Fluid structure interaction modelling on flapping wings

Flapping wings display complex flows which can be used to generate large lift forces. Flexibility in wings is widely used by natural flyers to increase the aerodynamic performance. The influence of wing flexibility on the flow can be computed using numerical analysis with Fluid Structure Interaction (FSI). The influence of inertial, elastic and aerodynamic forces is quantified using a 2D wing. A sinusoidal flapping motion is imposed on the leading edge of the vertical wing. The inertial force on the wing dominates for high mass ratios and the wing deflection is rather independent of the flow. For a low mass ratio, the wing deformation scales with the increasing elasticity. The maximum lift and lowest drag were found for the wing with large flexibility and low mass so the passive deformation by aerodynamic forces creates a favourable shape for lift production. Flexible translating and revolving wings at an angle of attack of 45 degrees show that chordwise flexibility decreases both lift and drag, however the lift over drag ratio is increased. The flow around both wings forms a coherent structure with a Root Vortex (RV), Tip Vortex (TV), Leading Edge Vortex (LEV) and Trailing Edge Vortex (TEV). The LEV on the revolving wing is stable for approximately up to half the span because vorticity is transported outward in the vortex core. The flowfield and LEV breakdown are consistent with experimental data of the same wing. The translating wing builds up circulation but the LEV detaches quickly near the centre of the wing. Chordwise bending reduces the angle of attack which decreases the distance to the core of the shed LEVs

Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans

Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein that is abundantly present in biliary ductal cells and epithelial cells lining the gastrointestinal tract. Here, we have determined the role of P-gp in the metabolic disposition of the antineoplastic agent docetaxel (Taxotere) in humans. Pharmacokinetic profiles were evaluated in five cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2 i.v. over a 1-h period) and in combination with a new potent inhibitor of P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition half-life and total plasma clearance of docetaxel were not altered by treatment with oral R101933 (P > or = 0.27). The cumulative fecal excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14% (mean +/- SD) of the dose with the single agent to less than 0.5% in the presence of R101933 (P = 0.0016). Levels of the major cytochrome P450 3A4-mediated metabolites of docetaxel in feces were significantly increased after combination treatment with R101933 (P = 0.010), indicating very prominent and efficient detoxification of reabsorbed docetaxel into hydroxylated compounds before reaching the systemic circulation. It is concluded that intestinal P-gp plays a principal role in the fecal elimination of docetaxel by modulating reabsorption of the drug after hepatobiliary secretion. In addition, the results indicate that inhibition of P-gp activity in normal tissues by effective modulators, and the physiological and pharmacological consequences of this treatment, cannot be predicted based on plasma drug monitoring alone

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios

Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis

Background: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. Methods: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. Results: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD −13.68; 95 % CI −18.38 to −8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31–0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64–2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81–5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. Conclusions: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made

On the Complexity of the Asymmetric VPN Problem

We give the first constant factor approximation algorithm for the asymmetric Virtual Private Network (VPN) problem with arbitrary concave costs. We even show the stronger result, that there is always a tree solution of cost at most 2 OPT and that a tree solution of (expected) cost at most 49.84 OPT can be determined in polynomial time. Furthermore, we answer an outstanding open question about the complexity status of the so called balanced VPN problem by proving its NP-hardness

Live well, die well – an international cohort study on experiences, concerns and preferences of patients in the last phase of life: the research protocol of the iLIVE study

Introduction Adequately addressing the needs of patients at the end of life and their relatives is pivotal in preventing unnecessary suffering and optimising their quality of life. The purpose of the iLIVE study is to contribute to high-quality personalised care at the end of life in different countries and cultures, by investigating the experiences, concerns, preferences and use of care of terminally ill patients and their families. Methods and analysis The iLIVE study is an international cohort study in which patients with an estimated life expectancy of 6 months or less are followed up until they die. In total, 2200 patients will be included in 11 countries, that is, 200 per country. In addition, one relative per patient is invited to participate. All participants will be asked to fill in a questionnaire, at baseline and after 4 weeks. If a patient dies within 6 months of follow-up, the relative will be asked to fill in a post-bereavement questionnaire. Healthcare use in the last week of life will be evaluated as well; healthcare staff who attended the patient will be asked to fill in a brief questionnaire to evaluate the care that was provided. Qualitative interviews will be conducted with patients, relatives and healthcare professionals in all countries to gain more in-depth insights. Ethics and dissemination The cohort study has been approved by ethics committees and the institutional review boards (IRBs) of participating institutes in all countries. Results will be disseminated through the project website, publications in scientific journals and at conferences. Within the project, there will be a working group focusing on enhancing the engagement of the community at large with the reality of death and dying. Trial registration number NCT04271085

Barriers and drivers of public engagement in palliative care, Scoping review

Background The integral model of Palliative Care recognizes the community as essential element in improving quality of life of patients and families. It is necessary to find a formula that allows the community to have a voice. The aim of this scoping review is to identify barriers and facilitators to engage community in PC.Methods Systematic search was conducted in NICE, Cochrane Library, Health Evidence, CINAHL and PubMed database. Keywords: Palliative care, End of life care, community networks, community engagement, public engagement, community participation, social participation, barriers and facilitators.Results Nine hundred seventy-one results were obtained. Search strategy and inclusion criteria yielded 13 studies that were read in detail to identify factors influencing community engagement in palliative care, categorized into: Public health and public engagement; Community attitudes towards palliative care, death and preferences at the end of life; Importance of volunteers in public engagement programs; Compassionate communities.Conclusion Societal awareness must be a facilitated process to catalyse public engagement efforts. National policy initiatives and regional system support provide legitimacy and focus is essential for funding. The first step is to get a sense of what is important to society, bearing in mind cultural differences and to channel those aspects through health care professionals; connecting the most assistential part with community resources. The process and long-term results need to be systematically evaluated

Barriers and drivers of public engagement in palliative care, Scoping review

Background The integral model of Palliative Care recognizes the community as essential element in improving quality of life of patients and families. It is necessary to find a formula that allows the community to have a voice. The aim of this scoping review is to identify barriers and facilitators to engage community in PC.Methods Systematic search was conducted in NICE, Cochrane Library, Health Evidence, CINAHL and PubMed database. Keywords: Palliative care, End of life care, community networks, community engagement, public engagement, community participation, social participation, barriers and facilitators.Results Nine hundred seventy-one results were obtained. Search strategy and inclusion criteria yielded 13 studies that were read in detail to identify factors influencing community engagement in palliative care, categorized into: Public health and public engagement; Community attitudes towards palliative care, death and preferences at the end of life; Importance of volunteers in public engagement programs; Compassionate communities.Conclusion Societal awareness must be a facilitated process to catalyse public engagement efforts. National policy initiatives and regional system support provide legitimacy and focus is essential for funding. The first step is to get a sense of what is important to society, bearing in mind cultural differences and to channel those aspects through health care professionals; connecting the most assistential part with community resources. The process and long-term results need to be systematically evaluated

Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins

Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFβ-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFβ. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-κB family member RELB. We show that RELB represses TGFβ target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFβ gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth

Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC