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We explored the influence of D 2 O on the fibrillation kinetics and structural dynamics of amyloid intrinsically disordered proteins (IDPs), including α-synuclein, amyloid-β 1-42, and K18. Our findings revealed that fibrillation of IDPs was accelerated in D 2 O compared to that in H 2 O, exhibiting faster kinetics in contrast to the structured protein, insulin. Structural investigations using electrospray ionization ion mobility mass spectrometry and small-angle X-ray scattering combined with molecular dynamics simulations demonstrated that IDPs did not show significant structural changes that could influence accelerated fibrillation in D 2 O. Umbrella sampling of protein protofibrils verified that an increased level of hydrogen bonding of D 2 O and enhanced hydrophobic interactions stabilized β-sheet structured fibrils in D 2 O. These findings indicate that stabilizing β-sheet fibrils and a more hydrophobic microenvironment in D 2 O result in enhanced and faster fibrillation of IDPs. The study highlights the importance of considering D 2 O's differential impact on protein interactions when conducting structural and kinetic analyses, particularly for native peptides and proteins.

The effect of frailty transition and burden on the risk of all-cause mortality in South Korea remains unclear. This study aimed to investigate the risk of all-cause mortality using the most recent frailty index (FI), changes in FI, and frailty burden. We analyzed data from the Korean Genome and Epidemiology Study (2013-2020). A total of 3,134 participants aged 53-87 years with a computable FI based on the osteoporotic fracture index during their initial visit. The FI was updated biennially during re-examinations and changes between the initial and last visits were categorized into four groups: (1) improved or maintained to non-frail, (2) worsened to pre-frail, (3) improved or maintained to pre-frail, and (4) worsened or maintained to frail. We used the Cox proportional hazards model, adjusted for age, sex, education, lifestyle factors, and diseases. During the follow-up, 218 participants died. Compared to those who were robust at the last visit, pre-frailty and frailty were associated with an increased risk of all-cause death. Of those who visited > 2 times, 62.3% improved or remained robust, and had a decreased risk of all-cause death. Those with > 63% of pre-frailty or frailty burden significantly higher risk of death, with > 60% increase compared to their non-frail counterparts. Maintaining or achieving robustness is associated with a decreased risk of mortality. To prevent premature death and extend healthy life expectancy, identifying biological aging through surrogate measures and implementing interventions to maintain or achieve a robust health status are needed., (© 2024. The Author(s).)

Anticancer chemo-immunotherapy has gained considerable attention across various scientific domains as a prospective approach for the comprehensive eradication of malignant tumors. Recent research has particularly been focused on traditional anthracycline chemo drugs, such as doxorubicin and mitoxantrone. These compounds trigger apoptosis in tumor cells and evoke immunogenic cell death (ICD). ICD is a pivotal initiator of the cancer-immunity cycle by facilitating the release of damage-associated molecular patterns (DAMPs). The resultant DAMPs released from cancer cells effectively activate the immune system, resulting in an increase in tumor-infiltrating T cells. In this study, we have innovated a co-delivery strategy involving folate-modified liposomes to deliver doxorubicin and monophosphoryl lipid A (MPLA) simultaneously to tumor tissue. The engineered liposomes exploit the overexpression of folate receptors within the tumor tissues. Delivered doxorubicin initiates ICD at the tumor cells, further enhancing the immunogenic stimulus. Additionally, MPLA helps T cell priming by activating antigen-presenting cells. This intricate interplay culminates in a synergistic effect, ultimately resulting in an augmented and potentiated anticancer chemo-immunotherapeutic liposomal treatment.

Backgruound: To investigate the association between the time-varying resting heart rate (RHR) and change in RHR (∆RHR) over time and the risk of diabetes mellitus (DM) by sex., Methods: We assessed 8,392 participants without DM or atrial fibrillation/flutter from the Korean Genome and Epidemiology Study, a community-based prospective cohort study that was initiated in 2001 to 2002. The participants were followed up until December 31, 2018. Updating RHR with biennial in-study re-examinations, the time-varying ∆RHR was calculated by assessing the ∆RHR at the next follow-up visit., Results: Over a median follow-up of 12.3 years, 1,345 participants (16.2%) had DM. As compared with RHR of 60 to 69 bpm, for RHR of ≥80 bpm, the incidence of DM was significantly increased for both male and female. A drop of ≥5 bpm in ∆RHR when compared with the stable ∆RHR group (-5< ∆RHR <5 bpm) was associated significantly with lower risk of DM in both male and female. However, an increase of ≥5 bpm in ∆RHR was significantly associated with higher risk of DM only in female, not in male (hazard ratio for male, 1.057 [95% confidence interval, 0.869 to 1.285]; and for female, 1.218 [95% confidence interval, 1.008 to 1.471])., Conclusion: In this community-based longitudinal cohort study, a reduction in ∆RHR was associated with a decreased risk of DM, while an increase in ∆RHR was associated with an increased risk of DM only in female.

(1) Background : Peptides are appealing as pharmacological materials because they are easily produced, safe, and tolerable. Despite increasing gum-care awareness, periodontitis is still prevalent and is influenced by factors like high sugar consumption, smoking, and aging. Porphyromonas gingivalis is considered a major etiologic agent of periodontitis and activates the NLR family pyrin domain containing 3 (NLRP3) but is absent in melanoma 2 (AIM2) inflammasomes, resulting in pro-inflammatory cytokine release. (2) Methods : We examined the anti-inflammatory effects of 18 peptides derived from human stromal cell-derived factor-1 (SDF-1) on THP-1 macrophages. Inflammation was induced by P. gingivalis , and the anti-inflammatory effects were analyzed using molecular biological techniques. In a mouse periodontitis model, alveolar bone resorption was assessed using micro-CT. (3) Results : Of the 18 SDF-1-derived peptides, S10 notably reduced IL-1β and TNF-α secretion. S10 also diminished the P. gingivalis -induced expression of NLRP3, AIM2, ASC (apoptosis-associated speck-like protein), caspase-1, and IL-1β. Furthermore, S10 attenuated the enhanced TLR (toll-like receptor) signaling pathway and decreased the phosphorylation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). In addition, S10 mitigated alveolar bone loss in our P. gingivalis -induced mouse model of periodontitis. (4) Conclusions : S10 suppressed TLR/NF-κB/NLRP3 inflammasome signaling and the AIM2 inflammasome in our P. gingivalis -induced murine periodontitis model, which suggests that it has potential use as a therapeutic treatment for periodontitis.

Background: Non-alcoholic fatty liver disease (NAFLD) encompasses a heterogeneous spectrum ranging from simple steatosis to fibrosis and cirrhosis. Fibrosis, associated with long-term overall mortality and liver-related events, requires evaluation. Traditionally, liver biopsy has been the gold standard for diagnosing fibrosis. However, its invasive nature, potential complications, and sampling variability limit widespread use. Consequently, various non-invasive tests have been developed as alternatives for diagnosing fibrosis in NAFLD patients., Aim: This study aimed to compare the accuracy of non-invasive tests (NITs) and evaluate the diagnostic accuracy of acoustic radiation force impulse (ARFI), one of the point shear wave techniques, compared to conventional methods, assessing its effective role in diagnosis., Methods: This is a retrospective study; a total of 136 patients diagnosed with fatty liver disease through ultrasonography were enrolled. The anthropometric data of the patients were collected on the day of admission and blood tests, measurements of ARFI, and a point shear test were conducted using abdominal ultrasound; a biopsy was performed the following day. In addition, we calculated the aspartate aminotransferase-to-platelet ratio index (APRI) index based on four factors (FIB-4) and the NAFLD fibrosis score (NFS). Subsequently, we assessed the diagnostic accuracy of NITs within various subgroups based on the extent of obesity, steatosis, or NAFLD activity score., Results: ARFI has been shown to have the highest diagnostic value among various NITs, with AUROC values of 0.832, 0.794, 0.767, and 0.696 for ARFI, APRI, FIB-4, and NFS, respectively. In the morbidly obese subgroup, the AUROC values of ARFI, APRI, FIB-4, and NFS were 0.805, 0.769, 0.736, and 0.674. In the group with severe steatosis or non-alcoholic steatohepatitis (NASH), the AUROC values were 0.679, 0.596, 0.661, and 0.612, respectively, for severe steatosis and 0.789, 0.696, 0.751, and 0.691, respectively, for NASH., Conclusions: In conclusion, ARFI is not affected by various factors and maintains diagnostic accuracy compared to serum NITs. Therefore, we can recommend ARFI as a valuable diagnostic test to screen for advanced fibrosis in patients with NAFLD.

In this study, selenium (Se)-rich antimony selenide (Sb 2 Se 3 ) films were fabricated by applying a solution process with the solvents ethylenediamine and 2-mercaptoethanol to optimize the photoelectrochemical (PEC) performance of the Sb 2 Se 3 photocathode. Various antimony (Sb)-Se precursor solutions with different molar ratios of Sb and Se (Sb : Se = 1 : 1.5, 1 : 3, 1 : 4.5, 1 : 7.5, and 1 : 9) were prepared to attain Se-rich fabrication conditions. As a result, the Se-rich Sb 2 Se 3 films fabricated using the Sb-Se precursor solution with a molar ratio of Sb : Se = 1 : 7.5 exhibited an improved PEC performance, compared to the stoichiometric Sb 2 Se 3 film. The charge transport was improved by the abundant Se element and thin selenium oxide (Se 2 O 3 ) layer in the Se-rich Sb 2 Se 3 film, resulting in a decrease in Se vacancies and substitutional defects. Moreover, the light utilization in the long wavelength region above 800 nm was enhanced by the light-trapping effect because of the nanowire structure in the Se-rich Sb 2 Se 3 film. Hence, the optimal Se-rich Sb 2 Se 3 photocathodes showed an improved photocurrent density of -0.24 mA cm -2 at the hydrogen evolution reaction potential that was three times higher than that of the stoichiometric Sb 2 Se 3 photocathodes (-0.08 mA cm -2 )., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Cuprous oxide (Cu 2 O) has been intensively in the limelight as a promising photocathode material for photoelectrochemical (PEC) water splitting. The state-of-the-art Cu 2 O photocathode consists of a back contact layer for transporting the holes, an overlayer for accelerating charge separation, a protection layer for prohibiting the photocorrosion, and a hydrogen evolution reaction (HER) catalyst for reducing the overpotential of HER, as well as a Cu 2 O layer for absorbing sunlight. In this review, the fundamentals and recent research progress on these components of efficient and durable Cu 2 O photocathodes are analyzed in detail. Furthermore, key strategies on the development of Cu 2 O photocathodes for the practical PEC water-splitting system are suggested. It provides the specific guidelines on the future research direction for the practical application of a PEC water-splitting system based on Cu 2 O photocathodes.

Background: Adverse lipid profiles are observed in postmenopausal women. However, there is insufficient evidence of the association between lipids and reproductive aging in Korean women. We aimed to characterize lipid changes with respect to timing relative to menopause in Korean middle-aged women., Methods: This study included 1,436 premenopausal women who had a natural menopause during the follow-up period (median = 15.76 years) from the Korean Genome and Epidemiology Study (KoGES) Ansan and Anseong cohort. Lipid levels were measured every 2 years, and the magnitudes of annual lipid changes and differences in the changes by premenopausal body mass index were estimated using piecewise linear mixed-effects models., Results: All lipid levels increased greatly from 3 or 5 years before menopause to 1 year after menopause in all women, regardless of their premenopausal body mass index. During the period, high-density lipoprotein cholesterol (HDL-C) levels increased at 0.42 mg/dL per year (95% confidence interval [CI], 0.29 to 0.55 mg/dL). Nevertheless, non-HDL-C levels simultaneously increased at 3.42 mg/dL per year (95% CI, 3.11 to 3.72 mg/dL), and an annual change in the non-HDL-C to HDL-C ratio was 0.05 (95% CI, 0.04 to 0.06). One year after menopause, changes in all lipid parameters significantly slowed down, except for the non-HDL-C to HDL-C ratio ( P < 0.001 for all). The ratio continued to increase until 3 years after menopause, but thereafter, the change leveled off., Conclusion: Women experienced remarkable increases in lipid levels during menopausal transition, highlighting the need for early intervention strategies for cardiovascular disease prevention in women., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Cisplatin resistance along with chemotherapy-induced neuropathic pain is an important cause of treatment failure for many cancer types and represents an unmet clinical need. Therefore, future studies should provide evidence regarding the mechanisms of potential targets that can overcome the resistance as well as alleviate pain. Here, we show that the emergence of cisplatin resistance is highly associated with EGFR hyperactivation, and that EGFR hyperactivation is arisen by a transcriptional increase in the pain-generating channel, TRPV1, via NANOG. Furthermore, TRPV1 promotes autophagy-mediated EGF secretion via Ca 2+ influx, which activates the EGFR-AKT signaling and, consequentially, the acquisition of cisplatin resistance. Importantly, TRPV1 inhibition renders tumors susceptible to cisplatin. Thus, our findings indicate a link among cisplatin resistance, EGFR hyperactivation, and TRPV1-mediated autophagic secretion, and implicate that TRPV1 could be a crucial drug target that could not only overcome cisplatin resistance but also alleviate pain in NANOG + cisplatin-resistant cancer., (© 2023. The Author(s).)

Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. In a recent phase I study, Venetoclax (ABT-199) targeting Bcl-2 also exhibited disappointing response rates in patients with relapsed/refractory DLBCL, suggesting that targeting only Bcl-2 is not sufficient for achieving successful efficacy due to the concurrent oncogenic function of c-Myc expression and drug resistance following an increase in Mcl-1. Therefore, co-targeting c-Myc and Mcl-1 could be a key combinatorial strategy to enhance the efficacy of Venetoclax. In this study, BR101801 a novel drug for DLBCL, effectively inhibited DLBCL cell growth/proliferation, induced cell cycle arrest, and markedly inhibited G0/G1 arrest. The apoptotic effect of BR101801 was also observed by increased Cytochrome C, cleaved PARP, and Annexin V-positive cell populations. This anti-cancer effect of BR101801 was confirmed in animal models, where it effectively inhibited tumor growth by reducing the expression of both c-Myc and Mcl-1. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL., Competing Interests: None., (AJCR Copyright © 2023.)

During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms' tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prevention strategies for atrial fibrillation (AF) are lacking. This study aimed to identify modifiable risk factors (MRFs) and estimate their impact on AF in the midlife general population. We assessed 9049 participants who were free of prevalent AF at baseline from the Korean Genome and Epidemiology Study. Cox models with time-varying assessment of risk factors were used to identify significant MRFs for incident AF. The MRF burden was defined as the proportion of visits with MRFs during follow-up. Over a median follow-up of 13.1 years, 182 (2.01%) participants developed AF. Three MRFs, including systolic blood pressure (SBP) ≥ 140 mmHg, obesity with central obesity, and an inactive lifestyle were significantly associated with incident AF. Among participants with 3, 2, 1, and 0 MRFs at baseline, 16 (3.9%), 51 (2.5%), 90 (1.8%) and 25 (1.5%) had incident AF, respectively. Compared to participants with three MRFs, those with one or no MRFs had a decreased risk of AF (hazard ratio [95% CI] for one MRF, 0.483 [0.256-0.914]; and for no MRF, 0.291 [0.145-0.583]). A decreasing MRF burden was associated with reduced AF risk (hazard ratio [95% CI] per 10% decrease in burden for SBP ≥ 140 mmHg, 0.937 [0.880-0.997]; for obesity with central obesity, 0.942 [0.907-0.978]; for inactivity, 0.926 [0.882-0.973]). Maintaining or achieving MRF ≤ 1 was associated with decreased AF risk, suggesting that minimizing the burden of MRF might help prevent AF., (© 2022. The Author(s).)

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

Amyloid proteins that undergo self-assembly to form insoluble fibrillar aggregates have attracted much attention due to their role in biological and pathological significance in amyloidosis. This study aims to understand the amyloid aggregation dynamics of insulin (INS) in H 2 O using two-dimensional infrared (2D-IR) spectroscopy. Conventional IR studies have been performed in D 2 O to avoid spectral congestion despite distinct H-D isotope effects. We observed a slowdown of the INS fibrillation process in D 2 O compared to that in H 2 O. The 2D-IR results reveal that different quaternary structures of INS at the onset of the nucleation phase caused the distinct fibrillation pathways of INS in H 2 O and D 2 O. A few different biophysical analysis, including solution-phase small-angle X-ray scattering combined with molecular dynamics simulations and other spectroscopic techniques, support our 2D-IR investigation results, providing insight into mechanistic details of distinct structural transition dynamics of INS in water. We found the delayed structural transition in D 2 O is due to the kinetic isotope effect at an early stage of fibrillation of INS in D 2 O, i.e. , enhanced dimer formation of INS in D 2 O. Our 2D-IR and biophysical analysis provide insight into mechanistic details of structural transition dynamics of INS in water. This study demonstrates an innovative 2D-IR approach for studying protein dynamics in H 2 O, which will open the way for observing protein dynamics under biological conditions without IR spectroscopic interference by water vibrations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Several point mutations can modulate protein structure and dynamics, leading to different natures. Especially in the case of amyloidogenic proteins closely related to neurodegenerative diseases, structural changes originating from point mutations can affect fibrillation kinetics. Herein, we rationally designed mutant candidates to inhibit the fibrillation process of amyloid-β with its point mutants through multistep in silico analyses. Our results showed that the designed mutants induced kinetic self-assembly suppression and reduced the toxicity of the aggregate. A multidisciplinary biophysical approach with small-angle X-ray scattering, ion mobility-mass spectrometry, mass spectrometry, and additional in silico experiments was performed to reveal the structural basis associated with the inhibition of fibril formation. The structure-based design of the mutants with suppressed self-assembly performed in this study could provide a different perspective for modulating amyloid aggregation based on the structural understanding of the intrinsically disordered proteins.

Cu 2 O/CuO heterostructure is a well-known strategy to improve the performance of Cu 2 O photocathodes for photoelectrochemical (PEC) water splitting. The CuO thickness in the Cu 2 O/CuO heterostructure is considered as a critical factor affecting the PEC performance because it is highly related to the light utilization and charge separation/transport. In this study, the Cu 2 O/CuO photocathode tailoring the CuO thickness was investigated to examine the CuO thickness influence on the PEC performance. Cu 2 O/CuO photocathodes were prepared by the electrodeposition and subsequent thermal annealing process and the Cu 2 O/CuO heterostructure was controlled by the annealing temperature and time. It was demonstrated that the increased CuO thickness enhances the light absorption in the long wavelength region and improves the charge separation by the reinforced band bending. However, the thick CuO hinders the efficient charge transport in the Cu 2 O/CuO heterostructure, resulting in the decreased PEC performance. Therefore, it is necessary to optimize the CuO thickness for the enhanced PEC performance of Cu 2 O/CuO photocathodes. Consequently, the Cu 2 O/CuO photocathode consisting of the similar CuO thickness with its minority carrier diffusion length (∼90 nm) was fabricated by annealing at 350 °C for 20 min, and it shows the optimal PEC performance (-1.2 mA cm -2 at 0 V vs. RHE) in pH 6.5 aqueous solution, resulting from the enhanced light utilization and the reinforced band bending., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Cuprous oxide (Cu 2 O) is a promising photocathode material for photoelectrochemical (PEC) water splitting. Recently, the PEC performances of Cu 2 O-based devices have been considerably improved by introducing nanostructures, semiconductor overlayers, and hydrogen evolution reaction (HER) catalysts. However, Cu 2 O devices still suffer from poor stability in aqueous solution, especially in strong acidic or alkaline conditions, despite the use of an intrinsically stable oxide overlayer as a protection layer. Thus, it is essential to fully understand the stability of the entire Cu 2 O photocathodes in these conditions for establishing suitable protection strategies to achieve durable PEC water splitting. In this work, the stability of bare and protected Cu 2 O nanowire (NW) photocathodes was evaluated in detail using microscopy techniques and compositional analyses. The insights gained in this work will guide the design and synthesis of durable photoelectrodes for PEC water splitting.

