Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.

BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Diagnostic accuracy of the jetting sign and a dilatation ratio of left renal vein in CT urography for detecting anterior nutcracker syndrome.

AIM: To investigate the diagnostic value of computed tomography (CT) urography findings of anterior nutcracker syndrome (NCS). MATERIALS AND METHODS: The study included patients with left renal vein (LRV) compression at the aortomesenteric portion at CT urography who underwent renal venography or cystoscopy. Patients with a renocaval pressure gradient of ≥3 mmHg on renal venography or bloody urine jetting from the left ureteral orifice on cystoscopy were defined as the NCS group; the remaining patients comprised the non-NCS group. CT findings were analysed using the jetting of contrast medium flow from the LRV to the inferior vena cava (jetting sign), aortomesenteric distance, presence of collateral veins, and a dilatation ratio of LRV diameter at the aortomesenteric portion (arterial phase/delayed phases). Clinical findings, including age, gender, and body-mass-index, were also analysed. CT features and clinical findings were compared between the NCS and non-NCS groups. Diagnostic performance of CT parameters was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 70 patients (21 men, mean age 44.4 ± 17.2 years) with NCS (n=13) and non-NCS (n=57) were included. Younger age (<40 years), presence of the jetting sign, and a lower dilatation ratio of LRV diameter between the arterial and delayed phases (<1.7) were found to be significant independent factors for predicting the NCS group (OR 24.5, 18.9, 19.4, respectively, p<0.05 for all). The combination of the presence of the jetting sign and a dilatation ratio of LRV diameter of <1.7 obtained the highest AUC of 0.88. CONCLUSION: The jetting sign and the dilatation ratio of LRV diameter between the arterial and delayed phases can both be very useful in the diagnosis of anterior nutcracker syndrome during CT urography.

Crystal growth and scintillation properties of YAG:Ce3+ for γ and α detection.

A bulk single crystal of yttrium aluminum garnet (Y3Al5O12:Ce3+, YAG:Ce3+) with good optical quality and free of cracks has been grown successfully by the Kyropoulos method. The dimension of the as grown crystal boule was Ø 20 × 30 cm3. The cut and polished crystal sample of dimensions 1 × 1 × 0.5 cm3 was used for further measurements. The phase purity was confirmed by powder X-ray diffraction pattern analysis. The scintillation properties, such as X-ray emission spectrum, pulse height spectra, energy resolution, and scintillation decay time, were investigated using a 137Cs γ-ray source. The recorded X-ray emission spectrum shows a broad band between 500 and 700 nm with a peak at around 540 nm, which is attributed to the 5d-4f transition of the Ce3+ ion. The pulse-shape discrimination (PSD) of α and γ signals in a YAG:Ce3+ crystal has been studied by using different pulse shapes. The grown YAG:Ce3+ crystal which is non-hygroscopic, chemically inert, fast inorganic scintillator could be used for radiation detection application in nuclear, and high energy physics.

Acclimatization of Pisum sativum L., grown in soil contaminated with veterinary antibiotics, an attribute of dose hormetic response of root metabolites.

Plant-veterinary antibiotic interaction has been widely studied, however, to the best of our knowledge acclimatization studies with regard to changes in plant root metabolites has not been reported so far. The purpose of this study was to examine the changes in the metabolome of pea roots under antibiotic stress and their role in acclimatization. Pisum sativum L. was grown in soil contaminated with three commonly used veterinary antibiotics - kanamycin (KA), sulfamethazine (SA), and tetracycline (TC). In response to antibiotic stress, plants accumulated different types of low molecular weight compounds that provided protection from stress by contributing to ROS detoxification, protection of membrane integrity, efficient signaling, cell wall function, and cellular osmotic adjustment (glucose, galactose, myo-inositol, stigmasterol, octadecadienoic acid, l-proline). The concentration of amino acid, sugar, and triglyceride metabolites in KA and TC samples showed a dose-dependent biphasic (hormesis) fluctuation. This was mirrored in the metabolite abundance as well as the physiological attributes (mycorrhizal colonization, GST function, nutrient assimilation), which helped in the acclimatization without the loss of normal plant function. SA, on the other hand, had progressive toxic effects with increasing concentration. PCA revealed the differences to be due to SA treatments and in sterol and terpenoid metabolites.

Globular adiponectin acts as a melanogenic signal in human epidermal melanocytes.

