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The transition to renewable energy sources, such as offshore wind farms, is essential in mitigating climate change. Taiwan has set ambitious targets to harness wind energy from the Taiwan Strait, but offshore wind farm installations are highly dependent on weather conditions, particularly wind speeds. This study examines the relationship between the El Niño-Southern Oscillation (ENSO) and offshore wind farm installation by assessing weather windows—periods with wind speeds below 12 m per second at a height of 100 m for at least 12 h. Our analysis shows that during La Niña years, the number of feasible weather windows decreases by up to 40 %, particularly between October and June, compared to neutral and El Niño years. This decrease can be as high as fourfold in December, significantly impacting installation schedules. Seasonal variations are also notable, with wind speeds exceeding 12 m s−1 in winter 66.4 % of the time, compared to 29.4 % in spring, making spring and summer the most favorable periods for installation. However, even during these favorable seasons, La Niña years can bring higher wind speeds, necessitating careful planning. These results underscore the importance of integrating ENSO forecasts into project planning to avoid installation delays and optimize installation timelines. By leveraging seasonal and interannual climate variability predictions, decision-makers can improve the resilience of offshore wind farm projects and ensure efficient energy transition strategies.

Background: Proper identification of the polymicrobial microorganisms in patients with limb-threatening diabetic foot ulcers (LTDFUs) using conventional culture is insufficient. This prospective study evaluates the potential value of adjuvant molecular testing assisting in identify fastidious micro-organisms in LTDFUs compared to standard treatment alone. Methods: Ninety patients with LTDFUs received interdisciplinary and standard antibiotic treatment in a referral diabetic foot center. A simultaneous 16S amplicon sequencing (16S AS) specimen along with conventional culture collected at admission was used to retrospectively evaluate the microbiological findings and its association with amputation outcomes. Results: The microorganism count revealed by 16S AS overwhelmed that of conventional culturing (17 vs. 3 bacteria/ulcer respectively). The Stenotrophomonas spp. revealed in 29 patients were highly correlated with major (above ankle) amputation (OR: 4.76, 95% CI 1.01–22.56), while only one had been concomitantly identified by conventional culturing. Thus, there were 27 cases without proper antibiotics coverage during treatment. Conclusions: Adjuvant molecular testing assisted identification of fastidious pathogens such as Stenotrophomonas infection and might be associated with major amputation in patients with LTDFUs.

Abstract Background Immune checkpoint inhibitors (ICI) are promising treatment options for various cancers. However, their use is associated with immune-related adverse events (irAEs), including ICI-induced diabetes mellitus (ICI-DM). This study aimed to investigate the clinical features of ICI-DM, with a particular focus on alterations to pancreatic volume. Methods We conducted a retrospective review of 2829 patients who received ICI treatment at the Chang Gung Memorial Hospital, Linkou, between January 2014 and December 2021. New-onset diabetes or diabetic ketoacidosis (DKA) was identified in ten patients receiving ICI therapy. Pancreatic volumes were assessed by manual segmentation of computed tomography (CT) images before and after ICI-DM diagnosis. Results Among these ten patients, nivolumab was the most commonly used ICI (50.0%), followed by pembrolizumab (30.0%) and atezolizumab (20.0%). One patient received combination therapy with nivolumab and ipilimumab. The median age was 63.01 years (range: 40.1 − 87.8). ICI-DM developed after a median of 13.5 cycles (range: 2 − 42) of ICI treatment or 9.85 months (range:1.5 − 21.3) since ICI initiation. The initial presentation was DKA in 60.0% of patients. All patients had low or undetectable C-peptide levels (range:

Dry eye disease (DED) is a common multifactorial disease affecting a substantial proportion of the population worldwide. Objective tests and subjective symptoms evaluation are necessary to assess DED. Although various treatments have been introduced, accurately evaluating the efficacy of those treatments is difficult because of the disparity between diagnostic tests and patient-reported symptoms. We reviewed the questionnaires used to evaluate DED and the improvements of quality of life with various treatments. In addition, we highlighted the importance of patient-reported outcomes (PRO) assessments for evaluating the effect of DED treatments. Given that the assessment of DED treatment effectiveness substantially relies on individual ocular experiences, acquiring qualitative PRO data is essential for comprehensive evaluation and optimal treatment management. Clinicians should not only focus on improving objective symptoms but also prioritize the well-being of patients in clinical management.

Mitochondrial dysfunction was reported to be involved in the development of lung diseases including chronic obstructive pulmonary disease (COPD). However, molecular regulation underlying metabolic disorders in the airway epithelia exposed to air pollution remains unclear. In the present study, lung bronchial epithelial BEAS-2B and alveolar epithelial A549 cells were treated with diesel exhaust particles (DEPs), the primary representative of ambient particle matter. This treatment elicited cell death accompanied by induction of lipid reactive oxygen species (ROS) production and ferroptosis. Lipidomics analyses revealed that DEPs increased glycerophospholipid contents. Accordingly, DEPs upregulated expression of the electron transport chain (ETC) complex and induced mitochondrial ROS production. Mechanistically, DEP exposure downregulated the Hippo transducer transcriptional co-activator with PDZ-binding motif (TAZ), which was further identified to be crucial for the ferroptosis-associated antioxidant system, including glutathione peroxidase 4 (GPX4), the glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione-disulfide reductase (GSR). Moreover, immunohistochemistry confirmed downregulation of GPX4 and upregulation of lipid peroxidation in the bronchial epithelium of COPD patients and Sprague-Dawley rats exposed to air pollution. Finally, proteomics analyses confirmed alterations of ETC-related proteins in bronchoalveolar lavage from COPD patients compared to healthy subjects. Together, our study discovered that involvement of mitochondrial redox dysregulation plays a vital role in pulmonary epithelial cell destruction after exposure to air pollution.

Abstract Background Glycemic monitoring has become critical during the COVID-19 pandemic because of poor prognosis in diabetes. Vaccines were key in reducing the spread of infection and disease severity but data were lacking on effects on blood sugar levels. The aim of the current study was to investigate the impact of COVID-19 vaccination on glycemic control. Methods We performed a retrospective study of 455 consecutive patients with diabetes who completed two doses of COVID-19 vaccination and attended a single medical center. Laboratory measurements of metabolic values were assessed before and after vaccination, while the type of vaccine and administrated anti-diabetes drugs were analyzed to find independent risks associated with elevated glycemic levels. Results One hundred and fifty-nine subjects received ChAdOx1 (ChAd) vaccines, 229 received Moderna vaccines, and 67 received Pfizer–BioNtech (BNT) vaccines. The average HbA1c was raised in the BNT group from 7.09 to 7.34% (P = 0.012) and non-significantly raised in ChAd (7.13 to 7.18%, P = 0.279) and Moderna (7.19 to 7.27%, P = 0.196) groups. Both Moderna and BNT groups had around 60% of patients with elevated HbA1c following two doses of COVID-19 vaccination, and the ChAd group had only 49%. Under logistic regression modeling, the Moderna vaccine was found to independently predict the elevation of HbA1c (Odds ratio 1.737, 95% Confidence interval 1.12–2.693, P = 0.014), and sodium-glucose co-transporter 2 inhibitor (SGLT2i) was negatively associated with elevated HbA1c (OR 0.535, 95% CI 0.309–0.927, P = 0.026). Conclusions Patients with diabetes might have mild glycemic perturbations following two doses of COVID-19 vaccines, particularly with mRNA vaccines. SGLT2i showed some protective effect on glycemic stability. Hesitancy in having vaccinations should not be indicated for diabetic patients with respect to manageable glycemic change. Trial registration Not applicable.

Herein, it is shown how the novel layout and arrangement of electrodes of a vertical‐cavity surface‐emitting laser (VCSEL) array can simultaneously improve its high‐speed data transmission performance and the brightness of the output beam. In contrast to the layout of the traditional VCSEL array with its isolated mesas and a single electrode to electrical parallel arrangement of all active elements, the new inverse design can effectively reduce the pitch size between neighboring light emission apertures thereby allowing significant downscaling of the whole active area of the array and high brightness output. Moreover, there are two separate electrodes in demonstrated compact 7 × 7 VCSEL array, one for pure dc current injection and the other for large ac signal modulation. Compared with the single electrode reference device, the demonstrated array shows heavier dampening of the electrical–optical (E–O) frequency response, a wider maximum 3‐dB E–O bandwidth (17 vs 13 GHz), and a Gaussian‐like optical far‐field pattern with a higher brightness output (65.95 vs 40.8 kW cm−2 sr−1), under the same high output power (≈145 mW). The advantages of this novel VCSEL array lead to a much better quality of 32 Gbps eye‐opening with a higher brightness output.

Abstract We propose a novel way to search for axion(-like) particles in heavy-ion collisions using prompt photons as the probe and the property of conversion between photon and axion(-like) particles under a strong magnetic field generated in the non-central collisions. The expected result reveals that a new phase space region of the coupling constant for photon and axion(-like) particles can be covered in the future high energy nuclear colliders.

Abstract Aims/Introduction: To investigate the association between specific bacterial pathogens and treatment outcome in patients with limb‐threatening diabetic foot infection (LT‐DFI). Materials and Methods: Consecutive patients treated for LT‐DFI in a major diabetic foot center in Taiwan were analyzed between the years 2014 and 2017. Patients with positive wound culture results at first aid were enrolled. Clinical factors, laboratory data, and wound culture results were compared. Lower‐extremity amputations and in‐hospital mortality were defined as a poor outcome. Results: Among the 558 patients, 272 (48.7%) patients had lower extremity amputation and 22 (3.9%) patients had in‐hospital mortality. Gram‐negative bacterial (GNB) infection was the independent factor following factors adjustment. When all the 31 microorganisms were analyzed, only E. coli (adjusted odds ratio [aOR], 3.01; 95% CI, 1.60–5.65), Proteus spp. (aOR, 2.99; 95% CI, 1.69–5.29), and Pseudomonas aeruginosa (aOR, 2.00; 95% CI 1.20–3.32) were associated with poor outcome. The analysis of specific GNB species in association with major‐ or minor‐ amputation have been reported. No specific pathogen was associated with cause of death in patients with mortality within 30 days. The antimicrobial‐resistant strains were not associated with a poor treatment outcome. Conclusions: The presence of GNB was associated with limb amputations. This study provides insight into more timely and appropriate management of the diabetic foot infection.

Study region: Choushui River alluvial fan in central Taiwan. Study focus: Excessive land subsidence is occurring in the Choushui alluvial fan, Taiwan. Groundwater pumping in the region is not monitored so pumping volumes are estimated from information based on electricity consumption. Groundwater pumping data alone cannot be used to accurately estimate the spatial rate and distribution of subsidence due to the low spatial correlation between estimated pumping volumes and subsidence from heterogeneous geologic materials. Time-dependent spatial regression is a reliable tool for estimating the spatial distribution of annual rate of subsidence based on spatial mapping of pumped groundwater volumes and monitored land subsidence. New hydrological insights for the region: Estimates of pumping quantities indicate that the locations of subsidence from overexploitation of groundwater from the underlying aquifer system is not always spatially correlated with major pumping areas or with the observed locations of maximum water-level drawdown. Considering time-dependent spatial regression models, the average RMSE of annual subsidence is 0.65 cm for the Choushui alluvial fan, indicating the high level of correlation between measured and estimated subsidence. These findings show that annual subsidence can be reliably estimated and predicted under the field pumping conditions of the study site. The influences of reduced withdrawals based on the relation between annual subsidence and pumping volumes can be evaluated for improved best management practices.

