Lipidomics Analysis Unravels Aberrant Lipid Species and Pathways Induced by Zinc Oxide Nanoparticles in Kidney Cells.

Zinc oxide nanoparticles (ZnO NPs) are widely used in versatile applications, from high technology to household products. While numerous studies have examined the toxic gene profile of ZnO NPs across various tissues, the specific lipid species associated with adverse effects and potential biomarkers remain elusive. In this study, we conducted a liquid chromatography-mass spectrometry based lipidomics analysis to uncover potential lipid biomarkers in human kidney cells following treatment with ZnO NPs. Furthermore, we employed lipid pathway enrichment analysis (LIPEA) to elucidate altered lipid-related signaling pathways. Our results demonstrate that ZnO NPs induce cytotoxicity in renal epithelial cells and modulate lipid species; we identified 64 lipids with a fold change (FC) > 2 and p < 0.01 with corrected p < 0.05 in HK2 cells post-treatment with ZnO NPs. Notably, the altered lipids between control HK2 cells and those treated with ZnO NPs were associated with the sphingolipid, autophagy, and glycerophospholipid pathways. This study unveils novel potential lipid biomarkers of ZnO NP nanotoxicity, representing the first lipidomic profiling of ZnO NPs in human renal epithelial cells.

Involvement of tumor necrosis factor receptor-associated factor 6 (TRAF6) in NF-κB activation and antiviral immunity: Molecular and functional characterization of TRAF6 in red-spotted grouper (Epinephelus akaara).

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a member of the TRAF family of adaptor proteins involved in the signal transduction pathways of both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. In this study, red-spotted grouper (Epinephelus akaara) TRAF6 (EaTraf6) was identified and characterized. The open reading frame of EaTraf6, 1713 bp in length, encodes a putative protein of 570 amino acids and has a predicted molecular weight and theoretical isoelectric point of 64.11 kDa and 6.07, respectively. EaTraf6 protein contains an N-terminal RING-type zinc finger domain, two TRAF-type zinc finger domains, a coiled-coil region (zf-TRAF), and a conserved C-terminal meprin and TRAF homology (MATH) domain. EaTraf6 shared the highest amino acid sequence identity with its ortholog from Epinephelus coioides, and phylogenetic analysis showed all fish TRAF6s clustered together and apart from other species. qRT-PCR results revealed that EaTraf6 was ubiquitously expressed in all examined tissues, with the highest level detected in the blood. In the immune challenge, EaTraf6 exhibited modulated mRNA expression levels in the blood and spleen. The subcellular localization analysis revealed that the EaTraf6 protein was predominantly present in the cytoplasm; however, it could translocate into the nucleus following poly (I:C) stimulation. The antiviral function of EaTraf6 was confirmed by analyzing the expression of host antiviral genes and viral genomic RNA during viral hemorrhagic septicemia virus infection. Additionally, luciferase reporter assay results indicated that EaTraf6 is involved in the activation of the NF-κB signaling pathway upon poly (I:C) stimulation. Finally, the effect of EaTraf6 on cytokine gene expression and its role in regulating macrophage M1 polarization were demonstrated. Collectively, these findings suggest that EaTraf6 is a crucial immune-related gene that significantly contributes to antiviral functions and regulation of NF-κB activity in the red-spotted grouper.

Motion correction of 3D dynamic contrast-enhanced ultrasound imaging without anatomical B-Mode images: Pilot evaluation in eight patients.

