Search

5,20-Bis(ethoxycarbonyl)-[28]hexaphyrin was synthesized by acid catalyzed cross-condensation of meso-diaryl-substituted tripyrrane and ethyl 2-oxoacetate followed by subsequent oxidation. This hexaphyrin was found to be a stable 28π-antiaromatic compound with a dumbbell-like conformation. Upon oxidization with PbO2 , this [28]hexaphyrin was converted into an aromatic [26]hexaphyrin with a rectangular shape bearing two ester groups at the edge side. The [28]hexaphyrin can incorporate two NiII or CuII metals by using the ester carbonyl groups and three pyrrolic nitrogen atoms to give bis-NiII and bis-CuII complexes with essentially the same dumbbell-like structure. The antiaromatic properties of the [28]hexaphyrin and its metal complexes have been well characterized.

Traditional severity criteria of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were determined retrospectively but found inappropriate for therapeutic decisions. Data of 203 patients with SOS/VOD were collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised severity criteria recently proposed from European Society for Blood and Marrow Transplantation (EBMT). According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised EBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. The 100-day overall survival (OS) of mild, moderate, severe and very severe groups was 83.3, 84.3, 94.6, and 58.6%, respectively. Very severe SOS/VOD showed a significantly lower OS than the others (58.6 vs. 89.3%, p

The emergence of multi-drug resistant bacteria forces the therapeutic world into a position, where the development of new and alternative kind of antibiotics is highly important. Herein, we report the development of triazine-based amphiphilic small molecular antibacterial agents as mimics of lysine- and arginine-based cationic peptide antibiotics (CPAs). These compounds were screened against a panel of both Gram-positive and Gram-negative bacterial strains. Further, anti-inflammatory evaluation of these compounds led to the identification of four efficient compounds, DG-5, DG-6, DL-5, and DL-6. These compounds displayed significant potency against drug-resistant bacteria, including methicillin-resistant S. aureus (MRSA), multidrug-resistant P. aeruginosa (MDRPA), and vancomycin-resistant E. faecium (VREF). Mechanistic studies, including cytoplasmic membrane depolarization, confocal imaging and flow cytometry suggest that DG-5, DG-6, and DL-5 kill bacteria by targeting bacterial membrane, while DL-6 follows intracellular targeting mechanism. We also demonstrate that these molecules have therapeutic potential by showing the efficiency of DG-5 in preventing the lung inflammation of lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. More interestingly, DL-6 exhibited impressive potency on atopic dermatitis (AD)-like skin lesions in BALB/c mice model by suppressing pro-inflammatory cytokines. Collectively, these results suggest that they can serve a new class of antimicrobial, anti-inflammatory and anti-atopic agents with promising therapeutic potential.

Background: The PI3K/AKT/mTOR pathway is an established therapeutic target in indolent B-cell non-Hodgkin lymphoma (B-NHL). Several PI3K inhibitors are approved to treat relapsed/refractory (R/R) follicular lymphoma (FL) and, more recently, marginal zone lymphoma (MZL). Nonetheless, potential class-specific and PI3K-isoform-related toxicities may limit their clinical utility. Capivasertib is an oral, potent, selective inhibitor of the 3 AKT isoforms that demonstrated a manageable safety profile (n>1500) and survival benefit in combination with other agents in patients (pts) with solid tumors. Unlike PI3K inhibitors, colitis or pneumonitis have not been a concern with monotherapy. Preclinically, capivasertib was active both in vitro in a large panel of B-NHL cell lines and in vivo in PTEN-null GCB-DLBCL PDX models, where it downregulated the oncogenic factor MYC. In the JVM2 mantle cell lymphoma (MCL) cell line, capivasertib showed superior activity vs PI3Ka/d (AZD8835) and PI3Kb/d (AZD8186) inhibitors. Of note, AKT activation following dysregulation of PTEN has been frequently described in FL (where >85% of tFL or FL/DLBCL exhibited a GCB phenotype). Therefore, capivasertib may represent an effective treatment option for pts with R/R B-NHL. Trial Design: This modular phase II study will enroll pts in 3 cohorts according to B-NHL type. Core inclusion criteria include: age ≥18 years and ECOG PS ≤2. Module-specific criteria include: cohort 1A: R/R FL after ≥2 prior systemic lines (max 5), including an anti-CD20 monoclonal antibody (mAb) and an alkylating agent; cohort 1B: R/R MZL of splenic, nodal, and extranodal subtypes after ≥2 prior systemic lines (max 5) including ≥1 anti-CD20 mAb; cohort 1C: R/R MCL after ≥2 prior systemic lines (max 4), previously exposed to anti-CD20 mAb and a BTK inhibitor. Pts with FL grade 3B, transformed disease, blastoid or TP53 mutation MCL, active CNS disease, diabetes requiring insulin, or being Funding: AstraZeneca Clinical Trial Registration: NCT050080552 Citation Format: Michael Wang, Ho-Jin Shin, Alex F. Herrera, Moshe Levy, Wong Seog Kim, Tae Min Kim, Jin Seok Kim, Dok Hyun Yoon, Vincent Ribrag, Miguel Canales, John Radford, Dima El-Sharkawi, Brandy Hemmer, Richa Manwani, Veerendra Munugalavadla, Robert Chen, Andrew Mortlock, Alessandra Forcina, Franck Morschhauser. Trial in progress: A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor in patients with relapsed or refractory B-cell non-hodgkin lymphoma (CAPITAL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT127.

By growing rat muscle tissues on a polymer backbone, we demonstrated the movement of the cell powered microrobot. From the viewpoint of a walking microrobot driven by muscle, the cell powered microrobot has novel originality and great significance in the robotics field. The proposed microrobot has the following characteristics: (1) the self-assembled hybrid microrobot consists of biotic muscle cells and PDMS backbone, which is well-known as a biocompatible material. (2) The surface of PDMS backbone is engineered into a groove pattern, which promotes higher order cell concentration and realizes higher generative force of the muscle cells than a 2D culture surface. (3) PDMS is easily fabricated by the? a? micromolding procedure and thus high throughput and mass-production of the cell powered microrobot become possible. (4) The long term monitoring result of the primary cultured cardiomyocytes on engineered surfaces is firstly reported and analyzed. Consequently, the walking robot showed reliable and long-term actuation performances. During the organization of the cardiomyocyte-PDMS hybrid microrobot, the groove surface provided an adverse environment in the initial stages of cell attachment and at adaptation to the surfaces by the modifications in the specific gene expression of the isoforms of troponin and connexin. However, once the cells settled down, more vigorous and synchronous propelling forces were generated through the tighter cell-cell contacts, intracellular arrangements of vesicles and cytoskeltons and higher stimuli according to the microenvironment on the groove surfaces. As quantitative results, the stress of 2­5 nN/m2 was calculated, which was induced on the flat surface of the microcantilever by the contractile force of the cardiomyocytes. Then, the force of the cardiomyocytes cultured on the groove surface microcantilever increased up to 60% higher than that on the flat surface cantilever. Finally, the forward movement of the micro-robot with the groove surface was monitored, and the measured speed was about 140 ms-1.

The rapid increase in carbapenemase-producing Enterobacterales is a global health concern. During 2017-2020, a total of 44 Escherichia coli isolates co-harbouring blaNDM-5 and blaOXA-181 were collected from patients at 17 hospitals in Seoul and characterized based on antimicrobial susceptibility, resistance genes and plasmid replicons detected using polymerase chain reaction (PCR). Clonal relatedness was estimated using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). All isolates had an identical multidrug resistance profile, including resistance to carbapenems, cephalosporins, ciprofloxacin, tetracycline, and trimethoprim/sulfamethoxazole, and susceptibility to amikacin, colistin, and tigecycline. Resistance genes (blaCTX-M-15, blaCMY-2, blaTEM-1B, blaOXA-1, aac(6’)-Ib-cr, and qnrS) and plasmid replicons (IncFIA, IncFIB, and IncX3) was observed in almost all isolates. All isolates belonged to ST410 and were genetically similar (>88% similarity), with some PFGE types shared among isolates from different hospitals. Analysis of the whole genome revealed that the isolates clustered together with other strains of the international high-risk clone ST410 B4/H24RxC from other countries. These findings underline the ongoing spread of the high-risk clone of NDM-5- and OXA-181-producing E. coli ST410 B4/H24RxC among hospitals in Seoul. Continuous monitoring and implementation of infection control measures are crucial to track and prevent further spread of these resistant strains.

OBJECTIVES Knowledge on early adulthood isolated diastolic hypertension (IDH) is limited. We compared the clinical and central hemodynamic characteristics of early adulthood IDH, isolated systolic hypertension (ISH) and normotension. METHODS A total of 509 untreated young adults (18-35 years) who underwent ambulatory blood pressure monitoring (ABPM; ABPM cohort), 148 who underwent both ABPM and applanation tonometry (ABPM-tonometry cohort) and 26 newly recruited normotensives were analyzed. Their pulse wave images were analyzed after categorizing them into type A vs. B vs. C. RESULTS In the ABPM cohort (men, 86.6%), systolic-diastolic hypertension was the most common subtype (68.0%), while IDH was the rarest (5.1%). The subtype composition showed age-dependency; the proportion of IDH and systolic-diastolic hypertension increased across the age tertiles, while that of ISH declined. Patients with IDH were significantly older and shorter than those with ISH. Despite having a significantly lower 24-h average systolic blood pressure (SBP), patients with IDH exhibited discordantly high central systolic blood pressures at levels comparable to those of patients with ISH. Pulse pressure amplification was the lowest in patients with IDH and highest in those with ISH (P < 0.001), accounting for the discordance. Augmentation index differed significantly between them (P < 0.016). The waveform composition differed across the subtypes (type A vs. B/C: IDH = 61.5 vs. 38.5%; ISH = 3.0 vs. 97.0%; normotension = 30.8 vs. 69.2%, P < 0.001); the averaged waveform plots demonstrated a clear morphological disparity between IDH (type A) and ISH (type B/C). CONCLUSIONS Early adulthood IDH is a unique entity clearly distinguishable from ISH in terms of clinical and central hemodynamic characteristics.

Background In 2020, a categorized list of wetland preferences, major habitats, and life forms of 4145 vascular plant taxa occurring in the Korean Peninsula was published by the National Institute of Biological Resources. We analyzed the list and explored the distribution patterns of the five categorized groups according to wetland preference, along with the information on the major habitats and the life forms of the plants belonging to those categories. Results Out of 4145 taxa, we found that 729 wetland plant taxa (18%) occur in Korea: 401 obligate wetland plants and 328 facultative wetland plants. Among the 729 wetland taxa, the majority (73%) was hygrophytes and the remaining 27% was aquatic macrophytes. Furthermore, almost all of the wetland taxa are herbs; so, woody plants are only 4.7%. The 16 carnivorous taxa distributed in Korea were characterized as obligate wetland plants. Conclusions We expect the categorized information would promote understanding of the characteristics of the plant species and would be an important source for understanding, conservation, and restoration of wetland ecosystems.

In September 2018, an outbreak of Listeriosis cases in Korea was traced to food involved, using retrospective cohort studies and PFGE analyses. This study aimed to describe the first L.monocytogenes outbreak identified in Korea. We confirmed the presence of Serovar (4C) and virulence genes, and evaluated the genetic correlation between isolates by restriction digestion patterns of ApaI and AscI. Based on the epidemiological association, it is presumed that the seasoned crab meat with bean sprouts are contaminated by cross contamination during the bean sprouts washing (relative risk was 1.24; p-value: 0.0021 and they possessed virulence genes. Therefore, active laboratory surveillance is necessary to recognize the risk of L. monocytogenes in Korea.

