Evaluation of PSMA target diagnostic PET tracers for therapeutic monitoring of [177Lu]ludotadipep of prostate cancer: Screening of PSMA target efficiency and biodistribution using [18F]DCFPyL and [68Ga]PSMA-11.

We have compared the similarity of the in vivo distribution of the prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agents [18F]DCFPyL, [68Ga]galdotadipep, and [68Ga]PSMA-11. This study is designed for a further selection of a PSMA-targeted PET imaging agent for the therapeutic evaluation of [177Lu]ludotadipep, our previously developed prostate-specific membrane antigen (PSMA)-targeted prostate cancer therapeutic radiopharmaceutical. In vitro cell uptake was performed to evaluate the affinity to PSMA using PSMA + PC3-PIP, and PSMA- PC3-flu was used for the study. MicroPET/CT 60 min dynamic imaging and biodistribution were performed at 1, 2, and 4 h after injection. Autoradiography and immunohistochemistry were performed to evaluate the PSMA + tumor target efficiency. In the microPET/CT image, [68Ga]PSMA-11 showed the highest uptake in the kidney among all three compounds. [18F]DCFPyL and [68Ga]PSMA-11 showed similar patterns of in vivo biodistribution and high tumor targeting efficiency, similar to those of[68Ga]galdotadipep. All three agents showed high uptake in tumor tissue on autoradiography, and PSMA expression was confirmed by immunohistochemistry. Thus, [18F]DCFPyL or [68Ga]PSMA-11 can be used as a PET imaging agent to monitor [177Lu]ludotadipep therapy in prostate cancer patients.

DGG-300273, a novel WNT/ß-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/ß-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/ß-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/ß-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat.

BACKGROUND: Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis. METHODS: We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens. RESULTS: Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study. CONCLUSIONS: In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.

Associations between obesity, weight change and decreased renal function in Korean type 2 diabetic patients: a longitudinal follow-up study.

BACKGROUND: We aimed to examine the associations between the risk of decreased renal function, obesity, and weight changes in Korean type 2 diabetic patients with normal renal function. METHODS: Type 2 diabetic patients (n = 1060) who visited the diabetic clinic at Soonchunhyang University Bucheon Hospital between 2001 and 2007 with follow up surveys completed in 2016 to 2017 were recruited into the study. Decreased renal function was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2. Weight change was calculated between baseline and each follow-up survey. Multivariate analysis was used to evaluate the longitudinal association of baseline obesity and weight changes with the risk of decreased renal function. RESULTS: This study revealed that baseline obesity was associated with the risk of decreased renal function after adjusting for clinical variables in type 2 diabetic patients (odds ratio [OR] 1.40; 95% confidence intervals [CI] 1.08-2.04; p = 0.025). Follow-up (mean = 12 years) revealed that weight gain > 10% was associated with the risk of decreased renal function after adjusting for clinical variables in type 2 diabetic patients with normal renal function at baseline (OR 1.43; CI 1.11-2.00; p = 0.016). Weight loss was not associated with the risk of decreased renal function in type 2 diabetic patients with normal renal function at baseline. CONCLUSIONS: Baseline obesity was associated with the increased risk of decreased renal function in Korean type 2 diabetic patients with normal renal function. Weight gain > 10% independently predicted the risk of decreased renal function. Large prospective studies are needed to clarify causal associations between obesity, weight change, and decreased renal function in patients with type 2 diabetes.

Association between alcohol consumption status and obesity-related comorbidities in men: data from the 2016 Korean community health survey.