DNA-dependent protein kinase (DNA-PK), an essential component of the non-homologous end-joining (NHEJ) repair pathway, plays an important role in DNA damage repair (DDR). Therefore, DNA-PK inhibition is a promising approach for overcoming radiotherapy or chemotherapy resistance in cancers. In this study, we demonstrated that BR101801, a potent DNA-PK inhibitor, acted as an effective radiosensitizer in various human solid cancer cells and an in vivo xenograft model. Overall, BR101801 strongly elevated ionizing radiation (IR)-induced genomic instability via induction of cell cycle G 2 /M arrest, autophagic cell death, and impairment of DDR pathway in human solid cancer cells. Interestingly, BR101801 inhibited not only phosphorylation of DNA-PK catalytic subunit in NHEJ factors but also BRCA2 protein level in homologous recombination (HR) factors. In addition, combination BR101801 and IR suppressed tumor growth compared with IR alone by reducing phosphorylation of DNA-PK in human solid cancer xenografts. Our findings suggested that BR101801 is a selective DNA-PK inhibitor with a synergistic radiosensitizing effect in human solid cancers, providing evidence for clinical applications., Competing Interests: None., (AJCR Copyright © 2021.)

Oncogenic KRAS G12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRAS G12D -mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRAS G12D -induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRAS G12D -driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hemoglobin (Hb) is a major oxygen-transporting protein with allosteric properties reflected in the structural changes that accompany binding of O 2 . Glycated hemoglobin (GHb), which is a minor component of human red cell hemolysate, is generated by a nonenzymatic reaction between glucose and hemoglobin. Due to the long lifetime of human erythrocytes (∼120 days), GHb is widely used as a reliable biomarker for monitoring long-term glucose control in diabetic patients. Although the structure of GHb differs from that of Hb, structural changes relating to the oxygen affinity of these proteins remain incompletely understood. In this study, the oxygen-binding kinetics of Hb and GHb are evaluated, and their structural dynamics are investigated using solution small-angle X-ray scattering (SAXS), electrospray ionization mass spectrometry equipped with ion mobility spectrometry (ESI-IM-MS), and molecular dynamic (MD) simulations to understand the impact of structural alteration on their oxygen-binding properties. Our results show that the oxygen-binding kinetics of GHb are diminished relative to those of Hb. ESI-IM-MS reveals structural differences between Hb and GHb, which indicate the preference of GHb for a more compact structure in the gas phase relative to Hb. MD simulations also reveal an enhancement of intramolecular interactions upon glycation of Hb. Therefore, the more rigid structure of GHb makes the conformational changes that facilitate oxygen capture more difficult creating a delay in the oxygen-binding process. Our multiple biophysical approaches provide a better understanding of the allosteric properties of hemoglobin that are reflected in the structural alterations accompanying oxygen binding.

To improve the surface characteristics of Ti-6Al-4V dental implants and the binding between the bone and implant surface, biocompatible oxide films were formed by plasma electrolytic oxidation (PEO). The PEO treatment was performed using electrolyte solutions containing Ca (calcium acetate monohydrate), P(calcium glycerophosphate), Mn (manganese(II) acetate tetrahydrate), and Si (sodium metasilicate nonahydrate), which are the major constituents of bone, for 3 min at 280 V. The morphology and crystalline phase of the PEO-treated surfaces were characterized using field-emission scanning electron microscopy, energy-dispersive X-ray spectrometry, X-ray diffraction, and Fourier transform infrared spectroscopy. All the obtained PEO-treated samples exhibited a morphology comprising porous structures. Oval and irregular pore structures were observed as the Mn content increased. As the Si content increased, the areas occupied by the pores increased. When both, Si and Mn were used for the PEO treatment, the number of nano- to micro-sized pores gradually decreased with the increasing ratios of the constituents.

The purpose of this study was to investigate electrochemical analysis of nano- and micro-sized pore formed Ti-6Al-4V alloys in solution containing Ca, P, Mn and Si ions via plasma eletrolytic oxidation for bio-implant materials. The coatings were produced on Ti-6Al-4V alloy for dental implant using the plasma electrolytic oxidation (PEO) method in electrolytes with the various concentration of 0, 5, and 20% Mn and Si, respectively. Electrochemical potentiodynamic polarization and AC impedance behaviors were carried out in 0.9% NaCl solution at 36.5 ± 1 °C using potentiostat (Potentiostat, EG&G, 362) and electrochemical impedance spectroscope (EIS, EG&G, 1025). The potentiodynamic polarization test with a scan rate of 1.667 mV s -1 was carried out from -1500 mV to 2000 mV. The frequency range used for EIS was 10²-10 5 Hz. The amplitude of AC signal was 10 mV and 5 points per decade was used. From the potentiodynamic polarization test, PEO treated alloy in electrolyte containing Ca, P, Mn, and Si show a lower corrosion potential than that on the bulk surface. In the case of Mn and Si doped surface, the corrosion resistance increase compared to non-doped surface with Mn and Si elements, and the current density was lower than that of the bulk surface. From the AC impedance test, in the case of Mn and Si doped surface, polarization resistance values were higher than other specimens, and nano- and micro-sized pores were covered with corrosion product consisted Mn and Si elements.

KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape. In addition, the anticancer effect of RT22-ep59 was observed in the high-EpCAM-expressing pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells, but it had little effect on the low-EpCAM-expressing pancreatic cancer cells. Additionally, co-treatment with RT22-ep59 and gemcitabine synergistically inhibited cell viability, migration, and invasion in 3D-cultures and exhibited synergistic anticancer activity by inhibiting the RAF/ERK or PI3K/AKT pathways in cells with high-EpCAM expression. In an orthotopic mouse model, combined administration of RT22-ep59 and gemcitabine significantly inhibited tumor growth. Furthermore, the co-treatment suppressed cancer metastasis by blocking EMT signaling in vitro and in vivo. Our results demonstrated that RT22-ep59 synergistically increased the antitumor activity of gemcitabine by inhibiting RAS signaling by specifically targeting KRAS. This indicates that co-treatment with RT22-ep59 and gemcitabine might be considered a potential therapeutic strategy for pancreatic cancer patients harboring KRAS mutation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study is to compare the antibacterial activity of currently purchasable denture cleansers against Candida albicans ., Materials and Methods: This study used tablet-type denture cleansers, Polident®, Coolingdent® and Fittydent®, along with liquid denture cleansers, Hexamedine®, Listerine® and Apple vinegar®. The antibacterial activities of denture cleansers were evaluated based on the number of C. albicans and concentrations of the denture cleansers., Results: In the 0.5 × 10 6 cfu/ml culture medium, the C. albicans ' death rate of Polident® was significantly lower than those of Fittydent®, Hexamedine®, Listerine®, and Apple vinegar®( P <.05). In the 0.5 × 10 7 cfu/, the C. albicans ' death rates of Polident® and Coolingdent® were significantly lower than those of Fittydent®, Hexamedine®, Listerine® and Apple vinegar®( P <.05). The C. albicans ' death rates of Polident® and Coolingdent® were significantly decreased at 0.02 g and 0.01 g. The C. albicans ' death rate of Fittydent® was significantly decreased at 0.005 g ( P <.05). The C. albicans ' death rate of Hexamedine® was significantly decreased at 1/16 dilution. The C. albicans ' death rate of Listerine® was decreased at 1/8 dilution, and the antibacterial activity of Apple vinegar® was decreased at 1/4 dilution ( P <.05)., Conclusion: As the number of C. albicans increased, the antibacterial activities of the denture cleansers decrease. In the tablet-type denture cleanser, all denture cleansers showed 100% C. albicans ' death rate when used at a dose of 1 tablet. One denture cleanser showed the same antibacterial effect with only 1/3 of a tablet. In the liquid type denture cleanser, the level of dilution required was different for each denture cleanser., (© 2021 The Korean Academy of Prosthodontics.)

