bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the impact of plant growth regulators on anther retention and Fusarium head blight in spring wheat (Triticum aestivum L.) infected by Fusarium graminearum in field conditions
Authors: Lee Younyoung , Brûlé-Babel Anita L. , Lawley Yvonne E. , Henriquez Maria-Antonia
Published: November 2023

Fusarium head blight (FHB) resistance in wheat is often associated with undesirable agronomic traits such as tall plant height and a propensity for lodging. Plant height in wheat is genetically controlled by some semi-dwarfing alleles that alter the plant's sensitivity to gibberellins (GAs). The presence of semi-dwarfing alleles increases the frequency of anther retention, which may contribute to FHB susceptibility by providing an initiation site for infection. The application of plant growth regulators (PGRs) may enable farmers to grow the most resistant cultivars while controlling plant height to minimize lodging risk. In this study, five spring wheat cultivars that differed in level of FHB resistance, height, and semi-dwarfing alleles were tested to determine the effect of PGRs, specifically Manipulator™ and Ethrel™, on plant height, anther retention, and FHB resistance level and the interactions between them in Winnipeg and Carman, Manitoba in 2019 and 2020. Combined field results showed that Ethrel™ significantly reduced plant height. Both PGRs did not affect the anther retention or FHB resistance levels of the tested cultivars under dry conditions. There were significant interactions between variables, but they were relatively small compared to the main treatment and cultivars. Based on the results of this study, producers could benefit from the higher levels of FHB resistance often associated with tall cultivars and use PGRs to manage plant height and lodging without increased risk of FHB.
The physical acceptability conditions and the strategies to obtain anisotropic compact objects
Authors: Suárez-Urango Daniel , Becerra Laura M. , Ospino Justo , Núñez Luis A.
Published: November 2023

We studied five methods to include anisotropy, or unequal stress distributions, in general relativistic matter configurations. We used nine acceptability conditions that the metric and physical variables must meet to determine if our models were astrophysically viable. Our analysis found the most effective way to introduce anisotropy while keeping a simple density profile. We also found a practical “rule of thumb” that relates the density at the boundary to the density at the centre of relativistic matter distributions. Additionally, we calculated the configuration radius and encountered that values observed by NICER for PSR J0740+6620 are consistent with several acceptable matter configurations, both isotropic and anisotropic.
Isogeometric analysis in computation of complex-geometry flow problems with moving boundaries and interfaces
Authors: Tezduyar Tayfun E. , Takizawa Kenji , Bazilevs Yuri
Published: November 2023

Flows with moving boundaries and interfaces (MBI) are a large class of problems that include fluid–particle and fluid–structure interactions, and in broader terms, moving solid surfaces. They also include multi-fluid flows, and as a special case of that, free-surface flows, sometimes in combination with moving solid surfaces. In some classes of MBI problems the solid surfaces could be in fast, linear or rotational relative motion or could come into contact. In almost all real-world applications, the solid surfaces would have complex geometries. All these problems are frequently encountered in engineering analysis and design, pose some of the most formidable computational challenges, and have a common core computational technology need. Bringing solution and analysis to them motivated the development of a good number of core computational methods and special methods targeting specific classes of MBI problems. This paper is an overview of some of those core and special methods. The focus is on isogeometric analysis, complex geometries, incompressible-flow Space–Time Variational Multiscale (ST-VMS) and Arbitrary Lagrangian–Eulerian VMS (ALE-VMS) methods, compressible-flow ST Streamline-Upwind/Petrov–Galerkin (ST-SUPG) and ALE-SUPG methods, and some of the special methods developed in connection with these core ST and ALE methods. The incompressible-flow ST-VMS and ALE-VMS and compressible-flow ST-SUPG and ALE-SUPG are moving-mesh methods, where the mesh moves to have mesh-resolution control near the fluid–solid interfaces, enabling high-resolution boundary-layer representation, an essential feature when the accuracy in representing the boundary layer is a priority. The computational examples presented are car and tire aerodynamics with road contact and tire deformation, ventricle–valve–aorta flow, and gas turbine flow.
FRACTIONAL DYNAMICS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH THE EFFECT OF CHEMOIMMUNOTHERAPY TREATMENT
Authors: JAN RASHID , RAZAK NORMY NORFIZA ABDUL , ALYOBI SULTAN , KHAN ZARYAB , HOSSEINI KAMYAR , PARK CHOONKIL , SALAHSHOUR SOHEIL , PAOKANTA SIRILUK
Published: November 2023

