Safety and immunogenicity of the Euvichol-S oral cholera vaccine for prevention of Vibrio cholerae O1 infection in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial.

BACKGROUND: In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. FINDINGS: Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. INTERPRETATION: A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.

Effects of Mitochondrial Transplantation on Transcriptomics in a Polymicrobial Sepsis Model.

Previously, we demonstrated that mitochondrial transplantation has beneficial effects in a polymicrobial sepsis model. However, the mechanism has not been fully investigated. Mitochondria have their own genes, and genomic changes in sepsis are an important issue in terms of pathophysiology, biomarkers, and therapeutic targets. To investigate the changes in transcriptomic features after mitochondrial transplantation in a polymicrobial sepsis model, we used a rat model of fecal slurry polymicrobial sepsis. Total RNA from splenocytes of sham-operated (SHAM, n = 10), sepsis-induced (SEPSIS, n = 7), and sepsis receiving mitochondrial transplantation (SEPSIS + MT, n = 8) samples was extracted and we conducted a comparative transcriptome-wide analysis between three groups. We also confirmed these results with qPCR. In terms of percentage of mitochondrial mapped reads, the SEPSIS + MT group had a significantly higher mapping ratio than the others. RT1-M2 and Cbln2 were identified as highly expressed in SEPSIS + MT compared with SEPSIS. Using SHAM expression levels as another control variable, we further identified six genes (Fxyd4, Apex2l1, Kctd4, 7SK, SNORD94, and SNORA53) that were highly expressed after sepsis induction and observed that their expression levels were attenuated by mitochondrial transplantation. Changes in transcriptomic features were identified after mitochondrial transplantation in sepsis. This might provide a hint for exploring the mechanism of mitochondrial transplantation in sepsis.

The Mediating Effects of Food Content Watching Motivation on the between Watching Time and Nutrition Quotient of Adolescents in Seoul, Korea.

Food-related content varies widely and is increasingly popular. Using various media, teenagers can easily access food content, which could affect they eating habits. This study was conducted to confirm the effects of watching motivation on the relationship between food content watching time and eating habits among adolescents in Seoul, Korea. Exactly 806 participants were surveyed about their food content watching status, including watching time and watching motivation. The Nutrition Quotient for adolescents (NQ-A) questionnaire was used to confirm eating habits. Exploratory factor analysis was conducted to classify watching motivation's subfactors. A parallel multimedia model was used to analyze the effect of watching motivation on the relationship between food content watching time and eating habits. As a result of this study, following the factor analysis, watching motivation was classified into information acquisition, emotional satisfaction, and enjoyment. The influence of food content watching time on NQ-A scores through information acquisition motivation was positively significant, whereas that through emotional satisfaction motivation was negatively significant. Enjoyment motivation did not indirectly affect the relationship between food content watching time and NQ-A scores. Hence, attention should be paid to these mediating factors when analyzing the relationship between watching food-related content and eating habits. Developing and distributing content that meets viewing motivations should help improve adolescents' eating habits.

Improving the EMI shielding of graphene oxide (GNO)-coated glass-fiber-GNO-MA-grafted polypropylene (PP) composites and nylon 1D-2D nanocomposite foams.

The proliferation of the latest electronic gadgets and wireless communication devices can trigger electromagnetic interference (EMI), which has a detrimental impact on electronic devices and humans. Efficient EMI shielding materials are required for EMI-SE and they should be durable in external environments, lightweight, and cost-effective. GNO-coated glass-fiber-GNO-maleic anhydride-grafted polypropylene (MAPP) composite and carbon fiber-reinforced nylon 1D-2D nanocomposite foam were successfully prepared via a cost-effective thermal process. The composites were characterized using scanning electron microscopy (SEM), Raman spectroscopy, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The PP and nylon-based composites with ∼13% filler showed maximum electrical conductivity (EC) of 878 mS cm-1 and 1381 mS cm-1, respectively. The GNO-coated glass-fiber-GNO-MAPP foam displays a maximum EMI-SE of 120.6 dB, while the nylon graphene-carbon nanotube-metal nanoplatelet foam exhibits a maximum EMI-SE of 139.1 dB in the X-band region. The GFCFFeGMAPP composite possesses a minimum thickness of 2.56 mm and blocks most incoming radiation. These are some of the highest EMI-SE values reported so far for glass fiber and nylon-based composites, and the nylon-based composite showed excellent properties compared to the glass fiber-based composite. Thus, we believe that the developed composites can be used in a wide range of real applications, such as in military vehicles, aviation, automobiles, and the packaging of electronic circuits.

