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Background The combination of diabetes mellitus (DM) and chronic kidney disease (CKD) is associated with a high risk of mortality. Annual assessment of the estimated glomerular filtration rate (eGFR) is recommended for patients with DM. We investigated the effect of variability in annual eGFR values on all-cause mortality in patients with type 2 DM. Methods In this retrospective cohort study, we enrolled patients with eGFR data between 01 Aug 2017 and 31 July 2018. We defined the index eGFR as the first available eGFR value within the enrollment year and collected additional annual eGFR data from the previous three years. A total of 3592 patients with type 2 DM were enrolled, including 959 patients with CKD (index eGFR 2) and 2633 patients without CKD. We assessed eGFR variability by using the standard deviation (SD) of the three annual eGFR and index eGFR values. We divided patients into subgroups according to the median SD of their annual eGFR (7.62 mL/min/1.73 m2). The primary endpoint was all-cause mortality after the index eGFR was assessed. Results During a median follow-up of 19 months (interquartile range: 18‒20 months), 127 (3.5%) deaths occurred among all 3592 enrolled patients. The highest mortality risk was observed in the high SD with CKD group, with a hazard ratio (HR) of 2.382 [95% confidence interval (CI) 1.346‒4.215] in comparison to the low SD without CKD group after adjusting for the associated factors. In patients without CKD, a high SD was an independent risk factor for mortality (HR = 2.105, 95% CI 1.256‒3.528). According to the C-index, the mortality prediction ability was better for the index eGFR + SD model than for the index eGFR alone model (0.671 vs. 0.629, P Conclusion There was a synergistic effect of eGFR variability with single-measured eGFR for the prediction of mortality in patients with type 2 DM. The SD of the annual eGFR values was also an independent predictor of mortality in patients with an eGFR > 60 mL/min/1.73 m2.

The canonical β-catenin-dependent wingless (Wnt) pathway is associated with endothelial function. We examined the effect of plasma dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, on the prediction of major adverse cardiac events (MACEs). We enrolled patients who had undergone selective coronary angiography for angina. DKK-1 levels were determined using plasma collected at the outpatient visit after fasting. MACEs served as the primary endpoint. All 470 enrolled patients were divided into four groups according to their median plasma DKK-1 levels and the presence of obstructive coronary artery disease (CAD). Forty-eight patients reached the primary endpoint during a median follow-up time of 4.8 years. Kaplan–Meier survival analysis indicated that the group with high DKK-1 and obstructive CAD had a significantly higher mortality rate than the other three groups (log-rank test p = 0.001). Compared with the low plasma DKK-1 without significant coronary obstruction group, the high DKK-1 with obstructive CAD group had a hazard ratio of 10.640 (95% confidence interval: 1.350–83.874) for MACEs, as determined by multivariable Cox proportional hazard regression analysis. In conclusion, we observed a synergistic effect between high plasma DKK-1 and obstructive CAD on the prediction of MACEs in patients with angina.

Background: Inflammation has been proposed to play potential roles in the development and progression of chronic kidney disease (CKD). We evaluated the relationship of neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation marker, with CKD in normal-weight and overweight/obese adults. Methods: This cross-sectional study included 2846 apparently healthy adults who underwent a health examination between August 2000 and April 2002. Normal-weight was defined as a body mass index (BMI, kg/m2) of 18.5–24, while overweight/obesity was defined as a BMI of ≥24. CKD was defined as an estimated glomerular filtration rate (eGFR) of

Aims/Introduction The convergence of tuberculosis (TB) and diabetes mellitus (DM) is a new challenge in Asia as a result of the rising prevalence of diabetes mellitus with higher TB infection rates, and also because diabetes mellitus itself enhances TB disease activity and consequently the spread of TB. We aimed to address the risk presented by diabetes mellitus for TB infection. Materials and Methods Patients with diabetes mellitus were retrospectively recruited. The baseline assessments included age, sex, body mass index, fasting blood glucose, glycated hemoglobin, urine albumin‐to‐creatinine ratio and estimated glomerular filtration rate. TB was determined by meeting the international classification of disease, for TB diagnosis and receiving anti‐TB treatment for at least 2 months. Results In total, 9,750 individuals with diabetes mellitus were recruited. The event rate of TB was 47 (0.48%). Younger age, lower proportion of men, higher fasting blood glucose and glycated hemoglobin values, and better renal function (estimated glomerular filtration rate and urine albumin‐to‐creatinine ratio) were observed in the metformin‐exposed groups. Old age and male sex were associated with higher TB infection risk on multivariate analysis. Metformin users had a significantly lower risk for TB infection, whereas insulin users had a higher risk for TB infection. However, glycemic status had no effect on TB infection risk. Conclusions This study provides clinical evidence from a survey of TB in individuals with diabetes mellitus. Old age, male sex and insulin use were risk factors for TB infection. Metformin remains the first choice of treatment for diabetes mellitus and has a potential protective effect against TB infection.