BACKGROUND: Dynamic contrast-enhanced ultrasound (DCE-US) is highly susceptible to motion artifacts arising from patient movement, respiration, and operator handling and experience. Motion artifacts can be especially problematic in the context of perfusion quantification. In conventional 2D DCE-US, motion correction (MC) algorithms take advantage of accompanying side-by-side anatomical B-Mode images that contain time-stable features. However, current commercial models of 3D DCE-US do not provide side-by-side B-Mode images, which makes MC challenging. PURPOSE: This work introduces a novel MC algorithm for 3D DCE-US and assesses its efficacy when handling clinical data sets. METHODS: In brief, the algorithm uses a pyramidal approach whereby short temporal windows consisting of three consecutive frames are created to perform local registrations, which are then registered to a master reference derived from a weighted average of all frames. We applied the algorithm to imaging studies from eight patients with metastatic lesions in the liver and assessed improvements in original versus motion corrected 3D DCE-US cine using: (i) frame-to-frame volumetric overlap of segmented lesions, (ii) normalized correlation coefficient (NCC) between frames (similarity analysis), and (iii) sum of squared errors (SSE), root-mean-squared error (RMSE), and r-squared (R2 ) quality-of-fit from fitted time-intensity curves (TIC) extracted from a segmented lesion. RESULTS: We noted improvements in frame-to-frame lesion overlap across all patients, from 68% ± 13% without correction to 83% ± 3% with MC (p = 0.023). Frame-to-frame similarity as assessed by NCC also improved on two different sets of time points from 0.694 ± 0.057 (original cine) to 0.862 ± 0.049 (corresponding MC cine) and 0.723 ± 0.066 to 0.886 ± 0.036 (p ≤ 0.001 for both). TIC analysis displayed a significant decrease in RMSE (p = 0.018) and a significant increase in R2 goodness-of-fit (p = 0.029) for the patient cohort. CONCLUSIONS: Overall, results suggest decreases in 3D DCE-US motion after applying the proposed algorithm.

Modulation of Cisplatin Sensitivity through TRPML1-Mediated Lysosomal Exocytosis in Ovarian Cancer Cells: A Comprehensive Metabolomic Approach.

BACKGROUND: The lysosome has emerged as a promising target for overcoming chemoresistance, owing to its role in facilitating the lysosomal sequestration of drugs. The lysosomal calcium channel TRPML1 not only influences lysosomal biogenesis but also coordinates both endocytosis and exocytosis. This study explored the modulation of cisplatin sensitivity by regulating TRPML1-mediated lysosomal exocytosis and identified the metabolomic profile altered by TRPML1 inhibition. METHODS: We used four types of ovarian cancer cells: two cancer cell lines (OVCAR8 and TOV21G) and two patient-derived ovarian cancer cells. Metabolomic analyses were conducted to identify altered metabolites by TRPML1 inhibition. RESULTS: Lysosomal exocytosis in response to cisplatin was observed in resistant cancer cells, whereas the phenomenon was absent in sensitive cancer cells. Through the pharmacological intervention of TRPML1, lysosomal exocytosis was interrupted, leading to the sensitization of resistant cancer cells to cisplatin treatment. To assess the impact of lysosomal exocytosis on chemoresistance, we conducted an untargeted metabolomic analysis on cisplatin-resistant ovarian cancer cells with TRPML1 inhibition. Among the 1446 differentially identified metabolites, we focused on 84 significant metabolites. Metabolite set analysis revealed their involvement in diverse pathways. CONCLUSIONS: These findings collectively have the potential to enhance our understanding of the interplay between lysosomal exocytosis and chemoresistance, providing valuable insights for the development of innovative therapeutic strategies.

Galectin 9 restricts viral replication in teleost via autophagy-antiviral pathway and polarizes M2 macrophages for anti-inflammatory response: New insights into functional properties of fish Galectin-9 from Planiliza haematocheilus.

Galectin 9 (Gal9) is a tandem repeat type ß-galactoside-binding galectin that mediates various cellular biochemical and immunological functions. Many studies have investigated the functional properties of Gal9 in mammals; however, knowledge of fish Gal9 is limited to antibacterial studies. In this context, our aim was to clone Gal9 from Planiliza haematocheilus (PhGal9) and investigate its structural and functional characteristics. We discovered the PhGal9 open reading frame, which was 969 base pairs long and encoded a 322 amino acid protein. PhGal9 had a projected molecular weight of 35.385 kDa but no signal peptide sequence. PhGal9 mRNA was ubiquitously produced in all investigated tissues but was predominant in the intestine, spleen, and brain. Its mRNA expression was increased in response to stimulation by Poly(I:C), LPS, and L. garvieae. The rPhGal9 exhibited a dose-dependent agglutination potential toward gram-positive and gram-negative bacteria at a minimum concentration of 50 µg/mL. Overexpression of PhGal9 promoted M2-like phenotype changes in mouse macrophages, and RT-qPCR analysis of M1 and M2 marker genes confirmed M2 polarization with upregulation of M2 marker genes. In the antiviral assay, the expression levels of Viral Hemorrhagic Septicemia Virus (VHSV) glycoproteins, phosphoproteins, nucleoproteins, non-virion proteins, matrix proteins, and RNA polymerase were significantly reduced in PhGal9-overexpressed cells. Furthermore, the mRNA expression of autophagic genes (sqstm1, tax1bp1b, rnf13, lc3, and atg5) and antiviral genes (viperin) were upregulated in PhGal9 overexpressed cells. For the first time in teleosts, our study demonstrated that PhGal9 promotes M2 macrophage polarization by upregulating M2-associated genes (egr2 and cmyc) and suppressing M1-associated genes (iNOS and IL-6). Furthermore, our results show that exogenous and endogenous PhGal9 prevented VHSV attachment and replication by neutralizing virion and autophagy, respectively. Gal9 may be a potent modulator of the antimicrobial immune response in teleost fish.

Chirality-enhanced transport and drug delivery of graphene nanocarriers to tumor-like cellular spheroid.

Chirality, defined as "a mirror image," is a universal geometry of biological and nonbiological forms of matter. This geometry of molecules determines how they interact during their assembly and transport. With the development of nanotechnology, many nanoparticles with chiral geometry or chiroptical activity have emerged for biomedical research. The mechanisms by which chirality originates and the corresponding synthesis methods have been discussed and developed in the past decade. Inspired by the chiral selectivity in life, a comprehensive and in-depth study of interactions between chiral nanomaterials and biological systems has far-reaching significance in biomedicine. Here, we investigated the effect of the chirality of nanoscale drug carriers, graphene quantum dots (GQDs), on their transport in tumor-like cellular spheroids. Chirality of GQDs (L/D-GQDs) was achieved by the surface modification of GQDs with L/D-cysteines. As an in-vitro tissue model for drug testing, cellular spheroids were derived from a human hepatoma cell line (i.e., HepG2 cells) using the Hanging-drop method. Our results reveal that the L-GQDs had a 1.7-fold higher apparent diffusion coefficient than the D-GQDs, indicating that the L-GQDs can enhance their transport into tumor-like cellular spheroids. Moreover, when loaded with a common chemotherapy drug, Doxorubicin (DOX), via π-π stacking, L-GQDs are more effective as nanocarriers for drug delivery into solid tumor-like tissue, resulting in 25% higher efficacy for cancerous cellular spheroids than free DOX. Overall, our studies indicated that the chirality of nanocarriers is essential for the design of drug delivery vehicles to enhance the transport of drugs in a cancerous tumor.

Radiologic Follow-up of Ruptured Arachnoid Cysts With or Without Hemorrhage: Five Case Reports and a Review of the Literature.

Arachnoid cysts are usually asymptomatic and discovered incidentally. However, cysts may occasionally rupture because of minor head trauma. We describe the radiologic follow-up of 5 patients with ruptured arachnoid cysts featuring spontaneous resolution, subdural hygroma formation, and cystic and subdural hemorrhage. From January 2004 through July 2020, 5 patients (1.3%) with ruptured arachnoid cysts were evaluated out of 388 patients with arachnoid cysts encountered at our institution at that time. The 5 patients were all male, and they ranged in age from 6-17 years (median, 12 years). The median duration of radiologic follow-up was 3.5 years (range, 2.3-10.1 years). All of the ruptured arachnoid cysts were overlying the temporal lobe with Galassi type II. The median cyst diameter was 4.9 cm (range, 4.4-8.9 cm). Four patients had a history of recent minor head trauma. There were no particular neurologic symptoms in their past medical history in all patients. In the follow-up, two patients' cysts resolved spontaneously without hemorrhage. One patient's cyst resolved post-burr-hole drainage for chronic subdural hemorrhage. Another patient, whose cyst led to a hemorrhage and chronic subdural hemorrhage, recovered following a craniotomy, hematoma removal, and cyst fenestration. Another patient, presenting with hygroma, cystic hemorrhage, and chronic subdural hemorrhage, was treated with burr-hole drainage. Three patients recovered postoperatively. Arachnoid cysts rarely rupture, and surgical intervention is required for some cases associated with hemorrhage. Postoperatively, all patients had good outcomes without complications in this series.

Identification, expression profiling, and functional characterization of cystatin C from big-belly seahorse (Hippocampus abdominalis).

Cystatins are natural inhibitors of lysosomal cysteine proteases, including cathepsins B, L, H, and S. Cystatin C (CSTC) is a member of the type 2 cystatin family and is an essential biomarker in the prognosis of several diseases. Emerging evidence suggests the immune regulatory roles of CSTC in antigen presentation, the release of different inflammatory mediators, and apoptosis in various pathophysiologies. In this study, the 390-bp cystatin C (HaCSTC) cDNA from big-belly seahorse (Hippocampus abdominalis) was cloned and characterized by screening the pre-established cDNA library. Based on similarities in sequence, HaCSTC is a homolog of the teleost type 2 cystatin family with putative catalytic cystatin domains, signal peptides, and disulfide bonds. HaCSTC transcripts were ubiquitously expressed in all tested big-belly seahorse tissues, with the highest expression in ovaries. Immune challenge with lipopolysaccharides, polyinosinic:polycytidylic acid, Edwardsiella tarda, and Streptococcus iniae caused significant upregulation in HaCSTC transcript levels. Using a pMAL-c5X expression vector, the 14.29-kDa protein of recombinant HaCSTC (rHaCSTC) was expressed in Escherichia coli BL21 (DE3), and its protease inhibitory activity against papain cysteine protease was determined with the aid of a protease substrate. Papain was competitively blocked by rHaCSTC in a dose-dependent manner. In response to viral hemorrhagic septicemia virus (VHSV) infection, HaCSTC overexpression strongly decreased the expression of VHSV transcripts, pro-inflammatory cytokines, and pro-apoptotic genes; while increasing the expression of anti-apoptotic genes in fathead minnow (FHM) cells. Furthermore, HaCSTC overexpression protected VHSV-infected FHM cells against VHSV-induced apoptosis and increased cell viability. Our findings imply the profound role of HaCSTC against pathogen infections by modulating fish immune responses.

Molecular characterization, immune expression, and functional delineation of peroxiredoxin 1 in Epinephelus akaara.

Peroxiredoxin 1 is a member of the typical 2-Cys peroxiredoxin family, which serves diverse functions in gene expression, immune and inflammatory responses, and tumor progression. In this study, we aimed to analyze the structural, functional, and immunomodulatory properties of peroxiredoxin 1 from Epinephelus akaara (EaPrx1). The open reading frame of EaPrx1 is 597 base pairs in length, encoding 198 amino acids, with a molecular weight of approximately 22 kDa. The in silico analysis revealed that EaPrx1 shares a conserved thioredoxin fold and signature motifs that are critical for its catalytic activity and oligomerization. Further, EaPrx1 is closely related to Epinephelus lanceolatus Prx1 and clustered in the Fishes group of the vertebrate clade, revealing that EaPrx1 was conserved throughout evolution. In terms of tissue distribution, a high level of EaPrx1 expression was observed in the spleen, brain, and blood tissues. Likewise, in immune challenge experiments, significant transcriptional modulations of EaPrx1 upon lipopolysaccharide, polyinosinic:polycytidylic acid, and nervous necrosis virus injections were noted at different time points, indicating the immunological role of EaPrx1 against pathogenic infections. In the functional analysis, rEaPrx1 exhibited substantial DNA protection, insulin disulfide reduction, and tissue repair activities, which were concentration-dependent. EaPrx1/pcDNA™ 3.1 (+)-transfected fathead minnow cells revealed high cell viability upon arsenic toxicity, indicating the heavy metal detoxification activity of EaPrx1. Taken together, the transcriptional and functional studies imply critical roles of EaPrx1 in innate immunity, redox regulation, apoptosis, and tissue-repair processes in E. akaara.

The long multi-epitope peptide vaccine combined with adjuvants improved the therapeutic effects in a glioblastoma mouse model.

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC597-104 and EphA2682-689) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells' distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8+ T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo. In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM.

Identification of reactive oxygen species modulator 1 (Romo 1) from black rockfish (Sebastes schlegelii) and deciphering its molecular characteristics, immune responses, oxidative stress modulation, and wound healing properties.

