bluuebunny/crossref_metadata_2025 huggingface dataset:
Light-activated macromolecular phase separation modulates transcription by reconfiguring chromatin interactions
Authors: Kim Yoon Jung , Lee Michael , Lee Yi-Tsang , Jing Ji , Sanders Jacob T. , Botten Giovanni A. , He Lian , Lyu Junhua , Zhang Yuannyu , Mettlen Marcel , Ly Peter , Zhou Yubin , Xu Jian
Published: March 2023

Biomolecular condensates participate in the regulation of gene transcription, yet the relationship between nuclear condensation and transcriptional activation remains elusive. Here, we devised a biotinylated CRISPR-dCas9–based optogenetic method, light-activated macromolecular phase separation (LAMPS), to enable inducible formation, affinity purification, and multiomic dissection of nuclear condensates at the targeted genomic loci. LAMPS-induced condensation at enhancers and promoters activates endogenous gene transcription by chromatin reconfiguration, causing increased chromatin accessibility and de novo formation of long-range chromosomal loops. Proteomic profiling of light-induced condensates by dCas9-mediated affinity purification uncovers multivalent interaction-dependent remodeling of macromolecular composition, resulting in the selective enrichment of transcriptional coactivators and chromatin structure proteins. Our findings support a model whereby the formation of nuclear condensates at native genomic loci reconfigures chromatin architecture and multiprotein assemblies to modulate gene transcription. Hence, LAMPS facilitates mechanistic interrogation of the relationship between nuclear condensation, genome structure, and gene transcription in living cells.
Early dispersal of domestic horses into the Great Plains and northern Rockies
Authors: Taylor William Timothy Treal , Librado Pablo , Hunska Tašunke Icu Mila , Shield Chief Gover Carlton , Arterberry Jimmy , Luta Wiƞ Anpetu , Nujipi Akil , Omniya Tanka , Gonzalez Mario , Means Bill , High Crane Sam , Dull Knife Barbara , Wiƞ Wakiƞyala , Tecumseh Collin Cruz , Ward Chance , Pasqual Theresa A. , Chauvey Lorelei , Tonasso-Calviere Laure , Schiavinato Stéphanie , Seguin-Orlando Andaine , Fages Antoine , Khan Naveed , Der Sarkissian Clio , Liu Xuexue , Wagner Stefanie , Leonard Beth Ginondidoy , Manzano Bruce L. , O’Malley Nancy , Leonard Jennifer A. , Bernáldez-Sánchez Eloísa , Barrey Eric , Charliquart Léa , Robbe Emilie , Denoblet Thibault , Gregersen Kristian , Vershinina Alisa O. , Weinstock Jaco , Rajić Šikanjić Petra , Mashkour Marjan , Shingiray Irina , Aury Jean-Marc , Perdereau Aude , Alquraishi Saleh , Alfarhan Ahmed H. , Al-Rasheid Khaled A. S. , Trbojević Vukičević Tajana , Buric Marcel , Sauer Eberhard , Lucas Mary , Brenner-Coltrain Joan , Bozell John R. , Thornhill Cassidee A. , Monagle Victoria , Perri Angela , Newton Cody , Hall W. Eugene , Conver Joshua L. , Le Roux Petrus , Buckser Sasha G. , Gabe Caroline , Belardi Juan Bautista , Barrón-Ortiz Christina I. , Hart Isaac A. , Ryder Christina , Sponheimer Matthew , Shapiro Beth , Southon John , Hibbs Joss , Faulkner Charlotte , Outram Alan , Patterson Rosa Laura , Palermo Katelyn , Solé Marina , William Alice , McCrory Wayne , Lindgren Gabriella , Brooks Samantha , Eché Camille , Donnadieu Cécile , Bouchez Olivier , Wincker Patrick , Hodgins Gregory , Trabert Sarah , Bethke Brandi , Roberts Patrick , Jones Emily Lena , Running Horse Collin Yvette , Orlando Ludovic
Published: March 2023

