Domain adaptive and fully automated carotid artery atherosclerotic lesion detection using an artificial intelligence approach (LATTE) on 3D MRI.

PURPOSE: To develop and evaluate a domain adaptive and fully automated review workflow (lesion assessment through tracklet evaluation, LATTE) for assessment of atherosclerotic disease in 3D carotid MR vessel wall imaging (MR VWI). METHODS: VWI of 279 subjects with carotid atherosclerosis were used to develop LATTE, mainly convolutional neural network (CNN)-based domain adaptive lesion classification after image quality assessment and artery of interest localization. Heterogeneity in test sets from various sites usually causes inferior CNN performance. With our novel unsupervised domain adaptation (DA), LATTE was designed to accurately classify arteries into normal arteries and early and advanced lesions without additional annotations on new datasets. VWI of 271 subjects from four datasets (eight sites) with slightly different imaging parameters/signal patterns were collected to assess the effectiveness of DA of LATTE using the area under the receiver operating characteristic curve (AUC) on all lesions and advanced lesions before and after DA. RESULTS: LATTE had good performance with advanced/all lesion classification, with the AUC of >0.88/0.83, significant improvements from >0.82/0.80 if without DA. CONCLUSIONS: LATTE can locate target arteries and distinguish carotid atherosclerotic lesions with consistently improved performance with DA on new datasets. It may be useful for carotid atherosclerosis detection and assessment on various clinical sites.

Effects of Percutaneous Neuromuscular Electrical Stimulation for Neck Pain in Patients With Cervical Spondylosis.

CONTEXT: Cervical spondylosis (CS) is a very common, age-related, chronic, disc-degeneration condition. Alternative medicine has been widely used to treat neck pain in CS. However, no randomized controlled trials have focused on the effects and safety of percutaneous neuromuscular electrical stimulation (PNMES) for neck-pain relief in patients with CS. OBJECTIVE: The study aimed to evaluate the effects and safety of PNMES for treating neck pain in patients with cervical spondylosis (CS). DESIGN: The research team designed a two-arm, double-blinded, randomized, sham-controlled trial. SETTING: The study was conducted at the People's Hospital of Yan'an in Yan'an, China. PARTICIPANTS: Participants were 124 patients with neck pain from CS at the hospital. INTERVENTION: Participants were randomly divided into an intervention group and a control group in a ratio of 1:1. The intervention group received PNMES (PNMES group), and the control group received sham PNMES for 30 minutes daily 3 times weekly, for 12 weeks. OUTCOME MEASURES: The outcome measures included: (1) a visual analog scale (VAS), (2) a test of cervical range of motion (ROM), and (3) the neck disability index (NDI) score. All outcome measurements were measured immediately postintervention and in a follow-up at 4 weeks postintervention. In addition, AEs were also recorded duration the period of treatment. RESULTS: Immediately postintervention and at the follow-up, the PNMES group exhibited decreases in the mean VAS (P < .01) and NDI score (P < .01) that were significantly greater than those of the control group. Additionally, the increase in the mean ROM was significantly higher in the PNMES group than that in the control group, both immediately postintervention and at the follow-up (P < .01). No AEs were found in either group. CONCLUSIONS: The results of this study have demonstrated that PNMES is more effective than sham PNMES for neck-pain relief in patients with CS.

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells.

BACKGROUND/AIMS: Lung cancer is one of the most prevalent malignancies in the world. The 5-year survival rate for non-small cell lung cancer (NSCLC) patients is only approximately 15%, with metastasis as the primary cause of death. This study was aimed to investigate cytotoxic effect of external qi of Yan Xin Qigong (YXQ-EQ) toward human lung adenocarcinoma A549 cells as well as its effect on signaling pathways promoting migration, invasion and epithelial-to-mesenchymal transition (EMT) in A549 cells. METHODS: Cytotoxic effect of YXQ-EQ was evaluated using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] and cologenic assays. Apoptosis of treated cells was determined by Annexin V/propidium iodide staining and flow cytometry analysis, while cell migration and invasion were determined using transwell assays and EMT was assessed by morphological changes in cells. Protein expression and phosphorylation were examined by immunoblot analyses. RESULTS: YXQ-EQ induced apoptosis in A549 cells, resulting in a pronounced reduction in viability and clonogenic formation. This was associated with inhibition of phosphorylation of AKT and ERK1/2 and reduced expression of anti-apoptotic proteins BCL-xL, XIAP and survivin. Furthermore, YXQ-EQ inhibited EGF/EGFR signaling and EGF mediated migration and invasion of A549 cells. While TGF-ß1 induced phosphorylation of SMAD2/3 and EMT in A549 cells, YXQ-EQ suppressed TGF-ß/SMAD signaling and induced cell death in these cells in the presence of TGF-ß1. CONCLUSION: Our findings suggest that YXQ-EQ could exert anti-lung cancer effects via inhibiting signaling pathways that are important for NSCLC cell survival and NSCLC metastasis.

Application value of endoscopic submucosal dissection and endoscopic mucosal resection for treatment of rectal carcinoids.

OBJECTIVE: The objective of this study is to explore the clinical effect and safety of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for treatment of rectal carcinoids. METHODS: A retrospective analysis was conducted on 42 patients with rectal carcinoids who were hospitalized and subjected to surgical treatment in our hospital from January 2010 to November 2015. The patients were categorized into two groups based on treatment received: ESD (n = 22) and EMR (n = 20). The patients were analyzed and compared to determine differences in lesion size, operation time, histopathologically curative resection rate, intraoperative complications, complete lesion resection rate, and postoperative recurrence rate between the two groups. RESULTS: Operation time (25.2 ± 20.1 min) and wound surface diameter (36.2 ± 10.1 mm) were significantly higher in the ESD group than those in the EMR group (12.6 ± 8.4 min and 18.6 ± 5.9 mm, respectively) (P < 0.05). The differences in complete lesion and histopathologically curative resection rates between the two groups were not statistically significant (P > 0.05). Delayed hemorrhage was the primary postoperative complication in both groups. Postoperative follow-up was performed for 3-71 months, and the median follow-up time was 45 months. Recurrence was noted 32 months after surgery in one patient in the EMR group (4.5%), whereas recurrence was not detected in the ESD group. CONCLUSION: ESD and EMR are safe and effective methods for treatment of rectal carcinoids. Moreover, ESD had less risk of recurrence, more complete resection rate which could provide more information for postoperative treatment.

External Qi of Yan Xin Qigong inhibits activation of Akt, Erk1/2 and NF-ĸB and induces cell cycle arrest and apoptosis in colorectal cancer cells.

BACKGROUND/AIMS: Colorectal cancer (CRC) is the second leading cause of cancer death in the Western countries. Novel approaches of treatment are needed for CRC. The purpose of the present study was to investigate cytotoxic effect of external Qi of Yan Xin Qigong (YXQ-EQ) on human colorectal cancer cells. METHODS: The effect of YXQ-EQ on viability, cell cycle progression and apoptosis in colorectal cancer HT-29 cells was investigated. Phosphorylation of Akt and Erk1/2, activation of NF-ĸB and the expression of proteins involved in regulation of cell cycle and apoptosis were examined by Western blot analysis. RESULTS: YXQ-EQ markedly decreased viability and blocked colony formation of HT-29 cells. YXQ-EQ downregulated cyclin D1 expression and increased accumulation of cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1), resulting in G1 cell cycle arrest. YXQ-EQ induced apoptosis in HT-29 cells in association with decreased expression of antiapoptotic proteins Bcl-xL, XIAP, survivin and Mcl-1 and elevated expression of proapoptotic protein Bax. YXQ-EQ significantly repressed phosphorylation of Akt and Erk1/2 and NF-ĸB activation in HT-29 cells, suggesting that YXQ-EQ may exert cytotoxic effect through regulating signaling pathways critical for cell proliferation and survival. Furthermore, YXQ-EQ treated PBS and an YXQ-EQ treated plant extract induced apoptosis in HT-29 cells. CONCLUSION: These findings show that YXQ-EQ has potent cytotoxic effect on HT-29 cells and suggest that YXQ-EQ could be potentially used for colorectal cancer treatment either directly or indirectly via carriers.

External Qi of Yan Xin Qigong Induces apoptosis and inhibits migration and invasion of estrogen-independent breast cancer cells through suppression of Akt/NF-kB signaling.