Currently, immunotherapy is seen to be the most effective cancer treatment. This is especially true while treating chronic lymphocytic leukemia (CLL), a slow-growing B-lymphocyte neoplasm that gradually compromises the immune system. Mathematical modeling is acknowledged as a key technique for analyzing theoretical and practical challenges in this field of cancer research and others. We were inspired to develop a mathematical model because of its dearth in investigations of chemotherapy-induced immunotherapy for CLL. This study effort formulates the dynamics of lymphocytic leukemia utilizing fractional calculus to conceptualize the complex processes of this viral illness. The basic idea of fractional calculus has been shown using the Atangana–Baleanu framework. For the suggested model’s chaotic and dynamic behavior, a new numerical approach is described. We inspect the stability and convergence of the suggested numerical technique in our work. The fluctuation of various system input elements has demonstrated the oscillatory and chaotic behavior of the system. Moreover, we have demonstrated how the suggested mechanism of lymphocytic leukemia infection is affected by fractional order. Through numerical simulations, the most important input parameters are emphasized, and the policymakers are given control intervention suggestions.
Resolution of the n-person Prisoners’ Dilemma by Kalai’s Preplay Negotiation Procedure
Authors: Nishihara Ko
Published: November 2023

In this paper, we apply the preplay negotiation procedure proposed by Kalai [1981] [Preplay negotiations and the prisoner’s dilemma, Math. Soc. Sci. 1, 375–379] to the [Formula: see text]-person prisoners’ dilemma with [Formula: see text] and examine whether it promotes cooperation. First, we demonstrate that every perfect equilibrium is a proper equilibrium for any extensive-form game in which players have only two alternatives in each information set. We show that if the preplay is carried out once, the preplay game has a proper equilibrium that realizes cooperation. We also show that if the preplay is executed twice, the game has a proper equilibrium that realizes cooperation regardless of the entering action profile (the starting point of the preplays). Finally, we demonstrate that the preplay game consisting of at least two preplays has a proper equilibrium that realizes cooperation.
Research on the Influence of Depth and Breadth of Equity Reform on the Performance of State Owned Enterprises Based on Dynamic Panel Data Model
Authors: Yang Guilin , Yang Guihua , Yang Wanping
Published: November 2023

In order to explore the necessity of mixed ownership reform of state-owned enterprises and clarify the direction of mixed ownership reform of state-owned enterprises in China, this paper uses dynamic panel data model and bootstrap-DEA method to study the impact of “depth” and “breadth” of equity reform of state-owned enterprises in China on the performance of state-owned enterprise. The results show that there is an inverted U-shaped relationship between performance and the level of equitable reform of state-owned enterprises. When the depth of equity reform is 36.6%, the performance of mixed reform enterprises is the best. There is a positive U-shaped relationship between the breadth of equity reform and the performance of state-owned enterprises. When the breadth of equity reform is 12.47%, the performance of mixed reform enterprises is the worst. At the same time, it is found that the average performance of the sample enterprises shows an obvious downward trend, while the performance variance of the sample enterprises shows an obvious upward trend, and this trend has not changed significantly after China launched a new round of state-owned enterprise reform in 2015. According to the above research findings, this paper believes that the intervention of government forces is conducive to promoting the survival of the fittest of state-owned enterprises and the overall optimal allocation of social resources, but we should pay attention to the adoption of market-oriented means and should not directly interfere with the mixed reform of state-owned enterprises. At the same time, the mixed reform of state-owned enterprises in China is either relatively thorough, giving up the dominance of the largest state-owned shareholder, giving other shareholders a greater say, or not to carry out mixed reform, or symbolic mixed reform, otherwise it may aggravate the internal friction of the mixed reform state-owned enterprises, resulting in worse performance.
NEW TECHNIQUE OF ELECTROCARDIOGRAM DENOISING BASED ON 1D DOUBLE-DENSITY COMPLEX DWT AND STATIONARY BIONIC WAVELET TRANSFORM
Authors: TALBI MOURAD
Published: November 2023