We aimed to assess the ankle-brachial index (ABI) in patients with Graves’ disease. In the cross-sectional assessments, 81 patients with drug-naïve Graves’ disease and 235 with euthyroidism were enrolled. ABI and vascular cell adhesion molecule-1 (VCAM-1) levels were assessed. In the prospective follow-up, 32 patients with Graves’ disease were assessed again after antithyroid drugs for at least 4 weeks, and 32 age- and sex-matched controls with euthyroidism were also followed up. Patients with Graves’ disease had a higher VCAM-1 level (1309 ± 292 vs. 1009 ± 168 ng/mL, P

Purpose Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are tumor-associated antigens. An increased serum level of CEA and CA19-9 separately has been reported in diabetes. In this study, we examined the composite effect of elevated serum levels of both CEA and CA19-9 on subjects with type 2 diabetes and prediabetes. Patients and Methods A total of 3568 adults who attended a health examination were enrolled into this cross-sectional study. Subjects were grouped into four groups according to the median serum CEA and CA19-9 levels. Results Subjects with high CEA and high CA19-9 levels had the highest proportions of diabetes (43.9%) and prediabetes (33.04%). There was a statistically significant trend in the proportion of diabetes across the four groups (P < 0.001). Multivariable logistic regression analysis revealed higher risks of type 2 diabetes in subjects with high CEA and low CA19-9 levels (odds ratio [OR] = 2.10, 95% confidence interval [CI]: 1.39-3.18, P < 0.001) and in those with high CA19-9 and low CEA levels (OR = 2.18, 95% CI: 1.42-3.34, P < 0.001) than in those with low CEA and low CA19-9 levels; among these four groups, the highest risk of type 2 diabetes was observed in subjects with high CEA and high CA19-9 levels (OR = 2.65, 95% CI: 1.81-3.88, P < 0.001). The risk of prediabetes was significantly higher only in subjects with high CEA and high CA19-9 levels compared to those with low CEA and low CA19-9 levels (OR = 1.32, 95% CI: 1.08-1.61, P = 0.006). Conclusion CEA and CA19-9 had a synergistic ability to increase the risk of type 2 diabetes and prediabetes.

Purpose An "obesity paradox" has been observed in patients with type 2 diabetes. However, the optimal body mass index (BMI) for survival may be influenced by the stage of diabetes. We examined the relationship between BMI and mortality in patients with type 2 diabetes and the influence of diabetic retinopathy (DR). Patients and Methods This is a retrospective cohort composing patients with type 2 diabetes who were admitted due to poor glucose control. Presence of DR was confirmed by ophthalmologists. The primary outcome was all-cause mortality. The association between BMI and mortality was assessed using a Cox proportional hazards model with adjustment for age, sex, and traditional risk factors. Results A total of 2053 patients were enrolled. Over median follow-up of 6.7 years, there were 1060 deaths. Patients were classified into five categories based on admission BMI (kg/m2): 30. Mortality risk was significantly higher in the

BackgroundCurrent predictive models for patients undergoing coronary angiography have complex parameters which limit their clinical application. Coronary catheterization reports that describe coronary lesions and the corresponding interventions provide information of the severity of the coronary artery disease and the completeness of the revascularization. This information is relevant for predicting patient prognosis. However, no predictive model has been constructed using the text content from coronary catheterization reports before.ObjectiveTo develop a deep learning model using text content from coronary catheterization reports to predict 5-year all-cause mortality and 5-year cardiovascular mortality for patients undergoing coronary angiography and to compare the performance of the model to the established clinical scores.MethodThis retrospective cohort study was conducted between January 1, 2006, and December 31, 2015. Patients admitted for coronary angiography were enrolled and followed up until August 2019. The main outcomes were 5-year all-cause mortality and 5-year cardiovascular mortality. In total, 11,576 coronary catheterization reports were collected. BioBERT (bidirectional encoder representations from transformers for biomedical text mining), which is a BERT-based model in the biomedical domain, was utilized to construct the model. The area under the receiver operating characteristic curve (AUC) was used to assess model performance. We also compared our results to the residual SYNTAX (SYNergy between PCI with TAXUS and Cardiac Surgery) score.ResultsThe dataset was divided into the training (60%), validation (20%), and test (20%) sets. The mean age of the patients in each dataset was 65.5 ± 12.1, 65.4 ± 11.2, and 65.6 ± 11.2 years, respectively. A total of 1,411 (12.2%) patients died, and 664 (5.8%) patients died of cardiovascular causes within 5 years after coronary angiography. The best of our models had an AUC of 0.822 (95% CI, 0.790–0.855) for 5-year all-cause mortality, and an AUC of 0.858 (95% CI, 0.816–0.900) for 5-year cardiovascular mortality. We randomly selected 300 patients who underwent percutaneous coronary intervention (PCI), and our model outperformed the residual SYNTAX score in predicting 5-year all-cause mortality (AUC, 0.867 [95% CI, 0.813–0.921] vs. 0.590 [95% CI, 0.503–0.684]) and 5-year cardiovascular mortality (AUC, 0.880 [95% CI, 0.873–0.925] vs. 0.649 [95% CI, 0.535–0.764]), respectively, after PCI among these patients.ConclusionsWe developed a predictive model using text content from coronary catheterization reports to predict the 5-year mortality in patients undergoing coronary angiography. Since interventional cardiologists routinely write reports after procedures, our model can be easily implemented into the clinical setting.

In this cross-sectional study, enrollment included 818 female adults undergoing bone mineral density (BMD) assessment during the health examination. Subjects with osteoporosis had the lowest circulating platelet concentrations. The circulating platelet concentration was positively correlated with BMD. A high platelet concentration had independently low odds of osteoporosis.Platelets play an important role in bone metabolism. However, the association between circulating platelet counts and bone mineral density (BMD) has been inconsistently reported. We aimed to investigate the relationship between platelet counts and osteoporosis in Chinese women.In this cross-sectional study, a total of 818 female adults who underwent BMD assessment during the health examination were enrolled. Blood cell counts and biochemistry data were recorded.Subjects with osteoporosis had the lowest platelet counts (238 ± 59 × 10The circulating platelet concentration was significantly correlated with BMD in Chinese women.

We aimed to develop and validate a model for predicting mortality in patients with angina across the spectrum of dysglycemia. A total of 1479 patients admitted for coronary angiography due to angina were enrolled. All-cause mortality served as the primary endpoint. The models were validated with five-fold cross validation to predict long-term mortality. The features selected by least absolute shrinkage and selection operator (LASSO) were age, heart rate, plasma glucose levels at 30 min and 120 min during an oral glucose tolerance test (OGTT), the use of angiotensin II receptor blockers, the use of diuretics, and smoking history. This best performing model was built using a random survival forest with selected features. It had a good discriminative ability (Harrell’s C-index: 0.829) and acceptable calibration (Brier score: 0.08) for predicting long-term mortality. Among patients with obstructive coronary artery disease confirmed by angiography, our model outperformed the Global Registry of Acute Coronary Events discharge score for mortality prediction (Harrell’s C-index: 0.829 vs. 0.739, p &lt, 0.001). In conclusion, we developed a machine learning model to predict long-term mortality among patients with angina. With the integration of OGTT, the model could help to identify a high risk of mortality across the spectrum of dysglycemia.

Background Esophageal injury is a severe surgical complication of a transsternal approach to high thoracic vertebral metastasis, which can result in mediastinitis and life-threatening consequences. A covered stent can be placed in the esophagus to prevent mediastinal leakage. However, tracheomalacia is a rare complication following esophageal stenting. Case Description A 56-year-old man had a pathologic fracture of the T3 vertebral body with spinal cord compression, myelopathy, and neurogenic bladder. An esophageal injury was noticed during the transsternal approach. Immediate suture repair, drainage tube placement, and subsequent esophageal stenting were carried out. One month after discharge, the endoscopic examination revealed nonhealing of the esophagus, and a new covered stent was replaced. Episodes of severe stridor and dyspnea led to the patient being sent to the emergency department. Computed tomography scan of the chest revealed a focal collapse of the trachea at the thoracic inlet, and tracheomalacia was suspected. The covered stent was removed, despite nonhealing of the esophagus. His stridor, dyspnea, and constant coughing subsided afterwards. The endoscopic examination at 3 months after stent removal showed complete healing of the esophagus. Conclusions Esophageal stenting can be used to prevent mediastinal leakage due to esophageal injury in the transsternal approach for high thoracic vertebral metastasis, but the stent might be a cause of tracheomalacia. Stent removal should be considered if upper airway obstruction occurs. Awareness of the radial force of the stent, esophageal composition (e.g., status post suture repair), and esophageal diameter must be considered for optimal stent tolerance to avoid complications.

Deep learning-based software is developed to assist physicians in terms of diagnosis, however, its clinical application is still under investigation. We integrated deep-learning-based software for diabetic retinopathy (DR) grading into the clinical workflow of an endocrinology department where endocrinologists grade for retinal images and evaluated the influence of its implementation. A total of 1432 images from 716 patients and 1400 images from 700 patients were collected before and after implementation, respectively. Using the grading by ophthalmologists as the reference standard, the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to detect referable DR (RDR) were 0.91 (0.87–0.96), 0.90 (0.87–0.92), and 0.90 (0.87–0.93) at the image level, and 0.91 (0.81–0.97), 0.84 (0.80–0.87), and 0.87 (0.83–0.91) at the patient level. The monthly RDR rate dropped from 55.1% to 43.0% after implementation. The monthly percentage of finishing grading within the allotted time increased from 66.8% to 77.6%. There was a wide range of agreement values between the software and endocrinologists after implementation (kappa values of 0.17–0.65). In conclusion, we observed the clinical influence of deep-learning-based software on graders without the retinal subspecialty. However, the validation using images from local datasets is recommended before clinical implementation.

Background: We aimed to develop and validate a model to predict mortality in patients with stable angina across the spectrum of dysglycemia.Methods: A total of 1479 patients admitted for coronary angiography due to angina were enrolled. All-cause mortality was followed up and served as the primary endpoint. We compared the performance of different machine learning models for survival analysis and used least absolute shrinkage and selection operator (LASSO) to select important features. Performance was evaluated using Harrell’s C-index and the Brier score. The models were validated with five-fold cross validation to predict long-term mortality.Results: The features selected by LASSO were age, heart rate, plasma glucose levels at 30 min and 120 min during an oral glucose tolerance test (OGTT), use of angiotensin II receptor blockers, use of diuretics, and smoking history. The best performing model was built using a random survival forest with selected features. It had a good discriminative ability (Harrell’s C-index: 0.829) and acceptable calibration (Brier score: 0.08) for predicting long-term mortality. Among patients with obstructive coronary artery disease confirmed by angiography, our model outperformed the Global Registry of Acute Coronary Events discharge score for mortality prediction (Harrell’s C-index: 0.829 vs. 0.739, P < 0.001).Conclusions: We developed a machine learning model to predict long-term mortality among patients with stable angina. With the integration of OGTT, the model could help to identify patients with stable angina at high risk of mortality across the spectrum of dysglycemia.

BackgroundPeripheral artery disease (PAD) in the lower extremities is a common complication of type 2 diabetes and has been shown to be associated with mortality. The ankle-brachial index (ABI) is a simple noninvasive method to screen PAD, but this method has limited sensitivity. We hypothesized that using the percentage of mean arterial pressure (%MAP) in combination with the ABI would improve the prediction of mortality.MethodsWe retrospectively collected data from patients with type 2 diabetes who had undergone ABI and %MAP measurements at our hospital. We separated the cohort into four groups according to their ABI and %MAP values, and we examined whether these indices were associated with mortality.ResultsA total of 5569 patients (mean age, 65 ± 11 years) were enrolled. During the follow-up period (median, 22.9 months), 266 (4.8%) of the enrolled patients died. The combination of ABI and %MAP was significantly more effective than ABI alone for predicting mortality (C index of 0.62, 95% confidence interval [CI] of 0.57 to 0.65 vs. C index of 0.57, 95% CI of 0.53 to 0.62; P = 0.038). In multivariate analysis (with a reference group defined by ABI > 0.90 and %MAP ≤ 45%), the highest risk of mortality was seen in patients with ABI ≤ 0.90 and %MAP > 45% (hazard ratio = 2.045 [95% CI 1.420, 2.945], P ConclusionsThe use of %MAP alongside ABI appears to significantly improve the prediction of all-cause mortality in patients with type 2 diabetes.

Background: Peripheral artery disease (PAD) in lower extremities is a common complication in type 2 diabetes and has shown to be associated with mortality. The ankle-brachial index (ABI) is a simple noninvasive method to screen PAD, but has limited sensitivity. We hypothesized that using the percentage of mean arterial pressure (%MAP) and the ABI in combination would improve prediction of mortality.Methods: We retrospectively collected the data of patients with type 2 diabetes who had undergone measurement of ABI and %MAP at our hospital. We separated the cohort into four groups according to the ABI and %MAP values, and examined these indices were associated with mortality.Results: A total of 5101 patients (mean age, 65 ± 11 years) were enrolled. During the follow-up period (median, 22.9 months), 266 (4.8%) of enrolled patients died. The combination of ABI and %MAP was significantly better at predicting mortality than ABI alone. (C index: 0.62 [95% CI: 0.57, 0.65] vs. 0.57 [95% CI: 0.53, 0.62], P = 0.038). In multivariate analysis (with ABI >0.90 and %MAP ≤45% as the reference group), the highest risk of mortality was seen in patients with ABI ≤0.90 and %MAP >45% (hazard ratio = 1.983 [95% CI: 1.380, 2.848], P < 0.001).Conclusions: Adding %MAP to ABI appears to significantly improve the predictive ability for all-cause mortality in patients with type 2 diabetes.

Purpose Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are tumor-associated antigens. An increased serum level of CEA and CA19-9 separately has been reported in diabetes. In this study, we examined the composite effect of elevated serum levels of both CEA and CA19-9 on subjects with type 2 diabetes and prediabetes. Patients and Methods A total of 3568 adults who attended a health examination were enrolled into this cross-sectional study. Subjects were grouped into four groups according to the median serum CEA and CA19-9 levels. Results Subjects with high CEA and high CA19-9 levels had the highest proportions of diabetes (43.9%) and prediabetes (33.04%). There was a statistically significant trend in the proportion of diabetes across the four groups (P < 0.001). Multivariable logistic regression analysis revealed higher risks of type 2 diabetes in subjects with high CEA and low CA19-9 levels (odds ratio [OR] = 2.10, 95% confidence interval [CI]: 1.39–3.18, P < 0.001) and in those with high CA19-9 and low CEA levels (OR = 2.18, 95% CI: 1.42–3.34, P < 0.001) than in those with low CEA and low CA19-9 levels; among these four groups, the highest risk of type 2 diabetes was observed in subjects with high CEA and high CA19-9 levels (OR = 2.65, 95% CI: 1.81–3.88, P < 0.001). The risk of prediabetes was significantly higher only in subjects with high CEA and high CA19-9 levels compared to those with low CEA and low CA19-9 levels (OR = 1.32, 95% CI: 1.08–1.61, P = 0.006). Conclusion CEA and CA19-9 had a synergistic ability to increase the risk of type 2 diabetes and prediabetes.

A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC50 value of 27.8 ± 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BIIB021 whose IC50 values are 43.0 ± 0.9 nM and 56.8 ± 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment.

Autofluorescence imaging is gaining popularity as an adjunctive test for oral potentially malignant disorders (OPMD). This study evaluated the efficacy of autofluorescence imaging based on the current standard oral mucosal disorder checklist in Taiwan. In total, 126 patients suspected to have mucosal disorders at the Division of Oral and Maxillofacial Surgery, Tri-Service General Hospital, Taipei, Taiwan, were enrolled. Following a conventional oral examination by using the oral mucosal disorder checklist and an autofluorescence imaging examination, all participants underwent histopathological examination to access epithelial dysplasia. Among 126 patients, 68 patients were diagnosis as having an OPMD and 63 having epithelial dysplasia. Autofluorescence imaging exhibited a sensitivity, specificity, positivity predictive value (PPV), negative predictive value (NPV), and accuracy of 77.94%, 35.42%, 63.10%, 53.13%, and 60.34%, respectively, for OPMD and of 88.89%, 43.86%, 63.64%, 78.13%, and 67.50%, respectively, for epithelial dysplasia. After the exclusion of 48 non-OPMD cases according to the checklist, the sensitivity, specificity, PPV, NPV, and accuracy of autofluorescence imaging became 87.50%, 72.73%, 94.23%, 53.33%, and 85.07%, respectively, for epithelial dysplasia. The efficacy of epithelial dysplasia identification and OPMD risk assessment can be increased after the exclusion of the non-OPMD cases through autofluorescence imaging. Autofluorescence imaging is a useful adjunct that can assist specialists in assessing OPMD patients prone to dysplasia without compromising patient care.

Endothelin-1 (ET-1) is associated with endothelial dysfunction and vasoconstriction. Increased circulating ET-1 levels are associated with long-term cardiovascular mortality. Renalase, released from kidney, metabolizes catecholamines and regulates blood pressure. An increase in circulating renalase levels has been reported in patients with chronic kidney disease (CKD) and is associated with coronary artery disease (CAD). We hypothesized the existence of a synergistic effect of serum renalase levels and CKD on ET-1 levels in patients with CAD. We evaluated 342 non-diabetic patients with established CAD. ET-1 and renalase levels were measured in all patients after an overnight fast. Patients with CKD had higher ET-1 (1.95 ± 0.77 vs. 1.62 ± 0.76 pg/ml, P the median of 36.2 ng/ml) exhibited the highest serum ET-1 (P value for the trend

A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7–31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000–43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.

Analyzing and capturing the spirit in the historic Tang Dynasty poems for creating a machine that can compose new poetry is a difficult but fun challenge. In this research, we propose a rhyming knowledge-aware deep neural network for Chinese poetry generation. The model fuses rhyming knowledge that represents phonological tones into a long short-term memory (LSTM) model. This work will help us understand more about what kind of mechanism within the neural network contributes to different styles of the generated poems. The experimental results demonstrate that the proposed method is able to guide the style of those poems towards higher phonological compliance, fluency, coherence, and meaningfulness, as evaluated by human experts. We believe that future research can adopt our approach to further integrate more knowledge such as sentiments, POS, and even stylistic patterns found in poems by famous poets into poem generation.

Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and Aβ42‐expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation‐induced early death and Aβ42‐induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of γ‐secretase. Taken together, this study revealed that Akt is involved in the aging process and Aβ toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.

Arecoline is the primary alkaloid in betel nuts, which are known as a risk factor for oral submucosal fibrosis and oral cancer. Lung cancer is a severe type of carcinoma with high cell motility that is difficult to treat. However, the detailed mechanisms of the correlation between Arecoline and lung cancer are not fully understood. Here, we investigated the effect of Arecoline on migration in lung cancer cell lines and its potential mechanism through the muscarinic acetylcholine receptor 3 (mAChR3)-triggered EGFR/Src/FAK pathway. Our results indicate that different concentrations of Arecoline treatment (10 &micro, M, 20 &micro, M, and 40 &micro, M) significantly increased the cell migration ability in A549 and CL1-0 cells and promoted the formation of the filamentous actin (F-actin) cytoskeleton, which is a crucial element for cell migration. However, migration of H460, CL1-5, and H520 cell lines, which have a higher migration ability, was not affected by Arecoline treatment. The EGFR/c-Src/Fak pathway, which is responsible for cell migration, was activated by Arecoline treatment, and a decreased expression level of E-cadherin, which is an epithelial marker, was observed in Arecoline-treated cell lines. Blockade of the EGFR/c-Src/Fak pathway with the inhibitors of EGFR (Gefitinib) or c-Src (Dasatinib) significantly prevented Arecoline-promoted migration in A549 cells. Gefitinib or Dasatinib treatment significantly disrupted the Arecoline-induced localization of phospho-Y576-Fak during focal adhesion in A549 cells. Interestingly, Arecoline-promoted migration in A549 cells was blocked by a specific mAChR3 inhibitor (4-DAMP) or a neutralizing antibody of matrix metalloproteinase (MMP7 or Matrilysin). Taken together, our findings suggest that mAChR3 might play an essential role in Arecoline-promoted EGFR/c-Src/Fak activation and migration in an A549 lung cancer cell line.

Objectives This study aimed to evaluate the adverse clinicopathologic features of oral squamous cell carcinoma (OSCC), including margin status, depth of invasion, lymphovascular invasion, perineural invasion, and extranodal extension that significantly affect survival outcomes. Materials and methods This retrospective cross-sectional study included 341 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The Kaplan–Meier method was used to estimate survival outcomes. A multivariable Cox regression model was used to evaluate the associations of various clinicopathologic features with 5-year overall survival (OS) outcomes in patients with pN0 and pN+ tumors. Results Overall, the patients had 5-year OS and progression-free survival rates of 60.0 and 47.9%, respectively. In the pN0 group, the multivariate analysis identified a positive margin (odds ratio [OR] = 16.3, 95% confidence interval [95% CI]: 3.7–72.3; P = 0.001), depth of invasion >5 mm (OR = 2.1, 95% CI: 1.2–3.7; P = 0.012), presence of lymphovascular space invasion (OR = 5.4, 95% CI: 1.3–22.0; P = 0.018), and presence of perineural invasion (OR = 4.3, 95% CI: 1.7–11.1; P = 0.002) as independent and significant prognosticators of OS. In the pN+ group, only the presence of extranodal extension independently predicted OS (OR = 1.7, 95% CI: 1.1–2.7; P = 0.0026). Conclusions When determining survival prognosis for patients with a pN0 status, we recommended including all adverse features. In contrast, extranodal extension was the most important prognostic factor for patients with a pN+ status.

MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.

Background: Oral squamous cell carcinoma (OSCC) is the most frequently found malignant tumor of the oral cavity, and the annual death rate of OSCC patients has been increasing rapidly among the Taiwanese population. Aim: The aim of this study is to evaluate if poor nutrition is a potential adverse prognostic factor in patients with OSCC. Methods: This cross-sectional study included 322 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The pretreatment body mass index (BMI) and serum uric acid and albumin levels were measured as common indicators of the nutritional status, and overall survival (OS) was analyzed using the Kaplan–Meier method and a Cox regression model. Results: The optimal cut-off values were 24.0 kg/m[2], 5.05 mg/dL, and 3.85 g/dL for BMI, serum uric acid, and serum albumin, respectively. The multivariate Cox regression analysis indicated lower BMI (hazard ratio [HR] = 1.557, 95% confidence interval [95% CI]: 1.070–2.265; P = 0.021), lower serum uric acid (HR = 1.857, 95% CI: 1.265–2.724; P = 0.002), and lower serum albumin (HR = 2.011, 95% CI: 1.278–3.163; P = 0.003) as independent and significant prognosticators of OS. Advanced stage, depth of invasion of more than 5 mm, and extranodal extension were prognostic predictors of poor OS. Conclusion: A lower preoperative BMI and lower serum uric acid and albumin levels are predictors of significantly worse survival among OSCC patients. Maintaining a healthy nutritional status is crucial to improving the survival of patients with oral cancer. The treatment for patients with poor nutritional status should be more aggressive and cautious.

This study reports the design and synthesis of 2-(phenylsulfonyl)quinoline N-hydroxyacrylamides (8a–k). Structure-activity relationship studies focusing on regio-effect of N-hydroxyacrylamide moiety and influence of the sulfonyl linker revealed that N-hydroxy-3-[3-(quinoline-2-sulfonyl)-phenyl]-acrylamide (8f) showed remarkable enzymatic and cellular activity. The GI50 values of 8f for HL-60, HCT116, PC-3, and A549 cells were found to be 0.29, 0.08, 0.15, and 0.27 μM, respectively. The compounds are therefore more potent than FDA approved PXD-101 and SAHA. They also have an effect on the acetylation degree of histone H3 and α-tubulin. In in vivo studies, 8f showed marked inhibition of the growth of HCT116 xenografts.

This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11-23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 μM, respectively. Compound 23 showed moderate inhibitory activity against tubulin polymerization with an IC50 value of 5.9 μM. In a western blot analysis, 23 caused induction of HSP70 and degradation of Akt, revealing that it possesses HSP90 inhibitory activity.

A high efficient power structure, Hyper AMOLED, for wearable OLED display is developed which includes low driving voltages of pixel circuit and OLED device. The battery life of wearable devices can be significantly extended based on the new power structure.

Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.

We investigated if brain-derived neurotrophic factor (BDNF) accumulation after glucose intake could predict cardiovascular outcomes. We enrolled patients admitted for angiography due to angina. After their conditions stabilized, serum BDNF levels were detected at 0, 30, and 120 min during oral glucose tolerance test (OGTT). Area under the curve (AUC) of BDNF was calculated. The first occurrence of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality served as the primary composite endpoint. Of 480 enrolled patients, 428 completed the follow-up, and 36 primary endpoint events occurred during a median follow-up of 4.4 years. The area under the receiver operating characteristic curve significantly increased from 0.61 (95% confidence interval (CI): 0.52–0.73) for the Framingham risk score (FRS) alone model to 0.72 (95%CI: 0.63–0.81) for the AUC of BDNF plus FRS model (p = 0.016) for predicting the primary endpoint, but not to 0.65 (95%CI: 0.55–0.75) for the fasting BDNF plus FRS model (p = 0.160). Grouped by median AUC of BDNF of 38.0 (ng/mL) × h, the low BDNF group had a significantly higher risk of the endpoint than the high BDNF group (hazard ratio = 3.410, 95%CI: 1.520–7.653, p = 0.003). In conclusion, AUC of BDNF during OGTT could be superior to fasting BDNF for predicting a low cardiovascular risk.

This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.

Escin (β-escin) is used as traditional folk medicine. The anti-tumour effects of escin have been demonstrated in vitro in certain cell lines, but its effect on bladder cancer has not been well investigated. In this study, the apoptotic activity of escin dissolved in dimethyl sulfoxide (DMSO) in bladder cancer cells and normal peripheral blood mononuclear cells (PBMC) and SV-HUC1 cells (controls) was determined. Cell cytotoxicity was assessed using the MTT assay. Cell cycle, Reactive oxygen species (ROS) generation, annexin V-FITC staining (for detecting early apoptosis), and changes in mitochondrial membrane potential were evaluated using flow cytometry. Expression of apoptosis-related proteins such as Fas (CD95) death receptor/FADD (Fas-associated protein with death domain) and BCL2 family of proteins was assessed using immunoblotting. Escin dose-dependently inhibited the growth of human bladder cancer cells, and showed IC50 of ~40 μM. The cell population in the sub-G1 phase, annexin-V staining, Fas expression, ratio of BAX/BCL2, cleavage of activated caspase-3/-8/-9, increase in poly (ADP-ribose) polymerase (PARP) levels, and suppression of nuclear factor kappa B (NF-κB) were observed after 24 h of escin treatment. Escin decreased mitochondrial membrane potential and increased cytochrome C release via generation of reactive oxygen species, which led to apoptosis of bladder cancer cells. Furthermore, escin effectively inhibited bladder tumour growth in a xenograft mouse model. Together, these results demonstrate that escin induces apoptosis in human bladder cancer cells through the Fas death receptor and mitochondrial pathways and inhibits bladder tumour growth. Escin is a potential chemotherapeutic agent for bladder cancer.

To investigate the effects of statins on all-cause mortality risk at different low-density lipoprotein cholesterol (LDL-C) levels, and to compare the mortality risk between statin users and non-users with identical LDL-C levels in a type 2 diabetes cohort.In total, 10,582 outpatients aged ≥18 years with type 2 diabetes mellitus (T2DM) between 2009 and 2012 were enrolled in this retrospective cohort study in central Taiwan. All-cause mortality events were followed up until the end of 2014. According to the medical records during the follow-up period, the patients were classified into statin (+) and statin (-) groups. Patients were categorized into different LDL-C segments based on their mean LDL-C levels during the 2.8-year follow-up.Non-cardiovascular mortality accounted for more than half the deaths. Overall, statin therapy significantly reduced the all-cause mortality risk in both univariable and multivariable models (hazard ratios = 0.39 and 0.38, respectively). Sub-group analyses showed that the lowest mortality risk occurred in the 80-89 mg/dL segment in the statin (-) group and in the 90-99 mg/dL segment in the statin (+) group. Statin therapy significantly reduced the mortality risk at all LDL-C levels except for low LDL-C (60 mg/dL).In addition to reducing LDL-C levels, statin therapy reduced all-cause mortality risk in Taiwanese patients with T2DM. Statins further reduced the mortality risk at most LDL levels. However, at low LDL-C levels, the positive effects of statins may have been nullified.

A specifically designed reference electrode was developed for analyzing the electrochemical behaviors of alloy materials in supercritical water (SCW) environments and identifying the associated electrochemical parameters. The internal Zr/ZrO2 reference electrodes constructed for high-temperature conditions were manufactured and adopted to measure the electrochemical corrosion potential (ECP) of the sample in SCW environments. Before the electrochemical analysis, the oxidation behaviour of zirconium would be investigated in SCW environment. The mass gain of zirconium is assumed due to formation of ZrO2 and there was only 78% of the original thickness of zirconium existed after the 1300 h immersion test in SCW environments with 8.3 ppm dissolved oxygen. In deaerated SCW environments, the thickness of zirconium is about 88% of the original one. The outcome indicated that the laboratory-made Zr/ZrO2 reference electrode was able to continuously operate for several months and delivered consistent and steady ECP data of the sample in SCW environments.

Background: The oral glucose tolerance test (OGTT) is recommended to screen for diabetes in patients with coronary artery disease. We hypothesized that testing for glycated hemoglobin (HbA1c), in addition to the OGTT, in screening for abnormal glucose regulation may help to reveal patients with β-cell function impairment. Methods: Patients with no history of diabetes who were admitted for coronary angiography were recruited to undergo an OGTT and HbA1c test 2–4 weeks after hospital discharge. β-cell function and insulin resistance were assessed using the homeostasis model assessment (HOMA-β and HOMA-IR, respectively). For patients with normal glucose tolerance (NGT) based on the OGTT, we compared HOMA-β between two subgroups of patients using an HbA1c cutoff of 39 mmol/mol or 42 mmol/mol. For patients with prediabetes based on an OGTT, we compared the HOMA-β between two subgroups of patients using an HbA1c cutoff of 48 mmol/mol. Results: A total of 1044 patients were analyzed. In patients with NGT by OGTT (n=432), those with an HbA1c ≥42 mmol/mol had a lower HOMA-β compared to those with an HbA1c 1c ≥48 mmol/mol had a lower HOMA-β compared to those with an HbA1c Conclusions: The use of HbA1c in addition to the OGTT in screening for abnormal glucose regulation helped to reveal patients with early β-cell function impairment.

This study investigated the clinical effectiveness of intervention with an open-mouth exercise device designed to facilitate maximal interincisal opening (MIO) and improve quality of life in patients with head and neck (H&N) cancer and oral submucous fibrosis (OSF). Sixty patients with H&N cancer, OSF, and trismus (MIO

Background There is a high hospitalization rate for diabetic patients. Since retinopathy and albuminuria are both important manifestations of microvascular disease in diabetes, our aim was to investigate the effect of retinopathy and albuminuria on long-term mortality in type 2 diabetic inpatients through this observational cohort study. Methods Type 2 diabetic inpatients given a primary diagnosis of poor glucose control were consecutively enrolled during their hospitalization periods. Clinical information was collected through review of each patient’s medical records, and mortality data were obtained from the national registry in Taiwan. Results A total of 761 type 2 diabetic inpatients were enrolled in the study with a median follow-up period of 6.6 years (interquartile range, 4.0–9.6 years). Patients in the Albuminuria(−)/Retinopathy(+), Albuminuria(+)/Retinopathy(−) and Albuminuria(+)/Retinopathy(+) groups had significantly higher risks of all-cause mortality and cardiovascular mortality than those in the Albuminuria(−)/Retinopathy(−) group. However, among patients with albuminuria, there was no significant difference in cumulative mortality between those with and without retinopathy (P = 0.821). A decrease in the estimated glomerular filtration rate (eGFR), but not retinopathy, was an independent predictor of all-cause mortality (95% CI 0.647‒0.893; P