BACKGROUND: This study was performed to investigate the association between the amount of alcohol consumption or binge drinking and obesity-related comorbidities in Korean men. METHODS: A total of 103,048 men aged 19 years or older were investigated in the 2016 Korean Community Health Survey. The participants were divided into five groups according to the standard number of alcoholic drinks consumed per week. RESULTS: Of the total participants, 20.7% were in the high alcohol consumption group, consuming more than 28 drinks per week. After adjustment for clinical factors, high alcohol consumption was significantly associated with higher odds ratios (ORs) of obesity (OR, 1.449; 95% confidence interval [CI], 1.412 to 1.591; P < 0.0001), hypertension (OR, 1.76; 95% CI, 1.636 to 1.894; P < 0.0001), and dyslipidemia (OR, 1.356; 95% CI, 1.247 to 1.474; P < 0.0001). In contrast, mild to moderate alcohol consumption was associated with a lower risk of diabetes (OR, 0.799; 95% CI, 0.726 to 0.88; P = 0.0015) and high alcohol consumption was not associated with a higher risk of diabetes (OR, 0.945; 95% CI, 0.86 to 1.039; P = 0.0662). Among drinkers, except for social drinkers, binge drinking was significantly associated with higher risks of obesity, hypertension, diabetes, and dyslipidemia. CONCLUSIONS: High alcohol consumption was associated with higher risks of obesity, hypertension, and dyslipidemia in Korean men. In contrast, high consumption was not associated with a higher risk of diabetes. In particular, binge drinkers were associated with higher risks of obesity, hypertension, diabetes, and dyslipidemia compared to non-binge drinkers.

Anti-inflammatory and Antioxidant Effects of Selenium on Orbital Fibroblasts of Patients With Graves Ophthalmopathy.

PURPOSE: In the present study, the authors investigated the effects of selenium on inflammation, hyaluronan production, and oxidative stress in primary cultured orbital fibroblasts of patients with Graves ophthalmopathy (GO). METHODS: Orbital adipose/connective tissue specimens were obtained during the course of orbital surgery for patients with GO (n = 7) and other noninflammatory problems (n = 5). After incubation with various concentrations of sodium selenite for 48 hours, supernatants from primary cultures were collected. Hyaluronan and cytokine levels were measured using commercially available enzyme-linked immunosorbent assay kits. To determine the effect of selenium on reactive oxygen species (ROS) production stimulated by H2O2 (100 µM) for 30 minutes, the cells were pretreated with various concentrations of sodium selenite for 60 minutes. RESULTS: Interleukin (IL)-6 and tumor necrosis factor-alpha levels were significantly higher in orbital fibroblasts of patients with GO than in orbital fibroblasts of control patients. Hyaluronan production was suppressed by selenium in cultured orbital fibroblasts of patients with GO. Inflammatory cytokines such as IL-1α, IL-8, and tumor necrosis factor-alpha were suppressed by selenium in cultured orbital fibroblasts of patients with GO. IL-1ß and IL-6 were not suppressed by selenium in cultured orbital fibroblasts of patients with GO. Selenium pretreatment reduced intracellular ROS generation stimulated by H2O2 in cultured orbital fibroblasts of patients with GO. CONCLUSIONS: In conclusion, hyaluronan production, inflammatory cytokines, and intracellular ROS generation were suppressed by selenium in cultured orbital fibroblasts of patients with GO. Several inflammatory cytokines may be suppressed by selenium in cultured orbital fibroblasts of patients with GO. This study provide the basis for use of selenium in the treatment of GO.

Inter- and Intra-Molecular Organocatalysis of SN2 Fluorination by Crown Ether: Kinetics and Quantum Chemical Analysis.

We present the intra- and inter-molecular organocatalysis of SN2 fluorination using CsF by crown ether to estimate the efficacy of the promoter and to elucidate the reaction mechanism. The yields of intramolecular SN2 fluorination of the veratrole substrates are measured to be very small (<1% in 12 h) in the absence of crown ether promoters, whereas the SN2 fluorination of the substrate possessing a crown ether unit proceeds to near completion (~99%) in 12 h. We also studied the efficacy of intermolecular rate acceleration by an independent promoter 18-crown-6 for comparison. We find that the fluorinating yield of a veratrole substrate (leaving group = -OMs) in the presence of 18-crown-6 follows the almost identical kinetic course as that of intramolecular SN2 fluorination, indicating the mechanistic similarity of intra- and inter-molecular organocatalysis of the crown ether for SN2 fluorination. The calculated relative Gibbs free energies of activation for these reactions, in which the crown ether units act as Lewis base promoters for SN2 fluorination, are in excellent agreement with the experimentally measured yields of fluorination. The role of the metal salt CsF is briefly discussed in terms of whether it reacts as a contact ion pair or as a "free" nucleophile F-.

