged local density of states (LDOS), which circumvents computational difficulties posed by previous eigenproblem-based formulations and allows us to perform full topology optimization of three-dimensional (3d) leaky cavity modes. We present theoretical results for both 2d and fully 3d computations in which every pixel of the design pattern is a degree of freedom ("topology optimization"), e.g. for lithographic patterning of dielectric slabs in 3d. More importantly, we argue that such optimization techniques can be applied to design cavities for which (unlike silicon-slab single-mode cavities) hand designs are difficult or unavailable, and in particular we design minimal-volume multi-mode cavities (e.g. for nonlinear frequency-conversion applications).

Structured spheres generated by an in-fibre fluid instability.

From drug delivery to chemical and biological catalysis and cosmetics, the need for efficient fabrication pathways for particles over a wide range of sizes, from a variety of materials, and in many different structures has been well established. Here we harness the inherent scalability of fibre production and an in-fibre Plateau-Rayleigh capillary instability for the fabrication of uniformly sized, structured spherical particles spanning an exceptionally wide range of sizes: from 2 mm down to 20 nm. Thermal processing of a multimaterial fibre controllably induces the instability, resulting in a well-ordered, oriented emulsion in three dimensions. The fibre core and cladding correspond to the dispersed and continuous phases, respectively, and are both frozen in situ on cooling, after which the particles are released when needed. By arranging a variety of structures and materials in a macroscopic scaled-up model of the fibre, we produce composite, structured, spherical particles, such as core-shell particles, two-compartment 'Janus' particles, and multi-sectioned 'beach ball' particles. Moreover, producing fibres with a high density of cores allows for an unprecedented level of parallelization. In principle, 10(8) 50-nm cores may be embedded in metres-long, 1-mm-diameter fibre, which can be induced to break up simultaneously throughout its length, into uniformly sized, structured spheres.

Increase in concentration of soluble CD86 after segmental allergen challenge in patients with allergic asthma.

STUDY OBJECTIVE: To investigate the effects of segmental allergen challenge on the concentration of soluble CD86 (sCD86) in BAL fluids in patients with allergic asthma. METHODS: BAL fluid and peripheral blood were collected at baseline, 24 h after segmental saline solution or allergen challenge by fiberoptic bronchoscopy and venepuncture, respectively, from 10 patients with allergic asthma. Total and differential cell counts in BAL fluid were performed, and sCD86 levels in both BAL fluid and serum were measured by enzyme-linked immunosorbent assay. RESULTS: In allergic asthmatics, there was no significant increase in BAL sCD86 concentrations after saline solution challenge (median, 2.0 IU/L; 25th to 75th percentiles, 0 to 3.4) compared with baseline control subjects (median, 1.2 IU/L; 25th to 75th percentiles, 0 to 3.6 IU/mL; p = 0.735); however, sCD86 concentrations were significantly elevated after allergen challenge (median, 8.1 IU/L; 25th to 75th percentiles, 4.4 to 17.0 IU/mL; p < 0.001). The concentrations of sCD86 in BAL fluid after allergen challenge exceeded levels that could be accounted for passive transudation from the circulation, based on the magnitude of increases in BAL albumin concentrations. CONCLUSIONS: These data indicate that allergen challenge results in a significant local accumulation of sCD86 within the airways, and that the local release of sCD86 may play a role in allergen-induced inflammatory processes in the asthmatic airways.

CD4+CD25+ regulatory T lymphocytes in malignant pleural effusion.

BACKGROUND: Active suppression by CD4(+)CD25(+) regulatory T lymphocytes plays an important role in the downregulation of T-cell responses to foreign and self-antigens. OBJECTIVE: To analyze whether the CD4(+)CD25(+) regulatory T lymphocytes exist and function normally in malignant pleural effusion. METHODS: The percentages of CD4(+)CD25(+) T lymphocytes in pleural effusion and peripheral blood from patients with lung cancer with malignant effusion, pleural lavage and peripheral blood from patients with lung cancer without effusion, and peripheral blood from healthy control subjects were determined by flow cytometry. The expressions of forkhead transcription factor Foxp3 and cytotoxic lymphocyte-associated antigen-4 were also examined. CD4(+)CD25(+) and CD4(+)CD25(-) T cells from pleural effusion and peripheral blood were isolated, and were cultured to observe the effects of CD4(+)CD25(+) cells on proliferation response of CD4(+)CD25(-) T cells in vitro. MAIN RESULTS: There were increased numbers of CD4(+)CD25(+) T cells in malignant pleural effusion from patients with lung cancer compared with pleural lavage from patients with lung cancer without pleural effusion, and that these cells have constitutive high-level expression of Foxp3 and cytotoxic lymphocyte-associated antigen-4. Furthermore, CD4(+)CD25(+) T cells mediate potent inhibition of proliferation response of CD4(+)CD25(-) T cells, and anticytotoxic lymphocyte-associated antigen-4 monoclonal antibody could reduce the inhibitory activity of CD4(+)CD25(+) T cells. CONCLUSIONS: The increased CD4(+)CD25(+) T cells found in malignant pleural effusion express high levels of Foxp3 transcription factor and potently suppress the proliferation of CD4(+)CD25(-) T cells, and cytotoxic lymphocyte-associated antigen-4 is involved in the suppressive activity of pleural CD4(+)CD25(+) T cells.