The horse is central to many Indigenous cultures across the American Southwest and the Great Plains. However, when and how horses were first integrated into Indigenous lifeways remain contentious, with extant models derived largely from colonial records. We conducted an interdisciplinary study of an assemblage of historic archaeological horse remains, integrating genomic, isotopic, radiocarbon, and paleopathological evidence. Archaeological and modern North American horses show strong Iberian genetic affinities, with later influx from British sources, but no Viking proximity. Horses rapidly spread from the south into the northern Rockies and central plains by the first half of the 17th century CE, likely through Indigenous exchange networks. They were deeply integrated into Indigenous societies before the arrival of 18th-century European observers, as reflected in herd management, ceremonial practices, and culture.
Exaggerated responses to a virus long gone
Authors: Brodin Petter
Published: March 2023

Multisystem inflammatory syndrome in children is caused by abnormal cell activation
Rewilding the city
Urban Jungle
Ben Wilson
Doubleday, 2023. 304 pp.
Authors: Dunn Rob
Published: March 2023

Urban environments can and should be rich reservoirs of biodiversity
Repurposed drug battles ‘brain-eating’ amoeba
Authors: Kornei Katherine
Published: March 2023

A drug for urinary tract infections may also treat
Balamuthia mandrillaris
In Science Journals
Authors: Vignieri Sacha , Stern Peter , Lavine Marc S. , Funk Michael A. , Yeston Jake , Nusinovich Yevgeniya , Wong Wei , Smith H. Jesse , Alderton Gemma , Osborne Ian S. , Hines Pamela J. , Scanlon Seth Thomas , Smith Keith T. , Hurtley Stella M. , Fogg Christiana N.
Published: March 2023

Highlights from the
Science
family of journals
THE EFFECTS OF ENERGY SUPPLY SHOCKS AND INTEREST RATE LIBERALIZATION IN CHINA
Authors: XUE YIHAO , LIANG QIAOYU , TONG BING
Published: March 2023

Based on a New Keynesian model with a transient interest rate peg and energy inputs in production, we examine the impact of China’s interest rate liberalization on the transmission of energy supply shocks. Theoretical analysis shows that in the face of negative supply shocks, output decreases less or even increases while inflation rises more under a fixed interest rate compared with a flexible interest rate. We construct the Divisia energy index based on Chinese data to test the model predictions. We identify energy supply shocks following the strategy of Kilian ( 2009 ) and obtain impulse responses using the local projection (LP) method proposed by Jordà ( 2005 ). The empirical results are generally consistent with our model predictions.
Ramsey’s theorem for pairs, collection, and proof size
Authors: Kołodziejczyk Leszek Aleksander , Wong Tin Lok , Yokoyama Keita
Published: March 2023

We prove that any proof of a [Formula: see text] sentence in the theory [Formula: see text] can be translated into a proof in [Formula: see text] at the cost of a polynomial increase in size. In fact, the proof in [Formula: see text] can be obtained by a polynomial-time algorithm. On the other hand, [Formula: see text] has nonelementary speedup over the weaker base theory [Formula: see text] for proofs of [Formula: see text] sentences. We also show that for [Formula: see text], proofs of [Formula: see text] sentences in [Formula: see text] can be translated into proofs in [Formula: see text] at a polynomial cost in size. Moreover, the [Formula: see text]-conservativity of [Formula: see text] over [Formula: see text] can be proved in [Formula: see text], a fragment of bounded arithmetic corresponding to polynomial-time computation. For [Formula: see text], this answers a question of Clote, Hájek and Paris.
A Hybrid Model of Primary Ensemble Empirical Mode Decomposition and Quantum Neural Network in Financial Time Series Prediction
Authors: Wang Caifeng , Yang Yukun , Xu Linlin , Wong Alexander
Published: March 2023

Financial time series are nonlinear, volatile and chaotic. Inspired by quantum computing, this paper proposed a new model, called primary ensemble empirical mode decomposition combined with quantum neural network (PEEMD-QNN) in predicting the stock index. PEEMD-QNN takes the advantages of the PEEMD which retains the main component of modal component and QNN. To demonstrate that our PEEMD-QNN model is robust, we used the new model to predict six major stock index time series in China at a specific time. Detailed experiments are implemented for both of the proposed prediction models, in which empirical mode decomposition combined with QNN (EMD-QNN), QNN and BP neural network are compared. The results demonstrate that the proposed PEEMD-QNN model has higher accuracy than BP neural network, QNN model and EMD-QNN model in stock market prediction.
An Enhanced Grey Wolf Optimisation–Deterministic Convolutional Neural Network (GWO–DCNN) Model-Based IDS in MANET
Authors: Prashanth S. K. , Iqbal Hena , Illuri Babu
Published: March 2023