In this paper, we propose a new electrocardiogram (ECG) denoising technique based on the application of a 1D double-density complex discrete wavelet transform (DWT) denoising method in the stationary bionic wavelet transform (SBWT) domain. SBWT was introduced in our previous work for speech enhancement. The first step in this proposed ECG denoising technique consists of applying the SBWT to the noisy ECG signal to obtain two noisy wavelet coefficients wtb1 and wtb2. The coefficients wtb1 and wtb2 are, respectively, the details and approximation coefficients. To estimate the level, [Formula: see text], of the additive white noise corrupting the original ECG signal, we use wtb1 which is then thresholded using soft thresholding function. The noisy approximation wtb2 is denoised by using 1D double-density complex DWT denoising method. The latter requires the use of this noise level, [Formula: see text]. The results obtained from SNR computations show the performance of the ECG denoising technique proposed in this work.
Synthesis of Graphene Quantum Dots: A Comprehensive Review
Authors: Majumder Tanmoy , Bhattacharjee Abhishek
Published: November 2023

Semiconductor quantum dots such as CdSe, PbSe, PbS, CdS, CuInS, CuInSe, etc. have been extensively studied for their size-tunable optical absorption and emission properties, which enable their applications in different optoelectronics applications. Although despite having high photoaborption and photosensing properties these semiconductor quantum dots possess certain limitation due to their high level of toxicity and complex synthesis process. Graphene quantum dots (GQDs) are a zero-dimensional (0D) nontoxic nanomaterial of the carbon family, and have sparked a lot of attention in the domains of optoelectronics and electronics. In this review, a number of GQD synthesis methods such as laser ablation, hydrothermal, solvothermal, thermal pyrolysis, electrochemical, chemical oxidation and cutting have been summarized in detail.
Galactic rotation curves of spiral galaxies and dark matter in f(ℛ,T) gravity theory
Authors: Mohan Gayatri , Goswami Umananda Dev
Published: November 2023

Galactic rotation curve is a powerful indicator of the state of the gravitational field within a galaxy. The flatness of these curves indicates the presence of dark matter (DM) in galaxies and their clusters. In this paper, we focus on the possibility of explaining the rotation curves of spiral galaxies without postulating the existence of DM in the framework of [Formula: see text] gravity, where the gravitational Lagrangian is written by an arbitrary function of [Formula: see text], the Ricci scalar and of [Formula: see text], the trace of energy–momentum tensor [Formula: see text]. We derive the gravitational field equations in this gravity theory for the static spherically symmetric spacetime and solve the equations for metric coefficients using a specific model that has minimal coupling between matter and geometry. The orbital motion of a massive test particle moving in a stable circular orbit is considered and the behavior of its tangential velocity with the help of the considered model is studied. We compare the theoretical result predicted by the model with observations of a sample of 19 galaxies by generating and fitting rotation curves for the test particle to check the viability of the model. It is observed that the model could almost successfully explain the galactic dynamics of these galaxies without the need of DM at large distances from the galactic center.
Cosmology of new Tsallis holographic dark energy-based reconstructed models in teleparallel theories
Authors: Waheed Saira
Published: November 2023

Reconstruction of Lagrangian functions present in the action of modified gravity theories is one of the most captivating subjects in recent cosmology. This paper reconstructs the form of Lagrangian function of some teleparallel theories based on a recently proposed holographic dark energy model namely new Tsallis HDE. For this purpose, we assume ordinary matter contents as perfect fluid with background geometry as flat FRW spacetime. On the first place, we reconstruct [Formula: see text] function by taking some well-known IR cutoff choices into account like Hubble radius, event horizon, Granda–Oliveros cutoff and conformal time as different cases. Moreover, we consider two entropy corrected forms of new Tsallis HDE with the simplest choice for IR cutoff. We explore the graphical behavior of different cosmic quantities, e.g. dark energy EoS parameter, the generalized second law of thermodynamics, the null energy condition, speed of sound and trajectories in [Formula: see text] plane for these reconstructed solutions and discuss their viability. Then we extend our work to [Formula: see text] theory and reconstruct the Lagrangian function for new Tsallis HDE with three simple choices of IR cutoff (Hubble radius and event horizon), and Granda–Oliveros cutoff and discuss the significance of obtained solutions graphically through same cosmic measures. It is found that presented models are consistent with the recent cosmic data values, however, stability can be achieved in some certain cases only.
Optimization and analysis of machining performance for the milling process during milling of W-Al-Si-C alloy material
Authors: Kumar Manoj , Oza Ankit D. , Bhole Kiran S. , Kumar Manoj , Gupta Manish , Lala Sumit Das
Published: November 2023

This study determined the optimum HSS cutting tool technique parameters for milling W-Al-Si-C rods using Taguchi methodology. This paper explains the empirical results of the selection of appropriate cutting settings that assure lower power consumption in high-end Computer Numerical Control (CNC) machines. An experiment employing the Taguchi methodology on an extruded W-Al- Si-C rod was performed on a CNC lathe with cutting speed, feed rate, and depth of cut as the process parameters. The performance characteristics (energy usage) were quantified by a data collection system. Minor energy process parameters were selected after data analysis. Experimental results are presented to demonstrate the worth of the chosen methodology. A total of 350[Formula: see text]rpm, 0.37[Formula: see text]mm/rev feed rate, and 1[Formula: see text]mm of cut depth produced the best MRR result. The maximum material removal rate (MRR) is obtained at lower levels of spindle speed and depth of cut, i.e., 1.452[Formula: see text]g/sec.
Demand-driven Urban Facility Visit Prediction
Authors: Zhang Yunke , Li Tong , Yuan Yuan , Xu Fengli , Yang Fan , Sun Funing , Li Yong
Published: November 2023

Predicting citizens’ visiting behaviors to urban facilities is instrumental for city governors and planners to detect inequalities in urban opportunities and optimize the distribution of facilities and resources. Previous works predict facility visits simply using observed visit behavior, yet citizens’ intrinsic demands for facilities are not characterized explicitly, causing potential incorrect learned relations in the prediction results. In this article, to make up for this deficiency, we present a demand-driven urban facility visit prediction method that decomposes citizens’ visits to facilities into their unobservable demands and their capability to fulfill them. Demands are expressed as the function of regional demographic attributes by a neural network, and the fulfillment capability is determined by the urban region’s spatial accessibility to facilities. Extensive evaluations of datasets of three large cities confirm the efficiency and rationality of our model. Our method outperforms the best state-of-the-art model by 8.28% on average in facility visit prediction tasks. Further analyses demonstrate the reasonableness of recovered facility demands and their relationship with citizen demographics. For instance, senior citizens tend to have higher medical demands but lower shopping demands. Meanwhile, estimated capabilities and accessibilities provide deeper insights into the decaying accessibility with respect to spatial distance and facilities’ diverse functions in the urban environment. Our findings shed light on demand-driven urban data mining and demand-based urban facility planning.
Endurance capacity impairment in cold air ranging from skin cooling to mild hypothermia
Authors: Wallace Phillip J. , Hartley Geoffrey L. , Nowlan Josh G. , Ljubanovich Johnathan , Sieh Nina , Taber Michael J. , Gagnon Dominique D. , Cheung Stephen S.
Published: November 2023

We developed a novel protocol that cooled skin temperature, or skin plus core temperature (Δ−0.5°C or Δ−1.0 °C), to determine a dose-response of cold exposure on endurance capacity at 70% peak power output. Skin cooling significantly impaired exercise tolerance time by ∼31%, whereas core cooling led to a further reduction of 30%–40% with no difference between Δ−0.5°C and Δ−1.0°C. Overall, simply cooling the skin impaired endurance capacity, but this impairment is further magnified by core cooling.
Barbell Technique for Three-Dimensional Bone Augmentation
Authors: Nunes Marcelo Pereira , de Macedo Luís Guilherme Scavone , Santamaria Mauro Pedrine , Ribeiro João Carlos , Moy Peter Karyen , Pelegrine André Antonio
Published: November 2023

Introduction. Appositional bone augmentation is considered a challenging surgical problem to correct for the deficient alveolar ridge. To overcome this challenge, a novel concept was recently published called “Barbell Technique.” This technique has been used more commonly for horizontal bone augmentation. To our knowledge, this is the first report on using the Barbell Technique for vertical bone augmentation. Case Report. This report describes and demonstrates the clinical feasibility of the use of this concept in the reconstruction of a tridimensional alveolar ridge defect in the anterior maxilla. Due to the severity of the defect, both hard and soft tissue deficiencies required augmentation. The first surgery involved a soft tissue grafting procedure while in the second surgical procedure, hard tissue augment was performed using the Barbell device to provide both vertical and horizontal support for the hard tissue graft. The donor material consisted of equal volume of xenograft and autogenous bone used to fill the defect and covered with a collagen barrier membrane. After a healing period of 9 months, the site was reopened. Bone formation clinically verified the correction of alveolar bone contour and volume permitted placement of two titanium implants after the removal of Barbell device. Conclusion. This case report demonstrates successful vertical and horizontal bone augmentation of a critical size defect in the anterior maxilla, correcting both hard and soft tissue contours, and providing the tissues needed to support dental implants in the anterior maxilla.
Diabetes Mellitus and Gastric Cancer: Correlation and Potential Mechanisms
Authors: Wang Li , Zhang Zhe
Published: November 2023

