bluuebunny/crossref_metadata_2025 huggingface dataset:
An augmented diffusion algorithm with bidirectional communication for a distributed active noise control system
Authors: Li Tianyou , Rao Li , Zhao Sipei , Duan Hongji , Lu Jing , Burnett Ian S.
Published: December 2023

Recent studies on diffusion adaptation for distributed active noise control (DANC) systems have attracted significant research interest due to their balance between computational burden and stability compared to conventional centralized and decentralized adaptation schemes. The conventional multitask diffusion FxLMS algorithm assumes that the converged solutions of all control filters are consistent to each other, which is unrealistic in practice hence results in inferior performance in noise reduction. An augmented diffusion FxLMS algorithm has been proposed to overcome this problem, which adopts a neighborhood-wide adaptation and node-based combination approach to mitigate the bias in the converged solution of the multitask diffusion algorithms. However, the improvement comes at the expense of a higher computational burden and communication cost. All existing DANC systems, including the multitask and augmented diffusion algorithms, assume one-way communication between nodes. By contrast, this paper proposes a bidirectional communication scheme for the augmented diffusion algorithm to further reduce the memory requirement, computational burden, and communication cost. Simulation results in the free field and with measured room impulse responses both demonstrate that the proposed augmented diffusion algorithm with bidirectional communication can achieve a faster convergence speed than that based on one-way communication with a lower memory, computation, and communication burden.
Quantifying uniaxial prestress and waveguide effects on dynamic elastography estimates for a cylindrical rod
Authors: Salehabadi Melika , Nammari Lara , Luna Aime , Crutison Joseph , Klatt Dieter , Royston Thomas J.
Published: December 2023

Dynamic elastography attempts to reconstruct quantitative maps of the viscoelastic properties of materials by noninvasively measuring mechanical wave motion in them. The target motion is typically transversely-polarized relative to the wave propagation direction, such as bulk shear wave motion. In addition to neglecting waveguide effects caused by small lengths in one dimension or more, many reconstruction strategies also ignore nonzero, non-isotropic static preloads. Significant anisotropic prestress is inherent to the functional role of some biological materials of interest, which also are small in size relative to shear wavelengths in one or more dimensions. A cylindrically shaped polymer structure with isotropic material properties is statically elongated along its axis while its response to circumferentially-, axially-, and radially-polarized vibratory excitation is measured using optical or magnetic resonance elastography. Computational finite element simulations augment and aid in the interpretation of experimental measurements. We examine the interplay between uniaxial prestress and waveguide effects. A coordinate transformation approach previously used to simplify the reconstruction of un-prestressed transversely isotropic material properties based on elastography measurements is adapted with partial success to estimate material viscoelastic properties and prestress conditions without requiring advanced knowledge of either.
Genetically engineered transfusable platelets using mRNA lipid nanoparticles
Authors: Leung Jerry , Strong Colton , Badior Katherine E. , Robertson Madelaine , Wu Xiaowu , Meledeo Michael A. , Kang Emma , Paul Manoj , Sato Yusuke , Harashima Hideyoshi , Cap Andrew P. , Devine Dana V. , Jan Eric , Cullis Pieter R. , Kastrup Christian J.
Published: December 2023

Platelet transfusions are essential for managing bleeding and hemostatic dysfunction and could be expanded as a cell therapy due to the multifunctional role of platelets in various diseases. Creating these cell therapies will require modifying transfusable donor platelets to express therapeutic proteins. However, there are currently no appropriate methods for genetically modifying platelets collected from blood donors. Here, we describe an approach using platelet-optimized lipid nanoparticles containing mRNA (mRNA-LNP) to enable exogenous protein expression in human and rat platelets. Within the library of mRNA-LNP tested, exogenous protein expression did not require nor correlate with platelet activation. Transfected platelets retained hemostatic function and accumulated in regions of vascular damage after transfusion into rats with hemorrhagic shock. We expect this technology will expand the therapeutic potential of platelets.
Threefold reduction of modeled uncertainty in direct radiative effects over biomass burning regions by constraining absorbing aerosols
Authors: Zhong Qirui , Schutgens Nick , van der Werf Guido R. , Takemura Toshihiko , van Noije Twan , Mielonen Tero , Checa-Garcia Ramiro , Lohmann Ulrike , Kirkevåg Alf , Olivié Dirk J. L. , Kokkola Harri , Matsui Hitoshi , Kipling Zak , Ginoux Paul , Le Sager Philippe , Rémy Samuel , Bian Huisheng , Chin Mian , Zhang Kai , Bauer Susanne E. , Tsigaridis Kostas
Published: December 2023

