bluuebunny/crossref_metadata_2025 huggingface dataset:
Thrombectomy in M2 occlusion compared to M1 occlusion: treatment effects of Thrombolysis In Cerebral Infarction (TICI) 2b and TICI 3 recanalization on functional outcome
Authors: Kniep Helge , Meyer Lukas , Broocks Gabriel , Faizy Tobias D , Bechstein Matthias , Brekenfeld Caspar , Flottmann Fabian , van Horn Noel , Geest Vincent , Winkelmeier Laurens , Alegiani Anna , Deb-Chatterji Milani , Hanning Uta , Thomalla Goetz , Fiehler Jens , Gellissen Susanne
Published: March 2023

Background

Emerging data suggest that mechanical thrombectomy (MT) might also be safe and efficient for medium and distal occlusions. This study aims to compare average treatment effects on functional outcome of different degrees of recanalization after MT in patients with M2 occlusion and M1 occlusion.

Methods

All patients enrolled in the German Stroke Registry (GSR) between June 2015 and December 2021 were analyzed. Inclusion criteria were stroke with primary M1 occlusion or M2 occlusion, and availability of relevant clinical data. 4259 patients were included, thereof 1353 with M2 occlusion and 2906 with M1 occlusion. Treatment effects were analyzed using double-robust inverse-probability-weighted regression-adjustment (IPWRA) estimators to control for confounding covariates. Binarized endpoint metrics were defined as good outcome with modified Rankin Scale (mRS) ≤2 at 90 days, and linearized endpoint metrics were defined as mRS shift pre-stroke to 90 days. Effects were evaluated for near complete recanalization (Thrombolysis In Cerebral Infarction scale (TICI) 2b) and complete recanalization (TICI 3).

Results

Treatment effect estimation for TICI ≥2b versus TICI <2b in M2 occlusions showed an increase in the probability of a good outcome from 27% to 47% with a number-needed-to-treat (NNT) of 5. For M1 occlusions the probability of a good outcome increased from 16% to 38% with NNT 4.5. TICI 3 versus TICI 2b increased the probability of a good outcome by 7 percentage points in M1 occlusions; for M2 occlusions the beneficial effect was not significant.

Conclusions

Results suggest that successful recanalization with TICI ≥2b versus TICI <2b after MT in M2 occlusions provides significant patient benefit with treatment effects comparable to M1 occlusions. The probability of functional independence increased by 20 percentage points (NNT 5) and stroke-related mRS increase was reduced by 0.9 mRS points. In contrast to M1 occlusions, complete recanalization TICI 3 versus TICI 2b had lower additional beneficial effect.
Total artificial heart implantation: supportive care preparedness planning framework
Authors: Stevens Erin , Lampert Brent C , Whitson Bryan A , Rush Laura J , Mokadam Nahush A , Barrett Todd A
Published: March 2023

Background

The total artificial heart (TAH) is an implanted device approved as a modality to stabilize patients with severe biventricular heart failure or persistent ventricular arrhythmias for evaluation and bridge to transplantation. According to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), about 450 patients received a TAH between 2006 and 2018. Patients being evaluated for a TAH are often critically ill and a TAH offers the best chance at survival. Given the prognostic uncertainty of these patients, there is a crucial need for preparedness planning to help patients and their caregivers plan for living and supporting a loved one with a TAH.

Aim

To describe an approach to preparedness planning and highlight the importance of palliative care.

Methods

We reviewed the current needs and approaches to preparedness planning for a TAH. We categorized our findings and suggest a guide to maximize conversations with patients and their decision makers.

Results

We identified four critical areas to address: the decision maker, minimal acceptable outcome/maximal acceptable burden, living with the device, and dying with the device. We suggest using a framework of mental and physical outcomes and locations of care as a way to identify minimal acceptable outcome and maximal acceptable burden.

Conclusion

Decision making for a TAH is complex. There is an urgency and patients do not always have capacity. Identifying legal decision makers and social support is critical. The surrogate decision makers should be included in preparedness planning including discussions about end-of-life care and treatment discontinuation. Having palliative care as members of the interdisciplinary mechanical circulatory support team can assist in these preparedness conversations.
Characterization of styrene-butadiene-styrene (SBS)-modified asphalt binders using the bending beam rheometer and the asphalt binder cracking device
Authors: Aurilio Mike , Tavassoti Pejoohan , Elwardany Michael , Baaj Hassan
Published: March 2023

The addition of styrene butadiene styrene (SBS) to asphalt binders has led to enhanced performance in pavements across the entire range of working temperatures. SBS-modified binders have also proven to be more difficult to characterize in terms of their rheological properties. Low-temperature properties of asphalt binders are typically evaluated using the bending beam rheometer (BBR), which was developed to measure creep stiffness. Recent refinements to the BBR analysis have led to the development of Δ Tc which is meant to provide more insight into the relaxation properties of the binder. The Asphalt Binder Cracking Device (ABCD) was developed to improve on this characterization by also taking into consideration the failure strength and coefficient of thermal contraction. Previous research has shown that the ABCD provides more valuable insight into the effect of SBS on the low-temperature properties of asphalt binders. This paper will evaluate the ability of these two low-temperature tests to characterize the performance of five different asphalt binders with increasing concentrations of SBS. It was found that the evaluation of the materials using Δ Tc was inconsistent with binder type and generally indicated that SBS reduced cracking resistance, while the ABCD critical temperature and the proposed Δ Tf parameter generally showed an improved correlation with SBS concentration.
Winter wheat responses to enhanced efficiency liquid nitrogen fertilizers in the Canadian Prairies
Authors: Owens J.L. , Wang Z. , Thomas B.W. , Hao X. , Coles K. , Rahmani E. , Karimi R. , Gill K. , Beres B.L.
Published: March 2023

To evaluate how enhanced efficiency liquid nitrogen (N) fertilizers affect winter wheat ( Triticum aestivum L.) production under irrigated and rain-fed environments, experiments were conducted at two irrigated and five rain-fed sites across the Canadian Prairies from 2013 to 2018 (22 site-years). The N fertilizers included urea ammonium nitrate (UAN) treated with ( i) urease inhibitor N-(n-butyl) thiophosphoric triamide (NBPT), ( ii) NBPT plus nitrification inhibitor dicyandiamide, and ( iii) nitrification inhibitor nitrapyrin (Nitrapyrin), as well as untreated UAN and urea, and polymer-coated urea (PCU). All fertilizers were applied by banding 50% at planting and 50% in-crop in early-spring, except PCU, where PCU was applied at planting and urea was applied in early-spring. Nitrous oxide (N2O) emissions and methane (CH4) uptake were measured at one rain-fed site from 2014 to 2017. NBPT increased grain yield by 1.2%–14% and 2.8%–4% under irrigated and rain-fed environments, respectively, relative to all the other N sources except untreated urea in the rain-fed environment. Total N uptake with NBPT was between 0% and 12% higher than the other N sources across irrigated and rain-fed environments. The results suggested that both grain yield and N use efficiency were optimized when UAN contained a urease inhibitor. All liquid enhanced efficiency fertilizers produced grain protein content greater than 11%, except Nitrapyrin under irrigated environments. Data from three site-years indicated that greenhouse gas emissions were unaffected by N source under rain-fed conditions. Liquid UAN with a urease inhibitor may have the most potential to optimize winter wheat production and N use efficiency in the Canadian Prairies.
A variety of soliton solutions of the extended Gerdjikov–Ivanov equation in the DWDM system
Authors: Raza Nauman , Batool Amna , Mehmet Baskonus Haci , Vidal Causanilles Fernando S.
Published: March 2023

In this paper, we use new extended generalized Kudryashov and improved [Formula: see text] expansion approaches to investigate Kerr law nonlinearity in the extended Gerdjikov–Ivanov equation in a dense wavelength division multiplexed system. These methods rely on a traveling wave transformation and an auxiliary equation. These approaches successfully extract trigonometric, rational and hyperbolic solutions, along with some appropriate conditions imposed on parameters. To explain the dynamics of soliton profiles, a graphical description of newly discovered solutions is also presented, which exhibits distinct physical significance. The considered methods are recognized as useful and influential tools for creating solitary wave solutions to nonlinear problems in the mathematical sciences.
Thermal performance analysis of magnetized convectively heated ferromagnetic nanoparticles for radiative cross nanofluid flow
Authors: Hussain I. , Hobiny A. , Khan W. A. , Tabrez M.
Published: March 2023

The main purpose of this work is to investigate the innovation of flow of two-dimensional (2D) ferrofluid flow passing upon stretched surface having the effect of a magnetic dipole. The said problem is selected since its use is very common in biomedical as well as engineering applications together with systems of drug targeting under magnetic effects. The impacts of magnetic dipole along with radiation parameter in flow of ferromagnetic cross fluid for a stretched region are investigated in detail by use of suitable similarity variables the nonlinear, ODEs are obtained. The desired ODEs are resolved numerically by using RK fifth-order method parallel to shooting scheme. Impacts of ferromagnetic interaction, viscous dissipation, Curie temperature, and Buongiorno parameters with convective boundary conditions are perceived for velocity, temperature and concentration fields. Furthermore, the terms like velocity, mass transfer and thermal gradients are under consideration and pictorial scrutinizing is done. Moreover, temperature of ferromagnetic fluid upsurges for enlargement in the values of ferrohydrodynamics interaction and Curie temperature parameters. Concentration of ferrofluid reveals a contrary tendency against the parameters of thermophoresis and Brownian motion. Owing to extensive application prospects of magnetized nanofluids, this area has received interest from engineers and researchers; nanofluids have a noteworthy preference over ordinary fluids.
EXACT TRAVELING WAVE SOLUTION OF GENERALIZED (4+1)-DIMENSIONAL LOCAL FRACTIONAL FOKAS EQUATION
Authors: JIANG ZHUO , ZHANG ZONG-GUO , HAN XIAO-FENG
Published: March 2023

In this paper, within the scope of the local fractional derivative theory, the (4+1)-dimensional local fractional Fokas equation is researched. The study of exact solutions of high-dimensional nonlinear partial differential equations plays an important role in understanding complex physical phenomena in reality. In this paper, the exact traveling wave solution of generalized functions is analyzed defined on Cantor sets in high-dimensional integrable systems. The results of non-differentiable solutions in different cases are numerically simulated when the fractal dimension is equal to [Formula: see text] = ln 2/ln 3. The results show that the exact solution of the local fractional Fokas equation represents the fractal waves on the shallow water surface. Through numerical simulation, we find that the exact solution of the local fractional Fokas equation can describe the fractal waves and waves characteristics of shallow water surface. It also shows that the study of traveling wave solutions of nonlinear local fractional equations has important significance in mathematical physics.
COMPLEXITY-BASED ANALYSIS OF THE VARIATIONS OF THE BRAIN’S REACTIONS IN DIFFERENT TYPES OF LOCOMOTIONS
Authors: PAKNIYAT NAJMEH , DAWI NORAZRYANA MAT , KREJCAR ONDREJ , FRISCHER ROBERT , NAMAZI HAMIDREZA
Published: March 2023

In this research, we apply complexity-based techniques to study the activations of the brain while the subjects perform different types of locomotion, including walking, jogging, and running. Therefore, we can study the effect of locomotion speed (or toughness level) on brain’s reactions. For this purpose, we analyzed the fractal dimension and approximate entropy of electroencephalogram (EEG) signals recorded from subjects while they walked, jogged, and ran for 20 s in the case of each activity. The analysis of 21 recorded samples showed that the complexity of EEG signals increases by increasing the locomotion speed. This result indicates a higher level of processing in the brain while the subjects perform a harder task. This analysis can be extended to the case of other physiological signals to study the effect of the level of exercise on different organs’ activations.
Containers and Spanning Containers in Fuzzy Graphs with Application to Human Trafficking
Authors: Ali Shanookha , Mathew Sunil , Mordeson J. N.
Published: March 2023

Containers in fuzzy graphs are studied in this paper. A container in a graph is a family of internally disjoint paths between a pair of vertices. Equivalently, a container in a fuzzy graph is a collection of internally disjoint strongest paths. Strongest paths often provide maximum contribution to a network’s traffic flow. Therefore analysis of strongest paths and containers helps examining the dynamics and complexities of networks. Apart from certain structural properties of containers, two classic results on graph degrees are also generalized to fuzzy setup. Spanning containers of blocks, fuzzy trees and locamin cycles are discussed. An algorithm to identify the maximum and minimum capacity of containers and an application related to human trafficking are also proposed.
Re-evaluating metamorphism in the southern Natal Province, South Africa
Authors: Blereau Eleanore , Spencer Christopher
Published: March 2023

The metamorphic conditions of the Natal Metamorphic Province (NMP) have been the focus of previous studies to assist with Rodinia reconstructions but there are limited constraints on the age of metamorphism. We use a combination of modern techniques to provide new constraints on the conditions and timing of metamorphism in the two southernmost terranes: the Mzumbe and Margate. Metamorphism reached granulite facies, 780–834°C at 3.9–7.8 kbar in the Mzumbe Terrane and 850–892°C at 5.7–6.1 kbar in the Margate Terrane. The new pressure and temperature constraints are supportive of isobaric cooling in the Margate Terrane as previously proposed. Peak metamorphism of the two terranes is shown to have occurred
c.
40 myr apart, which contrasts strongly with previous assumptions of coeval metamorphism. While the age of peak metamorphism of the Margate Terrane (1032.7 ± 4.7 Ma) coincides with the tectonism and magmatism associated with the emplacement of the Oribi Gorge Suite (
c.
1050–1030 Ma), the age of metamorphism of the Mzumbe Terrane (987.4 ± 8.1 Ma) occurs
c.
30–40 myr after tectonism is previously thought to have finished. We propose that models of advective cooling during transcurrent shearing can explain the metamorphic conditions and timing of the NMP.
Semantic Interaction Matching Network for Few-Shot Knowledge Graph Completion
Authors: Luo Pengfei , Zhu Xi , Xu Tong , Zheng Yi , Chen Enhong
Published: March 2023

The prosperity of knowledge graphs, as well as related downstream applications, has raised the urgent need for knowledge graph completion techniques that fully support knowledge graph reasoning tasks, especially under the circumstance of training data scarcity. Although large efforts have been made on solving this challenge via few-shot learning tools, they mainly focus on simply aggregating entity neighbors to represent few-shot references, whereas the enhancement from latent semantic correlation within neighbors has been largely ignored. To that end, in this article, we propose a novel few-shot learning solution named
SIM,
a
S
emantic
I
nteraction
M
atching network that applies a Transformer framework to enhance the entity representation with capturing semantic interaction between entity neighbors. Specifically, we first design an entity-relation fusion module to adaptively encode neighbors with incorporating relation representation. Along this line, Transformer layers are integrated to capture latent correlation within neighbors, as well as the semantic diversification of the support set. Finally, a similarity score is attentively estimated with the attention mechanism. Extensive experiments on two public benchmark datasets demonstrate that our model outperforms a variety of state-of-the-art methods by a significant margin.
Compressed Screen Content Image Super Resolution
Authors: Wang Meng , Xu Jizheng , Zhang Li , Li Junru , Zhang Kai , Wang Shiqi , Ma Siwei
Published: March 2023

