Single Doublet Research Articles

Underpinnings of reservoir and techno-economic analysis for Himalayan and Son-Narmada-Tapti geothermal sites of India

The high capital cost and risks associated with the extraction process of geothermal energy are key factors in the project economics. This paper presents a comprehensive technoeconomic study based on reservoir heat and flow simulations along with the levelized cost of energy (LCOE) for two geothermal sites (Himalayan and Son-Narmada-Tapti i.e. SONATA) in India.Dual porosity reservoir simulation models were constructed and were used to obtain the cumulative and the dynamic thermal energy potentials of these sites. The simulation studies suggest that both sites are equally potent for geothermal energy extraction. Comparatively, the proven cumulative energy potentials for the Himalayan and SONATA sites are found to be 4.92–5.10 and 3.62–3.7 TW h, respectively, for the 30 years of production at a rate of 92 kg/s. This difference can be attributed mainly to higher temperatures and deeper sites at the Himalayan Province. Sensitivity analyses were conducted to assess the impact of various parameters, including porosity, permeability, fracture spacing, and thermal conductivity. The results suggest that porosity and permeability are the key enablers of efficient energy production. The economic feasibility study suggests that the LCOE costs are high for these sites ($148/MWh for the Himalayan and $137/MWh for the SONATA). These two sites have CO2 mitigation potential in the range of 3.12 and 11.36 Megatons from a single doublet well configuration considering the CO2 emissions from conventional coal-fired thermal power plants. Overall, SONATA can be the better prospect considering the logistics and operational challenges along with reservoir heat potential.

Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours.

Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.

Versatile properties of dynein molecules underlying regulation in flagellar oscillation

Dynein is a minus-end-directed motor that generates oscillatory motion in eukaryotic flagella. Cyclic beating, which is the most significant feature of a flagellum, occurs by sliding spatiotemporal regulation by dynein along microtubules. To elucidate oscillation generated by dynein in flagellar beating, we examined its mechanochemical properties under three different axonemal dissection stages. By starting from the intact 9 + 2 structure, we reduced the number of interacting doublets and determined three parameters, namely, the duty ratio, dwell time and step size, of the generated oscillatory forces at each stage. Intact dynein molecules in the axoneme, doublet bundle and single doublet were used to measure the force with optical tweezers. The mean forces per dynein determined under three axonemal conditions were smaller than the previously reported stall forces of axonemal dynein; this phenomenon suggests that the duty ratio is lower than previously thought. This possibility was further confirmed by an in vitro motility assay with purified dynein. The dwell time and step size estimated from the measured force were similar. The similarity in these parameters suggests that the essential properties of dynein oscillation are inherent to the molecule and independent of the axonemal architecture, composing the functional basis of flagellar beating.

Abstract 2693: Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models

Abstract The BRAFV600E mutation occurs in approximately 7% of colorectal cancer (CRC). BRAF plus EGFR inhibition (encorafenib with cetuximab) is an FDA approved treatment option for adult patients with metastatic CRC. Ultimately, patients develop resistance leading to disease progression. The addition of a MEK inhibitor, binimetinib, did not confer overall survival benefit. We hypothesized that addition of ERK inhibition would increase magnitude and duration of response to BRAF plus EGFR inhibition by overcoming MAPK-related acquired resistance mechanisms. ERK is the terminal master regulator kinase of the RAS-MAPK pathway, therefore, targeting this node is likely to be effective in the context of numerous mechanisms of acquired resistance that reactivate the MAPK pathway. Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. The efficacy of ulixertinib, in combination with EGFR inhibition (cetuximab), plus BRAF inhibition (encorafenib), was assessed in CRC cell line derived xenograft models harboring BRAFV600E mutations. The triple combination resulted in superior tumor growth inhibition compared to dosing of any single agent or doublet. RNA sequencing was performed on treated tumor samples. Expression of the mutant BRAF allele was readily confirmed from RNA sequencing data. Gene expression analysis showed differential expression of MAPK pathway genes in triple combination treated groups versus single or doublet therapy. A complete response to ulixertinib in combination with cetuximab and encorafenib for the treatment of a patient with metastatic CRC has been reported (Stuhlmiller, Timothy Joseph, et al. "Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523)." (2022): e15101-e15101). The patient was treated under the Expanded Access Protocol (NCT04566393) for compassionate use access to ulixertinib. Preclinical data and clinical complete response warrants further investigation of ulixertinib plus BRAF and EGFR inhibition. Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2693.

