Coscinoderines A-J: Trisubstituted Pyridinium-Containing Norterpenoids Isolated from Coscinoderma bakusi, a Tropical Marine Sponge.

Ten new norterpene alkaloids, coscinoderines A-J (1-10), were isolated from the marine sponge Coscinoderma bakusi. Each coscinoderine contains a 1,2,5-trisubstituted pyridinium moiety bearing a terpene unit at the C-2 position. Their structures were elucidated by analysis of NMR and HRMS data, and the absolute stereochemistry of 4 with a 2-methylbutyl group attached to the nitrogen was determined from a comparison of the calculated and measured ECD spectra. The isolation of coscinoderines expands the repertoire of pyridinium alkaloids isolated from marine sponges.

Forsythiaside A Activates AMP-Activated Protein Kinase and Regulates Oxidative Stress via Nrf2 Signaling.

Forsythiaside A (FA) is an active constituent isolated from Forsythia suspensa, a beneficial herb used in traditional medicine known for its antioxidant and anti-inflammatory properties. Although various studies have suggested that FA has the protective effects, its impacts on arachidonic acid (AA) plus iron in vitro models and carbon tetrachloride (CCl4)-induced mouse liver damage in vivo have not been explored. In this study, HepG2 cells were subjected to AA + iron treatment to induce apoptosis and mitochondrial impairment and determine the molecular mechanisms. FA exhibited protective effects by inhibiting cell damage and reactive oxygen species (ROS) production induced by AA + iron, as assessed via immunoblot and flow cytometry analyses. Further molecular investigations revealed that FA resulted in the activation of extracellular-signal-related protein kinase (ERK), which subsequently triggered the activation of AMP-activated protein kinase (AMPK), a critical regulator of cellular oxidative stress. Additionally, FA modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which is a significant antioxidant transcription factor regulated by the AMPK pathway. For in vivo studies, mice were orally administered FA and then subjected to induction of CCl4-based hepatotoxicity. The protective effect of FA was confirmed via blood biochemistry and immunohistochemical analyses. In conclusion, our findings demonstrated the protective effects of FA against oxidative stress both in vitro and in vivo, thus indicating that FA is a potential candidate for liver protection. Our study sheds light on the mechanistic pathways involved in the antioxidant effects of FA, highlighting the hepatoprotective potential of naturally occurring compounds in traditional herbs, such as FA.

Anti-Inflammatory and Antiatopic Effects of Rorippa cantoniensis (Lour.) Ohwi in RAW 264.7 and HaCaT Cells.

This study evaluated the effects of Rorippa cantoniensis (Lour.) ohwi extract (RCE) on factors associated with inflammation-related skin lesions in RAW 264.7 and HaCaT cells. RCE inhibited the levels of proinflammatory mediators and cytokines such as nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In addition, RCE significantly inhibited the expression of chemokines and cytokines such as MDC/CCL22, TARC/CCL17, RANTES/CCL5, CTSS, IL-6, IL-1ß, and TNF-α in HaCaT cells costimulated by TNF-α and interferon (IFN)-γ in a concentration-dependent manner. These results suggest that RCE attenuated the TNF-α- and IFN-γ-induced release of proinflammatory chemokines and cytokines probably by suppressing the activation of MAPK (JNK and p38), NF-κB, and STAT1 signaling. Moreover, RCE significantly increased the expression of skin components such as hyaluronic acid and aquaporin, which play important roles in the physical and chemical barriers of the skin. These results suggest that RCE has significant anti-inflammatory and antiatopic activities, which may be beneficial for the topical treatment of inflammatory skin disorders.

Clinical Performance of the Osmotic Shock-MALDI MS Method to Detect Klebsiella pneumoniae Carbapenemase in Clinical Isolates.

