Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary ...mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.
Naringenin is a major flavanone found in grapes, tangelos, blood oranges, lemons, pummelo, and tangerines. It is known to have anti-inflammatory, antioxidant, anticancer, antimutagenic, ...antifibrogenic, and antiatherogenic pharmacological properties. This study aims to investigate the anti-inflammatory effects of naringenin in ethanol-induced gastric damage in vivo and ethanol-stimulated KATO III cells in vitro. Our results showed that pretreatment with naringenin significantly protected mice from ethanol-induced hemorrhagic damage, epithelial cell loss, and edema with leucocytes. It reduced gastric ulcers (GU) by suppressing ethanol-induced nuclear factor-κB (NF-κB) activity and decreasing the levels of nitric oxide (NO), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and myeloperoxidase (MPO). In addition, pretreatment with naringenin might inhibit the secretion of TNF-α, IL-6, and IL-8, as well as the proteins cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) via the suppression of NF-κB and mitogen-activated protein kinase (MAPK) signaling in ethanol-stimulated stomach epithelial KATO III cells. Together, the results of this study highlight the gastroprotective effect of naringenin in GU of mice by inhibiting gastric secretion and acidity, reducing inflammation and oxidative stress, suppressing NF-κB activity, and restoring the histological architecture. These findings suggested that naringenin has therapeutic potential in the alleviation of ethanol-induced GU.
Metastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by ...US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.
Although the incidence and mortality rates associated with tuberculosis (TB) have been decreasing in many countries, TB remains a major public health concern. Obligatory facial masking and reduced ...health-care capacity because of COVID-19 may substantially influence TB transmission and care. The Global Tuberculosis Report 2021 published by the World Health Organization indicated a TB rebound at the end of 2020, which coincided with the COVID-19 pandemic. We explored this rebound phenomenon in Taiwan by investigating whether TB incidence and mortality are affected by COVID-19 because of their common route of transmission. In addition, we investigated whether the incidence of TB varies across regions with different incidences of COVID-19. Data (2010-2021) regarding annual new cases of TB and multidrug-resistant TB were collected from the Taiwan Centers for Disease Control. TB incidence and mortality were assessed in Taiwan's seven administrative regions. Over the last decade, TB incidence decreased continually, even during 2020 and 2021, the years coinciding with the COVID-19 pandemic. Notably, TB incidence remained high in regions with low COVID-19 incidence. However, the overall decreasing trends of TB incidence and mortality remained unchanged during the pandemic. Facial masking and social distancing may prevent COVID-19 transmission but exhibit limited efficacy in reducing TB transmission. Thus, during health-related policymaking, policymakers must consider TB rebound, even in the post-COVID-19 era.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate whether a simplified and personalized Tai-Chi program could be beneficial for practitioners. A prospective quasi-experimental observer-blinded controlled trial was done in Beitou ...District of Taipei City.
Community-dwelling adults aged 65 and older without debilitating disease (N = 50) participated the study. Those who were willing to participate in exercise program were assigned to individualized Tai-Chi (iTC) group (n = 20), receiving iTC training for 8 weeks, and traditional Tai-Chi (tTC) group (n = 15), receiving tTC training for 8 weeks. Those who were not willing to participate in exercise training were included in the control group (n = 15). Functional balance tests, the Berg Balance Scale (BBS), timed up-and-go (TUG) test, functional-reach test, and measurement of lower-extremity muscle strength were conducted before and 8 weeks after the intervention.
Significant improvements were noted in all functional balance tests and strength assessments of 16 major lower-limb muscle groups in participants of the iTC group compared to the control group, whereas only BBS and muscle strength of hips and ankles were improved in the tTC group. Practitioners of iTC outperformed tTC in BBS and strength of two major muscles.
Personalized Tai-Chi training designed based on an objective measurement and conducted according to graded intensity and complexity benefitted practitioners after a short period.
Trial registration number: ClinicalTrials.gov ID: NCT03659396 , Unique Protocol ID: 1000087 Date of registration: 03/28/2017 The trial was registered retrospectively.
Overweight and obesity in preschoolers might develop into childhood and even adulthood obesity. Overweight and obesity have been shown to be negatively related with cardiorespiratory fitness (CRF) in ...children and adults but few studies did among preschoolers. We aimed to evaluate whether excess body adipose is negatively associated with CRF in both the submaximal and maximal effort of preschool children in exercise testing and to examine if there is difference to achieve maximal effort during exercise testing between preschoolers with normal and excess body adipose.
Data of 106 preschoolers aged 4-6 that received symptom-limited treadmill exercise testing was analyzed. Anthropometry was measured by vector bioelectrical impedance analysis. Excess body adipose was defined as (1) 'overweight' and 'obesity' by body mass index (BMI), (2) fat mass index (FMI) greater than the sex- and age-specific 75th percentile of whole subjects, and (3) fat-free mass index (FFMI) smaller than the sex- and age-specific 25th percentile. CRF was indicated by metabolic equivalent (MET) at anaerobic threshold (AT MET), peak MET, oxygen uptake efficiency slope (OUES) calculated by the 50% (OUES-50) and the entire (OUES-100) duration of the exercise testing.
Preschoolers with excess body adipose by three different definitions (BMI, FMI, and FFMI) all had poorer ability to perform maximal effort (p = 0.004, 0.043, and 0.007, respectively). Preschoolers with excess body adipose by BMI and FFMI classifications had lower OUES-50 (p = 0.018, and 0.001, respectively), and lower OUES-100 (p = 0.004, and 0.001, respectively) than peers with normal body adipose during exercise testing while those with excess body adipose by FMI classification showed no significant differences from peers with normal body adipose in both OUES-50 and OUES-100.