Screen content has become one of the prominent mediums in the increasingly connected world. With the prevalence of remote collaboration and communication such as virtual conferences and online education, recent years have witnessed a dramatic increase in the data volume of the screen content. Screen content compression serves as the fundamental technology in fostering the storage, transmission, and exhibition of screen content. In this article, we target the super-resolution of the compressed screen content images, intending to tackle the real-world challenge problems. A dataset is proposed for the super-resolution of the screen contents contaminated with different compression distortion levels. Subsequently, we introduce the principle of the multi-hypothesis into the super resolution and propose a new paradigm for the restoration of the compressed screen content images. The luminance and sharpness similarity metric is adopted in the network learning to better adapt to the screen content characteristic and ensure perceptual fidelity. Experimental results verify the superiority and effectiveness of the proposed method.
Influence of Mo Doping on Electronic and Magnetic Properties of Monolayer CrX3: A First-Principles Study
Authors: Safi A. L. , Chakraborty Sayantani , Ahmed Md. Azaharuddin , Panda Swarup , Chattopadhyay Bidisa
Published: March 2023

In recent years two dimensional (2D) materials with intrinsic magnetism have drawn intense research interest due to their potential application in spintronic devices. Among them, chromium trihalide family has received much attention due to the exhibition of wide range of electronic and magnetic properties. Aiming to improve their spintronic properties, we have investigated the electronic and magnetic properties of mono-layer (ML) Mo-doped CrX3 (X = Cl, Br and I) using density functional theory (DFT) + Hubbard U approach. Our results show that substitution of Mo atom at the Cr site is energetically favorable. Magnetic ground state of all the members is found to be ferromagnetic (FM) which undergoes a transition to antiferromagnetic (AFM) state by applying both the compressive as well as the tensile strain. FM exchange interaction parameter and the estimated Curie temperature (T

c
) of ML CrMoX6 are found to be significantly enhanced compared to the corresponding values of pristine CrX3. All the members of ML CrX3 show magneto-crystalline anisotropy energy (MAE) favoring an out-of-plane easy axis of magnetization. Our calculations further reveal that all three compounds exhibit semiconducting properties with reduced bandgap compared to the ML CrX3 family. This property can make them useful in spintronic applications.
A Single-Layer S/X- Band Shared Aperture Antenna with MIMO Characteristics at X-Band for Airborne Synthetic Aperture Radar Applications
Authors: Bandi Raja Babu , Kothapudi Venkata Kishore , Pappula Lakshman , Kalimuthu Rajkumar , Gottapu Srinivasa Kiran
Published: March 2023

New frequencies can be supported with very effective space use by using the shared aperture antenna This work presents on designing a dual-banddual-polarized (DBDP) S/X-band shared aperture antenna (SAA) for synthetic aperture radar (SAR) applications operating at S-band frequency (3.2 GHz) and X-band frequency (9.65 GHz). The single-layer SAA DBDP S-band antenna is designed in a square-shaped patch with coaxial feeding in both vertical and horizontal polarization. The X-band antenna design is in 1 × 3 vertical series with microstrip feeding and arranged at four corners of the proposed antenna. The S-band antenna is mainly used for airborne applications such as air traffic control and surface ship radar. In contrast, the X-band antenna application is maritime vessel traffic control, defense tracking, and vehicle speed detection for law enforcement. To verify the antenna, a prototype is fabricated and measured with s-parameters. The proposed design exhibits that the gain of the S-band is 7.2 dB and for the X-band is 12.4 dB, and the isolation is achieved more than −35 dB, and for this antenna, we achieved a bandwidth of 0.12 GHz for S-band and 0.27 GHz for X-band. However, the X-band antenna is a multi-input and multioutput antenna that is to be validated by using MIMO characteristic parameters such as envelope correlation coefficient (ECC), diversity gain (DG), channel capacity loss (CCL), mean effective gain, and mutual coupling. The MIMO characteristic parameter of X-band antenna values is found to be in a similar manner to both simulated and measured values. For this X-Band antenna, ECC, DG, CCL, and mutual coupling were achieved as below 0.05, 9.5 dB, 0.5 bps/Hz, and −30 dB to −55 dB, respectively. The total size of the antenna is 100 mm × 100 mm × 1.6 mm.
Equivalence for Various Forms of Quadratic Functional Equations and Their Generalized Hyers–Ulam–Rassias Stability
Authors: Sharma Ravinder Kumar , Chandok Sumit
Published: March 2023

In this manuscript, we study the properties and equivalence results for different forms of quadratic functional equations. Using the Brzdȩk and Ciepliński fixed‐point approach, we investigate the generalized Hyers–Ulam–Rassias stability for the 3‐variables quadratic functional equation in the setting of 2‐Banach space. Also, we obtain some hyperstability results for the 3‐variables quadratic functional equation. The results obtained in this paper extend several known results of the literature to the setting of 2‐Banach space.
Global Well-Posedness and Large-Time Behavior for the Equilibrium Diffusion Model in Radiation Hydrodynamics
Authors: Jiang Peng , Ni Jinkai , Zhu Lu
Published: March 2023