The World Health Organization recently highlighted the serious worldwide problem of the emergence of antibiotic-resistant or antibiotic multidrug-resistant bacteria. Carbapenem-resistant Enterobacterales, including carbapenemase-producing Enterobacterales (CPE), are major antibiotic-resistant bacteria that can be identified by various methods, including antibiotic susceptibility testing, PCR, and immunologic assays. However, there is a need for a faster, more accurate, low-cost, and easy method to detect CPE strains. We previously developed an osmotic shock matrix-assisted laser desorption/ionization mass spectrometry (OS-MALDI MS) method for directly detecting intact Klebsiella pneumoniae carbapenemase (KPC) using osmotic shock cell lysis. In this study, we evaluated the OS-MALDI MS method and compared it with two other methods (octyl-glucoside-aided direct KPC detection method [OG-MALDI MS] and Bruker's MBT subtyping module indirect method [MBT-SM MALDI MS]). We first completed an analytical performance evaluation of the OS-MALDI MS method according to Clinical and Laboratory Standards Institute guidelines. Clinical testing was performed with 437 clinical isolates, including 292 KPC-producing bacteria and 145 non-KPC-producing bacteria. The OS-MALDI MS method exhibited 95.9% sensitivity, 100.0% specificity, and 100.0% precision for detecting KPC. Accuracy of the OS-MALDI MS, OG-MALDI MS, and MBT-SM MALDI MS methods was 97.3%, 55.9%, and 50.2%, respectively. In conclusion, the OS-MALDI MS method clearly outperformed the other methods, exhibiting the highest accuracy and sensitivity of the three methods. We propose the OS-MALDI MS method as a practical, useful method for clinic environments, which may help guide appropriate antibiotic treatment and contribute to the prevention of the spread of CPE.

Scalarane Sesterterpenoids Isolated from the Marine Sponge Hyrtios erectus and their Cytotoxicity.

Eighteen scalarane sesterterpenoids (1-18), including eight new derivatives (1-8), were isolated from the sponge Hyrtios erectus (family Thorectidae), the extract of which showed cytotoxicity against the HeLa and MCF-7 cell lines. Of the new derivatives, six compounds (1-6) were found to contain a γ-hydroxybutenolide moiety capable of reversible stereoinversion at the hydroxylated carbon center. Under the influence of other adjacent functional groups, each derivative exhibited a different stereochemical behavior, which was fully deduced by ROESY experiments. All the isolated compounds were examined for their cytotoxicity by MTS assay using staurosporine as a positive control (IC50 0.18 and 0.13 µΜ against HeLa and MCF-7 cells, respectively), and they were found to show weak growth inhibitory activities against HeLa and MCF-7 cells, with a minimal IC50 value of 20.0 µΜ. The compounds containing a γ-hydroxybutenolide moiety (1-3, 10, 12) showed cytotoxicity, with IC50 values ranging from 24.3 to 29.9 µΜ, and the most potent derivative was heteronemin (16). Although the cytotoxicities of isolated compounds were insufficient to discuss the structure-activity relationship, this research could contribute to expanding the structural diversity of scalaranes and understanding the stereochemical behavior of γ-hydroxybutenolides.

Operative treatment options for Morton's neuroma other than neurectomy - a systematic review.

BACKGROUND: The effectiveness of operative treatments other than neurectomy for Morton's neuroma remains debatable despite several reported studies. This review aimed to evaluate the effects of operative treatments for Morton's neuroma other than neurectomy using an algorithmic approach and a structured critical framework to assess the methodological quality of reported studies. METHODS: Several electronic databases were searched for articles published until August 2021 that evaluated the outcomes of operative treatments other than neurectomy in patients diagnosed with Morton's neuroma. Data searches, extraction, analysis, and quality assessments were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the clinical outcomes were evaluated using objective, subjective, and negative outcomes; complications; and reoperation rate and type. RESULTS: After reviewing 11,213 studies, 22 studies were finally included. Although a number of studies with high level of evidence are limited, we divided them according to four categories: (1) neurolysis with or without nerve transposition, (2) minimally invasive nerve decompression, (3) metatarsal osteotomy, and (4) additional procedures after nerve transection or neurectomy. All categories showed reliable outcomes except minimally invasive nerve decompression. The proportion of postoperative neurogenic symptoms was lower with neurolysis than with neurectomy. CONCLUSION: Whether the alternative procedures were superior to neurectomy remains unclear as the number of good quality studies was limited. The proportion of postoperative neurogenic symptoms was lower with neurolysis than with neurectomy. Furthermore, performing simultaneous dorsal transposition of the nerve along with neurolysis is more recommended than neurolysis alone. Surgeons should be more careful with minimally invasive deep transverse intermetatarsal ligament release and metatarsal shortening osteotomy as their effectiveness remains inconclusive. Finally, we strongly recommend performing intramuscular embedding or intermuscular transposition of the nerve cutting end if neurectomy or nerve transection is inevitable. LEVEL OF EVIDENCE: Level III, systematic review.

