Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme

[EN] A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.Financial support from Spanish Ministry of Economy and Competitiveness (Projects PID2019-111436RB-C21 and SEV2016-0683) and the Generalitat Valenciana (Project PROMETEO/2017/060) is gratefully acknowledged. We thank Prof. Luis Fernandez (Group of Structural Mechanics and Materials Modellings-GEMM, University of Zaragoza, Spain) for donation of human GBM cell lines. We are grateful to Dr. Lawrence Humphreys (CIBER-BBN) for critical reading of the manuscriptCheca-Chavarria, E.; Rivero-Buceta, EM.; Sanchez Martos, MA.; Martinez Navarrete, G.; Soto-Sanchez, C.; Botella Asuncion, P.; Fernandez Jover, E. (2021). Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme. Molecular Pharmaceutics. 18(4):1558-1572. https://doi.org/10.1021/acs.molpharmaceut.0c009681558157218

Considerations in the Development of Flexible CCS Networks

This paper discusses considerations for the design of flexibly operated Carbon Capture and Storage (CCS) pipeline networks and is based on the findings of the Flexible CCS Network Development project (FleCCSnet), funded by the UK CCS Research Centre. The project considered the impact of flexibility across the whole CCS chain, as well as studying the interfaces between each element of the system; e.g. at the entry to the pipeline system from the capture plant and at the exit from the pipeline to the storage site. The factors identified are intended to allow CCS network designers to determine the degree of flexibility in the system, allowing them to react effectively to short, medium and long term variations in the availability and flow of CO2 from capture plants and the constraints imposed on the system by CO2 storage sites. The work of the project is reviewed in this paper which explores the flexibility of power plants operating with post combustion capture systems; quantifies the available time to store (line pack) liquid CO2 in the pipeline as a function of pipeline size, the inlet mass flow rate and operating pressure; and explores the influence that uncertainty in storage parameters have on the design of the pipeline. In addition, parameters influencing short and longer term network designs are discussed in terms of varying flow rates. Two workshops contributed to the direction of the project. The first workshop identified and confirmed key questions to be considered in order to understand the most likely impacts of variability in the CO2 sources and variability in CO2 sinks on CO2 transport system design and operation. The second workshop focused on transient issues in the pipeline and storage site. Although the case studies in the work are UK based, this work is applicable to other situations where large and small sources of CO2 feed into a transportation system. The work is expected to inform a broad range of stakeholders and allow network designers to anticipate potential problems associated with the operation of a CCS network. For an effective design of CCS infrastructure, all of the factors that will have a substantial impact on CO2 flow will have to be analysed at an early stage to prevent possible bottle necks in the whole chain

Analysis of Process Configurations for CO2 Capture by Precipitating Amino Acid Solvents

Precipitating amino acid solvents are an alternative to conventional amine scrubbing for CO2 capture from flue gas. Process operation with these solvents leads to the formation of precipitates during absorption that need to be re-dissolved prior to desorption of CO2. The process configuration is crucial for the successful application of these solvents. Different process configurations have been analyzed in this work, including a full analysis of the baseline operating conditions (based on potassium taurate), the addition of lean vapor compression, multiple absorber feeds, and the use of different amino acids as alternative solvents to the baseline based on potassium taurate. The analysis is carried out with an equilibrium model of the process that approximates the thermodynamics of the solvents considered. The results show that the precipitating amino acid solvents can reduce the reboiler duty needed to regenerate the solvent with respect to a conventional MEA process. However, this reduction is accompanied by an expenditure in lower grade energy needed to dissolve the precipitates. To successfully implement these processes into power plants, an internal recycle of the rich stream is necessary. This configuration, known as DECAB Plus, can lower the overall energy use of the capture process, which includes the energy needed to regenerate the solvent, the energy needed to dissolve the precipitates, and the energy needed to compress the CO2 to 110 bar. With respect to the energy efficiency, the DECAB Plus with lean vapor compression configuration is the best configuration based on potassium taurate, which reduces the reboiler duty for regeneration by 45% with respect to conventional MEA. Retrofitting this process into a coal fired power plant will result in overall energy savings of 15% with respect to the conventional MEA process, including compression of the CO2 stream to 110 bar. Potassium alanate was found to reduce the energy use with respect to potassium taurate under similar process configurations. Therefore, the investigation of potassium alanate in a DECAB Plus configuration is highly recommended, since it can reduce the energy requirements of the best process configuration based on potassium taurat

Enhanced operating flexibility and optimised off-design operation of coal plants with post-combustion capture

AbstractThe inherent nature of electricity necessitates a permanent balance between generation and demand in electricity systems. This has obvious implications for the operation of CCS power plants in decarbonised electricity systems with inflexible nuclear and variable renewable supply. The low variable costs of nuclear and some intermittent renewable technology allow them to run as base-load generators and shift fossil fuel plants from base-load to mid- merit plants. CCS power plants can be expected to increasingly operate in ways to balance variations, sometimes simultaneously, in the production of some intermittent renewable technologies and variations in electricity demand, resulting in more frequent ramping and start/stop cycles. As a result, they may also operate over a wide output range to maintain the quality and security of electricity supply by providing ancillary services, e.g. capacity and energy reserve, to the electricity network. This work characterises the operating envelope, the performance and the corresponding compressed CO2 flow of coal power plants for a range of loads, with or without voluntary by-pass of the capture unit. Optimised part-load operating strategies provide novel insights into the additional capabilities of CCS power plants specifically designed for enhanced operating flexibility

Lower Success Rate of Debridement and Implant Retention in Late Acute versus Early Acute Periprosthetic Joint Infection Caused by Staphylococcus spp. Results from a Matched Cohort Study

Background Surgical debridement, antibiotics and implant retention (DAIR) is currently recommended by international guidelines for both early acute (postsurgical) and late acute (hematogenous) periprosthetic joint infections (PJIs). However, due to a different pathogenesis of infection, a different treatment strategy may be needed. Questions/purposes (1) Compared with early acute PJIs, are late acute PJIs associated with a higher risk of DAIR failure? (2) When stratified by microorganism, is the higher risk of failure in late acute PJI associated with Staphylocococcus aureus infection? (3) When analyzing patients with S. aureus infection, what factors are independently associated with DAIR failure? Methods In this multicenter observational study, early acute and late acute PJIs treated with DAIR were retrospectively evaluated and matched according to treating center, year of diagnosis, and infection-causing microorganism. If multiple matches were available, the early acute PJI diagnosed closest to the late acute PJI was selected. A total of 132 pairs were included. Treatment success was defined as a retained implant during follow-up without the need for antibiotic suppressive therapy. Results Late acute PJIs had a lower treatment success (46% [60 of 132]) compared with early acute PJIs (76% [100 of 132]), OR 3.9 [95% CI 2.3 to 6.6]; p <0.001), but the lower treatment success of late acute PJIs was only observed when caused by Staphylococcus spp (S. aureus: 34% versus 75%; p <0.001; coagulase-negative staphylococci: 46% versus 88%; p = 0.013, respectively). On multivariable analysis, late acute PJI was the only independent factor associated with an unsuccessful DAIR when caused by S. aureus (OR 4.52 [95% CI 1.79 to 11.41]; p <0.001). Conclusions Although DAIR seems to be a successful therapeutic strategy in the management of early acute PJI, its use in late acute PJI should be reconsidered when caused by Staphylococcus spp. Our results advocate the importance of isolating the causative microorganism before surgery

Analysis of the structural chromosomal anomalies and distribution by chromosomes in the ECEMC’s series of newborn infants with congenital defects

Citogenética y Genética MolecularThis study was aimed at estimating the frequency of unbalanced structural chromosomal anomalies identified in the consecutive series of newborn infants with congenital defects, registered in the Spanish Collaborative Study of Congenital Malformations (ECEMC). These cases were cytogenetically studied at its laboratory since 1981 up to December 2009. A total of 4,681 cases were studied following a protocol established by ECEMC program, which starts by performing a high resolution karyotype (550-850 bands), and if the results are normal, it is followed by the analysis of subtelomeric regions and depending on the clinical manifestations, some FISH and MLPA analyses were applied in order to also rule out microdeletion syndromes. The parents and other relatives were also studied when necessary, according to ECEMC’s protocol. A total of 136 cases had unbalanced chromosomal structural anomalies. Data were analyzed either globally or in two periods including the years 1981-1994, and 1995-2009 which are before and after starting the use of FISH techniques in the ECEMC`s laboratory. Among the 136 total cases having unbalanced structural anomalies, 71.32% were cytogenetically detected, and the remaining 28.68% by FISH. Each type of anomaly was distributed by involved chromosome separating those affecting p and q arms. In the group of cytogenetically detected anomalies, deletions (42.55% of cases) were 2.1 times more frequent than duplications (20.22%). Deletions affecting short arms were 3 times more frequent than duplications. Among cases detected by FISH techniques, deletions were 15.49 times more frequent than duplications, the 22q11.2 microdeletion being the most common (38.46% of the cases), followed by the deletions in chromosomes 15 (15.38%) and 4 (10.26%). Some of these alterations were identified by the clinical suspicion of their specific syndromes (Wolf-Hirschhorn, Prader-Willi, Williams-Beuren, Miller-Dieker, etc), and this could somehow bias their frequencies (see Table 3). In addition, some other unexpected microdeletion syndromes were detected such as two cases with microdeletion 1p36, one case with each of the following microdeletions: 2q23.1, 5q31, and a deletion 12q13.3-q21.2, including the region of the known microdeletion syndrome 12q14, but it is possible that may be other not hitherto identified. To our knowledge, this study represents the first one analyzing the frequency of chromosomal alterations globally and by each one of the 23 chromosomes on a consecutive series of newborn infants with congenital defects which are detectable during the first three days of life. It is also remarkable that all the cases were studied with the same protocol and the same team of specialists.N

Lung Ultrasound as a First-Line Test in the Evaluation of Post-COVID-19 Pulmonary Sequelae

COVID-19; Lung ultrasound (LUS); Pulmonary sequelaeCOVID-19; Ecografía pulmonar (LUS); Secuelas pulmonaresCOVID-19; Ecografia pulmonar (LUS); Seqüeles pulmonarsBackground: Interstitial lung sequelae are increasingly being reported in survivors of COVID-19 pneumonia. An early detection of these lesions may help prevent the development of irreversible lung fibrosis. Lung ultrasound (LUS) has shown high diagnostic accuracy in interstitial lung disease (ILD) and could likely be used as a first-line test for post-COVID-19 lung sequelae. Methods: Single-center observational prospective study. Follow-up assessments of consecutive patients hospitalized for COVID-19 pneumonia were conducted 2–5 months after the hospitalization. All patients underwent pulmonary function tests (PFTs), high-resolution computed tomography (HRCT), and LUS. Radiological alterations in HRCT were quantified using the Warrick score. The LUS score was obtained by evaluating the presence of pathological B-lines in 12 thoracic areas (range, 0–12). The correlation between the LUS and Warrick scores was analyzed. Results: Three hundred and fifty-two patients who recovered from COVID-19 pneumonia were recruited between July and September 2020. At follow-up, dyspnea was the most frequent symptom (69.3%). FVC and DLCO alterations were present in 79 (22.4%) and 234 (66.5%) patients, respectively. HRCT showed relevant interstitial lung sequelae (RILS) in 154 (43.8%) patients (Warrick score ≥ 7). The LUS score was strongly correlated with the HRCT Warrick score (r = 0.77) and showed a moderate inverse correlation with DLCO (r = −0.55). The ROC curve analysis revealed that a LUS score ≥ 3 indicated an excellent ability to discriminate patients with RILS (sensitivity, 94.2%; specificity, 81.8%; negative predictive value, 94.7%). Conclusions: LUS could be implemented as a first-line procedure in the evaluation of Post-COVID-19 interstitial lung sequelae. A normal LUS examination rules out the presence of these sequelae in COVID-19 survivors, avoiding the need for additional diagnostic tests such as HRCT