BACKGROUND: Adiponectin is an adipocyte-derived cytokine that circulates as a full-length protein and a fragment containing the globular domain of adiponectin (gAd). A recent study has reported the antimelanogenic effects of full-length adiponectin. OBJECTIVES: To examine the involvement of gAd in melanogenesis and its mechanisms of action. METHODS: The effects of gAd on melanogenesis and its mechanisms of action were investigated in human epidermal melanocytes and reconstructed epidermis, including melanin content, cellular tyrosinase activity, cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity, expression and phosphorylation of signalling molecules. RESULTS: Exogenous gAd increased melanin content, and the mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes TRP1, but not TRP2, were increased by gAd. However, cAMP production and PKA activity were not affected by gAd. Moreover, attempts to elucidate the underlying mechanism behind the gAd-mediated effect revealed that gAd could regulate melanogenesis by upregulating MITF through phosphorylation of the cAMP response element-binding protein (CREB). In addition, upregulation of MITF was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK)-p38 mitogen-activated protein kinase (MAPK) signalling. Taken together, these findings indicate that promotion of melanogenesis by gAd occurs through increased expression of MITF, which is mediated by activation of the AMPK-p38 MAPK-CREB pathway. CONCLUSIONS: These findings suggest that gAd contributes to epidermal homeostasis via its effect on melanocyte biology, and products of adipose tissue could affect epidermal biology.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.

Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy.

Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114 patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis≥grade 2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension.

Performance of the Minto model for the target-controlled infusion of remifentanil during cardiopulmonary bypass.

We studied the predictive performance of the Minto pharmacokinetic model during cardiopulmonary bypass in patients undergoing cardiac surgery. Patients received remifentanil target-controlled infusion using the Minto model during total intravenous anaesthesia with propofol. From 56 patients, 275 arterial blood samples were drawn before, during and after bypass to determine the plasma concentration of remifentanil, and the predicted concentrations were recorded at each time. For pooled data, the median prediction error and median absolute prediction error were 21.3% and 21.8%, respectively, and 22.1% and 22.3% during bypass. Both were 148.4% during hypothermic circulatory arrest and measured concentrations were more than three times greater than predicted (26.9 (17.0) vs. 7.1 (1.6) ng.ml-1 ). The Minto model showed considerable bias but overall acceptable precision during bypass. The target concentration of remifentanil should be reduced when using the Minto model during hypothermic circulatory arrest.

A novel K+ competitive acid blocker, YH4808, sustains inhibition of gastric acid secretion with a faster onset than esomeprazole: randomised clinical study in healthy volunteers.

BACKGROUND: YH4808, a K+ -competitive acid blocker, is under clinical development for the treatment of acid-related disorders, such as gastroesophageal reflux disease. AIMS: To determine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH4808, compared to placebo and esomeprazole. METHODS: This double-blind, randomised, placebo- and active comparator (esomeprazole)-controlled study was conducted with 123 healthy male volunteers. We evaluated YH4808 (30-800 mg) properties, administered in single (N=55) and multiple (N=24) oral doses, and recorded the effects on 24-hour intragastric acidity. Results were compared to placebo (N=20) and esomeprazole 40 mg (N=24). RESULTS: Plasma YH4808 exposure increased dose-proportionally and declined in a multi-phasic manner. YH4808 ≥200 mg/d maintained intragastric acidity at pH >4 for longer times than esomeprazole during both day and night (%Time at pH >4: >70% vs 58% of a 24-hour period, respectively; and >50% vs 33% of a 9-hour night respectively). A twice-daily regimen of YH4808 more effectively controlled intragastric pH at night than a once-daily regimen. In evaluating the mean areas under the intragastric pH-time curves in 15-minute intervals for 2 hours after dosing, we found that YH4808 had a faster onset than esomeprazole. Moreover, unlike esomeprazole, YH4808 PK and PD were not significantly affected by the CYP2C19 genotype of the subjects. YH4808 was well-tolerated at all doses administered. CONCLUSION: This study showed that YH4808 produced a rapid, sustained suppression of gastric secretion with good tolerability. The results at YH4808 ≥200 mg/d provide a rationale for further clinical investigations in populations with acid-related diseases.

Molecular detection by analysis of the 16S rRNA gene of fecal coliform bacteria from the two Korean Apodemus species (Apodemus agrarius and A. peninsulae).