A Comparative Study on Longitudinal Dynamics Stability Between Two Aircraft Models

The present work presents a comparative study on the longitudinal dynamic’s stability behavior for two aircraft models, namely the Learjet 24 and the Cessna 182. The longitudinal flight dynamics behaviors are evaluated by introducing a disturbance to the elevator. This device uses a single doublet impulse as well as multiple doublet impulses. The governing equation of longitudinal flight motion, which was derived based on a small perturbation theory and a linearized process by dropping the second order and above to the disturbance quantities, allowed one to formulate the governing equation of flight motion in the form of an equation known as the longitudinal equation of flight motion. This equation describes the flight behavior of an aircraft and can be expressed in the disturbance quantity as translational velocity in the x-direction u, angle of attack 𝛼, and pitch angle 𝜃. The implementation in the case of the Cessna 182 and the Learjet 24, where the Cessna 182 uses a single doublet impulse or a multiple doublet impulse, demonstrates that the aircraft response in these three variable states is better than that of the Learjet 24.

Slow Phase Transition-Induced Scan Rate Dependence of Spin Crossover in a Two-Dimensional Supramolecular Fe(III) Complex

Slow Phase Transition-Induced Scan Rate Dependence of Spin Crossover in a Two-Dimensional Supramolecular Fe(III) Complex

Performance of Multi-Well Exploitation and Reinjection in a Small-Scale Shallow Geothermal Reservoir in Huailai County

The sustainable development of a shallow aquifer geothermal reservoir is strongly affected by the reinjection–production strategy. However, the reinjection–production strategy optimization of a small-scale exploitation unit with tens of meters of well spacing is site specific and has not yet been fulfilled. This study numerically investigates sustainable heat extraction based on various reinjection–production strategies which were conducted in a single-phase aquitard–aquifer geothermal system in Huailai County, Hebei Province, China. The response of the water level and production temperature is mainly discussed. The numerical results show that production without reinjection induces the highest production temperature and also the water level drawdown. Although reinjection in a single doublet well system is conducive to the control of water level drawdown, the introduction of the thermal breakthrough problem causes a decrease in the production temperature. The thermal breakthrough and sustainability of geothermal reservoirs highly depend on the well spacing between the production and reinjection wells, especially for the small-scale field. Therefore, a large well spacing is suggested. A multi-well system facilitates the control of water level drawdown while bringing intensive well interference and thermal breakthrough. Large spacing between the production and reinjection wells is also the basic principle for the design of the multi-well system. A decrease in openhole length leads to an increase in the production temperature and output thermal power. An increase in the production rate affects the thermal breakthrough highly and shortens the lifetime of the geothermal system. Furthermore, the extracted thermal energy is highly affected by the reduction in the reinjection temperature. The results in this study can provide references to achieve sustainable geothermal exploitation in small-scale geothermal reservoirs.

Effects of sintering temperature on microstructure, initial permeability and electric behaviour of Ni-Mn-Zn ferrites

The effects of sintering temperature on microstructure, initial permeability, and electrical behaviour of Ni0.5-xMnxZn0.5Fe2O4 (0.0 < x < 0.5) prepared using the precursor combustion method have been investigated. X-ray diffraction analysis confirmed the single phase cubic spinel structure of Ni0.5-xMnxZn0.5Fe2O4 (0.0 < x < 0.4) compositions sintered at 1100 °C. The Mn2+ substituent preferentially occupies tetrahedral sites as indicated by the Rietveld analysis and the increase in the IR absorption frequency of ν1 band with increasing Mn substitution. The SEM measurements have revealed homogeneous microstructures of the ferrites with narrow grain size distribution in the range 0.93μm–1.86 μm. Mössbauer spectra exhibit a superposition of two Zeeman sextets for the compositions x ≤ 0.2, a superposition of two Zeeman sextets, and a paramagnetic doublet for the compositions, x = 0.3 and 0.4, and one sextet and single quadrupole doublet for a composition, x = 0.5. The activation energy in the range 0.258 eV–0.612 eV suggests a polaron hopping type conduction mechanism in all the sintered ferrites. The dielectric constant in the range 0.057–55.21 and lower dielectric loss (10−2) imply better stoichiometry and homogeneity. The initial permeability increases at lower Mn substitution (x = 0.2) and exhibits a decrease as the Mn substitution increases. The dc resistivity, dielectric constant, and initial permeability values suggest the suitability of these ferrites for high frequency device applications.

Analysis of Enhanced Geothermal System Development Scenarios for District Heating and Cooling of the Göttingen University Campus

The huge energy potential of Enhanced Geothermal Systems (EGS) makes them perspective sources of non-intermittent renewable energy for the future. This paper focuses on potential scenarios of EGS development in a locally and in regard to geothermal exploration, poorly known geological setting—the Variscan fold-and-thrust belt —for district heating and cooling of the Göttingen University campus. On average, the considered single EGS doublet might cover about 20% of the heat demand and 6% of the cooling demand of the campus. The levelized cost of heat (LCOH), net present value (NPV) and CO2 abatement cost were evaluated with the help of a spreadsheet-based model. As a result, the majority of scenarios of the reference case are currently not profitable. Based on the analysis, EGS heat output should be at least 11 MWth (with the brine flow rate being 40 l/s and wellhead temperature being 140 °C) for a potentially profitable project. These parameters can be a target for subsurface investigation, reservoir modeling and hydraulic stimulation at a later stage. However, sensitivity analysis presented some conditions that yield better results. Among the most influential parameters on the outcome are subsidies for research wells, proximity to the campus, temperature drawdown and drilling costs. If realized, the EGS project in Göttingen might save up to 18,100 t CO2 (34%) annually.

A comment on instantons and their fermion zero modes in adjoint QCD_2

The adjoint 2-dimensional QCD with the gauge group SU(N)/Z_NSU(N)/ZN admits topologically nontrivial gauge field configurations associated with nontrivial \pi_1[SU(N)/Z_N] = Z_Nπ1[SU(N)/ZN]=ZN. The topological sectors are labelled by an integer k=0,\ldots, N-1k=0,…,N−1. However, in contrast to QED_2QED2 and QCD_4QCD4, this topology is not associated with an integral invariant like the magnetic flux or Pontryagin index. These instantons may admit fermion zero modes, but there is always an equal number of left-handed and right-handed modes, so that the Atiyah-Singer theorem, which determines in other cases the number of the modes, does not apply. The mod. 2 argument [1] suggests that, for a generic gauge field configuration, there is either a single doublet of such zero modes or no modes whatsoever. However, the known solution of the Dirac problem for a wide class of gauge field configurations indicates the presence of k(N-k) zero mode doublets in the topological sector k. In this note, we demonstrate in an explicit way that these modes are not robust under a generic enough deformation of the gauge background and confirm thereby the conjecture of Ref. [1]. The implications for the physics of this theory (screening vs. confinement issue) are briefly discussed.

Synthesis and Characterization of Symmetrically versus Unsymmetrically Proton-Bridged Hexa-Iron Clusters.

Syntheses and magnetic and structural characterization of hexa-iron complexes of derivatized salicylaldoximes are discussed. Complexation of Fe(BF4)2·6H2O with each ligand (H2L1 and H4L2) in a methanolic-pyridine solution resulted in hexa-iron compounds (C1 and C2, respectively), which each contain two near-parallel metal triangles of [Fe3–μ3-O], linked by six fluoride bridges and stabilized by a hydrogen-bonded proton between the μ3-O groups. Within each metal triangle of C2, Fe(III) ions are connected via the amine “straps” of (H4L2-2H). Variable-temperature magnetic susceptibility and Mössbauer data of C1 and C2 indicate the presence of dominant antiferromagnetic interactions between the high-spin (S = 5/2) Fe(III) centers. For C1, two quadrupole doublets are observed at room temperature and 5 K, consistent with structural data from which discrete but disordered [Fe3–μ3-O] and [Fe3–μ3-OH] species were inferred. For C2, a single sharp quadrupole doublet with splitting intermediate between those determined for C1 was observed, consistent with the symmetric [Fe3–μ3-O···H···μ3-O–Fe3] species inferred crystallographically from the very short μ3-O···μ3-O separation. The differences in the physical properties of the complexes, as seen in the Mössbauer, X-ray, and magnetic data, are attributed to the conformational flexibility imparted by the nature of the linkages between the closely related ligands.