Reactive oxygen species modulator 1 (Romo1) is a mitochondrial inner membrane protein that induces mitochondrial reactive oxygen species (ROS) generation. In this study, we identified the Romo1 homolog from the black rockfish (Sebastes schlegelii), named it as SsRomo1, and characterized it at the molecular as well as functional levels. An open reading frame consisting of 240 bp was identified in the SsRomo1 complementary DNA (cDNA) sequence that encodes a 79 amino acid-long polypeptide with a molecular weight of 8,293 Da and a theoretical isoelectric point (pI) of 9.89. The in silico analysis revealed the characteristic features of SsRomo1, namely the presence of a transmembrane domain and the lack of a signal peptide. Homology analysis revealed that SsRomo1 exhibits the highest sequence identity with its fish counterparts (>93%) and shares a similar percentage of sequence identity with mammals (>92%). Additionally, it is closely clustered together with the fish clade in the constructed phylogenetic tree. The subcellular localization analysis confirmed its mitochondrial localization within the fathead minnow (FHM) cells. Under normal physiological conditions, the SsRomo1 mRNA is highly expressed in the rockfish ovary, followed by the blood and testis, indicating the abundance of mitochondria in these tissues. Furthermore, the significant upregulation of SsRomo1 in cells treated with lipopolysachharide (LPS), polyinosinic:polycytidylic acid, and Streptococcus iniae suggest that the increased ROS production is induced by SsRomo1 to eliminate pathogens during infections. Incidentally, we believe that this study is the first to determine the involvement of SsRomo1 in LPS-mediated nitric oxide (NO) production in RAW267.4 cells, based on their higher NO production as compared to that in the control. Moreover, overexpression of SsRomo1 enhanced the wound healing ability of FHM cells, indicating its high invasion and migration properties. We also determined the hydrogen peroxide-mediated cell viability of SsRomo1-overexpressed FHM cells and observed a significant reduction in viability, which is possibly due to increased ROS production. Collectively, our observations suggest that SsRomo1 plays an important role in oxidative stress modulation upon immune stimulation and in maintenance of tissue homeostasis in black rockfish.

Prolonged or Transition to Metabolically Unhealthy Status, Regardless of Obesity Status, Is Associated with Higher Risk of Cardiovascular Disease Incidence and Mortality in Koreans.

The risk of chronic disease and mortality may differ by metabolic health and obesity status and its transition. We investigated the risk of cardiovascular disease (CVD) and cancer incidence and mortality according to metabolic health and obesity status and their transition using the nationally representative Korea National Health and Nutrition Examination Survey (KNHANES) and the Ansan-Ansung (ASAS) cohort of the Korean Genome and Epidemiology Study. Participants that agreed to mortality linkage (n = 28,468 in KNHANES and n = 7530 adults in ASAS) were analyzed (mean follow-up: 8.2 and 17.4 years, respectively). Adults with no metabolic risk factors and BMI <25 or ≥25 kg/m2 were categorized as metabolically healthy non-obese (MHN) or metabolically healthy obese (MHO), respectively. Metabolically unhealthy non-obese (MUN) and metabolically unhealthy obese (MUO) adults had ≥1 metabolic risk factor and a BMI < or ≥25 kg/m2, respectively. In KNHANES participants, MUN, and MUO had higher risks for cardiovascular mortality, but not cancer mortality, compared with MHN adults. MHO had 47% and 35% lower risks of cancer mortality and all-cause mortality, respectively, compared to MHN. Similar results were observed in the ASAS participants. Compared to those persistently MHN, the risk of CVD was greater when continuously MUN or MUO. Transitioning from a metabolically healthy state to MUO also increased the risk of CVD. Few associations were found for cancer incidence. Using a nationally representative cohort and an 18-year follow-up cohort, we observed that the risk of CVD incidence and mortality and all-cause mortality, but not cancer incidence or mortality, increases with a continuous or a transition to an unhealthy metabolic status in Koreans.

Therapeutic effect of steroids on vestibular neuritis: Systematic review and meta-analysis.

