Decrease In Fraction Research Articles

Evaluating metrics of circulating tumor DNA response and progression using a high sensitivity tumor-agnostic assay in metastatic HR+/HER2- breast cancer receiving endocrine therapy and a CDK4/6-inhibitor.

1043 Background: CDK4/6-inhibitors (-i) and endocrine therapy (ET) are first-line treatment for HR+/HER2- metastatic breast cancer (mBC). Clinical evaluation and cross-sectional imaging are used for treatment response assessment. The relationship between clinical/radiographic response and ctDNA dynamics using a high sensitivity tumor-agnostic assay is unknown in HR+/HER2- mBC. ctDNA monitoring in mBC may support clinical decision-making, enable new strategies for response assessment in clinical trials, and facilitate enrolment of patients lacking measurable disease (bone-only). Methods: Patients (pts) with HR+/HER2- mBC receiving ET and CDK4/6i were enrolled in a prospective cohort study. Plasma samples were collected at baseline (BL) and regularly on-treatment. Samples were analyzed using Guardant Infinity, a tumor-agnostic genomic and epigenomic platform. ctDNA-response (-R) was defined as a ≥50% decrease (dec) in methylation tumor fraction (mTF) from BL. ctDNA-progression (-P) was defined as a <50% dec in mTF from BL or any subsequent increase in mTF above an absolute mTF of 0.001% (cohort specific definition). Imaging outcomes and dates of treatment discontinuation (TD) were collected. Results: 57 pts with 350 clinical timepoints were evaluated. Median follow up was 28.2m (range: 1.6-66.0m). 42/57 (74%) pts received palbociclib and 40/57 (70%) received an aromatase inhibitor. ctDNA-R/-P was evaluable in 49/57 patients. ctDNA-P identified within the first 90d on CDK4/6i was not prognostic of TD (p=0.7972); when assessed between 90-180d it was prognostic of early TD (med: 6.3m vs. not reached; HR: 5.17, 95%CI: 1.04-25.7; p=0.0003). 156 matched radiographic and ctDNA assessments (blood collected within 30d of CT) were evaluable for ctDNA-R/-P and imaging concordance. Excluding those with clinician-identified sclerotic bone changes suggestive of treatment effect (n=5 events), adjudicated radiographic progression did not occur in the setting of ctDNA-R (NPV: 100%, sensitivity: 100%); no pts had clinical progression in the presence of ctDNA-R. ctDNA rise in the absence of radiographic progression occurred in 13 pts; 7/13 had TD (med: 10.1m, range: 3.0-21.9m) in the follow up period reflecting a molecular lead time. Blood first monitoring, using these metrics, could have avoided 104/150 (69%) staging CT scans in this cohort. Conclusions: ctDNA dynamics are associated with clinical outcomes in HR+/HER2- mBC. The use of a high sensitivity assay permits assessment of response in nearly all patients and suggests the possibility that radiographic surveillance could be reduced in patients with ctDNA-R. Prospective validation of these findings are required. Additional ctDNA-R/-P definitions and relationship with RECIST 1.1 criteria will be presented at the meeting.

Pertuzumab plus trastuzumab (P+T) in patients (pts) with solid tumors with ERBB2or ERBB3amplification (amp) or mutations (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3142 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with ERBB2/3amp or mut treated with P+T are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Dosing of P was 840 mg IV over 60 minutes (m), then 420 mg IV over 30-60 m Q3 weeks (wks); T was 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m Q3 wks until disease progression. Low accruing histology-specific cohorts with ERBB2/3amp and/or mut were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 82% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 28 pts with 11 tumor types with ERBB2/3amp +/- mut (25) or mut only (3) were enrolled. The table shows demographics and outcomes. 2 CR (vagina, ERBB2amp, DOR= 151 wks; sweat gland, ERBB2amp, DOR= 48 wks), 6 PR (esophagus [2], small intestine, urothelial carcinoma [UC], site unspecified [SU], vagina; all with ERBB2amp) and 8 SD16+ (cervix [3], small intestine [2], UC, SU, testis; 6/8 pts had ERBB2 amp only, 1 had ERBB2mut only, 1 had ERBB3amp only) were observed for a DC rate of 57% (1-sided 90% CI: 43 to 100) and OR rate of 29% (95% CI: 13 to 49). The null hypothesis was rejected (p<0.001). Median duration of PR was 30 wks (range, 15-116, n=6). Median duration of SD for 8 pts with SD16+ was 28 wks (range, 18-84). 4/19 pts with KRAStesting performed had KRASalterations. 5 pts had ≥1 grade 3 tx-related adverse event (AE) or grade 2-5 serious AE: anemia, cardiac arrest resulting in death, diarrhea, ejection fraction decrease, pleural effusion, supraventricular tachycardia and vomiting. Conclusions: P+T showed antitumor activity in pts with advanced solid tumors with ERBB2/3amp. Additional study is warranted to confirm the efficacy of P+T in this population. Clinical trial information: NCT02693535 . [Table: see text]

Interannual Variability of Water and Heat Fluxes in a Woodland Savanna (Cerrado) in Southeastern Brazil: Effects of Severe Drought and Soil Moisture

