bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of Nonstationary Stochastic Response of Linear Oscillators With Fractional Derivative Elements of Rational Order
Authors: Di Matteo Alberto , Spanos Pol D.
Published: December 2023

In this paper, a technique is developed for determining the nonstationary response statistics of linear oscillators endowed with fractional derivative elements. Notably, fractional operators are particularly effective in modeling solid mechanics problems as they offer the option of influencing both the elasticity and the energy dissipation capacity of the system. In this paper, particular attention is devoted to the case of fractional derivatives of rational order that approximates reasonably well any real order model. The oscillators are subjected to stationary stochastic excitations, and the pertinent nonstationary response statistical moments are determined by first introducing a finite number of oscillator response related states; this is afforded by the rational number order of the fractional operator. Next, the technique involves proceeding to treating the problem in the Laplace transform domain. This leads to multiple convolution integrals determined by representing the transfer function of the oscillator in a partial fraction form by a pole-residue formulation. In this manner, the response evolutionary power spectral density of the fractional oscillator is derived in a closed form, while nonstationary second-order statistics can be obtained by mundane numerical integration in the frequency domain. Applications to oscillators comprising one or two fractional derivative elements are presented, considering the case of a white noise excitation and of a random process possessing the classical Kanai–Tajimi spectrum. Reliability of the developed technique is assessed by juxtaposing its analytical results with pertinent Monte Carlo simulation data.
Synthesizing Negative-Imaginary Systems With Closed-Loop H∞-Performance Via Static Output Feedback Control
Authors: Behera Pravin , Dey Arnab , Patra Sourav
Published: December 2023

This paper develops an algorithm for synthesizing negative imaginary (NI) systems with a specified H∞-norm bound by exploiting the convex relaxation technique in the static output-feedback (SOF) control design framework. This scheme improves the robustness objective since the present framework can handle both NI and H∞-norm-bounded unstructured uncertainty of the system. The non-strict inequality involved in the NI system description that creates a major difficulty in the SOF control design, can efficiently be tackled by the developed convex relaxation-based iterative algorithm. The advantages of the algorithm are shown using several examples and the results are compared with the existing works.
REVIEWS OF ACOUSTICAL PATENTS
Authors: Fulop Sean A.
Published: December 2023

The purpose of these acoustical patent reviews is to provide enough information for a Journal reader to decide whether to seek more information from the patent itself. Any opinions expressed here are those of the reviewers as individuals and are not legal opinions. Patents are available via the internet at the USPTO website.
Subsecond fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans
Authors: Sands L. Paul , Jiang Angela , Liebenow Brittany , DiMarco Emily , Laxton Adrian W. , Tatter Stephen B. , Montague P. Read , Kishida Kenneth T.
Published: December 2023

In the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions. This hypothesis (and alternatives regarding dopamine’s role in punishment-learning) has limited direct evidence in humans. We report intracranial, subsecond measurements of dopamine release in human striatum measured, while volunteers (i.e., patients undergoing deep brain stimulation surgery) performed a probabilistic reward and punishment learning choice task designed to test whether dopamine release encodes only reward prediction errors or whether dopamine release may also encode adaptive punishment learning signals. Results demonstrate that extracellular dopamine levels can encode both reward and punishment prediction errors within distinct time intervals via independent valence-specific pathways in the human brain.
Effects of error, chimera, bias, and GC content on the accuracy of amplicon sequencing
Authors: Qin Yujia , Wu Liyou , Zhang Qiuting , Wen Chongqin , Van Nostrand Joy D. , Ning Daliang , Raskin Lutgarde , Pinto Ameet , Zhou Jizhong
Published: December 2023

Targeted amplicon sequencing is widely used in microbial ecology studies. However, sequencing artifacts and amplification biases are of great concern. To identify sources of these artifacts, a systematic analysis was performed using mock communities comprised of 16S rRNA genes from 33 bacterial strains. Our results indicated that while sequencing errors were generally isolated to low-abundance operational taxonomic units, chimeric sequences were a major source of artifacts. Singleton and doubleton sequences were primarily chimeras. Formation of chimeric sequences was significantly correlated with the GC content of the targeted sequences. Low-GC-content mock community members exhibited lower rates of chimeric sequence formation. GC content also had a large impact on sequence recovery. The quantitative capacity was notably limited, with substantial recovery variations and weak correlation between anticipated and observed strain abundances. The mock community strains with higher GC content had higher recovery rates than strains with lower GC content. Amplification bias was also observed due to the differences in primer affinity. A two-step PCR strategy reduced the number of chimeric sequences by half. In addition, comparative analyses based on the mock communities showed that several widely used sequence processing pipelines/methods, including DADA2, Deblur, UCLUST, UNOISE, and UPARSE, had different advantages and disadvantages in artifact removal and rare species detection. These results are important for improving sequencing quality and reliability and developing new algorithms to process targeted amplicon sequences.

IMPORTANCE

Amplicon sequencing of targeted genes is the predominant approach to estimate the membership and structure of microbial communities. However, accurate reconstruction of community composition is difficult due to sequencing errors, and other methodological biases and effective approaches to overcome these challenges are essential. Using a mock community of 33 phylogenetically diverse strains, this study evaluated the effect of GC content on sequencing results and tested different approaches to improve overall sequencing accuracy while characterizing the pros and cons of popular amplicon sequence data processing approaches. The sequencing results from this study can serve as a benchmarking data set for future algorithmic improvements. Furthermore, the new insights on sequencing error, chimera formation, and GC bias from this study will help enhance the quality of amplicon sequencing studies and support the development of new data analysis approaches.
Diverse domain architectures of CheA histidine kinase, a central component of bacterial and archaeal chemosensory systems
Authors: Berry Marissa A. , Andrianova Ekaterina P. , Zhulin Igor B.
Published: December 2023

Chemosensory systems in bacteria and archaea are complex, multi-protein pathways that enable rapid cellular responses to environmental changes. The CheA histidine kinase is a central component of chemosensory systems. In contrast to other histidine kinases, it lacks a sensor (input) domain and utilizes dedicated chemoreceptors for sensing. CheA is a multi-domain protein; in model organisms as diverse as
Escherichia coli
and
Bacillus subtilis
, it contains five single-copy domains. Deviations from this canonical domain architecture have been reported, however, a broad genome-wide analysis of CheA diversity is lacking. Here, we present the results of a genomic survey of CheA domain composition carried out using an unbiased set of thousands of CheA sequences from bacteria and archaea. We found that four out of five canonical CheA domains comprise a minimal functional unit (core domains), as they are present in all surveyed CheA homologs. The most common deviations from a classical five-domain CheA architecture are the lack of a P2/CheY-binding domain, which is missing from more than half of CheA homologs, and the acquisition of a response regulator receiver (CheY-like) domain, which is present in ~35% of CheA homologs. We also document other deviations from classical CheA architecture, including bipartite CheA proteins, domain duplications, and fusions, and reveal that phylogenetically defined CheA classes have pre-dominant domain architectures. This study lays a foundation for a better classification of CheA homologs and identifies targets for experimental investigations.

IMPORTANCE

We found that in contrast to the best-studied model organisms, such as
Escherichia coli
and
Bacillus subtilis
, most bacterial and archaeal species have a CheA protein with a different domain composition. We report variations in CheA architecture, such as domain duplication and acquisition as well as class-specific domain composition. Our results will be of interest to those working on signal transduction in bacteria and archaea and lay the foundation for experimental studies.
Petrogenesis of the early Permian Hongliujing granite complex in the Chinese Eastern Tianshan orogen: Evidence for crustal growth in the Central Tianshan microcontinent
Authors: He Zhen-Yu , Klemd Reiner , Lu Tian-Yu , Yan Li-Li , Xiang Hua
Published: December 2023

The generation and modification of silicic magma systems are essential processes in resolving the differentiation of continental crust. This understanding motivated the geochronological and geochemical study of the early Permian Hongliujing granite complex, consisting of quartz monzonite, granite, and leucogranite in the Central Tianshan microcontinent of the southern Central Asian Orogenic Belt. Laser ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS) zircon U-Pb dating of the Hongliujing complex rock units revealed almost identical ages (279 ± 2 Ma to 270 ± 2 Ma). The high-silica leucogranite and granite are characterized by positive Rb and negative Eu anomalies and Ba, Sr, P, and Ti depletions. The zircon trace elements are characterized by relatively low Ti and Th/U and high Yb/Gd. In contrast, the quartz monzonite and its mafic microgranular enclaves display minor negative Ba, Sr, P, Ti, and Eu anomalies, while the zircon trace elements are characterized by relatively high Ti and Th/U and low Yb/Gd. The complex has similar zircon Hf and whole-rock Nd isotopic compositions, with Hf and Nd model ages younger than 1.4 Ga, suggesting that their magmas were derived from an isotopically depleted mantle, with some contributions from crustal melts. The leucogranites further showed relatively large variations of εHf(t) and lower εNd(t) values, implying that their magma was affected by higher amounts of crustal contamination. We suggest that crystal-melt segregation was the major mechanism responsible for the evolution of the magmatic system, and that the early Permian magmatism represents a crust-forming episode triggered by slab rollback of the subducting South Tianshan oceanic plate beneath the eastern Central Tianshan microcontinent. Thus, our study reveals that microcontinents with Precambrian crustal basement were major sites of juvenile continental growth during the accretionary evolution of the Central Asian Orogenic Belt.
Incremental value of machine learning for risk prediction in tetralogy of Fallot
Authors: Ishikita Ayako , McIntosh Chris , Roche S Lucy , Barron David J , Oechslin Erwin , Benson Lee , Nair Krishnakumar , Lee Myunghyun M , Gritti Michael N , Hanneman Kate , Karur Gauri Rani , Wald Rachel M
Published: December 2023

Objective

Machine learning (ML) can facilitate prediction of major adverse cardiovascular events (MACEs) in repaired tetralogy of Fallot (rTOF). We sought to determine the incremental value of ML above expert clinical judgement for risk prediction in rTOF.

Methods

Adult congenital heart disease (ACHD) clinicians (≥10 years of experience) participated (one cardiac surgeon and four cardiologists (two paediatric and two adult cardiology trained) with expertise in heart failure (HF), electrophysiology, imaging and intervention). Clinicians identified 10 high-yield variables for 5-year MACE prediction (defined as a composite of mortality, resuscitated sudden death, sustained ventricular tachycardia and HF). Risk for MACE (low, moderate or high) was assigned by clinicians blinded to outcome for adults with rTOF identified from an institutional database (n=25 patient reviews conducted by five independent observers). A validated ML model identified 10 variables for risk prediction in the same population.

Results

Prediction by ML was similar to the aggregate score of all experts (area under the curve (AUC) 0.85 (95% CI 0.58 to 0.96) vs 0.92 (0.72 to 0.98), p=0.315). Experts with ≥20 years of experience had superior discriminative capacity compared with <20 years (AUC 0.98 (95% CI 0.86 to 0.99) vs 0.80 (0.56 to 0.93), p=0.027). In those with <20 years of experience, ML provided incremental value such that the combined (clinical+ML) AUC approached ≥20 years (AUC 0.85 (95% CI 0.61 to 0.95), p=0.055).

Conclusions

Robust prediction of 5-year MACE in rTOF was achieved using either ML or a multidisciplinary team of ACHD experts. Risk prediction of some clinicians was enhanced by incorporation of ML suggesting that there may be incremental value for ML in select circumstances.
Prehospital risk assessment and direct transfer to a percutaneous coronary intervention centre in suspected acute coronary syndrome
Authors: Demandt Jesse , Koks Arjan , Sagel Dennis , van Hattem Veerle A E , Haest Rutger J , Heijmen Eric , Thijssen H , Otterspoor Luuk C , van Veghel Dennis , Eerdekens Rob , el Farissi Mohamed , Teeuwen Koen , Wijnbergen Inge , van der Harst Pim , Pijls Nico H J , van 't Veer Marcel , Tonino Pim A L , Dekker Lukas R C , Vlaar Pieter J
Published: December 2023

Objective

Prehospital risk stratification and triage are currently not performed in patients suspected of non-ST-segment elevation acute coronary syndrome (NSTE-ACS). This may lead to prolonged time to revascularisation, increased duration of hospital admission and higher healthcare costs. The preHEART score (prehospital history, ECG, age, risk factors and point-of-care troponin score) can be used by emergency medical services (EMS) personnel for prehospital risk stratification and triage decisions in patients with NSTE-ACS. The aim of the current study was to evaluate the effect of prehospital risk stratification and direct transfer to a percutaneous coronary intervention (PCI) centre, based on the preHEART score, on time to final invasive diagnostics or culprit revascularisation.

Methods

Prospective, multicentre, two-cohort study in patients with suspected NSTE-ACS. The first cohort is observational (standard care), while the second (interventional) cohort includes patients who are stratified for direct transfer to either a PCI or a non-PCI centre based on their preHEART score. Risk stratification and triage are performed by EMS personnel. The primary endpoint of the study is time from first medical contact until final invasive diagnostics or revascularisation. Secondary endpoints are time from first medical contact until intracoronary angiography (ICA), duration of hospital admission, number of invasive diagnostics, number of inter-hospital transfers and major adverse cardiac events at 7 and 30 days.

Results

A total of 1069 patients were included. In the interventional cohort (n=577), time between final invasive diagnostics or revascularisation (42 (17–101) hours vs 20 (5–44) hours, p<0.001) and length of hospital admission (3 (2–5) days vs 2 (1–4) days, p=0.007) were shorter than in the observational cohort (n=492). In patients with NSTE-ACS in need for ICA or revascularisation, healthcare costs were reduced in the interventional cohort (€5599 (2978–9625) vs €4899 (2278–5947), p=0.02).

Conclusion

Prehospital risk stratification and direct transfer to a PCI centre, based on the preHEART score, reduces time from first medical contact to final invasive diagnostics and revascularisation, reduces duration of hospital admission and decreases healthcare costs in patients with NSTE-ACS in need for ICA or revascularisation.

Trial registration

NCT05243485.
Cardiovascular disease risk in patients with inflammatory arthritis nowadays still substantially elevated
Authors: Raadsen Reinder , Hansildaar Romy , Pouw Lianne C , Hooijberg Femke , Boekel Laura , Wolbink Gerrit Jan , van Kuijk Arno W R , Nurmohamed Michael T
Published: December 2023

Objectives

This study aims to assess current cardiovascular disease risk and prevalence of risk factors in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (SpA).

Methods

2050 consecutive patients with inflammatory arthritis (IA) and 939 controls were included, with 1308 patients with RA, 356 patients with PsA and 386 patients with SpA. In a prospective cohort setting, questionnaires regarding previous cardiovascular events and risk factors were used to assess cardiovascular risk and prevalence in patients with IA by calculating ORs using logistic regression models.

Results

‘Traditional’ cardiovascular (CV) risk factors were significantly elevated in patients with IA compared with controls. Cardiovascular disease (CVD) ORs were increased in patients with RA and PsA compared with controls, 1.61 (95% CI: 1.04 to 2.48) and 2.12 (95% CI: 1.23 to 3.66), respectively, and a trend towards increased odds was observed in patients with SpA (OR 1.43; 95% CI: 0.79 to 2.59). After adjusting for traditional risk factors, CV risk was not increased in patients with RA (OR; 0.95, 95% CI: 0.58 to 1.55), PsA (OR 1.19; 95% CI: 0.64 to 2.22) and SpA (OR; 0.91, 95% CI: 0.47 to 1.77).

