Determinants of early chronic kidney disease in patients with recently diagnosed type 2 diabetes mellitus: a retrospective study from the Taiwan Diabetes Registry.

BACKGROUND: We tried to identify the risk factor associate with early chronic kidney disease (CKD) in recently diagnosed type 2 diabetes mellitus patients by utilizing real-world data from Taiwan Diabetes Registry. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus recently diagnosed within 1 year. We divided the study participants into control group and early CKD group. Early CKD was defined as either CKD stage G1 with albuminuria, CKD stage G2 with albuminuria, or CKD stage G3a regardless of albuminuria (Urine-albumin to creatinine ratio (UACR) ≥ 3 mg/mmol). Control group was defined as CKD G1 or CKD G2 without albuminuria. Logistic regression analyses were used to compare differences in clinical characteristics between the subgroups. Linear regression models were employed to examine the factors predicting estimated glomerular filtration rate (eGFR) and UACR. RESULTS: Total 2217 patients with recently diagnosed type 2 diabetes mellitus were included. 1545 patients were assigned to control group and 618 patients were assigned to the early CKD group. Age (odds ratio (OR) 1.215, 95% confidence interval [CI] 1.122-1.316), systolic blood pressure (OR 1.203, 95% CI 1.117-1.296), glycated hemoglobin (OR 1.074, 95% CI 1.023-1.129) and triglyceride (OR 2.18, 95% CI 1.485-3.199) were found to be significant risk factors. Further, presence of bidirectional association between UACR and eGFR was found. CONCLUSIONS: We reported factors associated with early CKD in recently diagnosed type 2 diabetes mellitus patients. Variables that associated with eGFR and UACR were identified respectively, included a mutual influence between UACR and eGFR.

Deep sea minerals ameliorate diabetic-induced inflammation via inhibition of TNFα signaling pathways.

It has been well-documented that the consumption of deep sea water (DSW) has beneficial effects on myocardial hypertrophy and cardiac apoptosis induced by hypercholesterolemia. However, the molecular mechanisms for the anti-inflammatory effects of DSW on diabetic cardiomyopathy are still largely unclear. The main purpose of this present study was to test the hypothesis that DSW exerts anti-inflammatory effects through the suppression of the TNF-α-mediated signaling pathways. IP injection of streptozotocin (STZ) at the dose of 65 mg/kg was used to establish a diabetes rat model. DSW mineral extracts that diluted in desalinated water were prepared in three different dosages and administered to the rats through gavages for 4 weeks. These dosages are DSW-1X (equivalent to 37 mg Mg2+ /kg/day), 2X (equivalent to 74 mg Mg2+ /kg/day) and 3X (equivalent to 111 mg Mg2+ mg/kg/day). Immunofluorescence staining and Western blot showed that the protein expression level of TNF-α was markedly higher in the STZ-induced diabetic rat hearts than in the control group. Consequently, the phosphorylation levels of the TNF-α-modulated downstream signaling molecules and P38 mitogen-activated protein kinases (MAPKs) were notably elevated in heart tissues of STZ-induced diabetes. These higher phosphorylation levels subsequently upregulated NF-κB-modulated inflammatory mediators, such as cyclooxygenase (COX)-II and inducible nitric oxide synthase (iNOS). However, treatment with DSW as well as MgSO4 , the main mineral in DSW, significantly reversed all the alterations. These findings suggest that DSW has potential as a therapeutic agent for preventing diabetes-related cardiovascular diseases.

Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment.

Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine; we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells.

Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study.

AIMS/HYPOTHESIS: The effect of pioglitazone was compared with that of other second-line glucose-lowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metformin-based dual therapy. METHODS: A total of 204,323 individuals with type 2 diabetes aged ≥18 years who were stable metformin users and dementia-free before the initiation of second-line glucose-lowering medication were identified in the period 2000-2011 from Taiwan's National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged ≥65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose-lowering treatment groups. RESULTS: Individuals aged ≥65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged ≥18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucose-lowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone. CONCLUSIONS/INTERPRETATION: Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes.