The Brazilian Cerrado biome is known for its high biodiversity, and the role of groundwater recharge and climate regulation. Anthropogenic influence has harmed the biome, emphasizing the need for science to understand its response to climate and reconcile economic exploration with preservation. Our work aimed to evaluate the seasonal and interannual variability of the surface energy balance in a woodland savanna (Cerrado) ecosystem in southeastern Brazil over a period of 19 years, from 2001 to 2019. Using field micrometeorological measurements, we examined the variation in soil moisture and studied its impact on the temporal pattern of energy fluxes to distinguish the effects during rainy years compared to a severe drought spell. The soil moisture measures used two independent instruments, cosmic ray neutron sensor CRNS, and FDR at different depths. The measures were taken at the Pé de Gigante (PEG) site, in a region of well-defined seasonality with the dry season in winter and a hot/humid season in summer. We gap-filled the energy flux measurements with a calibrated biophysical model (SiB2). The long-term averages for air temperature and precipitation were 22.5 °C and 1309 mm/year, respectively. The net radiation (Rn) was 142 W/m2, the evapotranspiration (ET) and sensible heat flux (H) were 3.4 mm/d and 52 W/m2, respectively. Soil moisture was marked by a pronounced negative anomaly in the 2014 year, which caused an increase in the Bowen ratio and a decrease in Evaporative fraction, that lasted until the following year 2015 during the dry season, despite the severe meteorological drought of 2013/2014 already ending, which was corroborated by the two independent measurements. The results showed the remarkable influence of precipitation and soil moisture on the interannual variability of the energy balance in this Cerrado ecosystem, aiding in understanding how it responds to strong climate disturbances.

Effects of accessory pathway catheter ablation on left ventricular function in patients with dyssynchrony-induced cardiomyopathy associated with pre-excitation syndrome

Aim. To evaluate the effect of radiofrequency ablation (RFA) of accessory pathways on left ventricle (LV) function in patients with Wolff-Parkinson-White (WPW) syndrome and preexitation-induced dyssynchrony cardiomyopathy.Methods. The study included 22 patients with registered preexitation on the ECG and signs of dyssynchronous cardiomyopathy according to echocardiography (Echo): asynchronous movement of interventricular septum, ejection fraction (EF) decrease and/or global longitudinal strain of the left ventricle (GLS LV), heart chamber increase. The average age of patients at the time of RFA of the accessory pathways - 11 years [8;14].Results. A regular normalization of the QRS complex width was observed after RFA (p = 0.0002). To assess reverse LV remodeling, all patients underwent Echo on day 3 after RFA. In patients with an initially reduced LVEF, its increase was noted. In patients with initial dilatation and an increase in LV volume, normalization of these indicators was noted. However, dynamics of LVEF and its volume was not statistically significant in the early postoperative period. According to Speckle-tracking Echo during medical check-up, complete normalization of longitudinal deformation was observed in 13 patients (59%), this indicator improvement - in 7 patients (31.8%). The average GLS LV before RFA was -17.25 [-16.4; -19], after RFA - -21.5 [-19; -24] (p = 0.0001).Conclusion. Reverse remodeling and restoration of LV function after RFA of accessory pathways indicates a cause- and-effect relationship between the accessory pathways functioning and dyssynchronous cardiomyopathy development. Therefore, patients with signs of preexitation-induced dyssynchronous cardiomyopathy are indicated for RFA of accessory pathways, regardless of age and tachycardia paroxysms.

Tearing-mediated Reconnection in Magnetohydrodynamic Poorly Ionized Plasmas. I. Onset and Linear Evolution

In high-Lundquist-number plasmas, reconnection proceeds via the onset of tearing, followed by a nonlinear phase during which plasmoids continuously form, merge, and are ejected from the current sheet (CS). This process is understood in fully ionized, magnetohydrodynamic plasmas. However, many plasma environments, such as star-forming molecular clouds and the solar chromosphere, are poorly ionized. We use theory and computation to study tearing-mediated reconnection in such poorly ionized systems. In this paper, we focus on the onset and linear evolution of this process. In poorly ionized plasmas, magnetic nulls on scales below v A,n0/ν ni0, with v A,n0 the neutral Alfvén speed and ν ni0 the neutral–ion collision frequency, will self-sharpen via ambipolar diffusion. This sharpening occurs at an increasing rate, inhibiting the onset of reconnection. Once the CS becomes thin enough, however, ions decouple from neutrals and the thinning of the CS slows, allowing the onset of tearing in a time of order νni0−1 . We find that the wavelength and growth rate of the mode that first disrupts the forming sheet can be predicted from a poorly ionized tearing dispersion relation; as the plasma recombination rate increases and ionization fraction decreases, the growth rate becomes an increasing multiple of ν ni0 and the wavelength becomes a decreasing fraction of v A,n0/ν ni0.