Prognostic value of acoustic structure quantification in patients with Hashimoto's thyroiditis.

OBJECTIVES: Assessment of thyroid parenchymal echogenicity on ultrasonography is a predictor of future thyroid dysfunction. Our objective was to determine the prognostic value of acoustic structure quantification (ASQ) to predict the outcome of patients with Hashimoto's thyroiditis (HT). MATERIALS AND METHODS: We prospectively evaluated 90 patients with HT using ASQ from May to December 2013. Surveillance for the development of overt hypothyroidism was conducted over a median period of 40 months (3-55). ASQ were dichotomized based on optimal cutoff values obtained from ROC curve analysis. The probability of developing overt hypothyroidism was compared between the dichotomized subgroups using Kaplan-Meier analysis and log-rank tests. Multivariate Cox regression analysis was performed to determine significant prognostic factors. RESULTS: The cumulative rate of overt hypothyroidism was 67.7%. The median interval to overt hypothyroidism was 27.9 months (95% confidence interval, 12.0-38.0 months). There was no significant difference in the risk of overt hypothyroidism using qualitative echogenicity between groups (p = 0.669) according to Kaplan-Meier analysis. However, the ASQ average (p < 0.001), standard deviation (p = 0.015), and focal disturbance ratio (p < 0.001) were significantly associated with an increased risk of overt hypothyroidism. Multivariate Cox regression analysis revealed that a higher ASQ average (hazard ratio, 1.03; p = 0.03) and higher thyroid-stimulating hormone level (hazard ratio, 1.02; p = 0.02) were independent predictors of overt hypothyroidism. CONCLUSIONS: ASQ has potential as a prognostic biomarker for predicting the risk of overt hypothyroidism in patients with HT. KEY POINTS: • ASQ provides quantitative prognostic information of thyroid parenchymal echogenicity. • ASQ parameters improved the stratification of patients who are prone to develop overt hypothyroidism in HT. • ASQ can serve as prognostic biomarker in HT.

Preoperative serum thyroglobulin and changes in serum thyroglobulin during TSH suppression independently predict follicular thyroid carcinoma in thyroid nodules with a cytological diagnosis of follicular lesion.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) cannot distinguish a follicular thyroid carcinoma (FTC) from a follicular adenoma in follicular lesions. We designed this study to determine whether the preoperative thyroglobulin (Tg) and change in serum Tg during thyroid-stimulating hormone (TSH) suppression can predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion. METHODS: Among 854 patients who underwent thyroid surgery, the 198 patients who presented with thyroid nodules with a cytological diagnosis of follicular lesion were analyzed. Predictive factors for malignancy were evaluated using multivariate logistic regression models. Subgroup analyses of patients with TSH suppression therapy by levothyroxine were also conducted. RESULTS: Thirty-two patients (16%) had FTC, and 166 patients had confirmed benign nodules. The median preoperative serum Tg levels were significantly higher in patients with FTC compared to those with benign pathology (449 vs. 34 ng/mL, p < 0.001). The serum Tg (odds ratios (OR) 10.311, p < 0.001) and tumor volume (OR 4.500, p = 0.035) were found to be independent predictors for FTC in all patients with a cytological diagnosis of follicular lesion. Forty-eight patients received TSH suppression therapy. When we performed subgroup analyses on the patients with TSH suppression therapy, decrease less than 15% in serum Tg during TSH suppression was found to be an independent predictor of FTC (OR 13.918, p = 0.018). CONCLUSION: Preoperative serum Tg and changes in serum Tg during TSH suppression independently predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion.

Investigation of Acoustic Structure Quantification in the Diagnosis of Thyroiditis.