Increasing Trend of Nontuberculous Mycobacteria Isolation in a Referral Clinical Laboratory in South Korea.

Background and Objectives: Nontuberculous mycobacteria (NTM) infections are increasing worldwide. We evaluated the annual trends of NTM isolation on acid-fast bacillus (AFB) culture, compared to that of Mycobacterium tuberculosis, and the distribution of NTM species nationwide in South Korea. Materials and Methods: The study was conducted in a diagnostic center that is a major referral laboratory for the diagnosis of tuberculosis and NTM in South Korea. All laboratory results of AFB culture from January 2014 to December 2019 were collected. All NTM identified were definitively identified to the species level. Results: A total of 345,871 tests were performed for the diagnosis of mycobacteria. The isolation rate of NTM and M. tuberculosis was 3.7% (12,969 cases) and 4.4% (15,081 cases), respectively. The annual isolation rate of NTM increased gradually from 2.7% in 2014 to 4.8% in 2019, whereas that of M. tuberculosis decreased from 6.2% to 3.3%. There were 4988 cases of NTM identified to the species level. M. avium complex (MAC) was the most common species isolated from pulmonary sites (59.8%), followed by M. gordonae (9.2%), M. abscessus (7.0%), and M. fortuitum (5.5%). Extrapulmonary NTM were identified in 29 cases (0.6%). MAC was also the most common NTM species isolated from extrapulmonary sites (65.5%), followed by M. kansasii (10.3%), M. abscessus (6.9%), and M. fortuitum (6.9%). Conclusions: The annual isolation rate of NTM has increased gradually, whereas that of M. tuberculosis has decreased. Follow-up studies of the increases in NTM identification and NTM infections in South Korea are needed.

Shear Bond Strength of Different MDP-Containing Adhesive Systems on Enamel and Dentin from Primary Teeth.

OBJECTIVE: To compare the shear bond strength (SBS) after thermocycling of four universal adhesives applied in self-etch mode on dentin and etch-and-rinse mode on enamel. STUDY DESIGN: Flat 144 buccal or lingual dentin and enamel surfaces from 72 non-carious primary molars were prepared. Samples were segregated into 12 groups (n=12): Adper Single Bond 2 etch-and-rinse (SB_T) and Clearfil SE Bond self-etch (SE_S) applied to enamel and dentin served as controls. Scotch Bond Universal Adhesive (SBU), Clearfil S3 Bond Universal Adhesive (SEU), Tetric N-Bond Universal Adhesive (TEN), and All Bond Universal (BIS) were applied in etch-and-rinse mode to enamel and in self-etch mode to dentin. They were thermocycled for 5000 cycles. SBS testing and the evaluation of fracture mode were performed. RESULTS: SB_T showed statistically higher SBS than other adhesive groups using etch-and-rinse mode on enamel. SE_S and BIS had statistically higher SBS than other adhesive groups using self-etch mode on dentin. Mixed failure was the most common failure mode in each group. CONCLUSION: The universal adhesives did not show higher SBS than SB_T when using etch-and-rinse on enamel. All universal adhesives showed higher SBS than SB_T and had SBS similar to SE_S, except SBU when using self-etch mode on dentin.

Epidemiology of Congenital Bleeding Disorders: a Nationwide Population-based Korean Study.

BACKGROUND: Except for data in the Korea Hemophilia Foundation Registry, little is known of the epidemiology of congenital bleeding disorders in Korea. METHODS: Data were obtained from the Korean Health Insurance Review and Assessment Service (HIRA) database. RESULTS: From 2010 to 2015, there were 2,029 patients with congenital bleeding disorders in the Korean HIRA database: 38% (n = 775) of these patients had hemophilia A (HA), 25% (n = 517) had von Willebrand disease (vWD), 7% (n = 132) had hemophilia B (HB), and 25% (n = 513) had less common factor deficiencies. The estimated age-standardized incidence rate (ASR) of HA and HB was 1.78-3.15/100,000 and 0.31-0.51/100,000, respectively. That of vWD was 1.38-1.95/100,000. The estimated ASR of HA showed increase over time though the number of new patients did not increase. Most patients with congenital bleeding disorders were younger than 19 years old (47.8%), and most were registered in Gyeonggi (22.1%) and Seoul (19.2%). CONCLUSION: This is the first nationwide population-based study of congenital bleeding disorders in Korea. This study provides data that will enable more accurate estimations of patients with vWD. This information will help advance the comprehensive care of congenital bleeding disorders. We need to continue to obtain more detailed information on patients to improve the management of these diseases.