In this paper, we investigate the global well-posedness of the equilibrium diffusion model in radiation hydrodynamics. The model consists of the compressible Navier-Stokes equations coupled with radiation effect terms described by the fourth power of temperature. The global existence of classical solutions to the Cauchy problem in the whole space is established when initial data is a small smooth perturbation of a constant equilibrium state: moreover, an algebraic rate of convergence of solutions toward equilibrium is obtained under additional conditions on initial data. The proof is based on the refined energy method and Fourier’s analysis.
A Comprehensive Review of Various Topologies and Control Techniques for DC-DC Converter-Based Lithium-Ion Battery Charge Equalization
Authors: Sugumaran G. , Amutha Prabha N.
Published: March 2023

Worldwide, electric vehicle (EV) sales are booming nowadays due to the rapid increase in the cost of fossil fuels. Lithium-ion batteries are very familiar in the EV industry because of their high energy per unit mass relative to other electric energy storage systems. To obtain the required voltage, several lithium-ion batteries are connected serially. Due to manufacturing inconsistencies, the voltage of serially connected cells is not always equal, which might result in a charge imbalance. This imbalance may reduce the battery’s life span due to the action of undercharging and overcharging. Battery charge equalisation (BCE) is challenging because it requires a constant voltage level in each cell. Various topologies and control strategies have been proposed in the past literature to build and improve the BCE. This study extracts the recently proposed DC-DC converter-based topologies for BCE. This study then gives a comparative analysis of various control strategies used in BCE and ends with implementing control strategies with BCE topology using a DC-DC converter. This study incorporates contextualised topologies used by BCE with design, operation, and applications. Extensive simulation results are provided to compare the performance of DC-DC converter-based BCE topologies in balancing speed. Also, a comprehensive comparison of various converter topologies and control strategies has been carried out for future investigation.
PA‐LBF: Prefix‐Based and Adaptive Learned Bloom Filter for Spatial Data
Authors: Zeng Meng , Zou Beiji , Kui Xiaoyan , Zhu Chengzhang , Xiao Ling , Chen Zhi , Du Jingyu
Published: March 2023

The recently proposed learned bloom filter (LBF) opens a new perspective on how to reconstruct bloom filters with machine learning. However, the LBF has a massive time cost and does not apply to multidimensional spatial data. In this paper, we propose a prefix‐based and adaptive learned bloom filter (PA‐LBF) for spatial data, which efficiently supports the insertion and deletion. The proposed PA‐LBF is divided into three parts: (1) the prefix‐based classification. The Z‐order space‐filling curve is used to extract data, prefix it, and classify it. (2) The adaptive learning process. The multiple independent adaptive sub‐LBFs are designed to train the suffixes of data, combined with part 1, to reduce the false positive rate (FPR), query, and learning process time consumption. (3) The backup filter uses CBF. Two kinds of backup CBF are constructed to meet the situation of different insertion and deletion frequencies. Experimental results prove the validity of the theory and show that the PA‐LBF reduces the FPR by 84.87%, 79.53%, and 43.01% with the same memory usage compared with the LBF on three real‐world spatial datasets. Moreover, the time consumption of PA‐LBF can be reduced to 5× and 2.05× that of the LBF on the query and learning process, respectively.
Data from ΔNp63α Up-Regulates the Hsp70 Gene in Human Cancer
Authors: Wu Guojun , Osada Motonobu , Guo Zhongmin , Fomenkov Alexey , Begum Shahnaz , Zhao Ming , Upadhyay Sunil , Xing Mingzhao , Wu Feng , Moon Chulso , Westra William H. , Koch Wayne M. , Mantovani Roberto , Califano Joseph A. , Ratovitski Edward , Sidransky David , Trink Barry
Published: March 2023

Abstract
HSP70, a stress response protein, is known to be a determinant of cell death and cell transformation. We show that different isoforms of p63 have different transcriptional activities on hsp70 genes. ΔNp63α, an abundantly expressed isoform of p63, activates (in vitro and in vivo), whereas TAp63γ down-regulates the expression of hsp70. We further show that the transactivation domain at the NH2 terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription. In addition, ΔNp63α regulates transcription of the hsp70 gene through its interaction with the CCAAT binding factor and NF-Y transcription factors which are known to form a complex with the CCAAT box located in the hsp70 promoter. Moreover, ΔNp63α expression correlates with HSP70 expression in all head and neck cancer cell lines. Finally, we show colocalization of ΔNp63α and HSP70 in the epithelium and coexpression of both proteins in 41 primary head and neck cancers. Our study provides strong evidence for the physiologic association between ΔNp63α and hsp70 in human cancer, thus further supporting the oncogenic potential of ΔNp63α.
Data from Glycolytic Enzymes Can Modulate Cellular Life Span
Authors: Kondoh Hiroshi , Lleonart Matilde E. , Gil Jesus , Wang Jing , Degan Paolo , Peters Gordon , Martinez Dolores , Carnero Amancio , Beach David
Published: March 2023