Conclusion

CVD is currently still more prevalent in patients with IA compared with healthy controls and, more importantly, this elevated risk is highly influenced by an increased prevalence of ‘traditional’ CV risk factors. More attention to, as well as improvements in, identification and treatment of ‘traditional’ risk factors, need to be made for not only RA, but other IA conditions as well.
Lifestyle factors predict gout outcomes: Results from the NOR-Gout longitudinal 2-year treat-to-target study
Authors: Uhlig Till , Karoliussen Lars Fridtjof , Sexton Joseph , Kvien Tore K , Haavardsholm Espen A , Hammer Hilde Berner
Published: December 2023

Objective

Gout is associated with lifestyle, body mass index (BMI) and comorbidities, including dyslipidaemia. We studied how in actively treated patients, anthropometric measures and lipid levels changed over 2 years and whether they predicted gout outcomes.

Methods

Patients with a recent gout flare and elevated serum urate (sUA) received gout education and treat-to-target urate-lowering therapy over 1 year. Anthropometric measures with BMI, waist circumference (WC) and waist–height ratio (WHR) as well as lipid levels were measured yearly over 2 years. We examined whether baseline anthropometric measures and lipid levels were related to flares and to achieving the sUA target.

Results

At baseline, patients (n=211) were with mean age of 56.4 years and 95% were male. Over 2 years, anthropometric measures were largely unchanged while cholesterol and low-density lipoprotein cholesterol (LDL-C) were reduced at year 1. Anthropometric measures were associated with presence of tophi. Higher baseline WC (OR: 0.96 per cm, 95% CI: 0.93 to 0.99) decreased and high level of high-density lipoprotein cholesterol (OR: 5.1 per mmol/L, 95% CI: 1.2 to 22.1) increased the chance of sUA target achievement at year 2. High LDL-C (OR: 1.8 per mmol/L, 95% CI: 1.2 to 2.6) predicted the chance of having a gout flare during year 2.

Conclusion

In actively treated patients with gout, anthropometric measures were largely unchanged over 2 years and lipid levels were reduced. High WC and lipid levels predicted unfavourable gout outcomes after 2 years.
Symptom-related screening programme for early detection of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the SYSPPE study
Authors: Marin-Romero Samira , Ballaz-Quincoces Aitor , Gómez-Cuervo Covadonga , Marchena-Yglesias Pablo Javier , Lopez-Miguel Patricia , Francisco-Albesa Iria , Pedrajas-Navas Jose Maria , Lumbierres Marina , Aibar-Arregui Miguel Angel , Bosco Lopez-Saez Juan , Perez-Pinar Montserrat , Baeza-Martinez Carlos , Riera-Mestre Antoni , Peris-Sifre Marisa , Porras-Ledantes Jose Antonio , Criado-Garcia Juan , Elias-Hernandez Teresa , Otero Remedios , Barca-Hernando Maria , Muriel Alfonso , Klok Frederikus A , Jara-Palomares Luis
Published: December 2023

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long-term complication of acute pulmonary embolism (PE). We aimed to evaluate the impact of a symptom screening programme to detect CTEPH in PE survivors.

Methods

This was a multicentre cohort study of patients diagnosed with acute symptomatic PE between January 2017 and December 2018 in 16 centres in Spain. Patients were contacted by phone 2 years after the index PE diagnosis. Those with dyspnoea corresponding to a New York Heart Association (NYHA)/WHO scale≥II, visited the outpatient clinic for echocardiography and further diagnostic tests including right heart catheterisation (RHC). The primary outcome was the new diagnosis of CTEPH confirmed by RHC.

Results

Out of 1077 patients with acute PE, 646 were included in the symptom screening. At 2 years, 21.8% (n=141) reported dyspnoea NYHA/WHO scale≥II. Before symptom screening protocol, five patients were diagnosed with CTEPH following routine care. In patients with NYHA/WHO scale≥II, after symptom screening protocol, the echocardiographic probability of pulmonary hypertension (PH) was low, intermediate and high in 76.6% (n=95), 21.8% (n=27) and 1.6% (n=2), respectively. After performing additional diagnostic test in the latter 2 groups, 12 additional CTEPH cases were confirmed.

Conclusions

The implementation of this simple strategy based on symptom evaluation by phone diagnosed more than doubled the number of CTEPH cases. Dedicated follow-up algorithms for PE survivors help diagnosing CTEPH earlier.