In Vitro Antitumor Activity of Aloperine on Human Thyroid Cancer Cells through Caspase-Dependent Apoptosis.

The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with aloperine treatment. This study suggests the potential therapeutic use of aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers.

Honokiol, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells.

Thyroid cancer is the most common endocrine malignancy, the global incidence rate of which is rapidly rising. Surgery and radioiodine therapies are common and effective treatments only for nonmetastasized primary tumors. Therefore, effective treatment modalities are imperative for patients with radioiodine-resistant thyroid cancer. Honokiol, a biophenolic compound derived from Magnolia spp., has been shown have diverse biological and pharmacological activities, including anti-inflammatory, antioxidative, antiangiogenic, and anticancer properties. In the present study, three human thyroid cancer cell lines, namely anaplastic, follicular, and poorly differentiated thyroid cancer cells, were used to evaluate the chemotherapeutic activity of honokiol. Cell viability, cell cycle, apoptosis, and autophagy induction were determined through flow cytometry and western blot analysis. We found that honokiol treatment can suppress cell growth, induce cell cycle arrest, and enhance the induction of caspase-dependent apoptosis and autophagy in cancer cells. Moreover, honokiol treatment modulated signaling pathways including Akt/mTOR, ERK, JNK, and p38 in the studied cells. In addition, the antitumorigenic activity of honokiol was also confirmed in vitro and in vivo. Our data provide evidence that honokiol has a unique application in chemotherapy for human thyroid cancers.

Piperlongumine Suppresses Proliferation of Human Oral Squamous Cell Carcinoma through Cell Cycle Arrest, Apoptosis and Senescence.

Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells. Moreover, PL-mediated anti-human OSCC behavior was inhibited by an ROS scavenger N-acetyl-l-cysteine (NAC) treatment, suggesting that regulation of ROS was involved in the mechanism of the anticancer activity of PL. These findings suggest that PL suppresses tumor growth by regulating the cell cycle and inducing apoptosis and senescence and is a potential chemotherapy agent for human OSCC cells.

Impacts of elevated glycaemic haemoglobin and disease duration on the sensorimotor control of hands in diabetes patients.

BACKGROUND: To understand the impacts of disease chronicity and hyperglycaemia on sensorimotor control of hands of diabetic patients, this study investigated the differences in hand sensation, strength and motor control by applying the pinch-holding-up activity test for patients with diabetes mellitus (DM) with different levels of glycaemic control and disease chronicity. METHODS: One hundred and fifty-nine patients with clinically defined DM were included. Semmes-Weinstein monofilament, static two-point discrimination and moving two-point discrimination, maximal pinch strength precision pinch performance tests and nerve conduction studies (NCS) of the subjects were carried out. Forty-seven (29.6%) patients were in the HbA(1c) < 7% category, and 112 (70.4%) patients were in the >7% group. There were 87 (54.7%) patients with the disease duration <10 years, and 72 (45.3%) patients with disease duration ≧10 years. RESULTS: The severity of hyperglycaemia significantly impacts the results for Semmes-Weinstein monofilament, precision pinch force control, sensory and motor NCS tests (p < 0.05). In addition, the chronicity of disease influences the motor control of precision pinch performance and the amplitude of motor NCS (p < 0.05) for the diabetes patients. CONCLUSIONS: The evidence suggests that disease chronicity and hyperglycaemia have impacts on sensorimotor control in the hands of DM patients. In addition, the efficiency of prehensile forces of hand-to-object interactions in the pinch-holding-up activity test could be significant for identifying hand function, as well as pathologic changes in median nerve function, for patients with DM.

The associations among hand dexterity, functional performance, and quality of life in diabetic patients with neuropathic hand from objective- and patient-perceived measurements.