// Li-Ting Wang 1 , Jing-Ping Liou 2 , Yu-Hsuan Li 2 , Yi-Min Liu 2 , Shiow-Lin Pan 3,* and Che-Ming Teng 1,* 1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan 3 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan * These authors contributed equally to this work Correspondence: Shiow-Lin Pan, email: // Che-Ming Teng, email: // Keywords : MPT0G030, PKCδ, E-cadherin, HDAC, differentiation Received : May 16, 2014 Accepted : June 30, 2014 Published : July 1, 2014 Abstract Accumulation of genetic and epigenetic changes contributes to cancer development and progression. Compared with gene mutations or deletions, epigenetic changes are reversible, which alter the chromatin structure remodeling instead of changes in DNA sequence, and therefore become a promising strategy for chemotherapy. Histone deacetylases (HDACs) are a class of enzymes that responsible for the epigenetic regulation of gene expression. MPT0G030 is a potent and selective class I HDAC inhibitor which showed broad-spectrum cytotoxicity against various human cancer cell lines. in vitro fluorometric HDAC activity assay showed that MPT0G030 effectively inhibited Class I HDACs (HDAC1~3), which were overexpressed in many malignant neoplasms. Interestingly, MPT0G030 not only induced histone acetylation and tumor suppressor p21 transcription, but also redistributed E-cadherin and activated Protein Kinase C δ (PKCδ), which was linked to cell apoptosis and differentiation. Further, activation of PKCδ was demonstrated to be modulated through HDAC1. The in vivo anticancer activity of MPT0G030 and the importance of PKCδ were confirmed in the HT-29 tumor xenograft models. Taken together, those results indicate that MPT0G030, a class I HDAC inhibitor, has great potential as a new drug candidate for cancer therapy.

A series of 3-aroylindole hydroxamic acids (10–17) were developed based on the concept of a structural combination of tubulin and histone deacetylase (HDAC) inhibitors. This was accomplished by introducing hydroxamic acid-containing moieties at the N1 position of the tubulin assembly inhibitor, compound 9 (SCB01A, BPR0L075, phase II trial). Most of synthetic compounds produced in this way displayed comparable HDAC inhibitory activity, and four (10, 12–14) of them also inhibit tubulin assembly. Notably, compound 12 possesses not only tubulin and HDAC inhibitory activity but also shows HDAC6 selectivity over other HDAC isoforms. In addition, it exhibits remarkable inhibitory activity against the growth cancer cells in vitro and in vivo (PC3 and RPMI-8226 cells). Notably, it suppresses the growth of multiple myeloma xenografts without leading to the death of teated animals like reference compound. In sum, this study provided potential compounds with safer profiles for cancer treatment.

ObjectiveNormoalbuminuric chronic kidney disease (NA-CKD) is recognised as a distinct phenotype of diabetic kidney disease, but the role of diabetic retinopathy (DR) in predicting long-term mortality among these patients remains unclear. Here, we aimed to investigate the effects of DR and CKD on mortality in type 2 diabetic patients with normoalbuminuria.DesignWe conducted this study as a retrospective cohort study.SettingWe collected clinical information from the medical records of a public medical centre in central Taiwan.ParticipantsPatients with type 2 diabetes (n=665) who were hospitalised due to poor glucose control were consecutively enrolled and followed for a median of 6.7 years (IQR 4.1‒9.6 years). Patients with either urinary protein excretion >150 mg/day or urine albumin excretion >30 mg/day were excluded.Primary outcome measureAll-cause mortality served as the primary follow-up outcome, and the mortality data were obtained from the national registry in Taiwan.ResultsThe patients with CKD and DR showed the highest mortality rate (log-rank pConclusionsDR is an independent predictor for all-cause and cardiovascular mortality in type 2 diabetic inpatients with normoalbuminuria. Moreover, DR with CKD shows the highest risks of all-cause and cardiovascular mortality among these patients. Funduscopy screening can provide additive information on mortality in patients with type 2 diabetes, even among those with NA-CKD.

This paper presents an amplitude-shift-keying (ASK) demodulator for RF identification tags, which can be embedded on panel displays. The ASK demodulator was implemented in 3-mum low-temperature polycrystalline silicon (LTPS) thin-film transistor (TFT) technology. Since the threshold voltages of LTPS TFTs are higher than CMOS transistors, the conventional demodulator implementation will degrade the demodulator sensitivity significantly. The novel full-wave demodulator circuit was proposed to resolve the issue of high threshold voltage and reduce the ripples of the demodulated envelope. Operated at 8 V, the demodulator consumes 1.6 mW of power. The input carrier frequency was tested up to 13.56 MHz, and the highest ASK modulated data rate is 100 kb/s. The circuit size of the LTPS TFT demodulator is 500 mum times 450 mum.