K-ras mutation detected by peptide nucleic acid-clamping polymerase chain reaction, Ki-67, S100P, and SMAD4 expression can improve the diagnostic accuracy of inconclusive pancreatic EUS-FNB specimens.

OBJECTIVES: We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases. METHODS: Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed. RESULTS: K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases. CONCLUSIONS: K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose.

Endoplasmic reticular stress as an emerging therapeutic target for chronic pain: a narrative review.

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome. Recent preclinical studies have shown that endoplasmic reticulum (ER) stress could be a central hub for triggering multiple molecular cascades involved in the development of chronic pain. Several ER stress inhibitors and unfolded protein response modulators, which have been tested in randomised clinical trials or apprpoved by the US Food and Drug Administration for other chronic diseases, significantly alleviated hyperalgesia in multiple preclinical pain models. Although the role of ER stress in neurodegenerative disorders, metabolic disorders, and cancer has been well established, research on ER stress and chronic pain is still in its infancy. Here, we critically analyse preclinical studies and explore how ER stress can mechanistically act as a central node to drive development and progression of chronic pain. We also discuss therapeutic prospects, benefits, and pitfalls of using ER stress inhibitors and unfolded protein response modulators for managing intractable chronic pain. In the future, targeting ER stress to impact multiple molecular networks might be an attractive therapeutic strategy against chronic pain refractory to steroids, NSAIDs, or opioids. This novel therapeutic strategy could provide solutions for the opioid crisis and public health challenge.

Population pharmacokinetics of piperacillin/tazobactam in critically ill Korean patients and the effects of extracorporeal membrane oxygenation.

OBJECTIVES: To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients. METHODS: Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24 h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation. RESULTS: A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16 g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130-170 mL/min/1.73 m2. CONCLUSIONS: ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8 mg/L or when patients have an eGFR of 130-170 mL/min/1.73 m2.

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC. Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50-130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC. Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Deep learning-based virtual cytokeratin staining of gastric carcinomas to measure tumor-stroma ratio.

The tumor-stroma ratio (TSR) determined by pathologists is subject to intra- and inter-observer variability. We aimed to develop a computational quantification method of TSR using deep learning-based virtual cytokeratin staining algorithms. Patients with 373 advanced (stage III [n = 171] and IV [n = 202]) gastric cancers were analyzed for TSR. Moderate agreement was observed, with a kappa value of 0.623, between deep learning metrics (dTSR) and visual measurement by pathologists (vTSR) and the area under the curve of receiver operating characteristic of 0.907. Moreover, dTSR was significantly associated with the overall survival of the patients (P = 0.0024). In conclusion, we developed a virtual cytokeratin staining and deep learning-based TSR measurement, which may aid in the diagnosis of TSR in gastric cancer.

Value Frameworks: Adaptation of Korean Versions of Value Frameworks for Oncology.

This study sought to adapt the existing value framework (VF) to produce a reliable and valid Korean oncology VF. Two VFs developed by The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) were selected for examination in the present study. Forward and backward translations were conducted for six high-priced drugs indicated for non-small-cell lung cancer and multiple myeloma. Inter-rater reliability was measured based on the intraclass correlation coefficient (ICC) and variation was described using the coefficient of variation. The relative weights of factors critically considered by Korean oncologists were derived following the analytic hierarchy process (AHP), and focus group interviews (FGIs) were used to obtain qualitative data regarding the applications of these two VFs in the Korean setting. The ICCs of the Korean VFs were 0.895 (0.654-0.983) for ASCO and 0.726 (0-0.982) for ESMO translations, suggesting excellent reliability for ASCO and good reliability for ESMO. AHP demonstrated that clinical benefit has the highest priority, which is consistent with the ASCO VF. The FGIs suggested that the result for AHP is acceptable and that both ESMO and ASCO VFs should be used complementarily. Although further evaluation with a larger sample size is needed, the Korean versions of ESMO/ASCO VFs are valid and reliable tools and are acceptable to Korean stakeholders, yet they should be applied with caution.