Preschoolers with excess body adipose had lower CRF significantly during treadmill exercise testing. Weight control and health promotion should start as early as possible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To determine the optimal surgical timing in high‐risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index.
Methods
From 1989 to 2018, 118 male patients ...diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients’ demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low‐risk (Simplified Fournier's Gangrene Severity Index ≤2) and high‐risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high‐risk Fournier's gangrene patients.
Results
The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low‐risk and high‐risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high‐risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non‐survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high‐risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007).
Conclusions
The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first‐line physicians to identify high‐risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high‐risk Fournier's gangrene patients.
Major depressive disorder (MDD) and dementia are both major contributors to the global burden of disease. Despite existing literature on the association between MDD and dementia, there is a lack of a ...nationwide longitudinal cohort study that considers the competing risk of death. Therefore, this study assessed the bidirectional associations between MDD and dementia over an 11-year period in population-based settings, accounting for death as a competing risk.
We conducted two population-based retrospective cohort studies in Taiwan. We identified 80,742 patients diagnosed with MDD in 2009–2010 and matched them with patients without MDD by sex, age, and year of diagnosis to assess the relative risk of dementia. We also identified 80,108 patients diagnosed with dementia in 2009–2010 and matched them with patients without dementia by sex, age, and year of diagnosis to assess the relative risk of MDD. All patients were followed until they received a diagnosis of new onset MDD or new onset dementia, their death, or the end of 2019. Cause-specific hazards models were used to estimate adjusted hazard ratios (aHRs).
The incidence density (ID) of dementia was higher in patients with MDD than in patients without MDD (7.63 vs. 2.99 per 1000 person-years), with an aHR of 2.71 (95% confidence interval CI: 2.55–2.88). The ID of MDD was higher in patients with dementia than in patients without dementia (12.77 vs. 4.69 per 1000 person-years), with an aHR of 2.47 (95% CI: 2.35–2.59).
This population-based study found a bidirectional association between MDD and dementia. Our findings suggest the need to identify dementia in patients with MDD and vice versa.
•In MDD-dementia link studies, reliable estimates from a longitudinal design considering death as a competing risk are rare.•This 11-year cohort study offers more precise MDD-dementia association estimates by considering death as a competing risk.•MDD could be a risk factor for dementia and vice versa.•Bidirectional associations between MDD and dementia were observed regardless of age, sex, and disease duration.
Objectives
To explore the trends in Fournier's gangrene (FG) incidence and mortality rate in Taiwan and to investigate the contributing factors to such changes.
Methods
Between 2002 and 2016, ...hospitalized FG patients who underwent subsequent surgical intervention were included in this retrospective study. Incidence, outcomes, age‐adjusted Charlson Comorbidity Index (ACCI), hospitalization cost, surgical timing, and the number of multidisciplinary specialists involved in the first‐line management of FG in each year were collected. Simple linear regression and Pearson correlation coefficient (r) were used for the subsequent analysis.
Results
The national cohort enrolled 2183 FG patients from 2002 to 2016 in Taiwan. The age‐standardized incidence rate of FG was between 0.4 and 0.8 per 100 000 population, and overall mortality was 7.8% in these 15 years. We illustrated the downward trendline of FG mortality with a 0.62 coefficient of determination. The mortality of FG patients who underwent surgery within 24 h and after 24 h were found to be 8.3 ± 3.9% and 14.6 ± 25.2%, respectively (p = 0.02). The numbers of urologists, anesthesiologists, emergency doctors, and physicians per 100 000 population had a strong negative linear correlation with FG mortality (r = 0.8, p < 0.001). ACCI score had a moderate linear relationship with FG mortality (r = 0.57, p = 0.027). The hospitalization cost showed a weak linear correlation with FG mortality (r = −0.03, p = 0.92).
Conclusions
We demonstrated the downward trend of the FG mortality rate in Taiwan from 2002 to 2016. Besides underlying comorbidities and surgical timing, sufficient multidisciplinary specialists are essential for the survival benefit of FG patients in Taiwan experience.
The reactivation of the Chelungpu Fault triggered the 1999 Chi-Chi Mw 7.6 earthquake, resulting in substantial ground surface ruptures and severe damage. After the earthquake, the surveys organized ...by the Central Geology Survey (CGS) of Taiwan and the National Center for Research on Earthquake Engineering (NCREE) immediately investigated a variety of cases related to engineering structures damaged by substantial ground deformation. The investigations gathered valuable in-situ data before human activities disturbed the local setting and altered co-seismic features of interest, providing opportunities for studying the interaction between surface rupture and engineering structures. This study outlines the reconnaissance of damaged engineering structures in Shigang District that cover three typical types of foundations and analyzes the fault geometry and fault slip at the local scale to construct a geomechanical model for numerical simulation. In addition, 3-dimensional (3D) modeling was performed for each case study to investigate the damage mechanisms of the structures subjected to the substantial ground deformations by using PFC3D (Particle Flow Code 3D), which is based on the discrete element method (DEM). The results of the DEM analyses, which have been calibrated with the in-situ data, showed the ability to evaluate the overall ground deformation, the detection of structural movement, and the critical elements of progressive collapse during faulting. This study demonstrates that the 3D DEM simulation is a reliable analysis tool for studying earthquake fault rupture-overburden layer-engineering structure interactions and can produce useful information for hazard assessment with an acceptable computation time. The 3D DEM analysis is therefore suggested to be applied to assess the potential damage scenarios for the engineering structures located in active fault zones.
•Analysis of earthquake fault rupture-overburden layer-engineering structure interaction in the Chelungpu fault zone•Integrated field investigations, geomechanical analysis, and 3D DEM modeling•Damaged cases of engineering structures with different foundation types in the Shigang District were simulated.•Current abilities and limitations of the full-scale 3D DEM model are discussed.
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