Decrease In Fraction Research Articles

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.

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P&amp;lt; 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P&amp;lt; 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [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 PO4-17-02.

Age- and sex-related changes in vertebral trabecular bone architecture in Neolithic and Mediaeval populations from Poland.

This paper investigates trabecular bone ontogenetic changes in two different Polish populations, one prehistoric and the other historical. The studied populations are from the Brześć Kujawski region in Kujawy (north-central Poland), one from the Neolithic Period (4500-4000 BC) and one from the Middle Ages (twelfth-sixteenth centuries AD), in total 62 vertebral specimens (32 males, 30 females). Eight morphometric parameters acquired from microCT scan images were analysed. Two-way ANOVA after Box-Cox transformation and multifactorial regression model were calculated. A significant decrease in percentage bone volume fraction (BV/TV; [%]) with age at death was observed in the studied sample; Tb.N (trabecular number) was also significantly decreased with age; trabecular separation (Tb.Sp) increased with advancing age; connectivity density (Conn.D) was negatively correlated with biological age and higher in the Neolithic population. These data are found to be compatible with data from the current biomedical literature, while no loss of horizontal trabeculae was recorded as would be expected based on modern osteoporosis.

Abstract 2147: Impact Of Donor Age On Microvasculature Self-assembly Of Induced Pluripotent Stem Cell Derived Endothelial Progenitors

Introduction: Current vascular tissue-engineering using induced pluripotent stem cells (iPSCs) predominantly relies on somatic cells obtained from newborn or fetal donors. However, iPSCs sourced from aged individuals exhibit epigenetic differences in angiogenic genes that may hinder their utility in iPSC derived vasculature. We hypothesized that, due to these differences, iPSCs from aged donors will exhibit decreased vasculogenic potential. Methods: We differentiated iPSCs into endothelial progenitors (iEPs) and encapsulated them in an interpenetrating polymer network hydrogel containing norbornene-functionalized hyaluronic acid and Collagen I at cell densities and hydrogel stiffness optimal for vasculogenesis. Seven days after encapsulation, the hydrogels were fixed, and the resulting microvasculature imaged. We then utilized a previously developed computational pipeline to quantify several vasculogenic properties. Results: We derived iEPs from four separate iPSC lines: 2 sourced from neonatal donors (ND) and 2 from mature donors (MD). Irrespective of donor age, differentiation yielded ~15% (n=4) iEPs of the total cell population. The two ND lines developed a similar plexus, whereas this structure was diminished in one adult line and absent in the second. Between iEPs matched for sex and somatic cell origin, there is a 50% decrease in vessel volume fraction and number of links between vessels, a 66% reduction in the percentage of vessels connected to the largest vessel, and a 43% reduction in branch points between vessels ( Fig. 1 ). Conclusion: Overall, these data suggest MD iEPs are less likely to form dense interconnected microvasculature as compared to ND iEPs. Interestingly, the average diameter did not change across all cell lines. This suggests that while MD iEPs exhibited cell clustering, they were less likely to branch out and interconnect with other clusters of iPSC-EPs to form interconnected networks

Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway.

Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91 ± 1.76 vs. 40.47 ± 3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8 ± 2.7 vs. 28.5 ± 5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6 ± 9.5 vs. 93.5 ± 13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0 ± 8.3 vs. 67.9 ± 13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.

Baicalin alleviates angiotensin II-induced cardiomyocyte apoptosis and autophagy and modulates the AMPK/mTOR pathway.

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension-induced heart injury remains unclear. Invivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. Invitro, H9C2 cells were stimulated with Ang II (1 μM) and treated with Baicalin (12.5, 25 and 50 μM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II-induced cell apoptosis invivo and invitro. Baicalin treatment reversed the up-regulation of Bax, cleaved-caspase 3, cleaved-caspase 9, and the down-regulation of Bcl-2. Meanwhile, Baicalin treatment alleviated Ang II-induced increase of autophagosomes, restored autophagic flux, and down-regulated LC3II, Beclin 1, as well as up-regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3-methyladenine treatment alleviated the increase of autophagosomes and the up-regulation of Beclin 1, LC3II, Bax, cleaved-caspase 3, cleaved-caspase 9, down-regulation of SQSTM1/p62 and Bcl-2 expression after Ang II treated, which similar to co-treatment with Baicalin. Baicalin treatment reduced the ratio of p-AMPK/AMPK, while increased the ratio of p-mTOR/mTOR. Baicalin alleviated Ang II-induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway.

Melanopsin-mediated amplification of cone signals in the human visual cortex.

The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and irradiances are higher. Although melanopsin and cone photoresponses can be mediated via separate pathways, the connectivity of melanopsin cells across all levels of the retina enables them to modify cone signals. The downstream effects of melanopsin-cone interactions on human vision are however, incompletely understood. Here, we determined how the change in daytime melanopsin activation affects the human cone pathway signals in the visual cortex. A 5-primary silent-substitution method was developed to evaluate the dependence of cone-mediated signals on melanopsin activation by spectrally tuning the lights and stabilizing the rhodopsin activation under a constant cone photometric luminance. The retinal (white noise electroretinogram) and cortical responses (visual evoked potential) were simultaneously recorded with the photoreceptor-directed lights in 10 observers. By increasing the melanopsin activation, a reverse response pattern was observed with cone signals being supressed in the retina by 27% (p = 0.03) and subsequently amplified by 16% (p = 0.01) as they reach the cortex. We infer that melanopsin activity can amplify cone signals at sites distal to retinal bipolar cells to cause a decrease in the psychophysical Weber fraction for cone vision.

Tailoring nano-heterogeneity to enhance magnetostriction in Goss grain-oriented Fe81Ga19 alloy thin sheets by aging treatment

The magnetostriction of Fe–Ga thin sheets can be significantly improved by secondary recrystallization, but the effect of the nano-heterogeneity on the magnetostriction of Fe–Ga thin sheets with preferred texture is still an open question. This paper studies the feasibility of tailoring nano-heterogeneity to enhance the magnetostriction of <001>-oriented Fe–Ga thin sheets by aging treatment. The secondary recrystallization of Goss ({110}<001>) texture with magnetostriction of 220 ± 12 ppm is achieved in Fe81Ga19 thin sheets after annealing at 950 °C. The magnetostriction and magnetic properties exhibit nonlinear changes with the increase of aging temperature. A peak magnetostriction of 244 ± 5 ppm is obtained in Fe81Ga19 thin sheets after aging at 450 °C, about 11% more than that of Fe–Ga thin sheets after secondary recrystallization. The effect of aging treatment on the magnetostriction of Fe–Ga thin sheets depends on the characteristics of the nano-scale L60 phase and causes lattice distortion. The increase of the volume fraction of the nano-scale L60 phase at the aging temperature of 450 °C leads to a much larger distortion and enhancement of the magnetostriction. As the aging temperature is lower than 400 °C or higher than 550 °C, the decrease of volume fraction or the coarsening of L60 phases, respectively, results in the decrease in the distortion of the A2 matrix.

Pinwheel Outflow Induced by Stellar Mass Loss in a Coplanar Triple System

We develop a physical framework for interpreting complex circumstellar patterns whorled around asymptotic giant branch (AGB) stars by investigating stable, coplanar triple systems using hydrodynamic and particle simulations. The introduction of a close tertiary body causes an additional periodic variation in the orbital velocity and trajectory of the AGB star. As a result, the circumstellar outflow builds a fine non-Archimedean spiral pattern superimposed upon the Archimedean spiral produced by the outer binary alone. This fine spiral can be approximated by off-centered circular rings that become tangent to each other at the location of the Archimedean spiral. The superimposed fine pattern fades out relatively quickly as a function of distance from the center of the system, in contrast to the dominant Archimedean spiral pattern, which presents a much slower fractional density decrease with radius. The different rates of radial decrease of the density contrast in the two superimposed patterns, coupled with their different time and spatial scales, lead to an apparent, but illusory radial change in the observed pattern interval, as has been reported, for example, in CW Leo. The function describing the detailed radial dependence of the expansion velocity is different in the two patterns, which may be used to distinguish them. The shape of the circumstellar whorled pattern is further explored as a function of the orbital eccentricity and the inner companion’s mass. Although this study is confined to stable, coplanar triple systems, the results are likely applicable to moderately noncoplanar systems and open interesting avenues for studying noncoplanar systems.