bluuebunny/crossref_metadata_2025 huggingface dataset:
Greater glycemic control following low-load, high-repetition resistance exercise compared with moderate-intensity continuous exercise in males and females: a randomized control trial
Authors: Beaudry Kayleigh M. , Surdi Julian C. , Pancevski Kristian , Tremblay Cory , Devries Michaela C.
Published: March 2024

Exercise has long been known for its beneficial effects on insulin sensitivity (IS) and glucose handling with both moderate-intensity continuous (MIC) exercise and resistance exercise (RE) inducing beneficial effects. In recent years, low-load, high-repetition (LLHR) RE has emerged as a strategy to increase muscle mass and strength to levels similar to traditional RE; however, the effects of LLHR RE on glucose handling has yet to be investigated. The purpose of this trial was to compare the acute effects of LLHR RE to MIC exercise on post-exercise glycemic control and insulin sensitivity in males and females. Twenty-four ( n = 12/sex) participants completed acute bouts of MIC exercise (30 min at 65% V̇O₂peak) and LLHR (3 circuits, 6 exercises/circuit, 25–35 repetitions/exercise/circuit) matched for time with muscle biopsies immediately pre and post exercise and an oral glucose tolerance test (OGTT) 90 min following exercise. Blood glucose concentrations ( p = 0.002, ηp 2 = 0.37), glucose AUC ( p = 0.002, ηp 2 = 0.35) and max glucose concentration ( p = 0.003, ηp 2 = 0.34) were lower during the post exercise OGTT following LLHR RE compared to MIC exercise. There was a main effect of trial on TBC1D1 Ser237 phosphorylation ( p = 0.04, ηp 2 = 0.19) such that it was greater following MIC exercise compared to LLHR RE. Furthermore, phosphorylated ACC Ser79 increased following MIC exercise with no change following LLHR RE ( p < 0.001, ηp 2 = 0.50). Phosphorylation of PTEN Ser380 was greater in males than females during LLHR RE ( p = 0.01, ηp 2 = 0.27). These findings suggest that LLHR RE is a feasible exercise modality to improve post-exercise glycemic control in both males and females. Trial registration number: NCT06217679.
Relationship between COVID-19 pandemic-related experienced stress and lifestyle habits among university students from Québec, Canada
Authors: Filiatrault Mathieu , Leblay Lise , Guay Valérie , Desmarais Chantal , Garnier Adèle , Larose Simon , Litalien David , Mercier Catherine , Saulais Laure , Drouin-Chartier Jean-Philippe
Published: March 2024

Whether COVID-19-related experienced stress influenced lifestyle habits remains to be thoroughly evaluated among university students. This study examined the relationship between COVID-19-related experienced stress and subsequent lifestyle habits among undergraduate students. This cross-sectional study included 708 undergraduate students from Université Laval (Québec, Canada) participating in the Expériences Pandémiques (ExPan) cohort. Data on COVID-19-related experienced stress and lifestyle were self-reported using a questionnaire completed between February and April of 2022. A stress index (SI) was computed by summing scores associated with 31 situational statements related to the pandemic (e.g., not being able to see friends, dealing with job loss). A healthy lifestyle score (HLS) ranging from zero to seven was calculated based on seven lifestyle habits: moderate-to-vigorous physical activity, sleep quality, fruit and vegetable intake, tobacco and electronic cigarette use, alcohol consumption, cannabis use, and hard or sedative-hypnotic drugs use. In multivariable-adjusted models, a negative association between the SI and the HLS was found (β10% increment SI = −0.23, 95% CI = −0.30, −0.16 HLS point; P < 0.0001). The SI was also negatively associated with sleep quality, and fruit and vegetable consumption, while being positively associated with at-risk alcohol consumption, cannabis use, and hard or sedative-hypnotic drug use. Subgroup analyses suggested a negative relationship between the SI and HLS among participants who did not receive academic accommodations (e.g., additional time for evaluations, personal notetaker), but not those who received such accommodations. This study suggests that COVID-19-related experienced stress was negatively associated with healthy lifestyle habits in this cohort of undergraduate students.
Palmer amaranth (Amaranthus palmeri S. Wats.) and waterhemp (Amaranthus tuberculatus (Moq.) J.D. Sauer) biovigilance in Canadian Agro-ecosystems
Authors: Sharpe Shaun M. , Martin Sara L. , Page Eric R. , Geddes Charles M.
Published: March 2024

