Behçet's disease (BD) is a multi-systemic inflammatory disorder which can affect all types and sizes of blood vessels. This study aims to evaluate the prevalence and characteristics of vascular involvement in BD. Among 796 patients diagnosed with BD, 102 patients (81 male, 21 female) with vascular involvement were included, whose detailed clinical characteristics were recorded. The diagnosis of vascular lesions was made on clinical signs, by Doppler ultrasonography, and/or angiography using computed tomographic or magnetic resonance techniques. Vascular involvement occurred in 12.8 % of BD patients. Male to female ratio was 3.86:1. Mean age at onset of vascular involvement was 29.5 ± 11.3 years. Vascular lesion was the initial sign of BD in 28 patients, accounting for 27.5 %. Of 102 BD patients with vascular involvement, 72 had venous lesions (70.6 %) and 56 had arterial lesions (54.9 %), among which 26 (25.5 %) patients had both venous and arterial involvements. Female BD patients were more often involved with arterial lesions, whereas male BD patients developed venous lesions more often than females, P = 0.000. The most common type of vascular involvement was deep venous thrombosis in lower extremities (n = 49), other affected venous sites including inferior vena cava, superior vena cava, and cerebral venous. The prominent type of arterial lesions was dilatation (n = 25, including 24 cases of aneurysms); other types included eight cases of occlusion and 23 cases of stenosis. The main locations of arterial lesions were the aorta (n = 19), lower extremity arteries (n = 15), pulmonary arteries (n = 13), coronary arteries (n = 5), and subclavian arteries (n = 5). Compared with those without vascular lesions, ocular involvement, genital ulcers, and arthritis were significantly less frequent among patients with vasculo-BD (23.5 vs 35.2 %, P = 0.024; 54.9 vs 76.5 %, P = 0.000; 19.6 vs 30.5 %, P = 0.026), whereas a higher frequency of cardiac involvement was found in vasculo-BD patients (20.6 vs 3.6 %, P = 0.000). Vascular involvement is a complication in BD patients. This study illustrated that venous lesions are more frequently involved than arterial lesions. Vascular lesions correlated with a high frequency of cardiac involvement and a low incidence of ocular lesions, genital ulcers, and arthritis.

BACKGROUND: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare kind of cancer. METHODS: In this study, the authors evaluated 52 patients with pulmonary LELC who had long-term follow-up. Clinical characteristics, tumor markers, epidermal growth factor receptor (EGFR) mutation status, treatments, and outcomes were analyzed. RESULTS: Pulmonary LELC mostly affected young, nonsmoking patients. Most patients were in early or locally advanced stages and received multimodality treatment. Serum levels of neuron-specific enolase and cytokeratin 19 fragment 21-1 were elevated in 11 of 20 patients and 10 of 16 patients, respectively. Mutational analysis of EGFR was done in 11 patients, and all were wild type. The median overall survival (OS) for all the patients was not reached, and the 2-year and 5-year OS rate was 88% and 62%, respectively. The patients with early tumor stage, normal serum lactate dehydrogenase level, normal serum albumin level, without lymph node metastasis, and those who underwent complete resection had significantly better OS (P < .05); and the serum albumin level was an independent prognostic factor in a Cox regression model (P ¼ .005). For all patients who underwent complete resection, whether or not they received adjuvant chemotherapy did not affect OS (P > .05); whereas, for patients with stage IIIA disease who underwent complete resection, adjuvant chemotherapy was correlated with a significantly better prognosis (P < .05). CONCLUSIONS: Pulmonary LELC obviously is a distinct entity of lung cancer that has a better prognosis, because patients with LELC can receive multimodality treatment, and LELC has biologic behavior similar to that of nasopharyngeal carcinoma. The current results indicated that future collaborative efforts are needed to determine the optimal treatment methods for this uncommon malignancy.

Amlodipine is a commonly prescribed calcium channel blocker for the treatment of hypertension and ischemic heart disease. The drug is slowly cleared in humans primarily via dehydrogenation of its dihydropyridine moiety to a pyridine derivative (M9). Results from clinical drug-drug interaction studies suggest that CYP3A4/5 mediate metabolism of amlodipine. However, attempts to identify a role of CYP3A5 in amlodipine metabolism in humans based on its pharmacokinetic differences between CYP3A5 expressers and nonexpressers failed. Objectives of this study were to determine the metabolite profile of amlodipine (a racemic mixture and S-isomer) in human liver microsomes (HLM), and to identify the cytochrome P450 (P450) enzyme(s) involved in the M9 formation. Liquid chromatography/mass spectrometry analysis showed that amlodipine was mainly converted to M9 in HLM incubation. M9 underwent further O-demethylation, O-dealkylation, and oxidative deamination to various pyridine derivatives. This observation is consistent with amlodipine metabolism in humans. Incubations of amlodipine with HLM in the presence of selective P450 inhibitors showed that both ketoconazole (an inhibitor of CYP3A4/5) and CYP3cide (an inhibitor of CYP3A4) completely blocked the M9 formation, whereas chemical inhibitors of other P450 enzymes had little effect. Furthermore, metabolism of amlodipine in expressed human P450 enzymes showed that only CYP3A4 had significant activity in amlodipine dehydrogenation. Metabolite profiles and P450 reaction phenotyping data of a racemic mixture and S-isomer of amlodipine were very similar. The results from this study suggest that CYP3A4, rather than CYP3A5, plays a key role in metabolic clearance of amlodipine in humans.