BackgroundThe interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear.MethodsThe clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining.ResultsThe high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD.ConclusionsHB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

Abstract Background Diabetic foot infection (DFI) is a limb- and life-threatening complication for diabetic patients needing immediate and comprehensive treatment. Early referral of DFI patients to a diabetic foot center is recommended but there appears limited validated evidence, with the association between referral time and clinical outcomes of limb- preservation or in-hospital mortality still lacking. Methods This retrospective research studied consecutive type 2 diabetic patients with DFI treated at the major diabetic foot center in Taiwan from 2014 to 2017. Six hundred and sixty-eight patients presented with limb-threatening DFI. After stratifying their referral days into quartiles, the demographic information and clinical outcomes were analyzed. Results One hundred and seventy-two patients were placed in the first quartile (Q1) with less than 9 days of referral time; 164 in the second quartile (Q2) with 9-21 days; 167 in the third quartile (Q3) with 21-59 days; and 165 in the fourth quartile (Q4) with >59 days. End-stage renal disease (ESRD), major adverse cardiac events (MACE) and peripheral arterial disease (PAD) were noted as being higher in the Q4 group compared with the Q1 group (25.45% vs 20.35% in ESRD, 47.27% vs 26.16% in MACE and 78.79% vs 52.33% in PAD respectively). The Q1 group had more patients presenting with systemic inflammatory responsive syndrome (SIRS) (29.07% in Q1 vs 25.45% in Q4 respectively, P=0.019). Regarding poor outcome (major lower-extremity amputation (LEA) or in-hospital mortality), the Q4 group had 21.21% of patients in this category and the Q1 group had 10.47%. The odds ratio of each increased referral day on poor prognosis was 1.006 with 95% confidence interval 1.003–1.010 (P=

The shipper selects a suitable shipping route and plans for a voyage in order to import and export cargo on the basis of published sailing schedules. The reliability of the sailing schedule will influence the shipper’s logistics expense, which means that the logistics costs will depend on the reliability of schedules published by container shipping companies. Therefore, it is important to consider factors which can cause delays would for container ships sailing on sea routes. The reliability of published sailing schedules can be affected by a number of different factors. This study adopts the multi-criteria decision making (MCDM) method to estimate the importance of the delaying factors in a sailing schedule. In addition, the consistent fuzzy preference relations (CFPR) method is applied to identify the subjective importance (weights) of the delaying factors. The entropy weight method combined with the actual performance of the container shipping company are both used when estimating the objective importance (weights) of the delaying factors. According to the analysis results, the criteria can be divided into four quadrants with different management implications, which indicate that instructions for chase strategy, sailing schedule control, fleet allocation, transship operation arrangement and planning for ports in routes are often ignored by container shipping companies. Container shipping companies should consider adjusting their operational strategies, which would greatly improve their operational performance.

Abstract Dysregulation of hormones is considered a risk factor for obesity‐mediated breast tumorigenesis; however, obesity is associated with poor outcomes among women diagnosed with triple‐negative breast cancer (TNBC), which is a hormone‐independent breast cancer subtype. Thus, identifying the driving force behind the obesity‐breast cancer relationship is an urgent need. Here it is identified that diet‐induced obesity (DIO) facilitates tumorigenesis of TNBC cells. Mechanistically, DIO induces a metabolic addiction to fatty acid oxidation (FAO), accompanied by coordinated activation of Yes‐associated protein (YAP) signaling. Specifically, YAP governs mitochondrial redox homeostasis via transcriptional regulation of antioxidant‐related enzymes, which renders tumor cells capable of extenuating FAO‐elicited mitochondrial oxidative stress. Moreover, adipocytes‐derived fatty acids are identified to be responsible for enhancing the FAO‐YAP axis and antioxidative capacity, and higher expression of an obesity signature in breast cancer patients is positively correlated with YAP signaling and antioxidant genes. The findings uncover the crucial role of YAP in dictating mitochondrial redox homeostasis for obesity‐mediated metabolic adaptation and breast tumor progression.

Objective The use of sodium-glucose co-transporter 2 inhibitors (SGLT2is) may be associated with ketoacidosis. Therefore, the associated risk factors should be identified. In particular, information regarding the effects of the co-administration of anti-diabetic drugs is lacking. Methods We performed a retrospective study of 68 consecutive patients with diabetes who were taking an SGLT2i and attending a single medical center. After a period of treatment (median 78 days), their circulating ketone concentrations were measured. The concomitant use of other anti-diabetic drugs was analyzed to identify independent risk factors associated with ketosis. Results Twenty-five participants were taking empagliflozin, 23 were taking dapagliflozin, and 20 were taking canagliflozin. During the treatment period, no ketoacidotic events were recorded and their mean circulating ketone concentrations at the end of the study period were similar (0.3 mmol/L in the empagliflozin group, 0.26 mmol/L in the dapagliflozin group, and 0.25 mmol/L in the canagliflozin group). After adjustment for the use of anti-diabetic drugs, pioglitazone was found to be independently associated with a risk of high circulating ketone concentration (B value: 0.361, 95% confidence interval: 0.181–0.541). Conclusion SGLT2i-associated ketoacidosis was found to be infrequent, but the concomitant use of pioglitazone was associated with a higher risk of ketosis.

Background and AimsThe long-term survival in people with type 2 diabetes following first diagnosis of diabetic foot complications (FDDFC) is unclear. The object is to evaluate the mortality rate in subjects with type 2 diabetes following FDDFC and the impacts of the major cardiovascular comorbidities.MethodsNationwide data were analyzed for subjects with T2D and DFC between 2003 and 2017 according to ICD-9 coding. DFC was defined with the codes of ulcers, infections, or severe peripheral artery disease that required intervention (PAD) to mimic the real world diagnosis. Criteria of FDDFC were preceded by a period without any DFC for at least 5 years. Major cardiovascular comorbidities: established PAD and cardiovascular diseases (CVD: including coronary heart disease (CHD), stroke, or heart failure) before the index date as well as lower-extremity amputations (LEA) at the index episode were analyzed.ResultsAmong 300,115 subjects with DFC, a total of 103,396 patients had FDDFC. The mean 5-year survival rate of these subjects was 81.05%. Using subjects without associated major cardiovascular comorbidity as baseline, the adjusted hazard ratios (aHR) were1.43 (95% confidence interval 1.38–1.49) in group PAD-/CVD+, followed by 1.70 (1.59–1.80) in PAD+/CVD- and 1.98 (1.89–2.08) in PAD+/CVD+. The aHR was further increased in patients with PAD who additionally had heart failure (3.77, 3.50–4.05), stroke (2.06, 1.95–2.18), or CHD (1.89, 1.79–2.00). Subjects with PAD rather than other CVD were associated with LEA at FDDFC. Patients with major LEA (above the ankle) at FDDFC episode had lower 5-year survival rate (65.01%) followed by those with minor LEA (72.24%) and without LEA (81.61%).ConclusionsCardiovascular comorbidity as well as LEA status at the event of FDDFCs were both associated with patient survival outcomes. Earlier identification of this large population could lead to higher survival rates.

Abstract This study evaluates the performance of the Taiwan Earth System Model version 1 (TaiESM1) in simulating the observed climate variability in the historical simulation of the Coupled Model Intercomparison Phase 6 (CMIP6). TaiESM1 is developed on the basis of the Community Earth System Model version 1.2.2, with the inclusion of several new physical schemes and improvements in the atmosphere model. The new additions include an improved triggering function in the cumulus convection scheme, a revised distribution‐based formula in the cloud fraction scheme, a new aerosol scheme, and a unique scheme for three‐dimensional surface absorption of shortwave radiation that accounts for the influence of complex terrains. In contrast to the majority of model evaluation processes, which focus mainly on the climatological mean, this evaluation focuses on climate variability parameters, including the diurnal rainfall cycle, precipitation extremes, synoptic eddy activity, intraseasonal fluctuation, monsoon evolution, and interannual and multidecadal atmospheric and oceanic teleconnection patterns. A series of intercomparisons between the simulations of TaiESM1 and CMIP6 models and observations indicate that TaiESM1, a participating model in CMIP6, can realistically simulate the observed climate variability at various time scales and are among the leading CMIP6 models in terms of many key climate features.

Stiff-person syndrome (SPS) is highly associated with anti-glutamic acid decarboxylase (GAD) antibody. However, GAD antibodies alone appear to be insufficient to cause SPS, and they possibly are involved in only part of its pathophysiology. It is suspected that the symptoms of SPS get precipitated by external stimuli. Here, we briefly introduce the case of a patient with latent autoimmune diabetes who developed SPS through the action of subcutaneously injected insulin. A 43-year-old man was diagnosed with diabetes and initially well-controlled with oral hypoglycemic agents but progressed to requiring insulin within 1 year of diagnosis. Two months after the initiation of basal insulin therapy, he presented with abdominal stiffness and painful muscle spasms, involving the lower limbs, which resulted in walking difficulty, and thus, he refused insulin injections thereafter. He had been treated with oral anti-diabetic agents instead of insulin for 10 years until premixed insulin twice daily was started again due to poor diabetes control. Immediately after insulin injection, abdominal muscle rigidity and spasms were noted. When insulin was not administered, frequent episodes of diabetic ketoacidosis occurred. Serum GAD antibody test was positive and there was no positivity for islet antigen-2 antibody. A glucagon stimulation test demonstrated relative insulin deficiency, indicative of latent autoimmune diabetes in adults (LADA). Tolerable muscle rigidity was achieved when the dosage of basal insulin was split into two separate daily injections with lower amounts of units per injection. This case highlights a different form of autoimmune diabetes in SPS. To our knowledge, this is the first report of SPS described shortly after the initiation of insulin therapy that required basal insulin to achieve tolerable muscle symptoms and better glucose control, without the development of diabetic ketoacidosis.

ObjectiveBalanced nutrition is important for patients with diabetes, and nutrition might well influence diabetes-related complications, although there is limited evidence for this supposition at present. Consequently, we investigate the association between dietary behaviors and renal function decline among patients with diabetes.Research design and methodsFrom 2011 to 2013, a total of 2797 patients with type 2 diabetes participated in the Diabetes Shared Care Program at Chang Gung Memorial Hospital. All received nutritional consulting by dieticians and an eight-item list of unhealthy dietary behaviors, which included the excessive intake of carbohydrates, fats, protein, fruit, pickled foods, dessert and alcohol, as well as inadequate dietary vegetable. Estimated glomerular filtration rate (eGFR) decline ≥40% was defined as a surrogate end point for kidney damage. Independent dietary risk factors predicting poor renal outcomes were assessed.ResultsStable mean glycated hemoglobin (A1c) (7.78% to 7.75%, p=0.151), improved cholesterol (174.04 to 170.13 mg/dL, p

Despite rapidly evolving pathobiological mechanistic demystification, coupled with advances in diagnostic and therapeutic modalities, chronic obstructive pulmonary disease (COPD) remains a major healthcare and clinical challenge, globally. Further compounded by the dearth of available curative anti-COPD therapy, it is posited that this challenge may not be dissociated from the current lack of actionable COPD pathognomonic molecular biomarkers. There is accruing evidence of the involvement of protracted ‘smoldering’ inflammation, repeated lung injury, and accelerated lung aging in enhanced predisposition to or progression of COPD. The relatively novel uncharacterized human long noncoding RNA lnc-IL7R (otherwise called LOC100506406) is increasingly designated a negative modulator of inflammation and regulator of cellular stress responses; however, its role in pulmonary physiology and COPD pathogenesis remains largely unclear and underexplored. Our previous work suggested that upregulated lnc-IL7R expression attenuates inflammation following the activation of the toll-like receptor (TLR)-dependent innate immune system, and that the upregulated lnc-IL7R is anti-correlated with concomitant high PM2.5, PM10, and SO2 levels, which is pathognomonic for exacerbated/aggravated COPD in Taiwan. In the present study, our quantitative analysis of lnc-IL7R expression in our COPD cohort (n = 125) showed that the lnc-IL7R level was significantly correlated with physiological pulmonary function and exhibited COPD-based stratification implications (area under the curve, AUC = 0.86, p < 0.001). We found that the lnc-IL7R level correctly identified patients with COPD (sensitivity = 0.83, specificity = 0.83), precisely discriminated those without emphysematous phenotype (sensitivity = 0.48, specificity = 0.89), and its differential expression reflected disease course based on its correlation with the COPD GOLD stage (r = −0.59, p < 0.001), %LAA-950insp (r = −0.30, p = 0.002), total LAA (r = −0.35, p < 0.001), FEV1(%) (r = 0.52, p < 0.001), FVC (%) (r = 0.45, p < 0.001), and post-bronchodilator FEV1/FVC (r = 0.41, p < 0.001). Consistent with other data, our bioinformatics-aided dose–response plot showed that the probability of COPD decreased as lnc-IL7R expression increased, thus, corroborating our posited anti-COPD therapeutic potential of lnc-IL7R. In conclusion, reduced lnc-IL7R expression not only is associated with inflammation in the airway epithelial cells but is indicative of impaired pulmonary function, pathognomonic of COPD, and predictive of an exacerbated/ aggravated COPD phenotype. These data provide new mechanistic insights into the ailing lung and COPD progression, as well as suggest a novel actionable molecular factor that may be exploited as an efficacious therapeutic strategy in patients with COPD.