Morphodynamic signatures of MDA-MB-231 single cells and cell doublets undergoing invasion in confined microenvironments

Cancer cell metastasis is a major factor in cancer-related mortality. During the process of metastasis, cancer cells exhibit migratory phenotypes and invade through pores in the dense extracellular matrix. However, the characterization of morphological and subcellular features of cells in similar migratory phenotypes and the effects of geometric confinement on cell morphodynamics are not well understood. Here, we investigate the phenotypes of highly aggressive MDA-MB-231 cells in single cell and cell doublet (an initial and simplified collective state) forms in confined microenvironments. We group phenotypically similar single cells and cell doublets and characterize related morphological and subcellular features. We further detect two distinct migratory phenotypes, fluctuating and non-fluctuating, within the fast migrating single cell group. In addition, we demonstrate an increase in the number of protrusions formed at the leading edge of cells after invasion through geometric confinement. Finally, we track the short and long term effects of varied degrees of confinement on protrusion formation. Overall, our findings elucidate the underlying morphological and subcellular features associated with different single cell and cell doublet phenotypes and the impact of invasion through confined geometry on cell behavior.

Thromboembolism in Patients with Advanced Renal Cell Carcinoma Treated with Immunotherapy

Background: Patients with renal cell carcinoma (RCC) are at a higher risk of thromboembolism (TE) compared to other cancers. Immunotherapy (IO) is a mainstay in the treatment of advanced or metastatic RCC (aRCC). It is still unknown whether IO further increases the hypercoagulable status in this already high risk population. We present the first analysis of the incidence and outcomes of venous (VTE) and arterial (ATE) events in patients with aRCC treated with immunotherapy. Methods: All patients with aRCC treated with IO at the Cleveland Clinic from 1/2015 to 12/2019 were identified. Cumulative incidence analysis was done to calculate rates of TE over time, and Gray's test was used to determine difference in rates of TE among groups. Factors associated with overall survival (OS) were identified using Cox proportional hazards regression, and the impact of TE on OS was evaluated with TE analyzed as a time dependent covariate. Results: Of 351 pts, 75% were men (median age 65 years, 92% white). 81% had clear cell histology and 77% had International Metastatic RCC Database Consortium intermediate to poor risk disease. Median follow up 12.8 months (range 0.1-53 months). From RCC diagnosis to IO initiation, the cumulative incidence of TE was 6.1% (95%CI 3.3-9.1) at 6 months and 6.1% (95%CI 3.8-9.1 months) at 12 months. At the time of IO start, 12% of patients were on anticoagulation, not specifically for TE related events. IO was used as first line therapy in 43% of patients (median doses 8, range 1-81) and included single agent (54% nivolumab, 13% pembrolizumab, 0.6% durvalumab, 1% atezolizumab, 0.2% avelumab) or doublet (30% ipilimuamb and nivolumab). VTE occurred in 11% (n=37), of which 62% were DVT, 27% PE, or 11% both. DVT locations were 74% lower limb, 7% upper limb, 19% visceral vein. ATE occurred in 2% (n=6), 4 had cerebral vascular events and 2 had myocardial infarctions. There was no difference in TE rates in patients receiving single versus doublet IO (p= 0.7475) For all patients, the incidence of TE after initiation of IO was 4.4% (95%CI 2.6%-6.9%) at 6 months and 9.8% (95%CI 6.8%-13.4%) at 12 months. Of all TE events, 72% resulted in hospitalization (mean duration of hospitalization 4 days), 9% of which resulted in clot related mortality. TE related dose delay occurred in 21% of patients (mean delay of 13 days). There were no TE-related IO discontinuations. The impact of IMDC score and Khorana score with respect to OS were evaluated in separate multivariable models given overlap in variables for score calculation. TE (HR 3.23, 95% CI 2.07-5.03, p &amp;lt;0.0001) and poor IMDC score were associated with worse OS. In the second model, TE (HR 3.16, 95% CI 2.0-4.92, p &amp;lt;0.0001) and higher Khorana scores were associated with worse OS. (Figure 1) Conclusion: Patients treated with IO therapy had a high incidence of TE at 12 months from treatment initiation. TE is associated with risk of treatment delay, hospitalization and mortality. TE, IMDC poor risk, and Khorana score ≥ 2 are associated with poorer survival. Further investigations into IO-associated TE are needed to identify benefit from primary thromboprophylaxis. Disclosures Gupta: Astra Zeneca: Consultancy; BMS: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Exelixis: Other; Janssen: Other. Khorana:Leap: Research Funding; BMS: Honoraria, Research Funding; Merck: Research Funding; Array: Other: Research funding (to institution); Janssen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria.

Nonergodic behavior of the clean Bose-Hubbard chain

We study ergodicity breaking in the clean Bose-Hubbard chain for small hopping strength. We see the existence of a non-ergodic regime by means of indicators as the half-chain entanglement entropy of the eigenstates, the average level spacing ratio, {the properties of the eigenstate-expectation distribution of the correlation and the scaling of the Inverse Participation Ratio averages.} We find that this ergodicity breaking {is different from many-body localization} because the average half-chain entanglement entropy of the eigenstates obeys volume law. This ergodicity breaking appears unrelated to the spectrum being organized in quasidegenerate multiplets at small hopping and finite system sizes, so in principle it can survive also for larger system sizes. We find that some imbalance oscillations in time which could mark the existence of a glassy behaviour in space are well described by the dynamics of a single symmetry-breaking doublet and {quantitatively} captured by a perturbative effective XXZ model. We show that the amplitude of these oscillations vanishes in the large-size limit. {Our findings are numerically obtained for systems with $L < 12$. Extrapolations of our scalings to larger system sizes should be taken with care, as discussed in the paper.

In Silico, Molecular Docking and In Vitro Antimicrobial Activity of the Major Rapeseed Seed Storage Proteins.

BackgroundIn addition to their use as an edible oil and condiment crop, mustard and rapeseed (Brassica napus L., B. juncea (L.) Czern., B. nigra (L.) W.D.J.Koch, B. rapa L. and Sinapis alba L.) have been commonly used in traditional medicine for relieving pain, coughs and treating infections. The seeds contain high amounts of oil, while the remaining by-product meal after oil extraction, about 40% of seed dry weight, has a low value despite its high protein-content (~85%). The seed storage proteins (SSP) 2S albumin-type napin and 12S globulin-type cruciferin are the two predominant proteins in the seeds and show potential for value adding to the waste stream; however, information on their biological activities is scarce. In this study, purified napin and cruciferin were tested using in silico, molecular docking, and in vitro approaches for their bioactivity as antimicrobial peptides.Materials and MethodsThe 3D-structure of 2S albumin and 12S globulin storage proteins from B. napus were investigated to predict antimicrobial activity employing an antimicrobial peptide database survey. To gain deeper insights into the potential antimicrobial activity of these SSP, in silico molecular docking was performed. The purified B. napus cruciferin and napin were then tested against both Gram-positive and Gram-negative bacteria for in vitro antimicrobial activity by disc diffusion and microdilution antimicrobial susceptibility testing.Results In silico analysis demonstrated both SSP share similar 3D-structure with other well studied antimicrobial proteins. Molecular docking revealed that the proteins exhibited high binding energy to bacterial enzymes. Cruciferin and napin proteins appeared as a double triplet and a single doublet, respectively, following SDS-PAGE. SDS-PAGE and Western blotting also confirmed the purity of the protein samples used for assessment of antimicrobial activity. Antimicrobial susceptibility testing provided strong evidence for antimicrobial activity for the purified napin protein; however, cruciferin showed no antimicrobial activity, even at the highest dose applied.Discussion In silico and molecular docking results presented evidence for the potential antimicrobial activity of rapeseed cruciferin and napin SSP. However, only the in vitro antimicrobial activity of napin was confirmed. These findings warrant further investigation of this SSP protein as a potential new agent against infectious disease.

Combined kinetic analysis of overlapping multistep thermal decomposition of 5-nitro-2,4,6-triaminopyrimidine -1,3-di-N-oxide (ICM-102)

In this work, we studied the thermal decomposition of a promising novel energetic compounds, 5-nitro-2,4,6-triaminopyrimidine -1,3-di-N-oxide (ICM-102), in an inert atmosphere. This energetic compound with a high measured density, high thermal decomposition temperature, high detonation velocity, and extremely low mechanical sensitivities has the widely application prospect in military and civilian fields. Therefore, a reliable description of the thermal decomposition kinetics is important to prevent or control the decomposition in such applications. While previous kinetic studies published on this system use simplified methods that avoid the fact that the entire process cannot be described by a single kinetic doublet. Here, we have studied the decomposition process by first separating the overall reaction into its two constituent steps which were subsequently analysed independently. The deconvolution was carried out using Fraser-Suzuki function that is capable of fitting an asymmetric peak fitting function. The resulting kinetic models and parameters proved to be able to reconstruct the original experimental curves but are also capable of producing accurate predictions of curves recorded at heating schedule different from those employed to record the experimental data used in the kinetic analysis. Finally, we have simulated three types of major decomposition reactions of ICM-102: the hydrogen transfer reactions and the C-NO2 homolysis theoretically. The direct C-NO2 homolysis prevails with the activation barrier at 188.8 kJ mol−1. The hydrogen transfer intramolecular or intermolecular with the activation barriers at 187.3 and 190.9 kJ mol−1, respectively. The reduced activation barriers than experimental results are due to that the simulation is carried out in monomolecular or bimolecular reaction systems.

POF (paclitaxel/oxaliplatin/5-FU/leucovorin) versus SOX/CAPOX/FOLFOX as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer: Study protocol for a randomized controlled trial, FNF-014 trial.

TPS4647 Background: Postoperative chemotherapy (S-1, CAPOX, or Docetaxel/S-1) is a standard treatment for stage II/III gastric cancer in Asia. With regard to single agent or doublet, the need for improvement has consistently been pointed out because of the relatively poor outcome for patients with stage III gastric cancer. Triplet (FLOT) has shown significant survival benefits in perioperative setting. POF, our regiment similar to FLOT, demonstrated priority to doublet (FOLFOX) in advanced setting (2019 ASCO-GI). We conducted a randomized, multicenter, phase III study to compare triplet to doublet regimens for patients with stage III gastric cancer. Methods: This is currently enrolling patients (n = 544) with pathologic stage III gastric cancer after D2 lymph node dissection. Patients are randomized 1:1 and stratified by tumor stage (IIIA, IIIB, or IIIC, AJCC 8th) into POF or SOX/CAPOX/FOLFOX (chosen by the clinicians). SOX: oxaliplatin 130 mg/m2 on day 1, oral S-1 80mg/m2 divided by two on days 1 to 14 every 21 days for 8 cycles. CAPOX: oxaliplatin 130 mg/m2 on day 1, oral capecitabine 1000 mg/m2 twice daily on days 1 to 14 every 21 days for 8 cycles. FOLFOX: oxaliplatin 85 mg/m2, levo-leucovorin 200 mg/m2, and 5-FU 400 mg/m2 bolus on day 1, then 5-FU 2400 mg/m2 continuous infusion over 46 hours, every 14 days for 12 cycles. Three doublets were chosen by the clinicians. POF: paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-FU bolus, every 14 days for 12 cycles. Eligibility criteria: patients aged 18-70 years, primary histologically proven gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) of stage III with no evidence of metastatic disease, R0 resection with D2 lymph node dissection, good performance status (ECOG PS ≤1). Subjects must be able to take orally, and without other concomitant medical conditions that required treatment, initially treated with curative surgery followed by chemotherapy within 42 days. Life expectancy estimated more than 6 months. Adequate organ function. All patients provided written informed consent prior to treatment. Key exclusion criteria: patients with other primary malignancies, gastrointestinal bleeding. The primary end point is 3-year disease-free survival. Secondary end points are 3-year overall survival, 5-year overall survival, 5-year disease-free survival, and adverse events. Clinical trial information: NCT03788226 .

Evolution of CdTe Magic-Size Clusters with Single Absorption Doublet Assisted by Adding Small Molecules during Prenucleation.