Background: We evaluated the effects of ultrasonic activation on root canal filling quality of the single-cone (SC) obturation technique with calcium silicate sealers and gutta percha cones., Methods: Thirty-six human single-rooted premolars were obturated with gutta percha and sealer. For the continuous wave (CW) group (n = 12), AH Plus with a continuous wave technique was used. The SC group (n = 12) received EndoSequence BC sealer with a single-cone technique. The SCU (SC with the addition of ultrasonic activation) group (n = 12) received the same treatment. Micro-computed tomography was used to scan the teeth, and the void volume within the root canal was evaluated at the apical, middle, and coronal levels. Then cross-sections were observed under a light microscope and scanning electron microscope (SEM)., Results: Void volume was significantly lower in the SCU group than in the CW and SC groups. There were no statistically significant differences between the CW and SC groups. The SCU group had fewer voids than the CW and SC groups in the coronal and middle third areas. Specimens showed no apparent gaps or voids in any group. SEM images revealed both gap-free and gap-containing regions at different levels in all groups., Conclusions: Single-cone obturation with calcium silicate-based sealers might obtain enhanced filling quality when used with ultrasonic activation.

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To determine the prognostic value of atrial fibrillation (AF) in patients with heart failure (HF) and preserved, mid-range or reduced ejection fraction (EF)., Methods: Patients hospitalised for acute HF were enrolled in the Korean Acute Heart Failure registry, a prospective, observational, multicentre cohort study, between March 2011 and February 2014. HF types were defined as reduced EF (HFrEF, LVEF <40%), mid-range EF (HFmrEF, LVEF 40%-49%) or preserved EF (HFpEF, LVEF ≥50%)., Results: Of 5414 patients enrolled, HFrEF, HFmrEF and HFpEF were seen in 3182 (58.8%), 875 (16.2%) and 1357 (25.1%) patients, respectively. The prevalence of AF significantly increased with increasing EF (HFrEF 28.9%, HFmrEF 39.8%, HFpEF 45.2%; p for trend <0.001). During follow-up (median, 4.03 years; IQR, 1.39-5.58 years), 2806 (51.8%) patients died. The adjusted HR of AF for all-cause death was 1.06 (0.93-1.21) in the HFrEF, 1.10 (0.87-1.39) in the HFmrEF and 1.22 (1.02-1.46) in the HFpEF groups. The HR for the composite of all-cause death or readmission was 0.97 (0.87-1.07), 1.14 (0.93-1.38) and 1.03 (0.88-1.19) in the HFrEF, HFmrEF and HFpEF groups, respectively, and the HR for stroke was 1.53 (1.03-2.29), 1.04 (0.57-1.91) and 1.90 (1.13-3.20), respectively. Similar results were observed after propensity score matching analysis., Conclusions: AF was more common with increasing EF. AF was seen to be associated with increased mortality only in patients with HFpEF and was associated with an increased risk of stroke in patients with HFrEF or HFpEF., Trial Registration Number: NCT01389843., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stable photoelectrochemical (PEC) operation is a critical issue for the commercialization of PEC water-splitting systems. Unfortunately, most semiconductor photocathodes generating hydrogen in these systems are unstable in aqueous solutions. This is a huge limitation for the development of durable PEC water-splitting systems. Lanthanum iron oxide (LaFeO3) is a promising p-type semiconductor to overcome this drawback because of its stability in an aqueous solution and its proper energy level for reducing water. In this study, we fabricated a crystalline LaFeO3 thin film by radio frequency magnetron sputtering deposition and a post-annealing process in air for use as a PEC photocathode. Based on the morphological, compositional, optical and electronic characterizations, we found that it was ideal for a visible light-responsive PEC photocathode and tandem PEC water-splitting system with a small band gap absorber behind it. Furthermore, it showed stable PEC performance in a strong alkaline solution during PEC operation without any protection layers. Therefore, the crystalline sputtered LaFeO3 thin film suggested in this study would be feasible to apply as a PEC photocathode for durable, simple and low-cost PEC water splitting.

Flexible structures of intrinsically disordered proteins (IDPs) are crucial for versatile functions in living organisms, which involve interaction with diverse partners. Electrospray ionization ion mobility mass spectrometry (ESI-IM-MS) has been widely applied for structural characterization of apo-state and ligand-associated IDPs via two-dimensional separation in the gas phase. Gas-phase IDP structures have been regarded as kinetically trapped states originated from conformational features in solution. However, an implication of the states remains elusive in the structural characterization of IDPs, because it is unclear what structural property of IDPs is preserved. Recent studies have indicated that the conformational features of IDPs in solution are not fully reproduced in the gas phase. Nevertheless, the molecular interactions captured in the gas phase amplify the structural differences between IDP conformers. Therefore, an IDP conformational change that is not observed in solution is observable in the gas-phase structures obtained by ESI-IM-MS. Herein, we have presented up-to-date researches on the key implications of kinetically trapped states in the gas phase with a brief summary of the structural dynamics of IDPs in ESI-IM-MS., (© 2019 Wiley Periodicals, Inc.)

Background: The CHA 2 DS 2 -VASc score is used to assess risk of mortality as well as to stratify risk of stroke in patients with atrial fibrillation (AF). This study evaluated whether CHA 2 DS 2 -VASc score was predictive of 1 and 2 year risks of stroke and death in Asian patients with heart failure (HF)., Methods: Patients hospitalized for HF were enrolled in the Korean Acute Heart Failure (KorAHF) registry, a prospective observational multicenter cohort study, between March 2011 and February 2014. Patients with a history of cancer before hospitalization for HF were excluded. The discriminatory properties of the CHA 2 DS 2 -VASc score were quantified using C-statistics., Results: The study included 5158 patients with HF, 2091 with and 3067 without AF. Rates of stroke in these two groups were 4.5 and 2.8%, respectively, after 1 year, and 5.5 and 3.4%, respectively, after 2 years. Each 1-point increase in CHA 2 DS 2 -VASc score was associated with significantly increased risks of stroke and all-cause death in HF patients with and without AF (p-value < 0.05). The C-statistics of the CHA 2 DS 2 -VASc score for all-cause death in patients with and without AF were 0.600 and 0.630, respectively, at 1 year and 0.626 and 0.635, respectively, at 2 years. The C-statistics for stroke ranged from 0.593 to 0.639., Conclusions: Among patients with incident HF with and without AF, CHA 2 DS 2 -VASc score was significantly associated with the risks of stroke and death. However, CHA 2 DS 2 -VASc score was only a modest predictor of stroke and death, indicating the need for studies evaluating modified CHA 2 DS 2 -VASc scores. The majority of strokes occurred relatively shortly after hospitalization for HF and that mortality rates in patients with HF remain high. Thus, early treatment after HF to prevent stroke is essential.