Primary small cell carcinoma of esophagus (SCCE) is a rare disease with poor prognosis. The aims of this study are to review the clinical characteristics, treatment modalities, and outcomes of SCCE and to investigate the prognostic factors and optimal treatment options. Sixty-four patients diagnosed as SCCE in Sun Yat-sen University Cancer Center from 1990 to 2011 were retrospectively reviewed. There were 46 patients with limited disease (LD) and 18 with extensive disease. The median survival time (MST) and overall survival rate were calculated and compared by the Kaplan-Meier method and log-rank test, respectively. The prognostic factors were calculated by Cox hazards regression model. With a median follow up of 11.6 months, the MST of all the 64 patients was 12.6 months, 16.5 months for LD and 9.0 months for extensive disease. The 1-, 3-, and 5-year overall survivals were 52.5%, 20.9%, and 7.5%, respectively. In univariate analysis, patients with ECOG performance score <2 (P = 0.009), lesion length ≤5 cm (P = 0.009), T stage ≤2 (P = 0.004), LD (P = 0.000), and multimodality treatment (P = 0.016) had significant associations with MST. Multivariate analysis showed that ECOG performance score (P = 0.001), T stage (P = 0.023), limited-extensive stage (P = 0.007), and treatment modality (P = 0.008) were independent prognostic factors. Locoregional treatment combined with chemotherapy had a trend to increase MST from 15.3 to 20.0 months in LD patients (P = 0.126), while combined chemotherapy had a significant impact on MST in extensive disease patients (P = 0.000). SCCE is a highly malignant disease with poor prognosis. Patients might obtain survival benefit from the combination of locoregional treatment and systemic therapy. Prospective studies are needed to validate these factors.

Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.

Purpose: To evaluate the efficacy and toxicity of definitive concurrent chemoradiotherapy (CCRT) with docetaxel plus cisplatin (DP regimen) versus 5-fluorouracil plus cisplatin (PF regimen) in patients with oesophageal squamous cell carcinoma (ESCC). Patients and Methods: In this phase II randomized controlled trial, eighty-six patients with clinical stage II - IVa ESCC were randomized to receive radiotherapy concurrently with two cycles of the PF or DP regimen at 3-week intervals. The primary endpoint was overall survival (OS). The secondary end points included the overall response rate (ORR), progression-free survival (PFS) and treatment-related toxicities. Results: The ORRs were 84.4% in the DP group and 87.3% in the PF group (P = 0.653). After a median follow-up time of 25.1 months, the 1- and 2-year OS rates were 93.7% and 86.2% for the PF group and 87.3% and 69.1% for the DP group, respectively (P = 0.364). The 1- and 2-year PFS rates were 77.4% and 55.0% for the PF group and 78.8% and 69.4% for the DP group, respectively (P = 0.845). Grade 3/4 leukocytopenia/neutropenia (68.9% vs. 19.5%, P < 0.001) was significantly more common in the DP group. Conclusion: The treatment response, OS and PFS associated with using CCRT with the DP regimen were not superior to those associated with using CCRT with the PF regimen as a first-line treatment in patients with ESCC. Additionally, the DP regimen was associated with more severe haematological toxicities. This trial has been registered with the US National Institute of Health (clinicaltrials.gov, Identifier NCT 02969473).

Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6 could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders.

Type 2 diabetes mellitus (T2DM) is a pervasive metabolic syndrome that is characterized by insulin resistance, hyperglycemia and dyslipidemia. As full agonists of PPARγ, thiazolidinedione (TZD) drugs elicit antidiabetic effects by targeting PPARγ but is accompanied by weight gain, fluid retention and cardiovascular risk associated with their transcriptional agonism potency. We here identify a natural product chelerythrine as a unique selective PPAR modulator (SPPARM) with a potent PPARγ binding activity but much less classical receptor transcriptional agonism. Structural analysis reveals that chelerythrine exhibits unique binding in parallel with H3 of PPARγ. Unlike TZDs, chelerythrine destabilizes helix 12, especially residue tyrosine 473, resulting in a loose configuration of AF-2 and a selective cofactor profile distinct from TZDs, leading to a differential target gene profile in adipogenesis in db/db diabetic mice. Moreover, chelerythrine improved insulin sensitivity by more potently blocking the phosphorylation of PPARγ by CDK5 compared to TZDs. These data fundamentally elucidate the mechanism by which chelerythrine retains the benefits of improving insulin sensitivity while reducing the adverse effects of TZDs, suggesting that the natural product chelerythrine is a very promising pharmacological agent by selectively targeting PPARγ for further development in the clinical treatment of insulin resistance.