Expansion Phase Research Articles

Life of field emission forecast development and reduction option screening for a multi-train LNG hub

The Karratha Gas Plant (KGP) is a complex integrated facility which produces liquified natural gas (LNG), domestic gas (Domgas), condensate, propane and butane products. The multi-train facility has been operating for 40 years with several phases of expansion resulting in a range of gas turbine technology and energy efficiency levels across the facility. The challenge for the next phase of KGP operation is to manage declining North West Shelf (NWS) feed gas levels, and the addition of Other Resource Owners feed gas while reducing emissions and maintaining energy efficiency. A flexible emissions forecasting tool has been developed which allows unit and whole of facility emissions reduction and energy efficiency options to be assessed. The tool builds on current quarterly timestep production forecasts and models ambient temperature, unit turndown and turn-off strategies, and potential implementation of lower emissions technology. The ability to generate and compare life of field emissions profiles for extrapolated operating modes and proposed modifications allows unit strategies and phasing of emissions reduction modifications to be investigated and screened before further economic assessment and creation of marginal abatement cost curves (MACC).

Buffalo Bill's Wild West, cowboys, and the fate of the western in Italy

Abstract This article examines the first tour of Buffalo Bill's Wild West in Italy and the so-called ‘sfida dei butteri’ (the challenge of the Italian cowboys of the Pontine marshes), which took place in Rome in March 1890. Analysing nineteenth-century Italian newspapers and photographs, I demonstrate that populist, anti-capitalist, and anti-American sentiments marked the Italian media's responses to the American show. In the historical context of Italy's socioeconomic crisis and of the first phase of colonial expansion in Africa (1870–1922), the mixed reception of Buffalo Bill's Wild West, amplified by the media event of the sfida, shaped the fate of the western genre in Italy.

Ghost dark energy in Tsallis and Barrow cosmology

According to the thermodynamics-gravity conjecture, any modification to the entropy expression leads to the modified cosmological field equations. Based on this, we investigate the cosmological consequences of the modified Friedmann equations when the entropy associated with the horizon is in the form of Tsallis/Barrow entropy and the dark energy (DE) component is in the form of ghost dark energy (GDE). We perform a dynamical system analysis and see that the Tsallis GDE(TGDE) and Barrow GDE(BGDE) can exhibit a correct phase space evolution for suitable range of the free parameters(0<Δ<1 for BGDE and β<3/2 for TGDE). We find that in BGDE and TGDE (with Q=3b2H(ρD+ρm)), there exist an early radiation dominated phase of expansion which is absent for GDE model in standard cosmology. It is worth mentioning that seeking an unstable phase of matter dominated in TGDE leads to a new constraint on β (<3/2). Using the resulting range of free parameters from latter step we find that both models are capable to explain the cosmic evolution from deceleration to an accelerated phase. We observe that increasing Δ (β) parameters leads to a delay in the cosmic phase transition. We conclude that BGDE and TGDE are viable cosmological models which predict a consistent phase transition of the cosmic expansion for suitable ranges of the parameters. We also calculate the squared sound speed for both models and find out that they are unstable against perturbations. Next, we proceed the statefinder analysis and see that both models are significantly distinct from ΛCDM as well as with respect to each other at past epochs, while both of them catch the standard cosmology at far future. We also explore the impacts of the non-extensive parameters on the density perturbations and find out that the pattern of density contrast (δ) evolution in TGDE/BGDE is distinct from GDE in standard cosmology.