PURPOSE: To comprehend the associations among the dexterity and functional performance of the hands and quality of life in diabetic patients with neuropathic hands, via objective- and patient-perceived measurements. METHODS: The study participants were 144 diabetes patients who received objective evaluations, including the Purdue pegboard test, electrophysiological testing in sensory amplitude of the median nerve, and self-administrated measurements, including the Michigan Hand Outcomes Questionnaire (MHQ) and Diabetes-39 (D-39). Pearson's and Spearman's correlation tests were conducted to assess the relationships among hand neuropathy, hand dexterity and functions, and quality of life. RESULTS: The results show that the amplitude of the sensory nerve action potential of the median nerve was positively correlated with hand dexterity (r = 0.28-0.43; p < 0.01) and the total score of MHQ (r = 0.24-0.33; p < 0.01). Objective hand dexterity had mild to moderate relationships with most of the MHQ results, but only weak associations with some dimensions of the D-39 results. The MHQ results were negatively correlated with the D-39 scores, with mild to moderate relationships in the domains of energy/mobility and anxiety. CONCLUSIONS: In comparison with diabetic feet, neuropathic diabetic hands are an easily neglected problem, with insufficient empirical evidence in the literature to indicate its impact on functional performance and quality of life. This study showed that lesions related to neural functioning in the diabetic hand may negatively influence dexterity and functional hand performance and thus also affect the quality of life.

Association of TLR7 and TSHR copy number variation with Graves' disease and Graves' ophthalmopathy in Chinese population in Taiwan.

BACKGROUND: Graves' disease (GD) and Graves' ophthalmopathy (GO) are autoimmune disorders, which might be influenced by genetic factors. Copy number variation (CNV) is an important source of genomic diversity in humans, and influences disease susceptibility. This study investigated the association between CNV in the TSHR and TLR7 genes and the development of GD and GO in a Chinese population in Taiwan. METHODS: For this case-control study, sample from 196 healthy controls and 484 GD patients, including 203 patients with GO were studied. CNV was detected by real-time polymerase chain reaction (PCR) using TaqMan™ probes and the relative copy number (CN) was estimated by using the comparative Ct method. RESULTS: The differences in the distribution of TSHR CNV in healthy controls and GD patients were statistically significant (p value = 0.01). However, the difference in the distribution of TSHR CNV in the control group and the GO group was not statistically significant (p value = 0.06). For TLR7 CNV, the results were not significantly different when we compared the distribution in healthy controls and GD patients and in healthy controls and GO patients (p values for Fisher's exact test were 0.13 and 0.09, respectively). However, a lower than normal CNV for TLR7 (CNV < 2 for female and CNV < 1 for male) was found to have a protective effect against the development of GD (odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.07-0.75) after adjusting for age and gender. CONCLUSIONS: These results suggested that TSHR and TLR7 CNV might be associated with susceptibility to GD.

Proteomic analysis of retinopathy-related plasma biomarkers in diabetic patients.

Diabetic retinopathy occurs in approximately 25% of patients with type 1 or type 2 diabetes; the disease can cause poor vision and even blindness because high glucose levels weaken retinal capillaries, causing leakage of blood into surrounding areas. We adopted a proteomics-based approach using 2D-DIGE and MALDI-TOF/TOF MS to compare the differential plasma proteome between diabetic retinopathy with significant retinopathy occurrence within 5years after diagnosis of diabetes, and diabetic non-retinopathy without diagnosed retinopathy for more than 10years after diagnosis of diabetes. We identified 77 plasma proteins, which represent 28 unique gene products. These proteins mainly have inflammatory response and coagulation roles. Our approach identified several potential diabetic retinopathy biomarkers including afamin and the protein arginine N-methyltransferase 5, which may be associated with the progression and development of diabetes. In conclusion, we report a comprehensive patient-based plasma proteomic approach to the identification of potential plasma biomarkers for diabetic retinopathy screening and detection.

A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese.