Wild mouse feces can disseminate zoonotic microorganisms throughout a farm, which is a great threat to human health and can lead to economic loss through contaminated agricultural produce. To assess the microbial communities, especially fecal coliform bacteria, we used two methods. First, we isolated bacterial colonies onto the common media LB (lactose broth) agar, TSA (tryptic soy agar), and MRS (de Man, Rogosa, and Sharpe) agar, and then randomly select colonies from each plate and stocked them to the mother plate for genomic DNA isolation. Second, we analyzed bacterial colonies using the 16S rRNA gene molecular diagnostic method. Based on bacterial cultures and bacterial 16S rRNA gene markers, we detected four different bacterial species (Bacillus amyloliquefaciens, Escherichia coli, Staphylococcus xylosus, and Serratia liquefaciens) from fecal coliforms of the striped field mouse Apodemus agrarius and A. peninsulae in agricultural areas in South Korea. These results could help us to better understand the pathogen reservoirs of mice and initiate some preventive measures to mitigate the microbial risks associated with mouse fecal matter in agricultural production areas.

Randomised clinical trial: the efficacy and safety of oltipraz, a liver X receptor alpha-inhibitory dithiolethione in patients with non-alcoholic fatty liver disease.

BACKGROUND: Oltipraz is a synthetic dithiolethione with an antisteatotic effect by inhibiting the activity of liver X receptor alpha (LXR-α). Recent studies demonstrated the disruptive role of oltipraz on LXR-α-dependent lipogenesis in hepatocytes and a high-fat diet mouse model. AIM: To evaluate the efficacy and safety of oltipraz for reducing liver fat in subjects with non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a multicentre, double-blind, placebo-controlled, phase II study. Subjects with a liver fat >20% and hypertransaminasemia were randomised to the three groups: placebo (n = 22), 30 mg of oltipraz (n = 22) or 60 mg of oltipraz (n = 24) twice daily for 24 weeks. Changes in the liver fat from baseline to 24 weeks quantified using magnetic resonance spectroscopy were the primary outcome. RESULTS: Compared with the placebo group (-3.2 ± 11.1%), absolute changes in the liver fat content increased in a dose-dependent manner: -7.7 ± 7.0% and -13.9 ± 10.7% for the low-dose and high-dose groups (P = 0.13 and P < 0.01). Per cent reduction in the liver fat content was also significantly greater in the high-dose group than in the placebo group (-34.6 ± 29.4% vs. -0.6 ± 62.9%, P = 0.046). Body mass indices (-1.0 ± 0.9% vs. -0.5 ± 1.4%, P = 0.04) significantly decreased in the high-dose group compared to the placebo group. However, absolute changes in insulin resistance, liver enzymes, lipids and cytokines were not significantly different among groups. The incidence of adverse events was comparable among groups. CONCLUSIONS: Twenty-four-week oltipraz treatment significantly reduced the liver fat content in patients with NAFLD. Clinicaltrials.gov (NCT01373554).

An Accelerator Mass Spectrometry-Enabled Microtracer Study to Evaluate the First-Pass Effect on the Absorption of YH4808.

14 C-labeled YH4808, a novel potassium-competitive acid blocker, was intravenously administered as a microtracer at 80 µg (11.8 kBq or 320 nCi) concomitantly with the nonradiolabeled oral drug at 200 mg to determine the absolute bioavailability and to assess the effect of pharmacogenomics on the oral absorption of YH4808. The absolute bioavailability was low and highly variable (mean, 10.1%; range, 2.3-19.3%), and M3 and M8, active metabolites of YH4808, were formed 22.6- and 38.5-fold higher after oral administration than intravenous administration, respectively. The product of the fraction of an oral YH4808 dose entering the gut wall and the fraction of YH4808 passing on to the portal circulation was larger in subjects carrying the variants of the CHST3, SLC15A1, and SULT1B1 genes. A combined LC+AMS is a useful tool to construct a rich and highly informative pharmacokinetic knowledge core in early clinical drug development at a reasonable cost.

Combined untargeted and targeted metabolomic profiling reveals urinary biomarkers for discriminating obese from normal-weight adolescents.

BACKGROUND: Childhood and adolescent obesity may lead to obesity and related complications in adulthood. Biomarkers of obesity can be useful for screening for obesity complications and promoting early intervention during school age. Thus, the metabolomic differences in obese children and adolescents should be investigated for identification of potential biomarkers. OBJECTIVES: We investigated urinary biomarkers to distinguish metabolomic characteristics between obesity and normal weight in adolescents. METHODS: Adolescent subjects were divided into non-obese (n = 91) and obese (n = 93) groups according to body mass index. Untargeted and targeted metabolomic profiling of urine was performed using high-performance liquid chromatography (LC)-quadrupole time-of-flight mass spectrometry (MS), LC-MS/MS and flow injection analysis-MS/MS systems, respectively. RESULTS: Multivariate statistical analysis showed clear discrimination between the untargeted metabolomes of non-obese and obese groups. Seven endogenous metabolites were distinguished in the obese group, and inflammation-related metabolite markers showed strong predictive power for group classification. From targeted metabolomics, 45 metabolites mostly related to inflammation were significantly different in the obese group. CONCLUSIONS: Significantly different metabolome signatures were identified between normal-weight and obese adolescents. Combined untargeted and targeted metabolomics demonstrated that inflammation-driven insulin resistance, ammonia toxicity and oxidative stress may represent crucial metabolomic signatures in obese adolescents.