OBJECTIVES: The present meta-analysis sought to assess further evidence for the efficacy of steroids in vestibular neuritis (VN). METHODS: The PubMed, EMBASE and Cochrane Library databases were searched through 30 August 2019. The main outcome measure was dizziness handicap inventory (DHI) and secondary outcomes included complete caloric recovery and improvement of canal paresis (CP). The follow-up times were divided into short, mid and long-term. RESULTS: Among 276 records identified, 5 studies (n = 253) were included in the analysis. The therapeutic effect of steroid on VN was confirmed (Hedges' g = 0.172, 95% CI 0.05-0.30, p = .006). Although there was no significant difference between steroids and control in the DHI score (Hedges' g = -0.323, 95% CI -0.533 to -0.113, p < .01), significant effect was seen on complete caloric recovery and improvement in CP (Hedges' g = 0.364, 95% CI 0.18-0.55, p < .0001; Hedges' g = 0.592, 95% CI 0.32-0.59, p < .0001). CONCLUSIONS: The results suggest that corticosteroids have an effect on the results of caloric tests for VN recovery, especially in long-term follow-up. However, in terms of dizziness handicap, we did not find any evidence of positive effect on corticosteroid. More data are required before recommendations can be made regarding management in patients on corticosteroids.

Development of theranostic dual-layered Au-liposome for effective tumor targeting and photothermal therapy.

BACKGROUND: Photothermal therapy (PTT) is an emerging anti-cancer therapeutic strategy that generates hyperthermia to ablate cancer cells under laser irradiation. Gold (Au) coated liposome (AL) was reported as an effective PTT agent with good biocompatibility and excretory property. However, exposed Au components on liposomes can cause instability in vivo and difficulty in further functionalization. RESULTS: Herein, we developed a theranostic dual-layered nanomaterial by adding liposomal layer to AL (LAL), followed by attaching polyethylene glycol (PEG) and radiolabeling. Functionalization with PEG improves the in vivo stability of LAL, and radioisotope labeling enables in vivo imaging of LAL. Functionalized LAL is stable in physiological conditions, and 64Cu labeled LAL (64Cu-LAL) shows a sufficient blood circulation property and an effective tumor targeting ability of 16.4%ID g-1 from in vivo positron emission tomography (PET) imaging. Also, intravenously injected LAL shows higher tumor targeting, temperature elevation in vivo, and better PTT effect in orthotopic breast cancer mouse model compared to AL. The tumor growth inhibition rate of LAL was 3.9-fold higher than AL. CONCLUSION: Based on these high stability, in vivo imaging ability, and tumor targeting efficiency, LAL could be a promising theranostic PTT agent.

Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme.

Radiotherapy is an essential step during the treatment of glioblastoma multiforme (GBM), one of the most lethal malignancies. The survival in patients with GBM was improved by the current standard of care for GBM established in 2005 but has stagnated since then. Since GBM is a radioresistant malignancy and the most of GBM recurrences occur in the radiotherapy field, increasing the effectiveness of radiotherapy using high-Z metal nanoparticles (NPs) has recently attracted attention. This review summarizes the progress in radiotherapy approaches for the current treatment of GBM, the physical and biological mechanisms of radiosensitization through high-Z metal NPs, and the results of studies on radiosensitization in the in vitro and in vivo GBM models using high-Z metal NPs to date.

Europium-Diethylenetriaminepentaacetic Acid Loaded Radioluminescence Liposome Nanoplatform for Effective Radioisotope-Mediated Photodynamic Therapy.

