PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical ...models of cisplatin-resistant epithelial ovarian cancer.
Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1–5 q3wk or weekly (every 4 weeks, q4wk).
ORR was 23% (95% CI, 13%–37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5–6.9 months), and 23% (95% CI, 0%–51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease ORR = 30% (95% CI, 16%–49%); for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7–5.6 months), and 5.0 months (95% CI, 2.7–6.9 months) for patients with platinum-resistant disease.
Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183.
PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2).
EudraCT 2011-002172-16.
Different spin labels were incorporated to the membranes of cultured insect UFL-AG-286 cells in order to characterize their physical properties by Electron Paramagnetic Resonance spectroscopy (EPR). ...The spectrum of the spin label 12-SASL incorporated to cell membranes was similar as those obtained in membrane model systems composed of eggPC/cholesterol. However, the spectrum of the spin label CSL, chemically related to cholesterol, was drastically different in the two systems. Interestingly, when cell cholesterol content was reduced using methyl beta cyclodextrin, an EPR spectrum similar to those of model membranes was obtained. The analysis of these experiments suggests the existence of cholesterol rich regions in UFL-AG-286 cell membranes.
•Membranes of cultured insect cells were studied with spin label EPR.•Two kinds of spin labels (SL) with different chemical affinity were used.•EPR of SL chemically akin to cholesterol indicates its uneven distribution in intact cells.•Evidence of cholesterol enriched nanodomains in intact cell membranes.•Cholesterol depletion erases the EPR evidence of cell membrane domains.
Summary
Background
Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline ...phosphatase ALP and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long‐term effectiveness of second‐line treatments remains uncertain.
Aims
To evaluate the long‐term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation).
Methods
We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non‐responsive PBC patients (Paris‐II criteria) from Spain and Portugal who received OCA ± fibrates.
Results
Of 255 patients, median follow‐up was 35.1 months (IQR: 20.2–53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE‐PBC and 5‐year UK‐PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension.
Conclusion
Triple therapy was superior in achieving therapeutic goals in UDCA‐nonresponsive PBC. Decompensation was linked to pre‐existing portal hypertension.
Longitudinal, real‐world study on 255 UDCA‐nonresponsive PBC patients (Per Paris II criteria); median follow‐up of 35.1 months (IQR: 20–53). All patients received obeticholic acid (OCA), with 25% receiving later add‐on fibrate treatment (triple therapy). In multivariate analysis, triple therapy outperformed dual therapy across all surrogate biochemical endpoints of outcomes.
Arsenic bioaccumulation in the deposit-feeding polychaete
Arenicola marina has been investigated using biodynamic modelling. Radiotracer techniques were used to determine the rates of uptake of As as ...arsenate from water and sediment and its subsequent efflux in the laboratory. Lugworms accumulated As from solution linearly at concentrations of 2–20
μg
l
−1, with a corresponding uptake rate constant of 0.1648
±
0.0135
l
g
−1
d
−1. 7.8
±
0.8% (assimilation efficiency) of the As ingested bound to sediments was retained after egestion of unassimilated metal. Elimination of As followed a two-compartment model, with mean efflux rate constants (from the slow pool) very similar for As accumulated from solution and ingested sediments (0.0449
±
0.0034 and 0.0478
±
0.0225
d
−1, respectively) and a corresponding biological half-time of roughly 15
d. A biodynamic model was constructed and validated through the comparison of biodynamic model predictions against measured bioaccumulated concentrations in lugworms from five UK estuaries. The model accurately predicted bioaccumulated As concentrations in lugworms using mean values of relevant physiological parameters (uptake rate, efflux rate and growth rate constants), a site-specific ingestion rate (calculated according to mean worm size and sediment organic matter content and expressed as the rate of ingestion of the mass of fine sediment), a site-specific sediment concentration measured after HCl extraction, and a standard dissolved As concentration. This combination of parameters showed that sediment ingestion contributed 30–60% of the total As accumulated by lugworms at the studied sites, depending on the different geochemistry at each site. This study showed that it is difficult to predict accurately As bioaccumulation at sites with different chemistries, unless that chemistry is taken into account.
► Four different generation of thiol-DAB dendrimers were synthesized. ► Fluorescent nanocomposites of the thiol-DAB dendrimers with CdSe quantum dots were obtained. ► The fluorescent S-DAB-G5-CdSe ...nanocomposites are sensors for Cd(II) and Pb(II) ions.