Freezing-enhanced oxidation of iodide by hydrogen peroxide in the presence of antifreeze proteins from the Arctic yeast Leucosporidium sp.AY30.

Ice-binding proteins (IBPs), originating from Arctic or Antarctic microorganisms, have freeze-inhibiting characteristics, allowing these organisms to survive in polar regions. Despite their significance in polar environments, the mechanism through which IBPs affect the chemical reactions in ice by controlling ice crystal formation has not yet been reported. In this study, a new mechanism for iodide (I-) activation into triiodide (I3-), which is the abundant iodine species in seawater, by using hydrogen peroxide (H2O2) in a frozen solution with IBPs was developed. A significant enhancement of I- activation into I3- was observed in the presence of Arctic-yeast-originating extracellular ice-binding glycoprotein (LeIBP) isolated from Leucosporidium sp. AY30, and a further increase in the I3- concentration was observed with the introduction of H2O2 to the frozen solution (25 times higher than in the aqueous solution after 24 h of reaction). The reaction in the ice increased with an increase in LeIBP concentration. The in-situ pH measurement in ice using cresol red (CR) revealed protons accumulated in the ice grain boundaries by LeIBP. However, the presence of LeIBP did not influence the acidity of the ice. The enhanced freeze concentration effect of H2O2 by LeIBP indicated that larger ice granules were formed in the presence of LeIBP. The results suggest that LeIBP affects the formation and morphology of ice granules, which reduces the total volume of ice boundaries throughout the ice. This leads to an increased local concentration of I- and H2O2 within the ice grain boundaries. IBP-assisted production of gaseous iodine in a frozen environment provides a previously unrecognized formation mechanism of active iodine species in the polar regions.

Reductive Transformation of Hexavalent Chromium in Ice Decreases Chromium Toxicity in Aquatic Animals.

In this study, the toxicity of hexavalent chromium [Cr(VI)] reduced by citric acid in ice was measured using representative aquatic model invertebrates (i.e., rotifer, water flea, amphipod, and polychaete) and a vertebrate (zebrafish) by analyzing short- and/or long-term endpoints that are frequently applied to each animal. Cr(VI) reduction in the presence of citric acid was markedly enhanced in the ice phase compared to that in an aqueous solution through the freeze concentration effect. The highly concentrated Cr(VI) and citric acid in ice grain boundaries were also confirmed using in situ cryogenic confocal Raman spectroscopy. Overall, exposure to Cr(VI) resulted in higher acute and/or chronic effects on aquatic animals, such as drastic mortality, growth inhibition, and decrease in offspring number, whereas the animals were increasingly tolerant to Cr(VI) that was reduced in the ice phase. Sublethal concentrations of Cr(VI) significantly decreased the antioxidant capacity in the aquatic animals. However, when the same concentrations of Cr(VI) were reduced in ice, these treatments showed no modulation or increase in the antioxidant defense system. Taken together, our results suggest that Cr(VI) reduction into Cr(III) was successfully achieved in ice and that this methodology can decrease the actual toxicity of Cr(VI) in aquatic animals.

Alleviation of renal ischemia/reperfusion injury by exosomes from induced pluripotent stem cell-derived mesenchymal stem cells.