OBJECTIVE: The objective of this study was to evaluate the ability of acoustic structure quantification (ASQ) to diagnose thyroiditis. MATERIALS AND METHODS: The echogenicity of 439 thyroid lobes, as determined using ASQ, was quantified and analyzed retrospectively. Thyroiditis was categorized into five subgroups. The results were presented in a modified chi-square histogram as the mode, average, ratio, blue mode, and blue average. We determined the cutoff values of ASQ from ROC analysis to detect and differentiate thyroiditis from a normal thyroid gland. We obtained data on the sensitivity and specificity of the cutoff values to distinguish between euthyroid patients with thyroiditis and patients with a normal thyroid gland. RESULTS: The mean ASQ values for patients with thyroiditis were statistically significantly greater than those for patients with a normal thyroid gland (p < 0.001). The AUCs were as follows: 0.93 for the ratio, 0.91 for the average, 0.90 for the blue average, 0.87 for the mode, and 0.87 for the blue mode. For the diagnosis of thyroiditis, the cutoff values were greater than 0.27 for the ratio, greater than 116.7 for the mean, and greater than 130.7 for the blue average. The sensitivities and specificities were as follows: 84.0% and 96.6% for the ratio, 85.3% and 83.0%, for the average, and 79.1% and 93.2% for the blue average, respectively. The ASQ parameters were successful in distinguishing patients with thyroiditis from patients with a normal thyroid gland, with likelihood ratios of 24.7 for the ratio, 5.0 for the average, and 11.6 for the blue average. With the use of the aforementioned cutoff values, the sensitivities and specificities for distinguishing between patients with thyroiditis and euthyroid patients without thyroiditis were 77.05% and 94.92% for the ratio, 85.25% and 82.20% for the average, and 77.05% and 92.37% for the blue average, respectively. CONCLUSION: ASQ can provide objective and quantitative analysis of thyroid echogenicity. ASQ parameters were successful in distinguishing between patients with thyroiditis and individuals without thyroiditis, with likelihood ratios of 24.7 for the ratio, 5.0 for the average, and 11.6 for the blue average.

The relationship between serum adipocytokines and Graves' ophthalmopathy: A hospital-based study.

Adipocytokines are thought to be associated with inflammatory disorders and autoimmune diseases. However, limited information is available on the relationship between serum adipocytokine levels, Graves' disease (GD), and Graves' ophthalmopathy (GO). The present study examined the relationship between serum adipocytokine levels and GD and GO. A total of 80 patients with GD participated in this study. The medical records of patients were reviewed retrospectively. GO activity was assessed using the clinical activity score (CAS). GO severity was assessed by the modified NOSPECS classification and included soft tissue involvement, proptosis, and extraocular muscle involvement. Serum adiponectin, leptin, resistin, and retinol-binding protein 4 (RBP-4) levels were measured using commercially available enzyme-linked immunosorbent assays. The prevalence of GO was 36.3%. Serum adiponectin, leptin, and resistin levels were significantly higher in patients with GO than in those without GO. The CAS was positively correlated with serum adiponectin and leptin levels. The total eye score was positively correlated with serum adiponectin, leptin, resistin, and RBP-4 levels. A multivariate analysis revealed that serum leptin and resistin levels were associated with the presence of GO after adjusting for clinical factors. Free thyroxine was negatively correlated with serum leptin level. These results suggest that adipocytokines, such as leptin and resistin, may play a role in inflammatory and autoimmune processes of GD and GO. Future studies with larger numbers of patients are required to establish relationships between serum adipocytokines levels and GO and ascertain the role of adipocytokines in GD and GO.

Association of serum omentin levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: a hospital-based study.