Four different generation of thiol-DAB dendrimers were synthesized, S-DAB-Gx (x=1, 2, 3 and 5), and coupled with CdSe quantum dots, to obtain fluorescent nanocomposites as metal ions sensing. Cd(II) and Pb(II) showed the higher enhancement and quenching effects respectively towards the fluorescence of S-DAB-G5-CdSe nanocomposite. The fluorescence enhancement provoked by Cd(II) can be linearized using a Henderson–Hasselbalch type equation and the quenching provoked by Pb(II) can be linearized by a Stern–Volmer equation. The sensor responds to Cd(II) ion in the 0.05–0.7μM concentration range and to Pb(II) ion in the 0.01–0.15mM concentration range with a LOD of 0.06mM. The sensor has selectivity limitations but its dendrimer configuration has analytical advantages.
The organ and tissue donation interview is a vital step in obtaining the donation. Therefore, it is important to obtain as much information as possible regarding the relatives of the potential donor ...prior to this interview and know if there is a health care professional among the relatives who may act as an interlocutor.
The objective of this study is to assess the influence that relatives who are health care professionals may have if present at the interview for the organ and tissue donation request.
This is a descriptive study of all the organ donations from 1996 to 2019. Variables of the interview record form were completed by the Regional Transplant Coordination Office.
Quantitative variables are expressed as mean (standard deviation) or median (interquartile range), and qualitative variables are expressed in percentage. The χ2 test was used for inferential statistics.
Health care professionals were present as interlocutors in 8.4% of the total interviews conducted (9279). Organ donation was accepted in 86% of these interviews, while the relative who was a health care professional gave a 93.8% (729) positive response to the donation. Having a health care professional as an interlocutor favors the acceptance of the donation (odds ratio 9.325, 95% confidence interval: 5.054-17.205; P < .001).
Health care professionals have a very positive attitude toward donation. This attitude positively impacts other relatives’ acceptance of the donation.
•In almost 1 out of every 10 interviews on organ and tissue donation, there is a family member present.•The presence of health care professional relatives in organ donation interviews seems to be an important factor for establishing an affirmative response.
Neutral argon plasma (NAP) system could meet the requirements to achieve oncological cytoreduction of peritoneal carcinomatosis with miliary lesions, minimizing the associated morbidity. This phase ...I/II trial aims to establish the desirable dose that is safe and effective in eliminating tumor cells with lower penetration.
Patients diagnosed with different origins for peritoneal carcinomatosis and miliary implants were selected for the study. The safe and potentially effective dose (desirability) of NAP was evaluated according to three factors: distance (mm), application time (s) and power (%), to evaluate the response variables such as the presence of tumor cells (Y/N) and the depth of penetration.
Ten patients and 120 samples were evaluated and treated with NAP. There was no vascular or organ injury intraoperative using a pre-established dose of 100% (coagulation mode) at a distance of 2–3 cm. The distance was found to be correlated with the presence of the tumor cells in ex-vivo analysis, with an OR of 15.4 (4.0–111.4). The time and energy used were protective factors to eliminate tumor cells with an OR of 0.4 (0.1–0.9) and 0.8 (0.8–0.9), respectively. The safest and most effective desirability results were as follows i) energy 80% during 2–4 s with a distance of 2 cm (0.89), and ii) energy 100% during 2–4 s with a distance of 3 cm (0.90).
The use of NAP during a CRS and HIPEC is safe and effective for eradicating tumor cells on the peritoneal surface at suggested doses of energy, distance and duration.
ClinicalTrials.gov Identifier: NCT04904042.
•Mesentery and small bowel involvement increases morbidity in peritoneal carcinomatosis surgery.•Neutral Argon Plasma is safe and effective to eradicate the tumor cells in the peritoneal surface.•Desirable doses of energy, distance and time of: 80%/2 cm/2–4 s and 100%/3 cm/2–4 s.•Neutral Argon Plasma is an alternative in cytoreduction surgery with miliary involvement of the mesentery and small intestine.
•Simultaneous determination of amiodarone and N-desethylamiodarone in sludge.•Effective extraction with reduced matrix effects during LC–ESI(+)–MS determination.•Accumulation of the active drug and ...the N-desethyl species in sludge.•Persistence in lime stabilized sludge.•Identification of mono-iodinated forms of amiodarone and N-desethylamiodarone.