Blood transfusions temporarily improve the physical state of the patient but exert widespread effects on immune and non-immune systems. Perioperative allogeneic blood transfusions (ABT) are associated with various risks, including coagulopathy, incompatibility, transmission of infectious agents, and allergic reactions. Nevertheless, little is known about the global metabolic alterations that reflect the possible reactions of blood transfusions. In this study, we investigated metabolite changes generated by ABT in a rat model using metabolomics technology. To further profile the "metabolome" after blood transfusions, we used both liquid chromatography-quadrupole time-of-flight high-definition mass spectrometry and gas chromatography-mass spectrometry. ABT promoted a stimulatory microenvironment associated with a relative increase in glucose transporter 1/4 (GLUT1/GLUT4) expression. Supporting this result, glucose metabolism-related enzyme IRS1 and interleukin-6 (IL-6) were abnormally expressed, and levels of lysophosphatidylcholine (LysoPC) and its related enzyme phospholipase A2 (PLA2) were significantly altered in allogeneic groups compared to those in autologous groups. Finally, amino acid metabolism was also altered following ABT. Taken together, our results show a difference between autologous and allogeneic blood transfusions and demonstrate correlations with cancer-associated metabolic changes. Our data provide endogenous information for a better understanding of blood transfusion reactions.

Purpose: The purpose of this in vitro study was to evaluate the effect of surface grinding and polishing procedures using high speed zirconia diamond burs with different grit sizes on the phase transformation and flexural strength of zirconia., Materials and Methods: Forty disc shape specimens (15 × 1.25 mm) with a cylindrical projection in the center of each disc (1 × 3 mm) were fabricated with 3Y-TZP (Prettau, Zirkonzahn, Italy). The specimens were divided into 4 groups (n=10) according to the grinding and polishing procedures: Control group - grinding (coarse-grit diamond bur), Group 1 - grinding (coarse-grit diamond bur) + polishing, Group 2 - grinding (fine-grit diamond bur) + polishing, and Group 3 - grinding (fine grit diamond bur). Each specimen was analyzed by 3D-OM, XRD analysis, and biaxial flexural strength test., Results: Based on the surface morphology by 3D-OM images, polished specimens showed smoother surface and lower roughness value (Ra). In the result of XRD analysis, partial phase transformation from tetragonal to monoclinic zirconia occurred in all groups. Control group, ground with a coarse grit diamond bur, showed more t→m phase transformation and lower flexural strength than Groups 1 and 2 significantly., Conclusion: The flexural strength in all specimens after grinding and polishing showed over 500 MPa, and those were clinically acceptable. However, grinding with a coarse grit diamond bur without polishing induced the phase transformation and low strength. Therefore, surface polishing is required for the occlusal adjustment using a high speed zirconia diamond bur to reduce the phase transformation and to prevent the decrease of flexural strength of zirconia.

Pancreatic cancer exhibits an oncogenic KRAS mutation rate of ∼90%. Despite research and drug development efforts focused on KRAS, no targeted therapy has been clinically approved for the treatment of pancreatic cancer with KRAS mutation. Also, the efficacy of gemcitabine is poor due to rapidly acquired resistance. We developed RT11-i antibody, which directly targets the intracellularly activated GTP-bound form of oncogenic RAS mutants. Here, we investigated the combined effects of RT11-i and gemcitabine in vitro and in vivo, and the mechanism involved. RT11-i significantly sensitized pancreatic cancer cells to gemcitabine. Also, the co-treatment synergistically inhibited angiogenesis, migration, and invasion, and showed synergistic anticancer activity by inhibiting the RAF/MEK/ERK or PI3K/AKT pathways. Furthermore, co-treatment inhibited endothelial barrier disruption in tumor vessels, which is a critical step in vascular leakiness of metastasis, and improved vessel structural stability. Importantly, co-treatment significantly suppressed tumor growth in an orthotopic tumor model. Taken together, our findings show that RT11-i synergistically increased the antitumor activity of gemcitabine by inhibiting RAS downstream signaling, which suggests RT11-i and gemcitabine be viewed a potential combination treatment option for pancreatic cancer patients with KRAS mutation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This study examined the annual prevalence of atrial fibrillation (AF) and its associated comorbidities, as well as the prevalence of warfarin therapy in South Korean patients with AF., Methods: The National Health Insurance Service-National Sample Cohort database was searched for subjects aged ≥30 years diagnosed with AF from 2002-2013. The prevalence of AF was analyzed by sex and age, as was the current status of warfarin therapy in AF patients according to CHA 2 DS 2 -VASc score and comorbidities., Results: The age-standardized prevalence of AF in men and women was 0.15% and 0.14%, respectively, in 2002, increasing to 0.54% and 0.39%, respectively, in 2013. In 2013, the prevalence of AF in men and women aged 30-39 years was 0.08% and 0.03%, respectively, increasing to 2.35% and 1.71%, respectively, in those in aged ≥60 years. During 2002-2013, the prevalence of AF in men significantly increased among subjects aged ≥30 years and increased in women aged ≥60 years. The age-standardized prevalence of hypertension and diabetes mellitus among AF patients were markedly increased during 2002-2013. Of these AF patients, 86.1% had a CHA 2 DS 2 -VASc score of ≥2; however, only 39.1% of these were receiving warfarin., Conclusions: The age-standardized prevalence of AF increased 2.89-fold over the 12-year study period. The total number of patients with AF in South Korea has been drastically increasing, due to not only aging society but also increasing age-specific prevalence of AF, especially in middle-aged and elderly individuals. The rate of warfarin therapy increased slightly over the study period but remains low.

The purpose of this study was to investigate hydroxyapatite coatings containing Mn and Si on the oxidized Ti-6Al-4V alloy for dental applications. Dental implant fixture and Ti-6Al-4V ELI disk were used as substrates for plasma electrolytic oxidation (PEO) treatment. PEO treatment was performed at 280 V for 3 min in various solutions. The surface morphologies of the specimens after PEO treatment were observed with a field-emission scanning electron microscope, energy-dispersive X-ray spectroscopy, X-ray diffractometer, and Fourier transform infrared spectroscopy. The breakdown potential for pore formation depended on the added ions in electrolytes. Rough surface with micro-pores was formed after plasma discharge in the electrolytes containing Si and Mn ions. The surface morphologies of implant fixtures were covered with manganese-silicon compounds, as Mn concentration increased. From the XRD analysis, anatase peaks decreased, as Mn and Si contents increased. From the results of FT-IR analysis, Si-HA and Mn-HA was formed on the implant surface.