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54x10(-10); odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36-1.82), and serine racemase (SRR) (P = 3.06x10(-9); OR = 1.28; 95% CI = 1.18-1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65x10(-10); OR = 1.29, 95% CI = 1.19-1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.

Safety and efficacy of twice-daily exenatide in Taiwanese patients with inadequately controlled type 2 diabetes mellitus.

BACKGROUND/PURPOSE: Exenatide has been predominantly studied in non-Asian populations. The purpose of this study was to investigate the safety and efficacy of twice-daily (BID) exenatide versus placebo in a subpopulation of Taiwanese patients from a larger study on Asian patients. METHODS: Patients unable to achieve glycemic control with metformin alone or metformin in combination with sulfonylurea were randomly assigned to self-administer either 5 µg exenatide or placebo BID for 4 weeks, then 10 µg exenatide or placebo BID for an additional 12 weeks, in addition to their regular oral therapy. RESULTS: Fifty patients from Taiwan were enrolled in this study (54.0% male; age: 50.9 ± 9.4 years; weight: 71.0 ± 11.6 kg; 8.1 ± 1.0% hemoglobin A1c (HbA1c)). The exenatide-treated patients demonstrated a statistically significant greater reduction in HbA1c from baseline to the endpoint (least-squares [LS] mean [95% confidence interval (CI)]: -0.8% [-1.4 - -0.2]; p = 0.009) compared with patients who received placebo (LS mean [95% CI]: -0.1% [-0.7-0.4]) with an LS mean [95% CI] between-group difference of -0.7% (-1.3 - -0.1) (p = 0.025). A statistically significant higher number of exenatide-treated patients achieved HbA1c targets of ≤ 7% (p = 0.020) and ≤ 6.5% (p = 0.021) by the endpoint compared with patients who received placebo. Exenatide-treated patients experienced a statistically significant reduction in weight from baseline to endpoint (exenatide-placebo adjusted mean difference [95% CI]: -1.6 kg [-2.7 - -0.6]; p = 0.004) compared with the placebo group. The symptomatic hypoglycemia rate (mean patient/year ± standard deviation) was higher in exenatide-treated patients (4.86 mean patient/year ± 7.36) than placebo-treated patients (0.27 mean patient/year ± 1.32). Thirteen (50.0%) exenatide-treated patients and nine (37.5%) placebo-treated patients reported one or more treatment-emergent adverse events; nausea was the most frequently reported side effect (exenatide, 4 [15.4%]; placebo, 0 [0.0%]). CONCLUSION: This subgroup analysis of Taiwanese patients was consistent with the overall study results, which showed that exenatide BID is superior to placebo for improving glycemic control in Asian patients with type 2 diabetes who experienced inadequate glycemic control when using oral antidiabetic therapy.

A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes.

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (- 0.2% [95% CI - 0.4% to - 0.1%]) and from 8.1% to 7.8% in the placebo group (- 0.3% [95% CI - 0.5% to - 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.

Reversine, a 2,6-disubstituted purine, as an anti-cancer agent in differentiated and undifferentiated thyroid cancer cells.

PURPOSE: A novel and effective treatment is urgently needed to deal with the current treatment dilemma in incurable differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC). Reversine, a small synthetic purine analogue (2,6-disubstituted purine), has been shown to be effective in tumor suppression. METHODS: We performed in vitro evaluation of anti-tumor effects of reversine on proliferation, cell cycle, and apoptosis in human PDTC, ATC, and follicular thyroid cancer cell lines, respectively. RESULTS: Treatment of these three lines with reversine inhibited proliferation in a time- and dose-dependent manner. G2/M accumulation was demonstrated in cell cycle analysis. Reversine induced apoptosis in PDTC cells with caspase-3 and caspase-8 activation, but not caspase-9. Use of a pan-caspase inhibitor before treatment with reversine attenuated cell death. Reversine also showed in vivo growth inhibitory effects on ATC cells in a xenograft nude mice model. CONCLUSIONS: Data demonstrated that reversine is effective in inhibiting the growth of thyroid cancer cells by cell cycle arrest or apoptosis, especially with the more aggressive ATC and PDTC. Apoptosis was induced by the mitochondria-independent pathway. Reversine is therefore worthy of further investigation in clinical therapeutics.

Effect of 1PC111, a Fixed-dose Combination of Pitavastatin and Ezetimibe, Versus Pitavastatin or Ezetimibe Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia or Mixed Dyslipidemia: A Randomized, Double-blind, Multicenter, Phase III Study.

PURPOSE: This study aimed to show that the efficacy of 1PC111 is superior to that of either ezetimibe or pitavastatin alone (monotherapy) for the treatment of hypercholesterolemia. METHODS: This was a multicenter, randomized, double-blind, Phase III study. Patients with hypercholesterolemia or mixed dyslipidemia were randomized to receive 1PC111 (which was a fixed-dose combination of pitavastatin 2 mg and ezetimibe 10 mg), pitavastatin 2 mg, or ezetimibe 10 mg daily for 12 weeks. The primary end point was the difference in the percent change in LDL-C from baseline to week 12 between the 1PC111 and each monotherapy group. The secondary end points were the percent change in other lipid profiles from baseline to each visit. All patients were assessed for adverse events until end of study. FINDINGS: A total of 388 patients were randomly assigned to the 1PC111 (n = 128), pitavastatin (n = 132), or ezetimibe (n = 128) group. Generally, baseline characteristics were similar among the 3 groups. A statistically significant decrease in the LDL-C level at week 12 was observed in the 1PC111 group (-50.50% [14.9%]) compared with either the pitavastatin (-36.11% [11.4%]; P < 0.001) or ezetimibe (-19.85% [12.4%]; P < 0.001) group. Also, there was a statistically significant difference between 1PC111 and each monotherapy group in the reduction in total cholesterol, non-HDL-C, and apolipoprotein B levels. Moreover, there was a trend toward more efficient lowering of LDL-C levels in elderly patients (age ≥65 years) than in younger patients (age <65 years) by 1PC111 treatment. In patients given a class I recommendation for atherosclerotic cardiovascular disease prevention, the percentage of patients achieving the LDL-C target of <100 mg/dL at week 12 was significantly higher in the 1PC111 group than in both monotherapy groups (P < 0.001). Overall, the incidence of adverse events was similar among 3 groups. IMPLICATIONS: 1PC111 was more effective in improving lipid profiles and achieving the LDL-C goal than pitavastatin or ezetimibe alone for hypercholesterolemia treatment. Furthermore, 1PC111 may provide more benefit in treating elderly patients. CLINICALTRIALS: gov identifier: NCT04643093.

Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

The Effects of Bariatric Surgery on Renal, Neurological, and Ophthalmic Complications in Patients with Type 2 Diabetes: the Taiwan Diabesity Study.

BACKGROUND: Bariatric surgery has been shown to improve glycemic control in patients with type 2 diabetes. However, less is known whether it can also reduce diabetic renal, neurological, and ophthalmic complications. METHODS: This prospective multicenter cohort study compared renal, ophthalmic, and neurological complications between 49 patients with obesity/overweight receiving bariatric surgery and 338 patients receiving standard medical treatment after follow-up for 2 years. Patients received neurological examinations including toe tuning fork vibration test, ankle tendon reflex test, 10-g monofilament test, and ophthalmic examinations including visual acuity measurement and fundus examinations. Multiple regressions, propensity score weighting, and matching were employed to adjust for baseline differences. RESULTS: After 2 years of follow-up, patients with type 2 diabetes receiving bariatric surgery had greater reduction in BMI, HbA1c, and urine albumin-creatinine ratio, greater improvement in estimated glomerular filtration rate, and greater increase in tuning fork test score of right and left toes compared with the medical group. However, there is no improvement in 10 g-monofilament test, visual acuity, diabetic non-proliferative retinopathy, and proliferative retinopathy. Similar results were obtained using multiple regression adjustment, propensity-score weighting, or comparing age-, sex-, and BMI-matched subjects. CONCLUSIONS: After 2-year follow-up, patients with obesity/overweight and type 2 diabetes receiving bariatric surgery have increased glomerular filtration rate, reduced albuminuria, and improved tuning folk vibration sensation.