Background/aims We investigated the impact of obesity on the clinical outcomes following percutaneous coronary intervention (PCI). Methods We included South Koreans aged > 20 years who underwent the Korean National Health Screening assessment between 2009 and 2012. Obesity was defined using the body mass index (BMI), according to the World Health Organization's recommendations. Abdominal obesity was defined using the waist circumference (WC), as defined by the Korean Society for Obesity. The odds and hazard ratios in all-cause mortality were calculated after adjustment for multiple covariates. Patients were followed up to the end of 2017. Results Among 130,490 subjects who underwent PCI, the mean age negatively correlated with BMI. WC, hypertension, diabetes, dyslipidemia, fasting glucose, total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels correlated with the increased BMI. The mortality rates were higher in the lower BMI and WC groups than the higher BMI and WC groups. The non-obese with abdominal obesity group showed a mortality rate of 2.11 per 1,000 person-years. Obese with no abdominal obesity group had the lowest mortality rate (0.88 per 1,000 person-years). The mortality showed U-shaped curve with a cut-off value of 29 in case of BMI and 78 cm of WC. Conclusion The mortality showed U-shaped curve and the cut-off value of lowest mortality was 29 in case of BMI and 78 cm of WC. The abdominal obesity may be associated with poor prognosis in Korean patients who underwent PCI.

PurposeEvent-free survival at 24 months (EFS24) is known to be a surrogate marker for overall survival (OS) for patients with peripheral T-cell lymphoma (PTCL). We examined the role of EFS24 in PTCL compared to diffuse large B-cell lymphoma (DLBCL), and then assessed the clinical predictive factors of achieving EFS24. Materials and MethodsPatients with newly diagnosed PTCL treated with anthracycline-based chemotherapy were included. Subsequent OS was defined as the time elapsed from 24 months after diagnosis until death from any cause in those who achieved EFS24. ResultsOverall, 153 patients were evaluated, and 51 patients (33.3%) achieved EFS24. Patients who achieved EFS24 showed superior OS compared to patients who did not (p < 0.001). EFS24 could stratify the subsequent OS although it did not reach to that of the general population. After matching the PTCL group to the DLBCL group based on the international prognostic index, the subsequent OS in patients who achieved EFS24 was similar between the two groups (p=0.094). Advanced stage was a significant factor to predict the failing EFS24 by multivariable analysis (p < 0.001).ConclusionPatients with PTCL who achieve EFS24 could have a favorable subsequent OS. Since advanced disease stage is a predictor of EFS24 failure, future efforts should focus on developing novel therapeutic strategies for PTCL patients presenting with advanced disease.

Background/Aims: Although the use of surveillance 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is discouraged in patients with diffuse large B-cell lymphoma, its usefulness in different subtypes has not been thoroughly investigated. Methods: We retrospectively evaluated 157 patients who showed positive results on surveillance FDG-PET/CT every 6 months following complete response for up to 5 years. All of the patients also underwent biopsies. Results: Seventy-eight (49.6%) of 157 patients had true positive results; the remain ing 79 (50.3%), including eight (5.1%) with secondary malignancies, were confirmed to yield false positive results. Among the 78 patients with true positive results, the disease in seven (8.9%) had transformed to a different subtype. The positive pre dictive value (PPV) of FDG-PET/CT for aggressive B-cell non-Hodgkin’s lympho ma (NHL) was lower than that for indolent B-cell or aggressive T-cell NHL (p = 0.003 and p = 0.018, respectively), especially in patients with a low/low-intermediate international prognostic index (IPI) upon a positive PET/CT finding. On the other hand, indolent B-cell and aggressive T-cell NHL patients showed PPVs of > 60%, including those with low/low-intermediate secondary IPIs. Conclusions: The role of FDG-PET/CT surveillance is limited, and differs ac cording to the lymphoma subtype. FDG-PET/CT may be useful in detecting early relapse in patients with aggressive T-cell NHL, including those with low/low-in termediate risk secondary IPI; as already known, FDG-PET/CT has no role in ag gressive B-cell NHL. Repeat biopsy should be performed to discriminate relapse or transformation from false positive findings in patients with positive surveil lance FDG-PET/CT results.

Background: High-risk smoldering multiple myeloma (HR-SMM) is associated with a greater risk of progression to symptomatic disease, suggesting the need for early, efficacious therapeutic interventions to improve outcomes. The ongoing, randomized Phase 3 ITHACA study (NCT04270409) is evaluating efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with lenalidomide (R) and dexamethasone (d) (Isa-Rd) vs Rd in patients (pts) with HR-SMM. We report here preliminary results from the safety run-in part of this trial. Methods: The primary objective was to confirm the recommended dose of Isa in combination with Rd. Pts were eligible if diagnosed with SMM within 5 years and HR-SMM defined by the Mayo ‘20-2-20’ and/or updated PETHEMA model criteria. Minimal residual disease and imaging by MRI and low-dose whole-body CT/PET-CT will be assessed at fixed time points. Results: As of April 12, 2021, 23 pts (median age, 63 [28–85] years;median time from initial diagnosis, 1.14 [0.1–5.2] years) had received Isa 10 mg/kg once weekly then biweekly (QW-Q2W) in combination with Rd. The median number of cycles was 7 (range, 4–10) and median duration of treatment exposure was 29.7 (range, 16.0–38.0) weeks. Two pts met the Mayo clinical model criteria, 13 pts the PETHEMA model criteria, and 8 pts both models’ criteria for HR-SMM. No pt presented with focal lesions at baseline. Seven (30.4%) pts developed 8 grade ≥3 non-hematologic treatment-emergent adverse events (TEAEs): COVID-19 pneumonia, insomnia (2 each), papular rash, muscle spasm, retinal detachment and hyperglycemia (1 each);no pt experienced a grade 5 TEAE and no pt discontinued treatment due to a TEAE. Serious TEAEs were COVID-19 pneumonia (n=2, grade ≥3) and pneumonia, musculoskeletal chest pain and pyrexia (n=1 each, grade

Background Criteria for selection of FFP blood type has not been clearly established and use of group AB plasma is preferred by numerous transplantation protocols. Aims This study assesses the safety and efficacy of alternative group A or B plasma in ABO incompatible solid organ transplantation. Materials & methods Alternative use of group A or B plasma (incompatible plasma) was inevitable during the shortage of group AB plasma. Experience from select number of patients during the period of extreme group AB plasma shortage is described. Results The result of alternative use of group A or B plasma was within expectation, showing effective reduction of isoagglutinin titers for pre-operative desensitization and efficacy for treatment of post-operative patients. No immediate hemolytic transfusion reaction was reported. Discussion While validation in a larger cohort of patients is necessary, our limited experience have shown satisfactory clinical outcomes without adverse events. Conclusions Use of incompatible group A or B plasma is a viable option when group AB plasma is limited.

Colistin is often used as a drug of last resort against infections caused by multi-drug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacterales (CRE). Recently, the acquisition of mobile colistin resistance (mcr) genes by CRE has become a cause for concern. This study investigated the prevalence of mcr genes in CRE isolates in Seoul, Republic of Korea. In total, 3675 CRE strains were collected from patients between 2018 and 2019, and initially screened for mcr genes using multiplex polymerase chain reaction assays. Upon the identification of mcr-harbouring strains, colistin susceptibility tests, identification of carbapenemase and β-lactamase genes, and plasmid replicon typing were performed. Clonal analysis was conducted using pulsed-field gel electrophoresis. mcr genes were detected in 2.2% (80/3675) of CRE strains. There were three mcr-1 carriers, one mcr-4.3 carrier, one mcr-4.3/mcr-9 carrier, 58 mcr-9 carriers, one mcr-9/mcr-10 carrier and 16 mcr-10 carriers among various Enterobacterales species, of which 60 were Enterobacter cloacae complex (ECC) strains. The prevalence of mcr genes in ECC strains was 20.5%. Molecular detection confirmed that 21.3% and 13.8% of mcr-harbouring strains shared blaNDM-1 or blaKPC-2, respectively. In addition, an IncHI2 replicon was identified in 71.7% of mcr-9 strains. Comparative analysis revealed not only a notable diversity of mcr carriers, but also clonal spreading or nosocomial outbreaks of some ECC strains. These findings revealed a silent distribution of mcr genes in CRE strains with high genetic heterogeneity in Seoul, underscoring the urgent need for timely intervention to control and prevent mcr dissemination.

Larger left atrial appendage (LAA) volume is associated with a higher risk of late recurrence (LR) in patients undergoing radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). However, it is unclear whether LAA volume predicts LR, independent of established risk factors. We sought to evaluate the value of LAA volume in predicting LR after RFCA for AF and to develop a score prediction model including LAA volume for these patients. We retrospectively studied 992 patients who underwent RFCA for AF and cardiac computed tomography before RFCA at a single center. At 3 years after RFCA, 362 patients (36.5 %) experienced recurrence. The multivariate Cox regression model showed that age ≥ 75 years (10 points), non-paroxysmal AF (9 points), diabetes mellitus (4 points), left atrial volume index (1 point per 10 ml/m2 rounded to the nearest integer), and the second (4.7 to < 7 ml/m2; 4 points) and third (≥ 7 ml/m2; 5 points) tertiles of the LAA volume index were independent risk factors LR. The above-mentioned risk factors were included in the integrated score model, and the C-index of the proposed score model was 0.715 (95 % confidence interval [CI] 0.679–0.752). LAA volume is an independent predictor of LR and the predictive model including LAA volume showed good discrimination power. These findings provide evidence for the inclusion of LAA volume in the risk stratification for AF recurrence in patients undergoing RFCA for AF.

Background Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL. Methods This phase 2 study with Simon’s two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Results In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5–43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29–339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43–106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94–438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab. Conclusions In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.

Background Age-related macular degeneration (AMD) is the leading cause of blindness. Shift work has well-known adverse effects on health. However, few studies have investigated the relationship between shift work and AMD. This study was conducted to investigate the relationship between shift work and AMD. Methods This study used aggregated data from the 2010-2012 cycles of the Korea National Health and Nutrition Examination Survey. The work schedules were classified into 2 types: day work and shift work. AMD was determined using fundus photographs. The χ2 test and multiple logistic regression analysis were used to assess sex-stratified relationship between shift work and AMD. Results The odds ratio (OR) of AMD in male shift workers was higher (1.54 [95% confidence interval, CI: 1.01-2.36]) than that in male day workers after adjusting for covariates. After dividing into subgroups of the shift work pattern, the OR of AMD in male night shift workers was higher (1.75 [95% CI: 1.07-2.85]) than that in male day workers after adjusting for covariates. However, results of the female worker group were not significant. Conclusions The results of this study provide limited support for the hypothesis that shift work is related to AMD. Further prospective studies are needed to define the relationship between shift work and AMD.

Hemolytic uremic syndrome; Kidney failure; Ravulizumab Síndrome hemolítico urémico; Insuficiencia renal; Ravulizumab Síndrome hemolític urèmic; Insuficiència renal; Ravulizumab Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare, complex, multisystem disease of dysregulated complement activity, characterized by progressive thrombotic microangiopathy (TMA), acute kidney injury, and multiorgan dysfunction, which often progresses to chronic kidney disease. Results from the prospective clinical trial of ravulizumab (NCT02949128) reveal rapid resolution of TMA in patients with aHUS, with sustained efficacy and safety in a 26-week initial evaluation period. Methods The aim of this analysis was to characterize the long-term efficacy and the safety profile of ravulizumab in adults with aHUS who had completed the initial evaluation period of the trial. Complete TMA response, hematologic and kidney functions, and safety were evaluated for all patients available for follow-up in the extension period (median follow-up: 76.7 weeks; range: 0.6–118.3). This trial included a total of 58 patients, 49 of whom entered the extension period. Results A total of 4 additional patients achieved complete TMA response during the follow-up period. Normalization of platelet count, serum lactate dehydrogenase (LDH), and hemoglobin observed in the 26-week initial evaluation period was sustained until the last available follow-up, as were the improvements in the estimated glomerular filtration rate (eGFR) and patient quality of life. All efficacy endpoints were correlated with the sustained inhibition of complement C5. Most adverse events (AEs) occurred early during the initial evaluation period and decreased substantially during the extension period. No patient developed a meningococcal infection or died during the extension period. Conclusion This analysis reveals that ravulizumab administered every 8 weeks is efficacious with an acceptable safety profile for the long-term treatment of adults with aHUS and provides additional clinical benefit beyond 6 months of treatment.

