The perceptions and adoption of environmentally sustainable practices among anesthesiologists-a qualitative study.

PURPOSE: Previous surveys of anesthesiologists showed that despite a strong interest in implementing environmentally sustainable anesthetic practices, less than a third do so. Qualitative understanding of the capability, opportunity, and motivational factors that influence "green" behavior will inform the design of effective interventions to promote environmentally sustainable practices in the operating room (OR). METHODS: We conducted 23 semistructured interviews with anesthesiologists, with data saturation achieved. Applying the Behavior Change Wheel, interview questions addressed "capability," "opportunity," and "motivation" determinants of behavior. RESULTS: Preference for sevoflurane and syringe reuse were most commonly cited as existing environmentally sustainable anesthetic practices. Several participants reported lack of knowledge and feedback as impediments to sustainable anesthetic practices. Reported physical barriers included inadequate recycling facilities and abundance of supplies. Interviewees also discussed the importance of habitual behavior in improving skill sets and reducing cognitive load required to perform environmentally sustainable practices. General awareness of environmental issues and aggregation of marginal gains were reasons for environmentally sustainable measures in the OR. Organizational practice and culture played a significant role in the propagation of sustainable anesthetic practices, with senior staff often carrying a greater influence. While the majority preferred a top-down approach to effect change, others favored the use of incentives. CONCLUSION: This study provides insight into the factors that influence the adoption of environmentally sustainable practices in the OR. Measures to promote these practices include education and training, feedback on efforts, engagement of senior anesthetists as role models and for change management, environmental restructuring, and policy designs that balance a top-down vs bottom-up approach to influencing change.

RéSUMé: OBJECTIF: Des enquêtes antérieures auprès d'anesthésiologistes ont montré que, malgré un vif intérêt pour la mise en œuvre de pratiques anesthésiques durables sur le plan environnemental, moins d'un tiers les mettent en pratique. La compréhension qualitative de la capacité, des possibilités et des facteurs de motivation qui influencent les comportements « verts ¼ éclairera la conception d'interventions efficaces pour promouvoir des pratiques durables sur le plan environnemental en salle d'opération. MéTHODE: Nous avons mené 23 entretiens semi-structurés avec des anesthésiologistes, avec une saturation des données atteinte. En appliquant la roue du changement de comportement, les questions d'entrevue portaient sur les déterminants du comportement liés à la « capacité ¼, à l'« occasion ¼ et à la « motivation ¼. RéSULTATS: La préférence pour le sévoflurane et la réutilisation des seringues ont été le plus souvent citées comme des pratiques anesthésiques durables. Plusieurs participants ont signalé que le manque de connaissances et de rétroaction constituait un obstacle à des pratiques anesthésiques durables. Parmi les obstacles physiques signalés, mentionnons l'insuffisance des installations de recyclage et l'abondance des fournitures. Les personnes interrogées ont également discuté de l'importance du comportement habituel pour améliorer les compétences et réduire la charge cognitive requise pour mettre en œuvre des pratiques durables. La prise de conscience générale des questions environnementales et l'agrégation des gains marginaux étaient les raisons citées pour lesquelles des mesures écologiquement viables ont été prises en salle d'opération. La pratique organisationnelle et la culture ont joué un rôle important dans la diffusion de pratiques anesthésiques durables, les cadres supérieurs ayant souvent une plus grande influence. Alors que la majorité préférerait une approche descendante pour apporter des changements, d'autres étaient en faveur de l'utilisation d'incitatifs. CONCLUSION: Cette étude donne un aperçu des facteurs qui influencent l'adoption de pratiques durables sur le plan environnemental en salle d'opération. Les mesures visant à promouvoir ces pratiques comprennent l'éducation et la formation, la rétroaction sur les efforts, l'engagement des anesthésistes plus établis ou senior en tant que modèles et gestionnaires du changement, la restructuration environnementale et la conception de politiques qui équilibrent une approche descendante vs une approche ascendante pour influencer le changement.

[The study of the protection function of the sphingosine kinase 1 in the nerve cell damage caused by acrylamide].

