Neural cell adhesion molecule 1 is a cellular target engaged plasma biomarker in demyelinating Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot-Marie-Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity. METHODS: Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls. Disease severity was measured using Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), and plasma concentrations of NCAM1 and p75 were analyzed by enzyme-linked immunosorbent assay. Eight sural nerves from CMT patients were examined to determine the relation of histopathology and plasma NCAM1 levels. RESULTS: Plasma concentration of NCAM1, but not p75, was specifically increased in demyelinating subtypes of CMT (median = 7100 pg/mL, p < 0.001), including CMT1A, but not in axonal subtype (5964 pg/mL, p > 0.05), compared to the control (3859 pg/mL). CMT1A patients with mild or moderate severity (CMTNSv2 < 20) showed higher levels of plasma NCAM1 than healthy controls. Immunofluorescent NCAM1 staining for the sural nerves of CMT patients showed that NCAM1-positive onion bulb cells and possible demyelinating Schwann cells might be associated with the specific increase of plasma NCAM1 in demyelinating CMT. CONCLUSIONS: The plasma NCAM1 levels in demyelinating CMT might be a surrogate biomarker reflecting pathological Schwann cell status and disease progression.

Novel conformation of hyaluronic acid with improved cosmetic efficacy.

BACKGROUND: Hyaluronic acid presents a valuable cosmetic ingredient that occurs naturally. Its direct links to skin aging has led to its broad application. The aim of this study was to improve the cosmetic efficacy of high molecular weight hyaluronic acid (HMWHA) without chemical modifications and evaluate such improvements through clinical and in vitro studies. METHODS: A novel formulation of HMWHA (SCAI-HA) was prepared and investigated to comparatively assess 6 clinical and 2 in vitro parameters concerning its dermatological cosmetic efficacy and biological properties. The dermatological and cellular parameters examined in this study include skin hydration, transepidermal water loss (TEWL), skin elasticity, wrinkles, facial sagging, dermal density, cytotoxicity, and collagen synthesis. RESULTS: SCAI-HA exhibited the ability to improve the tested dermatological parameters (hydration, elasticity, wrinkles, and density) to magnitudes comparable to those of HMWHA. In addition, SCAI-HA showed notably improved capacities for attenuating facial sagging and TEWL and promoting cellular collagen synthesis in normal human dermal fibroblasts. CONCLUSION: SCAI-HA presents a novel conformation of HMWHA with improved cosmetic efficacy in mitigating (i) facial sagging, (ii) TEWL, and promoting, and (iii) collagen synthesis. These findings denote the enhancement of SCAI-HA as a cosmetic ingredient with potential anti-aging properties.

Factors Associated with Person-Centered Care among Hospice Nurses.

Purpose: The purpose of this study was to examine person-centered care, nursing professionalism, the nursing work environment, and empathy capacity among hospice ward nurses and to identify the factors affecting person-centered care. Methods: Data were collected using a self-report questionnaire completed by 120 nurses at 30 inpatient hospice institutions in South Korea from August 24, 2020 to September 8, 2020. The independent t-test, one-way analysis of variance, and Pearson correlation analysis were conducted using SPSS version 26.0. Results: The scores were 3.76±0.45 for person-centered care, 3.58±0.47 for nursing professionalism, 3.24±0.57 for the nursing work environment, and 4.00±0.46 for empathy capacity. There were positive correlations between the variables. Factors that influenced the person-centered care of hospice nurses were being a manager (ß=0.20, P=0.002), high nursing professionalism (ß=0.20, P=0.012), a better nursing work environment (ß=0.15, P=0.033), and high empathy capacity (ß=0.51, P<0.001). The explanatory power was 65.3%. Conclusion: To reinforce the person-centered care competency of hospice nurses, it is necessary to improve nursing professionalism, the nursing work environment, and empathy competency. Opportunities for nurses to practice independently must be expanded for nurses to develop nursing professionalism. Sufficient nursing personnel and material resources must be provided to nurses to cultivate a positive work environment. Empathy should be improved by implementing integrated education programs that include nursing practice situations.

Changing characteristics of the empathic communication network after empathy-enhancement program for medical students.

The Empathy-Enhancement Program for Medical Students (EEPMS) comprises five consecutive weekly sessions and aims to improve medical students' empathic ability, an essential component of humanistic medical professionalism. Using a graph theory approach for the Ising network (based on l1-regularized logistic regression) comprising emotional regulation, empathic understanding of others' emotion, and emotional expressivity, this study aimed to identify the central components or hubs of empathic communication and the changed profile of integration among these hubs after the EEPMS. Forty medical students participated in the EEPMS and completed the Depression Anxiety Stress Scale-21, the Empathy Quotient-Short Form, the Jefferson Scale of Empathy, and the Emotional Expressiveness Scale at baseline and after the EEPMS. The Ising model-based network of empathic communication was retrieved separately at two time points. Agitation, self-efficacy for predicting others' feelings, emotional concealment, active emotional expression, and emotional leakage ranked in the top 20% in terms of nodal strength and betweenness and closeness centralities, and they became hubs. After the EEPMS, the 'intentional emotional expressivity' component became less locally segregated (P = 0.014) and more directly integrated into those five hubs. This study shows how to quantitatively describe the qualitative item-level effects of the EEPMS. The key role of agitation in the network highlights the importance of stress management in preserving the capacity for empathic communication. The training effect of EEPMS, shown by the reduced local segregation and enhanced integration of 'intentional emotional expressivity' with hubs, suggests that the EEPMS could enable medical students to develop competency in emotional expression, which is an essential component of empathic communication.

Neutrophils dominate the immune cell composition in non-small cell lung cancer.

The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC. The results show that the immune cell composition is fundamentally different in lung adenocarcinoma as compared with lung squamous cell carcinoma, and that neutrophils are the most prevalent immune cell type. Using T-cell receptor-ß sequencing and tumour reactivity assays, we predict that tumour reactive T cells are frequently present in NSCLC. These results should help to guide the design of clinical trials and the direction of future research in this area.

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma.

Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1(fl/fl) (Kras/Irs-1(-/-)) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1(+/+) and Kras/Irs-1(-/-) mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.

Effect of low-dosage electron beam irradiation on antioxidant activities of navel oranges during storage at a low temperature of 3°C.

Effects of low-dosage electron beam irradiation on antioxidant activities of Navel oranges during storage at a low temperature of 3°C were studied. Oranges were irradiated at dosages of 0.2, 0.4, 0.6, 0.8, and 1.0 kGy and changes in antioxidant compounds and antioxidant activities were investigated. No changes in total phenolic contents or flavonoid contents were observed with an increase in radiation dosage. Also, no differences between non-irradiated and irradiated oranges in DPPH radical scavenging and ABTS radical scavenging activities, FRAP values, and reducing powers were observed. Electron beam irradiation at dosages less than 1 kGy does not affect levels of antioxidant compounds and antioxidant activities of Navel oranges.

Effectiveness of a community-based multidomain cognitive intervention program in patients with Alzheimer's disease.

AIM: The aim of the present study was to evaluate the efficacy of a multidomain program in patients with Alzheimer's disease (AD). METHODS: A total of 53 patients with probable AD participated in the present study. The participants were classified to a cognitive programming group (n = 32) and control group (n = 21). Participants in the cognitive intervention program received multidomain cognitive stimulation including art, music, recollection and horticultural therapy, each period of intervention lasting 1 h. This program was repeated five times per week over a period of 6 months at the Seongdong-gu Center for Dementia. The Mini-Mental State Examination, the Korean version of Consortium to Establish a Registry for Alzheimer's Disease, Clinical dementia rating scales, and the Korean version of the Quality of Life-Alzheimer's Disease were used to evaluate cognitive ability at baseline and after intervention. After 6 months, cognitive abilities were compared between patients actively participating in cognitive intervention and the pharmacotherapy only group. RESULTS: Patients receiving cognitive intervention showed significant cognitive improvement in the word-list recognition and recall test scores versus the control. There was no change in the overall Clinical dementia rating score, but the domain of community affairs showed a significant improvement in the cognitive intervention group. Quality of Life-Alzheimer's Disease of caregivers was slightly improved in the cognitive intervention group after 6 months. DISCUSSION: Multidomain cognitive intervention by regional dementia centers has great potential in helping to maintain cognitive function in patients with dementia, increase their social activity and reduce depression, while enhancing the quality of life of caregivers.

Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis.

IPF is a progressive lung disorder characterized by fibroblast proliferation and myofibroblast differentiation. Although neutrophil accumulation within IPF lungs has been negatively correlated with outcomes, the role played by neutrophils in lung fibrosis remains poorly understood. We have demonstrated previously that NE promotes lung cancer cell proliferation and hypothesized that it may have a similar effect on fibroblasts. In the current study, we show that NE(-/-) mice are protected from asbestos-induced lung fibrosis. NE(-/-) mice displayed reduced fibroblast and myofibroblast content when compared with controls. NE directly both lung fibroblast proliferation and myofibroblast differentiation in vitro, as evidenced by proliferation assays, collagen gel contractility assays, and αSMA induction. Furthermore, αSMA induction occurs in a TGF-ß-independent fashion. Treatment of asbestos-recipient mice with ONO-5046, a synthetic NE antagonist, reduced hydroxyproline content. Thus, the current study points to a key role for neutrophils and NE in the progression of lung fibrosis. Lastly, the study lends rationale to use of NE-inhibitory approaches as a novel therapeutic strategy for patients with lung fibrosis.

Plasticity of airway epithelial cell transcriptome in response to flagellin.

Airway epithelial cells (AEC) are critical components of the inflammatory and immune response during exposure to pathogens. AECs in monolayer culture and differentiated epithelial cells in air-liquid interface (ALI) represent two distinct and commonly used in vitro models, yet differences in their response to pathogens have not been investigated. In this study, we compared the transcriptional effects of flagellin on AECs in monolayer culture versus ALI culture using whole-genome microarrays and RNA sequencing. We exposed monolayer and ALI AEC cultures to flagellin in vitro and analyzed the transcriptional response by microarray and RNA-sequencing. ELISA and RT-PCR were used to validate changes in select candidates. We found that AECs cultured in monolayer and ALI have strikingly different transcriptional states at baseline. When challenged with flagellin, monolayer AEC cultures greatly increased transcription of numerous genes mapping to wounding response, immunity and inflammatory response. In contrast, AECs in ALI culture had an unexpectedly muted response to flagellin, both in number of genes expressed and relative enrichment of inflammatory and immune pathways. We conclude that in vitro culturing methods have a dramatic effect on the transcriptional profile of AECs at baseline and after stimulation with flagellin. These differences suggest that epithelial responses to pathogen challenges are distinctly different in culture models of intact and injured epithelium.

Physicochemical and Sensory Properties of Appenzeller Cheese Supplemented with Shrimp Powder.

The effects of adding shrimp (Periclimenes imperator) powder to Appenzeller cheese on quality and characteristics during ripening were investigated. Cheese samples were prepared containing 1.0%, 2.0%, and 3.0% shrimp powder. Changes in the lactic acid bacterial populations, pH, water-soluble nitrogen concentrations, consumer acceptability, colour and texture were monitored during ripening. The addition of shrimp powder did not affect the appearance or consumer sensory characteristics of the cheeses. Likewise, cheese cohesiveness, fracturability, and springiness were not significantly altered. It was concluded that the quality of the Appenzeller cheese was not affected by adding shrimp powder.

Effects of hesperidin loaded poly(lactic-co-glycolic acid) scaffolds on growth behavior of costal cartilage cells in vitro and in vivo.

It has been widely accepted that costal cartilage cells (CCs) have more excellent initial proliferation capacity than articular cartilage cells. Biodegradable synthetic polymer poly(lactic-co-glycolic acid) (PLGA) was approved by Food and Drug Administration. Hesperidin has antifungal, antiviral, antioxidant, anti-inflammatory, and anticarcinogenic properties. Hesperidin loaded (0, 3, 5, and 10 wt.%) PLGA scaffolds were prepared and in vitro and in vivo properties were characterized. Scaffolds were seeded with CCs isolated from rabbit, which were kept in culture to harvest for histological analysis. Hesperidin/PLGA scaffolds were also implanted in nude mice for 7 and 28 days. Assays of 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfo-phenyl)-2H-tetrazolium, monosodium salt (WST), and scanning electron microscope were carried out to evaluate attachment and proliferation of CCs in hesperidin/PLGA scaffolds. Glycosaminoglycan assay was performed to confirm the effects of hesperidin on extracellular matrix formation. Reverse-transcriptase polymerase chain reaction was carried out to confirm the expression of the specific genes for CCs. In these results, we demonstrated that cell attachment and proliferation on hesperidin/PLGA scaffolds were more excellent compared with on PLGA scaffold. Specially, 5 wt.% hesperidin/PLGA scaffold represented the best results among other scaffolds. Thus, 5 wt.% hesperidin/PLGA scaffold will be applicable to tissue engineering cartilage.

GC/MS analysis of high-performance liquid chromatography fractions from Sophora flavescens and Torilis japonica extracts and their in vitro anti-neosporal effects on Neospora caninum.

We analyzed alcoholic extracts of herbs possessing anti-neosporal activity against Neospora (N.) caninum. To identify the chemical components of Sophora (S.) flavescens and Torilis (T.) japonica associated with anti-neosporal activity, specific fractions were isolated by high-performance liquid chromatography (HPLC). In vitro activity of the fractions against N. caninum was then assessed. Gas chromatography/ mass spectrometry (GC/MS) was used to identify and quantify specific anti-neosporal molecules in the herbal extracts. Almost all HPLC fractions of S. flavescens and T. japonica had higher levels of anti-neosporal activity compared to the not treated control. Active constituents of the extracts were sophoridane, furosardonin A, and tetraisopropylidene-cyclobutane in S. flavescens; 5,17-ß-dihydroxy-de-A-estra-5,7,9,14-tetraene, furanodiene, and 9,12-octadecadienoic acid (Z,Z)-(CAS,1) in T. japonica.

Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics.

OBJECTIVE: Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin. METHODS: We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics. RESULTS: Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.-130G>A and haplotype 2 containing two polymorphisms, g.-609G>A and g.-396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539 ± 76 (reference group) vs. 633 ± 102 (variant group) ml/min; P=0.006] and secretion clearance [439 ± 81 (reference group) vs. 531 ± 102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group. CONCLUSION: Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.

Identification and functional characterization of novel MATE1 genetic variations in Koreans.

Multidrug and toxin extrusion 1 (MATE1, SLC47A1), an organic cation transporter, plays an important role in the renal and biliary elimination of various clinical drugs, including the anti-diabetic drug metformin. The goal of this study was to identify and characterize novel genetic variants of MATE1. Five variants in the promoter region and two nonsynonymous variants, p.D64G and p.L125F, were identified in 48 DNA samples from healthy Koreans. MATE1 promoter haplotype 3 containing g.-1975C>A showed a significant increase in reporter activity. Three transcription factors, Nkx-2.5, SREBP-1, and USF-1 were predicted to bind to the promoter in the region of g.-1975C>A. Results from electrophoretic mobility shift assays showed that the g.-1975A allele exhibits greater binding affinity to all of these transcription factors than the g.-1975C allele. In particular, we found that Nkx-2.5 and USF-1 induce MATE1 transcription. Our study suggests that the common promoter haplotype of MATE1 changes MATE1 transcriptional activity regulated by Nkx-2.5, SREBP-1, and USF-1.

Clinical features of patients on home oxygen therapy due to chronic respiratory failure at one university hospital.

BACKGROUND/AIMS: Home oxygen therapy (HOT) costs a great deal every year and demand for the service is growing. In Korea, health insurance has covered HOT since November 1, 2006. The objective of this study was to evaluate clinical features of patients who used long-term HOT due to chronic respiratory failure and to determine the appropriateness of oxygen prescriptions. METHODS: Between November 2006 and April 2010, patients prescribed long-term HOT were enrolled in the study at a tertiary university referral hospital and their medical records and telephone survey information were evaluated. In total, 340 patients were evaluated retrospectively. RESULTS: Regarding the initial indications for HOT, their mean PaO(2) was 49.8 mmHg and mean SpO(2) was 82.2%. Underlying diseases included chronic obstructive pulmonary disease (COPD, 19.8%), lung cancer (12.6%), and interstitial lung disease (11.2%). The admission rate within 1 year was 53.4% and the average number of admissions was 1.64/patient. Other underlying diseases for which oxygen was prescribed, despite not meeting the insurance coverage criteria, were lung cancer (36.6%) and interstitial pneumonia (16.6%). CONCLUSIONS: Home oxygen prescriptions have increased since health insurance coverage was extended. However, cases of oxygen prescriptions frequently do not meet the coverage criteria. It is important to discuss extending the coverage criteria to other disease groups, such as interstitial lung disease and lung cancer, in terms of cost-effectiveness. Further, physicians prescribing oxygen therapy should be educated regarding the criteria.

Discovery of a novel class of 2-aminopyrimidines as CDK1 and CDK2 inhibitors.

A series of new 2-(2-aminopyrimidin-4-yl)phenol derivatives were synthesized as potential antitumor compounds. Substitution with pyrrolidine-3,4-diol at the 4-position of phenol provided potent inhibitory activity against CDK1 and CDK2. X-ray crystal structural studies were performed to account for the effect of the substituent on both the enzymatic and cell growth inhibitory activities.

Antioxidative and antiviral properties of flowering cherry fruits (Prunus serrulata L. var. spontanea).

The phenolic compounds of many fruits have been known to be efficient cellular protective antioxidants. In this study, antioxidative and antiviral properties of flowering cherry cultivars (Prunus yedoensis, Prunus sargentii, Prunus lannesiana, and Prunus cerasus) in Korea were investigated. The antioxidant property was assayed for specific activities including 2,2-diphenyl-1-picrylhydrazyl (DPPH) hydroxy radical scavenging activity, reducing power capacity, and superoxide dismutase (SOD) like activity. In addition, antiviral activity was determined by inhibition studies on the infection cycle of porcine epidemic diarrhea virus (PEDV), measured as minimum concentration of cherry extracts that inhibited 50% of cytopathic effect (CPE) on PEDV. Our results show that the four varieties of cherries contain substantially high antioxidants and antiviral activities. In particular, P. cerasus contains higher antioxidants and antiviral activities as well as polyphenolic content than other varieties. Our data indicate that Korean native cherry cultivars could be beneficial supplements of dietary antioxidants and natural antiviral agents.

Anti-inflammatory phenylpropanoid glycosides from Clerodendron trichotomum leaves.

The chromatographic separation of MeOH extract from Clerodendron trichotomum Thunberg leaves led to the isolation of three phenylpropanoid compounds. Using spectroscopic methods, the structures of these compounds were determined as beta-(3', 4'-dihydroxyphenyl)ethyl-O-alpha-L-rhamnopyranosyl (1-->3)-beta-D-(4-O-caffeoyl)-glucopyranoside, acteoside (verbascoside) (1), beta-(3', 4'-dihydroxyphenyl)ethyl-O-alpha-L-rhamnopyranosyl (1-->3)-beta-D-(6-O-caffeoyl)-glucopyranoside, isoacteoside (2), beta-(3', 4'-dihydroxyphenyl) ethyl-O-alpha-L-rhamnopyranosyl (1-->3)-beta-D-glucopyranoside, and decaffeoylacteoside (3). We measured the anti-inflammatory activity of these three phenylpropanoid compounds both in vitro (DPPH reduction assay, TBARS assay on Cu (2+)-induced oxidized LDL, PGE(2) assay) and in vivo (acetic acid induced vascular permeability in mice and carrageenan-induced hind paw edema in rats). 80% methanol fraction and acteoside had the activity.