Photodynamic therapy (PDT) is an effective anticancer strategy with a higher selectivity and fewer adverse effects than conventional therapies; however, shallow tissue penetration depth of light has hampered the clinical utility of PDT. Recently, reports have indicated that Cerenkov luminescence-induced PDT may overcome the tissue penetration limitation of conventional PDT. However, the effectiveness of this method is controversial because of its low luminescence intensity. Herein, we developed a radiolabeled diethylenetriaminepentaacetic acid chelated Eu3+ (Eu-DTPA)/photosensitizer (PS) loaded liposome (Eu/PS-lipo) that utilizes ionizing radiation from radioisotopes for effective in vivo imaging and radioluminescence-induced PDT. We utilized Victoria blue-BO (VBBO) as a PS and observed an efficient luminescence resonance energy transfer between Eu-DTPA and VBBO. Furthermore, 64Cu-labeled Eu lipo demonstrated a strong radioluminescence with a 2-fold higher intensity than Cerenkov luminescence from free 64Cu. In our radioluminescence liposome, radioluminescence energy transfer showed a 6-fold higher energy transfer efficiency to VBBO than Cerenkov luminescence energy transfer (CLET). 64Cu-labeled Eu/VBBO lipo (64Cu-Eu/VBBO lipo) showed a substantial tumor uptake of up to 19.3%ID/g by enhanced permeability and retention effects, as revealed by in vivo positron emission tomography. Finally, the PDT using 64Cu-Eu/VBBO lipo demonstrated significantly higher in vitro and in vivo therapeutic effects than Cerenkov luminescence-induced PDT using 64Cu-VBBO lipo. This study envisions a great opportunity for clinical PDT application by establishing the radioluminescence liposome which has high tumor targeting and efficient energy transfer capability from radioisotopes.

Consumption of Fish and ω-3 Fatty Acids and Cancer Risk: An Umbrella Review of Meta-Analyses of Observational Studies.

Multiple studies have suggested that ω-3 fatty acid intake may have a protective effect on cancer risk; however, its true association with cancer risk remains controversial. We performed an umbrella review of meta-analyses to summarize and evaluate the evidence for the association between ω-3 fatty acid intake and cancer outcomes. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception to December 1, 2018. We included meta-analyses of observational studies that examined associations between intake of fish or ω-3 fatty acid and cancer risk (gastrointestinal, liver, breast, gynecologic, prostate, brain, lung, and skin) and determined the level of evidence of associations. In addition, we appraised the quality of the evidence of significant meta-analyses by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We initially screened 598 articles, and 15 articles, including 57 meta-analyses, were eligible. Among 57 meta-analyses, 15 reported statistically significant results. We found that 12 meta-analyses showed weak evidence of an association between ω-3 fatty acid intake and risk of the following types of cancer: liver cancer (n = 4 of 6), breast cancer (n = 3 of 14), prostate cancer (n = 3 of 11), and brain tumor (n = 2 of 2). In the other 3 meta-analyses, studies of endometrial cancer and skin cancer, there were no assessable data for determining the evidence levels. No meta-analysis showed convincing, highly suggestive, or suggestive evidence of an association. In the sensitivity analysis of meta-analyses by study design, we found weak associations between ω-3 fatty acid intake and breast cancer risk in cohort studies, but no statistically significant association in case-control studies. However, the opposite results were found in case of brain tumor risk. Although ω-3 fatty acids have been studied in several meta-analyses with regard to a wide range of cancer outcomes, only weak associations were identified in some cancer types, with several limitations. Considering the nonsignificant or weak evidence level, clinicians and researchers should cautiously interpret reported associations between ω-3 fatty acid consumption and cancer risks.

Comparison of balance outcomes according to treatment modality of vestibular schwannoma.

OBJECTIVES: We sought to compare balance outcomes according to treatment modality of vestibular schwannoma (VS) via a meta-analysis that divided measuring tools of balance outcomes into three categories based on type. METHODS: A comprehensive review of the literature from January 1966 to September 2017 was performed, looking for studies about long-term balance outcomes after microsurgery (MS), radiotherapy (RT), or observation for VS. A comprehensive meta-analysis was used to analyze effect sizes, explore possible causes of heterogeneity, and check publication bias with a funnel plot and Egger's regression. RESULTS: Among 633 references, 34 were included in the meta-analysis. Perceived dizziness improvement rate was significantly higher in the MS group than in the RT group (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.08 to 2.40; P < .05, I2 = 4.18], but no significant difference was observed between the two groups with regard to validated dizziness questionnaire score (standardized mean difference: 0.04; 95% CI: -0.36 to 0.44; P = .84, I2 = 69.61) or dizziness or disequilibrium-related symptom incidence rate (OR: 0.91; 95% CI: 0.50 to 1.68; P = .77, I2 = 0). In a subanalysis conducted within the groups after intervention, the MS group demonstrated a lower vertigo incidence rate (P < .001), and the RT group experienced a significant reduction in validated dizziness questionnaire score (P < .05). CONCLUSIONS: Our results indicate that MS should be considered at least equal to RT in regard to resolving long-term dizziness and improving balance outcomes. Furthermore, well-designed studies are necessary to predict balance outcomes after VS treatment and to choose from among possible treatment options. LEVEL OF EVIDENCE: 2a Laryngoscope, 130:178-189, 2020.