This review summarizes the correlation between diabetes mellitus (DM) and gastric cancer (GC) from the perspectives of epidemiology, drug use, and potential mechanisms. The association between DM and GC is inconclusive, and the positive direction of the association reported in most published meta-analyses suggests that DM may be an independent risk factor for GC. Many clinical investigations have shown that people with DM and GC who undergo gastrectomy may have better glycemic control. The potential link between DM and GC may involve the interaction of multiple common risk factors, such as obesity, hyperglycemia and hyperinsulinemia, H. pylori infection, and the use of metformin. Although in vitro and in vivo data support that H. pylori infection status and metformin can influence GC risk in DM patients, there are conflicting results. Patient survival outcomes are influenced by multiple factors, so further research is needed to identify the patients who may benefit.
A Cross-Sectional Study Exploring Mental Health among Patients Suffering from Dengue in Pakistani Tertiary Care Hospitals
Authors: Faiza  , Jawad Fatima , Chaudhary Namra , Younas Mahnoor , Fatima Sadaf , Ayub Fiza , Awan Allah Bukhsh , Khan Tahir Mehmood
Published: November 2023

Background. Dengue, known as “Tropical flu,” is a widespread disease that has recently become endemic in many Asian countries. Dengue disease still lacks research in many aspects, specifically the impact of patient factors and disease prognosis on mental health. This is a cross-sectional study that evaluated the impact of different patient factors on depression, stress, and anxiety in patients with acute dengue infection. Methods. An interview-based data were collected through a questionnaire containing patient sociodemographic parameters, clinical parameters, and DASS 21 questions. Independent sample

T

-test, one-way ANOVA test, and post hoc test were performed to determine the degree of association of psychological manifestations with clinical signs and symptoms considering a level of significance of

p
<
0.05

. Results. The patients from 39 years to 49 years of age had a higher association with stress, depression, and anxiety. The participants at primary and matriculation level education had a higher association with dengue-associated anxiety. Among the three levels of fever, i.e., mild (<102°F), moderate (102-103°F), and severe (>103°F), the participants suffering from severe fever experienced more anxiety and so was those with intense pain and stress. Conclusions. According to the DASS-21 tool, patients with severe pain and high-degree fever during dengue had significant stress and anxiety symptoms, respectively, than the patients with mild or moderate pain and fever. Middle-aged patients with low literacy levels were also found to have significant associations with stress, anxiety, and depression. To our knowledge, this is one of the first studies in Pakistan that in-depth explored the impact of patient factors’ variability on psychological illnesses related to dengue. These findings may warrant practitioners to integrate timely psychological screening and care for dengue patients.
Quality of Life Assessments Utilized in Vitiligo Clinical Trials
Authors: Pathak Gaurav N. , Chandy Rithi J. , Naini Vidisha , Feldman Steven R. , Rao Babar K.
Published: November 2023

Introduction. Vitiligo is an acquired autoimmune disease associated with high psychosocial burden. As novel treatments are being developed in clinical trials, assessing vitiligo disease burden extends beyond physical manifestations. Including quality of life (QoL) measures in vitiligo clinical trials can better capture disease‐specific psychosocial concerns and facilitate cross comparisons amongst interventions. Objective. To determine the frequency and types of QoL measures utilized in vitiligo clinical trials and comment on how this has changed longitudinally. Methods. A search of vitiligo clinical trials using clinicaltrials.gov was conducted. Phase 2 and phase 3 trials published in English from January 2000 to July 2023 were eligible for this review. Characteristics of clinical trial parameters were compared to those of non‐QoL reporting clinical trials using Pearson’s χ2 tests (or Fisher’s if low n). Results. A total of 60 clinical trials were eligible for this review, of which 40% included a QoL measure in their study design. Phase 3 clinical trials (p = 0.002), larger (100+ participants) trials (p = 0.063), U.S. trials (p = 0.029), and pharmaceutical interventions (p = 0.022) were more likely to include QoL measures in their design. The number of clinical trials has been increasing over time, with 8 trials from 2000 to 2010, 32 total trials from 2011 to 2020, and 20 trials from 2021 to 2023. The most commonly used QoL measures were the Dermatology Life Quality Index (DLQI, 55.2%), Children′s Dermatology Life Quality Index (CDLQI, 13.8%), and Vitiligo‐specific quality of life instrument (VitiQoL, 13.8%). Over time, the VitiQoL and CDLQI have been used more frequently. Conclusion. Although vitiligo is associated with high psychological and emotional burden, less than half of vitiligo trials utilize QoL measures. The general dermatology QoL measures, namely the DLQI and CDLQI, are the most commonly used QoL assessments. As the number of clinical trials is increasing, vitiligo‐specific questionnaires may better capture unique vitiligo‐specific concerns. Standardizing the types of and implementation of QoL questionnaires in clinical trials can aid in assessing outcome measures across clinical trials worldwide and allow for better data interpretation, comparability, and clinical application of results.
Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum
Authors: Grabski Isabella N. , Heymach John V. , Kehl Kenneth L. , Kopetz Scott , Lau Ken S. , Riely Gregory J. , Schrag Deborah , Yaeger Rona , Irizarry Rafael A. , Haigis Kevin M.
Published: November 2023

