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Background: The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC)., Methods: Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2., Results: PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2., Conclusions: Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent.

Papain-like protease (PLpro) is one of two cysteine proteases involved in the proteolytic processing of the polyproteins of Severe acute respiratory syndrome coronavirus (SARS-CoV). PLpro also shows significant in vitro deubiquitinating and de-ISGylating activities, although the detailed mechanism is still unclear. Here, the crystal structure of SARS-CoV PLpro C112S mutant in complex with ubiquitin (Ub) is reported at 1.4 Å resolution. The Ub core makes mostly hydrophilic interactions with PLpro, while the Leu-Arg-Gly-Gly C-terminus of Ub is located in the catalytic cleft of PLpro, mimicking the P4-P1 residues and providing the first atomic insights into its catalysis. One of the O atoms of the C-terminal Gly residue of Ub is located in the oxyanion hole consisting of the main-chain amides of residues 112 and 113. Mutations of residues in the PLpro-Ub interface lead to reduced catalytic activity, confirming their importance for Ub binding and/or catalysis. The structure also revealed an N-cyclohexyl-2-aminethanesulfonic acid molecule near the catalytic triad, and kinetic studies suggest that this binding site is also used by other PLpro inhibitors. Overall, the structure provides a foundation for understanding the molecular basis of coronaviral PLpro catalysis.

Background: Little is known about the emergency department (ED) visits from drug-related injury among older adults in Taiwan. This study seeks to identify risk factors associated with adverse drug events (ADEs) leading to ED visits., Methods: We prospectively conducted a case-control study of patients 65years and older presenting to the ED. ED visits between March 1, 2009 and Feb 28, 2010 identified by investigators for suspected ADEs were further assessed by using the Naranjo Adverse Drug Reaction probability scale. For each patient with an ADE, a control was selected and time-matched from the ED population of the study hospital. The association between the risk of adverse drug events and triage, age, gender, serum alanine transaminase (ALT), serum creatinine, number of medications, and Charlson Comorbidity Index scores were analyzed using logistic regression., Results: Of 20,628 visits, 295 ADEs were physician-documented in older adults. Independent risk factors for ADEs included number of medications (adjusted odds ratio [OR]=4.1; 95% confidence interval [CI] 2.4-6.9 for 3-7 drugs; adjusted OR=6.4; 95% CI 3.7-11.0 for 8 or more drugs) and increased concentration of serum creatinine (adjusted OR=1.5; 95% CI 1.1-2.2). Diuretics, analgesics, cardiovascular agents, anti-diabetic agents and anticoagulants were the medications most commonly associated with an ADE leading to ED visits., Conclusions: This study suggests that prevention efforts should be focused on older patients with renal insufficiency and polypharmacy who are using high risk medications such as anticoagulants, diuretics, cardiovascular agents, analgesics, and anti-diabetic agents., (© 2013. Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. All rights reserved.)

Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and cyclooxygenase-1 (COX-1) is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of preneoplastic cells. We also successfully applied a ligand-docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer.

Background: The aim of this study was to identify the preoperative risk factors that may predict the requirement of massive blood transfusion during pediatric living donor liver transplantation., Material and Methods: The anesthesia charts of pediatric patients undergoing living donor liver transplantation were reviewed retrospectively. Patients were grouped into 2 categories based on the amount of intraoperative blood transfusion. Group I (GI) consists of patients who received massive blood transfusion and Group II (GII) consists of patients who did not receive massive blood transfusion. The patients' characteristics and preoperative data were compared between groups with the Mann-Whitney U test. Predictive risk factors for massive blood transfusion were analyzed by binary regression. A p value of <0.05 was regarded as significant. Data are given as mean ±SD., Results: A total of 198 pediatric patients were included in this study. Thirteen (6.5%) of the 198 pediatric patients undergoing living donor liver transplantation met the criteria of massive blood transfusion. The mean estimated blood volume of GI and GII was 724±322 and 1097±830 ml, respectively. The mean quantity of blood products given were 1018±591 and 187±220 ml for GI and GII, respectively. RBC was given to 67% of the patients, FFP was given to 18%, and only 1% received platelet transfusion. The patients who required massive blood transfusion were younger in age and had smaller body size, with prolonged INR (international normalized ratio) observed. INR, a measure of blood clotting time, was the only predictive factor that can impact intraoperative massive blood loss and subsequent blood transfusion. Each prolongation of 0.1 unit of INR elevates by 1.083-fold the risk of massive blood transfusion (95% C.I.=1.030-1.139, P=0.002)., Conclusions: Preoperative INR was the only predictive risk factor for massive blood transfusion during pediatric living donor liver transplantation. Increasing the ratio of FFP transfusion in patients with prolonged INR before or during pediatric LDLT is recommended.

Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation.

Purpose: Formulate phospho-sulindac (P-S, OXT-328) in a Pluronic hydrogel to be used as a topical anti-inflammatory agent and study its efficacy, safety and pharmacokinetics in an arthritis model., Methods: LEW/crlBR rats with Freund's adjuvant-induced arthritis were treated with P-S formulated in Pluronic hydrogel (PSH). We determined the clinical manifestations of arthritis including the locomotor activity of the rats; evaluated joints for inflammation, bone resorption, cartilage damage, COX-2 expression and NF-κB activation; assayed plasma IL-6 and IL-10 levels; and studied the pharmacokinetics of P-S in rats after topical or oral administration., Results: PSH applied at the onset of arthritis or when arthritis was fully developed, suppressed it by 56-82%, improved the locomotor activity of the rats 2.1-4.4 fold, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation and COX-2 expression but not plasma IL-6 and IL-10 levels. There were no side effects. PSH produced rapidly high local levels of P-S with <14% of P-S reaching the circulation, while orally administered P-S was rapidly metabolized generating much lower joint levels of P-S., Conclusions: Topical application of PSH is efficacious and safe in the treatment of Freund's adjuvant-induced arthritis; has a favorable pharmacokinetic profile; and likely acts by suppressing key pro-inflammatory signaling pathways.