An approach is reported for the exclusive production of CdTe magic-size clusters (MSCs) that exhibit an optical absorption doublet peaking at 385/427 nm, with an explanation of the synthesis procedure. The MSCs, defined as dMSC-427, were produced from the reaction of cadmium oleate (Cd(OA)2) and tri-n-octylphosphine telluride in octadecene at 100 °C, with the addition of acetic acid (HOAc) or acetate (M(OAc)2) during the prenucleation stage (40 °C). Without such an addition or when it was performed in the postnucleation stage (100 °C), quantum dots (QDs) developed. The production of dMSC-427 or QDs is hypothesized to be related to the solubility of the Cd precursor, such as Cd(OA)1(OAc)1 or Cd(OA)2, respectively. Also, the reactions that lead to Cd(OA)1(OAc)1 are proposed. The present study provides an in-depth understanding of the two-pathway model proposed for the prenucleation stage of binary colloidal QDs, as well as of the formation of MSCs and/or QDs.

Interdependencies between physical, design and operational parameters for direct use geothermal heat in faulted hydrothermal reservoirs

Interest in direct use geothermal systems is increasing due to their ability to supply renewable, environmentally friendly heat. Such systems are mostly developed in conduction dominated geological settings where faults are often encountered. Interdependencies between physical, design and operational parameters make it difficult to assess the performance of such systems. Interaction with faults could potentially have adverse effects on system lifetime, generated Net Present Value (NPV) and produced energy. In this work a single doublet system in the enthalpy range of 140 kJ/kg to 350 kJ/kg is analysed using COMSOL Multiphysics. A choice of design (well spacing and placement), physical (layered reservoir, fault flow properties, fault throw) and operational (injection and production flow rates) parameters are considered in a full factorial design that includes 2430 3D reservoir simulations. Results show that fault flow properties characterization is more significant than fault throw structural characterization. For the considered reservoir properties, increasing the flow rate four times results in an NPV increase of a factor seven, despite the shorter system lifetime. A sealing fault renders the system lifetime less sensitive to the doublet positioning. Synthetic model results shown can serve as guidelines to reducing full scale field models. Importance and relevance of these results remains very high for horizontally homogeneous, layered reservoirs. The analysis expands the understanding of interdependencies for direct use geothermal systems and informs on their further development.

Accelerating geothermal development with a play-based portfolio approach

Abstract Over the past decade in the Netherlands, most operators have only developed a single doublet. The learning effect from these single events is suboptimal, and operators have only been capable of developing doublets in areas with relatively low exploration risk. This ‘stand-alone’ approach can be significantly improved by a collective approach to derisk regions with similar subsurface characteristics. Such a play-based portfolio approach, which is common in the oil and gas industry, can help to accelerate the development of the geothermal industry through unlocking resource potential in areas marked by high upfront geological risk, effectively helping reduce costs for the development. The basis of the methodology is to deploy new information to the play portfolio by trading off with the risk of the first wells, resulting in a strong geological risk reduction. The added value of the portfolio approach is demonstrated for the Netherlands in this paper through a comparison with a ‘stand-alone’ development. In the stand-alone approach, each new project will be equally risky, and therefore relatively unprofitable. In the case of a portfolio approach, all experience about the play is used optimally for derisking. In case of success, subsequent projects will have a higher chance of being successful, due to the experience gained in previous projects. Even if a project fails, this may help in increasing the probability of success for subsequent projects. For plays that are initially considered too risky for the market to start developing, the value of information (VoI) of a play-based portfolio approach will help by derisking the play to such an extent that it becomes attractive for the market to develop, even at high initial risk. It can be demonstrated for several geothermal plays in the Netherlands that by adopting the portfolio approach, the probability of a play being developed becomes higher, the number of successfully developed projects increases and the average profitability of the project will also be higher. Five more advantages are: (1) continuous improvement by integrated project development, (2) cost reduction through synergy, efficiency and standardisation, (3) optimisation of the surface heat demand and infrastructure, (4) the possibility of structural research and development (R&amp;D) and innovation, and (5) financing advantages. The advantages reinforce each other. A preliminary estimate of the geothermal potential of the Netherlands adopting the portfolio approach is between 90 and 275 Petajoules (PJ). For about 350 doublets being developed, producing about 70 PJ, the value of the advantage of the play-based portfolio approach is €2 billion for the three main plays: Rotliegend, Triassic and Jurassic/Cretaceous. The learning effects of synergy, efficiency and standardisation are expected to be significant.