Clinical Considerations for Dental Management of Children with Molar-Root Incisor Malformations.

Molar root-incisor malformation (MRIM) or molar-incisor malformation (MIM) is a new type of dental anomaly characterized by dysplastic roots of permanent first molars, occasionally second primary molars, and the crowns of maxillary central incisors. MRIM involving permanent first molars and second primary molars is characterized by normal crowns with short, thin, and narrow roots, whereas MRIM involving permanent maxillary central incisors exhibits constrictions of the crown in the cervical area. In the first case, we extracted the affected first permanent molars at the optimal timing to minimize space deficiencies and induce space closure. In addition, composite resin restorations were performed on the anterior central incisors. In the second case, a mandibular lingual arch was used to stabilize the affected teeth in order to mitigate discomfort by reducing rotational biting forces.

Association between triglyceride glucose index and arterial stiffness in Korean adults.

BACKGROUND: The triglyceride glucose (TyG) index has been suggested as a simple surrogate marker of insulin resistance. However, there are limited data regarding the association between the TyG index and arterial stiffness in adults. Therefore, we evaluated the relationship between the TyG index and arterial stiffness as measured based on brachial ankle pulse wave velocity (baPWV) in Korean adults. METHODS: A total of 3587 subjects were enrolled in this study. Anthropometric and cardiovascular risk factors were measured. The TyG index was calculated as ln[fasting triglycerides(mg/dl) × fasting glucose(mg/dl)/2], and the insulin resistance index of homeostasis model assessment (HOMA-IR) was estimated. Arterial stiffness was determined by measuring baPWV. RESULTS: The subjects were stratified into four groups based on the TyG index. There were significant differences in cardiovascular parameters among the groups; the mean baPWV increased significantly with increasing TyG index. According to the logistic regression analysis after adjusting for multiple risk factors, the odds ratio (95% CI) for increased baPWV (> 75th percentile) for the highest and lowest quartiles of the TyG index was 2.92 (1.92-4.44) in men and 1.84 (1.15-2.96) in women, and the odds ratio for increased baPWV for the highest and lowest quartiles of the HOMA-IR was 1.80 (1.17-2.78) in men and 1.46 (1.06-2.47) in women, respectively. CONCLUSION: The TyG index is more independently associated with increased arterial stiffness than HOMA-IR in Korean adults.

TGF-ß Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition.

BACKGROUND/AIMS: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-ß (TGF-ß) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-ß type I receptor kinase, EW-7197, on HIF1α-derived TGF-ß signaling in cholestatic liver fibrosis. METHODS: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-ß signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. RESULTS: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. CONCLUSION: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-ß signaling.

Performance of two commercially available BCR-ABL1 quantification assays that use an international reporting scale.

BACKGROUND: Quantifying the BCR-ABL1 rearrangement is important for monitoring chronic myelogenous leukemia (CML). To standardize BCR-ABL1 quantification, the World Health Organization (WHO) established the first international genetic reference panel. Here, we compared the BCR-ABL1 levels determined using international scale (IS)-based commercially available assays. METHODS: BCR-ABL1 transcripts were quantified using two IS-based assays. 10-1, 10-2, 10-3, 10-4, 10-5 and 10-6 dilutions of the b3a2 positive RNA were used for evaluating linearity, precision, and limit of detection. Correlation of the assay was evaluated by using DNA obtained from CML patients carrying the BCR-ABL1 b3a2 and b2a2 types. RESULTS: Both Ipsogen and Asuragen assays showed fine linearity with reasonable %CV. LOD of each assay was calculated as 0.003% for Ipsogen, and 0.005% for Asuragen. By comparing the results that were lower than 10% by either one of the assay, Ipsogen and Asuragen results showed an overall good linear correlation with a tendency for the Ipsogen assay to show slightly higher levels than the Asuragen assay for b3a2 transcript. For b2a2, the tendency was opposite, with Asuragen showing higher values than the Ipsogen. CONCLUSIONS: Two commercially available IS-based BCR-ABL1 assays showed an overall good quantitative correlation. It should be taken into consideration that each assay tended to produce higher values than the other, depending on the BCR-ABL1 subtypes, suggesting that a separate conversion factor for each subtype can be more helpful when BCR-ABL1 transcript levels are converted into IS.

EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-ß/Smad and ROS signaling.

Fibrosis is an inherent response to chronic damage upon immense apoptosis or necrosis. Transforming growth factor-beta1 (TGF-ß1) signaling plays a key role in the fibrotic response to chronic liver injury. To develop anti-fibrotic therapeutics, we synthesized a novel small-molecule inhibitor of the TGF-ß type I receptor kinase (ALK5), EW-7197, and evaluated its therapeutic potential in carbon tetrachloride (CCl4) mouse, bile duct ligation (BDL) rat, bleomycin (BLM) mouse, and unilateral ureteral obstruction (UUO) mouse models. Western blot, immunofluorescence, siRNA, and ChIP analysis were carried out to characterize EW-7197 as a TGF-ß/Smad signaling inhibitor in LX-2, Hepa1c1c7, NRK52E, and MRC5 cells. In vivo anti-fibrotic activities of EW-7197 were examined by microarray, immunohistochemistry, western blotting, and a survival study in the animal models. EW-7197 decreased the expression of collagen, α-smooth muscle actin (α-SMA), fibronectin, 4-hydroxy-2, 3-nonenal, and integrins in the livers of CCl4 mice and BDL rats, in the lungs of BLM mice, and in the kidneys of UUO mice. Furthermore, EW-7197 extended the lifespan of CCl4 mice, BDL rats, and BLM mice. EW-7197 blocked the TGF-ß1-stimulated production of reactive oxygen species (ROS), collagen, and α-SMA in LX-2 cells and hepatic stellate cells (HSCs) isolated from mice. Moreover, EW-7197 attenuated TGF-ß- and ROS-induced HSCs activation to myofibroblasts as well as extracellular matrix accumulation. The mechanism of EW-7197 appeared to be blockade of both TGF-ß1/Smad2/3 and ROS signaling to exert an anti-fibrotic activity. This study shows that EW-7197 has a strong potential as an anti-fibrosis therapeutic agent via inhibition of TGF-ß-/Smad2/3 and ROS signaling.

Improvement of the fluorescence intensity during a flow cytometric analysis for rice protoplasts by localization of a green fluorescent protein into chloroplasts.

Protoplasts have been a useful unicellular system for various molecular biological analyses based on transient expression and single cell analysis using fluorescence-activated cell sorting (FACS), widely used as a powerful method in functional genomics. Despite the versatility of these methods, some limits based on low fluorescence intensity of a flow cytometric analysis (FCA) using protoplasts have been reported. In this study, the chloroplast targeting of fluorescent proteins (FPs) led to an eight-fold increase in fluorescence intensity and a 4.5-fold increase of transfection ratio from 14.7% to 65.7% as compared with their targeting into the cytoplasm. Moreover, the plot data of FCA shows that 83.3% of the K-sGFP population is under the threshold level, regarded as a non-transgenic population with background signals, while 65.7% of the K-sGFP population is spread on overall intervals. To investigate the reason underlying this finding, mRNA/protein levels and transfection efficiency were analyzed, and results suggest that mRNA/protein levels and transfection ratio are not much different between K-sGFP and KR-sGFP. From those results, we hypothesized that the difference of fluorescence intensity is not only derived from cellular events such as molecular level or transfection efficiency. Taken together, we suggest that the translocation of FPs into chloroplasts contributes to the improvement of fluorescence intensity in FCA and, apparently, plays an important role in minimizing the loss of the transfected population. Our study could be usefully applicable for highly sensitive FACS and FCA-investigations of green tissue.

Evaluating Prediction Models with Hearing Handicap Inventory for the Elderly in Chronic Otitis Media Patients.

BACKGROUND: This retrospective, cross-sectional study aimed to assess the functional hearing capacity of individuals with Chronic Otitis Media (COM) using prediction modeling techniques and the Hearing Handicap Inventory for the Elderly (HHIE) questionnaire. This study investigated the potential of predictive models to identify hearing levels in patients with COM. METHODS: We comprehensively examined 289 individuals diagnosed with COM, of whom 136 reported tinnitus and 143 did not. This study involved a detailed analysis of various patient characteristics and HHIE questionnaire results. Logistic and Random Forest models were employed and compared based on key performance metrics. RESULTS: The logistic model demonstrated a slightly higher accuracy (73.56%), area under the curve (AUC; 0.73), Kappa value (0.45), and F1 score (0.78) than the Random Forest model. These findings suggest the superior predictive performance of the logistic model in identifying hearing levels in patients with COM. CONCLUSIONS: Although the AUC for the logistic regression did not meet the benchmark, this study highlights the potential for enhanced reliability and improved performance metrics using a larger dataset. The integration of prediction modeling techniques and the HHIE questionnaire shows promise for achieving greater diagnostic accuracy and refining intervention strategies for individuals with COM.

Development of a Multiplex Real-Time PCR Assay for the Simultaneous Detection of Two Fungal Pathogens Causing Pneumonia.

Infectious diseases caused by fungal sources are of great interest owing to their increasing prevalence. Invasive fungal infections, including invasive pulmonary aspergillosis caused by Aspergillus fumigatus, and Pneumocystis pneumonia caused by Pneumocystis jirovecii, are significant causes of morbidity and mortality among immunocompromised patients. The accurate and timely detection of these pathogens in this high-risk population is crucial for effective patient management. We developed a multiplex real-time polymerase chain reaction (PCR) assay, RF2 mRT-PCR, specifically designed to detect two respiratory fungi, P. jirovecii and A. fumigatus, and evaluated its performance in specimens of patients with lower respiratory tract infection. The performance was evaluated using 731 clinical samples, 55 reference species, and one synthetic DNA. The reproducibility test yielded a probit curve with a lower limit of detection of 19.82 copies/reaction for P. jirovecii and 64.20 copies/reaction for A. fumigatus. The RF2 mRT-PCR assay did not cross-react with non-A. fumigatus Aspergillus species or other common bacterial and viral species, and showed 100% in vitro sensitivity and specificity with reference assays. Additionally, it simultaneously detected A. fumigatus and P. jirovecii in co-infected samples. Therefore, the RF2 mRT-PCR assay is an efficient and reliable tool for in vitro diagnosis of A. fumigatus and P. jirovecii pulmonary infections.

Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer.

Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).

Suppression of Toll-like receptor 4 activation by endogenous oxidized phosphatidylcholine, KOdiA-PC by inhibiting LPS binding to MD2.

OBJECTIVE: Activation of Toll-like receptor 4 (TLR4) triggers immune and inflammatory events by sensing endogenous danger signals as well as invading pathogens and contributes to the development of chronic inflammatory diseases. In this study, we investigated effect of 1-palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3-phosphocholine (KOdiA-PC), an oxidized phosphatidylcholine, on TLR4 activation and the underlying regulatory mechanism. METHODS: RAW264.7 macrophages were used for the study. The levels of TNF-α, IFN-ß, and COX-2 mRNA and protein were determined by quantitative PCR and ELISA, respectively. Activation of TLR4-signaling was examined by immunoblot and luciferase reporter assays. In vitro binding assay was performed to determine LPS binding to MD2. Macrophage migration was analyzed using a transwell-culture system. RESULTS: KOdiA-PC prevented the activation of TLR4-signaling components including ERK, JNK, p38, NF-κB, and IRF3 leading to decrease of TNF-α, IFN-ß, and COX-2 expression. In vitro binding assay revealed that KOdiA-PC interrupted LPS binding to MD2, a TLR4 co-receptor. Consistently, KOdiA-PC suppressed LPS-induced macrophage migration. CONCLUSION: The results demonstrate that KOdiA-PC can modulate TLR4 activation by regulating ligand-receptor interaction. Therefore, endogenously generated, oxidized phospholipids may play a role in resolving inflammation by terminating TLR activation and macrophage recruitment to the inflamed site.

Control of lateral dimension in metal-catalyzed germanium nanowire growth: usage of carbon sheath.

We report on the catalytic growth of thin carbon sheathed single crystal germanium nanowires (GeNWs), which can solve the obstacles that have disturbed a wide range of applications of GeNWs. Single crystal Ge NW core and amorphous carbon sheath are simultaneously grown via vapor-liquid-solid (VLS) process. The carbon sheath completely blocks unintentional vapor deposition on NW surface, thus ensuring highly uniform diameter, dopant distribution, and electrical conductivity along the entire NW length. Furthermore, the sheath not only inhibits metal diffusion but also improves the chemical stability of GeNWs at even high temperatures.