Objective: To study the protective effect and effect of SphK1 overexpression on the injury of nerve cells induced by acrylamide. Methods: ACR with 99% purity was prepared into 1.25 mmol/L and 2.5 mmol/L solutions. SH-SY5Y cells were divided into control group (NC group) , experimental group and SphK1 activator group. The experimental group was given ACR solution with final concentration of 1.25 mmol/L and 2.5 mmol/L respectively for 24 h. In the SphK1 activator group, on the basis of the exposure concentration of the experimental group, the SphK1 specific activator (12-) phorbol tetradecanoate (-13-) acetate (PMA) solution[prepared by dimethyl sulfoxide (DMSO) , the final concentration was 100 nmol/l], and other treatments were the same as the experimental group. Control group (NC group) added PMA solution into normal cells. Western blot was used to detect the expression of SphK1 protein; CCK-8 was used to detect the proliferation of SH-SY5Y cells; hoechst33342 method was used to observe the morphological changes of nerve cells; flow cytometry was used to analyze the apoptosis of cells. Results: Compared with NC group, the expression of SphK1 protein in the experimental group and the SphK1 activator group was significantly lower (P<0.05) . Compared with the experimental group, the expression of SphK1 protein in each concentration of SphK1 activator group was increased, and the difference was statistically significant (P<0.05) . In addition to 1.25 mmol/L SphK1 activator group, compared with NC group, the relative growth survival rate of experimental group and 2.5 mmol/L SphK1 activator group were lower, the difference was statistically significant (P<0.05) . Compared with the experimental group, the relative survival rate of cells in the SphK1 activator group was higher, and the difference was statistically significant (P<0.05) . With the increase of exposure concentration, the cells in the experimental group showed the morphological characteristics of early apoptosis at ACR 1.25 mmol/L and late apoptosis at ACR 2.5 mmol/L. Compared with NC group, the apoptosis rate of experimental group and SphK1 activator group at ACR 2.5 mmol/L was significantly different (P<0.05) ; compared with experimental group, the apoptosis rate of SphK1 activator group at ACR 2.5 mmol/L was lower, the difference was statistically significant (P<0.05) . Conclusion: The SphK1 excessive expression plays the protective function to the nerve cell damage caused by acrylamide.

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer.

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain.

Cholesterol metabolism is important for neuronal function in the central nervous system (CNS). The oxysterol 27-hydroxycholesterol (27-OHC) is a cholesterol metabolite that crosses the blood-brain barrier (BBB) and may be a useful substitutive marker for neurodegenerative diseases. However, the effects of 27-OHC on learning and memory and the underlying mechanisms are unclear. To determine this mechanism, we investigated learning and memory and cholesterol metabolism in rat brain following the injection of various doses of 27-OHC into the caudal vein. We found that 27-OHC increased cholesterol levels and upregulated the expression of liver X receptor-α (LXR-α) and adenosine triphosphate (ATP)-binding cassette transporter protein family member A1 (ABCA1). In addition, 27-OHC decreased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low-density lipoprotein receptor (LDLR) in rat brain tissues. These findings suggest that 27-OHC may negatively modulate cognitive effects and cholesterol metabolism in the brain.

Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models.

BACKGROUND: Fibroblast growth factor receptor (FGFR) signalling has been implicated in pancreas carcinogenesis. We investigated the effect of FGFR inhibition in pancreatic cancer in complementary cancer models derived from cell lines and patient-derived primary tumour explants. METHODS: The effects of FGFR signalling inhibition in pancreatic cancer were evaluated using anti-FRS2 shRNA and dovitinib. Pancreatic cancers with varying sensitivity to dovitinib were evaluated to determine potential predictive biomarkers of efficacy. Primary pancreatic explants with opposite extreme of biomarker expression were selected from 13 tumours for in vivo dovitinib treatment. RESULTS: Treatment with anti-FRS2 shRNA induced significant in vitro cell kill in pancreatic cancer cells. Dovitinib treatment achieved similar effects and was mediated by Akt/Mcl-1 signalling in sensitive cells. Dovitinib efficacy correlated with FRS2 phosphorylation status, FGFR2 mRNA level and FGFR2 IIIb expression but not phosphorylation status of VEGFR2 and PDGFRß. Using FGFR2 mRNA level, a proof-of-concept study using primary pancreatic cancer explants correctly identified the tumours' sensitivity to dovitinib. CONCLUSION: Inhibiting FGFR signalling using shRNA and dovitinib achieved significant anti-cancer cancer effects in pancreatic cancer. The effect was more pronounced in FGFR2 IIIb overexpressing pancreatic cancer that may be dependent on aberrant stimulation by stromal-derived FGF ligands.

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours.

BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. METHODS: PX-866 was administered at escalating doses (4-8 mg daily) with docetaxel 75 mg m⁻² intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. RESULTS: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1-569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. CONCLUSION: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.

Soybean isoflavone alleviates ß-amyloid 1-42 induced inflammatory response to improve learning and memory ability by down regulation of Toll-like receptor 4 expression and nuclear factor-κB activity in rats.