The antitumor effects of external Qi of Yan Xin Qigong (YXQ-EQ) have been widely described over the past three decades. To gain a better understanding of the mechanisms underlying YXQ-EQ's antitumor effects, in the present study we investigated its effects on growth, migration, invasion and apoptosis of breast cancer cells and the underlying molecular mechanisms. We show that YXQ-EQ treatment caused a time-dependent reduction in viability, blocked clonogenic growth and induced apoptosis in estrogen-independent breast cancer MDA-MB-231 cells. Furthermore, YXQ-EQ treatment blocked migration and invasion of MDA-MB-231 cells. Biochemically, YXQ-EQ treatment markedly inhibited constitutive and EGF-induced Akt phosphorylation. YXQ-EQ also substantially repressed NF-kappaB activity, resulting in decreased expression of anti-apoptotic Bcl-2, Bcl-X(L), XIAP and survivin proteins. These findings suggest that YXQ-EQ may induce apoptosis and inhibition of migration and invasion of MDA-MB-231 cells through the repression of Akt/NF-kappaB signaling.

Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.

Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.

Phenolic antioxidants from green tea produced from Camellia taliensis.

The chemical constituents of green tea prepared from the leaves of Camellia taliensis (W. W. Smith) Melchior (Theaceae) were investigated for the first time. Of these, 19 phenolic compounds including 8 hydrolyzable tannins (1-8), 6 catechin derivatives (9-14), 3 quinic acid aromatic esters (15-17), and 2 simple phenolics (18, 19) were identified, along with caffeine (20). Their antioxidant activities were evaluated by DPPH radical scavenging and tyrosinase inhibitory assays. Moreover, the chemical composition was compared with that in the cultivated tea plant, C. sinensis var. assamica, by HPLC analysis. It was noted that C. taliensis has similar chemical features with the cultivated tea plant; that is, both of them contain rich flavan-3-ols and caffeine. In addition, there are abundant hydrolyzable tannins as specific characteristic constituents contained in the leaves of C. taliensis. Therein, 1,2-di-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl-beta-D-glucopyranose (8), as a major compound in C. taliensis, showed remarkable antioxidant activity. The results suggested that C. taliensis could be a valuable plant resource for the production of tea.

External Qi of Yan Xin Qigong induces G2/M arrest and apoptosis of androgen-independent prostate cancer cells by inhibiting Akt and NF-kappa B pathways.

Long-term clinical observations and ongoing studies have shown antitumor effects of external Qi of Yan Xin Qigong (YXQG-EQ) that originated from traditional Chinese medicine (TCM). In order to understand the molecular mechanisms underlying the antitumor effects of YXQG-EQ, we investigate the effects of YXQG-EQ on growth and apoptosis in androgen-independent prostate cancer PC3 cells. We found that exposure to YXQG-EQ led to G2/M arrest associated with reduced cyclin B1 expression and apoptosis in PC3 cells. YXQG-EQ treatment inhibited constitutive and epidermal growth factor-induced Akt phosphorylation, basal and TNF-alpha-induced NF-kappaB activation, and downregulated anti-apoptotic Bcl-2 and Bcl-xL expression. In contrast, exposure to YXQG-EQ increased phosphorylation of Akt and Erk1/2 in human umbilical vein endothelial cells (HUVEC), and had no cytotoxic effect on either HUVEC or peripheral blood mononuclear cells (PBMC). These results indicate that YXQG-EQ has profound effects on growth and apoptosis of prostate cancer cells by targeting survival pathways including the Akt and NF-kappa B pathways.

Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index.

Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRbeta-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the negatively charged TR agonist (3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344), which distributes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB07811 with 3,5,3'-triiodo-l-thyronine (T(3)) and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacologic effects of liver targeting were evident in the normal rat, where MB07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA. These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.

Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-beta-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma.

Cytotoxic nucleosides have proven to be ineffective for the treatment of hepatocellular carcinoma (HCC) due, in part, to their inadequate conversion to their active nucleoside triphosphates (NTP) in the liver tumor and high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drug class associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugs selectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such as hepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy was applied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-beta-D-arabinofuranoside (cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC, generating >19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in the plasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-fold and >28-fold improvement, respectively, over araC administration.

External Qi of Yan Xin Qigong differentially regulates the Akt and extracellular signal-regulated kinase pathways and is cytotoxic to cancer cells but not to normal cells.