Docetaxel (DTX), a taxane-based anticancer drug, and osthol (OTH), a coumarin-derivative compound, have shown anticancer effects against different types of cancers through various mechanisms. However, these drugs have low solubility in water and low oral bioavailability, and thus their clinical application is difficult. To overcome these problems, we encapsulated DTX and OTH in methoxy poly(ethylene glycol)-b-poly(caprolactone) (mPEG-b-PCL) and conducted studies in vitro and in vivo. We selected a 1:4 ratio as the optimal ratio of DTX and OTH, through combination index analysis in A549 cancer cells, and prepared micelles to evaluate the encapsulation efficiency, drug loading, particle size, and zeta potential. The in vitro drug-release profile showed that DTX/OTH-loaded mPEG-b-PCL micelles could slowly release DTX and OTH. In the clonogenic assay, DTX/OTH-loaded mPEG-b-PCL micelles showed 3.7 times higher inhibitory effect than the DTX/OTH solution. Pharmacokinetic studies demonstrated that micelles in combination with DTX and OTH exhibited increased area under curve and decreased clearance values, as compared with single micelles.

While continued lenalidomide and low-dose dexamethasone (Rd) treatment could improve survival outcomes for multiple myeloma (MM), the association of depression on the adherence to Rd regimen in myeloma patients has never been studied even though depression is a common symptom among MM patients. This study aims to evaluate the impact of depression prior to Rd treatment on adherence to the treatment among patients with MM. This multicenter cohort study was conducted from January 2015 to October 2018 at five tertiary hospitals in Korea. Patients who completed fewer than 4 cycles, 4–11 cycles, and more than 12 cycles were categorized as the poor adherence group (PAG), moderate adherence group (MAG), and good adherence group (GAG), respectively. Among141 patients, 41.8% of them had depression before beginning Rd treatment and 46% of participants were in the GAG. Compared with patients in the GAG (30.3%), patients in the PAG were more likely to have depression at baseline (90.0%) and had the higher distress scores (6.35 vs. 4.28, P < 0.01). Presence of depression prior to Rd treatment was significantly associated with poor adherence (IRR = 6.67, 95% CI = 1.45, 30.61) after adjusting for age, sex, education, ECOG, ISS stage, number of previous treatments, and disease status prior to Rd treatment. Patients with depression had a substantially high risk of poor adherence compared to patients without depression. Given that Rd treatment is mainly offered by outpatient clinics, active interventions to reduce depression should be considered for MM patients prior to Rd treatment.

Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.

The emergence of third-generation cephalosporin resistance in Escherichia coli is increasing at an alarming rate in many countries. Thus, the aim of this study was to analyze co-infecting bla CTX-M-producing pathogenic E. coli isolates linked to three school outbreaks. Among 66 E. coli isolates, 44 were identified as ETEC O25, an ETEC isolate serotype was O2, and the other 21 were confirmed as EAEC O44. Interestingly, six patients were co-infected with EAEC O44 and ETEC O25. For these isolates, molecular analysis [antibiotic susceptibility testing, identification of the β-lactamase gene, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE)] was performed for further characterization. In addition, the transmission capacity of bla CTX-M genes was examined by conjugation experiments. Whole-genome sequencing (WGS) was performed on representative EAEC O44 and ETEC O25 isolates associated with co-infection and single-infection. All isolates were resistant to cefotaxime and ceftriaxone. All EAEC isolates carried the bla CTX-M-14 gene and all ETEC isolates the bla CTX-M-15 gene, as detected by multiplex PCR and sequencing analysis. Sequence type and PFGE results indicated three different patterns depending on the O serotype. WGS results of representative isolates revealed that the ETEC O25 strains harbored bla CTX-M-15 located on IncK plasmids associated with the Δbla TEM-bla CTX-M-15-orf477 transposon. The representative EAEC O44 isolates carried bla CTX-M-14 on the chromosome, which was surrounded by the ISEcp1-bla CTX-M-14-IS903 transposon. To the best of our knowledge, this is the first report of co-infection with chromosomally located bla CTX-M-14 and plasmid-encoding bla CTX-M-15 in pathogenic E. coli. Our findings indicate that resistance genes in clinical isolates can spread through concurrent combinations of chromosomes and plasmids.

Lenalidomide and low-dose dexamethasone (Rd) are a standard treatment for older adults with multiple myeloma (MM). Lenalidomide monotherapy has rarely been evaluated for newly diagnosed transplant-ineligible MM patients. This multicenter phase II trial evaluated a response-adapted strategy for elderly patients with newly diagnosed MM without high-risk features. Patients were administered single-agent lenalidomide for the first 21 days of two 28-day cycles. Patients with progressive disease received Rd. The primary endpoint was progression-free survival using the uniform response assessment from the International Myeloma Working Group . Of the 34 enrolled patients, 28 were included in the efficacy analysis. The overall response rate (ORR, ≥ partial response [PR]) to single-agent lenalidomide or lenalidomide plus prednisone was 64.3%. Ten patients received Rd after disease progression, with an Rd ORR of 70%. The ORR of response-adapted lenalidomide-based therapy was 75%. After the median follow-up of 35.6 months, the median progression-free survival was 33.5 months (95% confidence interval [CI], 16.9-50.2), and the median overall survival was 51.8 months (95% CI, 22.0-81.6). The most common adverse event was neutropenia (46.7%), and 17 patients (56.7%) experienced infection including pneumonia. Response-adapted lenalidomide-based therapy was feasible in newly diagnosed, transplant-ineligible MM patients without high-risk features.