The evolution and spread of herbicide-resistant weeds threatens long-term sustainability of Canadian agro-ecosystems. Herbicide-resistant weeds increase management inputs and costs, increase off-target and environmental exposure to pesticides, reduce yield quality and quantity, and impede harvest efficiency. Amaranthus species including Palmer amaranth ( Amaranthus palmeri S. Wats.) and waterhemp ( Amaranthus tuberculatus (Moq.) J.D. Sauer) are particularly concerning due to both their propensity towards herbicide resistance evolution, their history of invasion, and their spread in agro-ecosystems. A biovigilance approach is taken to build awareness of these pigweeds' initial invasion and spread in the USA. Characteristics of their identification, potential hybridization, and known herbicide resistance evolution are reviewed. Fourteen species of Amaranthus are found in Canada, nine of which (including waterhemp) possess herbicide-resistant biotypes. A total of 45 hybrids between various Canadian Amaranthus species with each other or Palmer amaranth have been noted. Hybrids have been experimentally produced or observed from herbarium specimens, with three cases of herbicide resistance transfer notably with Palmer amaranth or waterhemp. Mitigation strategies will depend on successful species identification and herbicide resistance status determination. Common pathways for Palmer amaranth introductions in the northern USA include both animal feed systems with grain screenings and crop production systems including seed and equipment contamination. Regional awareness campaigns will be critical to support Canadian farmers in identifying and quickly mitigating invasions of Palmer amaranth and waterhemp to prevent establishment and spread of infestations into new areas.
On the symmetries of elementary fermions
Authors: Marsch Eckart , Narita Yasuhito
Published: March 2024

This paper deals with the symmetries of elementary fermions and their derivation from fundamental physical principles such as the Lorentz invariance and from the spinor-helicity formalism employed to three-vectors. The generators of the Lorentz group are discussed, and the physics of the associated chiral spins is used to establish the chiral symmetry SU(2). The helicity of spin is defined which, when being applied to the hadronic isospin, yields the symmetry group SU(4). The Kronecker product of these two basic symmetries defines a unified symmetry $$SU(2) \otimes SU(4)$$

S
U
(
2
)
⊗
S
U
(
4
)

of the basic light fermions, namely the chiral doublets of the single lepton and triple quarks of the first family. Breaking this symmetry, according to mechanisms that are used in the electroweak interactions of the Standard Model (SM) of quantum field theory, yields quantum electrodynamics (QED) with symmetry group U(1), weak interactions with symmetry group SU(2), and what we like to name quantum hadrodynamics (QHD, akin to quantum chromodynamics QCD of the SM) with symmetry group SU(3). The gauge bosons associated with QED and QHD remain massless, but the weak bosons and the V bosons, related to the transformation of the quarks into a lepton and vice versa, become massive by the Higgs mechanism. Their masses are defined by the Higgs vacuum and the two coupling constants involved in the unified model. The V-boson mass is predicted to be 35.4 GeV. Furthermore, a possible explanation of hadron confinement is given in terms of the two hadronic charge operators. Moreover, the concept of hypercharge as used in the SM is not needed. Various versions of the extended Dirac equation that include the above symmetry groups are derived.
Multitask Adversarial Networks Based on Extensive Nonlinear Spiking Neuron Models
Authors: Fu Jun , Peng Hong , Li Bing , Liu Zhicai , Lugu Rikong , Wang Jun , Ramírez-de-Arellano Antonio
Published: March 2024

Deep learning technology has been successfully used in Chest X-ray (CXR) images of COVID-19 patients. However, due to the characteristics of COVID-19 pneumonia and X-ray imaging, the deep learning methods still face many challenges, such as lower imaging quality, fewer training samples, complex radiological features and irregular shapes. To address these challenges, this study first introduces an extensive NSNP-like neuron model, and then proposes a multitask adversarial network architecture based on ENSNP-like neurons for chest X-ray images of COVID-19, called MAE-Net. The MAE-Net serves two tasks: (i) converting low-quality CXR images to high-quality images; (ii) classifying CXR images of COVID-19. The adversarial architecture of MAE-Net uses two generators and two discriminators, and two new loss functions have been introduced to guide the optimization of the network. The MAE-Net is tested on four benchmark COVID-19 CXR image datasets and compared them with eight deep learning models. The experimental results show that the proposed MAE-Net can enhance the conversion quality and the accuracy of image classification results.
Topological interpretation of black hole phase transition in Gauss–Bonnet gravity
Authors: Fairoos C.
Published: March 2024

Phase transitions of Einstein–Gauss–Bonnet black holes are studied using Duan’s [Formula: see text]-field topological current theory, where black holes are treated as topological defects in the thermodynamic parameter space. The kinetics of thermodynamic defects are studied using Duan’s bifurcation theory. In this picture, a first-order phase transition between small/large black hole phases is interpreted as the interchange of winding numbers between the defects as a result of some action at a distance. We observe a first-order phase transition between small/large black holes for [Formula: see text] Einstein–Gauss–Bonnet theory similar to Reissner–Nordström black holes in AdS space. This implies that these black hole solutions share the same topology and phase structure. We have also studied the phase transition of neutral black holes in [Formula: see text] and found a transition between unstable small and large stable black hole phases similar to the case of neutral black holes in AdS space. Recently, it has been conjectured that black holes with similar topological structure exhibit the same thermodynamic properties. Our results strengthen the conjecture by connecting the topological nature of black holes to phase transitions.
Accelerating Gauss–Bonnet universe with constrained parameters
Authors: Dixit A. , Shekh S. H. , Bhoyar S. R. , Dhabe M. C.
Published: March 2024

