Universal Inhibitor Research Articles

1524P Preliminary phase I safety and activity of IMM-1-104, an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumors

1524P Preliminary phase I safety and activity of IMM-1-104, an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumors

Optimization of a DNA-launched SARS-CoV-2 replicon with RNA splicing inhibitor Isoginkgetin.

We have previously developed a bacterial artificial chromosome (BAC)-vectored SARS-CoV-2 replicon, namely BAC-CoV2-Rep, which, upon transfection into host cells, serves as a transcription template for SARS-CoV-2 replicon mRNA to initiate replicon replication and produce nanoluciferase (Nluc) reporter from the subgenomic viral mRNA. However, an inherent issue of such DNA-launched replicon system is that the nascent full-length replicon transcript undergoes process by host RNA splicing machinery, which reduces replicon replication and generates spliced mRNA species expressing NLuc reporter independent of replicon replication. To mitigate this problem, we employed Isoginkgetin, a universal eukaryotic host splicing inhibitor, to treat cells transfected with BAC-CoV2-Rep. Isoginkgetin effectively increased the level of full-length replicon transcripts while concurrently reducing the level of Nluc signal derived from spliced replicon mRNA, making the Nluc reporter signal more correlated with replicon replication, as evidenced by treatment with known SARS-CoV-2 replication inhibitors including Remdesivir, GC376, and EIDD-1931. Thus, our study emphasizes that host RNA splicing is a confounding factor for DNA-launched SARS-CoV-2 replicon systems, which can be mitigated by Isoginkgetin treatment.

A Universal Aptamer for Influenza A Viruses: Selection, Recognition, and Infection Inhibition.

It is crucial to develop universal inhibitors for viral inhibition due to the rapid mutation of viruses. Herein, a universal aptamer inhibitor was developed that enabled a single DNA molecule to recognize several hemeagglutinin (HA) protein subtypes, inducing broad neutralization against influenza A viruses (IAVs). Through a multi-channel enrichment (MCE) strategy, a high-affinity aptamer named UHA-2 was obtained, with its dissociation constants (Kd) for three different HA proteins being 1.5 ± 0.2 nM (H5N1), 3.7 ± 0.4 nM (H7N9), and 10.1 ± 1.1 nM (H9N2). The UHA-2 aptamer had a universal inhibition effect, by which it could broadly neutralize influenza A H5N1, H7N9, H9N2, H1N1, and H3N2 viruses. Universal aptamer inhibitors have the advantages of acquisition in vitro, stability, simple structure, small size, etc. This study not only develops a novel universal aptamer to achieve a broad inhibition effect on various IAVs, but also opens up an efficient strategy for the development of universal inhibitors against viruses.

Study of the effectiveness of inhibiting corrosion processes in mineralized water-oil environments

Corrosion is a phenomenon that strongly affects many industries. Everything related to metallurgy, shipbuilding, or the oil industry is negatively affected by corrosion processes. This is a big problem, because the number of industrial accidents due to corrosion reaches more than 75%. Therefore, in this work, the effectiveness of inhibition of corrosion processes in mineralized water-oil environments was investigated in detail. The main goal of the article is to study the regularity of corrosion processes in water-oil media of different composition and at different temperature regimes for effective selection of the inhibition mechanism and type of corrosion inhibitor.
 An effective method of reducing the impact of corrosion processes today is the use of inhibitors. This is expedient not only from the point of view of the effectiveness of the action, but also from the point of view of economic expediency. Inhibitors are added to corrosive environments in order to stop or reduce corrosion processes. They can be used as protective barriers that form a protective layer, and as absorbers that prevent oxidation processes. In the future, the type of inhibitor is selected depending on the type of metal and the conditions of the reactions responsible for the occurrence and course of corrosion.
 Currently, the use of corrosion inhibitors is recognized as the most effective way to reduce the intensity of corrosion destruction of metal structures. At the same time, it is impossible to obtain a universal inhibitor that meets the requirements of high efficiency, manufacturability, toxicological safety, and at the same time is obtained in an economically feasible way. Among various corrosion inhibitors, organic ones have shown their effectiveness in protecting low-alloy steels of oil industry equipment.
 Metal samples of St20 steel, the most widely used for the manufacture of oil pipelines and oil production equipment, were used as corroding materials in the study. The pH was changed by adding a solution of acetic acid. The degree of corrosion was determined by the massometric method. The volume of the test solution was 150 cm3, the pH of the solution was adjusted with a 5% acetic acid solution. Alkylimidozoline was used as an inhibitor.
 Judging by the research results, the mineral composition of the aqueous solution largely affects the rate of corrosion. The presence of oil significantly reduces the rate of corrosion due to both blocking the access of oxygen to the system by the oil film and due to the corrosion inertness of the chemical components of the oil. However, it was also found that with an increase in the content of carboxylic acids, the presence of oil does not affect the corrosion rate in any way. Arguably, the alkylamidazoline inhibitor showed a high degree of protection at room temperature, in contrast to studies at high temperatures.