Exploration of Biomarkers for Amoxicillin/Clavulanate-Induced Liver Injury: Multi-Omics Approaches.

To explore potential biomarkers for amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial in 32 healthy subjects based on multi-omics approaches. Every subject was administered amoxicillin/clavulanate for 14 days. The liver-specific microRNA-122 (miR-122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC-DILI. We also identified urinary metabolites, such as azelaic acid and 7-methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration. In conclusion, this study provides potential biomarkers for AC-DILI based on currently known mechanisms using comprehensive multi-omics approaches.

Targeted Next-Generation Sequencing for Comprehensive Genetic Profiling of Pharmacogenes.

Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. Therefore, we developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PKs) and pharmacodynamics (PDs). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences. Notably, variants that occurred at low frequency were enriched with likely protein-damaging variants and previously unreported variants. Furthermore, in vitro evaluation of four pharmacogenes, including cytochrome P450 2C19 (CYP2C19), confirmed that many of these rare variants have considerable functional impact. The present study suggests that targeted NGS panels are readily applicable platforms to facilitate comprehensive profiling of pharmacogenes, including common but also rare variants that warrant screening for personalized medicine.

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin-exacerbated respiratory disease.

BACKGROUND: To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. METHODS: An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/Q-ToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. RESULTS: A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE4 and LTE4 /PGF2 α ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE4 and LTE4 /PGF2 α ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE4 levels were significantly correlated with the fall in FEV1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). CONCLUSIONS AND CLINICAL RELEVANCE: Serum metabolite level of LTE4 and LTE4 /PGF2 α ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/Q-ToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.

Associations between osteoporosis and coronary artery disease in postmenopausal women.

OBJECTIVE: Coronary artery disease (CAD) and osteoporosis are major causes of mortality and morbidity in postmenopausal women. We aimed to investigate the association between osteoporosis and CAD in asymptomatic postmenopausal women at a single center. METHODS: This study included 863 postmenopausal women without histories of cardiovascular diseases who visited the Health Promotion Center from June 1, 2004 to May 31, 2015. All subjects were screened for bone mineral density (BMD) by dual-energy X-ray absorptiometry and for the degree of CAD by multidetector computed tomography. RESULTS: Low BMD including osteopenia and osteoporosis was found to be significantly associated with old age, low body mass index, and a higher prevalence of diabetes mellitus. The incidences of CAD including a high coronary artery calcium score (≥100), obstructive coronary artery disease, and multivessel disease were significantly higher in subjects with low BMD. After adjusting for age and cardiovascular risk factors, osteoporosis was associated with a high coronary artery calcium score (p = 0.015) and with obstructive coronary artery disease (p = 0.002). There was a trend toward significance with multivessel disease (p = 0.052). CONCLUSIONS: High coronary artery calcium score and obstructive coronary artery disease, as revealed by multidetector computed tomography, were associated with osteoporosis in asymptomatic postmenopausal women, independent of cardiovascular risk factors and age.

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity.

The preadipocyte-to-adipocyte differentiation (adipogenesis) is a key process in fat mass increase and thus it is regarded as a compelling target for preventing or treating obesity. Of adipogenic hormone receptors, peroxisome proliferator-activated receptor gamma (PPARγ) has crucial roles in adipogenesis and lipid accumulation within adipocytes. Here we demonstrate that the NEDD8 (neuronal precursor cell expressed, developmentally downregulated 8)-based post-translation modification (neddylation) of PPARγ is essential for adipogenesis. During adipogenesis, NEDD8 is robustly induced in preadipocytes and conjugates with PPARγ, leading to PPARγ stabilization. When the neddylation process was blocked by NEDD8-targeting siRNAs (or viral vectors) or an inhibitor MLN4924, adipocyte differentiation and fat tissue development were substantially impaired. We also demonstrate that MLN4924 effectively prevents the high-fat diet-induced obesity and glucose intolerance in mice. This study provides a better understanding of how the PPARγ signaling pathway starts and lasts during adipogenesis and a potential anti-obesity strategy that targets the neddylation of PPARγ.