BACKGROUND/AIMS: Renal ischemia followed by reperfusion (I/R) is a leading cause of acute kidney injury (AKI), which is closely associated with high morbidity and mortality. Studies have shown that induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) exert powerful therapeutic effects in renal ischemia. However, the efficacy of iMSC-derived exosomes (iExo) on I/R injuries remains largely unknown. METHODS: Human iPSCs were differentiated into iMSCs using a modified one-step method. Ultrafiltration, combined with purification, was used to isolate iExo from iMSCs. iExo was administered following I/R injury in a mouse model. The effect of iExo on I/R injury was assessed through changes in renal function, histology, and expression of oxidative stress, inflammation, and apoptosis markers. Further, we evaluated its association with the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. RESULTS: Mice subjected to I/R injury exhibited typical AKI patterns; serum creatinine level, tubular necrosis, apoptosis, inflammatory cytokine production, and oxidative stress were markedly increased compared to sham mice. However, treatment with iExo attenuated these changes, significantly improving renal function and tissue damage, similar to the renoprotective effects of iMSCs on I/R injury. Significant induction of activated ERK 1/2 signaling molecules was observed in mice treated with iExo compared to those in the I/R injury group. CONCLUSION: The present study demonstrates that iExo administration ameliorated renal damage following I/R, suggesting that iMSC-derived exosomes may provide a novel therapeutic approach for AKI treatment.

Physiological and molecular responses of the Antarctic harpacticoid copepod Tigriopus kingsejongensis to salinity fluctuations - A multigenerational study.

Since Antarctica and the surrounding Southern Ocean are facing global climate change, biota inhabiting those coastal regions is now challenged by environmental fluctuations including coastal freshening. In this study, the effects of salinity range of 0-75 (practical salinity unit, PSU) on the Antarctic harpacticoid copepod Tigriopus kingsejongensis was investigated by measurement of 96 h survival rate, lifespan, and sex ratio with further analysis of multigenerational growth parameters and mRNA expressions under salinity of 15-45. Different stages of the copepods (i.e., nauplius, male, and female) generally showed tolerance to hypo- and hypersalinity, wherein female copepods were more tolerant than males when exposed to salinity fluctuations. Lifespan was significantly shortened by hypo- and hypersalinity compared to control salinity (34), but there was no significant difference in the sex ratio between salinity treatments. Multigenerational experiments across five generations revealed that exposure to salinities of 15 and 45 reduced body length compared to that in control salinity and the first generation of each salinity group. Our results provide evidence regarding T. kingsejongensis on their preferred salinity ranges, physiological limit to salinity fluctuations, and population dynamics in future salinity.

Optimal delipidation solvent to secure extracellular matrix from human perirenal adipose tissue.

The objective of this study was to select the optimal delipidation solvent for preparation of human perirenal adipose tissue-derived extracellular matrix (ECM). Human perirenal adipose tissue can be obtained in large amounts during surgery, and it can be an alternative source of human ECM. Delipidation is an essential procedure for the ECM preparation, because lipid strongly inhibits regeneration of target tissue. Isopropanol has been widely used as a delipidation solvent for adipose tissue. However, because adipose tissue is mostly composed of nonpolar lipid, a nonpolar solvent might be more effective for delipidation. We evaluated the delipidation efficiency of acetone, chloroform, methanol, ether, ethanol, isopropanol, water, chloroform/methanol, ethanol/heptane, ether/methanol, hexane/ethanol, and butanol/methanol solvents for ECM extraction from human perirenal adipose tissue. Among them, acetone-treated adipose tissue showed the greatest delipidation efficiency (93.05%), significantly lower residual DNA content, and the greatest residual collagen concentration (42.49 ± 0.05 µg/g). In addition, acetone-treated tissue also had well-preserved ultrastructure with high porosity and significantly low in vitro cytotoxicity. These results suggested that acetone may be an optimal delipidation solvent for extraction of ECM from human perirenal adipose tissue.

The complete mitochondrial genome of the Arctic fairy shrimp Branchinectapaludosa (Müller, 1788) (Anostraca, Branchinectidae) from Sirius Passet, North Greenland.

Here we report the complete mitochondrial genome of the Arctic fairy shrimp, Branchinectapaludosa (Müller, 1788) (Anostraca, Branchinectidae), which was collected in the High Arctic of North Greenland. A complete 16,059 bp mitochondrion of B.paludosa was sequenced and assembled with the Illumina next generation sequencing platform. The B.paludosa mitogenome contains 13 PCGs, 22 tRNAs and 2 rRNA genes that are commonly observed in most metazoans and shows the conserved gene arrangement pattern of Anostraca. Our results of the phylogenomic analysis are consistent with the previous phylogenetic relationship, based on nuclear 18S ribosomal DNA. The B.paludosa mitogenome will be useful for understanding the geographical distribution and phylogenetic relationship of anostracans.

Acridine Based Small Molecular Hole Transport Type Materials for Phosphorescent OLED Application.

Two small molecular hole-transporting type materials, namely 4-(9,9-dimethylacridin-10(9H)-yl)-N-(4-(9,9-dimethylacridin-10(9H)-yl)phenyl)-N-phenylaniline (TPA-2ACR) and 10,10'-(9-phenyl-9H-carbazole-3,6-diyl)bis(9,9-dimethyl-9,10-dihydroacridine) (PhCAR-2ACR), were designed and synthesized using a single-step Buchwald-Hartwig amination between the dimethyl acridine and triphenylamine or carbazole moieties. Both materials showed high thermal decomposition temperatures of 402 and 422 °C at 5% weight reduction for PhCAR-2ACR and TPA-2ACR, respectively. TPA-2ACR as hole-transporting material exhibited excellent current, power, and external quantum efficiencies of 55.74 cd/A, 29.28 lm/W and 21.59%, respectively. The achieved device efficiencies are much better than that of the referenced similar, 1,1-Bis[(di-4-tolylamino)phenyl]cyclohexane (TAPC)-based device (32.53 cd/A, 18.58 lm/W and 10.6%). Moreover, phenyl carbazole-based PhCAR-2ACR showed good device characteristics when applied for host material in phosphorescent OLEDs.

Modeling of endothelial cell dysfunction using human induced pluripotent stem cells derived from patients with end-stage renal disease.

BACKGROUND: Endothelial cell (EC) dysfunction is a frequent feature in patients with end-stage renal disease (ESRD). The aim of this study was to generate human induced pluripotent stem cells, differentiate ECs (hiPSC-ECs) from patients with ESRD, and appraise the usefulness of hiPSC-ECs as a model to investigate EC dysfunction. METHODS: We generated hiPSCs using peripheral blood mononuclear cells (PBMCs) isolated from three patients with ESRD and three healthy controls (HCs). Next, we differentiated hiPSC-ECs using the generated hiPSCs and assessed the expression of endothelial markers by immunofluorescence. The differentiation efficacy, EC dysfunction, and molecular signatures of EC-related genes based on microarray analysis were compared between the ESRD and HC groups. RESULTS: In both groups, hiPSCs and hiPSC-ECs were successfully obtained based on induced pluripotent stem cell or EC marker expression in immunofluorescence and flow cytometry. However, the efficiency of differentiation of ECs from hiPSCs was lower in the ESRD-hiPSCs than in the HC-hiPSCs. In addition, unlike HC-hiPSC-ECs, ESRD-hiPSC-ECs failed to form interconnecting branching point networks in an in vitro tube formation assay. During microarray analysis, transcripts associated with oxidative stress and inflammation were upregulated and transcripts associated with vascular development and basement membrane extracellular matrix components were downregulated in ESRD-hiPSC-ECs relative to in HC-hiPSC-ECs. CONCLUSION: ESRD-hiPSC-ECs showed a greater level of EC dysfunction than HC-hiPSC-ECs did based on functional assay results and molecular profiles. hiPSC-ECs may be used as a disease model to investigate the pathophysiology of EC dysfunction in ESRD.

The complete mitochondrial genome of the terebellid polychaete Thelepus plagiostoma (Terebellida; Terebellidae).

Here, we report the complete mitogenome information of the terebellid polychaete, Thelepus plagiostoma (Schmarda, 1861). Genome sequencing by Illumina HiSeq platform permitted assembly of a circular mitochondrial genome of 15,628 bp from T. plagiostoma consisting of 67% AT nucleotides, 13 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a non-coding region in the typical annelid gene composition. Gene order of the T. plagiostoma mitochondrion is identical to those of the Terebelliformia mitogenomes. Phylogenetic reconstruction places T. plagiostoma within the monophyletic subclass Sedentaria, a sister to Pista cristata in the suborder Terebelliformia.