Bacteriophage SPO1 protein Gp46 suppresses functions of HU protein in Francisella tularensis.

The nucleoid-associated protein HU is a common bacterial transcription factor, whose role in pathogenesis and virulence has been described in many bacteria. Our recent studies showed that the HU protein is an indispensable virulence factor in the human pathogenic bacterium Francisella tularensis, a causative agent of tularemia disease, and that this protein can be a key target in tularemia treatment or vaccine development. Here, we show that Francisella HU protein is inhibited by Gp46, a protein of Bacillus subtilis bacteriophage SPO1. We predicted that Gp46 could occupy the F. tularensis HU protein DNA binding site, and subsequently confirmed the ability of Gp46 to abolish the DNA-binding capacity of HU protein. Next, we showed that the growth of Francisella wild-type strain expressing Gp46 in trans corresponded to that of a deletion mutant strain lacking the HU protein. Similarly, the efficiency of intracellular proliferation in mouse macrophages resembled that of the deletion mutant strain, but not that of the wild-type strain. These results, in combination with findings from a recent study on Gp46, enabled us to confirm that Gp46 could be a universal inhibitor of HU proteins among bacterial species.

Ionic liquid-caged nucleic acids enable active folding-based molecular recognition with hydrolysis resistance.

Beyond storage and transmission of genetic information in cellular life, nucleic acids can perform diverse interesting functions, including specific target recognition and biochemical reaction acceleration; the versatile biopolymers, however, are acutely vulnerable to hydrolysis-driven degradation. Here, we demonstrate that the cage effect of choline dihydrogen phosphate permits active folding of nucleic acids like water, but prevents their phosphodiester hydrolysis unlike water. The choline-based ionic liquid not only serves as a universal inhibitor of nucleases, exceptionally extending half-lives of nucleic acids up to 6500000 times, but highly useful tasks of nucleic acids (e.g. mRNA detection of molecular beacons, ligand recognition of aptamers, and transesterification reaction of ribozymes) can be also conducted with well-conserved affinities and specificities. As liberated from the function loss and degradation risk, the presence of undesired and unknown nucleases does not undermine desired molecular functions of nucleic acids without hydrolysis artifacts even in nuclease cocktails and human saliva.

Polymethoxyflavone from Citrus depressa as an inhibitor against various variants of SARS-CoV-2 spike protein