The purpose of this study is to investigate the parametrization form of the deceleration parameter in relation to the redshift z. The parameter is represented by the equation [Formula: see text], which offers the desirable quality of allowing the sign to be flipped from a decelerating phase to an accelerating phase. We have investigated the Hubble parameter by evaluating the specified parametric form of q and derived constraints on the related free parameters [Formula: see text], [Formula: see text] and [Formula: see text] with confidence limits of 1[Formula: see text] and 2[Formula: see text] by using the [Formula: see text]-minimization approach. Furthermore, we have constrained the current value of the deceleration parameter [Formula: see text] and obtained that the current universe is accelerating. We have examined the characteristics of our model by assuming the two distinct forms of [Formula: see text] and [Formula: see text]. In addition, we have examined the evolutionary paths of energy density, pressure and EoS parameters in order to deduce the universe’s accelerating behavior. In order to verify the feasibility of our cosmological model, we also investigate the behavior of various energy conditions.
I – V Characteristics of Hf0.5Zr0.5O2 films prepared via sol–gel and pulsed laser deposition methods
Authors: Liu Jianbo , Li Xiaohui , Li Xiaola , Bai Jing , Xu Yunhua
Published: March 2024

Stable [Formula: see text] (HZO) sols were obtained by adding acetylacetone (AcAc), and the mechanism through which AcAc improved the quality of the sol and the gel film was analyzed. Absorption spectroscopy results show that AcAc can chelate with [Formula: see text] and [Formula: see text], thus improving the hydrolysis resistance of the sol and the gel film, which optimizes their quality. Then, Pt/HZO/Pt structures were prepared via the sol–gel (SG) and pulsed laser deposition (PLD) methods, and their [Formula: see text] curves were studied. The Pt/HZO/Pt structure prepared via the SG (PLD) method shows a pronounced bipolar resistance switching (BRS) (unipolar resistance switching (URS)) effect. It was found that there are several defects on the surface of the HZO film prepared via the SG method, which permit oxygen ions to enter/exit HZO, thus resulting in the BRS effect. However, there are fewer defects on the surface of the HZO film prepared via the PLD method, which results in the URS effect.
Numerical analysis of multi-dimensional Navier–Stokes equation based on Yang–Abdel–Cattani fractional operator
Authors: Aychluh Mulualem , Ayalew Minilik , Suthar D. L. , Purohit S. D.
Published: March 2024

The Navier–Stokes equation is a key governing equation for the motion of viscous fluid flow. The main target of our work is to obtain the solution to multi-dimensional Navier–Stokes equations in the Yang–Abdel–Cattani fractional sense. The results of the model are in terms of the three-parameter Prabhakar function. Three examples are discussed that depend on the recommended method for a novel Yang–Abdel–Cattani arbitrary order operator. The obtained results are plotted with the help of MATLAB R2016a mathematical software.
Drone-Based Bug Detection in Orchards with Nets: A Novel Orienteering Approach
Authors: Betti Sorbelli Francesco , Coró Federico , Das Sajal K. , Palazzetti Lorenzo , Pinotti Cristina M.
Published: March 2024

The use of drones for collecting information and detecting bugs in orchards covered by nets is a challenging problem. The nets help in reducing pest damage, but they also constrain the drone’s flight path, making it longer and more complex. To address this issue, we model the orchard as an aisle-graph, a regular data structure that represents consecutive aisles where trees are arranged in straight lines. The drone flies close to the trees and takes pictures at specific positions for monitoring the presence of bugs, but its energy is limited, so it can only visit a subset of positions. To tackle this challenge, we introduce the Single-drone Orienteering Aisle-graph Problem (SOAP), a variant of the orienteering problem, where likely infested locations are prioritized by assigning them a larger profit. Additionally, the drone’s movements have a cost in terms of energy, and the objective is to plan a drone’s route in the most profitable locations under a given drone’s battery. We show that SOAP can be optimally solved in polynomial time, but for larger orchards/instances, we propose faster approximation and heuristic algorithms. Finally, we evaluate the algorithms on synthetic and real datasets to demonstrate their effectiveness and efficiency.
Building Category Graphs Representation with Spatial and Temporal Attention for Visual Navigation
Authors: Hu Xiaobo , Lin Youfang , Fan Hehe , Wang Shuo , Wu Zhihao , Lv Kai
Published: March 2024

Given an object of interest, visual navigation aims to reach the object’s location based on a sequence of partial observations. To this end, an agent needs to (1) acquire specific knowledge about the relations of object categories in the world during training and (2) locate the target object based on the pre-learned object category relations and its trajectory in the current unseen environment. In this article, we propose a Category Relation Graph (CRG) to learn the knowledge of object category layout relations and a Temporal-Spatial-Region attention (TSR) architecture to perceive the long-term spatial-temporal dependencies of objects, aiding navigation. We establish CRG to learn prior knowledge of object layout and deduce the positions of specific objects. Subsequently, we propose the TSR architecture to capture relationships among objects in temporal, spatial, and regions within observation trajectories. Specifically, we implement a Temporal attention module (T) to model the temporal structure of the observation sequence, implicitly encoding historical moving or trajectory information. Then, a Spatial attention module (S) uncovers the spatial context of the current observation objects based on CRG and past observations. Last, a Region attention module (R) shifts the attention to the target-relevant region. Leveraging the visual representation extracted by our method, the agent accurately perceives the environment and easily learns a superior navigation policy. Experiments on AI2-THOR demonstrate that our CRG-TSR method significantly outperforms existing methods in both effectiveness and efficiency. The supplementary material includes the code and will be publicly available.
The Effect of Spray Testing Condition on the Corrosion Performance of Hydrothermally Sealed Anodic Oxide on a 5005 Aluminum Alloy: Comparison between Neutral Salt Spray, Acetic Salt Spray and Prohesion Testing Methods
Authors: Ramdé Tambi , Fedel Michele , Rossi Stefano
Published: March 2024