Characterization of the complete mitochondrial genome of the scale worm, Eunoe nodosa (Phyllodocida; Polynoidae) from the Beaufort Sea.

To increase the mitogenome data available for robust phylogeny, we sequenced the complete mitochondrial DNA of the scale worm Eunoe nodosa (Sars, 1861) in the family Polynoidae of the order Phyllodocida. The complete mitogenome has 15,366 bp and has 28.9% A, 13.2% C, 19.0% G, and 38.8% T. Using MITOS and tRNAscan-SE, we identified the 13 typical protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a non-coding region. Phylogenomic analysis based on 27 in-group taxa belonging to five families of the subclass Errantia show congruence with the published phylogenetic relationship within the Polynoidae, in which E. nodosa lies in the clade of shallow water species.

Event-related brain response to visual cues in individuals with Internet gaming disorder: relevance to attentional bias and decision-making.

This study investigated attentional bias toward game-related cues in Internet gaming disorder (IGD) using electrophysiological markers of late positive potential (LPP) and identifying the sources of LPP. In addition, the association between LPP and decision-making ability was investigated. The IGD (n = 40) and healthy control (HC; n = 39) participants viewed a series of game-related and neutral pictures, while their event-related potentials (ERPs) were recorded. LPPs were calculated as the mean amplitudes between 400 and 700 ms at the centro-parietal (CP3, CP1, Cpz, CP2, and CP4) and parietal (P3, P1, Pz, P2, and P4) electrode sites. The source activations of LPP were estimated using standardized low-resolution brain electromagnetic tomography (sLORETA). In addition, decision-making ability was evaluated by the Cambridge Gambling Task. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HC group. sLORETA showed that the IGD group was more active in the superior and middle temporal gyri, which are involved in social perception, than in the HC group, whereas it was less active in the frontal area. Individuals with IGD have deficits in decision-making ability. In addition, in the HC group, the lower the LPP when looking at the game-related stimuli, the better the quality of decision-making, but not in the IGD group. Enhanced LPP amplitudes are associated with emotional arousal to gaming cues and decision-making deficits in IGD. In addition, source activities suggest that patients with IGD perceive game-related cues as social stimuli. LPP can be used as a neurophysiological marker of IGD.

Regulation of osteoclastogenesis by mast cell in rheumatoid arthritis.

BACKGROUND: In the pathogenesis of rheumatoid arthritis (RA), the role of mast cells has not been revealed clearly. We aimed to define the inflammatory and tissue-destructive roles of mast cells in rheumatoid arthritis (RA). METHODS: Serum and synovial fluid (SF) concentration levels of tryptase, chymase, and histamine were quantified using ELISA. After activating mast cells using IL-33, the production of TNF-α, IL-1ß, IL-6, IL-17, RANKL, and MMPs was determined using real-time PCR and ELISA. Osteoclastogenesis was assessed in CD14+ monocytes from peripheral blood and SF, which were cultured with IL-33-activated mast cells, by counting TRAP-positive multinucleated cells. RESULTS: The concentration levels of serum tryptase, chymase, and histamine and SF histamine were higher in patients with RA than in controls. FcεR1 and c-kit-positive mast cells were higher in RA synovium than in osteoarthritic (OA) synovium. Stimulation of mast cells by IL-33 increased the number of trypatse+chymase- and tryptase+chymase+ mast cells. IL-33 stimulation also increased the gene expression levels of TNF-α, IL-1ß, IL-6, IL-17, RANKL, and MMP-9 in mast cells. Furthermore, IL-33 stimulated human CD14+ monocytes to differentiate into TRAP+ multinucleated osteoclasts. When CD14+ monocytes were co-cultured with mast cells, osteoclast differentiation was increased. Additionally, IL-33-activated mast cells stimulated osteoclast differentiation. The inhibition of intercellular contact between mast cells and monocytes using inserts reduced osteoclast differentiation. CONCLUSIONS: IL-33 increased inflammatory and tissue-destructive cytokines by activation of mast cells. Mast cells stimulated osteoclast differentiation in monocytes. Mast cells could stimulate osteoclastogenesis indirectly through production of tissue-destructive cytokines and directly through stimulation of osteoclast precursors.