Long-term clinical observations and ongoing studies have shown significant antitumor effect of external Qi of Yan Xin Qigong which originated from traditional Chinese medicine. In order to understand the molecular and cellular mechanisms underlying the antitumor effect of external Qi of Yan Xin Qigong, we have examined its cytotoxic effect on BxPC3 pancreatic cancer cells and its effect on the Akt and extracellular signal-regulated kinase pathways. We found that external Qi of Yan Xin Qigong dramatically inhibited basal phosphorylation levels of Akt and extracellular signal-regulated kinases, epidermal growth factor-mediated phosphorylation of extracellular signal-regulated kinases, and phosphatidylinositol 3-kinase activity. External Qi of Yan Xin Qigong also inhibited constitutive and inducible activities of nuclear factor-kappa B, a target of the Akt and epidermal growth factor receptor pathways. Furthermore, a single 5min exposure of BxPC3 cells to external Qi of Yan Xin Qigong induced apoptosis, accompanied by a dramatic increase of the sub-G1 cell population, DNA fragmentation, and cleavage of caspases 3, 8 and 9, and poly(ADP-ribose) polymerase. Prolonged treatment with external Qi of Yan Xin Qigong caused rapid lysis of BxPC3 cells. In contrast, treatment of fibroblasts with external Qi of Yan Xin Qigong induced transient activation of extracellular signal-regulated kinases and Akt, and caused no cytotoxic effect. These findings suggest that external Qi of Yan Xin Qigong may differentially regulate these survival pathways in cancer versus normal cells and exert cytotoxic effects preferentially on cancer cells, and that it could potentially be a valuable approach for therapy of pancreatic carcinomas.

A liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of isoniazid and ethambutol in human plasma.

Isoniazid and ethambutol are commonly used in various combination treatments for tuberculosis, and for this reason a rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for simultaneous quantification of these two drugs in human plasma. After a simple protein precipitation using methanol, the analytes and the internal standard metformin were chromatographed on a C18 column and detected by MS/MS. An atmospheric pressure chemical ionization interface was chosen to reduce ion suppression from sample matrix components and provide high sensitivity. The LC retention times for isoniazid and ethambutol were 2.46 and 2.27 min, respectively. The method was linear in the concentration range of 10.0-5000 ng/mL for each analyte using 100 microL plasma. The intra- and inter-day precisions, expressed as the relative standard deviation (RSD), were less than 5.7 and 6.4%, determined from QC samples for isoniazid and ethambutol, and the accuracies were within +/-2.1% and +/-4.5% in terms of relative error, respectively. The method was successfully employed in a pharmacokinetic study after oral administration of a multicomponent formulation containing 150 mg isoniazid, 500 mg ethambutol, 150 mg rifampicin and 250 mg pyrazinamide.

Total Synthesis of the Cytotoxic Threo, Trans, Erythro, Cis, Threo Annonaceous Acetogenin Trilobin.

A synthesis of trilobin, a new stereochemical varient of the adjacent bis-tetrahydrofuran subgroup of the Annonaceous acetogenins, is described. The synthesis involves three stereochemically defining carbon-carbon bond-forming steps. The first of these introduces the C23-C24 stereocenters and the left side chain by means of an S(E)2' addition of the nonracemic 11-carbon gamma-oxygenated allylic indium reagent derived from the alpha-oxygenated allylic stannane 4 to a C24-C16 core aldehyde 3. The second develops the C15-C16 stereocenters and a segment of the right chain through BF(3)-promoted S(E)2' addition of the nonracemic 6-carbon gamma-oxygenated allylic stannane 11 to the C16-C34 aldehyde 10. The third employs the addition of the dialkylzinc reagent 17 to the C10-C34 aldehyde 15 in the presence of a chiral bis-sulfonamide catalyst to establish the C10 stereocenter while adding the C1-C9 residue of the right chain. The C36 stereocenter and the butenolide are appended through condensation of the C1-C34 ester with the protected (S)-lactaldehyde 23.

Total Synthesis of the Nonadjacent Bis-Tetrahydrofuran Annonaceous Acetogenin Squamostatin-D.

A total synthesis of the Annonaceous acetogenin squamostatin-D is described. Key adjacent stereocenters were introduced through enantioselective addition of chiral oxygenated allylic tin and indium reagents to aldehyde subunits. The isolated stereocenter at C12 was constructed through addition of a functionalized organozinc reagent to an aldehyde subunit in the presence of a chiral bis-sulfonamide-titanium catalyst.