In this work, the output of different accelerated tests on anodic aluminum oxide (AAO) coatings developed on AA5005 aluminum alloy (sulfuric acid bath and hydrothermal sealing) has been investigated. In particular, three corrosion testing methods, namely neutral salt spray test (NSS), acetic acid salt spray (AASS) and prohesion test, have been performed on the sealed AAO-coated panels in order to investigate the reliability of the obtained results to the electrochemical impedance ones. NSS and prohesion testing results are found to align with findings from electrochemical impedance spectroscopy (EIS). The acetic salt spray test appears to be highly corrosive, causing rapid depletion of the oxide layer’s protective capabilities, as indicated the EIS analysis. The findings suggest that the deterioration of the oxide layer’s barrier properties appears to be more pronounced than what optical image analysis suggests.
Short Term Silver Electrode Microstructure Changes Under Epoxidation Conditions for Solid Oxide Electrolysis Cells
Authors: Jenkins C. D. , Tian J. , Milcarek R. J.
Published: March 2024

Ethylene epoxidation is an important reaction forming ethylene oxide (EO), which is a precursor to many other critical chemicals. This study links short-term EO production to the effects on the microstructure of Ag/yttria-stabilized zirconia cells with and without electrochemical promotion of catalysis (EPOC). Nano-scale features, called striations, were observed on the silver under all epoxidation reaction conditions tested, using a scanning electron microscope. While appearing in both cases, the striations for the EPOC case are finer in size (∼150 to 250 nm) compared to the no current case (∼400 to 500 nm). These features did not appear when epoxidation conditions were not present. Striation formation was further linked to the epoxidation reaction through electrochemical impedance spectroscopy and gas chromatography. Ethylene conversion to EO declines over the course of hours as striations form, indicating that striations have a negative influence on the reaction. Distribution of relaxation times was performed to determine the effect striation formation has on the electrochemical performance of the cells. It was observed that the low-frequency peaks in the DRT analysis significantly decrease as striations formed over the course of 10 h.
Relating Chemo-Mechanical Hysteresis and Formation Protocols for Anode-Free Lithium Metal Batteries
Authors: Chang Wesley , Thorsteinsson Gunnar , Janakiraman Umamaheswari , Chowdhury Rahul Reza , Herman Zoe , Katzman Libby , Steingart Daniel A.
Published: March 2024

Cell formation is an energy and time-intensive empirically-guided process crucial to manufacturing secondary lithium-ion batteries. As the rechargeable battery industry moves towards manufacturing lithium metal batteries—where a metallic lithium negative electrode is used instead of a porous graphite composite—the cell formation process may need reconsidering. The effects of formation rate and cycling protocol on lithium metal battery performance are poorly understood. In this work, we used operando acoustic transmission to measure physical changes during the formation cycles and the effect of formation cycling protocols on the long-term cycling of anode-free lithium metal pouch cells—where all the lithium inventory comes from the positive electrode and is deposited as metallic lithium on copper foil during initial charge. We show that a faster C/3 formation protocol results in comparable cycling performance and cell stiffness change to a slower C/10 formation step. Variations in acoustic metrics across different electrolytes tested are attributed to differences in gas formation, cell swelling, and lithium deposition morphology. NMC811 cathodes paired with a high-concentration ether electrolyte are shown to be particularly prone to gas formation, which is mitigated by using a localized high-concentration ether electrolyte and single-crystal NMC532. The results highlight differences in formation behavior between anode-free lithium metal cells and lithium-ion cells. These are important to consider when bringing new manufacturing plants online for lithium metal batteries.
A cell atlas of thoracic aortic perivascular adipose tissue: a focus on mechanotransducers
Authors: Thompson Janice M. , Watts Stephanie W. , Terrian Leah , Contreras G. Andres , Rockwell Cheryl , Rendon C. Javier , Wabel Emma , Lockwood Lizbeth , Bhattacharya Sudin , Nault Rance
Published: March 2024

This study describes the atlas of cells in the thoracic aorta perivascular adipose tissue (taPVAT) of the Dahl-SS rat, an important hypertension model. We show that mechanotransducers are widely expressed in these cells. Moreover, PIEZO1 expression is shown to be restricted to the taPVAT and is functionally implicated in stress relaxation. These data will serve as the foundation for future studies investigating the role of taPVAT in this model of hypertensive disease.
Common Mental Disorder and Associated Factors among Women Attending Antenatal Care Follow-Up in North Wollo Public Health Facilities, Amhara Region, Northeast Ethiopia: A Cross-Sectional Study
Authors: Addisu Amanuel , Kumsa Henok , Adane Seteamlak , Diress Gedefaw , Tesfaye Aragaw , Arage Mulugeta Wodaje , Mekuria Kendie , Moges Solomon , Bantie Getasew Mulat , Melese Amare Alemu , Tenaw Lebeza Alemu
Published: March 2024