Left ventricular global longitudinal strain is a long-term predictor of pacemaker-associated cardiomyopathy

Abstract Background Implantation of a permanent pacemaker is an effective treatment for symptomatic bradycardia. However, chronic right ventricular pacing (RVP) may lead to compromised left ventricular (LV) function, atrial fibrillation, heart failure, and increased mortality via pacing induced electrical and mechanical dyssynchrony. A decrease in LV ejection fraction (LVEF) of ≥ 10% with a baseline LVEF > 50% prior to RVP and no alternative explanation for the decline in LVEF is termed pacing-induced cardiomyopathy (PICM). Predictive clinical and imaging-derived measures to identify patients at high risk for pacemaker induced cardiomyopathy (PMIC) are lacking, but essential. Objective The study is a prospective, single center, double-blinded trial evaluating the impact of right ventricular pacing on left ventricular function and clinical outcome. Methods In 105 patients (59 male / 46 female), who underwent a dual-chamber pacemaker implantation at the Charité Campus Virchow Klinikum, RVP burden, LVEF and left ventricular global longitudinal strain (LV-GLS) were obtained. Mean follow-up per patient was 29.6 ±13.9 months. We used a stepwise analytic approach including ROC analysis, univariate testing, binary regression as well as Cox-regression models and Kaplan-Meier analysis to compare low RVP burden (< 30%) and high RVP burden (≥ 30%) cohorts according to change in echocardiographic parameters and clinical outcome (all-cause mortality). Results Mean LVEF was 61 ± 6% and mean LV-GLS was 18 ± 4% at baseline. We identified 7 patients with a LVEF decline in the course of the study. In Pearson’s Chi-squared test, patients with a high RVP burden were more likely to develop LVEF and LV-GLS deterioration (6 patients versus 1 patient for LVEF, p<0.05; 28 versus 16 patients for LV-GLS, p<0.001). In multivariable binary logistic regression, LV-GLS (OR: 1.410, 95% CI: 1.201-1.610, p<0.001) deterioration was significantly associated with a LVEF decline and a high RVP burden ≥ 30% (OR: 1.358, 95% CI: 1.160-1.534, p<0.01). In a log-rank test, time to LVEF decline was significantly shorter in patients with a RVP burden ≥ 30% compared to a RVP burden < 30% (45.2±2.9 versus 55.7±1.0 months, p<0.05). In the Cox-regression analysis, LV-strain decline within 12 months (HR: 7.210, 95% CI: 4.239-9.516, p<0.05) was a significant predictor for a later LVEF decline. In a log-rank test, time to LVEF deterioration was significantly shorter in patients with LV-strain decline within 12 months compared to those without (34.7 ± 4.2 versus 53.7 ± 1.4 months, p<0.001). No significant difference in all-cause mortality between patients with a high RVP burden compared to those with low RVP burden (log-rank test, p=0.2). Conclusion A decline in LV-GLS is a sensitive long-term parameter of subsequent LVEF deterioration in patients with normal preimplant LVEF, who require RVP ≥ 30%. and is associated with a poor clinical outcome.

#951 Structural and functional indicators of the left heart in the aspect of contrast-induced nephropathy

Abstract Background and Aims To study the structural and functional features of the left heart in patients with coronary artery disease depending on the development of contrast-induced nephropathy (CIN) against the background of radiopaque endovascular procedures (REP). Method The study included 303 patients with stable forms of coronary artery disease who underwent X-ray endovascular procedures (REP). Patients with eGFR, determined by serum creatinine concentration, less than 60 ml/minute were not included in the study. 20 healthy volunteers were examined as a control group. All patients were divided into 2 groups - patients with an uncomplicated postoperative period of REP (CIN- group, 206 patients, 67.99%) and patients who developed contrast-induced nephropathy (CIN+ group, 97 patients, 32.01%). Subsequently, the CIN+ and CIN- groups were retrospectively compared based on baseline echocardiographic parameters. Results The present study demonstrated that EchoCG predictors of CIN in patients with stable forms of coronary artery disease are dilatation of the left ventricular (LV) cavity more than 136 ml (relative risk 1.65, p < 0.01), an increase in the index of impaired regional contractility of the LV to 1.2 points or higher (relative risk 1.77, p < 0.01) and a decrease in the e/a ratio of tissue Dopplerogram of the lateral edge of the mitral annulus to 0.7 relative units or less (relative risk 1.59, p < 0.01). Conclusion In patients with coronary artery disease after REP, despite the improvement in the index of impaired regional contractility and the index of LV sphericity, in the CIN+ group there is a more significant deterioration in the structural and functional properties of the LV myocardium, which manifested itself in an increase in systolic myocardial stress, a decrease in ejection fraction and an increase in the degree of diastolic dysfunction, which indicates a toxic effect of the radiocontrast drug not only on the kidneys, but also on the myocardium.