Ethnopharmacological relevanceIn traditional Taiwanese medicine, Citrus depressa Hayata serves as the raw material of Chen-Pi which has been widely used to treat respiratory ailments. Scientific investigations have validated the attributes of C. depressa, elucidating its valuable properties, including antioxidative, anti-inflammatory, anticancer, neuroprotion, hepatoprotection, and hypolipidemic effects. Aim of the studyThis study aims to isolate a universal inhibitor of the SARS-CoV-2 spike protein from C. depressa and confirm the mechanism by which these inhibitors disrupt the binding of the spike protein to hACE2. Materials and methodsThe whole fruit of C. depressa was subjected to ethanol extraction, following by partitioning to obtain water, butanol, and ethyl acetate fractions. To identify the inhibitory components in citrus fruits, we performed both the SPR assay and the SARS-CoV-2 pseudo-virus assays. Subsequently, we employed a bioassay-guided approach to efficiently isolate and characterize the bioactive constituents that hindered the interaction between the SARS-CoV-2 spike protein and hACE2, using a combination of MPLC and Semi-preparative HPLC for compound isolation. ELISA based spike protein binding assay evaluate the inhibitory activities of the extract and potential constituents against multiple spike protein variants. To further shed light on the inhibitory mechanism, candidate inhibitors were validated through the SPR assay and molecular docking. ResultsThe crude extract and ethyl acetate layer derived from C. depressa showed significant inhibitory activity on SARS-CoV-2 Omicron BA.4/5, with IC50 of 77.4 μg/mL and 100 μg/mL, respectively. Ten potential compounds from C. depressa have been identified with inhibitory activity against various SARS-CoV-2 spike proteins. 2′-hydroxy-4,4′,5′,6′-tetramethoxychalcone (Cd3) and 5-hydroxy-3′,4′,6,7,8-pentamethoxyflavone (Cd8) also showed good inhibitory activity to the spike protein, with KD of 0.79 μM and 37.3 nM, respectively. These findings are in line with prior study, indicating Cd3 and Cd8 can bind to key amino acid residue, disrupting the formation of the spike protein and h-ACE2 complex. ConclusionThis study presents the initial evidence showcasing the inhibitory effect of polymethoxyflavones (PMFs) on the spike protein of SARS-CoV-2. Moreover, the inhibitory activity of C. depressa extracts indicates their potential to prevent infections of different SARS-CoV-2 variants.

Involvement of a flavoprotein, acetohydroxyacid synthase, in growth and riboflavin production in riboflavin-overproducing Ashbya gossypii mutant

BackgroundPreviously, we isolated a riboflavin-overproducing Ashbya gossypii mutant (MT strain) and discovered some mutations in genes encoding flavoproteins. Here, we analyzed the riboflavin production in the MT strain, in view of flavoproteins, which are localized in the mitochondria.ResultsIn the MT strain, mitochondrial membrane potential was decreased compared with that in the wild type (WT) strain, resulting in increased reactive oxygen species. Additionally, diphenyleneiodonium (DPI), a universal flavoprotein inhibitor, inhibited riboflavin production in the WT and MT strains at 50 µM, indicating that some flavoproteins may be involved in riboflavin production. The specific activities of NADH and succinate dehydrogenases were significantly reduced in the MT strain, but those of glutathione reductase and acetohydroxyacid synthase were increased by 4.9- and 25-fold, respectively. By contrast, the expression of AgGLR1 gene encoding glutathione reductase was increased by 32-fold in the MT strain. However, that of AgILV2 gene encoding the catalytic subunit of acetohydroxyacid synthase was increased by only 2.1-fold. These results suggest that in the MT strain, acetohydroxyacid synthase, which catalyzes the first reaction of branched-chain amino acid biosynthesis, is vital for riboflavin production. The addition of valine, which is a feedback inhibitor of acetohydroxyacid synthase, to a minimal medium inhibited the growth of the MT strain and its riboflavin production. In addition, the addition of branched-chain amino acids enhanced the growth and riboflavin production in the MT strain.ConclusionThe significance of branched-chain amino acids for riboflavin production in A. gossypii is reported and this study opens a novel approach for the effective production of riboflavin in A. gossypii.

The Bacteriophage-Phage-Inducible Chromosomal Island Arms Race Designs an Interkingdom Inhibitor of dUTPases.

Stl, the master repressor of the Staphylococcus aureus pathogenicity islands (SaPIs), targets phage-encoded proteins to derepress and synchronize the SaPI and the helper phage life cycles. To activate their cycle, some SaPI Stls target both phage dimeric and phage trimeric dUTPases (Duts) as antirepressors, which are structurally unrelated proteins that perform identical functions for the phage. This intimate link between the SaPI's repressor and the phage inducer has imposed an evolutionary optimization of Stl that allows the interaction with Duts from unrelated organisms. In this work, we structurally characterize this sophisticated mechanism of specialization by solving the structure of the prototypical SaPIbov1 Stl in complex with a prokaryotic and a eukaryotic trimeric Dut. The heterocomplexes with Mycobacterium tuberculosis and Homo sapiens Duts show the molecular strategy of Stl to target trimeric Duts from different kingdoms. Our structural results confirm the participation of the five catalytic motifs of trimeric Duts in Stl binding, including the C-terminal flexible motif V that increases the affinity by embracing Stl. In silico and in vitro analyses with a monomeric Dut support the capacity of Stl to recognize this third family of Duts, confirming this protein as a universal Dut inhibitor in the different kingdoms of life. IMPORTANCE Stl, the Staphylococcus aureus pathogenicity island (SaPI) master repressor, targets phage-encoded proteins to derepress and synchronize the SaPI and the helper phage life cycles. This fascinating phage-SaPI arms race is exemplified by the Stl from SaPIbov1 which targets phage dimeric and trimeric dUTPases (Duts), structurally unrelated proteins with identical functions in the phages. By solving the structure of the Stl in complex with a prokaryotic (M. tuberculosis) and a eukaryotic (human) trimeric Dut, we showed that Stl has developed a sophisticated substrate mimicry strategy to target trimeric Duts. Since all these Duts present identical catalytic mechanisms, Stl is able to interact with Duts from different kingdoms. In addition, in silico modeling with monomeric Dut supports the capacity of Stl to recognize this third family of Duts, confirming this protein as a universal Dut inhibitor.