Background:

KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues.

Methods:

We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival.

Results:

KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by PCA, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types.

Conclusions:

KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions.

Impact:

Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.
PDGFRβ Signaling Cooperates with β-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis
Authors: Hu Jia , Hameed Meera R. , Agaram Narasimhan P. , Whiting Karissa A. , Qin Li-Xuan , Villano Anthony M. , O'Connor Rachael B. , Rozenberg Julian M. , Cohen Sonia , Prendergast Katherine , Kryeziu Sara , White Richard L. , Posner Mitchell C. , Socci Nicholas D. , Gounder Mrinal M. , Singer Samuel , Crago Aimee M.
Published: November 2023

Purpose:

This study sought to identify β-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRβ), affect these targets to alter natural history or treatment response in patients.

Experimental Design:

In vitro experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.

Results:

CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell–induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.

Conclusions:

The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.
Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: November 2023

N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.
Table S6 from Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription
Authors: Frigault Melanie M. , Mithal Arushi , Wong Harvey , Stelte-Ludwig Beatrix , Mandava Vinay , Huang Xin , Birkett Joseph , Johnson Amy J. , Izumi Raquel , Hamdy Ahmed
Published: November 2023

Supplementary Table 6 captures the maximal downregulation timepoint for novel and known DEGs post enitociclb treatment in MYC+ DLBCL patients.
Figure S2 from Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription
Authors: Frigault Melanie M. , Mithal Arushi , Wong Harvey , Stelte-Ludwig Beatrix , Mandava Vinay , Huang Xin , Birkett Joseph , Johnson Amy J. , Izumi Raquel , Hamdy Ahmed
Published: November 2023

Supplementary Figure 2: Downregulation of MYC and MCL1 is detected in the whole blood of Enitociclib-treated DH-DLBCL as well as other MYC+ NHL patients
Interference of Herbal Medicine with Axitinib in Metastatic Renal Cell Cancer Treatment: A Case Study
Authors: Himmelreich Friederike , Jetter Alexander , Kiessling Michael K. , Kadvany Yannick , Trojan Andreas
Published: November 2023

Introduction: The awareness and the clinical relevance of the potential interactions between standard and complementary medicine are increasing in medical oncology. Nonetheless, the research and experience of the efficacy, safety, and toxicity of herbal substances are poorly documented. Case Presentation: Here, we report the case of a 68-year-old female patient who had been diagnosed with advanced renal cell cancer with metastasis in the liver and pancreas and had undergone surgical resection with hemi-hepatectomy and resection of metastasis in the pancreas in November 2021. Thereafter, chemotherapy was immediately initiated with three-weekly infusions of pembrolizumab and daily intake of the tyrosine kinase inhibitor axitinib. Surprisingly, 3 months after initiation of systemic treatment, the patient developed early progression and metastasis in the liver, which was then treated with selective internal radiotherapy. Despite continued axitinib and pembrolizumab treatment, a short-term follow-up in November 2022 revealed another metastatic lesion in her pancreas. Due to the presumed lack of response to treatment, the plasma concentration of axitinib was measured and found to demonstrate subtherapeutic levels of exposure. Upon extended anamnesis, the patient reported regular intake of herbal substances prescribed by her oncology acupuncturist for gastrointestinal complaints associated with the primary operation. Conclusion: Further clinical-pharmacological workup strikingly demonstrated a reduction of the therapeutic concentration of axitinib of about 90%, likely caused by herbal drugs such as Dang gui and Bai zhu.
The Factors Influencing Shoulder Mobility Disorders in Patients after Radical Breast Cancer Surgery: A Cross-Sectional Study
Authors: Zhang Xin , Wang Chao , Fan Jialin , Murakami Shinichiro , Xie Hualong , Huo Ming
Published: November 2023