Simulation comparison of the positive and negative surface discharges induced by metal particles in a plate–surface–plate structure under DC excitation in atmospheric air

Surface discharge induced by metal particles is a common insulation failure in many high-voltage equipment. In order to further understand the mechanisms of this surface discharge, a 2D simulation model of a plate–surface–plate structure with a pin is established and verified by experiments in this paper to simulate the actual discharge configurations, and the evolution characteristics of the positive and negative surface discharges are compared. The evolutions of both positive and negative discharges could be divided into two phases: the bridging phase and the expansion phase. As the electric field in the gap between the streamer and the dielectric surface is strengthened by the effect of the space charge, the ionization sources and the secondary electrons excited on the dielectric surface, the dielectric surface presents attraction to the streamer, and subsequently the two streamer routes first touch the dielectric surface and then arrive at the grounding electrode. However, the channel branching is the most distinctive characteristic of the positive and negative discharges. In the positive discharge, the channel first branches, then merges, and finally expands, and the gaps of pin to dielectric surface and pin to grounding electrode are broken down by two slender positive branches, respectively. The negative discharge presents a stout channel without branching, which develops and expands simultaneously. This is ascribed to the thinner space charge layer, the weaker shielding effect of the internal electric field and the more active movement of the internal charges in the positive discharge. Another important factor for the discharge branching is the appropriate matching of the sheath thickness and the curvature radius of the channel’s head.

Abstract PS15-07: Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic Study

Abstract Abstract Background: Resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a major obstacle to the management of hormone-receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (mBC). Targeting the AR signaling pathway has been demonstrated with promising results in this population. This phase Ic study aimed to assess the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) characteristics of the combination of proxalutamide, a high-affinity AR antagonist, with ETs in androgen receptor (AR)+/HR+/HER2- mBC. Methods: Patients in part 1 regimen-finding phase received proxalutamide plus specific ETs (letrozole [cohort A], exemestane [cohort B], or fulvestrant [cohort C]) and were assessed for dose-limiting toxicity (DLT), PK, PD, and anti-tumor activity. Part 2 expansion phase evaluated the safety and efficacy of proxalutamide plus fulvestrant. The primary endpoint was safety and tolerability. Results: Between June 18, 2019, and Sep 15, 2022, 38 (18 in part 1 and 20 in part 2) patients were treated. Efficacy analysis indicated that the ORR was 16.7% (2/12, 95% CI, 2.1%-48.4%) for cohort C and 15.0% (3/20; 95% CI, 3.2%-37.9%) for part 2. Patients achieved a median progression-free survival (PFS) of 6.4 months (95% CI, 2.7-19.3) in cohort C while an mPFS of 11.0 months (95% CI, 5.5- not estimable) in part 2. In part 1, no DLTs were reported. Grade 3 or more treatment-emergent adverse events (TEAEs) were observed in 11 (29.7%) patients (7 [18.9%] in part 1 and 4 [10.8%] in part 2) and mainly included neutrophil count decreased (8.1%) and platelet count decreased (5.4%). Seven (18.9%) had serious AEs (4 [10.8%] in part 1 and 3 [8.1%] in part 2)[1]. PD results showed a greater reduction of estradiol in cohort C compared with that in cohort B. In addition, proxalutamide was absorbed rapidly into the body with the plasma concentrations of proxalutamide and metabolites reaching a nearly steady state on day 29. Patients with AR/ER of ≤1 seemed to achieve longer PFS over those of &amp;gt;1 (8.4 months vs. 4.1 months). Conclusions: These findings suggested favorable clinical outcomes and safety profiles of the combination of proxalutamide and fulvestrant in AR+/HR+/HER2- mBC patients who have progressed on the first-line therapy, and maybe with better efficacy in patients with lower AR/ER ratio. Trial registration: NCT20191063 Citation Format: Hui-Ping Li, Guohong Song, Hanfang Jiang, Xu Liang, Xiaojia Wang, Hua Yang, Lili Zhang, Youzhi Tong. Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-07.

The Kinematic and Chemical Properties of the Close-in Planet Host Star 8 UMi

A recent study by Hon et al. reported that a close-in planet around the red clump star, 8 UMi, should have been engulfed during the expansion phase of its parent star’s evolution. They explained the survival of this exoplanet through a binary-merger channel for 8 UMi. The key to testing this formation scenario is to derive the true age of this star: is it an old “imposter” resulting from a binary merger, or a genuinely young red clump giant? To accomplish this, we derive kinematic and chemical properties for 8 UMi using astrometric data from Gaia DR3 and the element-abundance pattern measured from a high-resolution (R ∼ 75,000) spectrum taken by SOPHIE. Our analysis shows that 8 UMi is a normal thin-disk star with orbital rotation speed of V ϕ = 244.96 km s−1, and possesses a solar metallicity ([Fe/H] = −0.05 ± 0.07) and α-element-abundance ratio ([α/Fe] = +0.01 ± 0.03). By adopting well-established relationships between age and space velocities/elemental abundances, we estimate a kinematic age of 3.50−2.00+3.00 Gyr, and a chemical age of 3.25−1.50+2.50 Gyr from [C/N] and 3.47 ± 1.96 Gyr from [Y/Mg] for 8 UMi, respectively. These estimates are consistent with the isochrone-fitting age ( 1.90−0.30+1.15 Gyr) of 8 UMi, but are all much younger than the timescale required in a binary-merger scenario. This result challenges the binary-merger model; the existence of such a closely orbiting exoplanet around a giant star remains a mystery yet to be resolved.

Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial

ObjectiveTo evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors.MethodsIn this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid...

Tracking shifts in Society Islands marine subsistence through time: Intra‐site analysis of faunal remains and fishing gear

AbstractWe discuss new data from Colonization Phase and Early Expansion/Development Phase assemblages in the pre‐contact Society Islands. We focus on analysis of marine faunal remains and fishing gear to infer diachronic shifts in subsistence practices at two well‐dated coastal sites. Both Colonization Phase (AD 950–1200) and Early Expansion Phase (AD 1200–1450) faunal assemblages are dominated by fish and mollusks as opposed to animal domesticates. Colonization Phase assemblages see higher capture of Scombrids and higher capture of marine mammals and turtle. Early Expansion fishhook assemblages and faunal remains document a movement towards increased capture of reef fish as well as the adoption of local styles and locally specific fishing practices. Overall, the diachronic trend in the Society Island diets is towards a decrease in turtle, marine mammal, and wild bird remains and an increase in terrestrial domesticated species roughly two hundred years after colonization, similar to patterns seen elsewhere in Eastern Polynesia.

Impact of sub-national synchronization on the behavior of national business cycles in emerging economies with inflation targeting

PurposeThe purpose of this paper is to assess sub-national business cycle (BC) synchronization's impact on national cycles in four emerging markets economies with inflation targeting (IT-EMEs): Brazil, Colombia, South Korea and Mexico.Design/methodology/approachThe authors use panel data models with fixed-effects and distributed lags.FindingsThe authors disclosed that sub-national synchronization increased national cycle amplitudes during expansion and recession phases. The authors also noticed that South Korea exhibited a more pronounced effect compared to Latin American countries, and this seemed to be associated with differences in the homogeneity of the production structures in the regions of these countries.Research limitations/implicationsThe authors cautioned that contrasting the findings with prior research on the effects of regional BC synchronization in IT-EMEs or with studies in different geographical contexts, is not possible due to the absence of prior research endeavors with this specific focus.Originality/valueThis study constitutes a first attempt to explain the impact of subnational cycle synchronization on the magnitude of national cycles in four IT-EMEs.

Clinical Application of Botulinum Toxin A on Nasal Reconstruction with Expanded Forehead Flap for Asian Patients.

Because of its unique advantages, frontal expansion has become a common tool for Asian nasal reconstruction, but it has the limitations of prolonging the duration and pain in the expansion area. Based on the fact that the denervation effect of botulinum toxin type A (BTX-A) has been widely used in the reconstruction of superficial organs, we hypothesized that BTX-A would shorten the length of nasal reconstruction sequence and alleviate the discomfort of patients. A comparative retrospective study was conducted of consecutive patients underwent sequential treatment of nasal reconstruction between June 2010 and July 2012. Data on demographics, BTX-A injection plan and expansion duration were collected and analyzed. Phased pain intensity outcomes were evaluated by visual analogue scale (VAS). Photographs were collected during the follow-up period. Thirty patients were enrolled in the study; 15 (50%) with and 15 (50%) without BTX-A pre-injection. Demographic data were homogeneous. The duration of the observation group (BTX-A pretreated) (133.87 ± 13.64 days) was significantly shortened versus the control group (164.27 ± 14.08 days, P<0.001). At the initial stage, no significant difference was found in the VAS scores (P=0.64). At the medium stage, the VAS score of the observation group (2.07 ± 0.80) was significantly lower than the control group (3.00 ± 0.53, P<0.01). At the terminal stage, the VAS score of the observation group (1.93 ± 0.59) was significantly lower than the control group (2.73 ± 0.70) but with a narrower disparity. Pre-injection of BTX-A is effective in shortening the duration of the expansion phase, as well as relieving the pain associated with expansion. The journal asks authors to assign a level of evidence to each article. For a complete description of Evidence-Based Medicine ratings, see the Table of Contents or the online Instructions for Authors at www.springer.com/00266 .

Shock Cooling and Breakout Emission for Optical Flares Associated with Gravitational-wave Events

The astrophysical origin of stellar-mass black hole (BH) mergers discovered through gravitational waves (GWs) is widely debated. Mergers in the disks of active galactic nuclei (AGNs) represent promising environments for at least a fraction of these events, with possible observational clues in the GW data. An additional clue to unveil AGN merger environments is provided by possible electromagnetic emission from postmerger accreting BHs. Associated with BH mergers in AGN disks, emission from shocks emerging around jets launched by accreting merger remnants is expected. Here we compute the properties of the emission produced during breakout and the subsequent adiabatic expansion phase of the shocks, and we then apply this model to optical flares suggested to be possibly associated with GW events. We find that the majority of the reported flares can be explained by breakout and shock cooling emission. If the optical flares are produced by shock cooling emission, they would display moderate color evolution, possibly color variations among different events, and a positive correlation between delay time and flare duration and would be preceded by breakout emission in X-rays. If the breakout emission dominates the observed lightcurve, we predict the color to be distributed in a narrow range in the optical band and the delay time from GW to electromagnetic emission to be longer than ∼2 days. Hence, further explorations of delay time distributions, flare color evolution, and associated X-ray emission will be useful to test the proposed emission model for the observed flares.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

BackgroundLenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC.MethodsIn this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy.ResultsSixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients.ConclusionsTislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC.Trial registrationClinicalTrials.gov (NCT 04401800).

Bouncing Cosmology in f(R,G)$f(R,\mathcal {G})$ Gravity with Thermodynamic Analysis

AbstractThe evolution of the universe in a modified gravity theory that includes the terms Ricci scalar () and the Gauss‐Bonnet invariant () is studied. The function is obtained using the e‐folding number and reconstruction technique by assuming an appropriate parameterization of the scale factor . In this model, the various cosmological parameters are analyzed to explicate the bouncing scenario of the universe with the help of the contraction and expansion phases of the universe before and after the bouncing point of the model, respectively. A violation of the null energy condition is found. Additionally, the ghost condensate nature of the model in the neighborhood of the bouncing point () is seen. Furthermore, the deceleration parameter is not defined at the bouncing point, i.e., at and approaches a finite value in later times (). Finally, the evolution of the Hawking temperature and the validity of the second law of thermodynamics in the bouncing scenario of our model are discussed.

40 Years of the Suzuki Piano School in Brazil

This paper discusses the arrival and expansion of the Suzuki Piano School (SPS) in Brazil. To this end, research was carried out on the topic, in which data were collected in semi-structured interviews, data provided by the Suzuki Association of the Americas (SAA) and by course organizers in Brazil. It was found that 2022 marks 40 years since the arrival of the SPS in Brazil. The first experiences of applying SPS in Brazil began in 1982 through the work of piano teacher Maria Elena Withers Pessoa. The importance of the International Suzuki Festival in Peru for the training of Brazilian teachers was noted, especially when the provision of courses was rare in Brazil. The third, and most recent, expansion phase of the SPS has been taking place since 2016, as a result of the recurring visit to Brazil by Peruvian teacher trainer Flor Canelo. The research data also indicates that the Suzuki Piano Community is growing in Brazil, but there is still room for expansion, as the majority of teachers are concentrated in the South and Southeast regions, having only completed the first stage of training. Finally, the data highlighted the impacts of the COVID-19 pandemic on the modality and intensity of SPS course offerings in Brazil, motivating the creation of other types of Suzuki events and integrating Suzuki teachers and students from different Brazilian regions.

Improving Tuber Yield of Tiger Nut (Cyperus esculentus L.) through Nitrogen Fertilization in Sandy Farmland.

The cultivation of tiger nut (Cyperus esculentus L.) on marginal lands is a feasible and effective way to increase food production in Northern China. However, the specific influence of nitrogen fertilizer application on the growth dynamics, tuber expansion, overall yield, and nitrogen use efficiency (NUE) of tiger nuts cultivated on these sandy lands is yet to be fully elucidated. From 2021 to 2022, we conducted a study to determine the effect of N fertilizers on the leaf function morphology, canopy apparent photosynthesis (CAP), tuber yield, and NUE of tiger nut. The results indicate that the tuber yield and NUE are closely related to the specific leaf area (SLA), leaf area index (LAI), leaf nitrogen concentration per area (NA), CAP, and tuber expansion characteristics. Notably, significant enhancements in the SLA, LAI, NA, and CAP during the tuber expansion phase ranging from the 15th to the 45th day under the 300 kg N ha-1 treatment were observed, subsequently leading to increases in both the tuber yield and NUE. Moreover, a maximum average tuber filling rate was obtained under the N300 treatment. These improvements led to substantial increases in the tuber yield (32.1-35.5%), nitrogen agronomic efficiency (NAE, 2.1-5.3%), nitrogen partial factor productivity (NPP, 4.8-8.1%), and nitrogen recovery efficiency (NRE, 3.4-5.7%). Consequently, 300 kg N ha-1 of N fertilizers is the most effective dose for optimizing both the yield of tiger nut tubers and the NUE of tiger nut plants in marginal soils. Structural equation modeling reveals that N application affects the yield and NUE through its effects on leaf functional traits, the CAP, and the tuber filling characteristics. Modeling indicates that tuber expansion characteristics primarily impact the yield, while CAP predominantly governs the NUE. Above all, this study highlights the crucial role of N fertilizer in maximizing the tiger nut tuber yield potential on marginal lands, providing valuable insights into sustainable farming in dry areas.

The International Refugee Regime and the Liberal International Order: Dialectics of Contestation

Abstract The international refugee regime finds itself in a delicate balance between two conflicting principles of the liberal order: the particularism of sovereign states and the universalism of human rights. This article proposes a theory of endogenous contestation, rooted in the dialectic of law, propelling liberal aspirations, and politics, vindicating sovereign control. In doing so, we identify three shifts in the international refugee regime. Following 1945, legal consolidation in a propitious geopolitical context engendered a phase of regime expansion. The provisional “triumph” of liberalism in the early 1990s bolstered the regime’s geographical and normative clout but fueled political backlash. This set the stage for a new phase of regime contestation, where liberal democracies adapted political practices to ostensibly uphold the asylum norm while precluding access to it. The article concludes by exploring whether this subversion signals a gradual evolution or a fundamental shift in the nature of the liberal refugee regime.

‘Don’t Pick, Don’t Lick’: Connecting Young Children’s Risky Play in Nature to Science Education in Australian Bush Kinders

AbstractThe forest school approach to nature learning has gathered momentum in the UK and across parts of Europe including Scandinavia for well over 50 years. In other contexts that include Canada, China, New Zealand and Australia, nature-based early childhood education and care settings, influenced by European forest school approaches, are in a rapid expansion phase as educators and policy makers acknowledge the benefits for children from time spent in nature. It is known that science education opportunities exist in these nature-based settings, yet this area has only garnered limited research attention to date. An example of a nature-based approach to early childhood education which emerged in the 2010s is the Australian ‘bush kinder’. Four- to five-year-old preschool children experience and learn from nature through play in bush kinders. This paper highlights the intersections that occur between risky play and science teaching and learning in the context of bush kinders. Through analysing research in early years science education, guiding curriculum frameworks and early childhood learning, I propose the importance of children’s risky play to early childhood science education. Drawing on vignettes from ethnographic fieldwork data, the merits of risky play in bush kinders to embed science knowledge is illustrated here. Participant observation was used to build a profile of each site and to gather data relating to how educators draw on children’s risky play to seek out opportunities to teach children about physical, chemical and biological science.

THE EFFECT OF AUTOMESOCONCENTRATE OF PLATELETS ON THE STAGES OF REGENERATION OF THE LIVER REMNANT OF RATS UNDER THE CONDITIONS OF PERFORMING VOLUMETRIC EXPERIMENTAL LIVER RESECTIONS

Introduction. Liver regeneration occurs in three stages, each of which is regulated by different factors: the initiation phase is regulated by interleukin 6 (IL-6) and tumor necrosis factor (TNFα); expansion phase – by hepatocyte growth factor (HGF) and transforming growth factor alpha (TGFα); the terminal phase – transforming growth factor beta (TGFβ) and activins. The work determined the level of markers of the main stages of liver regeneration after resection of 65-70% of the parenchyma of this organ in rats under the conditions of using different doses and schemes of administration of automesoconcentrate of platelets (AMС). The purpose of the study is to establish the characteristics of changes in the level of cytokines and growth factors in the homogenate of the liver of rats after resection of 65-70% of the parenchyma of this organ under the conditions of the use of different doses and schemes of AMС administration.&#x0D; Materials and methods. The study was conducted on white Wistar rats aged 1.5-2 months, weighing 150-180 g. AMС was injected: into the parenchyma of the liver remnant during resection at a dose of 0.5 ml/kg (group I); into the tail vein in the postoperative period at a dose of 0.5 ml/kg 3 hours and 48 hours after liver resection (group II); into the tail vein in the postoperative period at a dose of 1.0 ml/kg 3 hours and 48 hours after resection.&#x0D; Research results and discussion. It was shown that on the 7th day after liver resection, the level of TNF-α and IL-6 increased in all experimental groups, followed by a decrease on the 10th day to control values in the group of animals that received AMA intravenously at a dose of 1 ml/kg masses of animals. It was established that the values of HGF and TGFα in the liver homogenate of animals that underwent liver resection were significantly higher than in the control group on the 7th day of the experiment. At the later stages of the experiment, a decrease in the levels of HGF and TGFα in the liver homogenate was observed in the animals of groups I and III, but the studied indicators did not reach control values. In animals of group II, indicators of HGF and TGFα content remained at the highest level. The increase in the content of TGFβ and activins in the homogenate of the liver of rats in all experimental groups indicates the intensification of the terminal phase of liver regeneration on the 10th day after liver resection.&#x0D; Conclusions. Therefore, under the action of a dose of АМС equal to 1 ml/kg, the regeneration processes occur most intensively, the peak of which occurs 7-10 days after the resection. Administration of AMA into the liver parenchyma at a lower dose of 0.5 ml/kg or intravenous administration of the same dose does not contribute to the complete restoration of regenerative processes in the liver, as indicated by increased levels of TGFα and HGF on the 10th day after liver resection and administration of AMA.

Abstract CT044: A phase 0/1b study of AZD1390 plus radiotherapy in newly-diagnosed, MGMT-unmethylated glioblastoma patients

Abstract Background: ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with GBM is ongoing (NCT03423628). To test this hypothesis, this Phase 0/1b study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, a first-in-class ATM inhibitor, in combination with radiation in newly-diagnosed GBM patients (NCT05182905). Methods: Presumed newly-diagnosed GBM patients received 3 days of AZD1390 prior to planned resection at 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo tissue radiation, quantifying pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold (2 nM unbound drug levels in Gd-non-enhancing tumor region) with unmethylated MGMT promoter were eligible for the expansion phase of study drug, combining AZD1390 with 6 weeks of radiotherapy. Results: Seventeen patients were enrolled into the study. All tested patients (n=14) exceeded the PK threshold and qualified for the expansion phase. Three patients were excluded from the PK analysis due to dosing deviation (n=1) and non-GBM diagnosis (n=2). The mean unbound concentration of AZD1390 in Gd-nonenhancing tumor was 12.4 and 4.4 pmol/g, respectively, for the 4-6 and 23-25-hours cohort. Following 5Gy ex vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (median 0.2% for 4-6-hours cohorts and 1.9% for 23-25-hours cohort vs 32.3% for control cohort, average 99% and 95% reduction, respectively, p&amp;lt;0.01 for both cohorts vs control). As of 11/30/2023, 3 patients with unmethylated MGMT promoter are undergoing therapeutic dosing of AZD1390 plus radiotherapy, with median clinical follow-up of 2.3 months. Conclusion: AZD1390 is well-tolerated in newly-diagnosed GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and substantially suppressing radiation-induced increases in pRAD50 levels. These data are the first in GBM patients demonstrating AZD1390-mediated pharmacodynamic and pharmacokinetic response. Citation Format: Nader Sanai, Siddhi Desai, Tigran Margaryan, Jennifer Molloy, Costanza LoCascio, Mackenna Elliott, Jocelyn Harmon, Amy Hong, Ernesto Luna Melendez, John Wanebo, Kelly Braun, William Kennedy, Michael Garcia, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta. A phase 0/1b study of AZD1390 plus radiotherapy in newly-diagnosed, MGMT-unmethylated glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT044.

Abstract CT094: Targeting CSF1R with BLZ945 results in effective peripheral and tumor immune microenvironment modulation in advanced solid tumors and may be associated with limited efficacy in recurrent non-mesenchymal glioblastoma

Abstract Colony-stimulating factor 1 receptor (CSF-1R) signaling is involved in regulating monocyte differentiation, and the recruitment and survival of tumor-associated macrophages (TAMs). BLZ945 is a small molecule, highly selective, orally bioavailable, potent kinase inhibitor of CSF-1R that has shown the ability to reduce the recruitment of TAMs in animal models and promote infiltration of effector T cells into the tumor in preclinical models. Given the potential effects of BLZ945 on effector T-cell activity, a combination of BLZ945 with the programmed death 1 (PD-1) inhibitor spartalizumab was investigated in 1) a dose escalation phase I clinical trial with advanced solid tumor patients; and 2) an expansion phase II clinical trial in adult patients with relapsed/refractory glioblastoma (GBM) after standard of care and other lines of therapy (NCT02829723). The percentages of non-classical and intermediate monocytes in the PBMC fraction were decreased after treatment at multiple doses and schedules of treatment tested in the escalation phase. Screening and on-treatment paired tumor biopsy samples from the escalation phase were analyzed by RNA sequencing. Downregulated genes have been noted as macrophage-specific genes, suggesting that treatment with BLZ945 is downregulating macrophages in the tumor microenvironment. There appeared to be a trend for a reduction in TAM gene signatures and increase in T-cell inflammation signatures upon treatment with single-agent BLZ945 or BLZ945 + spartalizumab. RNA-sequencing analysis from archival surgical resection GBM samples from the expansion phase, revealed a potential correlation between PDGFRA gene expression and best percent change in tumor size. This suggests that non-mesenchymal GBM, for which PDGFRA is part of the defining signature, are more sensitive to the treatment. DNA-sequencing of these archival samples also revealed mutations in p53 in the tumors with partial responses but no mutations in EGFR or TERT. Citation Format: Carlos Rodrigo Gil Del Alcazar, Virginia Xu, Chia-chi Lin, Marta Gil-Martin, Aung Naing, Liqiong Fan, Fang Yang, David Quinn, Jincheng Wu, Cornelia Quadt, Jennifer Mataraza. Targeting CSF1R with BLZ945 results in effective peripheral and tumor immune microenvironment modulation in advanced solid tumors and may be associated with limited efficacy in recurrent non-mesenchymal glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT094.