Background: Phosphatase of regenerating liver (PRL) family is classified as class IVa of protein tyrosine phosphatase (PTP4A) that removes phosphate groups from phosphorylated tyrosine residues on proteins. PRL phosphatases have been implicated in a number of tumorigenesis and metastasis processes and are highly conserved. However, the understanding of PRL expression profiles during embryonic development is very limited., Results: In this study, we demonstrated and characterized the comprehensive expression pattern of Drosophila PRL, amphioxus PRL, and zebrafish PRLs during embryonic development by either whole mount immunostaining or in situ hybridization. Our results indicate that Drosophila PRL is mainly enriched in developing mid-guts and central nervous system (CNS) in embryogenesis. In amphioxus, initially PRL gene is expressed ubiquitously during early embryogenesis, but its expression become restricted to the anterior neural tube in the cerebral vesicle. In zebrafish, PRL-1 and PRL-2 share similar expression patterns, most of which are neuronal lineages. In contrast, the expression of zebrafish PRL-3 is more specific and preferential in muscle., Conclusions: This study, for the first time, elucidated the embryonic expression pattern of Drosophila, amphioxus, and zebrafish PRL genes. The shared PRL expression pattern in the developing CNS among diverse animals suggests that PRL may play conserved roles in these animals for CNS development.

Dosimetric comparisons between RapidArc (RA) and conventional Intensity-Modulated Radiation Therapy (IMRT) techniques for nasopharyngeal carcinoma (NPC) were performed to address differences in dose coverage of the target, sparing of organs-at-risk (OARs), delivery of monitor units (MUs) and time, to assess whether the RA technique was more beneficial for treatment of NPC. Eight NPC patients (Stages I-IV), who had completed RA treatment, were selected for this study. Computed tomography data sets were re-planned using 7-fields fixed beam IMRT. Quantitative measurements of dose-endpoint values on the dose-volume histograms were carried out for evaluation of: (i) dose homogeneity (D5% - D(95%)); (ii) degree of conformity (CI9(5%)); (iii) tumor control probability (TCP); (iv) doses to OARs; (v) normal tissue complication probability (NTCP); (vi) treatment time; and (vii) MUs. RA plans achieved better dose conformity and TCP in planning target volumes (PTVs). Target dose homogeneity was not as high as for IMRT plans. Doses to tempero-mandibular joints, clavicles, parotid glands and posterior neck, and their NTCPs were significantly lower in RA plans (P < 0.05). Mean doses to the brainstem and spinal cord were slightly lower in IMRT plans. RA plans allowed for a mean reduction in MUs by 78% (P = 0.006), and a four-fold reduction in treatment delivery times, relative to IMRT plans. RA plans showed superior, or comparable, target coverage and dose conformity in PTVs, but at the expense of inferior dose homogeneity. RA plans also achieved significant improvements in dose reduction to OARs and healthy tissue sparing. A significant reduction in treatment delivery time for RA treatment technique was also noted.

Objectives: We determined whether racial/ethnic disparities existed in coverage by type of 100% smoke-free private workplace, restaurant, and bar laws from 2000 to 2009., Methods: We combined US census population data and the American Nonsmokers' Rights Foundation US Tobacco Control Database to calculate the percentage of individuals in counties covered by each type of law by race/ethnicity from 2000 to 2009., Results: More of the US Hispanic and Asian populations were covered by 100% smoke-free restaurant and bar laws than non-Hispanic White and non-Hispanic Black populations. Asian coverage by smoke-free bars laws increased from 36% to 75%, and Hispanic coverage increased from 31% to 62%, compared with 6% to 41% for non-Hispanic Blacks and 8% to 49% for non-Hispanic Whites., Conclusions: Hispanics and Asians benefited more from the rapid spread of smoke-free law coverage, whereas non-Hispanic Blacks benefited less. These ethnic disparities suggest a likely effect of geographic region and may provide a basis for more effective, community-based, and tailored policy-related interventions, particularly regarding areas with high concentrations of non-Hispanic Blacks.

Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase- and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Expression of Rab25, which is located in the 1q amplicon present at high frequency in many cancer lineages, promotes cancer cell survival under multiple stress conditions. While Rab proteins play essential roles in all stages of vesicle trafficking, the functions and endogenous cargoes for Rab25 remain to be fully elucidated. Osteoprotegerin (OPG) is a secreted glycoprotein that binds the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) thus preventing it from activating the TNF-family death receptors. In the present study, we demonstrated that Rab25 regulates OPG at both the transcription and secretion level., Methods: The effect of Rab25 on OPG expression and its effect on TRAIL-induced cell were examined in both ovarian and breast cells. Signal transduction pathways regulation of OPG expression was examined in cells using pharmacogenetic approaches., Results: Expression of Rab25 to levels similar to those in tumors with RAB25 amplification, increased OPG mRNA expression and secretion from ovarian and breast cancer cell lines, whereas down regulation with Rab25 specific siRNA decreased OPG secretion and sensitized cells to TRAIL-induced cell death. Critically, exogenous OPG mimicked the effects of Rab25 on cell death supporting the contention that Rab25-induced accumulation of OPG protects cancer cells from the effects of TRAIL. Rab25 cooperates with EGFR-mediated MAPK signaling to increase TRAIL production and release. Importantly, priming cells with EGFR inhibitors increased sensitivity to TRAIL-induced cells death regardless of the Rab25 background., Conclusion: Increased OPG expression induced by Rab25 may provide a mechanistic advantage for cancer development and progression.

Background: After liver transplantation (LT), re-exploration of the abdomen to check for bleeding is sometime required. Our study aimed to identify the predictive factors by analysis of preoperative and intraoperative presentations that may impact the re-exploration for hemostasis., Material/methods: We selected 522 consecutive recipients from the Liver Transplant Program database and medical records between January 1, 1994 and December 1, 2009 in our hospital. Demographic data (age, sex, body mass index, weight, MELD score), preoperative laboratory tests (Hb, platelet, albumin, bilirubin, INR, APTT), and intraoperative presentations (ascites and blood loss, crystalloids, 5% albumin infused, blood products used (such as LPRBC, RBC, FFP, platelet, cryoprecipitate), urine output, Hb at end of operation, and anesthesia) were collected for primary comparison. Potential predictors found by univariate comparison at p<0.1 were put into a multiple binary logistic regression model., Results: Thirty-eight (7.3%) recipients required re-exploration for hemostasis after LDLT; 80% needed re-exploration only once. In univariate analysis, recipients transfused with FFP >10 ml/kg had a 4.2-fold increased risk of re-exploration (p<0.001). Thirteen potential predictors by univariate comparison at p<0.1 were selected into a multiple binary logistic regression. Fresh frozen plasma (FFP) transfused was the sole predictor., Conclusions: Each elevation of 1ml of transfused FFP per kg is associated with a 1.033-fold increased incidence of re-exploration for hemostasis. Patients transfused with more than 10 ml/kg FFP during LT require more intensive management within 72 hours due to increase risk of postoperative bleeding.

Derailed endocytosis is a hallmark of cancer. The endocytic pathway, as demonstrated by our laboratory, is a frequent target of genomic aberrations in cancer and plays a critical role in the maintenance of cellular polarity, stem cell function, bioenergetics, proliferation, motility, invasion, metastasis, apoptosis and autophagy. The Rab GTPases, along with their effectors, are critical regulators of this endocytic machinery and can have a huge impact on the cellular itinerary of growth and metabolism. Rab25 is an epithelial-cell-specific member of the Rab GTPase superfamily, sharing close homology with Rab11a, the endosomal recycling Rab GTPase. RAB25 has been implicated in various cancers, with reports presenting it as both an oncogene and a tumour-suppressor gene. At the cellular level, Rab25 was shown to contribute to invasiveness of cancer cells by regulating integrin trafficking. Recently, our laboratory uncovered a critical role for Rab25 in cellular energetics. Assimilating all of the existing evidence, in the present review, we give an updated overview of the complex and often context-dependent role of Rab25 in cancer.

Purpose: To investigate the metabolism of phospho-aspirin (PA, MDC-22), a novel anti-cancer and anti-inflammatory agent., Methods: The metabolism of PA was studied in the liver and intestinal microsomes from mouse, rat and human., Results: PA is rapidly deacetylated to phospho-salicylic acid (PSA), which undergoes regioselective oxidation to generate 3-OH-PSA and 5-OH-PSA. PSA also can be hydrolyzed to give salicylic acid (SA), which can be further glucuronidated. PA is far more stable in human liver or intestinal microsomes compared to those from mouse or rat due to its slowest deacetylation in human microsomes. Of the five major human cytochrome P450 (CYP) isoforms, CYP2C19 and 2D6 are the most active towards PSA. In contrast to PSA, conventional SA is not appreciably oxidized by the CYPs and liver microsomes, indicating that PSA is a preferred substrate of CYPs. Similarly, PA, in contrast to PSA, cannot be directly oxidized by CYPs and liver microsomes, indicating that the acetyl group of PA abrogates its oxidation by CYPs., Conclusions: Our findings establish the metabolism of PA, reveal significant inter-species differences in its metabolic transformations, and provide an insight into the role of CYPs in these processes.

Purpose: To evaluate the antitumor efficacy of solid lipid nanoparticle-encapsulated phospho-sulindac (SLN-PS) in human lung cancer., Methods: PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice., Results: SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (≈ 14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors., Conclusions: Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation.

RAB25 belongs to the Rab family of small GTPases and is implicated in the development of various types of human cancer. To evaluate the role of RAB25 in ovarian cancer, RAB25 was knocked down by siRNA in HEY and ES‑2 human ovarian cancer cells. Autophagy, cell growth and cell apoptosis were evaluated. The results showed that knockdown of RAB25 increased acidic vesicle organelles and GFP-microtubule-associated protein 1 light chain 3 punctate fluorescence in ovarian cancer cells. Autophagy that promoted by knockdown of RAB25 was not observed in cells where the ERK1/2 signaling pathway had been inhibited by U0126. Knockdown of RAB25 reduced cell cycle progression and cell growth. Apoptosis of ovarian cancer cells could be induced by knockdown of RAB25. These results support the tumorigenic role of RAB25 in ovarian cancer cells.

Phospho-sulindac (P-S, OXT-328), a novel sulindac derivative, has shown superior anticancer efficacy and safety compared to sulindac. In this study, we investigated the efficacy of topical P-S hydrogel in the treatment of non-melanoma skin cancer in preclinical models. P-S is a potent inhibitor of A431 epidermoid carcinoma in vitro and achieves this effect by inhibiting cell proliferation and inducing apoptosis. The anticancer efficacy of topical and oral P-S was further evaluated in mice bearing A431 intradermal xenografts. Compared to the controls, topical P-S hydrogel inhibited the A431 xenografts by 70.5% (p<0.01), while oral P-S inhibited it by 43.4% (p<0.05), being significantly less effective than topical P-S (p=0.017). Topical P-S hydrogel generated significant levels (>500 nmol/g tumor tissue) of intact P-S in the tumors, accounting for 92.5% of the total metabolites in the A431 xenografts. This local delivery of high levels of intact P-S to the A431 xenografts is an important contributor to the potent activity of topical P-S and no local or systemic side effects were noted in the treatment group. Thus, topical P-S is a promising treatment modality against non-melanoma skin cancer and merits further evaluation.

Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferation and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment of mixtures of cultured breast CSCs and breast cancer cells with PS preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p = .06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p < .05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/β-catenin pathway by stimulating the degradation of β-catenin and its relocalization to the cell membrane and also blocked the epithelial-mesenchymal transition and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling., (Copyright © 2012 AlphaMed Press.)

Little research has been conducted on the influence of macroeconomic environments on smoking among blue-collar workers, a group with high smoking prevalence and that is especially vulnerable to the effects of changing economic circumstances. Using data from 52,418 construction workers in the Tobacco Use Supplement to the United States Current Population Survey, we examined the association of labor market shock, cigarette prices, and state antismoking sentiments with smoking status and average number of cigarettes smoked daily. Data analysis included the use of multiple linear and logistic regressions, which employed the sampling and replicate weights to account for sampling design. Unemployed, American-Indian, lower-educated and lower-income workers had higher smoking rates. Labor market shock had a quadratic association, which was non-significant for smoking status and significant for number of cigarettes. The association of cigarette prices with smoking status became non-significant after adjusting for state-level antismoking sentiment. State-level antismoking sentiment had significant quadratic association with smoking status among employed workers and significant quadratic association with number of cigarettes for all smokers. The study highlights how both workplace-based smoking cessation interventions and antismoking sentiments could further contribute to disparities in smoking by employment status., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Purpose: Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs)., Experimental Approach: The CYP/FMO-catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach., Key Results: The CYP isoforms catalyse the oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac respectively. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho-sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho-sulindac may be due to their greater lipophilicity, a key parameter for CYP binding., Conclusions and Implications: CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses ("the nanomolar rule"). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed.

Background: Adverse drug events (ADE) have been studied widely in hospitalised and emergency department (ED) patients. Less is known about the ED visits of drug-related injury in Taiwan. This study seeks to determine the incidence, risk and patient outcomes of ADE in an ED population., Methods: We conducted a prospective observational cohort study of patients 18 years and older presenting to the ED of an urban, tertiary medical centre. ED visits between 1 March 2009 and 28 February 2010 identified by investigators for suspected ADE were further assessed by using the Naranjo Adverse Drug Reaction probability scale. Outcomes (ED disposition, injury severity and preventability) and associated variables (triage, gender, drug category, number of drugs, Charlson comorbidity index score and ADE mechanism) were measured., Results: Of 58,569 ED visits, 452 patients (0.77%) had physician-documented ADE. 24% of patients with ADE were hospitalised with life-threatening conditions, with a mortality rate of 10.0%. The majority of ADE were considered preventable (73.4%), and the unintentional overdose was the most common cause. Cardiovascular agents accounted for the most ADE (25.8%) and consisted of 65.3% of ADE in patients aged 65,years and older. Risk factors for ADE-related hospitalisation were elderly age (odds ratio (OR) 1.9, 95% confidence interval (CI) 1.1-3.4), severity of ADE (OR 6.9, 95% CI 3.3-14.5) and higher Charlson comorbidity index scores (OR 3.4, 95% CI 2.0-5.7)., Conclusion: ADE-related ED visits are not uncommon in Taiwan and many cases are preventable. ED-based surveillance may provide useful information for monitoring outpatient ADE., (© 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Objective: The aims of current study were: 1) to evaluate the incidence of lung atelectasis; and 2) to investigate whether or not the position of the endotracheal (ET) tube is associated with this complication., Methods: The medical records and chest roentgenograms of 183 pediatric patients who underwent living-donor liver transplantation were retrospectively reviewed and analyzed. Patients without atelectasis were grouped in group I (GI) and those with atelectasis in group II (GII). The patients' characteristics and ET tube level between groups were compared with unpaired Student's t test. Multiple binary logistic regressions were also performed to identify the important risk factors associated with lung atelectasis., Results: Right upper lung (RUL) atelectsis could be found in ET tube at any level from T1 to T5, with incidence rates of 12.7%, 15.2%, 26.3%, 6.7%, and 100% for T1, T2, T3, T4, and T5, respectively. The incidence of atelectasis is 16.6%, and all of the atelectasis occurred in the RUL. No significant difference between groups was observed in the patients' characteristics, except for the amount of preoperative ascites. The likelihood of this risk factor could not be confirmed by multivariate binary logistic regression analysis., Conclusions: The incidence of lung atelectasis in our study was 16.6%, which all occurred in the RUL. No predictive risk factor from the patients' characteristics could be found, and no correlation between the level of the ET tube and the occurrence of RUL atelectasis could be observed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to compare the hemodynamic changes caused by clamping of the inferior vena cava and portal vein in biliary atresia (BA) versus glycogen storage disease (GSD) patients undergoing living-donor liver transplantation (LDLT) without venovenous bypass., Methods: We reviewed retrospectively the anesthesia charts of pediatric LDLT patients. Age, weight, height, blood loss, blood product use and fluid replacement between groups were compared with Mann-Whitney test, and systolic blood pressure (SBP), heart rate (HR), central venous pressure (CVP) before clamping of the inferior vena cava, and 4 measurements during anhepatic phase and 5 minutes after reperfusion were compared with analysis of variance., Results: One hundred four BA patients (GI) and 12 GSD patients (GII) showed mean total blood loss among GI to be more than among GII, but the blood products and crystalloids infused during the operation were not significantly different. The changes of SBP, HR, and CVP after clamping of the IVC were significantly different between groups. CVP of GII was lower than GI, indicating that venous return among GII was more affected, subsequently showing lower SBP and higher HR., Conclusions: Total clamping of the inferior vena cava resulted a greater decrease in CVP in GII with subsequently lower SBP and faster HR compared with GI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The potassium content of University of Wisconsin solution (UW) is 125 mEq/L and that of histidine-tryptophan-ketoglutarate solution (HTK) only 9 mEq/L. The aim of the present study was to analyze their effects to change potassium levels on reperfusion among patients undergoing living-donor liver transplantation., Methods: Anesthesia records of adult living-donor liver transplant patients were reviewed retrospectively. Patients received liver graft preserved in UW were grouped in group I (GI) and HTK in group II (GII). The potassium levels in the anheptic phase were compared with those 5 minutes after reperfusion using paired Student t tests. P values of <.05 were regarded to be significant., Results: Eighty-five GI patients showed the potassium significantly decreased from 3.76±0.70 to 3.60±0.74, whereas the change among 355 GII patients was almost unremarkable: 4.00±0.57 to 3.96±0.06 mEq/L., Conclusions: Although UW contains a higher potassium content, it seems to have no negative impact on changes in serum potassium levels; in contrast it decreased the potassium level significantly at 5 minutes after reperfusion. Both preservation solutions maintain the patients' potassium levels within the normal range., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: To compare the efficacy and dose requirements for intravenous (IV) patient-controlled analgesia (PCA) with morphine only versus morphine with ketorolac for living liver donors after partial hepatectomy., Patients and Methods: Eighty living liver donors who had undergone partial hepatectomy received 3 days of IV PCA for postoperative pain control. Some were prescribed a PCA with morphine alone (group I) or morphine with ketorolac (group II), while both had a rescue dose of IV fentanyl (25 μg). The daily consumption of morphine, pain score, and frequency of rescue fentanyl doses were compared retrospectively using the Mann-Whitney U test and the incidence of side effects with chi-square tests; a P value of .05 was regarded as significant. All the data are shown as mean values±standard deviations., Results: The 80 subjects were distributed as 57 group I and in 23 group II patients. The daily consumption of morphine, Visual Analogue Scale (VAS) and side effects were not different between the groups, but group II required significantly fewer rescue doses to achieve pain relief., Conclusion: Both regimens provided acceptable pain control with daily VAS less than 3. The use of ketorolac in the PCA did not reduce the daily total morphine requirements with a similar incidence of side effects but a significantly reduced requirement for rescue doses, which subsequently reduced the work load of personnel in the pain control service., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target., (Copyright © 2012 EMBO Molecular Medicine.)