Absorbing aerosols emitted from biomass burning (BB) greatly affect the radiation balance, cloudiness, and circulation over tropical regions. Assessments of these impacts rely heavily on the modeled aerosol absorption from poorly constrained global models and thus exhibit large uncertainties. By combining the AeroCom model ensemble with satellite and in situ observations, we provide constraints on the aerosol absorption optical depth (AAOD) over the Amazon and Africa. Our approach enables identification of error contributions from emission, lifetime, and MAC (mass absorption coefficient) per model, with MAC and emission dominating the AAOD errors over Amazon and Africa, respectively. In addition to primary emissions, our analysis suggests substantial formation of secondary organic aerosols over the Amazon but not over Africa. Furthermore, we find that differences in direct aerosol radiative effects between models decrease by threefold over the BB source and outflow regions after correcting the identified errors. This highlights the potential to greatly reduce the uncertainty in the most uncertain radiative forcing agent.
Early life adversity shapes social subordination and cell type–specific transcriptomic patterning in the ventral hippocampus
Authors: Kos Aron , Lopez Juan Pablo , Bordes Joeri , de Donno Carlo , Dine Julien , Brivio Elena , Karamihalev Stoyo , Luecken Malte D. , Almeida-Correa Suellen , Gasperoni Serena , Dick Alec , Miranda Lucas , Büttner Maren , Stoffel Rainer , Flachskamm Cornelia , Theis Fabian J. , Schmidt Mathias V. , Chen Alon
Published: December 2023

Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type–specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type–specific vulnerability to ELA.
Listen to your gut: Antibodies against gut commensals predict type 1 diabetes onset and therapeutic responses to T cell modulation
Authors: Clark Rachael A.
Published: December 2023

Immune responses to gut bacteria are associated with development of type 1 diabetes and predict the effectiveness of teplizumab, an anti-CD3 antibody, in delaying diabetes onset.
Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the
vastus lateralis
(lateral thigh) muscles of healthy adult participants
Authors: Han Kelong , Gevorkyan Hakop , Sadik Shaik Jafar , Crauwels Herta , Leemereise Claudia , Bontempo Gilda , Win Beta , Chounta Vasiliki , Seal Ciara , DeMoor Rebecca , D'Amico Ronald , Spreen William R. , Ford Susan L.
Published: December 2023

Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The
vastus lateralis
(lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth,
n
= 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m
2
. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.
Diagnostic performance of real-time quantitative PCR in tear samples in various subtypes of herpes simplex keratitis
Authors: Hoarau Gautier , Haigh Oscar , Vauloup-Fellous Christelle , Boucher Rafaël , Rouquette Alexandra , Faure Pascale , Limam Lamia , Labetoulle Marc , Rousseau Antoine
Published: December 2023

Diagnosis of herpes simplex keratitis (HSK) is mostly based on clinical findings, yet biological confirmation supports management of challenging cases. This study evaluated the place of real-time quantitative PCR (RT-qPCR) on tear samplings in the management of HSK. Clinical records of patients who underwent tear sampling tested by RT-qPCR for herpes simplex virus type 1 for an acute episode of corneal inflammation or defect between January 2013 and December 2021 were retrospectively reviewed, and results were compared to clinical diagnosis (i.e., HSK or not) based on biomicroscopic findings and medical history. Of 465 tested tear samples from 364 patients, a clinical diagnosis of active (ongoing) HSK was recorded in 240 cases, among which 76 were RT-qPCR positive (global sensitivity of 31.6%, specificity of 99.5%). Sensitivity of RT-qPCR was higher in epithelial (97.4%) and stromal keratitis with ulceration (48.7%), compared to other types of HSK (23.5% in keratouveitis, 13.6% in endotheliitis, 11.1% in postherpetic neurotrophic keratopathy, and 8.1% in stromal keratitis without ulceration). The highest viral loads were detected from epithelial and stromal keratitis with ulceration, while in HSK with no epithelial involvement, the viral load detected was 196-fold lower, on average. The proportion of clinically characterized HSK patients with negative tear samples was higher in patients receiving antiviral treatment (
P
< 0.0001). RT-qPCR, performed on tear samples, can help in confirming diagnosis in case of presumed HSK, including clinical forms with no obvious epithelial involvement. The sensitivity of tear sampling is much higher whenever epithelial keratitis is present.
Genetic syndromes associated with congenital heart disease
Authors: Duarte Valeria E , Singh Michael N
Published: December 2023