BACKGROUND: Whereas a few studies have reported associations of serum omentin levels with subclinical atherosclerosis in patients with diabetes, little information is available with respect to the associations of serum omentin levels and diabetic microvascular complications. The aim of this study was to investigate the relationships of serum omentin levels and vascular complications including cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM). METHODS: We recruited 97 patients who evaluated complications of diabetes. CAN was assessed by five standard cardiovascular reflex tests according to Ewing's protocol. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) were evaluated. Serum omentin levels were assessed by ELISA. Atherosclerotic burden was evaluated by measuring the brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI). RESULTS: The prevalence of CAN increased borderline significantly across the omentin tertiles (p = 0.05) and CAN point increased significantly and progressively across the omentin tertiles (p = 0.013). The prevalence of other microvascular complications (DPN, DN, and DR) did not differ among omentin tertiles. The mean levels of baPWV also increased significantly and progressively across the omentin tertiles (p = 0.002). Serum omentin levels were significantly positively correlated with CAN point (p = 0.004) and borderline significantly correlated with baPWV (p = 0.05) after multivariate adjustment. Regarding linear regression analysis for CAN point, univariate regression analysis demonstrated that CAN point associated with omentin, diastolic blood pressure (DBP) and hsCRP. Multiple regression analysis revealed that omentin levels, together DBP and baPWV correlated with CAN point. This present study suggests that serum omentin levels may be independently associate with CAN in patients with T2DM.

The relationship between cognitive performance and insulin resistance in non-diabetic patients with mild cognitive impairment.

OBJECTIVE: Insulin resistance (IR) is a distinct and early feature of type 2 diabetes mellitus and metabolic syndrome. IR is thought to play a vital role in cognitive impairment. We conducted this study to understand the early characteristics of cognitive dysfunctions attributable to IR. METHODS: This study included 85 consecutive non-diabetic elderly participants with mild cognitive impairment (MCI). IR was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR). Cognitive performances were analyzed as a function of scores on the HOMA-IR. RESULTS: The group analysis those with and without IR did not show any differences in the cognitive performance although higher HOMA-IR was closely associated with lower performances in immediate recall on the Seoul Verbal Learning Test (SVLT-I) (r = -0.244, p = 0.026) and Controlled Oral Word Association Test (COWAT) (r = -0.270, p = 0.013). In subgroup analysis by APOE status, SVLT-delayed (p = 0.027) and COWAT (p = 0.016) scores were found to be significantly lower in the IR than the non-IR among those with APOE ε4 allele. In multiple regression analysis, impairment on the COWAT remained significantly correlated with scores on HOMA-IR (ß = -0.271, t = -2.340, p = 0.022). However, IR status was identified to interact with APOE ε4 carriership toward poor performances in the COWAT (ß = -0.335, t = -2.285, p = 0.026). CONCLUSION: This study found a domain-specific impact of HOMA-IR scores on cognitive performances in non-diabetic patients with MCI. This association was profound only in APOE ε4carriers.

Using Acoustic Structure Quantification During B-Mode Sonography for Evaluation of Hashimoto Thyroiditis.

OBJECTIVES: This study aimed to evaluate the usefulness of Acoustic Structure Quantification (ASQ; Toshiba Medical Systems Corporation, Nasushiobara, Japan) values in the diagnosis of Hashimoto thyroiditis using B-mode sonography and to identify a cutoff ASQ level that differentiates Hashimoto thyroiditis from normal thyroid tissue. METHODS: A total of 186 thyroid lobes with Hashimoto thyroiditis and normal thyroid glands underwent sonography with ASQ imaging. The quantitative results were reported in an echo amplitude analysis (Cm(2)) histogram with average, mode, ratio, standard deviation, blue mode, and blue average values. Receiver operating characteristic curve analysis was performed to assess the diagnostic ability of the ASQ values in differentiating Hashimoto thyroiditis from normal thyroid tissue. Intraclass correlation coefficients of the ASQ values were obtained between 2 observers. RESULTS: Of the 186 thyroid lobes, 103 (55%) had Hashimoto thyroiditis, and 83 (45%) were normal. There was a significant difference between the ASQ values of Hashimoto thyroiditis glands and those of normal glands (P < .001). The ASQ values in patients with Hashimoto thyroiditis were significantly greater than those in patients with normal thyroid glands. The areas under the receiver operating characteristic curves for the ratio, blue average, average, blue mode, mode, and standard deviation were: 0.936, 0.902, 0.893, 0.855, 0.846, and 0.842, respectively. The ratio cutoff value of 0.27 offered the best diagnostic performance, with sensitivity of 87.38% and specificity of 95.18%. The intraclass correlation coefficients ranged from 0.86 to 0.94, which indicated substantial agreement between the observers. CONCLUSIONS: Acoustic Structure Quantification is a useful and promising sonographic method for diagnosing Hashimoto thyroiditis. Not only could it be a helpful tool for quantifying thyroid echogenicity, but it also would be useful for diagnosis of Hashimoto thyroiditis.