Abstract
An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM). A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest. Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity and, conversely, depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence. Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells. Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.
Data from FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response
Authors: Velalopoulou Anastasia , Karagounis Ilias V. , Cramer Gwendolyn M. , Kim Michele M. , Skoufos Giorgos , Goia Denisa , Hagan Sarah , Verginadis Ioannis I. , Shoniyozov Khayrullo , Chiango June , Cerullo Michelle , Varner Kelley , Yao Lutian , Qin Ling , Hatzigeorgiou Artemis G. , Minn Andy J. , Putt Mary , Lanza Matthew , Assenmacher Charles-Antoine , Radaelli Enrico , Huck Jennifer , Diffenderfer Eric , Dong Lei , Metz James , Koumenis Constantinos , Cengel Keith A. , Maity Amit , Busch Theresa M.
Published: March 2023

Abstract
In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFβ1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues.
Significance:
These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.
Data from Signaling and Transcriptional Changes Critical for Transformation of Human Cells by Simian Virus 40 Small Tumor Antigen or Protein Phosphatase 2A B56γ Knockdown
Authors: Moreno Carlos S. , Ramachandran Sumathi , Ashby Danita G. , Laycock Noelani , Plattner Courtney A. , Chen Wen , Hahn William C. , Pallas David C.
Published: March 2023

Abstract
One set of genes sufficient for transformation of primary human cells uses the combination of Ha-Ras-V12, the telomerase catalytic subunit hTERT, SV40 large tumor antigen (LT), and SV40 small tumor antigen (ST). Whereas SV40 LT inactivates the retinoblastoma protein and p53, the contribution of ST is poorly understood. The essential helper function of ST requires a functional interaction with protein phosphatase 2A (PP2A). Here we have identified changes in gene expression induced by ST and show that ST mediates these changes through both PP2A-dependent and PP2A-independent mechanisms. Knockdown of PP2A B56γ subunit can substitute for ST expression to fully transform cells expressing LT, hTERT, and Ras-V12. We also identify those genes affected similarly in two cell lines that have been fully transformed from a common parental line by two alternative mechanisms, namely ST expression or PP2A B56γ subunit knockdown. ST altered expression of genes involved in proliferation, apoptosis, integrin signaling, development, immune responses, and transcriptional regulation. ST reduced surface expression of MHC class I molecules, consistent with a need for SV40 to evade immune detection. ST expression enabled cell cycle progression in reduced serum and src phosphorylation in anchorage-independent media, whereas B56γ knockdown required normal serum levels for these phenotypes. Inhibitors of integrin and src signaling prevented anchorage-independent growth of transformed cells, suggesting that integrin and src activation are key ST-mediated events in transformation. Our data support a model in which ST promotes survival through constitutive integrin signaling, src phosphorylation, and nuclear factor κB activation, while inhibiting cell-cell adhesion pathways.
Data from Identification of Hypoxia-Regulated Proteins in Head and Neck Cancer by Proteomic and Tissue Array Profiling
Authors: Chen Yijun , Shi Gongyi , Xia Wei , Kong Christina , Zhao Shuchun , Gaw Allison F. , Chen Eunice Y. , Yang George P. , Giaccia Amato J. , Le Quynh-Thu , Koong Albert C.
Published: March 2023

Abstract
Hypoxia within solid tumors decreases therapeutic efficacy, and identification of hypoxia markers may influence the choice of therapeutic modality. Here, we used a proteomic approach to identify hypoxia-regulated proteins and validated their use as endogenous indicators of tumor hypoxia. Using two-dimensional gel electrophoresis and PowerBlot (antibody-based array), we identified a group of 20 proteins that are increased ≥1.5-fold during hypoxia. The majority of these proteins such as IκB kinase β (IKKβ), MKK3b, highly expressed in cancer (HEC), density-regulated protein 1, P150glued, nuclear transport factor 2, binder of ARL 2, Paxillin, and transcription termination factor I have not been previously reported to be hypoxia inducible. The increase in these proteins under hypoxia was mediated through posttranscriptional mechanisms. We additionally characterized the role of IKKβ, a regulator of the nuclear factor-κB transcription factor, during hypoxia. We demonstrated that IKKβ mediates cell survival during hypoxia and is induced in a variety of squamous cell carcinoma cell lines. Furthermore, we showed that IKKβ expression from tumor specimens correlated with tumor oxygenation in patients with head and neck squamous cell carcinomas. These data suggest that IKKβ is a novel endogenous marker of tumor hypoxia and may represent a new target for anticancer therapy.
Data from An Integrated View of Copy Number and Allelic Alterations in the Cancer Genome Using Single Nucleotide Polymorphism Arrays
Authors: Zhao Xiaojun , Li Cheng , Paez J. Guillermo , Chin Koei , Jänne Pasi A. , Chen Tzu-Hsiu , Girard Luc , Minna John , Christiani David , Leo Chris , Gray Joe W. , Sellers William R. , Meyerson Matthew
Published: March 2023

Abstract
Changes in DNA copy number contribute to cancer pathogenesis. We now show that high-density single nucleotide polymorphism (SNP) arrays can detect copy number alterations. By hybridizing genomic representations of breast and lung carcinoma cell line and lung tumor DNA to SNP arrays, and measuring locus-specific hybridization intensity, we detected both known and novel genomic amplifications and homozygous deletions in these cancer samples. Moreover, by combining genotyping with SNP quantitation, we could distinguish loss of heterozygosity events caused by hemizygous deletion from those that occur by copy-neutral events. The simultaneous measurement of DNA copy number changes and loss of heterozygosity events by SNP arrays should strengthen our ability to discover cancer-causing genes and to refine cancer diagnosis.
Data from Expression Profiling Reveals Novel Pathways in the Transformation of Melanocytes to Melanomas
Authors: Hoek Keith , Rimm David L. , Williams Kenneth R. , Zhao Hongyu , Ariyan Stephan , Lin Aiping , Kluger Harriet M. , Berger Aaron J. , Cheng Elaine , Trombetta E. Sergio , Wu Terence , Niinobe Michio , Yoshikawa Kazuaki , Hannigan Gregory E. , Halaban Ruth
Published: March 2023

Abstract
Affymetrix and spotted oligonucleotide microarrays were used to assess global differential gene expression comparing normal human melanocytes with six independent melanoma cell strains from advanced lesions. The data, validated at the protein level for selected genes, confirmed the overexpression in melanoma cells relative to normal melanocytes of several genes in the growth factor/receptor family that confer growth advantage and metastasis. In addition, novel pathways and patterns of associated expression in melanoma cells not reported before emerged, including the following: (a) activation of the NOTCH pathway; (b) increased Twist expression and altered expression of additional transcriptional regulators implicated in embryonic development and epidermal/mesenchymal transition; (c) coordinated activation of cancer/testis antigens; (d) coordinated down-regulation of several immune modulation genes, in particular in the IFN pathways; (e) down-regulation of several genes implicated in membrane trafficking events; and (f) down-regulation of growth suppressors, such as the Prader-Willi gene NECDIN, whose function was confirmed by overexpression of ectopic Flag-necdin. Validation of differential expression using melanoma tissue microarrays showed that reduced ubiquitin COOH-terminal esterase L1 in primary melanoma is associated with worse outcome and that increased expression of the basic helix-loop-helix protein Twist is associated with worse outcome. Some differentially expressed genes reside on chromosomal regions displaying common loss or gain in melanomas or are known to be regulated by CpG promoter methylation. These results provide a comprehensive view of changes in advanced melanoma relative to normal melanocytes and reveal new targets that can be used in assessing prognosis, staging, and therapy of melanoma patients.
Data from A Robust Algorithm for Copy Number Detection Using High-Density Oligonucleotide Single Nucleotide Polymorphism Genotyping Arrays
Authors: Nannya Yasuhito , Sanada Masashi , Nakazaki Kumi , Hosoya Noriko , Wang Lili , Hangaishi Akira , Kurokawa Mineo , Chiba Shigeru , Bailey Dione K. , Kennedy Giulia C. , Ogawa Seishi
Published: March 2023

Abstract
We have developed a robust algorithm for copy number analysis of the human genome using high-density oligonucleotide microarrays containing 116,204 single-nucleotide polymorphisms. The advantages of this algorithm include the improvement of signal-to-noise (S/N) ratios and the use of an optimized reference. The raw S/N ratios were improved by accounting for the length and GC content of the PCR products using quadratic regressions. The use of constitutional DNA, when available, gives the lowest SD values (0.16 ± 0.03) and also enables allele-based copy number detection in cancer genomes, which can unmask otherwise concealed allelic imbalances. In the absence of constitutional DNA, optimized selection of multiple normal references with the highest S/N ratios, in combination with the data regressions, dramatically improves SD values from 0.67 ± 0.12 to 0.18 ± 0.03. These improvements allow for highly reliable comparison of data across different experimental conditions, detection of allele-based copy number changes, and more accurate estimations of the range and magnitude of copy number aberrations. This algorithm has been implemented in a software package called Copy Number Analyzer for Affymetrix GeneChip Mapping 100K arrays (CNAG). Overall, these enhancements make CNAG a useful tool for high-resolution detection of copy number alterations which can help in the understanding of the pathogenesis of cancers and other diseases as well as in exploring the complexities of the human genome.
Data from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
Authors: Berger Raanan , Febbo Phillip G. , Majumder Pradip K. , Zhao Jean J. , Mukherjee Shayan , Signoretti Sabina , Campbell K. Thirza , Sellers William R. , Roberts Thomas M. , Loda Massimo , Golub Todd R. , Hahn William C.
Published: March 2023

Abstract
Androgen ablation is the primary treatment modality for patients with metastatic prostate cancer; however, the role of androgen receptor signaling in prostate cancer development remains enigmatic. Using a series of genetically defined immortalized and tumorigenic human prostate epithelial cells, we found that introduction of the androgen receptor induced differentiation of transformed prostate epithelial cells to a luminal phenotype reminiscent of organ-confined prostate cancer when placed in the prostate microenvironment. Moreover, androgen receptor expression converted previously androgen-independent, tumorigenic prostate epithelial cells into cells dependent on testosterone for tumor formation. These observations indicate that androgen receptor expression is oncogenic and addictive for the human prostate epithelium.
Data from Pten Loss Causes Hypertrophy and Increased Proliferation of Astrocytes In vivo
Authors: Fraser Melissa M. , Zhu Xiaoyan , Kwon Chang-Hyuk , Uhlmann Erik J. , Gutmann David H. , Baker Suzanne J.
Published: March 2023

Abstract
Somatic mutations of PTEN are found in many types of cancers including glioblastoma, the most malignant astrocytic tumor. PTEN mutation occurs in 25 to 40% of glioblastomas but is rarely observed in low-grade glial neoplasms. To determine the role of Pten in astrocytes and glial tumor formation, we inactivated Pten by a Cre-loxP approach with a GFAP-cre transgenic mouse that induced Cre-mediated recombination in astrocytes. Pten conditional knockout mice showed a striking progressive enlargement of the entire brain. Increased nuclear and soma size was observed in both astrocytes and neurons, which contributed in part to the increase in brain size. Pten-deficient astrocytes showed accelerated proliferation in vitro and aberrant ongoing proliferation in adult brains in vivo. In contrast, neurons lacking Pten did not show alterations in proliferation. This study shows cell-type dependent effects of Pten loss in the adult brain, including increased astrocyte proliferation that may render astroglial cells susceptible to neoplastic transformation or malignant progression.
Data from Tumor-Specific Low Molecular Weight Forms of Cyclin E Induce Genomic Instability and Resistance to p21, p27, and Antiestrogens in Breast Cancer
Authors: Akli Said , Zheng Ping-Ju , Multani Asha S. , Wingate Hannah F. , Pathak Sen , Zhang Ning , Tucker Susan L. , Chang Sandy , Keyomarsi Khandan
Published: March 2023

Abstract
The deregulated expression of cyclin E as measured by the overexpression of its low molecular weight (LMW) isoforms is a powerful predictor of poor outcome in patients with breast cancer. The mechanism by which these LMW forms give tumor cells a growth advantage is not known and is the subject of this article. In this article, we provide the pathobiological mechanisms of how these LMW forms are involved in disease progression. Specifically, we show that overexpression of the LMW forms of cyclin E but not the full-length form in MCF-7 results in (a) their hyperactivity because of increased affinity for cdk2 and resistance to inhibition by the cyclin-dependent kinase inhibitors p21 and p27, (b) resistance to the growth inhibiting effects of antiestrogens, and (c) chromosomal instability. Lastly, tumors from breast cancer patients overexpressing the LMW forms of cyclin E are polyploid in nature and are resistant to endocrine therapy. Collectively, the biochemical and functional differences between the full-length and the LMW isoforms of cyclin E provide a molecular mechanism for the poor clinical outcome observed in breast cancer patients harboring tumors expressing high levels of the LMW forms of cyclin E. These properties of the LMW forms cyclin E suggest that they are not just surrogate markers of poor outcome but bona fide mediators of aggressive disease and potential therapeutic targets for patients whose tumors overexpress these forms.
Data from The PKCα-D294G Mutant Found in Pituitary and Thyroid Tumors Fails to Transduce Extracellular Signals
Authors: Zhu Yimin , Dong Qihan , Tan Bee Jen , Lim Wee Guan , Zhou Shufeng , Duan Wei
Published: March 2023

Abstract
Protein kinase C (PKC) is a key regulator of cell proliferation, differentiation, and apoptosis and is one of the drug targets of anticancer therapy. Recently, a single point mutation (D294G) in PKCα has been found in pituitary and thyroid tumors with more invasive phenotype. Although the PKCα-D294G mutant is implicated in the progression of endocrine tumors, no apparent biochemical/cell biological abnormalities underlying tumorigenesis with this mutant have been found. We report here that the PKCα-D294G mutant is unable to bind to cellular membranes tightly despite the fact that it translocates to the membrane as efficiently as the wild-type PKCα upon treatment of phorbol ester. The impaired membrane binding is associated with this mutant's inability to transduce several antitumorigenic signals as it fails to mediate phorbol ester–stimulated translocation of myristoylated alanine–rich protein kinase C substrate (MARCKS), to activate mitogen-activated protein kinase and to augment melatonin-stimulated neurite outgrowth. Thus, the PKCα-D294G is a loss-of-function mutation. We propose that the wild-type PKCα may play important antitumorigenic roles in the progression of endocrine tumors. Therefore, developing selective activators instead of inhibitors of PKCα might provide effective pharmacological interventions for the treatment of certain endocrine tumors.
Data from High-level Coexpression of JAG1 and NOTCH1 Is Observed in Human Breast Cancer and Is Associated with Poor Overall Survival
Authors: Reedijk Michael , Odorcic Silvia , Chang Lynn , Zhang Hui , Miller Naomi , McCready David R. , Lockwood Gina , Egan Sean E.
Published: March 2023

Abstract
Aberrant activation of Notch receptors has been shown to cause mammary tumors in mice. We therefore used in situ hybridization to analyze expression of Notch ligands and receptors in human breast cancer. High levels of JAG1 and NOTCH1 were noted in a subset of tumors with poor prognosis pathologic features (P < 0.05). We therefore used tissue microarrays to analyze the expression of these genes in a collection of breast cancers from patients representing a wide spectrum of clinical stages, and from whom associated follow-up survival data was available (n = 184). Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes [5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1Hi vs. Lo (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1Hi vs. Lo (P = 0.02)]. Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003). These data (a) identify novel prognostic markers for breast cancer, (b) suggest a mechanism whereby Notch is activated in aggressive breast tumors, and (c) may identify a signaling pathway activated in poor prognosis breast cancer which can be therapeutically targeted.