Introduction: This study is a cross-sectional study that investigated the factors influencing shoulder mobility in terms of pain, grip strength, and supraspinatus muscle thickness in patients with impaired shoulder mobility during chemotherapy after radical breast cancer surgery. Methods: This study included 165 female patients with unilateral breast cancer who had shoulder joint mobility disorders during chemotherapy within 3 months after surgery. The clinical examination included the maximum active range of motion of the shoulder (flexion, extension, abduction, adduction, external rotation, and internal rotation), pain score (visual analog scale [VAS]), grip strength, and supraspinatus muscle thickness. Results: During shoulder abduction, supraspinatus muscle thickness was greatest at 90°, lowest at 0°, and higher at 60° than at 30° (p < 0.01). The factors influencing the active movement of shoulder flexion were the VAS score, body weight, grip strength, and supraspinatus contraction rate (R2 = 0.295), while the factors influencing active shoulder abduction were the VAS score, body weight, grip strength, supraspinatus muscle thickness (drooping position), and supraspinatus contraction rate (R2 = 0.295). Moreover, the factors influencing the active movement of shoulder external rotation were age, VAS score, body weight, grip strength, and supraspinatus muscle thickness (drooping position) (R2 = 0.258). There were no significant results from multiple linear regressions for shoulder extension, adduction, or internal rotation. Conclusion: Pain, weight, grip strength, supraspinatus muscle thickness, and supraspinatus distensibility are the main factors affecting shoulder flexion, abduction, and external rotation. In addition, supraspinatus muscle thickness and contraction rate may be a new index for assessing shoulder dysfunction.
Transcranial Magnetic Stimulation for Developmental Neuropsychiatric Disorders with Inflammation
Authors: Vaishnavi Sandeep
Published: November 2023

Background: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that may potentially be helpful for neuropsychiatric symptoms of developmental disorders with inflammatory aspects. TMS utilizes a varying magnetic field to induce electrical changes in the brain. Repetitive use of TMS modulates plasticity at multiple levels, particularly at the synapse and network level. Summary: As inflammation can affect synaptic plasticity negatively, TMS may theoretically be a tool to address this inflammation-induced dysfunction. There are also data to suggest that TMS can directly downregulate inflammation. Neuropsychiatric consequences of multiple disorders with inflammatory aspects, particularly neurodevelopmental disorders like autism, Tourette syndrome, and obsessive-compulsive disorder (OCD), maybe treated effectively with TMS. Treatment of OCD, treatment-resistant major depression, and nicotine cessation (all in adults) are currently FDA-cleared indications, while migraine is cleared for ages 12 and above. Key Messages: TMS will likely continue to grow in terms of indications as research continues to assess what brain networks are dysfunctional in various disorders and it becomes clearer how to modulate these networks. TMS may thus be best understood as a technology platform that can be utilized to modulate different brain networks affected in neuropsychiatric disorders. TMS is likely to become an increasingly important tool in targeting brain networks that could become dysfunctional in part due to inflammation in the developing brain and addressing consequent neuropsychiatric symptoms.
Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice
Authors: Wu Chenxia , Zheng Peiyao , Ma Lan , Xu Chen , Hu Luoxia , Yang Zhiyi , Fei Fan , Shen Zhuxia , Zhang Xue , Wu Ziheng , Cheng Hongqiang , Mao Wei , Ke Yuehai
Published: November 2023

BACKGROUND:

Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown.

METHODS:

APOE (apolipoprotein E) or LDLR (low-density lipoprotein receptor) null mice treated with SHP099 were fed a Western diet for 8 weeks, while
Shp2

MKO

:ApoE

−/−

or
Shp2

MKO

:Ldlr

−/−

mice and exo-AAV8-SHP2
E76K
/
ApoE

−/−

mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice.

RESULTS:

Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and LDLR null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and LDLR null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels.