Phospho-nonsteroidal anti-inflammatory drugs (phospho-NSAIDs) are novel NSAID derivatives with improved anticancer activity and reduced side effects in preclinical models. Here, we studied the metabolism of phospho-NSAIDs by carboxylesterases and assessed the impact of carboxylesterases on the anticancer activity of phospho-NSAIDs in vitro and in vivo. The expression of human liver carboxylesterase (CES1) and intestinal carboxylesterase (CES2) in human embryonic kidney 293 cells resulted in the rapid intracellular hydrolysis of phospho-NSAIDs. Kinetic analysis revealed that CES1 is more active in the hydrolysis of phospho-sulindac, phospho-ibuprofen, phospho-naproxen, phospho-indomethacin, and phospho-tyrosol-indomethacin that possessed a bulky acyl moiety, whereas the phospho-aspirins are preferentially hydrolyzed by CES2. Carboxylesterase expression leads to a significant attenuation of the in vitro cytotoxicity of phospho-NSAIDs, suggesting that the integrity of the drug is critical for anticancer activity. Benzil and bis-p-nitrophenyl phosphate (BNPP), two carboxylesterase inhibitors, abrogated the effect of carboxylesterases and resensitized carboxylesterase-expressing cells to the potent cytotoxic effects of phospho-NSAIDs. In mice, coadministration of phospho-sulindac and BNPP partially protected the former from esterase-mediated hydrolysis, and this combination more effectively inhibited the growth of AGS human gastric xenografts in nude mice (57%) compared with phospho-sulindac alone (28%) (p = 0.037). Our results show that carboxylesterase mediates that metabolic inactivation of phospho-NSAIDs, and the inhibition of carboxylesterases improves the efficacy of phospho-NSAIDs in vitro and in vivo.

Background: Small-cell lung cancer (also known as SCLC) is an aggressive form and untreated patients generally die within about 3 months. To obtain further insight into mechanism underlying malignancy with this cancer, an miRNA synergistic regulatory network was constructed and analyzed in the present study., Method: A miRNA microarray dataset was downloaded from the NCBI GEO database (GSE27435). A total of 546 miRNAs were identified to be expressed in SCLC cells. Then a miRNA synergistic network was constructed, and the included miRNAs mapped to the network. Topology analysis was also performed to analyze the properties of the synergistic network. Consequently, we could identified constitutive modules. Further, common target genes of each module were identified with CFinder. Finally, enrichment analysis was performed for target genes., Results: In this study, a miRNA synergistic network with 464 miRNAs and 2981 edges was constructed. According to the topology analysis, the topological properties between the networks constructed by LC related miRNAs and LC unrelated miRNAs were significantly different. Moreover, a module cilque0 could be identified in our network using CFinder. The module included three miRNAs (hsa-let-7c, hsa-let-7b and hsa-let-7d). In addition, several genes were found which were predicted to be common targets of cilque0. The enrichment analysis demonstrated that these target genes were enriched in MAPK signaling pathways., Conclusions: Although limitations exist in the current data, the results uncovered here are important for understanding the key roles of miRNAs in SCLC. However, further validation is required since our results were based on microarray data derived from a small sample size.

The needle-warming technique combines acupuncture and moxibustion, and it is commonly practised in China to relieve pain conditions. However, burning of moxa has many disadvantages. This study examined the temperature and safety profiles of such technique. First, skin temperature changes during needle-warming were examined in anesthetized animals to determine the safe distance for needle-warming moxibustion in human subjects. Then, the practical distance for needle-warming in human subjects were verified. Finally, the temperature profiles of the needle during needle-warming moxibustion were examined using an infrared camera. Our results show that during needle-warming moxibustion there is little heat being conducted into deep tissue via the shaft of the needle, and that the effective heating time to the acupoint is rather short compared to the period of moxibustion. These findings suggest that the needle-warming technique is an inefficient way of acupoint thermal stimulation and should be modified and improved using new technologies.

Background: More states and localities are passing restrictions on smoking in public places and workplaces., Purpose: To determine what, if any, association exists between enactment of strong laws making public places or workplaces smokefree on adoption of voluntary smokefree-home policies, particularly whether such laws are associated with increased smoking at home., Methods: Logistic regressions were used to estimate the OR of a person living with a 100% smokefree-home rule as a function of individual characteristics, household composition, and whether or not the residential region is covered by clean indoor air laws. The data came from successive waves of the Tobacco Use Supplement to Current Population Survey (TUS-CPS) for the years 1992-2007, and the American Nonsmokers' Rights Foundation database of state and local government clean indoor air laws. Analysis was conducted in 2010 and 2011., Results: Living in a county fully covered by a 100% clean indoor air law in workplaces or restaurants or bars is associated with an increased likelihood of having a voluntary 100% smokefree-home rule both for people living with smokers (OR=7.76, 95% CI=5.27, 11.43) and not living with smokers (OR=4.12, 95% CI=3.28, 5.16)., Conclusions: Strong clean indoor air laws are associated with large increases in voluntary smokefree-home policies both in the homes with and without smokers. These results support the hypothesis of norm spreading of clean indoor air laws., (Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

This study examines the effect of contraceptive knowledge on fertility during the period when Taiwan's family planning programs were in effect. This study contributes to previous studies by directly measuring individual's contraceptive knowledge and fertility, as well as applying an instrumental variable approach to gauge the effect of contraceptive knowledge on fertility. The results indicate that mass media and social networks play important roles in disseminating contraceptive knowledge. This study finds that women transform their knowledge into behavior-that is, contraceptive knowledge reduces fertility, no matter which fertility metric is measured (life-time fertility or probability of giving birth).

Two adult patients who underwent living donor liver transplantation with acute accumulation of right-side pleural effusion are reported. The chest X-ray of patient 1 showed no specific finding 3 days before the operation, and patient 2 was known to have pleural effusion and underwent pigtail drainage before transplant. After anesthesia induction and insertion of central venous catheters, a portable chest radiograph was taken to confirm the positions of the central venous catheters and endotracheal tube. A massive right-side pleural effusion was noted unexpectedly in both patients. Approximately 2,000 ml transudative fluid was surgically drained through the right diaphragm in patient 1 upon opening of the abdominal cavity. The acute accumulation of massive pleural fluid in patient 2 was caused by clamping of the pigtail drainage tube during patient transfer to the operating room; upon unclamping of the tube, 2,000 ml fluid was drained. The intraoperative and postoperative transplant courses of both patients were uneventful. Both were discharged from the hospital in stable condition. Our cases suggest that chest X-ray after induction of the anesthesia and before liver transplantation surgery is recommended. In addition to documenting the positions of the central venous catheters and endotracheal tube, a potential life-threatening pleural effusion requiring appropriate management may be detected.

Objectives: Liver retransplantation (Re-LT) is the effective therapy for irreversible liver graft failure after primary liver transplantation (LT). The challenges faced by the operative team in the Re-LT setting have been seldom elucidated. Our aim is to analyze the differences in fluid management in primary LT and Re-LT during the surgical procedure., Methods: The anesthesia charts of 16 patients who underwent both primary LT and Re-LT at our center in the space from October 1995 to May 2009 were analyzed. Group 1 (GI) consisted of patients who underwent primary LT, whereas patients in Group 2 (GII) were patients in GI but underwent Re-LT. GI was further divided into two subgroups depending on whether they had previous abdominal surgery before primary LT (GIB) or not (GIA). Wilcoxon signed-ranks test was used to compare GI and GII, and GIA and GIB. A p value less than 0.05 was regarded as significant. Data were given as mean ± standard deviation., Results: Blood loss was significantly increased from 48.9 ± 106 mL/kg in GI to 251.5 ± 242 mL/kg in GII. Consequently more blood products, crystalloids, sodium bicarbonate, calcium chloride, and neosynephrine were required to support the hemodynamics in GII. In GI, GIB tended to bleed more and required more blood transfusions than GIA., Conclusion: More bleeding is expected in Re-LT than primary LT. Additional anesthetic personnel, more intravenous lines, and blood and blood products should be readily available to deal with the emergent fluid and hemodynamic resuscitations in anesthesia for Re-LT., (Copyright © 2011. Published by Elsevier B.V.)

Aim: To inspect Denonvilliers' fascia and its relationship with neighboring oncologically and functionally important anatomic structures by laparoscopic approach., Methods: A total of 112 patients with middle or low rectal cancer were successfully treated by laparoscopic total mesorectal excision (TME). Digital versatile disk (DVD) recordings were retrieved for scrutiny of the whole dissection process of Denonvilliers' fascia and its contiguous anatomic structures., Results: As highlighted in the attached video footage, for nearly all male patients (91%, n = 58), the boundaries of Denonvilliers' fascia could be clearly recognized by laparoscopy. Denonvilliers' fascia, varying in nature from a fragile translucent fibrous layer to a tough leathery membrane, manifests itself as a trapezoidal "apron" covering the glistening fatty tissues of the anterior mesorectum. Anterior dissection in TME can be efficiently continued downwards "in front of" Denonvilliers' fascia. When the prostate is reached, the natural surgical plane halts, and the dissection plane should be shifted to behind this fascia. In contrast, in female patients, Denonvilliers' fascia was much less obvious as a distinct fibrous layer than in male patients. The most appropriate term for the structure in between the rectum and vagina may be rectovaginal septum, in which there is no natural surgical plane, rather than Denonvilliers' fascia., Conclusions: By laparoscopic approach, the nature of Denonvilliers' fasciae in male and female patients can be better defined and facilitates more precise laparoscopic total mesorectal excision for rectal cancer.

The endocytotic machinery imports, transports and exports receptors and associated molecules between the plasma membrane and various cytoplasmic chambers resulting in selective recycling, degradation, or secretion of molecules and signaling complexes. Trafficking of receptors, growth factors, nutrients, cytokines, integrins as well as pathogens dictates the kinetics and magnitude of signal transduction cascades. Understandably, alterations in the 'fate' of such cargo complexes have profound physiologic and pathophysiologic implications. Rab GTPases regulate endocytosis by decorating intracellular vesicles and targeting these vesicles along with their cargoes to appropriate subcellular compartments. In the last decade, the number of genetic diseases driven by germline mutations in Rab GTPases or their interacting proteins, has increased and there is growing evidence of aberrant Rab GTPase function in acquired pathophysiologies such as immune deficiency, infection, obesity, diabetes and cancer., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A vertical transect investigation on Picea schrenkiana var. tianschanica forests was conducted at five different longitudinal sites (Zhaosu, Gongliu, Wusu, Urumqi, and Hami) in Tianshan Mountains, and the distribution pattern of P. schrenkiana var. tianschanica population at each site was analyzed based on theoretical distribution model and aggregation intensity index. On the whole, the P. schrenkiana var. tianschanica population in Tianshan Mountains presented a clumped distribution, and the distribution pattern and clustering intensity were affected by the developmental stages of stem and the ranges of altitude to some degree. The clustering intensity increased with the increasing size (DBH) or developmental stage of stem, and had the highest values at high altitudes.

Background: This study aimed to evaluate the technical feasibility of laparoscopic total mesorectal excision (TME) for the treatment of low rectal cancer after concurrent chemoradiation therapy (CCRT) with bevacizumab and FOLFOX., Methods: Patients with clinical T3, T4, or N1-2 rectal cancer were subjected to a preoperative CCRT protocol with FOLFOX and bevacizumab (5 mg/kg) biweekly for 6 cycles followed by a standardized laparoscopic TME procedure, as detailed in the attached video., Results: The treatment protocol was completed by 28 patients. Scrutiny of the video indicated that the dissection plane was a little blurred due to preoperative CCRT, but this did not significantly increase the technical difficulties. Laparoscopic TME was efficiently performed with acceptable operation time (214.4 ± 44.4 min). However, the median blood loss (420 ml; range, 120-1,200 ml) in this series was significantly greater than in the historic series without bevacizumab therapy. Bevacizumab seems not to increase the severity of FOLFOX-related liver steatosis and sinusoidal dilation. One operative mortality (3.6%) occurred. Six patients (21.4%) presented with postoperative complications including upper gastrointestinal bleeding, deep vein thrombosis, pelvic abscess, wound infection, enterocutaneous fistula, and perineal fistula. The patients presented with mild postoperative pain and had a quick convalescence. The addition of bevacizumab to FOLFOX achieved a superior pathologic response for 78.3% of the patients, whose residual tumor cells were very few (< 10% microscopic field)., Conclusions: Based on the controllable surgical complications and minimal invasiveness in the current patient series, laparoscopic TME is shown to be technically feasible and can be recommended for patients with advanced lower rectal cancer requiring preoperative CCRT using bevacizumab as the additional therapeutic agent.

Cardiac dysfunction is common in patients with severe sepsis and septic shock. We present a 71-year-old woman with Escherichia coli urosepsis and sepsis-induced myocardial injury masquerading as non-ST elevated myocardial ischemia. Spontaneous psoas hematoma requiring blood transfusion and intracranial hemorrhage developed after antiplatelet and anticoagulant therapies, even in therapeutic doses. The patient was managed conservatively and recovered well with minor residual hemiparesis. Bleeding complications are a common risk of antithrombotic therapy. It is therefore crucial to weigh the impact of efficacy against safety. Old age, female gender, renal insufficiency and sepsis character increased the risk of bleeding in this patient. A misinterpretation of elevated cardiac troponin I may give rise to a diagnostic dilemma and cause unnecessary morbidity.