Congenital heart defects are the most common type of birth defect, affecting 1% of live births. The underlying cause of congenital heart disease is frequently unknown. However, advances in human genetics and genome technologies have helped expand congenital heart disease pathogenesis knowledge during the last few decades. When the cardiac defects are part of a genetic syndrome, they are associated with extracardiac conditions and require multidisciplinary care and surveillance. Some genetic syndromes can have subtle clinical findings and remain undiagnosed well into adulthood. Each syndrome is associated with specific congenital and acquired comorbidities and a particular clinical risk profile. A timely diagnosis is essential for risk stratification, surveillance of associated conditions and counselling, particularly during family planning. However, genetic testing and counselling indications can be challenging to identify in clinical practice. This document intends to provide an overview of the most clinically relevant syndromes to consider, focusing on the phenotype and genotype diagnosis, outcome data, clinical guidelines and implications for care.
Coronary microvascular dysfunction in patients undergoing transcatheter aortic valve implantation
Authors: Scarsini Roberto , Portolan Leonardo , Della Mora Francesco , Fabroni Margherita , Andreaggi Stefano , Mainardi Andrea , Springhetti Paolo , Dotto Alberto , Del Sole Paolo Alberto , Fezzi Simone , Pazzi Sara , Tavella Domenico , Mammone Concetta , Lunardi Mattia , Pesarini Gabriele , Benfari Giovanni , Ribichini Flavio Luciano
Published: December 2023

Objectives

This study aimed to evaluate the prognostic value of coronary microvascular dysfunction (CMD) at long term after transcatheter aortic valve implantation (TAVI) and to explore its relationship with extravalvular cardiac damage (EVCD). Moreover, we sought to test the correlation between angiography-derived index of microcirculatory resistance (IMRangio) and invasive IMR in patients with aortic stenosis (AS).

Methods

This was a retrospective analysis of the Verona Valvular Heart Disease Registry (Italy) including 250 patients (83 (80–86) years, 53% female) with severe AS who underwent TAVI between 2019 and 2021. IMRangiowas calculated offline using a computational flow model applied to coronary angiography obtained during the TAVI workup. CMD was defined as IMRangio≥30 units.

The primary endpoint was the composite of cardiovascular death and rehospitalisation for heart failure (HF). Advanced EVCD was defined as pulmonary circulation impairment, severe tricuspid regurgitation or right ventricular dysfunction.

The correlation between IMR and IMRangiowas prospectively assessed in 31 patients undergoing TAVI.

Results

The primary endpoint occurred in 28 (11.2%) patients at a median follow-up of 22 (IQR 12–30) months. Patients with CMD met the primary endpoint more frequently than those without CMD (22.9% vs 2.8%, p<0.0001). Patients with CMD were more frequently characterised by advanced EVCD (33 (31.4%) vs 27 (18.6%), p=0.024). CMD was an independent predictor of adverse outcomes (adjusted HR 6.672 (2.251 to 19.778), p=0.001) and provided incremental prognostic value compared with conventional clinical and imaging variables. IMRangiodemonstrated fair correlation with IMR.

Conclusions

CMD is an independent predictor of cardiovascular mortality and HF after TAVI.
Alcohol use disorder in the perioperative period: a summary and recommendations for anesthesiologists and pain physicians
Authors: Lane Olabisi , Ambai Vats , Bakshi Arjun , Potru Sudheer
Published: December 2023

Excessive alcohol consumption and alcohol use disorder (AUD) increase the risk of perioperative morbidity and mortality. Aspiration, malnutrition, coagulopathies, seizures, and hemodynamic alterations are only a few of the major concerns related to acute alcohol intoxication and AUD. There are also numerous physiological effects, changes in medication metabolism and pharmacology, and adverse events related to chronic alcohol consumption. These are all important considerations for the anesthesiologist in the perioperative management of a patient with AUD. Pain perception and thresholds are altered in patients with acute and chronic alcohol use. Medications used to manage AUD symptoms, particularly naltrexone, can have significant perioperative implications. Patients on naltrexone who continue or stop this medication in the perioperative period are at an increased risk for undertreated pain or substance use relapse. This review highlights key considerations for the anesthesiologist and pain physician in the perioperative management of patients with active AUD (or those in recovery). It discusses the effects of acute and chronic alcohol use on pain perception and thresholds, provides guidance on the perioperative management of naltrexone and low-dose naltrexone, and reviews a multimodal approach to pain management.
On the slice genus of generalized algebraic knots
Authors: Marchwicka Maria , Politarczyk Wojciech
Published: December 2023

We give examples of a linear combination of algebraic knots and their mirrors that are algebraically slice, but whose topological and smooth four-genus is two. Our examples generalize an example of non-slice algebraically slice linear combination of iterated torus knots obtained by Hedden, Kirk and Livingston. Our main tool is a genus bound from Casson–Gordon theory and a cabling formula that allows us to compute effectively these invariants.
Exploring Technology Opportunities with a Deep Learning-Based Clustering Approach: The Case of Pyrolysis Technology for Recycling Plastic Wastes
Authors: Wang Ming-Yeu
Published: December 2023

With the rapidly changing business environment, the dynamic capability of an enterprise begins with sensing and grasping technology opportunities. Considering that the knowledge gaps between science and technology hinder the exploration of technology opportunities, previous studies proposed methods to extract technology opportunities by identifying the knowledge gaps between science and technology literature. This study improves upon previous methods for identifying knowledge fields contained in the literature by introducing a deep learning-based clustering approach. This study also proposes a way to reduce experts’ workloads in determining gaps in the field between science and technology literature. The key idea of the proposed method is to include technologies other than the technology in question. Additionally, pyrolysis technology can convert plastic wastes into useful materials and is considered a green technology. Therefore, this study applies our improved method to explore the technology opportunities of pyrolysis technology. The results show that our method can effectively identify technology opportunities. In the case of plastic wastes, the results show that recovering carbon fibers from plastic wastes and recycling metals from e-waste plastics are expected to be prevailing technological fields.
Fusion of the 2nd with the 3rd Cervical Vertebrae (C2-C3): A Case Series with Possible Clinical Significance
Authors: Demeneopoulou Eirini , Papa Dorina , Giotas Ilias , Nikolaou Angelos , Tsakotos George , Karampelias Vasilios , Mariolis-Sapsakos Theodore , Filippou Dimitrios , Piagkou Maria
Published: December 2023

Purpose. The current case series describes three cases of fusion between the 2nd cervical vertebra, the axis (C2), and the 3rd cervical vertebra (C3), creating a C2-C3 osseous complex and highlighting its morphological type of fusion (partial or complete) and morphometric details. The developmental background of this complex is emphasized, pointing out the possible clinical significance. Materials and Methods. The osseous complexes were derived from disarticulated skeletons of body donors and were collected from the osseous collection of the Anatomy Department of the Medical School of the National and Kapodistrian University of Athens. Results. Three blocked vertebral complexes (2 partial and 1 complete C2-C3 osseous masses) were identified. In two cases, the vertebral bodies were partially fused and in one case were completely fused. In the 1st case, the C2-C3 complex had fused spinous processes and distinct transverse processes. Facets were completely fused on the left and partially fused on the right side. In the 2nd case, the C2-C3 complex had partially fused vertebral bodies and distinguishable spinous processes. In the 3rd case, the C2-C3 complex had completely fused vertebral bodies, facets, laminae, and transverse and spinous processes. Conclusions. Among the three (C2-C3) fused osseous complexes, the two were partially and the one was completely ossified. The fused vertebrae were characterized by osteophytic formations (at the dens and C3 area) and osteoporotic lesions. Taking into consideration the C2-C3 fusion, and possible coexisted variants, particular caution should be made in the upper cervical area, to interpret possible neurological manifestations and to reach a safe surgical plan.
Ethnobotanical Study on Medicinal Plants Used by the Local Communities of Ameya District, Oromia Regional State, Ethiopia
Authors: Tadesse Temesgen , Teka Alemtshay
Published: December 2023

In the present study, the diversity of medicinal plants and associated traditional medicinal knowledge of the rural community in the Ameya district in Ethiopia was assessed and documented. A survey was conducted through semistructured interviews, guided field walks, focus group discussions, and field observations. The snowball and purposeful sampling techniques were employed to select general and knowledgeable informants, respectively. Accordingly, a total of 210 respondents, 156 (74.3%) males and 54 (25.7%) females, were participated in this study. The informants were selected from seven kebeles (the lowest administrative units) following the recommendations of the local community for the availability of traditional medicinal plant use practice. Descriptive statistics, preference ranking, fidelity level, informant consensus factor, and direct matrix ranking were used to analyze and present the data. A total of 78 medicinal plants represented in 70 genera and 40 families were identified. Croton macrostachyus and Dodonaea viscosa were the most preferred species used to treat wounds, whereas Cucumis ficifolius and Phragmanthera macrosolen were the most popular species applied to treat stomachache. Leaves (38%) and roots (20%) were the most predominantly used plant parts for remedial preparation to treat 42 human ailments. The informant consensus factor (ICF) value ranged between 0.45 and 0.81, with the respiratory diseases category scoring the highest ICF value. The fidelity level (FL) value for the medicinal plants ranged from 24 to 95%. Considerable proportions (55.5%) of the medicinal plants were collected from wild habitats. Higher ICF (0.81) and FL (>90%) scores indicate the presence of rich traditional knowledge in the community. This knowledge can be used to select medicinal plants (such as Croton macrostachyus, Cucumis ficifolius, Dodonaea viscosa, and Phragmanthera macrosolen) for further pharmacological and phytochemical studies.
A Novel Approach towards Assessing the Impact of Air Quality and Major Public Health Emergencies on Light Industry: A Multiscale Investigation towards Improving the Risk Prevention System
Authors: Su Fang , Song Nini , Shang Haiyang , Fahad Shah
Published: December 2023

Measuring the systemic impact of major public health emergencies on the light industry and preventing various uncertain future external risks have become the key challenges to ensuring the stability of the light industry. This paper takes the occurrence of major public health emergencies as the background and focuses on environmental issues such as air pollution and indoor air quality degradation during emergencies. And to explore the multiscale impact of major public health emergencies on the light industry, typical light industry subsectors, and light industry enterprises. The findings of our study reveal that major public health emergencies have a negative impact on the light industry, particularly in the form of a short-term decline in exports, which tends to converge in the long run. Further, it is also revealed that there is heterogeneity in the impact on environmentally sensitive industries, labor-intensive industries, and others. At the microfirm level, major public health emergencies have shown a negative effect, especially the recent pandemic, which has a longer duration and a wider reach. Through multiscale research, this paper provides policy suggestions to improve the macrogovernance mechanism and risk prevention system for the light industry.
Figure 5 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , Carnevalli Larissa S.
Published: December 2023

Enhanced efficacy of camizestrant in combination with PI3K/AKT/mTOR inhibitors as doublets in CDK4/6-sensitive and -resistant models (1). A–D, Combination of camizestrant with PI3Kα inhibitor alpelisib (A), mTOR inhibitor everolimus (B), AKT inhibitor capivasertib (C), or CDK4/6 inhibitor palbociclib (D) delivers enhanced efficacy compared with monotherapy in D538G ESR1m PDX CTC-174. Statistical analysis was performed by one-tailed, unequal variance t test versus log (change in tumor volume) compared with vehicle control at the final day of treatment. E, Relative tumor volume plots of ST3632 PDX model treated with oral camizestrant at 10 mg/kg daily, oral palbociclib at 50 mg/kg daily, and oral abemaciclib 50 mg/kg daily, and with camizestrant + abemaciclib and camizestrant + palbociclib. Statistical analysis was performed by one-tailed, unequal variance t test versus log (change in tumor volume) at the final day of treatment. F,In vivo combination of camizestrant at 10 mg/kg daily with palbociclib 50 mg/kg, abemaciclib 50 mg/kg, and capivasertib 130 mg/kg in PDX ST1799 dosed for 40 days (gray area). For clarity, the graph is divided into four subgraphs due to the large number of treatment arms; where they appear, the vehicle, camizestrant, and palbociclib arms are the same in each subgraph. CDK, cyclin-dependent kinase. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, not significant.
Figure 1 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , S Carnevalli Larissa
Published: December 2023

Camizestrant (AZD9833) is a selective ER degrader and pure antagonist. A, Chemical structure of camizestrant. B, The indicated cell lines were treated with 100 nmol/L of the indicated compound for 48 hours. Levels of ERα were assessed by Western blotting and normalized to an untreated control and fulvestrant. Each point represents an independent experiment. C, MCF7 or CAMA-1 cells were treated with DMSO, 1 nmol/L estradiol, or 100 nmol/L of the indicated compound + 1 nmol/L estradiol for 24 hours. RNA expression was assessed by RNA sequencing. Data represent z-scores of normalized gene expression for genes in an ER activity signature. D, MCF7 and CAMA-1 cells were treated with the indicated concentration of the indicated compound for 7 days. Cell number was estimated with a Sytox Green assay normalized to an untreated control on the day of treatment (0.0) and an untreated control on day 7 after treatment (1.0). Data points represent the mean from three independent experiments performed in triplicate ± SD. E, Ishikawa cells were treated with the indicated concentration of fulvestrant or camizestrant, or 100 nmol/L AZD9496 for 24 hours, and ERα and PgR expressions were determined by Western blot. DMSO, dimethyl sulfoxide; PR, progesterone receptor.
Data from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , Carnevalli Larissa S.
Published: December 2023

Abstract
Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor–positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER–co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.
Significance:
Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Abstract A011: NRBF2 induces radioresistance by increasing autophagy mediated metabolite replenishment in glioblastoma
Authors: Shin Eunguk , Kang Hyunkoo , Lee Haksoo , Youn BuHyun
Published: December 2023

Glioblastoma (GBM) is the most lethal brain tumor. Despite the standard of care using radiotherapy and temozolomide, the 5-year recurrence rate of GBM after the treatments is nearly 90% and, notably, about 80% of GBM recurrences occur within radiation treatment fields. Cancer cells possess dynamical metabolic reprogramming to evade cancer therapy and promote their survival. For enhancing metabolic reprogramming and metabolic plasticity, cancer cells need diverse metabolic fuel sources. In this study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon ionizing radiation (IR) treatment on GBM cells. Nuclear receptor binding factor 2 (NRBF2), which is a positive regulator of the autophagy initiation step, was found to be upregulated in a GBM cells and GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. To inhibit NRBF2 mediated GBM radioresistance, we found that druggable inhibition with lidoflazine, thereby suppressing IR-induced migration, invasion, proliferation, autophagic flux and improving the survival of orthotopic GBM-bearing mice. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy. [This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00207904).]

Citation Format: Eunguk Shin, Hyunkoo Kang, Haksoo Lee, BuHyun Youn. NRBF2 induces radioresistance by increasing autophagy mediated metabolite replenishment in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A011.
Abstract A012: Role of STX1A in mediating Cathepsin G’s entry into human colorectal cancer cells
Authors: Rozen Valery , Wang Yuxiang , Wang Zhenghe
Published: December 2023

Neutrophils with anti-tumor potential have the capability to kill cancer cells in a contact-dependent manner. It has been reported that Cathepsin G (CG), a serine protease mainly expressed in neutrophils, aids in the targeting of cancer cells. Nevertheless, the molecular mechanisms underlying NETosis released CG remain unexplored. This study aims to focus attention on the prospective mechanisms that could offer soluble CG the potential to kill cancer cells. Our previous CRISPR knockout (KO) screen targeting membrane trafficking found that several KO genes, including STX1A, suppress CG’s induced apoptosis in cancer cells, indicating its role in assisting CG cell entry. Based on the results, special attention was directed towards STX1A and its effect on CG’s role in anti-cancer activity. This project aims to address the molecular mechanisms underlying CG induced apoptosis in cancer cells. Via a better understanding of the mediators that promote CG entry into cells, we intent to call attention to beneficial effects modulated by CG in the tumorigenic environment. STX1A KO HCT116 cells were generated via the use of a lentivrus, and protein levels in these cells as well as in wild type HCT116 were determined. Immunofluorescence (IF) was utilized to visualize the localization of CG in both cell types. Our preliminary results show decreased CG signals in HCT116 STX1A KO cells treated with CG compared to control, calling attention to a likely role mediated by STX1A involving CG’s entry into cancer cells. Confirming our hypothesis can have beneficial implications in innovative  therapeutic approaches targeting colorectal carcinoma and possibly other types of cancer.