CONCLUSIONS:

Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/LDLR null mice.
Chronic Hepatitis B Virus Infection and Risk of Stroke Types: A Prospective Cohort Study of 500 000 Chinese Adults
Authors: Hamilton Elizabeth M. , Yang Ling , Wright Neil , Turnbull Iain , Mentzer Alexander J. , Matthews Philippa C. , Chen Yiping , Du Huaidong , Kartsonaki Christiana , Pang Yuanjie , Pei Pei , Tian Huizi , Yang Xiaoming , Avery Daniel , Yu Canqing , Lv Jun , Clarke Robert , Li Liming , Millwood Iona Y. , Chen Zhengming
Published: November 2023

BACKGROUND:

Stroke is a leading cause of mortality and permanent disability in China, with large and unexplained geographic variations in rates of different stroke types. Chronic hepatitis B virus infection is prevalent among Chinese adults and may play a role in stroke cause.

METHODS:

The prospective China Kadoorie Biobank included >500 000 adults aged 30 to 79 years who were recruited from 10 (5 urban and 5 rural) geographically diverse areas of China from 2004 to 2008, with determination of hepatitis B surface antigen (HBsAg) positivity at baseline. During 11 years of follow-up, a total of 59 117 incident stroke cases occurred, including 11 318 intracerebral hemorrhage (ICH), 49 971 ischemic stroke, 995 subarachnoid hemorrhage, and 3036 other/unspecified stroke. Cox regression models were used to estimate adjusted hazard ratios (HRs) for risk of stroke types associated with HBsAg positivity. In a subset of 17 833 participants, liver enzymes and lipids levels were measured and compared by HBsAg status.

RESULTS:

Overall, 3.0% of participants were positive for HBsAg. HBsAg positivity was associated with an increased risk of ICH (adjusted HR, 1.29 [95% CI, 1.16–1.44]), similarly for fatal (n=5982; adjusted HR, 1.36 [95% CI, 1.16–1.59]) and nonfatal (n=5336; adjusted HR, 1.23 [95% CI, 1.06–1.44]) ICH. There were no significant associations of HBsAg positivity with risks of ischemic stroke (adjusted HR, 0.97 [95% CI, 0.92–1.03]), subarachnoid hemorrhage (adjusted HR, 0.87 [95% CI, 0.57–1.33]), or other/unspecified stroke (adjusted HR, 1.12 [95% CI, 0.89–1.42]). Compared with HBsAg-negative counterparts, HBsAg-positive individuals had lower lipid and albumin levels and higher liver enzyme levels. After adjustment for liver enzymes and albumin, the association with ICH from HBsAg positivity attenuated to 1.15 (0.90–1.48), suggesting possible mediation by abnormal liver function.

CONCLUSIONS:

Among Chinese adults, chronic hepatitis B virus infection is associated with an increased risk of ICH but not other stroke types, which may be mediated through liver dysfunction and altered lipid metabolism.
Improvement in Delivery of Ischemic Stroke Treatments but Stagnation of Clinical Outcomes in Young Adults in South Korea
Authors: Kim Jonguk , Kim Jun Yup , Kang Jihoon , Kim Beom Joon , Han Moon-Ku , Lee Jeong-Yoon , Park Tai Hwan , Lee Keon-Joo , Kim Joon-Tae , Choi Kang-Ho , Park Jong-Moo , Kang Kyusik , Lee Soo Joo , Kim Jae Guk , Cha Jae-Kwan , Kim Dae-Hyun , Lee Kyungbok , Lee Jun , Hong Keun-Sik , Cho Yong-Jin , Park Hong-Kyun , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi-Sun , Kim Dong-Eog , Ryu Wi-Sun , Choi Jay Chol , Kwon Jee-Hyun , Kim Wook-Joo , Shin Dong-Ick , Yum Kyu Sun , Sohn Sung Il , Hong Jeong-Ho , Lee Sang-Hwa , Lee Ji Sung , Lee Juneyoung , Gorelick Philip B. , Bae Hee-Joon
Published: November 2023

BACKGROUND:

There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population.

METHODS:

Using a prospective multicenter stroke registry in Korea, young adults (aged 18–50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed.

RESULTS:

A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (
P
trend
=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%–13.8% and 3.2%–9.2%, respectively;
P
trend
<0.01). Door-to-needle time improved (
P
trend
<.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%–47.0%), direct oral anticoagulants for atrial fibrillation (0.0%–56.2%), and statins for large artery atherosclerosis (76.1%–95.3%) increased (
P
trend
<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011–2013 and 2.3% in 2017–2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%–69.1%) and 0 to 2 (87.6%–86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%–5.5%;
P
trend
=0.04), although the difference was not significant after adjusting for sex and age.

CONCLUSIONS:

Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress.