COVID-19 associated mold infections: Review of COVID-19 associated pulmonary aspergillosis and mucormycosis.

COVID-19-associated mold infection (CAMI) is defined as development of mold infections in COVID-19 patients. Co-pathogenesis of viral and fungal infections include the disruption of tissue barrier following SARS CoV-2 infection with the damage in the alveolar space, respiratory epithelium and endothelium injury and overwhelming inflammation and immune dysregulation during severe COVID-19. Other predisposing risk factors permissive to fungal infections during COVID-19 include the administration of immune modulators such as corticosteroids and IL-6 antagonist. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) is increasingly reported during the COVID-19 pandemic. CAPA usually developed within the first month of COVID infection, and CAM frequently arose 10-15 days post diagnosis of COVID-19. Diagnosis is challenging and often indistinguishable during the cytokine storm in COVID-19, and several diagnostic criteria have been proposed. Development of CAPA and CAM is associated with a high mortality despiteappropriate anti-mold therapy. Both isavuconazole and amphotericin B can be used for treatment of CAPA and CAM; voriconazole is the primary agent for CAPA and posaconazole is an alternative for CAM. Aggressive surgery is recommended for CAM to improve patient survival. A high index of suspicion and timely and appropriate treatment is crucial to improve patient outcome.

STRESS granule-associated RNA-binding protein CAPRIN1 drives cancer progression and regulates treatment response in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common malignancy of the head and neck that is mainly diagnosed in southern China and Southeast Asia, with a strong etiological link to Epstein‒Barr virus infection. Those with advanced-stage disease have a significantly worse prognosis. There is an urgent need to identify novel therapeutic targets for the recurrent or metastatic nasopharyngeal carcinoma. With a particular focus on Cell Cycle Associated Protein 1 (CAPRIN1), one of the important RNA-binding proteints associated with stress granule formation, we used RT‒qPCR and immunohistochemistry to validate CAPRIN1 expression in NPC tissues and cell lines. Further, CAPRIN1 expression was knocked down using siRNA, and the effect on cell proliferation and migration was systematically assessed by in vitro assays. As a result, we demonstrated that CAPRIN1 was elevated in NPC compared to adjacent normal tissues. Knockdown of CAPRIN1 in NPC cells inhibited proliferation and migration, involving the regulation of cell cycle protein CCND2 and EMT signaling, respectively. Notably, we found that CAPRIN1 knockdown promoted cell apoptosis by regulation of the expression of apoptosis-related proteins cleaved-PARP and cleaved-Caspase3. Knockdown of CAPRIN1 increased NPC cell sensitivity to rapamycin, and increased NPC cell sensitivity to cisplatin and to X-rays. In conclusion, CAPRIN1 might drive NPC proliferation, regulate cell cycle and apoptosis, and affect tumor cell response to anti-cancer agents and X-ray irradiation. CAPRIN1 might serve as a potential target for NPC.

Dioscin attenuates oxLDL uptake and the inflammatory reaction of dendritic cells under high glucose conditions by blocking p38 MAPK.

Dioscin has been shown to affect the regulation of metabolic diseases, including diabetes; however, the mechanism of action is still unclear. Under high glucose (HG) conditions, the expression of scavenger receptors and the uptake of oxidized low­density lipoprotein (oxLDL) are upregulated in dendritic cells (DCs), which are critical steps in atherogenesis and inflammation. In this study, the focus was on the impact of dioscin on the function of DCs. Immature DCs were cultured with: 5.5 mM glucose medium (control group); 30 mM glucose medium (HG group); HG + 10 mM dioscin; HG + 20 mM dioscin; HG + 30 mM dioscin; and HG + 40 mM dioscin. For subsequent experiments, 30 mM dioscin was used as the experimental concentration. Dichlorodihydrofluorescein fluorescence was used to measure the intracellular production of reactive oxygen species (ROS) in DCs. The expression levels of the scavenger receptors, including class A scavenger receptors (SR­A), CD36 and lectin­like oxidized low­density lipoprotein receptor­1 (LOX­1) were determined via quantitative PCR. The protein expression of p38 mitogen­activated protein kinase (MAPK) was determined by western blotting. Furthermore, ELISA was used to detect the levels of interleukin (IL)­6, IL­10 and IL­12. Finally, DCs were incubated with diOlistic (Dil)­labeled oxLDL, and flow cytometry analysis was used to investigate the Dil­oxLDL­incorporated fraction. The incubation of DCs with dioscin inhibited the induction of ROS production, in a dose­dependent manner, under HG conditions. The upregulation of SR­A, CD36 and LOX­1 genes was partially abolished by dioscin, which also partially reversed p38 MAPK protein upregulation. Furthermore, increased secretion of IL­6 and IL­12, and decreased secretion of IL­10 in DCs, induced by HG, was also reversed by dioscin. To conclude, dioscin could attenuate the production of ROS, inflammatory cytokine secretion and oxLDL uptake by DCs in HG conditions by preventing the expression of scavenger receptors and p38 MAPK, thus playing a positive role in preventing atherogenesis.

MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma.

miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.

Identification of RRAS gene related to nasopharyngeal carcinoma based on pathway and network-based analyses.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a highly aggressive neoplasm mainly distributed in the eastern and southeastern parts of Asia. NPC has a poor prognosis among head and neck cancers, and molecular-targeted therapies showed limited clinical efficacy. METHODS: We reviewed publications in the PubMed database and extracted genes associated with NPC. The online tool WebGestalt was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for these genes. Next, the two parameters, Jaccard Coefficient (JC) and Overlap Coefficient (OC), were used to analyze the crosstalk of each pair of selected pathways. The new NPC-related genes were predicted by protein-protein interaction (PPI) network combined with hub genes extraction. Western blotting, qRT-PCR, and immunohistochemistry (IHC) were used to detect the expression of candidate genes in NPC cells and tissues, and cellular function assays were used to explore the effects of genes on NPC cells. RESULTS: A total of 552 genes were identified and used to build an NPC-related gene set (NPCgset). Pathways enriched in KEGG pathway analysis were further used for crosstalk analysis and were grouped into two modules: one was related to the carcinogenesis process, and the other was correlated with the immune response. Eight genes from the NPCgset were selected to build a PPI network, and two hub genes PIK3CA and AKT1 were chosen. Proteins interacting with PIK3CA were analyzed; among them, the expression of RRAS was down-regulated in NPC and associated with poor prognosis of NPC patients. Furthermore, RRAS suppressed proliferation, invasion and the epithelial-mesenchymal transformation (EMT) of the HK1 and 5-8F cell lines. CONCLUSIONS: Our study may help to explore the biological processes underlying NPCgset and suggests that RRAS may act as a tumor suppressor gene in NPC.

Total Synthesis of (+)-Antrocin and Its Diastereomer and Clarification of the Absolute Stereochemistry of (-)-Antrocin.

Using 2,2-dimethyl cyclohexanone as the starting compound, (+)-antrocin and its diastereomer have been synthesized. The absolute stereochemistry of (-)-antrocin, a natural sesqui-terpenoid and an antagonist in some types of cancer cells, was clarified using the character data of (+)-antrocin. The synthetic procedure involved two key steps: (1) the reaction of vinyl magnesium bromide with 2,2-dimethyl-6-t-butyl-dimethyl-silyoxy-methyl-1-cyclo-hexanone to give a vinyl cyclohexanol derivative and (2) a highly stereoselective intramolecular Diels-Alder (IMDA) reaction of the camphanate-containing triene intermediate. The relative energy levels of the possible transition states of the IMDA reaction of the camphanate-containing triene were obtained from density functional theory calculations, proving the stereospecific formation of the target molecule.

Inhibition of pentraxin 3 in glioma cells impairs proliferation and invasion in vitro and in vivo.

Pentraxin 3 (PTX3) is an inflammatory molecule that is involved in immune responses, inflammation, and cancer. Recent evidence suggests that PTX3 plays a critical role in tumor progression; however, its impact on the biological function of gliomas remains unknown. In the present study, immunohistochemical staining showed that patients with high-grade gliomas exhibited increased expression levels of PTX3 compared to those with low-grade gliomas (P < 0.001). Furthermore, knockdown of PTX3 in GBM8401 cells inhibits proliferation, increases p21 protein levels, and decreases cyclin D1 protein levels, resulting in cell cycle arrest at the G0/G1 phase. In addition, knockdown of PTX3 significantly decreases GBM8401 cell migration and invasion through the downregulation of matrix metalloproteinase-1 and -2 (MMP-1 and MMP-2) expression. In a GBM8401 xenograft animal model, PTX3 knockdown decreases tumor growth in vivo. In conclusion, PTX3 plays an important role in glioma cell proliferation and invasion, and may thus serve as a novel potential therapeutic target in the treatment of gliomas.