Background and Objectives: Traditional assessment of the readiness for the weaning from the mechanical ventilator (MV) needs respiratory parameters in a spontaneous breath. Exempted from the MV disconnecting and manual measurements of weaning parameters, a prediction model based on parameters from MV and electronic medical records (EMRs) may help the assessment before spontaneous breath trials. The study aimed to develop prediction models using machine learning techniques with parameters from the ventilator and EMRs for predicting successful ventilator mode shifting in the medical intensive care unit. Materials and Methods: A retrospective analysis of 1483 adult patients with mechanical ventilators for acute respiratory failure in three medical intensive care units between April 2015 and October 2017 was conducted by machine learning techniques to establish the predicting models. The input candidate parameters included ventilator setting and measurements, patients’ demographics, arterial blood gas, laboratory results, and vital signs. Several classification algorithms were evaluated to fit the models, including Lasso Regression, Ridge Regression, Elastic Net, Random Forest, Extreme Gradient Boosting (XGBoost), Support Vector Machine, and Artificial Neural Network according to the area under the Receiver Operating Characteristic curves (AUROC). Results: Two models were built to predict the success shifting from full to partial support ventilation (WPMV model) or from partial support to the T-piece trial (sSBT model). In total, 3 MV and 13 nonpulmonary features were selected for the WPMV model with the XGBoost algorithm. The sSBT model was built with 8 MV and 4 nonpulmonary features with the Random Forest algorithm. The AUROC of the WPMV model and sSBT model were 0.76 and 0.79, respectively. Conclusions: The weaning predictions using machine learning and parameters from MV and EMRs have acceptable performance. Without manual measurements, a decision-making system would be feasible for the continuous prediction of mode shifting when the novel models process real-time data from MV and EMRs.

Abstract Background The effect of combined insulin and dipeptidyl peptidase-4 inhibitor (DPP4i) therapy on major adverse cardiovascular events (MACEs) in patients with diabetic foot is unclear. Methods We conducted this nationwide cohort study using longitudinal claims data obtained from the Taiwan National Health Insurance program and included 19,791 patients with diabetic foot from 2007 to 2014. Patients receiving DPP4i-based therapy and/or insulin-based therapy after a diagnosis of diabetic foot were categorized into combined, DPP4i- or insulin-based groups, respectively. The risk of MACEs including nonfatal myocardial infarction, nonfatal stroke, cardiac death, and heart failure was assessed using Cox proportional hazards analysis and propensity score matching. Results Among the 19,791 patients with diabetic foot (mean age, 58.8 years [SD, 12.5]; men, 51.2%), 6466 received DPP4i-based therapy, 1925 received insulin-based therapy, and 11,400 received combined DPP4i and insulin therapy. The DPP4i-based and insulin-based groups had a lower risk of MACEs (HR 0.53, 95% CI 0.50–0.57 DPP4i only; HR 0.89, 95% CI 0.81–0.97 insulin only) than the combined group. After propensity score matching, the incidence of all complications in the DPP4i-based group was still significantly lower than that in the combined group (HR 0.55, 95% CI 0.51–0.59 for MACEs; HR 0.32, 95% CI 0.24–0.42 for nonfatal myocardial infarction; HR 0.70, 95% CI 0.63–0.78 for nonfatal stroke; HR 0.22, 95% CI 0.13–0.38 for cardiac death; HR 0.22, 95% CI 0.19–0.25 for any death; HR 0.16, 95% CI 0.13–0.20 for amputation). In the diabetic foot patients with end-stage renal disease (ESRD), the benefit of a lower incidence of MACEs in the DPP4i-based group disappeared (HR 0.77, 95% CI 0.58–1.08). Conclusions This study demonstrated that the patients with diabetic foot receiving DPP4i-based therapy had a lower risk of MACEs than those receiving combined therapy with DPP4i and insulin, but that the effect disappeared in those with concurrent ESRD.

Background: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. Objectives: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. Methods: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. Results: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below − 950 Hounsfield units (%LAA-950insp), 36 had mild or no emphysema (%LAA-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM2.5, PM10, and SO2 were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM2.5, PM10, and SO2 were associated with fewer and ameliorated COPD cases, while high PM2.5, PM10, and SO2 but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). Conclusion: Combined BMI, lnc-IL7R, PM2.5, PM10, and SO2 levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM2.5, PM10, and SO2 levels is pathognomonic of exacerbated/aggravated COPD in Taiwan.

Abstract Background Infectious gangrene of the foot is a serious complication of diabetes that usually leads to a certain level of lower-extremity amputation (LEA). Nevertheless, the long-term survival and factors associated with mortality in such patients have yet to be elucidated. Methods A total of 157 patients with type 2 diabetes who received treatment for infectious foot gangrene at a major diabetic foot center in Taiwan from 2002 to 2009 were enrolled, of whom 90 had major LEAs (above the ankle) and 67 had minor LEAs (below the ankle). Clinical data during treatment were used for the analysis of survival and LEA, and survival was tracked after treatment until December 2012. Results Of the 157 patients, 109 died, with a median survival time of 3.12 years and 5-year survival rate of 40%. Age [hazard ratio 1.04 (95% confidence interval 1.01–1.06)], and major LEA [1.80 (1.05–3.09)] were independent factors associated with mortality. Patients with minor LEAs had a better median survival than those with major LEAs (5.5 and 1.9 years, respectively, P