Trial registration number

NCT03953560.
Lactifluus subg. Lactariopsis (Russulales/Basidiomycota) from Brazilian tropical forests
Authors: Silva-Filho A.G.S. , Sá M.C.A. , Komura D.L. , Braga-Neto R. , Baseia I.G. , Marinho P. , Moncalvo J.-M. , Roy M. , Wartchow F.
Published: December 2023

Lactifluus subg. Lactariopsis is a well-supported group of milkcaps occurring predominantly in tropical and subtropical ecosystems. This subgenus contains agaricoid and pleurotoid representatives and is the only group with members containing a secondary velum. The results of taxonomic and phylogenetic research into Lactifluus subg. Lactariopsis collected in Brazilian tropical forests (Amazon, Atlantic Rainforests, and Caatinga biomes) of the North and Northeast is presented here. Two new species are described: Lf. aurantioceraceus in sect. Neotropici, and Lf. reniformis in sect. Multicipites, newly delimited here . In addition, Lf. neotropicus has had its distribution expanded to the Caatinga biome, Lf. dunensis was confirmed in Lf. sect. Neotropici with new records from French Guiana, and Lf. annulifer was re-collected from the type locality. A combined dataset of nuclear rDNA internal transcribed spacer region and nuclear large subunit amplified sequences was analyzed and, based on its phylogenetic hypothesis, the two novel taxa and the new section were confirmed .
Preventing broken hearts in women with breast cancer: a concise review on chemotherapy-mediated cardiotoxicity
Authors: Bews Hilary J. , Mackic Lana , Jassal Davinder S.
Published: December 2023

Cancer and cardiovascular disease are the leading causes of death for Canadian women. One in eight Canadian women will receive the life-changing diagnosis of breast cancer (BC) in their lifetime, with 1 in 34 dying from the disease. Although doxorubicin (DOX) and trastuzumab (TRZ) have significantly improved survival in women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive BC, approximately one in four women who receive this treatment are at risk of developing chemotherapy-induced cardiotoxicity. Cardiotoxicity is defined as a decline in left ventricular ejection fraction (LVEF) of >10% to an absolute value of <53%. Current guidelines recommend the serial monitoring of LVEF in this patient population using non-invasive cardiac imaging modalities including transthoracic echocardiography or multi-gated acquisition scan; however, this will only allow for the detection of established cardiotoxicity. Recent studies have demonstrated that a reduction in global longitudinal strain by speckle tracking echocardiography can identify pre-clinical systolic dysfunction prior to a decline in overall LVEF. Implementation of early detection techniques would allow for the prompt initiation of cardioprotective strategies. In addition to the early detection of chemotherapy-mediated cardiotoxicity, the prophylactic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, statins, exercise, and nutraceutical therapies have been studied in the setting of cardio-oncology.
3D seismic analysis of Cenozoic slope deposits and fluid-flow phenomena along the Nigerian Transform Margin
Authors: Olobayo Oluwatobi , Huuse Mads
Published: December 2023

3D seismic data provide new insights on
c.
2 km thick Cenozoic post-transform slope sediments and fluid-flow phenomena along the Nigerian Transform Margin. The study documents large-scale mass-transport deposits (MTDs), deep-water channels, sediment waves, and a range of fluid-flow phenomena such as pockmarks, pipes, seabed mound and gas hydrates. They are observed from Pliocene-aged sediments and distributed above structural highs, regional faults, and active and relict deep-water channels in the eastern part of the area, closest to the Niger Delta cone. The fluid-flow features are interpreted to be indicative of an active petroleum system in the deeper subsurface and from fluid migration along planes of deep-seated faults. MTDs are mapped at multiple levels and the volume of failed sediments increased through time within the western part of the study area. The repeated and increased volume of MTDs in the area is attributed to an increased rate of sedimentation through time and slope gradient during the late Cenozoic. The presence of repeated MTDs and fluid-flow phenomena on the Nigerian Transform Margin has implications for installations of offshore facilities as they constitute potential geohazards. The study also documents, for the first time, polygonal fault systems offshore Nigeria.
Parallel Acyclic Joins: Optimal Algorithms and Cyclicity Separation
Authors: Hu Xiao , Tao Yufei
Published: December 2023

We study equi-join computation in the massively parallel computation (MPC) model. Currently, a main open question under this topic is whether it is possible to design an algorithm that can process any join with load
O(N
polylog

N/p
1/ρ*

) — measured in the number of words communicated per machine — where
N
is the total number of tuples in the input relations, ρ
*
is the join’s fractional edge covering number, and
p
is the number of machines. We settle the question in the
negative
for the class of tuple-based algorithms (all the known MPC join algorithms fall in this class) by proving the existence of a join query with ρ
*
= 2 that requires a load of Ω (
N/p
1/3
) to evaluate. Our lower bound provides solid evidence that the “AGM bound” alone is not sufficient for characterizing the hardness of join evaluation in MPC (a phenomenon that does not exist in RAM). The hard join instance identified in our argument is cyclic, which leaves the question of whether
O(N
polylog
N/p
1/ρ*
) is still possible for acyclic joins. We answer this question in the
affirmative
by showing that any acyclic join can be evaluated with load
O(N
/

p
1/ρ*

), which is asymptotically optimal (there are no polylogarithmic factors in our bound). The separation between cyclic and acyclic joins is yet another phenomenon that is absent in RAM. Our algorithm owes to the discovery of a new mathematical structure — we call “canonical edge cover” — of acyclic hypergraphs, which has numerous non-trivial properties and makes an elegant addition to database theory.
The Clinicopathological Features and Prognostic Significance of HER2-Low in Early Breast Tumors Patients Prognostic Comparison of HER-Low and HER2-Negative Breast Cancer Stratified by Hormone Receptor Status
Authors: Gamrani Sanaa , Akhouayri Laila , Boukansa Sara , Karkouri Mehdi , El Fatemi Hinde
Published: December 2023