ß-amyloid 1-42 (Aß1-42)-induced learning and memory impairment in rats is believed to be associated with inflammation. Cytokine production is a key pathologic event in the progression of inflammatory processes. In this rat study, soybean isoflavones (SIF) was used to investigate it's protective effects on inflammation caused by ß-amyloid 1-42 (Aß1-42), which is associated with learning and memory impairment in Alzheimer disease. We characterized the learning and memory ability. cytokine profiles of circulating interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) in the serum and the expression of Toll like receptor4 (TLR4) and nuclear factor-κB p65 (NF-κB p65) mRNA and protein in the brain tissue following intracerebroventricular administration of Aß1-42 by miniosmotic pump for 14 days. The results showed that functional deficits of learning and memory in SIF treatment groups were significantly improved compared to the control group without SIF treatment in water maze test. The serum IL-1ß and TNF-α level were significantly increased, and the expressions of TLR4 and NF-κB p65 mRNA and protein in the brain were up-regulated, indicating inflammation response was initiated following administration of Aß1-42. After intragastric pre-treatment with SIF, inflammatory cytokines was significantly reduced and also SIF reversed the Aß1-42 induced up-regulation of TLR4 and NF-κB p65 mRNA and protein expression in the brain and expression of NF-κB p65 in nuclei. These results suggested that SIF reduced the cytokine cascade and inflammatory response induced by Aß1-42 which could result in the improvement of spatial learning and memory ability impairment in the rats.

Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer.

BACKGROUND: The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic. METHODS: Temsirolimus (20 mg Kg(-1) daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs). RESULTS: In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects. CONCLUSION: Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker.

Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies.

BACKGROUND: Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1-4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m(2)/day. RESULTS: Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m(2)/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m(2) administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h. CONCLUSIONS: Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.

Biologically active gamma-lactones and methylketoalkenes from Lindera benzoin.

Brine shrimp lethality-directed fractionation of the 95% EtOH extract of ripe berries from Lindera benzoin led to the isolation of three new C21 alkane-alkene gamma-lactones designated isolinderanolide, isolinderenolide, and linderanolide as well as the known series of C17 and C19 obtusilactones (isoobtusilactone A, obtusilactone A, isoobtusilactone, and obtusilactone) previously isolated from Lindera obtusiloba. The novel (6Z,9Z,12Z)-pentadecatrien-2-one, the known (6Z,9Z)-pentadecadien-2-one, and the known (+)-(Z)-nerolidol were also isolated as bioactive compounds. The structural elucidation and biological activities of these compounds are reported.

Bioactive neolignans from Endlicheria dysodantha.

From bioactivity-directed fractionation of the EtOH extract of Endlicheria dysodantha, dysodanthin A and dysodanthin B, which are new hexahydrobenzofuranoid neolignans, have been isolated. In addition, the known neolignans, compound 4, which is a burchellin analogue, and megaphone acetate [1] were isolated. All four neolignans showed activities in the brine shrimp lethality test; compounds 1-3 also inhibited the growth of crown gall tumors on potato discs and were cytotoxic to human tumor cells in culture. This is the first report of these neolignans isolated from the genus Endlicheria and of their completely assigned 1H-and 13C-nmr data.

Tubulosine: an antitumor constituent of Pogonopus speciosus.

From the antitumor-bioactive sap of Pogonopus speciosus, tubulosine [1] was isolated, by activity-directed fractionation using the brine shrimp lethality test, as the major antitumor constituent. 1H-nmr assignments, obtained from HETCOR and COSY, and X-ray crystallographic results are reported for the first time. Psychotrine [2] was also isolated, and its spectral data are also reported.

Majorenolide and majorynolide: a new pair of cytotoxic and pesticidal alkene-alkyne delta-lactones from Persea major.

From the EtOH extract of the bark of Persea major, two bioactive compounds, majorynolide [1] and majorenolide [2], were isolated by activity-directed fractionation using brine shrimp. Their structures have been elucidated on the basis of spectral data as a pair of new alkene-alkyne delta-lactones, each with an exocyclic alkylidene methine carbon. Both 1 and 2 are moderately cytotoxic, and 2 is selectively pesticidal.

Goniotriol from Goniothalamus giganteus.

The known styrylpyrone, goniotriol, has been isolated from Goniothalamus giganteus. Its bioactivities are reported, and its structure and relative stereochemistry have been determined by X-ray crystallography as 6R-(7R,8R-dihydro-7,8-dihydroxystyryl)-5S,6R-dihydro-5-hydroxy-2-p yrone.

Additional toxic, bitter saponins from the seeds of Chenopodium quinoa.

Quinoa (Chenopodium quinoa) is an important Native American food grain. Prior to consumption, the seeds must be washed with H2O to remove bitterness and improve nutritive value. From the warm-H2O extract of quinoa seeds from Mexico, saponins 1-4 were isolated by monitoring the fractionation with brine shrimp lethality and a taste test for bitterness. By chemical, spectral, and enzymatic methods, 1-4 were identified as glycosides of oleanolic acid. Saponin 4, 3-O-[(beta-D-xylopyranosyl)(1----3)]-beta-D-glucuronopyranosyl-6-O -methyl ester]-oleanolic acid, is a new natural compound.