Abstract The insulin-like growth factor (IGF)-1 signaling is relevant in regulating cell growth and cytokine secretions by glioblastomas. MicroRNAs determine the cell fate in glioblastomas. However, relationships between IGF-1 signaling and miRNAs in glioblastoma pathogenesis are still unclear. Our aim was to validate the IGF-1-mediated mRNA/miRNA regulatory network in glioblastomas. Using in silico analyses of mRNA array and RNA sequencing data from The Cancer Genome Atlas (TCGA), we identified 32 core enrichment genes that were highly associated with IGF-1-promoted cytokine-cytokine receptor interactions. To investigate the IGF-1-downregulated miRNA signature, microarray-based approaches with IGF-1-treated U87-MG cells and array data in TCGA were used. Four miRNAs, including microRNA (miR)-9-5p, miR-9-3p, miR-181d, and miR-130b, exhibited an inverse correlation with IGF-1 levels. The miR-181d, that targeted the most IGF-1-related cytokine genes, was significantly reduced in IGF-1-treated glioma cells. Statistical models incorporating both high-IGF-1 and low-miR-181d statuses better predicted poor patient survival, and can be used as an independent prognostic factor in glioblastomas. The C-C chemokine receptor type 1 (CCR1) and interleukin (IL)-1b demonstrated inverse correlations with miR-181d levels and associations with patient survival. miR-181d significantly attenuated IGF-1-upregulated CCR1 and IL-1b gene expressions. These findings demonstrate a distinct role for IGF-1 signaling in glioma progression via miR-181d/cytokine networks.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exhibit antibacterial and anti-inflammatory activities. Furthermore, diets rich in n-3 PUFAs are known to improve disease resistance and limit pathogen infection in commercial aquaculture fishes. In this study, we examined the effects of transgenic overexpression of n-3 PUFA biosynthesis genes on the physiological response to bacterial infection in tilapia. We first established tilapia strains with single or dual expression of salmon delta-5 desaturase and/or delta-6 desaturase and then challenged the fish with Vibrio vulnificus infection. Interestingly, our data suggest that n-3 PUFA-mediated alterations in gut microbiota may be important in determining disease outcome via effects on immune response of the host. Both liver- and muscle-specific single and dual expression of delta-5 desaturase and delta-6 desaturase resulted in higher n-3 PUFA content in transgenic fish fed with a LO basal diet. The enrichment of n-3 PUFAs in dual-transgenic fish is likely responsible for their improved survival rate and comparatively reduced expression of inflammation- and immune-associated genes after V. vulnificus infection. Gut microbiome analysis further revealed that dual-transgenic tilapia had high gut microbiota diversity, with low levels of inflammation-associated microbiota (i.e., Prevotellaceae). Thus, our findings indicate that dual expression of transgenic delta-5 and delta-6 desaturase in tilapia enhances disease resistance, an effect that is associated with increased levels of n-3 PUFAs and altered gut microbiota composition.

Objective To study the prevalence and trends of lower extremity complications of diabetes over an 8-year period in a single nation.Research design and methods Nationwide data for people with type 2 diabetes (T2D) and diabetic foot complications (DFCs) were analyzed over an 8-year period (2007–2014) from National Health Insurance Research Database using the International Classification of Diseases, Ninth Revision disease coding. The DFCs were defined as ulcers, infections, gangrene, and hospitalization for peripheral arterial disease (PAD). Trends of patient characteristics, foot presentation, and the execution of major procedures were studied, including lower-extremity amputations (LEAs).Results Along with the T2D population increasing over time, the absolute number of people with DFCs increased by 33.4%, but retained a prevalence of around 2% per year. The annual incident of LEAs decreased from 2.85 to 2.06 per 1000 T2D population (p=0.001) with the major LEA proportion decreasing from 56.2% to 47.4% (p

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as it shows a high capacity for metastasis and poor prognoses. Metabolic reprogramming is one of the hallmarks of cancer, and aberrant glycolysis was reported to be upregulated in TNBC. Thus, identifying metabolic biomarkers for diagnoses and investigating cross-talk between glycolysis and invasiveness could potentially enable the development of therapeutics for patients with TNBC. In order to determine novel and reliable metabolic biomarkers for predicting clinical outcomes of TNBC, we analyzed transcriptome levels of glycolysis-related genes in various subtypes of breast cancer from public databases and identified a distinct glycolysis gene signature, which included ENO1, SLC2A6, LDHA, PFKP, PGAM1, and GPI, that was elevated and associated with poorer prognoses of TNBC patients. Notably, we found a transcription factor named Y-box-binding protein 1 (YBX1) to be strongly associated with this glycolysis gene signature, and it was overexpressed in TNBC. A mechanistic study further validated that YBX1 was upregulated in TNBC cell lines, and knockdown of YBX1 suppressed expression of those glycolytic genes. Moreover, YBX1 expression was positively associated with epithelial-to-mesenchymal transition (EMT) genes in breast cancer patients, and suppression of YBX1 downregulated expressions of EMT-related genes and tumor migration and invasion in MDA-MB-231 and BT549 TNBC cells. Our data revealed an YBX1-glycolysis-EMT network as an attractive diagnostic marker and metabolic target in TNBC patients.

Aeolian erosion occurring in sand deserts causes significant socio-economical threats over extensive areas through mineral dust storm generation and soil degradation. To monitor a sequence of aeolian erosion in a sand desert area, we developed an approach fusing a set of remote sensing data. Vegetation index and Interferometric Synthetic Aperture Radar (InSAR) phase coherence derived from space-borne optical/SAR remote sensing data were used. This scheme was applied to Kubuqi Desert in Inner Mongolia where the effects of activity to combat desertification could be used to verify the outcome of the approach. We first established time series phase coherence and conducted a functional operation based on principal component analysis (PCA) to remove uncorrelated noise. Then, through decomposition of vegetation effect, where a regression model together with the Enhanced Vegetation Index (EVI) was employed, we estimated surface migration caused by aeolian interaction, that is, the aeolian erosion rate (AER). AER metrics were normalized and validated by additional satellite and ground data. As a result, the spatiotemporal migration of the target environment, which certainly induced dust storm generation, was traced and analyzed based on the correlations among surface characteristics. It was revealed that the derived AER successfully monitored the surface changes that occurred before and after the activities to combat desertification in the target area. Employing the established observation scheme, we expect a better understanding of the aeolian process in sand deserts with enhanced spatio-temporal resolution. In addition, the scheme will be beneficial for the evaluation of combating desertification activities and early warning of dust storm generations.