Alpha-2 macroglobulin activity in SARS-CoV-2 induced infection and in the post-COVID-19 period.

The universal proteinase inhibitor α2-macroglobulin (α₂-MG) exhibiting antiviral and immunomodulatory activities, is considered as an important participant in the infectious process. The activity of α₂-MG in the new coronavirus infection and post-covid syndrome (long COVID) has not been studied yet. We examined 85 patients diagnosed with community-acquired bilateral polysegmental pneumonia developed under conditions of a new coronavirus infection SARS-CoV-2. For assessment of the post-COVID period, 60 patients were examined 5.0±3.6 months after the coronavirus infection. Among these patients, 40 people had complications, manifested in the form of neurological, cardiological, gastroenterological, dermatological, bronchopulmonary symptoms. The control group included 30 conditionally healthy individuals with a negative PCR result for SARS-CoV-2 RNA and lack of antibodies to the SARS-CoV-2 virus. The α₂-MG activity in serum samples of patients with coronavirus infection dramatically decreased, up to 2.5% of the physiological level. This was accompanied by an increase in the activity of the α₁-proteinase inhibitor, elastase- and trypsin-like proteinases by 2.0-, 4.4- and 2.6-fold respectively as compared with these parameters in conditionally healthy individuals of the control. In the post-COVID period, despite the trend towards normalization of the activity of inhibitors, the activity of elastase-like and especially trypsin-like proteinases in serum remained elevated. In overweight individuals, the increase in the activity of trypsin-like proteinases was most pronounced and correlated with an increase in the antibody titer to the SARS-CoV-2 virus. In the post-COVID period, the α₂-MG activity not only normalized, but also exceeded the control level, especially in patients with dermatological and neurological symptoms. In patients with neurological symptoms or with dermatological symptoms, the α₂-MG activity was 1.3 times and 2.1 times higher than in asymptomatic persons. Low α₂-MG activity in the post-COVID period persisted in overweight individuals. The results obtained can be used to monitor the course of the post-COVID period and identify risk groups for complications.

ReACT (redox-activated chemical tagging) chemistry enables direct derivatization and fluorescence detection of S-adenosyl-L-homocysteine (SAH).

S-Adenosyl-L-homocysteine (SAH) is a universal byproduct and product inhibitor of the methyltransferase-catalyzed methylation reaction. Here based on ReACT (redox-activated chemical tagging) chemistry, direct derivatization and fluorescence measurement of SAH were achieved with features such as mild reaction conditions and simple operation.

Structural Basis of Botulinum Toxin Type F Binding to Glycosylated Human SV2A: In Silico Studies at the Periphery of a Lipid Raft.

Botulinum neurotoxins are the deadliest microbial neurotoxins in humans, with a lethal dose of 1 ng/kg. Incidentally, these neurotoxins are also widely used for medical and cosmetic purposes. However, little is known about the molecular mechanisms that control binding of botulinum neurotoxin type F1 (BoNT/F1) to its membrane receptor, glycosylated human synaptic vesicle glycoprotein A (hSV2Ag). To elucidate these mechanisms, we performed a molecular dynamics simulation (MDS) study of initial binding kinetics of BoNT/F1 to SV2A. Since this toxin also interacts with gangliosides, the simulations were performed at the periphery of a lipid raft in the presence of both SV2A and gangliosides. Our study suggested that interaction of BoNT/F1 with SV2A is exclusively mediated by N-glycan moiety of SV2A, which interacts with aromatic residues Y898, Y910, F946, Y1059 and H1273 of this toxin. Thus, in contrast with botulinum neurotoxin A1 (BoNT/A1), BoNT/F1 does not interact with protein content of SV2A. We attributed this incapability to a barrage effect exerted by neurotoxin residues Y1132, Q1133 and K1134, which prevent formation of long-lasting intermolecular hydrogen bonds. We also provided structural elements that suggest that BoNT/F1 uses the strategy of BoNT/A1 combined with the strategy of botulinum neurotoxin type E to bind N-glycan of its glycoprotein receptor. Overall, our study opened a gate for design of a universal inhibitor aimed at disrupting N-glycan-toxin interactions and for bioengineering of a BoNT/F1 protein that may be able to bind protein content of synaptic vesicle glycoprotein for therapeutic purposes.

Computational study of inhibitory mechanisms for Janus iron oxide nanoparticles on amyloid aggregations

Amyloid aggregation is a ubiquitous form of protein misfolding underlying the pathologies of Alzheimer’s disease (AD), Parkinson’s disease (PD), and type 2 diabetes (T2D), three primary forms of human amyloid diseases. β-casein-coated iron oxide nanoparticles (βCas IONPs) via a BPA-P(OEGA-co-DBM) copolymer linker was recently demonstrated to be a potential universal inhibitor against the amyloidosis of amyloid β (Aβ), α Synuclein (αS) and human islet amyloid polypeptide (IAPP) aggregations in both vitro and vivo.

THE DEVELOPMENT OF A UNIVERSAL CORROSION INHIBITOR

In the article, in order to eliminate of the corrosion process, a universal bactericidal inhibitor was developed, based on the condensation products of aminoethylethanolamine and fatty acids. The bactericidal properties of the developed inhibitor were investigated. In wells operated on offshore platforms of O.G.E.O. on May 28, SOCSR carried out chemical and microbiological analysis of formation waters. The number of bactericidal cells of the investigated inhibitor and their vital activity indicate the bactericidal effect of its organizing advantage. The topic posed in this article is topical and has great theoretical and practical importance. An inhibiting composition has been developed, obtained on the basis of processing the residue of condensation products of aminoethylethanolamine and fatty acids, which have high inhibitory properties in model solutions. The optimal conditions for the synthesis of this inhibitor have been determined. The inhibiting properties of the composition of the new series, moreover, with a different composition in hydrogen sulfide media of oil fields of formation waters, imitating siphate-reducing bacteria, with respect to the bactericidal effect, have been established. Keywords: corrosion, oilfield equipment, inhibitor protection, aggressive protection, aggressive environment, hydrogen sulfide, carbon dioxide, oxygen, carbonate, dispersed particle.

Dissecting the Nucleoside Antibiotics as Universal Translation Inhibitors.

Without question, natural products have provided the lion share of leads, if not drugs themselves, for the treatment of bacterial infections. The bacterial arms race, fueled by selection and survival pressures has delivered a natural arsenal of small molecules targeting the most essential of life processes. Antibiotics that target these critical intracellular processes face the formidable defense of both penetrating a bacterial cell membrane and avoiding efflux to exert their effect. These challenges are especially effective in Gram-negative (Gram-(-)) bacteria, which have a double membrane structure and efficient efflux systems from the combination of outer-membrane porins and inner membrane proton pumps. In this landscape of offense and defense, our clinically used antibiotics have only successfully targeted three intracellular processes for therapeutic intervention in Gram-(-) bacteria: dihydrofolate biosynthesis, transcription, and translation. Not surprisingly, such critical survival machinery is a popular target for bacterial warfare, and eight of our 14 classes of commonly used antibiotics target translation with the bacterial ribosome remaining one the most vetted targets for antimicrobial therapy. On the plus side, its anionic character attracts cationic inhibitors, which are generally more capable of penetrating the bacterial cell wall, and clinical resistance rates are usually manageable as mutation of such a highly evolved machine is difficult. On the down side, this highly evolved machine renders it difficult to inhibit selectively, and the inhibition of prokaryotic translation versus both eukaryotic cellular and mitochondrial translation is critical for clinical development and minimization of undesired toxicities.A class of natural products known as the "nucleoside antibiotics" have historically been recognized as universal inhibitors of the ribosome and can inhibit translation in prokaryotes, eukaryotes, and archaea. While they have served an essential role in dissecting the biochemical underpinnings of the enzymatic functions of the ribosome, they have not proven therapeutically useful as they target the highly conserved rRNA in the P-site and are toxic to mammalian cells. In this Account, we describe our studies on the natural product amicetin, a nucleoside antibiotic that we have demonstrated to break the rule of being a universal translation inhibitor. While the cytosine of amicetin mimics C75 of the 3'-CCA tail of the P-site tRNA akin to other nucleoside antibiotics, we advance a hypothesis that amicetin's unique interaction with the ribosomal protein uL16 exploits an untapped mechanism for selectively targeting the bacterial ribosome. A complex molecule comprised of a nucleoside, carbohydrates and amino acids, amicetin is also chemically unstable. Our initial attempts to stabilize and simplify this scaffold are presented with the ultimate goal of rebuilding the compound with improved penetrance to bacterial cells. If successful, this scaffold would demonstrate a path forward for a new class of antibiotics capable of selectively targeting the ribosomal P-site.

Selection of Unique Molecules for Cancer Treatment by Distance-Based Method: Hypericin Effect on Respiratory Chain

The heterogeneous composition of tumors presents a significant obstacle to the selection of a single molecule as a potential universal inhibitor of tumor growth. Lipid signaling and cellular metabolism have become the main targets of anticancer treatment in recent years. The protein kinase C (PKC) regulators Gö6976, rottlerin, hypericin, and phorbol myristyl acetate have been identified as agents affecting cellular metabolism. Measurable parameters describing metabolism, endocytosis, and respiration were subjected to a distance-based computational procedure for higher dimensions to complement and extend the knowledge gained from experimental data. The mutual distances of the parameters of the substances applied to the cancer cells in the presence and absence of lipids were calculated within the Lp spaces. The distance-based methods and comparisons of the generalized distances suggested to us the exceptional role of hypericin in heterogeneous systems. Furthermore, our results are confirmed by Western blotting of the levels of respiratory chain proteins and enzymes active in oxidative stress defense in cancer cell monolayers and spheroids. PKCα and PKCδ have been studied for lipid-activated cell signaling. In this study, we attempt to apply the concept of parametric distance in cell signal transduction and activation where the above methods have not yet been used.

Structural basis for an exceptionally strong preference for asparagine residue at the S2 subsite of Stenotrophomonas maltophilia dipeptidyl peptidase 7

The emergence of drug-resistant bacteria has become a major problem worldwide. Bacterial dipeptidyl peptidases 7 and 11 (DPP7s and DPP11s), belonging to the family-S46 peptidases, are important enzymes for bacterial growth and are not present in mammals. Therefore, specific inhibitors for these peptidases are promising as potential antibiotics. While the molecular mechanisms underlining strict specificity at the S1 subsite of S46 peptidases have been well studied, those of relatively broad preference at the S2 subsite of these peptidases are unknown. In this study, we performed structural and biochemical analyses on DPP7 from Stenotrophomonas maltophilia (SmDPP7). SmDPP7 showed preference for the accommodation of hydrophobic amino acids at the S2 subsite in general, but as an exception, also for asparagine, a hydrophilic amino acid. Structural analyses of SmDPP7 revealed that this exceptional preference to asparagine is caused by a hydrogen bonding network at the bottom of the S2 subsite. The residues in the S2 subsite are well conserved among S46 peptidases as compared with those in the S1 subsite. We expect that our findings will contribute toward the development of a universal inhibitor of S46 peptidases.

