Expansion Phase Research Articles

AN0025 in combination with definitive chemoradiotherapy (dCRT) in unresectable locally advanced or locally recurrent esophageal cancer (EC): A single-arm, open-label, multicenter, phase Ib study.

e16076 Background: AN0025 is a selective EP4 inhibitor that demonstrates antitumor activity by modulating the accumulation and function of macrophages and immunosuppressive myeloid cells in tumor microenvironment. The combination of AN0025 with CRT as neoadjuvant therapy has shown synergistic antitumor efficacy in locally advanced rectal cancer in a prior clinical trial (NCT03152370). Methods: This Phase Ib study includes a dose escalation phase followed by an expansion phase to evaluate the safety, tolerability, and feasibility of AN0025 plus dCRT for unresectable locally advanced or locally recurrent EC or esophagogastric junction cancer. Antitumor efficacy was assessed per RECIST v1.1. The eligible patients (pts) are candidates for dCRT, who received RT (2.0 Gy/fraction, totally 50-60 Gy) with concurrent weekly paclitaxel and carboplatin for 4 weeks, followed by two doses of consolidation chemotherapy on Week 8 and Week 12. AN0025 (250 mg or 500 mg QD) was administered orally for 15 weeks concurrently with dCRT. At the beginning of Week 17, pts would start AN0025 monotherapy in the maintenance phase. Results: As of Jan 12, 2024, 12 pts (11 males and 1 female, median age 62) with histologically confirmed esophageal squamous cell carcinoma (ESCC) were enrolled and received the study treatment, 5 at the 250 mg dose level and 7 at the 500 mg dose level. Among those 12 pts, 11 were locally advanced ESCCs and 1 was locally recurrent ESCC. The most common AN0025-related adverse events (AEs) were weight decreased (33%), anemia (33%), and white blood cell count decreased (25%). Two pts (17%) experienced Grade ≥3 AN0025-related AEs (one Grade 3 weight decreased and one Grade 3 esophageal fistula). No dose-limiting toxicity occurred at either dose level, and the maximum tolerated dose was not reached. The median follow-up was 14.2 months, with 8 pts remaining on study treatment and a maximum time on treatment of 2 years. The disease control rate (DCR) was 92% (11/12). The median progression-free survival (PFS) was not reached, with 6-month and 1-year PFS rates of 91% and 73%, respectively. The 1-year overall survival (OS) rate was 82%. Additionally, among the 8 pts with measurable lesion(s) at baseline, 1 (13%) achieved confirmed complete response (CR), and 6 achieved partial response (PR), including 5 confirmed PRs, giving an unconfirmed overall response rate (ORR) of 88% (7/8) and a confirmed ORR of 75% (6/8). AN0025 PK approached linearity at both 250 mg and 500 mg QD. AN0025 PK in combination with dCRT showed no interactions. Conclusions: This Phase Ib study suggests that AN0025 plus dCRT exhibits favorable safety and encouraging preliminary efficacy in unresectable locally advanced or locally recurrent EC, warranting further investigation. Clinical trial information: NCT05191667 .

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

A first-in-human study of CRISPR/Cas9-engineered tumor infiltrating lymphocytes (TILs) product GT316 as monotherapy in advanced solid tumors.

2549 Background: A next-generation TIL product GT316 was engineered with CRISPR/Cas9 to genetically disrupt two key immunoregulatory targets identified from a genome-wide CRISPR screening platform and demonstrated significantly enhanced anti-tumor efficacy and persistence in pre-clinical animal studies with ameliorated TIL exhaustion profile. A first-in-human trial was initiated to evaluate the preliminary safety and efficacy of GT316 in advanced solid tumors. Methods: The first-in-class study is to enroll patients (pts) with advanced treatment-refractory solid tumors, especially gynecological tumors. Once the optimal biological dose (OBD) is identified, a monotherapy expansion phase will be initiated for pts with various solid tumors. Enrolled pts were preconditioned with a nonmyeloablative (NMA) lymphodepletion regimen and treated by infusion of the GMP-grade G316 product followed by IL-2 administration. Results: As of January 22, 2024, the dose escalation study enrolled 4 pts, all of whom were female with a median age of 58 years with 1 to 9 prior lines of systemic treatment. The median number of infused TIL cells was 1.0E+10. All pts experienced TRAEs with the majority being grade 1 or 2. Grade 3/4 TRAEs included lymphocyte count decreased, white blood cell count decreased, monocyte count decreased and neutrophil count decreased, which were related to the NMA regimen. No dose-limiting toxicities (DLTs) or TIL-related grade≥3 TRAEs were observed. Median time on study was 33.4 wks (8–35 wks). One pt with treatment-refractory cervical cancer experienced a confirmed complete response (CR) after 4 wks and the duration of response is 32 wks by now (RECIST 1.1). One ovarian cancer pt with 9 lines of previous systemic therapies experienced a confirmed partial response (PR) after 4 wks and the duration of response is 22 wks by now (RECIST 1.1). Response data will be continuously collected. The other two ovarian cancer pts experienced stable disease (SD) and progressive disease (PD), respectively. Despite varying doses of TILs (3.2E+09 to 1.90E+10) and IL-2 (up to 3.0E+05 IU/kg), all pts receiving GT316 showed robust TIL expansion post-infusion, which is positively correlated with administrated IL-2 doses. Enhanced IFN-γ secretion could be detected in the serum of the CR and PR pts compared to the SD and PD pts, indicating potential tumor antigen-specific response. Conclusions: The first-in-human study of GT316, a CRISPR/Cas9-dual KO anti-exhaustion TIL product, demonstrates good tolerability with encouraging preliminary anti-tumor efficacy as a monotherapy in pts with advanced solid cancers. The infusion of GT316 was associated with robust TIL expansion and IFN-γ secretion. Updated data with additional follow-up will be continuously collected, and OBD will be determined based on the overall data of safety and preliminary efficiency. Clinical trial information: NCT06145802 .

Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors.

e15114 Background: This open-label, first-in-human, phase 1 study evaluates the safety, pharmacokinetics, and maximum tolerated dose (MTD) of ATG-017, an oral, potent, and highly selective inhibitor of ERK1/2, in patients with refractory advanced solid tumors. Methods: Twenty-one patients with solid tumors harboring activating alterations in the RAS-MAPK pathway were enrolled in the 3+3 design dose-escalation phase for continuous dosing: 5 mg QD (n=1), 5 mg BID (3), 10 mg BID (3), 20 mg BID (7), 30 mg BID (4), and 40 mg BID (3). Results: Safety: All patients reported at least 1 treatment-emergent adverse event (TEAE). Fourteen patients (66.7%) experienced serious adverse events. At 40mg BID, 2 of 3 patients experienced a dose-limiting toxicity (DLT) (grade 3 diarrhea and grade 3 retinopathy). At 30mg BID, 2 of 4 patients experienced a DLT (grade 3 acneiform dermatitis and grade 2 blurred vision). All DLTs resolved with drug interruption. At 20mg BID, a potentially biologically active dose, 7 patients were treated with no DLTs observed. At all dose levels, the most commonly observed TEAEs were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Pharmacokinetics: Between 5mg BID and 30mg BID, exposure increased proportionally. At doses 20mg BID or higher, the concentration in the whole dosing interval (≥ 328ng/mL, geometric mean) was higher than the target concentration (231 ng/mL) for effective ERK inhibition derived from preclinical PK/PD models. Efficacy: Of the 21 treated patients, one patient (4.8%) with mesonephric-like ovarian adenocarcinoma (KRAS G12V mutation) in the 30 mg BID cohort achieved a best response of partial response (sustained for six cycles of treatment), and 8 (38%) patients were assessed as having stable disease (sustained over an average of five cycles), based on RECIST v1.1. Conclusions: In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated. Clinical trial information: NCT04305249 .

A phase 1/2 study of favezelimab in combination with pembrolizumab for anti–PD-1–naive relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL): An updated analysis.

7055 Background: PD-1 inhibitors such as pembrolizumab are an important treatment option for patients (pts) with R/R cHL, but treatment failure remains a significant challenge. Dual immune checkpoint blockade with a PD-1 inhibitor and a lymphocyte-activation gene 3 (LAG-3) inhibitor shows promise as a treatment option for R/R cHL. In a multicohort phase 1/2 study (NCT03598608) evaluating the anti–LAG-3 monoclonal antibody favezelimab in combination with pembrolizumab for R/R hematologic malignancies, pembrolizumab plus favezelimab demonstrated sustained antitumor activity and acceptable safety in the cohort of pts with anti–PD-1–naive R/R cHL (cohort 1). We present updated results from this cohort after additional follow-up. Methods: Eligible pts were aged ≥18 years with R/R cHL; prior treatment with or ineligibility for autologous stem cell transplantation or no response to salvage chemotherapy; no prior PD-1 inhibitor; and an ECOG PS of 0 or 1. The study comprised a safety lead-in (pembrolizumab 200 mg IV Q3W plus favezelimab 200-mg starting dose, then dose escalation to 800 mg IV Q3W using a modified toxicity probability interval method) and a dose expansion phase (pembrolizumab 200 mg Q3W plus favezelimab at the established recommended phase 2 dose of 800 mg Q3W for up to 35 cycles). Primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Cohort 1 enrolled 30 pts. The median time from first dose to data cutoff (August 15, 2023) was 36.9 months (range, 29.4-48.6). Treatment-related adverse events (AEs) occurred in 27 pts (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3 or 4 treatment-related AEs occurred in 7 pts (23%). Five pts (17%) discontinued treatment due to treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 pts (67%); 3 pts (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 pt (3%) had a grade 4 event (hepatitis). The ORR was 83% (n = 25; 95% CI, 65-94); 11 pts (37%) had a complete response and 14 (47%) had a partial response. Median DOR was 17.0 months (range, 2.6-30.5), and an estimated 47% of responders remained in response at 24 months. Median PFS was 19.4 months (95% CI, 9.5-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusions: With additional follow-up, favezelimab plus pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in pts with anti–PD-1–naive R/R cHL. Further studies to investigate this combination are warranted. Clinical trial information: NCT03598608 .

Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies.

TPS6591 Background: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs promote production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. IRAK1/4 is a potential target for inhibition for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the study supported the further evaluation of R289. An open-label, phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The R289 phase 1b open label, single arm, multi-center study (NCT05308264) includes a dose escalation phase (up to 24 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases: patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 1 g qd with dose limiting toxicity (DLT) assessed at each dose level. The DLT evaluation period will be 28 days. After completion, patients without DLTs may remain at their respective dose levels if clinical benefit continues without toxicity. Dose Expansion Phase: R289 will be administered to up to 10 additional patients with LR-MDS at a dose not exceeding the MTD in the dose escalation phase. The primary endpoint is safety and tolerability of R289. Secondary endpoints include preliminary efficacy and pharmacokinetics of R289. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites. Clinical trial information: NCT05308264 .

Linear redshift parametrization of deceleration parameter in [formula omitted] gravity

In this study, we investigate the linear redshift parametrization of q(z) within the framework of f(R,Lm) gravity, using constraints derived from H(z)/Pantheon samples. We consider a non-linear functional form for f(R,Lm), specifically given by f(R,Lm)=R2+Lmn, where n represents a free parameter in the model. Subsequently, we derive the solution for the Hubble parameter by investigating the parametrization of q(z) and then apply this solution to the modified Friedmann equations. Our analysis focuses on exploring the behavior of the EoS parameter across different stages of the universe’s evolution, including radiation, matter, and dark energy eras. Furthermore, our results confirm the quintessence nature of the universe’s current accelerated expansion phase (−1<ω<−13), supporting the role of quintessence in driving the universe’s current acceleration. We also explore the redshift dependence of the deceleration parameter, statefinder, Om(z) diagnostics, energy density, pressure, and energy conditions to determine the universe’s accelerating behavior. Importantly, our findings suggest that the linear redshift parametrization of q(z), supported by additional terms in f(R,Lm) gravity, provides a compelling alternative to the cosmological constant.

Assessing Knowledge Management Readiness to Improve Data Quality by Prevent Incorrect Data Input on ERP System in Component Rebuild Center PT Kalcoal

To fulfil the demand of availability component for supporting the mining operation at PT Kalcoal. Recondition component daily activity of recondition is entanglement from one process to another until the end of process. For transform digitalization, recondition component activity will using Enterprise Resource Planning (ERP) in every process. The purpose of this study is to understand the level of knowledge management readiness in the component rebuild center in the Implementation of the ERP work system, to understand the strengths and areas for improvement for Knowledge Management, and to find tools that can be used to implement Knowledge Management in the component rebuild center. This research using quantitative method, collected through a questionnaire. Furthermore, qualitative data was used to enrich the primary data collected through focus group discussions. By using APO as tools of knowledge management readiness, the results showed that the component rebuild center is still in the expansion phase, where knowledge management efforts are present in the core activity process and the company sees the benefits of knowledge sharing. The component rebuild center can further develop itself by using people as its accelerator. Having committed change groups and leaders will create a culture of knowledge sharing that can be followed by all lines of business in the company. In order for employees to have a single source of knowledge, it is important to create a knowledge management tool that can be done by building a new portal that can be accessed by all employee users. For the source of knowledge to always align the needs and developments of the company, it is necessary to have the ability to grow and store information safely and freely for employees so that information is always updated and well-maintained.