We present an object-based image analysis (OBIA) approach to identify temporal changes in radar-intensity images and to locate land-cover changes caused by mass-wasting processes at small to large scales, such as landslides. Our approach is based upon change detection in SAR intensity images that remain in their original imaging coordinate system rather than being georeferenced and map-projected, in order to reduce accumulation of filtering artifacts and other unwanted effects that would deteriorate the detection efficiency. Intensity images in their native slant-range coordinate frame allow for a consistent level of detection of land-cover changes. By analyzing intensity images, a much faster response can be achieved and images can be processed as soon as they are made publicly available. In this study, OBIA was introduced to systematically and semiautomatically detect landslides in image pairs with an overall accuracy of at least 60% when compared to in-situ landslide inventory data. In this process, the OBIA feature extraction component was supported by derived data from a polarimetric decomposition as well as by texture indices derived from the original image data. The results shown here indicate that most of the landslide events could be detected when compared to a closer visual inspection and to established inventories, and that the method could therefore be considered as a robust detection tool. Significant deviations are caused by the limited geometric resolution when compared to field data and by an additional detection of stream-related sediment redeposition in our approach. This overdetection, however, turns out to be potentially beneficial for assessing the risk situation after landslide events.

Metastasis is the leading cause of death in lung adenocarcinomas. Identifying potential prognostic biomarkers and exploiting regulatory mechanisms could improve the diagnosis and treatment of lung cancer patients. We previously found that cluster of differentiation 109 (CD109) was upregulated in lung tumor tissues, and CD109 overexpression was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. However, the contribution of CD109 to lung tumorigenesis remains to be elucidated. In the present study, we identified that CD109 was upregulated in metastatic lung adenocarcinoma cells, and elevation of CD109 was correlated with epithelial-to-mesenchymal transition (EMT) traits in patients with lung adenocarcinoma. Functionally, CD109 expression was crucial for EMT gene expressions, tumor invasiveness, and cancer stemness properties. Moreover, elevation of CD109 was accompanied by upregulation of the yes-associated protein (YAP) signature in metastatic lung cancer cells and lung cancer patients, and activation of YAP was demonstrated to participate in CD109-elicited EMT gene expressions and tumor invasiveness. Our study reveals the molecular mechanism underlying CD109 in lung tumor aggressiveness, and CD109 could be a potential diagnostic and therapeutic target for lung cancer patients.

The dietary flavonoids luteolin and quercetin are reported to inhibit cancer mobility; however, the regulatory effect of luteolin and quercetin on RPS12 is still unclear. Here, we found that A431-III cells expressed a higher level of RPS12 than A431-P cells. The flavonoids luteolin and quercetin reduced RPS12 and c-Myc expressions via Akt/mTOR signalling. The Akt inhibitor LY294002 and mTOR inhibitor rapamycin reduced RPS12 and c-Myc expressions. The c-Myc inhibitor 10058-F4 reduced RPS12 expression and promoter transactivation. The overexpression of c-Myc increased RPS12 expression. Akt, mTOR, and c-Myc inhibitor blocked cell migration. Reducing RPS12 expression via 10058-F4 and shRNAs reduced cell invasion. This study reveals that RPS12 is upregulated via Akt/mTOR/c-Myc signalling and increased cell mobility. Luteolin and quercetin blocked Akt/mTOR/c-Myc signalling to reduce RPS12 level and downstream cell mobility. These data suggest a possible role of RPS12 in cell mobility and may be a potential therapy target for cervical cancer.

There are several methods for long head of the biceps (LHB) tenodesis, yet the optimal option is still debatable. Here we introduce a technique for arthroscopic suprapectoral biceps tenodesis with an all-suture anchor, the transtendinous biceps tenodesis technique. The LHB tenodesis is performed by using the Y-Knot anchor (1.3-mm). A standard suprapectoral approach is used for the tenodesis. A 1.3-mm drill bit is used to drill through the midportion of the biceps tendon and underlying bone to make a pilot hole. Next, the Y-Knot anchor is passed through the tendon and anchored on the underlying bone. A wrapping suture technique is then used to wrap around, tension, and secure the LHB tendon with the aid of a shuttling polydioxanone suture. The construct is fixed by tying down both suture limbs in a nonsliding fashion. This Technical Note describes an alternative method for all-arthroscopic suprapectoral biceps tenodesis using an all-suture anchor with a small diameter to minimize trauma to the tendon.

Bacterial-derived lipopolysaccharides (LPS) can cause defective intestinal barrier function and play an important role in the development of inflammatory bowel disease. In this study, a nanocarrier based on chitosan and fucoidan was developed for oral delivery of berberine (Ber). A sulfonated fucoidan, fucoidan-taurine (FD-Tau) conjugate, was synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy. The FD-Tau conjugate was self-assembled with berberine and chitosan (CS) to form Ber-loaded CS/FD-Tau complex nanoparticles with high drug loading efficiency. Berberine release from the nanoparticles had fast release in simulated intestinal fluid (SIF, pH 7.4), while the release was slow in simulated gastric fluid (SGF, pH 2.0). The effect of the berberine-loaded nanoparticles in protecting intestinal tight-junction barrier function against nitric oxide and inflammatory cytokines released from LPS-stimulated macrophage was evaluated by determining the transepithelial electrical resistance (TEER) and paracellular permeability of a model macromolecule fluorescein isothiocyanate-dextran (FITC-dextran) in a Caco-2 cells/RAW264.7 cells co-culture system. Inhibition of redistribution of tight junction ZO-1 protein by the nanoparticles was visualized using confocal laser scanning microscopy (CLSM). The results suggest that the nanoparticles may be useful for local delivery of berberine to ameliorate LPS-induced intestinal epithelia tight junction disruption, and that the released berberine can restore barrier function in inflammatory and injured intestinal epithelial.