Medication Adherence and Persistence of Open-Angle Glaucoma Patients in Korea: A Retrospective Study Using National Health Insurance Claims Data.

This study aimed to analyze medication adherence and persistence among open-angle glaucoma patients in Korea. A retrospective study was conducted using the Korean National Health Insurance (NHI) claims database from 2016 to 2019. Newly diagnosed open-angle glaucoma patients who were prescribed with the intraocular pressure (IOP)-lowering eyedrops were included. Adherence was measured using the medication possession ratio (MPR), and persistence was measured using the duration of therapy during the 24 month follow-up period. During the study period, 14,648 open-angle glaucoma patients were identified, and 3118 (21.3%) and 4481 patients (30.6%) were adherent to and persistent with their glaucoma treatment, respectively. The mean MPR was 48.8%, and the mean duration of therapy was 357.2 days. Logistic regression analysis showed that patients who are older, female, using prostaglandins as the index medication, and visiting secondary or tertiary hospitals were significantly associated with greater rates of adherence (odds ratio (OR) = 1.21, 1.12, 1.27, and 1.73, respectively) and persistence (OR = 1.11, 1.17, 1.16, 1.17, and 1.36, respectively) during the study period. Patients with open-angle glaucoma in Korea had substandard medication adherence and discontinued their treatment. Ophthalmologists should pay more attention to younger, male patients to improve adherence.

A Meta-Regression Analysis of Utility Weights for Breast Cancer: The Power of Patients' Experience.

To summarize utility estimates of breast cancer and to assess the relative impacts of study characteristics on predicting breast cancer utilities. We searched Medline, Embase, RISS, and KoreaMed from January 1996 to April 2019 to find literature reporting utilities for breast cancer. Thirty-five articles were identified, reporting 224 utilities. A hierarchical linear model was used to conduct a meta-regression that included disease stages, assessment methods, respondent type, age of the respondents, and scale bounds as explanatory variables. The utility for early and late-stage breast cancer, as estimated by using the time-tradeoff with the scales anchored by death to perfect health with non-patients, were 0.742 and 0.525, respectively. The severity of breast cancer, assessment method, and respondent type were significant predictors of utilities, but the age of the respondents and bounds of the scale were not. Patients who experienced the health states valued 0.142 higher than did non-patients (P <0.001). Besides the disease stage, the respondent type had the highest impact on breast cancer utility.

The Burden of Cervical Cancer in Korea: A Population-Based Study.

This study used the Korean National Health Insurance (NHI) claims database from 2011 to 2017 to estimate the incidence and the incidence-based cost of cervical cancer and carcinoma in situ of cervix uteri (CIS) in Korea. The primary outcome was the direct medical cost per patient not diagnosed with cervical cancer (C53) or CIS (D06) 2 years prior to the index date in the first year after diagnosis. A regression analysis was conducted to adjust for relevant covariates. The incidence of cervical cancer tended to decrease from 2013 to 2016, while that of CIS increased. In particular, the incidence rate of CIS in women in their 20 s and 30 s increased by 56.8% and 28.4%, respectively, from 2013 to 2016. The incidence-based cost of cervical cancer and CIS was USD 13,058 and USD 2695 in 2016, respectively, which increased from 2013. Multivariate regression analysis suggested that age was the most influential variable of the cost in both patient groups, and the cost was highest in those aged over 60, i.e., the medical cost was significantly lower in younger women than their older counterparts. These findings suggest that targeting younger women in cervical cancer prevention is a reasonable option from both economic and public health perspectives.

Incidence, cost and gender differences of oropharyngeal and noncervical anogenital cancers in South Korea.

BACKGROUND: Human papillomavirus (HPV) is associated with a significant public health burden, yet few studies have been conducted in Asia, especially on noncervical cancers. We estimated the incidence and cost of oropharyngeal and noncervical anogenital (anal, vulvar, vaginal, penile) cancer in Korea. METHODS: We conducted a retrospective cohort study using Korea's National Health Insurance (NHI) claim database from 2013 to 2016. The main outcome measures were the number of respective cancer incidences during the study period and the annual costs per patient in the first year after diagnosis, which was adjusted by relevant variables based on the regression analysis. RESULTS: During the study period, 8022 patients with these cancers were identified, and oropharyngeal cancer comprised 46% of them. The crude incidence rate for male oropharyngeal cancer was significantly higher than that of females (3.1 vs. 0.7 per 100,000 as of 2016, respectively). Additionally, the crude incidence of male oropharyngeal cancer increased from 2.7 in 2013 to 3.1 in 2016, whereas that of female and other cancers was stable during the study period. The mean annual incidence-based cost per patient in 2016 was highest for oropharyngeal cancers (21,870 USD), and it was significantly higher in males than in females based on then regression analysis (p < .001). CONCLUSIONS: Oropharyngeal cancer comprises the highest number of HPV-associated noncervical cancer incidences in Korea, and the incidence and cost of oropharyngeal cancer was significantly higher among males than females. More aggressive public health policy toward males may decrease gender gap of oropharyngeal cancer.

Comparison of sugammadex and pyridostigmine bromide for reversal of rocuronium-induced neuromuscular blockade in short-term pediatric surgery: A prospective randomized study.

BACKGROUND: Sugammadex reverses rocuronium-induced neuromuscular blockade quickly and effectively. This study compared efficacy of sugammadex and pyridostigmine for reversal of rocuronium-induced light block or minimal block in children scheduled for elective entropion surgery. METHODS: A prospective randomized study was conducted on 60 pediatric patients aged 1 to 11 years and scheduled for entropion surgery under sevoflurane anesthesia. Neuromuscular blockade was achieved by administration of 0.6 mg/kg rocuronium and assessed using train-of-four (TOF) ulnar nerve stimulation. Patients were randomly assigned to 2 groups receiving sugammadex 2 mg/kg or pyridostigmine 0.2 mg/kg plus glycopyrrolate 0.01 mg/kg. Primary outcomes were time from reversal agents administration to TOF ratio 0.9 and time from reversal agent administration to TOF ratio 1.0. Time from TOF ratio 0.9 to extubation, time from TOF ratio 1.0 to extubation, and postoperative adverse events were also recorded. RESULTS: There were no substantial differences in demographic variables. Time from reversal agents administration to TOF ratio 0.9 and time from reversal agents to TOF ratio 1.0 were significantly faster in sugammadex group: 1.30 ±â€Š0.84 versus 3.53 ±â€Š2.73 minutes (P < .001) and 2.75 ±â€Š1.00 versus 5.73 ±â€Š2.83 minutes (P < .001). Extubation time was shorter in sugammadex group. Incidence of skin rash, nausea, vomiting, and postoperative residual neuromuscular blockade (airway obstruction) was not statistically different between groups. Incidence of patients agitation in recovery room was lower in sugammadex group. CONCLUSION: Sugammadex provided more rapid reversal of rocuronium-induced neuromuscular blockade in pediatric patients undergoing surgery lasting 30 to 60 minutes than did pyridostigmine plus glycopyrrolate, with no differences in incidence of adverse events between groups.

Healthcare resource use and costs of diabetic macular oedema for patients with antivascular endothelial growth factor versus a dexamethasone intravitreal implant in Korea: a population-based study.

OBJECTIVES: To estimate the costs and healthcare resources of patients with diabetic macular oedema (DME) who received intravitreal antivascular endothelial growth factor (anti-VEGF) agents or a dexamethasone intravitreal implant (DEX-implant) in Korea. DESIGN: Retrospective cohort study. SETTING: The Korean National Health Insurance claim data from 1 January 2015 to 30 June 2017 were retrieved from the Health Insurance Review and Assessment Service. PARTICIPANTS: Adult patients with DME who were diagnosed with diabetic retinopathy or DME and received ranibizumab, aflibercept or a DEX-implant in conjunction with intravitreal injection were included. Patients whose primary diagnoses were age-related macular degeneration or retinal vein occlusion were excluded. MAIN OUTCOME MEASURES: Healthcare resource utilisation and costs related to DME in the 12-month postindex period. RESULTS: During the study period, 182 patients and 414 patients were identified in the anti-VEGF and DEX-implant groups, respectively, and there was no significant difference in the demographic characteristics between the two groups. The outpatient eye care-related medical costs were US$3002.33 for the anti-VEGF group vs US$2250.35 for the DEX-implant group (p<0.0001). After adjusting the relevant covariates based on the generalised linear model, the estimated outpatient eye care-related medical costs were 33% higher in the anti-VEGF group than in the DEX-implant group (p<0.0001, 95% CI 22% to 45%). The utilisation pattern of the two groups showed no significant difference except for the number of intravitreal injections, which was higher in the anti-VEGF group (2.69±2.29) than in the DEX-implant group (2.09±1.37, p<0.001). CONCLUSION: The average annual eye-related medical cost of the DEX-implant group was significantly lower than that of the anti-VEGF group during the study period, which was mainly due to decreased utilisation of eye care-related injections. Further long-term studies are needed.

Genomic alterations in signet ring and mucinous patterned colorectal carcinoma.

BACKGROUND: The genetic alterations (GAs) in two specific histological subtypes of colorectal cancer (CRC), signet ring cell colorectal carcinoma (SRC) and mucinous colorectal carcinoma (MC), are not well known. In the present study, we employed next-generation sequencing to perform genetic profiling of SRC and MC, and compared the spectrum of GAs with the alterations found in conventional type colorectal cancer (CON). MATERIALS AND METHODS: We selected 46 CRCs comprising 17 SRCs and mucinous carcinoma with signet ring cell component (SRCCs), 17 MCs, and 12 CONs with microsatellite stability or microsatellite instability-low. Deep sequencing was performed using a targeted cancer panel composed of 171 cancer-related genes. SMAD4 protein expression was evaluated by immunohistochemical staining. RESULTS: We detected 108 mutations in 18 different genes. Overall, 2.34 GAs were detected per tumor (range, 0-14). The overall frequency of GA and alteration in targetable genes was less prevalent in SRC/SRCC compared to the frequency of alteration in MC/CON (p = 0.040 and p < 0.001, respectively). The GA profile of SRC/SRCC included TP53 (8/17, 47.1%), SMAD4 (5/17, 29.4%), KRAS (4/17.23.5%), APC (4/17.23.5%), PIK3CA, ATM, BRAF, and PIK3R1 (1/17, 5.9%, each). KRAS mutation was significantly less prevalent in SRC/SRCC compared to the number of KRAS mutations in MC (12/17, 70.6%) and CON (9/12, 75.0%) (p = 0.015 and 0.01, respectively). Compared to the 152 non-hypermutated CONs from TCGA database, SMAD4 alteration was predominant in SRC/SRCC (p = 0.045) with aberrant loss of SMAD4 expression (13/17, 76.5%) compared to the SMAD4 alterations in CON (5/15, 33.3%) (p = 0.031). Accordingly, KRAS (12/17, 70.6%), APC (6/17, 35.3%), SMAD4, TP53 (4/17, 23.5%, each), PIK3CA (3/17, 17.6%), AKT1, ATM, BRAF, EGFR, and EZH2 (1/17, 5.9%, each) were altered in MC. APC and TP53 mutations were less frequent in MC compared to those in TCGA-CON (p < 0.001 and 0.003, respectively) whereas KRAS mutation was prevalent (p = 0.041). CONCLUSION: Alterations of known cancer associated genes and targetable genes in SRC/SRCC are infrequent. The profile of GAs in SRC/SRCC and MC differs from the GA profile of CON. Specifically, SMAD4 mutation and loss of SMAD4 expression is frequently found in SRC/SRCC. The genetic profiles revealed in the present study may aid in developing precision medicine for CRC treatment based on histological subtype.

Urinary Exosomal and cell-free DNA Detects Somatic Mutation and Copy Number Alteration in Urothelial Carcinoma of Bladder.

Urothelial bladder carcinoma (UBC) is characterized by a large number of genetic alterations. DNA from urine is a promising source for liquid biopsy in urological malignancies. We aimed to assess the availability of cell-free DNA (cfDNA) and exosomal DNA (exoDNA) in urine as a source for liquid biopsy in UBC. We included 9 patients who underwent surgery for UBC and performed genomic profiling of tumor samples and matched urinary cfDNA and exoDNA. For mutation analysis, deep sequencing was performed for 9 gene targets and shallow whole genome sequencing (sWGS) was used for the detection of copy number variation (CNV). We analyzed whether genetic alteration in tumor samples was reflected in urinary cfDNA or exoDNA. To measure the similarity between copy number profiles of tumor tissue and urinary DNA, the Pearson's correlation coefficient was calculated. We found 17 somatic mutations in 6 patients. Of the 17 somatic mutations, 14 and 12 were identified by analysis of cfDNA and exoDNA with AFs of 56.2% and 65.6%, respectively. In CNV analysis using sWGS, although the mean depth was 0.6X, we found amplification of MDM2, ERBB2, CCND1 and CCNE1, and deletion of CDKN2A, PTEN and RB1, all known to be frequently altered in UBC. CNV plots of cfDNA and exoDNA showed a similar pattern with those from the tumor samples. Pearson's correlation coefficients of tumor vs. cfDNA (0.481) and tumor vs. exoDNA (0.412) were higher than that of tumor vs. normal (0.086). We successfully identified somatic mutations and CNV in UBC using urinary cfDNA and exoDNA. Urinary exoDNA could be another source for liquid biopsy. Also, CNV analysis using sWGS is an alternative strategy for liquid biopsy, providing data from the whole genome at a low cost.

Effect of herbal extracts on bone regeneration in a rat calvaria defect model and screening system.

OBJECTIVES: The aim of this study was to evaluate the effects of herbal extracts on bone regeneration. Two known samples were screened. MATERIALS AND METHODS: We previously established a rat calvaria defect model using a combination of collagen scaffold and herbal extracts. An 8 mm diameter trephine bur with a low-speed dental hand piece was used to create a circular calvaria defect. The experimental group was divided into 4 classifications: control, collagen matrix, Danshen with collagen, and Ge Gan with collagen. Animals in each group were sacrificed at 4, 6, 8, and 10 weeks after surgery, and bone regeneration ability was evaluated by histological examination. RESULTS: Results revealed that both Danshen and Ge Gan extracts increased bone formation activity when used with collagen matrix. All groups showed almost the same histological findings until 6 weeks. However, after 6 weeks, bone formation activity proceeded differently in each group. In the experimental groups, new bone formation activity was found continuously up to 10 weeks. In the Danshen and Ge Gan groups, grafted materials were still present until 10 weeks after treatment, as evidenced by foreign body reactions showing multinucleated giant cells in chronic inflammatory vascular connective tissue. CONCLUSION: Histological analyses showed that Danshen and Ge Gan extractions increased bone formation activity when used in conjunction with collagen matrix.

DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. CONCLUSION: The dysregulation of SIRT1-DEPTOR-mTORC1 signaling is a critical determinant of ALD pathology; targeting SIRT1 and DEPTOR and selectively inhibiting mTORC1-S6K1 signaling may have therapeutic potential for treating ALD in humans. (Hepatology 2018).