Biomechanical Analysis of Orbital Development: A Finite Element Analysis by an Experimentally Validated Model.

Constructing orbital finite element models capable of simulating the development process and analyzing the biomechanical mechanism. Four normal orbits from 1-month-old New Zealand white rabbits were used in this study. Toshiba Aquilion Prime was used to determine the computed tomography scan and direct orbital pressure manometry using an improved manometer based on the TSD104 pressure sensor transducer. The finite element analysis was conducted using the ANSYS Workbench platform. The biomechanics of each orbital wall improved to varying degrees as the rabbit orbit grew and developed. The von Mises stress in both rabbits initially concentrated at the lower edge of the posterior orbital wall, expanded to the entire orbit, and ultimately became more significant in the biomechanics of the region that consisted of the posterior orbital and superior orbital walls. During the expansion phase, the biomechanics of both rabbits gradually developed from the nasal side to the occipital side for radial displacement. It is evident that the finite element model is a good fit for simulating the physiological development of the rabbit orbit. The maximum radial displacement and maximum von Mises stress appeared 2 intermissions during the development of the orbit, at about 50 to 60 days and 80 to 90 days. This study establishes a theoretical foundation for the creation of a biomechanical model of human orbital development by offering the first finite element model to simulate orbital development and analyze the biomechanical mechanism of orbital pressure on orbital development.

Situational analysis of hypertension management at primary health care level in São Paulo, Brazil: population, healthcare professional and health system perspectives

BackgroundGovernment-led, population-wide initiatives are crucial for advancing the management of hypertension − a leading cause of cardiovascular disease (CVD) morbidity and mortality. An urban population health initiative was conducted against this backdrop, focussing on hypertension in the primary health system in São Paulo, Brazil. Within the frame of the initiative and under the supervision and leadership of the municipal health authorities, a situational analysis was conducted on the needs in hypertension management, marking the first phase of a Design Thinking process. This article describes the situational analysis process and presents the identified elements to be strengthened considering hypertension diagnosis, treatment and control.MethodsFirst, a mixed-methods approach was used, starting with a literature review of municipal hypertension data followed by meetings (N = 20) with the local public health administration to assess health system level components. To investigate activities on hypertension diagnosis, treatment and control, nine primary healthcare units were selected from two districts of São Paulo city– Itaquera and Penha– which received an online form addressed to managers, participated in conversation circles of staff and patients, and underwent shadowing of community health agents.ResultsData gave rise to two main outputs: (i) a patient care journey map; and (ii) a matrix summarizing the identified needs at patient, healthcare professional and health system level for diagnosis, treatment and control of hypertension. Patient awareness and knowledge of hypertension was found to be insufficient and its management needs to be improved. For health professionals, disease awareness, technical training, more time dedicated to patients, and simplified guidelines and clinical decision-making tools for hypertension management were identified as principal needs. The situational analysis found that the healthcare systems efficiency might be improved by establishing defined treatment and care delivery goals with a focus on outcomes and implemented through action plans.ConclusionsThis situational analysis identified several needs related to hypertension control in São Paulo that are in line with global challenges to improve the control of CVD risk factors. Findings were also confirmed locally in an expansion phase of this situational analysis to additional primary care facilities. As a consequence, solutions were designed, promptly taken up and implemented by the municipal health secretariat.

Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors

BackgroundPreclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study.MethodsWe analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA).ResultsFirst, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1–2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies.ConclusionsVT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447).

A Feature Extraction Method for Prognostic Health Assessment of Gas Compressor Valves

Abstract This paper presents features derived from the pressure-volume (PV) diagram that is useful in estimating different valve faults in reciprocating compressors with a strong potential of remaining useful life prediction. The PV diagram is expected to deviate depending on valve wear conditions. The valve degradation types explored in this work are leakage, seat wear, and spring fatigue in the suction and discharge assemblies of a Dresser-Rand ESH-1 compressor commonly used in the petrochemical industry. The proposed method estimates the polytropic exponent on the compression and expansion phase as well as the discharge and suction valve loss power and uses them as features for a quadratic discriminant analysis. The features are created through in-cylinder pressure, suction pressure, discharge pressure, and crank angle measurements collected on a single-stage, dual-acting compressor operating on air with wear precisely machined and seeded into the poppets of the inlet and outlet valves. A very high classification accuracy is achieved in distinguishing the wear types, severity, and location with strong prognostic trends.

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.