Larger left atrial appendage (LAA) volume is associated with a higher risk of late recurrence (LR) in patients undergoing radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). However, it is unclear whether LAA volume predicts LR, independent of established risk factors. We sought to evaluate the value of LAA volume in predicting LR after RFCA for AF and to develop a score prediction model including LAA volume for these patients. We retrospectively studied 992 patients who underwent RFCA for AF and cardiac computed tomography before RFCA at a single center. At 3 years after RFCA, 362 patients (36.5 %) experienced recurrence. The multivariate Cox regression model showed that age ≥ 75 years (10 points), non-paroxysmal AF (9 points), diabetes mellitus (4 points), left atrial volume index (1 point per 10 ml/m

Fluvastatin (FLUVA), which is a common anti-hypercholesterolemia drug, exhibits potential anticancer activity as it suppresses the proliferation, angiogenesis, and metastasis of breast cancer cells via inhibiting 3-hydroxy-methyl glutaryl-coenzyme A (HMG-CoA) reductase. In this study, hyaluronan-conjugated FLUVA-encapsulating liposomes (HA-L-FLUVA) were evaluated for their anticancer efficacy in vitro and in vivo. The particle size, zeta potential, and encapsulation efficiency of HA-L-FLUVA were 158.36 &plusmn, 1.78 nm, &minus, 24.85 &plusmn, 6.26 mV, and 35%, respectively. Growth inhibition of breast cancer stem cells (BCSCs) by HA-L-FLUVA was more effective than that by free FLUVA. The half maximal inhibitory concentration (IC50) values of FLUVA, L-FLVUA, and HA-L-FLUVA were 0.16, 0.17, and 0.09 &mu, M, respectively. The in vivo anticancer effect of HA-L-FLUVA in combination with doxorubicin (DOX) was more effective than that of free FLUVA, free DOX, and HA-L-FLUVA. The longest survival of mice was achieved by treatment with FLUVA (15 mg/kg) and HA-L-FLUVA (15 mg/kg) + DOX (3 mg/kg), followed by HA-L-FLUVA (15 mg/kg), Dulbecco&rsquo, s phosphate buffered saline, and DOX (3 mg/kg). No more than 10% body weight loss was observed in the mice injected with FLUVA, indicating that the drug was not toxic. Taken together, these results indicate that HA-L-FLUVA could serve as an effective anticancer drug by inhibiting the growth of both breast cancer cells and cancer stem cells.

Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections, however, these are toxic. To overcome this problem, we designed and fabricated low-toxicity Soluplus&reg, polymeric micelles encapsulating FEN and conducted toxicity assays in vitro and in vivo. FEN-loaded Soluplus&reg, micelles had an average particle size of 68.3 &plusmn, 0.6 nm, a zeta potential of &minus, 2.3 &plusmn, 0.2 mV, a drug loading of 0.8 &plusmn, 0.03%, and an encapsulation efficiency of 85.3 &plusmn, 2.9%. MTT and clonogenic assays were performed on A549 cells treated with free FEN and FEN-loaded Soluplus&reg, micelles. The in vitro drug release profile showed that the micelles released FEN more gradually than the solution. Pharmacokinetic studies revealed lower total clearance and volume of distribution and higher area under the curve and plasma concentration at time zero of FEN-loaded Soluplus&reg, micelles than of the FEN solution. The in vivo toxicity assay revealed that FEN-loaded Soluplus&reg, micelle induced no severe toxicity. Therefore, we propose that preclinical and clinical safety and efficacy trials on FEN-loaded Soluplus&reg, micelles would be worthwhile.

Background: Challenging research environment while the multinational trials are increasing, standardization of IRB review has become more important. The inconsistency is often inevitable in that opinions on the ethical part may be different, but the standardization and understanding the differences is required to assure IRB review quality. Thus, we aimed to develop and suggest quality assessment measure of IRB named “Blind review” by reviewing the same research protocols by multiple IRB panels. We further describe an analyzed result of differences to understand the mechanism of IRB standardization.Methods: We present a description of the Blind review process. Based on the HRPP (Human research Protection Program) SOPs (Standard of Procedure), eight blind review results from January 2010 to December 2018 at a single institution with multiple panels were included using Severance Hospital HRPP database. Review results were analyzed with review scores ranged 0 to 60 points including GCP requirements and protocol issues. Panel agreement was estimated by observed multiple rater agreement. Differences between review scores according to expertise member and IRB member duration were analysed with Wilcoxon rank-sum test and Kruskal-Wallis test.Results: Observed multiple raters’ agreement was increased from 0.444 (95% CI: 0.167-1.000) in 2010 to 0.479 (95% CI: 0.271-0.708) in 2014~2018 as IRB review experiences increases. In order to analyze the review mechanism, three GCP requirements and three protocol issues were scored (range 0 to 60). Mean values for GCP requirement and protocol issues were 19.25±8.21 and 18.40±9.04, respectively. Mean score of the panels where experts participated (n=16, 28.13±10.47) is higher than control group (n=32, 25.16±10.96) (p=0.93). According to career duration of IRB members’, scores of the group whose career is less than 3 years was 25.0±10.0 (n=14), the score of group whose career is 3-5 years was 26.3±9.6 (n=23). The mean score of the group whose career was more than 5 years shown 27.3±14.2 (n=11), and it is statistically significant. (p=0.09)Conclusions: We suggest Blind Review as an effective measure for overseeing and ensuring IRB’s review quality and overall GCP compliance.

Prediction of recurrences after catheter ablation of atrial fibrillation (AF) remains challenging. We sought to investigate the long-term outcomes after AF catheter ablation. A total of 2221 consecutive patients who underwent catheter ablation for symptomatic AF were included in this study (mean age 55 &plusmn, 11 years, 20.3% women, and 59.0% paroxysmal AF). Extensive ablation, in addition to circumferential pulmonary vein isolation, was more often accomplished in patients with non-paroxysmal AF than in those with paroxysmal AF (87.4% vs. 25.3%, p &lt, 0.001). During a median follow-up of 54 months, sinus rhythm (SR) was maintained in 67.1% after index procedure. After redo procedures in 418 patients, 83.3% exhibited SR maintenance. Recurrence rates were similar for single and multiple procedures (17.4% vs. 16.7%, p = 0.765). Subanalysis showed that the extent of late gadolinium enhancement (LGE), as assessed by cardiac magnetic resonance, is greater in patients with recurrence than in those without recurrence (36.2 &plusmn, 23.9% vs. 21.8 &plusmn, 13.7%, p &lt, 0.001). Cox-regression analysis revealed that non-paroxysmal AF (hazard ratio (HR) 2.238, 95% confidence interval (CI) 1.905&ndash, 2.629, p &lt, 0.001), overweight (HR 1.314, 95% CI 1.107&ndash, 1.559, p = 0.020), left atrium dimension &ge, 45 mm (HR 1.284, 95% CI 1.085&ndash, 1.518, p = 0.004), AF duration (HR 1.020 per year, 95% CI 1.006&ndash, 1.034, p = 0.004), and LGE &ge, 25% (HR 1.726, 95% CI 1.330&ndash, 2.239, p &lt, 0.001) are significantly associated with AF recurrence after catheter ablation. This study showed that repeated catheter ablation improves the clinical outcomes of patients with non-paroxysmal AF, suggesting that AF substrate based on LGE may underpin the mechanism of recurrence after catheter ablation.