This randomized, controlled study was performed to compare the effects of extracorporeal shockwave therapy (ESWT) and ultrasound on the rehabilitation of knee osteoarthritis with popliteal cyamella. One hundred and twenty patients with bilateral moderate knee osteoarthritis (Altman III) and popliteal cyamella were selected and randomly assigned to four groups (GI–GIV). Patients in Groups I–III received isokinetic muscular strengthening exercises three times weekly for 8 weeks. Group II received pulse ultrasound treatment for popliteal cyamella three times weekly for 8 weeks, Group III received weekly shock wave therapy for popliteal cyamella for the first 6 weeks, and Group IV acted as controls. The therapeutic effects were evaluated by changes in the arthritic knees range of motion (ROM), visual analogue scale, Lequesne's index, and muscle peak torques after treatment and at follow-up 6 months later. Each treated group exhibited increased muscle peak torques and significantly reduced pain and disability after treatment and at follow-ups. However, only patients in Groups II and III showed significant improvements in ROM after treatment, and only participants in Group III showed immediate improvement in ROM after each treatment. Patients in Group III also showed the greatest increase in muscular strength and the greatest decrease in disability after treatment and at the follow-ups. ESWT is better than pulse ultrasound in rehabilitation of patients with knee osteoarthritis and popliteal cyamella results in more functional improvements.

Flavonoids are well-known antioxidants and have shown the ability to prevent tumor formation and recurrence. Especially in dietary flavonoids, they have provided convenience and consistence of intake for long-term prevention of tumor formation. Previous reports suggested that S100 calcium-binding protein A7 (S100A7) might activate epithelial−mesenchymal transition (EMT) signaling and promote the metastasis of tumor cells; however, the regulatory signaling was unclear. In this study, we found that S100A7 was highly expressed in cancer cells and could be reduced by luteolin (Lu) and quercetin (Qu) through Src/Stat3 signaling. We found that the protein levels of S100A7, phosphorylated Src (p-Src), and p-Stat3 were increased in A431-III cells. Flavonoids Lu and Qu reduce protein levels of p-Src, p-Stat3 and S100A7 in A431-III cells. Treatment of A431-III cells with Src inhibitor SU6656 and Stat3 inhibitor S3I-201 also reduced the protein levels of S100A7. Transactivation activity of 5′-upstream regions of S100A7 was activated by Stat3 but was reduced by treatment with Lu, Qu, SU6656 and S3I-201. The treatment also reduced the migratory and invasive abilities of A431-III cells. In a further analysis of EMT markers, the protein level of E-cad increased and that of Twist decreased after treatment with the inhibitors and flavonoids. Overexpression of S100A7 decreased the protein level of E-cad and increased the Twist level, whereas knockdown of S100A7 had the opposite effects. Treatment with S3I-201, Lu and Qu, compared to the control, were found to decrease metastasis of tumor cells in zebrafish larvae. These results suggest that Lu and Qu may inhibit Src/Stat3/S100A7 signaling to reduce tumorigenesis of cancer cells.

MicroRNAs are small noncoding RNAs that post-transcriptionally control the expression of genes involved in glioblastoma multiforme (GBM) development. Although miR-302b functions as a tumor suppressor, its role in GBM is still unclear. Therefore, this study comprehensively explored the roles of miR-302b-mediated gene networks in GBM cell death. We found that miR-302b levels were significantly higher in primary astrocytes than in GBM cell lines. miR-302b overexpression dose dependently reduced U87-MG cell viability and induced apoptosis through caspase-3 activation and poly(ADP ribose) polymerase degradation. A transcriptome microarray revealed 150 downregulated genes and 380 upregulated genes in miR-302b-overexpressing cells. Nuclear factor IA (NFIA), higher levels of which were significantly related to poor survival, was identified as a direct target gene of miR-302b and was involved in miR-302b-induced glioma cell death. Higher NFIA levels were observed in GBM cell lines and human tumor sections compared with astrocytes and non-tumor tissues, respectively. NFIA knockdown significantly enhanced apoptosis. We found high levels of insulin-like growth factor-binding protein 2 (IGFBP2), another miR-302b-downregulated gene, in patients with poor survival. We verified that NFIA binds to the IGFBP2 promoter and transcriptionally enhances IGFBP2 expression levels. We identified that NFIA-mediated IGFBP2 signaling pathways are involved in miR-302b-induced glioma cell death. The identification of a regulatory loop whereby miR-302b inhibits NFIA, leading to a decrease in expression of IGFBP-2, may provide novel directions for developing therapies to target glioblastoma tumorigenesis.

In the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation, an increase in the migration/invasion of U87 glioblastoma cells was detected by a wound healing assay, transwell analysis, and spheroid formation assay by inducing matrix metalloproteinase-9 (MMP-9) enzyme activity via a gelatin zymographic analysis. A dose- and time-dependent increase in cyclooxygenase-2 (COX-2) gene expression with elevated prostaglandin E2 (PGE2) production was identified in TPA- but not in 4α-TPA (a respective inactive compound)-treated U87 cells TPA-induced migration/invasion was significantly blocked by adding the COX-2-specific inhibitor, NS398, through a reduction in PGE2 production. Data from the pharmacological studies using specific chemical inhibitors showed that activation of protein kinase C (PKC) and extracellular signal-regulated kinases (ERKs) was involved in TPA-induced migration/invasion, COX-2 protein expression, and MMP-9 activation. Stimulation of intracellular peroxide production by TPA was detected by a DCHF-DA assay, and the addition of superoxide dismutase (SOD) or tempol significantly inhibited TPA-induced migration/invasion and COX-2 protein expression accompanied by a decrease in peroxide production. An increase in NADPH oxidase activity by TPA was examined, and TPA-induced migration/invasion was blocked by adding DPI, an NADPH oxidase inhibitor. Additionally, the natural flavonoids quercetin (QE), baicalein (BE), and myricetin (ME) effectively blocked TPA-induced migration/invasion while simultaneously inhibiting COX-2/PGE2 production, MMP-9 enzyme activity, and peroxide production in U87 cells. The contribution of ROS production to the migration/invasion of U87 glioblastoma cells via ERK-activated COX-2/PGE2 and MMP-9 induction was first investigated here, and agents such as QE, BE, and ME with the ability to block these events possess the potential to be developed for use against migration/invasion by glioblastomas.

Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development.