#1755 Cardio-protective effect of soy proteins during long-term consumption of Cynomolgus Monkeys high-saline diet

Abstract Background and Aims High salt intake is accompanied by the development of cardiovascular disorders, not always associated with an increase in blood pressure (BP). Recently, it has been found that the introduction of soy protein into the diet can have some nephroprotective and cardioprotective effects in chronic kidney disease. Considering the cardioprotective effect of soy proteins in chronic kidney disease, the question arose about the possibility of using soy proteins to neutralize the damaging effect of a high-salt diet on the cardiovascular system. This work aims to study the effect of long-term use of a diet high in NaCl and soy protein on myocardial remodeling in monkeys. Method The study was performed on male Macaca fascicularis. The animals were divided into three groups (6 animals each), comparable in weight and age (6-8 years, body weight - 5.15-9.7 kg). The control group received a standard diet (2 g NaCl/kg feed). The second was a high salt diet (8 g NaCl/kg feed), and the third was a high salt diet and SUPRO760 soy protein (200 g/kg feed). Echocardiography (EchoCG), registration of BP and heart rate were performed at baseline, after 4 and 12 months. EchoCG was performed with a sector transducer with a frequency of 3–5 MHz on the Chison SonoTouch 60 ultrasound system (China). EchoCG was performed in B_mode (two-dimensional scanning), M_mode (one-dimensional scanning), as well as in pulse and tissue Doppler modes. Statistical analysis was performed using parametric statistics: mixed ANOVA in comparing data from 3 study groups (with post hoc analysis using Tukey criterion) and single factor variance analysis for related samples in studying the dynamics of one or another index in each group during the 12-month follow-up. Differences were considered significant at p < 0.05. Results In animals of all three groups for 12 months, blood pressure (BPsis-109±10.09, BPdias – 60 ± 7.42 mm Hg) and heart rate (77 ± 12.61 min-1) did not change significantly (p>0. 05). However, in macaques on a high-salt diet, deterioration in left ventricular (LV) systolic and diastolic function was noted by the end of the study. Macaques of this group had a decrease in the LV shortening fraction (27.9±2.69%) and an increase in the thickness of the posterior wall of the LV in systole (0.69±0.039 cm), LV mass (19.60±2.83 g), compared with animals additionally receiving soy proteins (34.9±6.57%; 0.57 0.0559 cm; 14.86±2.94 g, respectively; all p < 0.05). In addition, the monkeys receiving soy isolate did not differ from the control in these parameters. By the time the study was completed, the animals in this group had significantly increased the magnitude of systolic excursion of the mitral annulus plane, and signs of improvement in LV diastolic function appeared in the form of an increase in the maximum rate of excursion of the mitral valve fibrous annulus in early diastole, as well as a decrease in the E/e' ratio. The thickness of the interventricular septum also decreased (0.42±0.04 cm; in the high-salt group - 0.51±0.08 cm), which can be interpreted as a sign of positive myocardial remodeling. Conclusion Thus, high salt intake leads to adverse structural and functional disorders of the heart in cynomolgus monkeys, not associated with an increase in blood pressure. The inclusion of soy isolate in the diet reduces the negative effects of a high-salt diet on the cardiovascular system.

Longitudinal myelin content measures of slowly expanding lesions using 7T MRI in multiple sclerosis.

Slowly expanding lesions (SELs) are thought to represent a subset of chronic active lesions and have been associated with clinical disability, severity, and disease progression. The purpose of this study was to characterize SELs using advanced magnetic resonance imaging (MRI) measures related to myelin and neurite density on 7Tesla (T) MRI. The study design was retrospective, longitudinal, observational cohort with multiple sclerosis (n=15). Magnetom 7T scanner was used to acquire magnetization-prepared 2 rapid acquisition gradient echo and advanced MRI including visualization of short transverse relaxation time component (ViSTa) for myelin, quantitative magnetization transfer (qMT) for myelin, and neurite orientation dispersion density imaging (NODDI). SELs were defined as lesions showing ≥12% of growth over 12months on serial MRI. Comparisons of quantitative measures in SELs and non-SELs were performed at baseline and over time. Statistical analyses included two-sample t-test, analysis of variance, and mixed-effects linear model for MRI metrics between lesion types. A total of 1075 lesions were evaluated. Two hundred twenty-four lesions (21%) were SELs, and 216 (96%) of the SELs were black holes. At baseline, compared to non-SELs, SELs showed significantly lower ViSTa (1.38vs. 1.53, p<.001) and qMT (2.47vs. 2.97, p<.001) but not in NODDI measures (p>.27). Longitudinally, only ViSTa showed a greater loss when comparing SEL and non-SEL (p=.03). SELs have a lower myelin content relative to non-SELs without a difference in neurite measures. SELs showed a longitudinal decrease in apparent myelin water fraction reflecting greater tissue injury.

Al-Co-Cr-Fe-Ni high-entropy coatings produced by non-vacuum electron beam cladding: Understanding the effect of Al by in-situ synchrotron X-ray diffraction

This study investigates the structure and properties of Al-Co-Cr-Fe-Ni high-entropy alloy (HEA) based coatings on steel substrates produced by non-vacuum electron beam cladding. Powder mixtures with Al molar ratios of 0.5, 1, and 1.5 were used for cladding, resulting in coatings with fcc, bcc + fcc, and bcc structures, respectively. The Fe content, which entered the coating from the substrate during cladding, increased from 9.9 up to 48.1 at. % with the decrease of the Al molar fraction from 1.5 to 0.5. In-situ synchrotron X-ray diffraction analysis showed that this effect can be attributed to the higher solidus temperatures of the compositions with higher Al content. Electron backscatter diffraction showed that differences in grain morphology and crystallographic texture were related to the crystallization temperatures in different zones of the coatings. The bcc coating with an Al molar ratio of 1.5 demonstrated superior hardness and wear resistance. Fcc coating, which received more Fe from the substrate, had lower hardness and was prone to plastic flow. However, the specific wear rate of the fcc coating was close to that of the bcc + fcc one due to the hardening of the fcc phase during sliding wear.