Purpose: To investigate the different roles of heterogeneous natural killer (NK)-cell subpopulations in multiple myeloma and to identify NK-cell subsets that support the robust anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC). Experimental Design: We performed single-cell RNA sequencing of NK cells from patients with newly diagnosed multiple myeloma (NDMM) and delineated adaptive NK cells in their bone marrow (BM). We further characterized the distinct immunophenotypic features and functions of adaptive NK cells by multicolor flow cytometry in 157 patients with NDMM. Results: Adaptive NK cells exhibit a significantly lower level of CD38 expression compared with conventional NK cells, suggesting that they may evade daratumumab-induced fratricide. Moreover, adaptive NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared with conventional NK cells. The composition of adaptive NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in patients with NDMM. Unlike conventional NK cells, sorted adaptive NK cells from the BM of patients with NDMM exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Conclusions: Our findings indicate that adaptive NK cells are an important mediator of ADCC in multiple myeloma and support direct future efforts to better predict and improve the treatment outcome of daratumumab by selectively employing adaptive NK cells.

This study aims to evaluate the association between body image dissatisfaction and quality of life and depression among patients after hematopoietic stem cell transplantation (HSCT).We conducted a cross-sectional survey at three university-based HSCT outpatient clinics and the Korea Blood Cancer Association. We assessed the body image using the body image scale; quality of life and depression were measured using the World Health Organization Quality of Life-BREF and the Patient Health Questionnaire 9, respectively. Univariate and multivariate linear regression models were used to find an association between body image, quality of life, and depression.Among 163 study participants, 71.8% were male, and the mean age of the participants was 48.3 (SD = 11.2). Over 70% of the participants reported that they felt less physically and sexually attractive due to HSCT, and 39.3% of the patients were dissatisfied with their body image. In fully adjusted models, patients with dissatisfied body image had significantly poorer quality of life (- 13.68, 95% confidence interval [CI] = - 18.16, - 9.21). Moreover, patients with body image dissatisfaction were 8.59 times (95% CI = 3.79, 19.48) more likely to have depressive symptoms than patients without it.The majority of HSCT patients experienced body image dissatisfaction, which was significantly associated with poor quality of life and depression. It would be essential to evaluate body image after HSCT and provide appropriate interventions for preventing further psychological consequences.

Given the unsatisfactory survival in patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for peripheral T-cell lymphomas (PTCLs), we conducted a prospective trial of busulfan (Bu), etoposide (E), cytarabine (A), and melphalan (M) (BuEAM), including IV Bu instead of carmustine (BCNU) as in standard BEAM, as a high-dose regimen in such patients. This study evaluated the efficacy and toxicity of BuEAM as a high-dose regimen for ASCT in patients with T-cell lymphomas. The high-dose chemotherapy at seven centers in Korea included Bu (3.2 mg/kg IV qd from day 6 to day 5), E (200 mg/m2 IV bid on day 4 and day 3), A (1 g/m2 IV qd on day 4 and day 3), and M (140 mg/m2 IV qd on day 2). Eighty-one patients were enrolled in this study. The main subtypes were peripheral T-cell lymphoma, not other specified (n = 32, 39.5%), NK/T-cell lymphoma (n = 22, 27.5%), and angioimmunoblastic T-cell lymphoma (n = 12, 14.8%). Upfront and salvage ASCTs were performed in 65 (80.2%) and 16 (19.8%) patients, respectively. The disease status of the patients before ASCT was 54 patients (66.7%) with complete response and 27 patients (33.3%) with partial response. The common grade-III toxicities were anorexia (8.6%), diarrhea (7.4%), and stomatitis (4.9%). No veno-occlusive disorder was noted. Fifty-six (69.1%) and seven (8.6%) patients achieved complete and partial response, respectively, after ASCT, although 17 patients (21.0%) showed progressive disease. At a median follow-up duration of 49.3 months, the estimated 3-year progression-free survival and overall survival were 55.2% and 68.2% in all patients. The BuEAM high-dose regimen for ASCT was well tolerated and seemed to be effective in patients with T-cell lymphomas.

There are still controversies about the use of interim positron emission tomography/computed tomography (PET/CT) in indolent non-Hodgkin lymphoma due to the variable fluorodeoxyglucose (FDG) avidity. Therefore, this study aimed to evaluate the roles of interim PET/CT in marginal zone lymphoma (MZL), a representative indolent lymphoma. We analyzed the data of 146 MZL patients. All were treated with rituximab-containing immunochemotherapy. Interim PET/CT scan was performed after 2–3 cycles of therapy, and the response was assessed using the Deauville 5-point scales (5-PS) and a semi-quantitative assessment using the SUVmax reduction rate (ΔSUVmax). Progression-free survival (PFS) was well stratified according to a visual assessment of interim PET/CT using 5-PS (p p = 0.031). The interim PET/CT response based on the 5-PS is useful for predicting PFS of patients with MZL in the post-rituximab era.