Activation of PI3K/AKT pathway occurs frequently in tumors and is correlated with radioresistance. The PI3K/AKT pathway can be an important target for improvement of radiotherapy. Although adding of chemotherapy to radiation therapy regimen enhances survival in patients with locally advanced pancreatic cancer, more effective therapies for increasing radiosensitivity are urgently needed. In this study, we investigated whether the novel PI3K inhibitor HS-173 could attenuate radiation-induced up-regulation of DNA damage repair processes and assessed its efficacy as a radio- and chemo-sensitizer. Radiosensitizing effects of HS-173 were tested in human pancreatic cells using clonogenic survival and growth assays. Mechanisms underlying the effects of HS-173 and radiation were determined by assessing cell cycle and DNA damage- repair pathway components, including ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The in vivo efficacy of HS-173 in cancer radiotherapy was evaluated using a human tumor xenograft model. HS-173 significantly increased the sensitivity of pancreatic cancer cells to radiation, an effect that was associated with G2/M cell cycle arrest. HS-173 also significantly attenuated DNA damage repair by potently inhibiting ATM and DNA-PKcs, the two major kinases that respond to radiation-induced DNA double-strand breaks (DSBs), resulting in sustained DNA damage. Moreover, the combination of HS-173 and radiation delayed tumor growth and impaired DNA repair in a pancreatic cancer xenograft model, reflecting enhanced radiosensitization. These results showed that HS-173 significantly improved radiotherapy by inhibiting the DNA damage-repair pathway in pancreatic cancer. We therefore suggest that HS-173 may be an effective radiosensitizer for pancreatic cancer., Competing Interests: CONFLICTS OF INTEREST The authors do not have any conflicts of interest to disclose.

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer. Here, we examined the ability of combined treatment with gemcitabine and YDC002, which degrades extracellular matrix (ECM), to efficiently treat chemoresistant and desmoplastic pancreatic cancer. Gemcitabine alone exhibited similarly low cytotoxicity toward pancreatic cancer cells throughout the concentration range (1-50 μM) used, whereas the combination of YDC002 and a subtherapeutic dose of gemcitabine (0.01-0.05 μM) resulted in potent anticancer effects through effective induction of apoptosis. Importantly, YDC002 combined with gemcitabine significantly attenuated the expression of major ECM components including collagens, fibronectin, and elastin in tumor spheroids and xenograft tumors compared with gemcitabine alone, resulting in potent induction of apoptosis, gemcitabine-mediated cytotoxicity, and an oncolytic effect through degradation of tumor ECM. Our results demonstrate that YDC002 can selectively degrade aberrant ECM and attenuate the ECM-induced chemoresistance observed in desmoplastic pancreatic tumor, resulting in a potent antitumor effect through effective induction of apoptosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atrial fibrillation (AF) is a major risk factor for ischemic stroke and associated with a 5-fold higher risk of stroke. In this retrospective cohort study, the incidence of and risk factors for ischemic stroke in patients with AF were identified. All patients (≥30 years old) without previous stroke who were diagnosed with AF in 2007-2013 were selected from the National Health Insurance Service-National Sample Cohort. To identify factors that influenced ischemic stroke risk, Cox proportional hazard regression analysis was conducted. During a mean follow-up duration of 3.2 years, 1022 (9.6%) patients were diagnosed with ischemic stroke. The overall incidence rate of ischemic stroke was 30.8/1000 person-years. Of all the ischemic stroke that occurred during the follow-up period, 61.0% occurred within 1-year after AF diagnosis. Of the patients with CHA2DS2-VASc score of ≥2, only 13.6% were receiving warfarin therapy within 30 days after AF diagnosis. Relative to no antithrombotic therapy, warfarin treatment for >90 days before the index event (ischemic stroke in stroke patients and death/study end in non-stroke patients) associated with decreased ischemic stroke risk (Hazard Ratio = 0.41, 95%confidence intervals = 0.32-0.53). Heart failure, hypertension, and diabetes mellitus associated with greater ischemic stroke risk. AF patients in Korea had a higher ischemic stroke incidence rate than patients in other countries and ischemic stroke commonly occurred at early phase after AF diagnosis. Long-term (>90 days) continuous warfarin treatment may be beneficial for AF patients. However, warfarin treatment rates were very low. To prevent stroke, programs that actively detect AF and provide anticoagulation therapy are needed.

Purpose: The aim of this study was to confirm the efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors (GISTs) reported in the GRID phase III trial in Korean patients., Materials and Methods: Fifty-seven Korean patientswith advanced GISTwho experienced both imatinib and sunitinib failure were enrolled in the management access program between December 2012 and November 2013 and treated with regorafenib (160 mg orally once daily in a 3 weeks on/1 week off)., Results: None of the patients achieved a complete or partial response while 25 patients (44%) showed stable disease for ≥ 12 weeks. With a median follow-up of 12.7 months (range, 0.2 to 27.6 months), the median progression-free survival and overall survival were 4.5 months (95% confidence interval [CI], 3.8 to 5.3) and 12.9 months (95% CI, 8.1 to 17.7), respectively. Interestingly, 15 patients (26%) experienced an exacerbation of their cancer-related symptoms (abdominal pain in eight and abdominal distension in five) during the rest period for regorafenib, but all were ameliorated upon the resumption of regorafenib. The most common grade 3 or 4 adverse event was a hand-foot skin reaction (25%). The regorafenib dose was reduced in 44 patients (77%) due to toxicity, which manifested mainly as a hand-foot skin reaction (n=31)., Conclusion: This study confirmed the efficacy and safety of regorafenib for advanced GIST after imatinib and sunitinib failure in Korean patients. Considering the exacerbation of the cancer-related symptoms observed during the rest periods, further exploration of the continuous dosing schedule of regorafenib is warranted in future clinical trials.

Background: Acute pulmonary thromboembolism (APTE) is a life-threatening condition, often manifesting with chest pain, dyspnea, and increased cardiac biomarkers including cardiac troponin I (CTI) and D-dimer. Therefore, APTE is often misdiagnosed with classical non-ST elevation myocardial infarction (NSTEMI), resulting in unnecessary coronary interventions and a delay of therapy., Objectives: Our aim was to distinguish APTE from NSTEMI based on CTI and D-dimer levels., Methods: Complete clinical and laboratory data sets from APTE patients (n = 123) were compared with matched NSTEMI patients (n = 123) who presented with chest pain. The APTE diagnosis was confirmed by chest tomography, angiography, or radionuclide ventilation-perfusion scan, while NSTEMI was established by clinical symptoms, cardiac biomarkers, and coronary angiography. Clinical characteristics, CTI (initial and peak), and D-dimer levels at presentation were retrospectively analyzed., Results: The clinical characteristics were not different between APTE and NSTEMI patients. However, significantly lower initial CTI (0.2 ± 0.5 vs. 4.4 ± 9.5 ng/ml) and peak CTI (0.7 ± 2.7 vs. 17.1 ± 20.4 ng/ml), but higher initial D-dimer (9.8 ± 9.4 vs. 1.6 ± 3.6 ng/ml), distinguished APTE from NSTEMI. By receiver operating characteristic curve analysis, the cutoff values for initial CTI, peak CTI, and D-dimer were 0.25, 0.98, and 3.18 ng/ml, respectively., Conclusion: Patients with APTE exhibited lower initial and peak CTI but higher D-dimer levels than NSTEMI patients. Assessing cardiac biomarkers is useful for differentiating APTE from NSTEMI. Further large randomized biomarker studies are urgently needed to facilitate a better APTE diagnosis since clinical characteristics are not particularly helpful., (© 2016 S. Karger AG, Basel.)

Purpose: The aim of this study was to analyze the shapes of lingual polished surfaces in lower complete dentures formed by polished surface impressions and to provide reference data for use when manufacturing edentulous trays and lower complete dentures., Materials and Methods: Twenty-six patients with mandibular edentulism were studied. After lower wax dentures were fabricated, wax was removed from the lingual side of the wax denture and a lingual polished surface impression was obtained with tissue conditioner. The definitive denture was scanned with a three-dimensional scanner, and scanned images were obtained. At the cross-sections of the lingual frenum, lateral incisors, first premolars, first molars, and anterior border of the retromolar pads, three points were marked and eight measurements were taken. The Kruskal-Wallis test and a post hoc analysis with the Mann-Whitney test were performed., Results: Each patient showed similar values for the same areas on the left and right sides without a statistically significant difference. The height of the contour of the lingual polished surface at the lingual frenum was halfway between the occlusal plane and lingual border, it moved gradually in a downward direction. The angle from the occlusal plane to the height of the contour of the lingual polished surface was increased as it progressed from the lingual frenum towards the retromolar pads., Conclusion: The shape of the mandibular lingual polished surface was convex at the lingual frenum, lateral incisors and gradually flattened towards the first molars and retromolar pads.

Pancreatic cancer is one of the most aggressive solid malignancies prone to metastasis. Epithelial-mesenchymal transition (EMT) contributes to cancer invasiveness and drug resistance. In this study, we investigated whether HS-173, a novel PI3K inhibitor blocked the process of EMT in pancreatic cancer. HS-173 inhibited the growth of pancreatic cancer cells in a dose- and time-dependent manner. Moreover, it significantly suppressed the TGF-β-induced migration and invasion, as well as reversed TGF-β-induced mesenchymal cell morphology. Also, HS-173 reduced EMT by increasing epithelial markers and decreasing the mesenchymal markers by blocking the PI3K/AKT/mTOR and Smad2/3 signaling pathways in pancreatic cancer cells. In addition, HS-173 clearly suppressed tumor growth without drug toxicity in both xenograft and orthotopic mouse models. Furthermore, to explore the anti-metastatic effect of HS-173, we established pancreatic cancer metastatic mouse models and found that it significantly inhibited metastatic dissemination of the primary tumor to liver and lung. Taken together, our findings demonstrate that HS-173 can efficiently suppress EMT and metastasis by inhibiting PI3K/AKT/mTOR and Smad2/3 signaling pathways, suggesting it can be a potential candidate for the treatment of advanced stage pancreatic cancer.

Background and Objectives: Atrial fibrillation (AF) is a common arrhythmia that is known as an important independent risk factor for stroke. However, limited information is available on AF in Korea. This study evaluated the incidence of AF, its associated co-morbidities and risk factors for AF in Korea., Subjects and Methods: The National Health Insurance Service database between 2002 and 2010 was used in the study. Individuals<30 years old and those diagnosed with AF between 2002 and 2004 were excluded. Hazard ratios (HRs) according to co-morbidities and risk factors for AF were determined using a Cox proportional hazard model. Population attributable fractions (PAFs) of AF risk factors were determined., Results: During a 6-year follow-up period, 3517 (1.7%) developed AF. The incidence rates in men and women aged 30-39 years were 0.82 and 0.55 per 1000 person-years, respectively; the incidence rates further increased with age to 13.09 and 11.54 per 1000 person-years in men and women aged≥80 years, respectively. The risk factors for incident AF were age, sex, body mass index (BMI), hypertension, ischemic heart disease (IHD) and heart failure. After adjusting for variables related to AF, the risk of AF was significantly associated with hypertension (HR 1.667), IHD (HR 1.639), heart failure (HR 1.521), and the PAFs for age, sex, BMI, hypertension, IHD, heart failure and diabetes mellitus were 30.6%, 10.1%, 3.4%, 16.6%, 8.2%, 5.3% and 0.8%, respectively., Conclusion: Incidence of AF increased with age and was higher in men than in women. A larger proportion of AF events was attributable to hypertension than to other co-morbidities.

Purpose: The purpose of this study was to analyze the antimicrobial, antioxidant activity and cytotoxicity of Dendropanax morbifera Léveille extract for assessing whether Dendropanax morbifera Léveille can be used for the development of natural mouthwash and denture cleaning solution., Materials and Methods: The extract was obtained from branches of Dendropanax morbifera Léveille. The solvent fractions were acquired by fractionating Dendropanax morbifera Léveille extract using n-hexane, ethyl acetate, chloroform and butanol solvent. Paper disc test was used to evaluate the antimicrobial and antifungal activity of Dendropanax morbifera Léveille extract and solvent fractions against Streptococcus mutans and Candida albicans. The analysis of antioxidant activity was carried out through DPPH radical scavenging assay. The cytotoxicity of Dendropanax morbifera Léveille extract was analyzed through MTT assay using normal human oral keratinocytes., Results: Dendropanax morbifera Léveille extract showed antimicrobial activity against Streptococcus mutans and especially Candida albicans. The solvent fractions of Dendropanax morbifera Léveille showed strong antimicrobial activity against Streptococcus mutans and Candida albicans in n-hexane and butanol solvent fraction, respectively. Dendropanax morbifera Léveille extract also showed outstanding antioxidant activity. Butanol, ethyl acetate, and chloroform solvent fraction of Dendropanax morbifera Léveille tended to have increased antioxidant activity as the concentration increased. Dendropanax morbifera Léveille extract showed high cell survival rate in cytotoxicity test., Conclusion: Dendropanax morbifera Léveille extract turned out to have antimicrobial, antioxidant activity and cytophilicity. Based on these results, it is expected that Dendropanax morbifera Léveille is applicable as an ingredient for natural mouthwash and denture cleanser.

The Al2 O3 passivation layer is beneficial for mesoporous TiO2 -based perovskite solar cells when it is deposited selectively on the compact TiO2 surface. Such a passivation layer suppressing surface recombination can be formed by thermal decomposition of the perovskite layer during post-annealing., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)