For the first time, a procedure for the simultaneous determination of the iodinated drug amiodarone and its major metabolite, N-desethylamiodarone, in sludge from urban sewage treatment plants (STPs) is proposed. Matrix solid-phase dispersion (MSPD) followed by on-line cationic exchange clean-up, in modular configuration, was used as sample preparation technique. Liquid chromatography with tandem mass spectrometry (LC–MS/MS), based on a hybrid quadrupole time-of-flight (QTOF) system, was employed for the selective determination of target compounds. The optimized procedure provided exhaustive recoveries with little effect of the sample matrix in the efficiency of electrospray ionization (ESI). The overall recoveries of the method ranged between 95 and 111%, for samples spiked at different concentration levels. The achieved limits of quantification (LOQs) remained below 10ngg−1 for both compounds, and the linear response range extended up to 2500ngg−1. Amiodarone and N-desethylamiodarone were ubiquitous in sludge samples, from different STPs located in the Northwest of Spain, with maximum concentrations above 300ngg−1 referred to the freeze-dried matrix. They were also present in stabilized sludge (mixed with lime and thermally dehydrated), which is mostly disposed in agriculture fields as fertilizer. Furthermore, mono-iodinated analogues of amiodarone and N-desethylamiodarone were also tentatively identified in some samples from their accurate MS and MS/MS spectra.
Radiotracer techniques were used to determine the rates of trace metal (Ag, Cd and Zn) uptake and elimination (33
psu, 10
°C) from water and sediment by the deposit-feeding polychaete
Arenicola ...marina, proposed as a test species for estuarine-marine sediments in whole-sediment toxicity tests. Metal uptake rates from solution increase with increasing dissolved metal concentrations, with uptake rate constants (±
SE) (l
g
−1
d
−1) of 1.21
±
0.11 (Ag), 0.026
±
0.002 (Zn) and 0.012
±
0.001 (Cd). Assimilation efficiencies from ingested sediments were measured using a pulse-chase radiotracer feeding technique in two different lugworm populations, one from a commercial supplier (Blyth, Northumberland, UK) and the other a field-collected population from the outer Thames estuary (UK). Assimilation efficiencies ranged from 2 to 20% for Zn, 1 to 6% for Cd and 1 to 9% for Ag for the Northumberland worms, and from 3 to 22% for Zn, 6 to 70% for Cd and 2 to 15% for Ag in the case of the Thames population. Elimination of accumulated metals followed a two-compartment model, with similar efflux rate constants for Zn and Ag and lower rates of elimination of Cd from the slow pool. Efflux rate constants (±
SE) of Zn and Ag accumulated from the dissolved phase were 0.037
±
0.002 and 0.033
±
0.006
d
−1 whereas Cd was eliminated with an efflux rate constant one order of magnitude lower (0.003
±
0.002
d
−1). When metals were accumulated from ingested sediments, the efflux rate constants for the slow-exchanging compartment were of the same order of magnitude for the three metals, and of the same order of magnitude as those derived after the dissolved exposure for Zn and Ag (0.042
±
0.004 and 0.056
±
0.012
d
−1 for Zn and 0.044
±
0.012 and 0.069
±
0.016
d
−1 for Ag for the Northumberland and Thames populations, respectively). Cd accumulated from ingested sediments was eliminated with a rate constant not different from the fast-exchanging compartment after the water-only exposure (0.025
±
0.012 and 0.020
±
0.004
d
−1 for the Northumberland and Thames populations, respectively). A biodynamic model was used to estimate the relative importance of the dissolved phase versus ingested sediment as source of metal for the worms, showing that more than 90% of the Zn and Cd and more than 70% of Ag in lugworms is accumulated from sediment ingestion at realistic environmental concentrations. The model also shows that metal accumulation is highly dependent on the ingestion rate and assimilation efficiency.
Since 1994 the results of the analyses of key chemical compounds (trace metals, polychlorinated biphenyls and polycyclic aromatic hydrocarbons) and the comparison with the corresponding sediment ...quality guidelines (SQGs) are used in decision-making for dredged material management in Spain. Nonetheless in the last decades a tiered testing approach is promoted for assessing the physical and chemical characteristics of dredged sediments and their potential biological effects in the environment. Bioassays have been used for sediment toxicity assessment in Spain but few or no experiences are reported on harbour sediments. We studied the incidence of toxicity in the 7d bioassay using rotifers (
Brachionus plicatilis) and the 48h bioassay using sea urchin (
Paracentrotus lividus) embryos over a series of experiments employing 22 different elutriates. The relative performance of this exposure phase was not comparable to data on the 10-d acute toxicity test using the burrowing amphipod
Corophium volutator and the polychaete
Arenicola marina, carried out on the whole sediments. These results evidence the importance of the exposure route and the test selected in decision-making, as the toxicity registered for the undiluted elutriates was largely due to the different solubility of sediment-bound contaminants. This work and other studies indicate that for many sediments, a complete battery of test is recommended together with physico-chemical analyses to decide whether dredged sediments are suitable for open water disposal or not.
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