The effects of growth inhibitory peptide on follicular thyroid cancer cell growth, migration, and invasion.

AIMS AND BACKGROUND: Thyroid cancer is the most common endocrine neoplasm worldwide. Although differentiated thyroid cancers are associated with a favorable survival, the prognosis worsens dramatically for patients with distant metastasis. Metastases from follicular thyroid carcinoma (FTC) occur earlier and are more aggressive than those from papillary thyroid carcinoma. For FTC that is resistant to radioactive iodine, new treatments are urgently needed. Human alpha-fetoprotein (HAFP) is a tumor-associated fetal protein that has been demonstrated to regulate tumorigenesis. Growth inhibitory peptide (GIP), a synthetic 34-mer peptide isolated from the third domain of HAFP, has been shown to have antitumor growth ability in various human cancers. However, the effects of GIP in FTC have not yet been studied. The aim of this study was to investigate the antitumor ability of GIP in FTC. METHODS AND STUDY DESIGN: Using both PBS and GIP control peptide as a negative control, the antiproliferative activity of GIP in the WRO human FTC cell line was determined using a tetrazolium-based colorimetric assay. In addition, cell migration and invasion assays were used to measure tumor metastasis inhibition effects in vitro. RESULTS: GIP did not inhibit WRO cell proliferation in a time- or dose-dependent manner. However, in WRO cells treated with GIP for 4 days, migration was significantly inhibited at concentrations of 50 and 100 microM (33.3% and 19.5%, respectively; both P <0.05). Cell invasion was also significantly inhibited at 50 and 100 microM (67.1% and 39.0%, respectively; both P<0.05). CONCLUSIONS: Although GIP failed to suppress FTC cell growth, it effectively interrupted both FTC cell migration and invasion abilities in vitro. Further validation in an animal model and elucidation of the underlying mechanisms will be required. GIP may potentially serve as an anti-FTC metastasis agent aiding current chemotherapy regimens.

Diabetes pay-for-performance program can reduce all-cause mortality in patients with newly diagnosed type 2 diabetes mellitus.

This study aimed to examine the effect of a diabetes pay-for-performance (P4P) program on all-cause mortality in patients with newly diagnosed type 2 diabetes mellitus. Using a Taiwanese representative nationwide cohort, we recruited 5478 patients with newly diagnosed type 2 diabetes enrolled in the P4P program within 5 years after a diagnosis of diabetes between January 1, 2002 and December 31, 2010 and individuals not enrolled in the P4P program were recruited as the control group matched 1:1 with the study group. We used multivariate Cox proportional hazard models analysis to investigate the effect of the P4P program and adherence on all-cause mortality. A total of 250 patients died in the P4P group compared to 395 in the control group (mortality rate 104 vs 169 per 10,000 person-years, respectively, P < .0001). The control group also had more comorbidities. Patients enrolled in the P4P program demonstrated significant long-term survival benefits, of which the adjusted hazard ratio (aHR) for all-cause mortality was 0.58 [95% CI (0.48-0.69)]. In the study group, better adherence to the P4P program resulted in a greater reduction in mortality, with aHRs [95% CI] of 0.48 [0.38-0.62] and 0.36 [0.26-0.49] in subjects with a minimum 1-year and 2-year good P4P adherence, respectively. Participating in the P4P program within 5 years after the diagnosis of diabetes resulted in a significant reduction in all-cause mortality, and this effect was particularly pronounced in the patients with better adherence to the P4P program.