Introduction. Common mental health disorders (CMD) during pregnancy are a public health concern because of the implications for the mother and infant’s health during pregnancy and after birth. The prevalence and factors related to common mental disorders vary globally. Therefore, this study assessed the magnitude and factors associated with common mental disorder among pregnant women attending ANC follow-up in North Wollo Zone, Northeast Ethiopia. Methods. An institutional-based cross-sectional study was conducted in North Wollo, Amhara Region, Northeast Ethiopia. A multistage sampling technique was used to select 777 study participants. The common mental disorder was assessed by using SRQ-20. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 23. Logistic regression analysis was done to identify the independent variables associated with common mental disorders. Independent variables with a p value less than 0.05 were considered significantly associated with CMD. Results. The magnitude of CMD was 18.1% (95% CI: 15.5, 21.0). Factors significantly associated with CMD were the educational level of participants (AOR=0.17, 95% CI: 0.06, 0.48), husband’s educational status (AOR=11.13, 95%: 4.18, 29.66), unplanned pregnancy (AOR=2.54, 95% CI: 1.26, 5.09), self-reported complication on the current pregnancy (AOR=0.11, 95% CI: 0.05, 0.21), self-reported complication during the previous delivery (AOR=3.38, 95% CI: 1.39, 8.18), undernutrition (AOR=2.19, 95%: 1.26, 3.81), high psychosocial risk (AOR=20.55, 95% CI: 9.69, 43.59), having a legal issue (AOR=2.06, 95%: 1.12, 3.79), and relationship problem (AOR=7.22, 95% CI: 3.59, 14.53). Conclusions and Recommendation. One in five pregnant women has common mental disorder. Educational status of the participants and their spouses, unplanned pregnancy, self-reported complication during current and previous pregnancy, psychosocial risk, and legal and relationship problems were the main determinants of common mental disorders. Therefore, screening pregnant women for mental disorders and provision of necessary mental health services are recommended to minimize the adverse health outcome of CMD during pregnancy.
Effect of Malaria and Schistosoma mansoni Coinfection on Selected Biochemical Profiles among Patients Attending Selected Health Institutions at Dembiya, Northwest Ethiopia
Authors: Abebe Wagaw , Lemma Wossenseged , Tegegne Yalewayker , Mekuanint Amare , Yenesew Abebe , Derso Adane
Published: March 2024

Background. Malaria and schistosomiasis are infectious diseases that cause biochemical abnormalities. Malaria and Schistosoma mansoni coinfection causes exacerbations of health consequences and comorbidities. The study area is found in Ethiopia, where coinfection of malaria and S. mansoni is common. However, there is limited data on the biochemical profiles of patients coinfected with malaria and S. mansoni schistosomiasis in the study area. Hence, this study aimed to assess the effect of malaria and S. mansoni schistosomiasis coinfection on selected biochemical profiles. Methods. An institutional-based comparative cross-sectional study was conducted from March 30 to August 10, 2022. Using a convenient sampling technique, 70 participants (35 cases and 35 controls) were enrolled in the study. Schistosoma mansoni was detected in stool samples using the wet mount and the Kato Katz method. To detect Plasmodium, both thick and thin blood films were prepared and stained with Giemsa. The blood sample was processed for the analysis of biochemical profiles. All data were analyzed using SPSS version 25. A p value of less than 0.05 was considered statistically significant. Results. The mean values of alanine aminotransferase and aspartate aminotransferase (37.1 U/L and 41.9 U/L, respectively) in coinfected participants were significantly higher than in the healthy control participants (17.4 U/L and 22.0 U/L, respectively) p<0.05. Also, the median values of creatinine, total bilirubin, and direct bilirubin (1.51 mg/dL, 2.35 mg/dL, and 0.91 mg/dL, respectively) in coinfected participants were significantly higher than in the healthy control participants (0.85 mg/dL, 0.42 mg/dL, and 0.12 mg/dL, respectively) p<0.05. However, median values of total protein (4.82 g/dL) and mean values of glucose (66.6 mg/dL) in coinfected participants were significantly lower than in the healthy control participants (total protein (7.64 g/dL) and glucose (91.9 mg/dL)) p<0.05. The results of biochemical profiles in healthy participants were significantly different from those with light, moderate, and heavy S. mansoni infection intensity in malaria and S. mansoni coinfection p<0.05. Schistosoma mansoni infection intensity had a positive correlation with biochemical profiles except for total protein and glucose, which correlated negatively in coinfected participants p>0.05. Conclusion. Biochemical profiles in coinfection were significantly changed as compared to healthy individuals. As a result, biochemical profile tests should be utilized to monitor and manage coinfection-related problems, as well as to reduce coinfection-related morbidity and death.
Improvements in Posttransplant Outcomes Over Two Decades in Older Patients with Acute Myeloid Leukemia in the EBMT ALWP Study
Authors: Bazarbachi Ali , Labopin Myriam , Moukalled Nour , Kröger Nicolaus , Rautenberg Christina , Schetelig Johannes , Finke Jürgen , Blau Igor Wolfgang , Blaise Didier , Stelljes Matthias , Eder Matthias , Platzbecker Uwe , Dreger Peter , Bethge Wolfgang , Tischer Johanna , Burns David , Sengeloev Henrik , Brissot Eolia , Giebel Sebastian , Nagler Arnon , Ciceri Fabio , Mohty Mohamad
Published: March 2024

Purpose:

Acute myeloid leukemia (AML) is a disease of older patients. Progress in allogeneic hematopoietic cell transplantation (allo-HCT) allowed the delivery of allo-HCT to older patients. We assessed changes over time in transplant characteristics and outcomes in patients with AML ages 65 years and above.

Patients and Methods:

We identified 7,215 patients with AML (median age 68 years, range 65–80) allografted between 2000 and 2021 in first complete remission (CR1; 64%), second or subsequent remission (CR2+; 14%), or active disease (22%).

Results:

Median follow-up was 40 months. The 3-year cumulative relapse incidence (RI) gradually and significantly decreased from 37% to 31%, then to 30% (P = 0.001) over the three time periods (2000–2009; 2010–2014; 2015–2021), whereas nonrelapse mortality (NRM) decreased from 31% and 31% to 27% (P = 0.003). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved from 32% to 38%, and then to 44% (P = 0.001) and from 37% to 42%, and then to 49% (P = 0.001), respectively. In multivariate analysis, significant improvement in the RI, LFS, and OS were noted after 2015, whereas NRM was not significantly affected. This improvement was observed regardless of disease status at transplant.

Conclusions:

In older patients with AML, we observed an impressive improvement over time in posttransplant outcomes, mostly attributed to decreased RI rather than decreased NRM, and regardless of disease status at transplant. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option.
Abstract 1029: Role of PCDHGA12/PRRX1 methylation for the diagnosis of lung cancer using bronchial washing fluid
Authors: Son Ji Woong , Oh Tae Jeong , Lee Minheyok , Park Chang Ryul , An Sungwhan
Published: March 2024

Bronchoscopy is a frequently used initial diagnostic procedure for patients with suspected lung cancer (LC). Cytological examinations of bronchial washing (BW) samples, obtained during bronchoscopy, often yield inconclusive results in the diagnosis of LC. Aberrant DNA methylation has previously been shown to be a useful biomarker for LC. DNA methylation analysis in BW specimens could serve as a valuable clinical adjunct to cytology. In this study, to identify potential methylation biomarkers for LC, methylation microarray analyses were performed on primary tumors and compared with adjacent non-tumor tissues of 13 patients with LC at various stages (I - IV). A stepwise validation process using bisulfite-pyrosequencing of cell lines and tissues identified six methylated genes (ADAMTS20, FOXC2, NKX2-5, OLIG3, PCDHGA12, and PRRX1) associated with LC. To assess methylation in BW samples, a highly sensitive and accurate 3-plex Linear Target Enrichment (LTE)-quantitative methylation-specific PCR (qMSP) in a single closed tube was developed. Clinical validation was performed using BW samples from patients with LC (n = 68) and non-LC (benign) (n = 33) and identified PCDHGA12 and PRRX1 methylation as the best performing marker combination for detecting LC. The 2-marker combination exhibited a sensitivity of 82.4% and a specificity of 87.9%, with an area under the curve of 0.891. Notably, its sensitivity was 100% for small cell LC. The 2-marker combination had a positive predictive value of 93.3% and a negative predictive value of 70.7%. Its sensitivity outperformed cytology. The methylation status of the 2-marker showed no correlation with gender, age or stage, but was associated with tumor location and histology. In conclusion, we identified PCDHGA12 and PRRX1 methylation as high potential biomarkers for LC diagnosis. This study shows that these biomarkers could be used as a diagnostic adjunct to cytology in the clinical practice for diagnosing LC in BW specimens.

Citation Format: Ji Woong Son, Tae Jeong Oh, Minheyok Lee, Chang Ryul Park, Sungwhan An. Role of PCDHGA12/PRRX1 methylation for the diagnosis of lung cancer using bronchial washing fluid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1029.
Abstract 1031: Targeting genomic biomarker in voided urine for prostate cancer detection
Authors: Thakur Mathew L. , Tomar Vivek S. , Dale Emma , Gomella Leonard G. , Navarro Hector T. , Kolesnikov Oleksandr , Leong Joon Yau , Dahlgren Olivia , Trabulsi Edouard J.
Published: March 2024

Introduction: Prostatic cancer (PCa) is the second most prevalent disease in men globally. In 2020 it lead to >14 million new cases and >375,000 deaths worldwide. Despite numerous detection methods, detecting PCa reliably and non-invasively continues to be challenging. PCa malignant cells (MC) express VPAC (combined for Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Peptide) in high density. A VPAC specific PACAP analogues (Kd=3.1 × 10−8M) developed in our laboratory was conjugated with a fluorophore and named TP4303. The goal was to assess if TP4303 will image PCa-MC shed in voided urine and present severity of PCa as grade group (GG).