10-Phenyltriazoyl Artemisinin is a Novel P-glycoprotein Inhibitor that Suppresses the Overexpression and Function of P-glycoprotein.

BACKGROUND: The effect of drugs on ATP-binding cassette transporters, especially permeabilityglycoprotein (P-gp), is an important consideration during new anti-cancer drug development. OBJECTIVE: In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a), were evaluated on P-gp expression and function. METHODS: Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods. RESULTS: The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp. CONCLUSION: The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.

Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype.

Fabry disease is a rare X-linked lysosomal storage disorder caused by an α-galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey.This study included 94 patients from 46 independent pedigrees: 38 adult males, 46 symptomatic females, and 10 pediatric males. Each diagnosis was based on an enzyme assay and GLA gene mutation analysis.The mean age at presentation was 24 years (range, 5-65 years); however, the diagnoses were delayed by 21 ±â€Š19 years after the onset of symptoms. Those patients with late-onset Fabry disease were diagnosed by family screening or milder symptoms at a later age. Forty different mutations were identified: 20 missense (50%), 10 nonsense (25%), 8 frameshift (20%), and 2 splice site (5%) mutations. Five of them were novel. IVS4+919G>A (c.936+919 G>A) was not detected among the 6505 alleles via newborn screening using dried blood spots. Enzyme replacement therapy (ERT) was performed in all the males and pediatric patients, whereas 75% of the symptomatic females underwent ERT for 4.2 ±â€Š3.6 years.This study described the demographic data, wide clinical spectrum of phenotypes, and GLA mutation spectrum of Fabry disease in Korea. Most of the patients had classical Fabry disease, with a 4 times higher incidence than that of late-onset Fabry disease, indicating an underdiagnosis of mild, late-onset Fabry disease.

Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis.

The Wnt/ß-catenin pathway has been implicated in hair follicle development and hair regeneration in adults. We discovered that CXXC-type zinc finger protein 5 (CXXC5) is a negative regulator of the Wnt/ß-catenin pathway involved in hair regrowth and wound-induced hair follicle neogenesis via an interaction with Dishevelled. CXXC5 was upregulated in miniaturized hair follicles and arrector pili muscles in human balding scalps. The inhibitory effects of CXXC5 on alkaline phosphatase activity and cell proliferation were demonstrated using human hair follicle dermal papilla cells. Moreover, CXXC5-/- mice displayed accelerated hair regrowth, and treatment with valproic acid, a glycogen synthase kinase 3ß inhibitor that activates the Wnt/ß-catenin pathway, further induced hair regrowth in the CXXC5-/- mice. Disrupting the CXXC5-Dishevelled interaction with a competitor peptide activated the Wnt/ß-catenin pathway and accelerated hair regrowth and wound-induced hair follicle neogenesis. Overall, these findings suggest that the CXXC5-Dishevelled interaction is a potential target for the treatment of hair loss.

Intramuscular hemangiomas on the masseter muscle and orbicularis oris muscle: a report of two cases.

Intramuscular hemangioma (IMH) is a rare vascular disease involving skeletal muscle, comprising only 0.8% of hemangiomas. About 10% to 15% of IMHs occur in the head and neck region, mostly involving the masseter muscle. IMH occurs mostly in childhood, but is often not found until unexpected enlargement, pain, or cosmetic asymmetry occurs in adulthood. Several non-surgical treatments including cryotherapy, sclerosant injection, and arterial ligature have been described, but complete surgical resection is the curative intervention. In this report, we present two rare cases of IMH. One IMH case in a 48-year-old male occurred in the masseter muscle feeding from the transverse facial artery. Embolization of the distal branch of the facial artery was first conducted, and then the buccal mass was removed surgically via the intraoral approach. A second IMH case in a 58-year-old female occurred in the orbicularis oris muscle feeding from the superior labial artery, and the mass was excised surgically without embolization.