Carnosol has been proved to have anti-breast cancer effect in previous research. But its ER subtype's specific regulation and mediation mechanisms remain unclear. The aim of this study is to observe the effect of carnosol on cell proliferation and its estrogen receptor α and β's specific regulation and mediation mechanisms with ER positive breast cancer T47D cell. With estrogen receptor α and β antagonists MPP and PHTPP as tools, the MTT cell proliferation assay was performed to observe the effect of carnosol on T47D cell proliferation. The changes in the T47D cell proliferation cycle were detected by flow cytometry. The effect of carnosol on ERα and ERβ expressions of T47D cells was measured by Western blot. The findings showed that 1 x 10(-5)-1 x 10(-7) mol x L(-1) carnosol could significantly inhibit the T47D cell proliferation, which could be enhanced by MPP or weakened by PHTPP. Meanwhile, 1 x 10(-5) mol x L(-1) or 1 x 10(-6) mol x L(-1) carnosol could significantly increase ERα and ERβ expressions of T47D cells, and remarkably increase ERα/ERβ ratio. The results showed that carnosol showed the inhibitory effect on the proliferation of ER positive breast cancer cells through target cell ER, especially ERβ pathway. In the meantime, carnosol could regulate expressions and proportions of target cell ER subtype ERα and ERβ.
Blotting, Western ; Breast Neoplasms ; metabolism ; pathology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Diterpenes, Abietane ; chemistry ; pharmacology ; Dose-Response Relationship, Drug ; Estrogen Receptor Modulators ; pharmacology ; Estrogen Receptor alpha ; antagonists & inhibitors ; metabolism ; Estrogen Receptor beta ; antagonists & inhibitors ; metabolism ; Female ; Flow Cytometry ; Humans ; Molecular Structure ; Pyrazoles ; pharmacology ; Pyrimidines ; pharmacology

BACKGROUNDLumbar spinal stenosis is a common problem that is receiving attention with the advent of novel treatment procedures. Prior positional MRI studies demonstrated lumbar canal diameter changes with flexion and extension. There have not been any studies to examine the amount of spinal canal diameter change relative to the amount of angular motion. The purpose of this study was to evaluate the correlation between the lumbar canal diameter change and the angular motion quantitatively.

METHODSPositional MRI (pMRI) images for 491 patients, including 310 males and 181 females (16 years-85 years of age), were obtained with the subjects in sitting flexion 40 degree, upright, and with extension of 10 degrees within a 0.6 T Positional MRI scanner. Quantitative measurements of the canal diameter and segmental angle of each level in the sagittal midline plane were obtained for each position. Then the diameter change and angular motion were examined for correlation during flexion and extension with linear regression analysis.

RESULTSThe lumbar segmental angles were lordotic in all positions except L1-2 in flexion. The changes of canal diameters were statistically correlated with the segmental angular motions during flexion and extension (P < 0.001). The amount of canal diameter change correlated with the amount of angular change and was expressed as a ratio.

CONCLUSIONSPositional MRI demonstrated the amount of spinal canal diameter change that was statistically correlated with the segmental angular motion of the spine during flexion and extension. These results may be used to predict the extent of canal diameter change when interspinous devices or positional changes are used to treat spinal stenosis and the amount of increased canal space may be predicted with the amount of angular or positional change of the spine. This may correlate with symptomatic relief and allow for improved success in the treatment of spinal stenosis.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Lumbar Vertebrae ; anatomy & histology ; physiology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Range of Motion, Articular ; physiology ; Spinal Canal ; anatomy & histology ; physiology ; Young Adult

Background/Aims: Laryngeal symptoms are largely treated with empiric proton pump inhibitor (PPI) therapy if no apparent pathology shown on ear, nose, and throat evaluation and reflux-related etiologies are suspected. However, treatment response remains unsatisfactory. This study aimed to investigate the clinical and physiological characteristics of patients with PPI-refractory laryngeal symptoms. Methods: Patients with persistent laryngeal symptoms despite PPI treatment for ≥ 8 weeks were recruited. A multidisciplinary evaluationcomprising validated questionnaires for laryngeal symptoms (reflux symptom index [RSI]), gastroesophageal reflux disease symptoms, psychological comorbidity (5-item brief symptom rating scale [BSRS-5]) and sleep disturbance (Pittsburgh sleep quality index [PSQI]), esophagogastroduodenoscopy, ambulatory impedance-pH monitoring, and high-resolution impedance manometry were performed.Healthy asymptomatic individuals were also recruited for comparison of psychological morbidity and sleep disturbances. Results: Ninety-seven adult patients and 48 healthy volunteers were analyzed. The patients had markedly higher prevalence of psychological distress (52.6% vs 2.1%, P < 0.001) and sleep disturbance (82.5% vs 37.5%, P < 0.001) than the healthy volunteers. There were significant correlations between RSI and BSRS-5 scores, and between RSI and PSQI scores (r = 0.26, P = 0.010, and r = 0.29, P = 0.004, respectively). Fifty-eight patients had concurrent gastroesophageal reflux disease symptoms. They had more prominent sleep disturbances (89.7% vs 71.8%, P < 0.001) than those with laryngeal symptoms alone but similar reflux profiles and esophageal motility. Conclusions PPI-refractory laryngeal symptoms are mostly associated with psychological comorbidities and sleep disturbances. Recognition of these psychosocial comorbidities may help optimize management in these patients.

INTRODUCTIONThis study evaluates the demographics of paediatric pedestrian injuries with the aim of identifying the group of children who is most vulnerable and the risk factors for major trauma (MT).

METHODSData was extracted from the integrated trauma system of a regional paediatric referral hospital. All paediatric cases involving road traffic accidents from January 2011 to December 2013 were studied. Demographics, injury mechanism, treatment and outcome were evaluated. Patients were categorised as MT or non-MT (NMT) based on their Injury Severity Score, admission to the intensive care unit, type of surgery (e.g. life/limb-saving) and death. Data analysis was done using nonparametric tests and Fisher's exact test.

RESULTSA total of 261 children were admitted for pedestrian injuries during the study period. The median age was ten years (range 14 months-16 years) and the median weight was 42.4 (range 8.6-93.7) kg. Half (i.e. 50.2%) of the children were primary-schoolers. The majority of the accidents occurred on roads (i.e. 83.1%), between 12 pm and 6 pm (i.e. 52.8%). Among the 261 children, 177 (67.8%) were unaccompanied by an adult at the time of the accident; 17 (6.5%) children sustained MT, while 244 (93.5%) suffered NMT. MT patients were more likely to have lost consciousness (p < 0.001) and been flung (p = 0.001).

CONCLUSIONMost paediatric pedestrian injuries involved primary-schoolers walking home from school unaccompanied by adults. This information should inform future road safety campaigns. Being flung and loss of consciousness predicted MT in children who sustained pedestrian injuries.

Accidents, Traffic ; statistics & numerical data ; Adolescent ; Age Factors ; Child ; Child, Preschool ; Female ; Humans ; Incidence ; Infant ; Injury Severity Score ; Male ; Pedestrians ; Risk Factors ; Singapore ; epidemiology ; Wounds and Injuries ; diagnosis ; epidemiology

INTRODUCTIONSingapore experienced its second riot in 40 years on 8 December 2013, in the area known as Little India. A retrospective review of 36 casualties treated at the emergency department was conducted to evaluate injury patterns.

METHODSCharacteristics including the rate of arrival, injury severity, type and location, and disposition of the casualties were analysed.

RESULTSThe injuries were predominantly mild (97.2%), with the most common injuries involving the head (50.0%) and limbs (38.9%). 97.2% of the casualties were managed as outpatient cases.

CONCLUSIONThe majority of the injuries in this incident were mild and could be managed as outpatient cases. Important lessons were learnt from the incident about the utilisation of manpower and safety of staff in the emergency department.

Adult ; Emergency Medical Services ; Emergency Medicine ; methods ; Emergency Service, Hospital ; Female ; Humans ; Injury Severity Score ; Male ; Patient Safety ; Retrospective Studies ; Riots ; Singapore ; Triage

Background/Aims: Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population. Methods: The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan. Results: Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10). Conclusions HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.

Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers. Recently, extracellular vesicles (EVs), naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins, lipids, and nucleic acids, have drawn wide attention due to their ability to promote wound healing and tissue regeneration. However, current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes. To circumvent these challenges, bioinspired cell-derived nanovesicles (CDNs) that mimic EVs were obtained by shearing mesenchymal stem cells (MSCs) through membranes with different pore sizes. Physical characterisations and high-throughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs. Moreover, these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway, resulting in enhancement of cell proliferation, cell migration, secretion of growth factors and extracellular matrix proteins, which all promoted tissue regeneration. Of note, MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEG-fibrin scaffold and animal model, accelerating wound healing in vitro and in vivo. These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.

Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.