Method: Consenting PCa patients (N=110) scheduled for radical prostatectomy provided voided urine. Urine was cyto-centrifuged. Cells on glass slide were fixed, incubated with TP4303, washed, treated with DAPI (4,6-diamidodino-2-phenylindole), cover slip placed and analyzed with Zeiss Axio Observer microscope, coupled with ZENN Microscopy software. The software determined percentage of PCa MC shed by each patient. The results were corroborated as per GG, determined by post-surgical histopathology and analyzed statistically.

Results:TP4303 imaged PCa in all subjects. The percent MC shed in urine increased from 13.1±14.4% for GG1 to 25.3±21.07% for GG3 (p=0.05) to 50.5±26.7% for GG5 (p=0.002). Similarly, the fluorescence intensity increased from 43.8±2.2 for GG1 to 48.8±7.0 for GG3 (p=0.01) to 51.5±14.4 for GG5 (p=0.15).

Conclusions: The data strongly suggests that TP4303 may not only detect PCa reliably and noninvasively, but may also predict the severity of PCa.

Supported by NIH: NC5R01CA249921

Citation Format: Mathew L. Thakur, Vivek S. Tomar, Emma Dale, Leonard G. Gomella, Hector T. Navarro, Oleksandr Kolesnikov, Joon Yau Leong, Olivia Dahlgren, Edouard J. Trabulsi. Targeting genomic biomarker in voided urine for prostate cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1031.
Abstract 1055: ORF1p expression from LINE-1 occurs in clear cell ovarian carcinoma precursors and is detectable in patients’ plasma samples
Authors: de Santiago Pamela R. , Sato Sho , Zhuravlev Yelena , Rendulich Hannah S. , Taylor Marty S. , Wu Connie , Dougher Meaghan C. , Schwartz Lauren , Walt David R. , Burns Kathleen H. , Drapkin Ronny
Published: March 2024

Long interspersed element 1 (LINE-1) retrotransposons are repetitive genomic sequences able to move across the genome by an autonomous “copy and paste” mechanism. Given the mutagenic potential of LINE-1, benign cells restrict its expression, although the molecular mechanisms involved are usually impaired in cancer. Clear cell ovarian carcinoma (CCOC) accounts for ~5-10% of ovarian cancers and is believed to arise from endometriosis. Women have a poor prognosis when it presents at an advanced stage, which emphasizes the need for a better understanding of the disease. In the present study, we found that ~85% of CCOC tumors express ORF1p, one of two proteins encoded by LINE-1. We show that CCOC cell lines retain ORF1p expression and release it into the extracellular media. By using single molecule array (Simoa) assays, we detected ORF1p in patient plasma, proposing ORF1p as a non-invasive biomarker for this disease. Finally, we found that LINE-1 retrotransposon de-repression is an early event in CCOC, as ORF1p is enhanced during the transition from typical to atypical endometriosis and that is retained in the invasive cancer.

Citation Format: Pamela R. de Santiago, Sho Sato, Yelena Zhuravlev, Hannah S. Rendulich, Marty S. Taylor, Connie Wu, Meaghan C. Dougher, Lauren Schwartz, David R. Walt, Kathleen H. Burns, Ronny Drapkin. ORF1p expression from LINE-1 occurs in clear cell ovarian carcinoma precursors and is detectable in patients’ plasma samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1055.
Abstract 1246: Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features
Authors: Ladewig Erik , Feng Weiran , Leslie Christina , Sawyers Charles
Published: March 2024

Translocations of the ETS family transcription factor ERG are found in nearly 150,000 newly diagnosed prostate cancers (PCas) each year in the United States underscoring the importance of defining the mechanism by which ERG promotes prostate epithelial transformation. A consequence of nearly all ERG translocations is the aberrant expression of ERG in prostate luminal cells under transcriptional control of TMPRSS2. Multiple lines of evidence implicate ERG translocations as an initiating event in prostate cancer. ERG expression is seen in prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy; expression in cancers is typically uniform; and, in the context of PI3K pathway activation, ERG is sufficient to induce cancers in mice. Yet, despite extensive research the mechanism by which ERG initiates prostate cancer is unclear. To gain insight into how ERG translocations cause prostate cancer, we performed both transcriptional profiling (scRNA-seq) and chromatin accessibility via Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) in single cells of an autochthonous mouse model at an early stage of disease initiation. Surprisingly, we observed in prostate epithelial cells broadly expressing ERG enhanced proliferation primarily in a hybrid subpopulation of cells having basal identity but with luminal morphology and cytokeratin expression. Through a series of lineage tracing and primary prostate epithelial transplantation experiments, we confirmed tumor initiating activity resided within a subpopulation of basal cells expressing luminal genes (e.g., Tmprss2 and Nkx3-1). A trajectory analysis from single-cell Chromatin accessibility indicated Erg+ cells began to lose basal (Trp63) accessibility and gained in STAT/NFAT TFs while retaining the ability to rapidly differentiate into luminal cells that reflect the lineage of ERG-positive cancers. These findings help resolve a preexisting debate about the cell of origin of ERG-driven prostate cancer and narrow the focus for future mechanistic studies to a basal-luminal subpopulation of tumor initiating cells.