Citation Format: Valery Rozen, Yuxiang Wang, Zhenghe Wang. Role of STX1A in mediating Cathepsin G’s entry into human colorectal cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A012.
Abstract A029: Identification of cancer-specific CPP from human telomerase peptide library and its drug delivery potential in anti-cancer strategy
Authors: Lee Yoon Seon , Lee Myung Jin , Shon Won Jun
Published: December 2023

A reverse-transcriptase-subunit of telomerase (hTERT) derived peptide has been identified as a cell-penetrating peptide (CPP) in our previous study. This hTERT derived CPP was delivered into a variety of cells including various cancer cell lines and primary blood cells. Moreover, the CPP was predominantly located in the cytoplasm of the cells, while a significantly higher proportion of TAT peptide was localized in the nucleus. In order to reduce adverse non-specific toxic side effects of current anticancer drug, we developed cancer-specific anticancer drug delivery system using hTERT derived CPP. The cell penetrating activity was Pep 98, a specific hTERT derived CPP, was evaluated in head and neck cancer cells. The permeability of specific telomerase derived Pep 98-FITC into cancer cells was 20-300 fold higher than control peptide groups in head and neck cancer cells. These result suggest that pep98 can be used to reduce the side effects and increase the efficacy of cancer therapy through the use of specific anticancer drug delivery system.We conjugated Pep 98 with STAT 3 inhibitor (NSC74859) which has been presented as a molecular therapeutic target for head and neck cancer and evaluated concentration of NSC74589 for anti-cancer activity in head and neck cancer cell line. The result showed that the concentration of Pep-98 conjugated NSC74589 could be reduced up to 1/10-20 dose level compared with NSC74589 alone in head and neck cancer cells. Pep 98-NSC74859 conjugates were found to be capable of specific killing head and neck cancer cells without affecting normal fibroblast cells.We have confirmed the possibility of developing a new head neck cancer anticancer drug with improved therapeutic efficacy through the conjugation of the STAT3 inhibitor with hTERT derived peptide.

Citation Format: Yoon Seon Lee, Myung Jin Lee, Won Jun Shon. Identification of cancer-specific CPP from human telomerase peptide library and its drug delivery potential in anti-cancer strategy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A029.
Abstract A044: The discovery of potent KAT6 inhibitors that demonstrate anti-tumor activity in preclinical models of ER+ breast cancer
Authors: Palanisamy Gopinath S. , Venkateshappa Chandregowda , Goyal Megha , Barratt Susanna A. , Hearn Brian R. , Daginakatte Girish , B Aravind A , S Samiulla D , Bera Kalisankar , S Sangeetha , Khare Leena , Parisian Alison D. , Heerding Dirk A. , Ng Raymond A. , Harmon Cyrus L. , Samajdar Susanta , Ramachandra Murali , Myles David C.
Published: December 2023

KAT6 paralogs KAT6A (MOZ; MYST3) and KAT6B (MORF; MOZ2; MYST4) are histone acetyltransferase (HAT) enzymes that acetylate histone H3 and thereby epigenetically regulate gene transcription by altering chromatin structure. Dysregulation of KAT6 activity (gene amplification, overexpression, fusion, mutation, etc.) is observed in breast and other cancers. In several subtypes of breast cancer, KAT6A is amplified as part of the 8p11-p12 amplicon and/or is overexpressed in 11 to 15% of overall breast cancer population. Overexpression of KAT6 correlates with worse clinical outcome in ER+/HER2− breast cancers. Here we present the discovery of novel and potent KAT6 inhibitors with robust in vitro and in vivo anti-tumor efficacy and high selectivity against other KAT family members KAT5 and KAT8. Our lead KAT6 inhibitor compounds demonstrate strong anti-proliferative effects in ER positive breast cancer cell lines with KAT6 dysregulation while demonstrating robust target engagement biomarker activity (inhibition of histone H3 acetylation at lysine residue 23). In addition, these compounds exhibit desirable ADME and pharmacokinetic properties including good oral bioavailability in tested species, supporting potential once daily dosing in humans. The lead compounds also demonstrate enhanced in vitro cellular efficacy in breast cancer cell lines when combined with OP-1250, a complete ER antagonist (CERAN), and CDK4/6 inhibitors, illustrating their combination potential. In addition, these lead compounds demonstrate excellent dose-dependent anti-tumor activity resulting in tumor growth inhibition and tumor regression in a KAT6A amplified ER+ breast cancer xenograft model, highlighting their potential as a novel therapy in ER+ breast cancer. Additional nonclinical efficacy testing, and safety profiling of these lead compounds is currently underway to select a clinical candidate.