The clinical outcome of advanced-stage Extranodal NK/T cell lymphoma (ENKTL) patients using conventional chemotherapy is extremely poor. The aim of this study was to investigate the outcomes of advanced-stage ENKTL patients treated with non-anthracycline-based chemotherapy followed by upfront autologous stem cell transplant (ASCT). From 8 institutions, 27 patients were recruited from February 2016 to May 2019. Patients were treated with 4 cycles of VIDL induction chemotherapy. Patients who achieved complete response (CR) or partial response (PR) underwent upfront ASCT. This study is registered with clinicaltrial.gov, # NCT02544425. Twenty patients (74.1%) completed 4 cycles of VIDL induction. The overall response rate of VIDL was 74.1%, including 17 (63.0%) with CR and 3 (11.1%) with PR. Primary toxicity of the induction regimen was grade 3 or 4 neutropenia, and no treatment-related mortality was reported. Seventeen patients proceeded with upfront ASCT, and 9 patients relapsed after ASCT, among whom, 4 was central nervous system (CNS) relapse. The median duration of response was 15.2 months (95% CI, 6.3-24.1 months). This study suggested that VIDL induction chemotherapy followed by upfront ASCT is feasible and effective for the treatment of advanced-stage ENKTL. However, CNS relapse prevention is needed in the treatment of advanced-stage ENKTL.

Background Many clinical trials on antihypertensive drugs have confirmed the usefulness of these drugs in regulating blood pressure effectively. However, all the drugs usually require long-term use; thus, economic burdens as well as some adverse effects, including headache, diarrhea, skin rash, edema, fever, and liver and kidney dysfunction, accompany their use. Therefore, we attempted to identify natural medications for treating hypertension. We investigated the antihypertensive effects of Dendropanax morbiferus H. Lév. extract (DP), enzymatically hydrolyzed DP extract (Hy-DP) and 5% unripe Rubus coreanus Miq. ethanol extract (5-uRCK). Methods Extracts of the unripe R. coreanus were made using 20 volumes of 5% ethanol at 100 °C for 4 h. The dried leaves of D. morbiferus were subjected to enzymatic hydrolysis by protease, trypsin, bromelain and papain to increase L-arginine and GABA levels. Vasorelaxant effects of these extracts were evaluated on rat aorta precontracted with phenylephrine. In addition, hippocampal neurons, RAW 264.7 macrophages and human umbilical vein endothelial cells (HUVECs) were used to exam nitric oxide (NO) production and NO synthase (NOS) gene expression. Results DP, Hy-DP and 5-uRCK dose-dependently relaxed isolated rat aortic rings contracted with phenylephrine; however, Hy-DP was more effective than DP. L-NAME and ODQ differentially inhibited Hy-DP- and 5-uRCK-induced relaxation; both L-NAME and ODQ completely blocked 5-uRCK-mediated relaxation. Endothelium-denuded aortic ring relaxation was induced much less by 5-uRCK than by Hy-DP. Therefore, 5-uRCK and Hy-DP induced vascular relaxation by endothelium-dependent and partially endothelium-dependent mechanisms, respectively. Hy-DP and 5-uRCK induced eNOS gene expression and NO production in endothelial cells but did not change iNOS/nNOS expression or NO production in macrophages or neuronal cells. Both Hy-DP and 5-uRCK effectively induced vascular relaxation via similar but slightly different mechanisms. The best effective combination was investigated after mixing Hy-DP and 5-uRCK at different ratios. The 2:1 Hy-DP:5-uRCK mixture inhibited ACE, cGMP- and cAMP-dependent phosphodiesterase activity and vascular relaxation better than the other mixtures. Conclusion In conclusion, Hy-DP and 5-uRCK exert antihypertensive effects through different endothelium-dependent or endothelium-independent mechanisms. These findings may greatly help elucidate the mechanisms of clinical efficacy of Hy-DP:5-uRCK mixtures used for blood pressure regulation.

Background Artemisia in East Asia includes a number of economically important taxa that are widely used for food, medicinal, and ornamental purposes. The identification of taxa, however, has been hampered by insufficient diagnostic morphological characteristics and frequent natural hybridization. Development of novel DNA markers or barcodes with sufficient resolution to resolve taxonomic issues of Artemisia in East Asia is significant challenge. Results To establish a molecular basis for taxonomic identification and comparative phylogenomic analysis of Artemisia, we newly determined 19 chloroplast genome (plastome) sequences of 18 Artemisia taxa in East Asia, de novo-assembled and annotated the plastomes of two taxa using publicly available Illumina reads, and compared them with 11 Artemisia plastomes reported previously. The plastomes of Artemisia were 150,858–151,318 base pairs (bp) in length and harbored 87 protein-coding genes, 37 transfer RNAs, and 8 ribosomal RNA genes in conserved order and orientation. Evolutionary analyses of whole plastomes and 80 non-redundant protein-coding genes revealed that the noncoding trnH-psbA spacer was highly variable in size and nucleotide sequence both between and within taxa, whereas the coding sequences of accD and ycf1 were under weak positive selection and relaxed selective constraints, respectively. Phylogenetic analysis of the whole plastomes based on maximum likelihood and Bayesian inference analyses yielded five groups of Artemisia plastomes clustered in the monophyletic subgenus Dracunculus and paraphyletic subgenus Artemisia, suggesting that the whole plastomes can be used as molecular markers to infer the chloroplast haplotypes of Artemisia taxa. Additionally, analysis of accD and ycf1 hotspots enabled the development of novel markers potentially applicable across the family Asteraceae with high discriminatory power. Conclusions The complete sequences of the Artemisia plastomes are sufficiently polymorphic to be used as super-barcodes for this genus. It will facilitate the development of new molecular markers and study of the phylogenomic relationships of Artemisia species in the family Asteraceae.

The development of colistin resistance in carbapenem-resistant strains poses a serious public health problem. In this study, we collected 249 carbapenem-resistant Escherichia coli isolates from patients in Seoul in 2018, and screened all isolates for colistin resistance and for the presence of mobile colistin resistance (mcr) genes. Colistin-resistant strains were further analyzed using multilocus sequence typing, antimicrobial susceptibility testing, detection of antibiotic resistance determinants, plasmid transconjugation, and whole-genome sequencing. Three of the 249 carbapenem-resistant isolates were resistant to colistin, and mcr-1 was detected in one isolate (SECR18-0888), which belonged to sequence type 156 and was resistant to all antibiotics tested except tigecycline. The mcr-1.1 gene was located on an ~62 kb self-transferable IncI2 plasmid along with the bla