High-dialysate-glucose-induced oxidative stress and mitochondrial-mediated apoptosis in human peritoneal mesothelial cells.

Human peritoneal mesothelial cells (HPMCs) are a critical component of the peritoneal membrane and play a pivotal role in dialysis adequacy. Loss of HPMCs can contribute to complications in peritoneal dialysis. Compelling evidence has shown that high-dialysate glucose is a key factor causing functional changes and cell death in HPMCs. We investigated the mechanism of HPMC apoptosis induced by high-dialysate glucose, particularly the role of mitochondria in the maintenance of HPMCs. HPMCs were incubated at glucose concentrations of 5 mM, 84 mM, 138 mM, and 236 mM. Additionally, N-acetylcysteine (NAC) was used as an antioxidant to clarify the mechanism of high-dialysate-glucose-induced apoptosis. Exposing HPMCs to high-dialysate glucose resulted in substantial apoptosis with cytochrome c release, followed by caspase activation and poly(ADP-ribose) polymerase cleavage. High-dialysate glucose induced excessive reactive oxygen species production and lipid peroxidation as well as oxidative damage to DNA. Mitochondrial fragmentation, multiple mitochondrial DNA deletions, and dissipation of the mitochondrial membrane potential were also observed. The mitochondrial dysfunction and cell death were suppressed using NAC. These results indicated that mitochondrial dysfunction is one of the main causes of high-dialysate-glucose-induced HPMC apoptosis.

Cytotoxic effect of triterpenoids from the root bark of Hibiscus syriacus.

In this study, 4 new triterpenoids-3ß- acetoxy-olean-11-en,28,13ß-olide (1), 3ß- acetoxy-11α,12α-epoxy-olean-28,13ß-olide (2), 19α-epi-betulin (3), and 20, 28-epoxy-17ß,19ß-lupan-3ß-ol (4)-and 12 known compounds, were isolated from the root bark of Hibiscus syriacus L. by using acetone extraction. Their structures were characterized by extensive spectroscopic analysis. To investigate cytotoxicity, A549 human lung cancer cells were exposed to the extract and the compounds identified from it. Significantly reduced cell viability was observed with betulin-3-caffeate (12) (IC50, 4.3 µM). The results of this study indicate that betulin-3-caffeate (12) identified from H. syriacus L. may warrant further investigation for potential as anticancer therapies.

Fire-retardant-treated low-formaldehyde-emission particleboard made from recycled wood-waste.

The objective of this study was to manufacture fire-retardant-treated low-formaldehyde-emission particleboard from recycled wood-waste particles using polymeric 4,4'-methylenediphenyl isocyanate (PMDI) and phenol-formaldehyde (PF) resins. The influence of the PMDI/PF ratio (ratio of particles sprayed with PMDI to particles sprayed with PF, w/w) after fire retardant treatment on formaldehyde emissions, mechanical properties, and surface fire resistant performance of the manufactured particleboard was investigated. The experimental results showed that the formaldehyde emissions linearly decreased with an increasing PMDI/PF ratio. Moreover, the bending strength, internal bond strength, and screw holding strength increased with an increasing PMDI/PF ratio. The thickness swelling of the particleboard was improved by using an increasing PMDI/PF ratio. Furthermore, the fire-retardant-treated low-formaldehyde-emission particleboards fabricated in our study could pass the third grade standard of surface fire resistant performance as specified by CNS 6532.

Endoscopic variceal ligation versus propranolol in prophylaxis of first variceal bleeding in patients with cirrhosis.