[Influence of Physical Symptoms and Lifestyle on Suicidal Ideation of Senior Grade Students in Elementary School]. / 초등학교 ê³ í•™ë „ 아동의 ì‹ ì²´ì¦ìƒ 및 생활습관이 자살생각에 미치는 영향.

PURPOSE: This study was conducted to analyze physical symptom-related and life-style factors affecting suicidal ideation of senior grade students in elementary school. METHODS: Physical symptom-related and life-style factors were used to investigate suicidal ideation among 663 elementary school students. From February 11 to 15, 2018, data were collected using a structured questionnaire and analyzed using the x2 test, Pearson correlation analysis, and logistic regression analysis in SPSS for Windows version 22.0. RESULTS: The factors affecting suicidal ideation were gender, family structure, economic status, academic performance, exposure to school violence during the past year, physical symptoms, drinking experience, smoking experience, sleeping time, and ramen noodle consumption. The regression analysis showed that exposure to school violence during the past year (odds ratio [OR]: 102.99, 95% confidence interval [CI]: 51.19~207.19, p=.001), number of physical symptoms (OR: 1.25, 95% CI: 1.12~1.41, p=.001), drinking experience (OR: 3.17, 95% CI: 1.66~6.06, p=.001), and game and internet usage time (OR: 2.08, 95% CI: 1.08~4.01, p=.029) affected suicidal ideation. CONCLUSION: This study revealed that physical symptoms and life-style significantly influenced suicidal ideation. Therefore, interventions to reduce suicidal ideation in children must focus on improving children's physical symptoms and life-style.

Effects of perioperative warm socks-wearing in maintaining core body temperature of patients undergoing spinal surgery.

AIMS AND OBJECTIVES: To investigate whether warming the feet with socks would prevent hypothermia among patients undergoing spinal surgery. BACKGROUND: Perioperative hypothermia is a common health problem among spinal surgery patients. RESEARCH DESIGN: This study used a quasi-experimental design. METHODS: Seventy-two patients were assigned to two groups. The control group (n = 36) received usual care without the warmed socks. The intervention group (n = 36) received usual care plus warmed socks during operation and recovery period. Data were collected during (180 min) and after the surgery (30 min) during the period of 7 February-10 April 2015. Core body temperature, shivering response and subjective thermal comfort of the two groups were compared over time using the repeated-measures ANOVA. RESULTS: The oesophageal temperature of the socks-wearing group was maintained between 36.36-36.45°C during surgery (mean = 36.41 ± 0.03, 95% CI = 36.34-36.47), whereas that of the control was between 35.75-35.97°C (mean = 35.98 ± 0.03, 95% CI = 35.92-36.04). The tympanic temperature in the recovery room of the socks-wearing group was between 36.28-36.38°C (mean = 36.37 ± 0.04, 95% CI = 36.29-36.45) and that of the control group was 35.90-36.04°C (mean = 35.95 ± 0.04, 95% CI = 35.88-36.05). Shivering response of the intervention group (mean = 0.04 ± 0.08, 95% CI = -0.13 to 0.21) was significantly lower than that of the control group (mean = 0.47 ± 0.08, 95% CI = 0.30-0.64) in the recovery room (F = 4.28, p < .001). As for subjective thermal comfort, the intervention group (mean = 4.86 ± 0.13, 95% CI = 4.62-5.13) was significantly lower than that of the control group (mean = 3.08 ± 0.13, 95% CI = 2.82-3.33) in the recovery room (F = 98.13, p < .001). As for the frequency of pethidine medication, the intervention group was significantly lower than that of the control (χ2  = 5.14, p = .023). CONCLUSION: The use of perioperative warmed socks for spinal surgery patients was effective in maintaining perioperative core temperature, preventing shivering and maintaining subjective thermal comfort. RELEVANCE TO CLINICAL PRACTICE: Considering cost-effectiveness of warmed socks, it might be worth trying option for the maintenance of core temperature in spinal surgery patients.