Citation Format: Erik Ladewig, Weiran Feng, Christina Leslie, Charles Sawyers. Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1246.
Abstract 1248: The BRD8/p53 epigenetic switch re-establishes tumor suppression in glioblastoma
Authors: Sun Xueqin Sherine , Mills Alea A.
Published: March 2024

Glioblastoma (GBM) is the most common and deadly adult primary brain malignancy. Median survival is just 12-14 months, with only about 5% of GBM patients surviving 5 years after diagnosis. This picture has not substantially improved over decades and there is an urgent need to discover more specific and effective treatments for this deadly malignancy. We discovered the bromodomain-containing chromatin regulator BRD8 as essential to GBM lacking p53 mutations (TP53WT), which make up ~71% of cases (1). BRD8 maintains malignancy by crippling p53-mediated tumor suppression in a way distinct from previously described mechanisms: it reprograms the p53 network through the EP400 histone acetyltransferase complex and by bromodomain-directed occupancy of the histone variant H2AZ at p53-induced targets, enforcing a repressive chromatin state that prevents p53-mediated transactivation. Importantly, targeting BRD8 in TP53WT GBM remodels chromatin by evicting H2AZ and enhancing chromatin accessibility, enabling p53 to bind and transactivate its targets. This chromatin remodeling cascade (referred to as the “BRD8/p53 epigenetic switch”) re-establishes p53 activity in TP53WT GBM, normalizing gene expression, evoking cell cycle arrest, inhibiting gliomagenesis, and prolonging survival in xenograft models of TP53WT GBM. Our recent work: (i) reveals that BRD8 opposes p53 function in non-malignant brain cells; (ii) shows that the bromodomain of BRD8 is unique amongst the bromodomain-containing protein family, as it is the only one that selectively reprograms the p53 network; and (iii) demonstrates that targeting BRD8 works synergistically with MDM2 inhibition. Our findings present a previously unappreciated mechanism by which cancer cells side-step p53, indicate that targeting BRD8 re-establishes p53-mediated tumor suppression in TP53WT GBM, highlight unique features of the bromodomain of BRD8, and propose therapies using co-inhibition of BRD8 and MDM2 as a dual-level tactic for boosting up p53. Thus, our work sheds light on new principles of chromatin biology and offers new promise for treating patients with this devastating malignancy.

(1)Sun et al., 2023 Nature 613 (7942):195-202.

Citation Format: Xueqin Sherine Sun, Alea A. Mills. The BRD8/p53 epigenetic switch re-establishes tumor suppression in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1248.
Abstract 1257: CHD5 suppresses glioblastoma by inhibiting MYC
Authors: Sun Xueqin Sherine , Mills Alea
Published: March 2024

Fundamentally, cancer is a disease caused by genetic and epigenetic alterations that converge to reprogram gene expression networks, leading to unrestrained proliferation. Glioblastoma (GBM) is the most prevalent and aggressive primary brain cancer, median survival being approximately one year and the 5-year survival rate being only 5%. Despite decades of effort, this devastating picture has not appreciably improved and effective therapies have been elusive for GBM patients. A better understanding of GBM biology is essential for developing more effective therapies. Although several genetic alterations have been implicated in gliomagenesis, driving genetic factors responsible for GBM are still obscure, and the interplay between genetic alterations and epigenetic dysregulation is largely undocumented during the gliomagenic process. Here, we show that CHD5 — a gene mapping to the 1p36 chromosomal region that is notoriously deleted in many cancers, is recurrently deleted in over 20% of GBM cases and is further downregulated through epigenetic means. To delineate how CHD5 loss promotes gliomagenesis, we established a glioma-prone mouse model harboring conditional alleles of Pten, Trp53, and Chd5. We developed an engineered mouse neural stem cell (NSCs)-based strategy to elicit glioma formation, as NSCs are the major cell-of-origin for GBM. We show that Chd5 loss significantly impairs NSCs differentiation while promoting proliferation, transformation, and gliomagenesis in vivo. Mechanistically, Chd5 forms a Chd3-containing but Chd4-independent NuRD complex that directly binds the Myc promoter and super enhancers to govern Myc expression in normal NSCs, with the Snf2 domain of Chd5 playing the most critical chromatin regulating role in the context of GBM. Chd5 loss triggers the remodeling of chromatin, enhances accessibility, and augments Myc expression, leading to the formation of highly aggressive glioma. Furthermore, reactivating CHD5 in human GBM xenograft models significantly extends survival. This work demonstrates the tumor suppressive role of CHD5 in gliomagenesis, providing therapeutic insights for cancers with 1p36 deletions. In parallel, this work presents a powerful strategy for rapidly interrogating gene function during gliomagenesis using engineering NSCs, and the generation of novel mouse models with classic clinical features of GBM, offering new approaches for elucidating GBM biology that can inform on therapeutic opportunities for treating patients with GBM.

Citation Format: Xueqin Sherine Sun, Alea Mills. CHD5 suppresses glioblastoma by inhibiting MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1257.