BACKGROUND AND AIM: To compare the efficacy and safety of endoscopic variceal ligation (EVL) with propranolol in prophylaxis on the rate of first esophageal variceal bleeding in patients with cirrhosis. METHODS: A prospective, randomized trial was conducted in 100 cirrhotic patients with no history of previous upper gastrointestinal bleeding and with esophageal varices endoscopically judged to be at high risk of hemorrhage. The end-points of the study were bleeding and death. RESULTS: Life-table curves showed that prophylactic EVL and propranolol were similarly effective for primary prophylaxis of variceal bleeding (11/50 [22%]vs 12/50 [24%]; P = 0.68) and overall mortality (14/50 [28%]vs 12/50 [24%]; P = 0.49). The 2-year cumulative bleeding rate was 18% (9/50) in the EVL group and 16% (8/50) in the propranolol group. The 2-year cumulative mortality rate was 28% (14/50) in the EVL group and 24% (12/50) in the propranolol group. Comparison of Kaplan-Meier estimates of the time to death of both groups showed no significant difference in mortality in both groups (P = 0.86). Patients undergoing EVL had few treatment failures and died mainly of hepatic failure. In the propranolol group, the mean daily dosage of the drug was 68.2 +/- 32.8 mg, which was sufficient to reduce the pulse rate by 25%. 20% of patients withdrew from propranolol treatment due to adverse events. CONCLUSIONS: Prophylaxis EVL is as effective and as safe as treatment with propranolol in decreasing the incidence of first variceal bleeding and death in cirrhotic patients with high-risk esophageal varices.

Ocular toxicity of intravitreal indocyanine green.

We report 6 cases of indocyanine green (ICG)-related ocular toxicity after intravitreal ICG usage. Five cases had preoperative diagnosis of macular hole, 1 case had preoperative rhegmatogenous retinal detachment complicated with proliferative vitreoretinopathy. All cases received vitrectomy, ICG-assisted internal limiting membrane (ILM) peeling and air-fluid exchange. All eyes had residual ICG left at the end of surgery. Patients were followed up with indirect ophthalmoscopy, visual acuity, color fundus photography, fluorescein angiography, and ocular coherence tomography. Circular foveal retinal pigment epithelium atrophy larger than the area of macular hole and surrounding cuff was noted in 4 of 5 cases with preoperative macular hole. The other eye with preoperative diagnosis of macular hole had shallow anterior chamber and low intraocular pressure lasting for 1 week postoperatively. Diffuse retinal pigment epithelial atrophy was noted in the eye with preoperative proliferative vitreoretinopathy. Four eyes demonstrated optic atrophy postoperatively. Ocular toxicity caused by ICG may present as pigment epithelial atrophy, which is characteristically larger than the previous area of macular hole and surrounding cuff. Disc atrophy, retinal toxicity, and ocular hypotony were also observed in some cases. To prevent toxicity, residual ICG and ICG-stained ILM must be removed as completely as possible.

Establishment of a mini-gene expression database for bladder tumor.

BACKGROUND AND PURPOSE: Transitional cell carcinoma has been diagnosed mostly in urinary bladder in southern Taiwan and has an exceptionally high mortality rate. To identify the genes associated with bladder cancer, we investigated differential gene expression. Six bladder tumor cDNA libraries were constructed and their sequences were compared and analyzed. METHODS: mRNA from bladder tumor cell lines or tissue samples were used to construct two regular cDNA libraries and four subtractive cDNA libraries after subtractive hybridization with cDNA derived from normal bladder epithelial cells. Subsequently, more than 100 cDNA inserts from each library were randomly isolated and sequenced, followed by sequence comparisons with nucleotide and protein sequence databases. RESULTS: After searching the Basic Local Alignment Search Tool (Blast) databases, the cDNA nucleotide sequences were grouped into novel, known, and common gene categories. Since tumor nucleotide sequences are informative and valuable for research, they were organized as a mini-gene expression database (http://bladder.nhri.org.tw/). Interestingly, in one subtractive cDNA library, the ATPase 6 gene was found to be highly expressed in normal bladder epithelial cells and elevated levels of ATPase 6 mRNA were later confirmed by reverse transcription-polymerase chain reaction. However, the role of ATPase 6 in bladder tumorigenesis remains to be investigated. CONCLUSIONS: The establishment of this database is an important step to enable systematic screening for bladder tumor-associated genes and may also be useful in developing diagnostic and/or therapeutic applications.