Background: In liver transplantation, blood loss can be massive, requiring timely and rapid fluid resuscitation. Maintaining proper documentation of fluids during such situations can be difficult and may often lead to counting errors. We report our method of documentation of fluid management during liver transplantation., Material/methods: Each unit of red blood cells (125 cc) that comes from the blood bank had a serial number of 10 Arabic numbers which were verified and double-checked. Each unit was then numbered and labeled as encircled absolute numbers (e.g., 1, 2, 3). Both the encircled number and the serial number of the bag were recorded in the anesthesia chart. Each liter of crystalloids and colloids were similarly numbered and labeled in sequence for ease of calculation. At the end of the operation, the nurse anesthetist ascertains that the number of units of blood products used matched with the number of units supplied by the blood bank. The total amounts of crystalloids and colloids given during the operation was also calculated, rechecked and written in a tabulated form., Results: Since the introduction of this method, we have detected and readily corrected 3 incidences of counting discrepancy in the total units of blood products transfused and the products supplied by the blood bank. Moreover, our records have now become transparent data that are easily retrievable for future scientific research., Conclusions: Our method of documentation of fluid management during liver transplantation is easy, accurate and effective.

Two sulfur-containing compounds, (S)-2-amino-5-((R)-1-carboxy-2-((E)-3-(4-hydroxy-3-methoxyphenyl)allylthio)ethyl-amino)-5-oxopentanoic acid (1) and (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-((E)-3-(4-hydroxyphenyl)allylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (2), and one 1H-pyrrole-2-carboxylic acid derivative, 6-(3-(1H-pyrrole-2-carbonyloxy)-2-hydroxypropoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid (3), together with eighteen known phenolic compounds, were isolated from the fruits of pineapple. Their structures were elucidated by a combination of spectroscopic analyses. Some of these compounds showed inhibitory activities against tyrosinase. The half maximal inhibitory concentration values of compounds 1, 4, 5, 6, 7 are lower than 1 mM. These compounds may contribute to the well-known anti-browning effect of pineapple juice and be potential skin whitening agents in cosmetic applications., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Ovarian epithelial cancer is the leading cause of death among gynecological malignancies. FSH may increase the risk of ovarian malignancy and play an important role in ovarian carcinogenesis. Our previous studies showed that FSH increases the expression of VEGF through survivin. In this study, the function and mechanism of FSH in ovarian cancer were further explored. We found that FSH promoted proliferation and prevented apoptosis of ovarian cancer cells by activating survivin through the SAPK/JNK and PI3K/AKT pathways. FSH also down-regulated the expression of programmed cell death gene 6 (PDCD6) and death receptor 5 (DR5), two molecules required for induction of apoptosis. RNA interference was applied to knock down survivin and PDCD6 expression, and we found that the blockage of survivin reversed the effects of FSH on apoptosis and proliferation, whereas knock down of PDCD6 enhanced these effects. The expression of DR5, cyclin D1, and cyclin E correlated with survivin expression, but PDCD6 did not. Using immunohistochemical staining, we further showed that ovarian serous cystadenocarcinoma samples had higher expression of survivin than did benign ovarian cystadenoma and borderline cystadenoma samples (P<0.01). Furthermore, survivin expression in the ovarian serous cystadenocarcinoma specimens was correlated with disease stage (P<0.05). Our results suggest that FSH promotes ovarian cancer development by regulating the expression of survivin, PDCD6, and DR5. Greater understanding of the molecular mechanisms of FSH in ovarian epithelial carcinogenesis and development will ultimately help in the development of a novel targeted therapy for ovarian cancer.

Two new spirostanoides, filiasparosides E (1) and F (2), one new furostanoside, filiasparoside G (3), and one new ecdysterone, stachysterone A-20, 22-acetonide (4), together with six known steroidal saponins, asparagusin A (5), filiasparoside A (6), filiasparoside B (7), aspafilioside A (8), aspafilioside B (9), and filiasparoside C (10) were isolated from the roots of Asparagus filicinus Buch.-Ham. Their structures were elucidated on the basis of spectroscopic and chemical evidence. Compounds 1-10 were investigated for their cytotoxicities against human breast adenocarcinoma MDA-MB-231 cell line and compounds 8-10 exhibited cytotoxic activities with IC(50) values ranging from 3.4 to 6.6microM.

Periodic Ag line arrays with different line pitches from 500 nm to 950 nm on ITO coated glass substrates have been fabricated by using electron-beam lithography (EBL) technique for studying the color light guide in a display system. The patterned Ag line array is used as a light outcoupling and color-selection component due to the emission wavelength changed by the Ag line arrays with different periodic distances that could achieve color variation. We have demonstrated that the ITO coated glass substrates containing periodic Ag line arrays with varied line pitches can be used as a color filter in a display device. This means that with a proper metallic nanostructure layer, the red, green, and blue colors in a display system can be obtained without a traditional color filter for modern multi-applications of optoelectronic display devices.

Resveratrol (3,4',5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinson's disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4'-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

The phytochemical profiles of Morus nigra roots and twigs were compared by HPLC with those of the old and young twigs of Morus alba which are known to contain oxyresveratrol and mulberroside A as major components. It was found that M. nigra root extract contains some unknown natural products with potential tyrosinase inhibitory activity. The extract (95% ethanol) of the roots of M. nigra was further investigated in this study. One new compound, 5'-geranyl-5,7,2',4'-tetrahydroxyflavone, and twenty-eight known phenolic compounds were isolated. Their structures were identified by mass spectrometry and NMR spectroscopy. Nine compounds, 5'-geranyl-5,7,2',4'-tetrahydroxyflavone, steppogenin-7-O-beta-D-glucoside, 2,4,2',4'-tetrahydroxychalcone, moracin N, kuwanon H, mulberrofuran G, morachalcone A, oxyresveratrol-3'-O-beta-D-glucopyranoside and oxyresveratrol-2-O-beta-D-glucopyranoside, showed better tyrosinase inhibitory activities than kojic acid. It was noteworthy that the IC(50) values of 2,4,2',4'-tetrahydroxychalcone and morachalcone A were 757-fold and 328-fold lower than that of kojic acid, respectively, suggesting a great potential for their development as effective natural tyrosinase inhibitors.