Citation Format: Gopinath S. Palanisamy, Chandregowda Venkateshappa, Megha Goyal, Susanna A. Barratt, Brian R. Hearn, Girish Daginakatte, Aravind A B, Samiulla D S, Kalisankar Bera, Sangeetha S, Leena Khare, Alison D. Parisian, Dirk A. Heerding, Raymond A. Ng, Cyrus L. Harmon, Susanta Samajdar, Murali Ramachandra, David C. Myles. The discovery of potent KAT6 inhibitors that demonstrate anti-tumor activity in preclinical models of ER+ breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A044.
Abstract A056: Treatment with dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 ablates tumor-associated androgen response elements (AREs) in prostate cancer
Authors: Sandoval Gabriel J , Centore Richard C , Topal Sal , Lahr Dave , Elliott GiNell , Gandevia Heena , Adam Ammar , Piel Jessica , Nguyen Holly M , Corey Eva , Chen Yu , Bellon Steven , Hentemann Murphy
Published: December 2023

The Androgen Receptor (AR) cistrome is critical in the development of prostate cell identity while its misregulation promotes prostate cancer development. The pioneer transcription factor Forkhead box A1 (FOXA1) has been shown to be essential for the recruitment of AR to androgen response elements (AREs) allowing for reprogramming of the AR cistrome resulting in prostate cell transformation. FHD-286 is a BRM/BRG1 dual ATPase inhibitor currently in clinical trials for AML. Here, we show that treatment of prostate cancer cell lines with FHD-286 results in ablation of FOXA1 mediated AREs at tumor-associated AR binding sites (T-ARBS). Dual ATPase treatment subsequently reduces the expression level of various oncogenic AR target genes, leading to a decrease in tumor cell viability. Both patient derived organoid and In vivo studies provide further validation by showing a decrease in tumor growth. Strikingly, inhibition of BAF complex activity bypasses AR resistance mechanisms commonly seen after castration and Enzalutamide treatment as cell lines containing AR-V7 splice variants and neuroendocrine organoids display sensitivity. Taken together, our data illustrates a novel mechanism of treating AR mediated prostate cancer though the inhibition tumor associated AREs by treatment with FHD-286.

Citation Format: Gabriel J Sandoval, Richard C Centore, Sal Topal, Dave Lahr, GiNell Elliott, Heena Gandevia, Ammar Adam, Jessica Piel, Holly M Nguyen, Eva Corey, Yu Chen, Steven Bellon, Murphy Hentemann. Treatment with dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 ablates tumor-associated androgen response elements (AREs) in prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A056.
Abstract A057: Small molecule microarray screening identifies novel androgen receptor ligands
Authors: Kobylarz Marek J , Shum Michelle G , Glore Wayne L , Saffren Ava , Carpenter Shannon , Pingili Mulini , Clay Andrew , Hopkins Tamara D , Gao Hua , Schinzel Anna C , Pop Marius S , Obholzer Nikolaus D , Freeman David B , Dinsmore Christopher J , Trotter Benjamin W , Lin Charles Y , Rahl Peter B
Published: December 2023

The androgen receptor (AR) is a well-established oncogenic driver of prostate cancer, and AR-targeting hormone therapy has proven an efficacious treatment option for patients with metastatic prostate cancer. Due to the importance of AR in prostate cancer disease progression, we leveraged small molecule microarray (SMM) screening technology to identify compounds that bind to transcriptional complexes of a common AR splice-variant, AR-V7, present along with AR in castration-resistant prostate cancer cell lysates. A subset of SMM hits were identified to modulate the AR Transcription Regulatory Network (TRN) in hormone-sensitive, but not castration-resistant prostate cancer models using a functional cell-based transcription signature approach. Several AR SMM hits directly engaged the AR ligand binding domain in a biophysical assay. One of these AR SMM hits altered AR nuclear translocation and antagonized steroid receptor co-activator recruitment to AR but did not antagonize the glucocorticoid receptor. Leveraging structural data for known AR ligands, we propose a computational model for binding of this molecule to the known AR ligand binding domain. Together, the data demonstrates that the AR SMM lysate screen successfully identified structurally novel small molecules that modulate the AR TRN and bind the AR ligand binding domain.

Citation Format: Marek J Kobylarz, Michelle G Shum, Wayne L Glore, Ava Saffren, Shannon Carpenter, Mulini Pingili, Andrew Clay, Tamara D Hopkins, Hua Gao, Anna C Schinzel, Marius S Pop, Nikolaus D Obholzer, David B Freeman, Christopher J Dinsmore, Benjamin W Trotter, Charles Y Lin, Peter B Rahl. Small molecule microarray screening identifies novel androgen receptor ligands [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A057.