Contribution of subcutaneous abdominal fat on ultrasonography to carotid atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: Whereas visceral abdominal adipose tissue (VAT) is associated with cardiometabolic risk, there is debate regarding the role of subcutaneous abdominal adipose tissue (SAT). The aim of this study was to investigate the relationships of subcutaneous and visceral abdominal fat with carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 234 patients (men 131, women 103, mean age: 53 years) with T2DM were enrolled. Carotid intima-media thickness (CIMT), abdominal subcutaneous fat thickness (SFT) and visceral fat thickness (VFT) were assessed by high-resolution B-mode ultrasonography (US). RESULTS: Compared to women, men had significantly higher VFT and lower SFT (p = 0.002, p = 0.04, respectively). In partial correlation coefficient analyses between CIMT and abdominal fat thickness after adjustment for body mass index (BMI), SFT showed a negative correlation with CIMT in men (r = -0.27, p = 0.03). VFT was not correlated with CIMT in either men or women. In women, SFT was not correlated with CIMT (r = -0.01, p = 0.93). VFT/SFT ratio was not correlated with CIMT in either men or women. In multivariate regression analyses adjusted for BMI and other CVD risk factors, SFT but not VFT was independently inversely associated with CIMT in men but not in women (p < 0.001). CONCLUSIONS: SFT assessed by US was inversely associated with carotid atherosclerosis in patients with T2DM, particularly men. Further research into the different roles of the two types of abdominal adipose tissue in both men and women is warranted.

Differential associations of central and brachial blood pressure with carotid atherosclerosis and microvascular complications in patients with type 2 diabetes.

BACKGROUND: We examined the relationship between central blood pressure (BP), brachial BP with carotid atherosclerosis and microvascular complications in type 2 diabetes mellitus (T2DM). METHODS: We recruited 201 patients who were evaluated for central BP, brachial BP, carotid ultrasonography, brachial-ankle pulse wave velocity (baPWV), ankle-brachial index (ABI) and microvascular complications. Central BP were calculated using a radial automated tonometric system. RESULTS: Agreement between central BP and brachial BP was very strong (concordance correlation coefficient between central and brachial SBP = 0.889, between central and brachial PP = 0.816). Central pulse pressure (PP) was correlated with mean carotid intima-media thickness (CIMT), baPWV and ABI, whereas brachial PP was borderline significantly correlated with CIMT. The prevalence of nephropathy(DN) and retinopathy(DR) according to the brachial PP tertiles increased, the prevalences of microvascular complications were not different across central PP tertiles. In multivariate analysis, the relative risks (RRs) for the presence of DR were 1.2 and 4.6 for the brachial PP tertiles 2 and 3 when compared with the first tertile. Also, the RRs for the presence of DN were 1.02 and 3 for the brachial PP tertiles 2 and 3 when compared with the first tertile. CONCLUSIONS: Agreement of central BP and brachial BP was very strong. Nonetheless, this study showed that higher brachial PP levels are associated with increased probability for the presence of microvascular complications such as DR/DN. However, there are no associations with central SBP and central PP with microvascular complications. Central BP levels than brachial BP are correlated with surrogate marker of macrovascular complications.

Metastasis of colon cancer to medullary thyroid carcinoma: a case report.