Broussochalcone A Is a Novel Inhibitor of the Orphan Nuclear Receptor NR4A1 and Induces Apoptosis in Pancreatic Cancer Cells.

The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity, and NR4A1 silencing and treatment with its inactivators has been shown to inhibit pancreatic cancer cells and tumor growth. In this study, we identified broussochalcone A (BCA) as a new NR4A1 inhibitor and demonstrated that BCA inhibits cell growth partly by inducing NR4A1-mediated apoptotic pathways in human pancreatic cancer cells. BCA downregulated specificity protein 1 (Sp1)-mediated expression of an anti-apoptotic protein, survivin, and activated the endoplasmic reticulum (ER) stress-mediated apoptotic pathway. These results suggest that NR4A1 inactivation contributes to the anticancer effects of BCA, and that BCA represents a potential anticancer agent targeting NR4A1 that is overexpressed in many types of human cancers.

Spinal subdural hematoma: A report of 3 cases related to antiplatelet agent use and traumatic compression fracture.

Spinal subdural hematoma is a rare condition presenting with symptoms of back pain and neurologic deficits. The etiology is largely idiopathic, followed by anti-coagulant use and vascular malformation. Traumatic subdural hematomas associated with compression fractures are rare, with only a few old case reports. Magnetic resonance imaging is the modality of choice for the diagnosis of spinal subdural hematoma. Treatment is surgical decompression when neurologic deficits exist; however, conservative management is a good option in patients without neurologic symptoms with reported spontaneous hematoma regression. Herein, we report 3 cases of spinal subdural hematoma, 2 spontaneous cases related to anti-platelet agent use and 1 with acute traumatic compression fracture. T1-weighted fat-saturated images clearly showed the hematoma and increased the confidence level of the diagnosis. In summary, we suggest that magnetic resonance imaging can clearly visualize the spinal subdural hematoma and is excellent for diagnosis and follow up. Anti-platelet agent use and compression fracture are probable etiologies of spinal subdural hematoma.

Effect of Tissue-Selective Estrogen Complex on Hip Structural Geometry in Postmenopausal Women: A 12-Month Study.

Background: Hip structural analysis (HSA) is a method for evaluating bone geometry reflecting bone structural and biomechanical properties. However, tissue-selective estrogen complex (TSEC) treatment effects on HSA have not been investigated. Objective: This study was performed to evaluate the effect of TSEC treatment on hip geometry in postmenopausal Korean women. The treatment was given for 12 months, and hip geometry was measured by HSA. Materials and Methods: A total of 40 postmenopausal women who received TSEC containing conjugated estrogen 0.45 mg and bazedoxifene 20 mg for treating vasomotor symptoms were included in this retrospective cohort study. The changes in bone mineral density and parameters of HSA including the outer diameter, cross-sectional area, cross-sectional moment of inertia, cortical thickness, section modulus, and buckling ratio as determined by dual-energy X-ray absorptiometry were compared before and after 12 months of TSEC treatment. Results: Mean age and years since menopause were 55.1 and 4.5 years, respectively. Total hip bone mineral density significantly increased by 0.74% after treatment (P=0.011). The changes in HSA were mainly demonstrated in the narrow femoral neck: cross-sectional area (P=0.003) and cortical thickness (P<0.001) increased significantly. For the shaft region, only SM decreased significantly after treatment (P=0.009). However, most parameters did not change significantly with TSEC treatment in the intertrochanteric and shaft regions. Conclusions: Our findings demonstrate that 12 months of TSEC treatment could improve bone geometry as measured by HSA. The findings suggest that TSEC might be an interesting option for the prevention of fracture as well as osteoporosis in postmenopausal women.