ROLE OF NF-κB TRANSCRIPTION FACTOR ACTIVATION IN THE PROCESSES OF CONNECTIVE TISSUE COMPONENTS DEGRADATION IN SKELETAL MUSCLES UNDER METABOLIC SYNDROME

Connective tissue, encompassing both cellular and non-cellular elements, plays an important role in the progression of numerous pathological processes across various organs and tissues. Within skeletal muscle tissue, the extracellular matrix not only plays a structural and supporting function, but it is a complex multicomponent system that performs a number of regulatory functions. At present, the effect of activation of the transcription factor NF-κB on the quantitative and qualitative composition of the components of the extracellular matrix in skeletal muscles under metabolic syndrome development is insufficiently studied. The aim of this work is to study the effect of ammonium pyrrolidinedithiocarbamate on the concentration of glycosaminoglycans, the concentration of individual fractions of glycosaminoglycans, the content of free L-oxyproline and sialic acids in the biceps femoris muscle of rats under metabolic syndrome. The study was conducted on 24 male Wistar rats weighing 200-260 g, which were randomly divided into 4 groups of 6 animals each. The first was control; the second made up the metabolic syndrome modeling group. Metabolic syndrome was reproduced by adding a 20% fructose solution to the standard vivarium diet as the only source of drinking water. Metabolic syndrome was modelled for 60 days. The third group received ammonium pyrrolidinedithiocarbamate administration at a dose of 76 mg/kg intraperitoneally (i/p) three times a week for 60 days. The fourth group underwent combined treatment involving the administration of both ammonium pyrrolidinedithiocarbamate and metabolic syndrome modeling. In a 10% homogenate of the biceps femoris muscle, the total concentration of glycosaminoglycans, the concentration of the heparin-heparan fraction of glycosaminoglycans, the keratan-dermatan fraction of glycosaminoglycans, the chondroitin fraction of glycosaminoglycans, and the content of free L-oxyproline and sialic acids were assessed. The introduction of ammonium pyrrolidinedithiocarbamate under metabolic syndrome modelling led to a decrease in the total concentration of glycosaminoglycans by 9.2% compared to the metabolic syndrome group. Under these conditions, the concentration of the heparin-heparan fraction increased by 121.1%, the keratan-dermatan fraction decreased by 32.8%, and the concentration of the chondroitin fraction decreased by 38.7% compared to the metabolic syndrome group. The concentration of free L-oxyproline and sialic acids in the biceps femoris muscle decreased by 19.8% and 24.4%, respectively, compared to the metabolic syndrome group. Blockade of activation of the transcription factor NF-κB by intraperitoneal administration of ammonium pyrrolidinedithiocarbamate against the background of metabolic syndrome modelling leads to a decrease in the depolymerization of glycoproteins and proteoglycans, reduces the intensity of collagenolysis and leads to a redistribution of concentrations of individual fractions of glycosaminoglycans, characterized by an increase in the content of the heparin-heparan fraction and a decrease in chondroitin and keratan-dermatan fractions in the biceps femoris muscle of rats.

STUDYING THE HYPOLYPIDEMIC ACTIVITY OF FLAVONOIDS AND ISOFLAVONOIDS OF THE ONONIS ARVENSIS L. METHODS BY IN SILICO

Introduction. Today, one of the reliably known causes of mortality in the Russian Federation is diseases of the cardiovascular system, a significant part of which is associated with atherosclerotic disease. Combination therapy for diseases of the cardiovascular system includes, among other things, the use of modern lipid-lowering drugs, the use of which is often limited due to their pronounced side effects. In this regard, it seemed appropriate to search for new compounds of natural origin that potentially have lipid-lowering activity with minimal side effects. According to the scientific literature, natural phenolic compounds, namely substances from the group of flavonoids and isoflavonoids, have a set of such characteristics. In this regard, steelgrass (Ononis arvensis L.), the chemical composition of which is extremely rich and diverse in terms of flavonoids and isoflavonoids, can be a ra-ther promising source for searching and screening compounds with a given activity. The aim of the study. The purpose of the work was to study and predict the hypolipidemic activity of flavonoids and isoflavonoids of Ononis arvensis L. using in silico methods. Material and methods. The objects of the study were the structural formulas of flavonoids and isoflavonoids of field steelhead. Calculation of mo-lecular properties was carried out using the Molinspiration chemoinformatic software. Computer prediction of lipid-lowering activity was carried out us-ing the PASS-online service. Molecular docking was performed using the CB-Dock2 services for blind docking and Webina 1.0.5 for active site docking. Hepatotoxicity, mutagenicity and cytotoxicity of the analyzed biologically active substances were studied using the ProTox-II resource. Results. As a result of in silico studies, it was found that most of the studied flavonoids and isoflavonoids correspond to the Lipinski rule and the drug-likeness concept. In addition, for all studied biologically active substances, activities associated with a decrease in lipid fractions in the body were predicted. The results of molecular docking indicate that all analyzed compounds are capable of potentially inhibiting the enzyme HMG-CoA reductase, which makes it possible to predict the required lipid-lowering effect. Studying the toxicity of the research objects, most of them in silico demonstrated a high level of safety. Conclusions. The prospects for further research on the development of targeted technology for obtaining herbal preparations from steelhead, enriched with flavonoids and isoflavonoids, as well as subsequent tests to confirm hypolipidemic activity in in vitro and in vivo experiments are shown.

Effect of Compressive Stress on Copper Bonding Quality and Bonding Mechanisms in Advanced Packaging.

The thermal expansion behavior of Cu plays a critical role in the bonding mechanism of Cu/SiO2 hybrid joints. In this study, artificial voids, which were observed to evolve using a focused ion beam, were introduced at the bonded interfaces to investigate the influence of compressive stress on bonding quality and mechanisms at elevated temperatures of 250 °C and 300 °C. The evolution of interfacial voids serves as a key indicator for assessing bonding quality. We quantified the bonding fraction and void fraction to characterize the bonding interface and found a notable increase in the bonding fraction and a corresponding decrease in the void fraction with increasing compressive stress levels. This is primarily attributed to the Cu film exhibiting greater creep/elastic deformation under higher compressive stress conditions. Furthermore, these experimental findings are supported by the surface diffusion creep model. Therefore, our study confirms that compressive stress affects the Cu-Cu bonding interface, emphasizing the need to consider the depth of Cu joints during process design.

Association between echocardiographic features, troponin levels, and survival time in hospitalized COVID-19 patients with cardiovascular events

IntroductionThis study aims to explore the predictive roles of echocardiographic parameters and biomarkers in determining outcomes among hospitalized COVID-19 patients experiencing cardiovascular events. MethodsA retrospective cohort study was conducted involving 49 COVID-19 patients who encountered cardiovascular events during hospitalization and underwent echocardiography. Our findings revealed notable associations between echocardiographic parameters and survival time. ResultsA decrease in left ventricular ejection fraction (LVEF) of 10% was linked to a 20% reduction in survival time (TR: 0.80, 95% CI: 0.67 – 0.96, p = 0.017). Similarly, an increase in left ventricular (LV) volume by 10 mL was associated with a 9% decrease in survival time (TR: 0.91, 95% CI: 0.84 – 0.98, p = 0.011). Moreover, an increase in left atrial (LA) volume by 10 mL corresponded to an 8% decrease in survival time (TR: 0.92, 95% CI: 0.86 – 0.99, p = 0.026). Additionally, each 1 cm increase in right ventricular (RV) diameter was linked to a 22% reduction in survival time (TR: 0.78, 95% CI: 0.61 – 0.99, p = 0.043). Furthermore, a 10 mL increase in right atrial (RA) volume was associated with a 12% decrease in survival time (TR: 0.88, 95% CI: 0.78 – 0.98, p = 0.017). Notably, a tenfold rise in troponin levels was linked to a 33% decrease in survival time (TR: 0.67, 95% CI: 0.48 – 0.93, p = 0.014). ConclusionsOur study emphasizes the significant associations between various echocardiographic parameters and troponin levels with reduced survival time among COVID-19 patients experiencing cardiovascular events. These findings highlight the potential utility of echocardiography and troponin assessment in predicting outcomes and guiding management strategies in this patient population.

Observational Assessment of Changes in Earth’s Energy Imbalance Since 2000

AbstractSatellite observations from the Clouds and the Earth’s Radiant Energy System show that Earth’s energy imbalance has doubled from 0.5 ± 0.2 Wm−2 during the first 10 years of this century to 1.0 ± 0.2 Wm−2 during the past decade. The increase is the result of a 0.9 ± 0.3 Wm−2 increase absorbed solar radiation (ASR) that is partially offset by a 0.4 ± 0.25 Wm−2 increase in outgoing longwave radiation (OLR). Despite marked differences in ASR and OLR trends during the hiatus (2000–2010), transition-to-El Niño (2010–2016) and post-El Niño (2016–2022) periods, trends in net top-of-atmosphere flux (NET) remain within 0.1 Wm−2 per decade of one another, implying a steady acceleration of climate warming. Northern and southern hemisphere trends in NET are consistent to 0.06 ± 0.31 Wm−2 per decade due to a compensation between weak ASR and OLR hemispheric trend differences of opposite sign. We find that large decreases in stratocumulus and middle clouds over the sub-tropics and decreases in low and middle clouds at mid-latitudes are the primary reasons for increasing ASR trends in the northern hemisphere (NH). These changes are especially large over the eastern and northern Pacific Ocean, and coincide with large increases in sea-surface temperature (SST). The decrease in cloud fraction and higher SSTs over the NH sub-tropics lead to a significant increase in OLR from cloud-free regions, which partially compensate for the NH ASR increase. Decreases in middle cloud reflection and a weaker reduction in low-cloud reflection account for the increase in ASR in the southern hemisphere, while OLR changes are weak. Changes in cloud cover in response to SST increases imply a feedback to climate change yet a contribution from radiative forcing or internal variability cannot be ruled out.

In Situ Generation of TiCN Ni‐Based Coatings by Laser Cladding and Study of Their Structure and Properties

The influence of the ratio of TiN powder, graphite powder, and Ni60 powder on the phase composition, microstructure, microhardness, and wear properties of the TiCN Ni‐based coating on H13 steel is investigated. The findings indicate that varying proportions of TiN powder, C powder, and Ni60 powder have a minimal impact on the coating's phase composition. The diffraction peak intensity of TiC0.3N0.7 increases with the addition of (C + TiN) in the blended powder, while the crystallinity of TiC0.3N0.7 in the Ni‐based coating with a 30% (C + TiN) mass fraction decreases. The grain structure of the 20% Ni‐based coating is fine and uniform, while the microstructure of the 30% Ni‐based coating is characterized by a large polymerization phase‐containing Ti elements, with the TiCN‐reinforced phase exhibiting irregular grain morphology. The microhardness HV0.5 of the coating with a 20% (C + TiN) mass fraction ranges from 725 to 772, with an average hardness of 747.8 HV0.5, which is 3.4 times the hardness of the substrate material and 1.3 times the hardness of the Ni‐based coating. As the mass fraction of (C + TiN) in the hybrid powder increases, the friction loss mass of the coating tends to decrease and then increase. The average wear of the Ni‐based coating with a 20% (C + TiN) mass fraction is ≈22.4% of that of the substrate and 50% of that of the Ni‐based coating, demonstrating excellent wear resistance. The wear mechanism is primarily characterized by brittle spalling and abrasive wear.

Effects of Pterostilbene on Heart and Lung Oxidative Stress Parameters in 2 Experimental Models of Cardiovascular Disease: Myocardial Infarction and Pulmonary Arterial Hypertension.

Myocardial infarction (MI) and pulmonary arterial hypertension (PAH) are 2 prevalent cardiovascular diseases. In both conditions, oxidative stress is associated with a worse prognosis. Pterostilbene (PTE), an antioxidant compound, has been studied as a possible therapy for cardiovascular diseases. This study aims to evaluate the effect of PTE on oxidative stress in the hearts of animals with MI and in the lungs of animals with PAH. Male Wistar rats were used in both models. In the MI model, the experimental groups were sham, MI, and MI + PTE. In the PAH model, the experimental groups were control, PAH, and PAH + PTE. Animals were exposed to MI through surgical ligation of the left coronary artery, or to PAH, by the administration of monocrotaline (60 mg/kg). Seven days after undergoing cardiac injury, the MI + PTE animals were treated with PTE (100 mg/kg day) for 8 days. After this, the heart was collected for molecular analysis. The PAH + PTE animals were treated with PTE (100 mg/kg day) for 14 days, beginning 7 days after PAH induction. After this, the lungs were collected for biochemical evaluation. We found that PTE administration attenuated the decrease in ejection fraction and improved left ventricle end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased reactive oxygen species levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in 2 experimental models of cardiac diseases: MI and PAH. PTE also improved cardiac function in infarcted rats and pulmonary artery flow in animals with PAH.

Effect of Cu Film Thickness on Cu Bonding Quality and Bonding Mechanism.

In the hybrid bonding process, the final stage of chemical mechanical polishing plays a critical role. It is essential to ensure that the copper surface is recessed slightly from the oxide surface. However, this recess can lead to the occurrence of interfacial voids between the bonded copper interfaces. To examine the effects of copper film thickness on bonding quality and bonding mechanisms in this study, artificial voids were intentionally introduced at the bonded interfaces at temperatures of 250 °C and 300 °C. The results revealed that as the thickness of the copper film increases, there is an increase in the bonding fraction and a decrease in the void fraction. The variations in void height with different copper film thicknesses were influenced by the bonding mechanism and bonding fraction.

Short-period flow oscillation during eruptions of Onikobe geyser, NE Japan: Insights from thermal infrared observation and acoustic measurements

Geysers are episodic features with variable eruption intervals that range from minutes to years. Although many previous studies on geysers have focused on subsurface properties and processes such as plumbing geometry and recharge process, it is known that erupting fluid column exhibits short-term behaviors such as individual water jets from the vent. In the present study, we conducted observations at Onikobe geyser, NE Japan, a relatively small geyser (geysering well) erupting water up to ∼6–8 m every ∼10 min and observed the erupting fluid column using a thermal infrared camera and an acoustic sensor. We succeed in tracking the water jets by analyzing spatio-temporal temperature map obtained from the thermal infrared observation, which clearly shows the eruptions at Onikobe geyser are not completely stationary but rather a series of intermittent jets with a short period interval of <1 s. We estimate the exit velocity by fitting a ballistic model under the air drag condition of inertial resistance to the jet trajectory. The exit velocity and the averaged gas volume fraction of the erupting fluid are estimated to be ∼4–79 m/s and ∼0.93–0.96, respectively. The exit velocity is ∼30 m/s during the first bursts, then it rapidly increases to ∼50–80 m/s for ∼15 s, and then decreases to ∼20–30 m/s until ∼10 s before the eruption ends. Time series analyses of the thermal infrared and acoustic signals during an eruption indicate harmonic spectra with integer multiple peaks. The fundamental frequency showing ∼4 Hz at the beginning gradually decreases to ∼2 Hz for ∼15 s, keeps almost constant in the following 30 s, and then slightly increases near the end of the eruption. These harmonic spectra may be caused by a resonance mechanism, non-linear fluid motion, and/or subsurface two-phase flow. We discuss the case of a closed organ-pipe resonance in a subsurface crack and attribute the frequency decrease to a decrease in the water level in the crack (an increase in the length of the resonating liquid-vapor column) and/or a decrease in the gas volume fraction of the liquid-vapor mixture in the crack. Since such harmonic characteristics are observed at other geysers, further simultaneous observation of the short-period oscillations on the erupting column proposed in this study with seismic observations of harmonic tremor may provide an improved understanding of geyser subsurface phenomena.

Abstract PS15-03: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader. In a phase 1/2 study (NCT04072952), vepdegestrant monotherapy had a favorable safety profile and encouraging clinical activity, and showed robust ER degradation. The phase 1b cohort of this study is evaluating vepdegestrant in combination with the cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (palbo). In xenograft models, vepdegestrant plus palbo showed substantially greater tumor growth inhibition vs fulvestrant plus palbo, supporting investigation in patients with breast cancer. Methods: Eligible patients for the phase 1b combination cohort had ER+/HER2- locally advanced/metastatic breast cancer and had received ≥1 prior endocrine therapy and ≤2 chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor treatment was permitted. Vepdegestrant was given orally once daily (QD) continuously at doses of 180 mg (n=2), 200 mg (n=21), 400 mg (n=3), or 500 mg (n=20); palbo 125 mg was given orally QD for 21 days followed by 7 days off treatment in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) in the first cycle and safety (adverse events [AEs] and laboratory abnormalities). Enrollment in these 4 dose levels is complete; we report data as of June 6, 2023. Results: Across 46 patients in the phase 1b cohort, 45 (97.8%) patients were female with a median age of 62.0 y (range: 29–78). Patients had received a median of 4 prior therapies (range: 1–11) in any setting, including 87.0% prior CDK4/6 inhibitors (78.3% prior palbo), 80.4% prior fulvestrant, and 76.1% prior chemotherapy (45.7% in the metastatic setting). There were no DLTs. Treatment-emergent AEs (TEAEs) leading to dose reductions or discontinuation of vepdegestrant occurred in 5 and 4 patients, respectively. TEAEs leading to dose reductions or discontinuation of palbo occurred in 34 and 8 patients, respectively. Grade 3/4 treatment-related AEs (TRAEs) to either vepdegestrant or palbo in ≥10% of patients were neutropenia (89.1%), decreased white blood cell count (15.2%), and decreased platelet count (10.9%); there were no grade 5 TRAEs and no patients had febrile neutropenia. The clinical benefit rate (rate of confirmed complete response, partial response, or stable disease ≥24 wks) in patients treated with vepdegestrant plus palbo was 63.0% (95% CI: 47.5–76.8). The objective response rate in evaluable patients with measurable disease at baseline (n=31) was 41.9% (95% CI: 24.5–60.9). Pharmacokinetics (PK) showed dose-dependent exposure for vepdegestrant, consistent with data for vepdegestrant administered as monotherapy; palbo exposure was similar across dose levels of vepdegestrant and modestly higher compared with historical palbo PK data. Circulating tumor DNA levels were evaluated in patients who received vepdegestrant 200 mg QD plus palbo and demonstrated substantial and sustained decreases in ESR1 mutant allele fraction across multiple treatment cycles. Conclusions: The combination of vepdegestrant plus palbo showed promising clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer who had received extensive prior treatment. The safety profile of vepdegestrant plus palbo was generally consistent with the known safety profiles of the 2 agents except for an increased occurrence of grade 3/4 neutropenia, which was readily managed with laboratory monitoring and dose reductions of palbo. There is an ongoing study lead-in to the global VERITAC-3 study (NCT05909397) that is evaluating 2 doses of palbo (100 mg and 75 mg) in combination with vepdegestrant 200 mg QD to determine the recommended phase 3 combination to compare with letrozole plus palbo as first-line treatment for ER+/HER2- advanced breast cancer. Citation Format: Erika Hamilton, Rinath Jeselsohn, Sara Hurvitz, Dejan Juric, Hyo Han, Melinda Telli, George Zahrah, Rita Nanda, Yuanyuan Zhang, Weiwei Tan, Elizabeth Duperret, Eric Zhi, Cecile Mather, Anne Schott. Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort [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 PS15-03.