Metastasis to the primary thyroid carcinoma is extremely rare. We report here a case of colonic adenocarcinoma metastasis to medullary thyroid carcinoma in a 53-yr old man with a history of colon cancer. He showed a nodular lesion, suggesting malignancy in the thyroid gland, in a follow-up examination after colon cancer surgery. Fine needle aspiration biopsy (FNAB) of the thyroid gland showed tumor cell clusters, which was suspected to be medullary thyroid carcinoma (MTC). The patient underwent a total thyroidectomy. Using several specific immunohistochemical stains, the patient was diagnosed with colonic adenocarcinoma metastasis to MTC. To the best of our knowledge, the present patient is the first case of colonic adenocarcinoma metastasizing to MTC. Although tumor-tumor metastasis to primary thyroid carcinoma is very rare, we still should consider metastasis to the thyroid gland, when a patient with a history of other malignancy presents with a new thyroid finding.

Malignancy Risk of Follicular Neoplasm (Bethesda IV) With Variable Cutoffs of Tumor Size: A Systemic Review and Meta-Analysis.

CONTEXT: The decision on diagnostic lobectomy for follicular neoplasms (FN) is challenging. OBJECTIVE: This meta-analysis investigates whether an appropriate size cutoff exists for recommending surgery for thyroid nodules diagnosed as FN by fine needle aspiration. METHODS: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched for studies reporting the malignancy rate of FN/suspicious for FN (FN/SFN) according to tumor size, using search terms "fine needle aspiration," "follicular neoplasm," "lobectomy," "surgery," and "thyroidectomy." RESULTS: Fourteen observational studies comprising 2016 FN/SFN nodules with postsurgical pathologic reports were included, and 2 studies included malignancy rates with various tumor sizes. The pooled malignancy risk of FN/SFN nodules according to size was: odds ratio (OR) 2.29 (95% CI, 1.68-3.11) with cutoff of 4 cm (9 studies), OR 2.39 (95% CI, 1.45-3.95) with cutoff of 3 cm (3 studies), and OR 1.81 (95% CI, 0.94-3.50) with cutoff of 2 cm (5 studies). However, tumors ≥2 cm also showed a higher risk (OR 2.43; 95% CI, 1.54-3.82) based on the leave-one-out meta-analysis after removal of 1 influence study. When each cutoff size was evaluated by summary receiver operating characteristic (sROC) curves, the cutoff of 4 cm showed the highest summary area under the curve (sAUC, 0.645) compared to other cutoffs (sAUC, 0.58 with 2 cm, and 0.62 with 3 cm), although there was no significant difference. CONCLUSION: Although the risk of malignancy increases with increasing tumor size, the risk remains significant at all tumor sizes and no cutoff limit can be recommended as a decision-making parameter for diagnostic surgery in Bethesda IV thyroid nodules.

Mast cell stabilizing effect of (-)-Elema-1,3,11(13)-trien-12-ol and thujopsene from Thujopsis dolabrata is mediated by down-regulation of interleukin-4 secretion in antigen-induced RBL-2H3 cells.

Several isolated compounds from the wood part of Thujopsis dolabrata were evaluated for their inhibitory effects against antigen-induced mast cell degranulation and interleukin-4 (IL-4) secretion, as well as IL-4 mRNA and protein expression in immunoglobulin E (IgE)-sensitized RBL-2H3 cells. Among the five isolated compounds, (-)-elema-1,3,11(13)-trien-12-ol (1) and thujopsene (2) exhibited the potent inhibitory activity against mast cell degranulation measured by ß-hexosaminidase release with IC values of 27.4 µM and 25.1 µM, respectively. These compounds also inhibited the release of IL-4 (IC values of 7.0, 6.7 µM, respectively), IL-4 mRNA expression (IC values of 16.5, 7.2 µM, respectively) and IL-4 protein expression (IC values of 17.0, 9.6 µM, respectively) in antigen-induced IgE-sensitized RBL-2H3 cells. These results suggested that (-)-elema-1,3,11(13)-trien-12-ol (1) and thujopsene (2) effectively inhibits mast cell degranulation as well as IL-4 production, suggesting that these compounds from Thujopsis dolabrata can be used as candidates for IgE-mediated allergic disorders.

Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer.

Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.