Introduction. There has been increased interest in HER2-low breast tumors recently, as these tumors may have distinct clinical and molecular characteristics compared to HER2-negative and HER2-positive tumors. A new nomenclature has been proposed for HER2 1+ and HER2 2+ tumors that are confirmed negative according to fluorescence in situ hybridization (FISH). These tumors are now referred to as HER2-low, and it is thought that they may represent a distinct subtype of breast cancer that warrants further investigation. In this study, we aimed to evaluate the clinicopathological characteristics and prognostic impact of this particular subtype in a North-African context where HER2-low breast cancer is a relatively understudied subtype, particularly in non-Western populations. Methods. We conducted a retrospective cohort study on 1955 breast tumors in Moroccan patients over 10 years, collected at the Pathology Department of Ibn Rochd University Hospital in Casablanca and at the pathology department of Hassan II University Hospital in Fes. We elaborated on their complete immunohistochemical profile based on the main breast cancer biomarkers: Ki-67, HER2, estrogen, and progesterone receptors. Their overall survival and disease free survival data were also retrieved from their respective records. Results. Out of 1955 BC patients, 49.3% were classified as HER2-low; of which 80.7% and 19.2% were hormone receptors positive and negative, respectively. The clinicopathologic features indicate that HER2-low subtype tumors behave much more like HER2-positive than HER2-negative tumors. The survival analysis showed that the HER2-low subtype-belonging patients present significantly the poorest prognosis in disease-free survival (

p
=
0.003

) in comparison with HER2-negative ones. When considering the hormonal status, hormonal-dependent tumors show a significant difference according to HER2 subtypes in disease-free survival (

p
<
0.001

). Yet no significant difference was shown among hormonal negative tumors. Moreover, patients with hormonal positive tumors and simultaneously belonging to the HER2-low subgroup present a significantly good prognosis in overall survival compared to the ones with hormonal negative tumors (

p
=
0.008

). Conclusion. Our study has shown that the HER2-low phenotype is common among hormone-positive patients. The clinicopathological features and prognostic data indicate that the hormonal receptors effect and HER2 heterogeneity are crucial factors to consider. It is important to note that this particular subgroup is different from the HER2-negative one and should not be treated in the same way. Therefore, this study offers a new perspective in the management of HER2-low patients and can serve as a basis for future prospective analyses.
Exploring the Effect of Compound Glycyrrhizin and Silybinin on the Metabolism of Pexidartinib in Rats Based on CYP3A4 and CYP2C9
Authors: Su Yanding , Wei Xinyi , Cheng Qian , Qi He , Chen Jianghui , Qiu Xiang-Jun
Published: December 2023

Pexidartinib offered a new therapeutic option for adult patients with symptomatic tenosynovial giant cell tumor (TGCT) who were refractory to surgical treatment and had severe morbidity or functional limitations. Meanwhile, the metabolism of pexidartinib was mainly mediated through the oxidation of cytochrome P450 (CYP) 3A and glucuronidation by uridine glucuronosyltransferase (UGT) 1A4 and attention shall be paid to CYP450-based drug-drug interactions during therapeutic dosing. This study aimed to examine the changes in the pharmacokinetics of pexidartinib by silymarin and compound glycyrrhizin on pexidartinib in vivo in rats by high-performance liquid chromatography (HPLC)-UV approach and to detect its expression in CYP3A4 and CYP2C9 using the western blot. The findings of chromatography experiments revealed that silybinin as well as compound glycyrrhizin increased the exposure of pexidartinib in rats and had a significant inhibitory effect on the metabolism of pexidartinib. The results of immunoblotting assays suggested that silybinin as well as compound glycyrrhizin inhibited the protein expression of CYP3A4 and CYP2C9 in rats. Therefore, the combination of pexidartinib with silybinin and compound glycyrrhizin should be monitored to avoid clinical adverse effects.
Abstract A004: Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating cancer
Authors: Ikeda Osamu , Kikuchi Aya , Tsuzuki Hirofumi , Matsuda Toshihiro , Weng Jane , Kawashima Tomoko , Kiso Tetsuo , Suzuki Atsushi , Nagashima Takeyuki , Suzuki Tomoyuki , Yamano Kazuya , Yoshida Taku
Published: December 2023

Background: Studies of diacylglycerol kinase ζ (DGKζ) in DGKζ-knockout mice have revealed its role as an intracellular immune checkpoint in T cells. Although enhancing antitumor immunity by pharmacological inhibition of DGKζ is desirable, selective DGKζ inhibitors for clinical use remain largely unexplored. Here, we report a novel, small-molecule, DGKζ inhibitor—ASP1570—which is currently under phase 1 development (NCT05083481), and describe its nonclinical properties and potential application in cancer immunotherapy.

Methods: ASP1570 was characterized by evaluating T cell receptor signaling and T cell function under immunosuppressive conditions relevant to the tumor microenvironment. Antitumor efficacy was evaluated in 2 types of syngeneic mouse models: anti-PD-1-antibody–sensitive MC38 and anti-PD-1-antibody–insensitive B16F1/F10.

Results: ASP1570 enhanced T cell activation with increased diacylglycerol downstream signaling and released anergic T cells from their hyporesponsive state. Further, ASP1570 restored T cell functions suppressed by multiple immunosuppressive signals (TGF-β, prostaglandin E2, adenosine, PD-1, CTLA-4, and TIGIT) and induced tumor-growth inhibition in MC38 and B16F1/F10 syngeneic mouse models. The antitumor efficacy of ASP1570 was cancelled by CD8+ T cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T cell activation.

Conclusions: ASP1570 potentially improves antitumor efficacy in both anti-PD-1-therapy–resistant and anti-PD-1-therapy–responsive tumors by overcoming multiple immunosuppressive signals.

Citation Format: Osamu Ikeda, Aya Kikuchi, Hirofumi Tsuzuki, Toshihiro Matsuda, Jane Weng, Tomoko Kawashima, Tetsuo Kiso, Atsushi Suzuki, Takeyuki Nagashima, Tomoyuki Suzuki, Kazuya Yamano, Taku Yoshida. Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating 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 A004.
Abstract A015: Prediction of immunotherapy response using mutations to cancer protein assemblies
Authors: Kong JungHo , Bachelder Robin , Zhao Xiaoyu , Park Sungjoon , Singhal Akshat , Carter Hannah , Ideker Trey
Published: December 2023

While immune checkpoint inhibitors (ICI) have substantially advanced cancer treatment, favorable responses are limited to a subset of patients and are not strongly predicted by histology or overall mutation burden. Here, we factor mutational burden across a landscape of known and putative multimeric protein assemblies, yielding Assembly Mutation Burden (AMB) scores for each patient. Predictive modeling identifies 14 assemblies in which mutation is associated with ICI response in 555 bladder cancer (BLCA) and non-small-cell lung cancer (NSCLC) patients, outperforming predictions based on genome-wide mutation burden alone. The assemblies capture immunogenic hallmarks and accurately predict treatment outcomes in a validation cohort of 68 immunotherapy-treated NSCLC patients. We explore a predictive assembly of 50 immunoregulatory complex proteins, in which we show CRISPR/Cas9 genetic disruptions influence ICI-treatment outcomes in mice. This study provides a roadmap for using knowledge of tumor cell biology to interpret the immunogenome.

Citation Format: JungHo Kong, Robin Bachelder, Xiaoyu Zhao, Sungjoon Park, Akshat Singhal, Hannah Carter, Trey Ideker. Prediction of immunotherapy response using mutations to cancer protein assemblies [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 A015.
Abstract A018: Optimizing cancer immunotherapy response prediction by tumor aneuploidy score and fraction of copy number alterations
Authors: Chang Tian-Gen , Cao Yingying , Shulman Eldad D , Ben-David Uri , Schäffer Alejandro A. , Ruppin Eytan
Published: December 2023

Identifying patients that are likely to respond to cancer immunotherapy is an important, yet highly challenging clinical need. Using 3139 patients across 17 different cancer types, we comprehensively studied the ability of two common copy-number alteration (CNA) scores—the tumor aneuploidy score (AS) and the fraction of genome single nucleotide polymorphism encompassed by copy-number alterations (FGA)—to predict survival following immunotherapy in both pan-cancer and individual cancer types. First, we show that choice of cutoff during CNA calling significantly influences the predictive power of AS and FGA for patient survival following immunotherapy. Remarkably, by using proper cutoff during CNA calling, AS and FGA can predict pan-cancer survival following immunotherapy for both high-TMB and low-TMB patients. However, at the individual cancer level, our data suggest that the use of AS and FGA for predicting immunotherapy response is currently limited to only a few cancer types. Therefore, larger sample sizes are needed to evaluate the clinical utility of these measures for patient stratification in other cancer types. Finally, we propose a simple, non-parameterized, elbow-point-based method to help determine the cutoff used for calling CNAs.

Citation Format: Tian-Gen Chang, Yingying Cao, Eldad D Shulman, Uri Ben-David, Alejandro A. Schäffer, Eytan Ruppin. Optimizing cancer immunotherapy response prediction by tumor aneuploidy score and fraction of copy number alterations [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 A018.
Abstract A022: CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction
Authors: Schomer Nathan , Chen Jinhong , Pang Wei , Zhou Tingru , Liu Xipan , Liang Wenhen , Guo Yali , Cheng Dai , Li Fang , Liang Jiaqi , Chen Yaoyu , Sheng Qing
Published: December 2023

Small cell lung cancer (SCLC), a malignant thoracic neoplasm genetically defined by dysregulation of the Retinoblastoma (RB1) gene and tumor suppressor protein 53 (TP53), remains one of the world’s deadliest tumors with a 5-year overall survival rate ranging from 5% to 10%.  Despite numerous clinical trials and recent FDA approval of immune checkpoint inhibitors, the prognosis for SCLC has not significantly improved in decades.  There remains a strong need for new therapeutic approaches. In this study, we found that the combined effect of dysregulation or deletion of RB1 and TP53, as is found in the majority of SCLC, results in sensitivity to CDK2 inhibition or ablation.  This relationship is reflected in the DepMap database, with cell lines harboring deleterious mutations in RB1 demonstrating markedly higher susceptibility to CDK2 inhibition.  This relationship is surprising given CDK2’s established role in suppressing the growth inhibition activity of RB and CDK2’s ability to thus facilitate G1/S transition. To validate this discovery, we evaluated the effects of CDK2 inhibition on a panel of SCLC cell lines.  ARTS-021 is a potent and highly selective orally administered inhibitor of CDK2 currently in clinical development.  In contrast to CCNE1 amplified cells, which undergo G1 arrest upon ARTS-021 treatment, SCLC cells treated with ARTS-021 exhibited minimal G1 accumulation.  Instead, ARTS-021 treatment induced apoptosis in SCLC cell lines with loss of functional RB1 and TP53, as demonstrated by a dose-dependent increase in Caspase 3/7 activity and the accumulation of cleaved PARP.  This phenotype was further demonstrated to be CDK2 dependent though generation of stable cell lines expressing a dox-inducible shRNA targeting CDK2.  Combination studies further demonstrated that this apoptotic phenotype can be enhanced synergistically through inhibition of the anti-apoptotic proteins BCL-2 and BCL-xL with clinical stage inhibitor Navitoclax.  In addition, combinations with currently approved standard of care chemotherapies were tested both in vitro and in vivo, and demonstrated potent combinatorial activity. These findings suggest that the clinical development of CDK2 inhibitors for SCLC may represent a novel therapeutic option for this difficult to treat malignancy.

Citation Format: Nathan Schomer, Jinhong Chen, Wei Pang, Tingru Zhou, Xipan Liu, Wenhen Liang, Yali Guo, Dai Cheng, Fang Li, Jiaqi Liang, Yaoyu Chen, Qing Sheng. CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction [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 A022.
Abstract A027: A photoactivatable microtubule-targeting rigidin prodrug
Authors: Kornienko Alexander , Bonnet Sylvestre
Published: December 2023

Analogues of marine alkaloid rigidins have been found to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was “caged” by coordination of its thioether group to a photosensitive ruthenium polypyridyl complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell lines monolayers, 3D lung cancer tumor spheroids (A549), and in a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also, remarkably, in hypoxic conditions (1% O2). In vivo, light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the efficacy of a ruthenium-based photocaged compounds in a tumor xenograft. In subsequent unpublished work, we fine-tuned the excited states in this complex by adding an amide functional group on the ruthenium cage. By doing so, a new caged complex was obtained that was activated by red light (instead of green light). We demonstrated the red light activation of this compound in solution and in vitro. This result demonstrates that functionalization of ruthenium cage with electron-withdrawing groups can radically enhance their photochemical properties, which is essential for this method development (red light penetrates better into tissues than green light).  We will present our results of in vivo testing of this caged compound activated by tumor penetrable red light, where significant tumor reduction is seen in mice xenografted with subcutaneous human uveal melanoma liver metastatic cells.

Citation Format: Alexander Kornienko, Sylvestre Bonnet. A photoactivatable microtubule-targeting rigidin prodrug [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 A027.
Abstract A030: Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model
Authors: Toivanen Kirsi , De Sutter Luna , Wozniak Agnieszka , Böhling Tom , Schöffski Patrick , Sihto Harri
Published: December 2023

Anagrelide is a phosphodiesterase 3A inhibitor that is used to treat essential thrombocythemia. The drug stabilizes the interaction of PDE3A and Schlafen 12 (SLFN12), resulting in complex stabilization, activation of SLFN12 RNase activity and cytotoxic effects in cancer cells. Gastrointestinal stromal tumors (GIST) exhibit high levels of PDE3A expression compared to other cancers or healthy tissue. Orally administered anagrelide has shown antitumor effects in patient-derived GIST xenograft (PDX) mouse models. In this study, we investigated the efficacy of subcutaneously administered, sustained-release anagrelide in UZLX-GIST2B, a PDX mouse model characterized by a KIT mutation in exon 9 and typical dose-dependent imatinib sensitivity. We assessed changes in tumor volume and evaluated histological drug responses including hyalinization, fibrosis, myxoid generation, and tumor necrosis. Anagrelide was administered either orally (2.5 mg/kg, twice a day) or subcutaneously (35 mg/kg and 70 mg/kg, every fourth day) for a duration of 11 days. Treatments with both 35 mg/kg and 70 mg/kg doses resulted in a significant reduction in average tumor volume compared to untreated control mice (both doses 25% vs.129%, P < 0.001) or mice treated with oral anagrelide (25% vs. 61%, P =0 .08, P < 0.05, respectively). The histological response in tumor tissue was positively correlated with dose level, and tumors treated with the highest dose exhibited grade 3 to 4 responses in all cases. These results suggest that sustained-release anagrelide holds promise as a therapeutic option for the treatment of GIST. Further preclinical studies are warranted to investigate the pharmacokinetics and toxicity of this treatment approach.

Citation Format: Kirsi Toivanen, Luna De Sutter, Agnieszka Wozniak, Tom Böhling, Patrick Schöffski, Harri Sihto. Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model [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 A030.