A universal scale inhibitor: A dual inhibition/dispersion performance evaluation under difficult brine stresses

Scale inhibition is of crucial importance in harvesting geothermal energy, an attractive, renewable and sustainable energy source. The majority of the geothermal reservoir waters around the world contain a variety of anions and cations, which are prone to inorganic precipitation when subjected to drastic changes in both temperature and pressure, causing failures and unwanted shut-downs. Our goal is to prevent the formation, precipitation and deposition of such scales by stabilizing their respective components. Herein, the ability of a methacrylate-structured, grafted co-polymer, coined PEGPHOS-LOW (with polyethylene glycol and phosphonate grafts), to control inorganic precipitation is evaluated for four artificial geothermal brines of variable scaling propensity towards common geothermal scales, such as amorphous silica, magnesium, aluminum and iron silicates, zinc, lead and iron sulfides and calcium carbonate. Inhibitor selection was based on previous results obtained with four, similar inhibitor grafted co-polymers (one containing only polyethylene glycol, PEG, one with only phosphonate grafts, and two containing variable ratios of both grafts) against individual scales. The working brines were designed based on the saturated conditions of geothermal well fluids. PEGPHOS-LOW is a polymer that contains 34 PEG20 grafts, and 14 phosphonate grafts. It is a dual scale control additive, as it can function both as a scale inhibitor (keeping the scaling species soluble) and as a dispersant (keeping the scale particles formed in a suspended form). It displays a dosage-dependent scale inhibition and dispersion behavior, however, very high concentrations are necessary for satisfactory effectiveness, due to the high scaling propensity of the brines.

Searching for a universal scale inhibitor: A multi-scale approach towards inhibitor efficiency

Scale inhibition is of crucial importance in harvesting geothermal energy, an attractive, renewable and sustainable energy source. The majority of the geothermal reservoir waters around the world contain a variety of anions and cations, which are prone to precipitation when subjected to vast transformations of both temperature and pressure, causing failures to many parts of the plants. Our goal is to prevent the formation, precipitation and deposition of such scales by stabilizing their respective components. Our working brines are designed based on the saturated conditions of geothermal well waters. Common inorganic scales tested include amorphous silica, magnesium silicate, aluminum silicate, iron (III) silicate, zinc sulfide, lead sulfide, iron (II) sulfide, and calcium carbonate. Against these scales, four interrelated methacrylate-structured polymers were tested as inhibitors, grafted either with polyethylene glycol (PEG), or phosphonic acid (PHOS) side-chains, or both. Based on several results obtained the inhibitor PEGPHOS-LOW (containing 34 PEG grafts and 14 phosphonate grafts) was selected as the most efficient, and was subsequently tested in artificial geothermal brines of variable stress, containing all the scales together.

Cost-effectiveness analysis comparing “PARP inhibitors-for-all” to the biomarker-directed use of PARP inhibitor maintenance therapy for newly diagnosed advanced stage ovarian cancer

ObjectivesClinical trials evaluating universal PARP inhibitor (PARPi) frontline maintenance therapy for advanced stage ovarian cancer have reported progression-free survival (PFS) benefit. It is unclear whether PARPi maintenance therapy will universally enhance value (clinical benefits relative to cost of delivery). We compared a “PARPi-for-all” to a biomarker-directed frontline maintenance therapy approach as a value-based care strategy. MethodsThe cost of two frontline PARPi maintenance strategies, PARPi-for-all and biomarker-directed maintenance, was compared using modified Markov decision models simulating the study designs of the PRIMA, VELIA, and, PAOLA-1 trials. Outcomes of interest included overall costs and incremental cost-effectiveness ratios (ICERs) reported in US dollars per quality adjusted progression-free life-year (QA-PFY) gained. ResultsPARPi-for-all was more costly and provided greater PFS benefit than a biomarker-directed strategy for each trial. The mean cost per patient for the PARPi-for-all strategy was $166,269, $286,715, and $366,506 for the PRIMA, VELIA, and PAOLA-1 models, respectively. For the biomarker-directed strategy, the mean cost per patient was $98,188, $167,334, and $260,671 for the PRIMA, VELIA, and PAOLA-1 models. ICERs of PARPi-for-all compared to biomarker-directed maintenance were: $593,250/QA-PFY (PRIMA), $1,512,495/QA-PFY (VELIA), and $3,347,915/QA-PFY (PAOLA-1). At current drug pricing, there is no PFS improvement in a biomarker negative cohort that would make PARPi-for-all cost-effective compared to biomarker-directed maintenance. ConclusionsThis study highlights the high costs of universal PARPi maintenance treatment, compared with a biomarker-directed PARPi strategy. Maintenance therapy in the front-line setting should be reserved for those with germline or somatic HRD mutations until the cost of therapy is significantly reduced.