At present, ensuring the security of MANET is a highly challenging chore due to the dynamic topology of the network. Hence, most of the existing Frameworks for Intrusion Detection Systems (IDS) seek to predict the attacks by utilising the clustering and classification mechanisms. Still, they face the major problems of reduced convergence speed, high error rate and increased complexity in the algorithm design. Therefore, this paper intends to utilise integrated optimisation and classification methods for accurately predicting the classified label. This framework comprises the working modules of preprocessing, feature extraction, optimisation and classification. Initially, the input datasets are preprocessed by filling the missing values, and normalising the redundant contents. After that, the Principal Component Analysis (PCA) technique is employed for selecting the set of features used for improving the classification performance. Consequently, the Grey Wolf Optimisation (GWO) technique is utilised for selecting the most optimal features based on the best fitness value, which reduces the overall complexity of IDS. Finally, the Deterministic Convolutional Neural Network (DCNN) technique is utilised for predicting whether the classified outcomes are normal or attacks. For validating the results, various performance metrics have been assessed during the analysis, and the obtained results are compared with the recent state-of-the-art models.
A Comprehensive Review and Open Issues on Supply Chain Management Models
Authors: Kalyani Dasari
Published: March 2023

The goal of SCM is to apply decisions, which end up with optimal organizational performance. Supply chain (SC) exists in service, manufacturing, and business organizations. Managing the reliability of processes and products in multi-stakeholder SC surroundings is a major challenge nowadays. As it provides protected control and traceability, trust, and immutability establishment among stakeholders with less-expensive solutions, blockchain has recently emerged as a most essential mechanism. This study critically evaluates 65 papers that discuss BCT in SCM, more specifically, an analysis of several performance measurements that are included in various papers is carried out. Additionally, a thorough analysis of the highest performance levels and various technical elements used in each task is conducted. Finally, the survey is extended with the identification of various research challenges, which may help the analysts to support improved future works on BCT in SCM. Chronological analysis is also performed.
Evaluation of Investment Strategies for Automated Material Handling Systems in Semiconductor/Display Fabrication
Authors: Son Seolhui , Chung Jaewoo
Published: March 2023

In the semiconductor and display industries, the automated material handling system (AMHS) represents an important component of fabrication facilities, which typically cost more than multi-billions of US dollars to build. One unit of fabrication facility consists of hundreds of processing steps with hundreds of expensive toolsets, and a production unit is completed after traveling over 9[Formula: see text]km for more than a month in the facility. Since all material handlings within the fabrication facility are performed by AMHS with minimal human intervention, the proper capacity of AMHS plays a very important role in fabrication operation. If the capacity is too large, it wastes the capacity of the production process as it potentially occupies too much space and investment. On the other hand, if the capacity of AMHS is too small, products under processing cannot be delivered to the expensive process toolsets on time, which causes a drop in productivity. This paper proposes an analytical method for assessing capacity planning strategies for the AMHS under various ramp-up scenarios. It proposes an analytical model consisting of three cost elements including fixed, operating, and delay costs measured by Erlang’s loss system to evaluate various investment alternatives based on the cost-of-ownership approach. We carefully prepared input data based on expert opinions to conduct an experiment that considers investment estimates for the three hypothetical alternatives. The experimental results illustrate that one-step strategy or lead strategy should be used depending on the fabrication facility’s ramp-up speed, which can be analyzed by the model proposed by this paper.
Some Results on Fuzzy Strong ϕ-b-Normed Linear Spaces
Authors: Das Abhishikta , Bag T.
Published: March 2023

This paper consists of the proof of the equivalence between two fuzzy strong [Formula: see text]-b-norms on finite-dimensional linear space and establish a Banach-type contraction theorem in this new setting.
Li–Na-based hybrid battery
Authors: Walle Kumlachew Zelalem , Pandeeswari Jayaraman , Jenisha Gunamony , Kotobuki Masashi
Published: March 2023

Li battery has been widely used in mobile electronic devices such as mobile phones and laptop computers and is currently expected as a power source for electric vehicles. Due to high cost and limited supply of Li sources, post-Li batteries like Na, K, Mg and Zn batteries have been researched intensively. However, the post-Li batteries face issues of low-energy density in monovalent ion (Na, K) batteries and slow ion diffusion in multivalent ion (Mg, Zn) batteries. The hybrid metal ion battery (HMIB) contains two different cations which can combine the benefits of fast ion diffusion of monovalent ions and high capacity of multivalent ions. Various types of HMIBs such as Na–Mg, Li–Mg, Li–Zn and so on have been studied. Among them, Li–Na HMIBs composed of Li-based cathodes and Na metal anode are the most promising as the post-Li battery owing to the application of matured Li technology and electrochemical/chemical similarity of Li to Na. In addition, dendric deposition of Na metal is suppressed by the shielding effect, allowing to employ Na metal anode in the Li–Na HMIB system. Na metal anode can provide higher capacity and reduce the material cost. Additionally, commercial Li cathode does not require further investment for manufacturing cathode materials, resulting in a significant reduction of development cost and rapid commercialization of the Li–Na HMIBs. Thus, in this review article, studies on the Li–Na HMIBs are summarized and analyzed, then future challenges for the development of Li–Na HMIBs are suggested.
A Design Framework for Ingestible Play
Authors: Li Zhuying , Wang Yan , Andres Josh , Semertzidis Nathan , Greuter Stefan , Mueller Florian
Published: April 2023

Ingestible sensors have become smaller and more powerful and allow us to envisage new human-computer interactions and bodily play experiences inside our bodies. Users can swallow ingestible sensors, which facilitate interior body sensing functions that provide data on which play experiences can be built. We call bodily play that uses ingestible sensors as play technologies “ingestible play”, and we have adopted a research-through-design (RtD) approach to investigate three prototypes. For each prototype, we conducted a field study to understand the player experiences. Based upon these results and practical design experiences, we have developed a design framework for ingestible play. We hope this work can guide the future design of ingestible play; inspire the design of play technologies inside the human body to expand the current bodily play design space; and ultimately extend our understanding of how to design for the human body by considering the bodily experience of one’s interior body.
Multiobjective Demand Double-Layer Energy Consumption Optimization Strategy for Microgrid Based on Improved HPSOFA
Authors: Zhang Bin , Wang Jue , Li Bo
Published: April 2023

In order to optimize the economy and environmental protection of microgrid, this paper establishes a demand response model based on comprehensive satisfaction, combines the advantages of the classical multiobjective particle swarm algorithm and multiobjective firefly algorithm, and proposes a hybrid particle swarm optimization and firefly algorithm (HPSOFA) to solve the joint economic and environmental dispatch problem of microgrid and improve the wind and light consumption capacity. The proposed improved algorithm introduces a random perturbation term and adaptive learning coefficients, and the algorithm is selected by the dominance relationship of individuals, which improves the diversity of populations and increases the possibility of the algorithm to solve the global optimum. The proposed algorithm is used to solve the test functions of different dimensions, and the results show that the Pareto front of HPSOFA has better distribution and accuracy, which verifies the effectiveness of the proposed algorithm. Simulation analysis is carried out using power data from a region of Liaoning Province, China, and experiments conclude that the operating cost and environmental cost of HPSOFA are significantly lower than other algorithms.
The Impact of Senior Executives’ Military Experience on Corporate GTFP
Authors: Liu Peng , Wang Tongxu
Published: March 2023

The influencing factors of corporate GTFP are a topic of considerable interest in the academia, but they are mainly limited to discussing the impact of formal institutions on corporate GTFP. Although a small amount of literature has studied the impact of clan culture, Confucian culture, and social trust on corporate GTFP based on informal institutions, they have ignored the factor of senior executives’ military experience. To fill this research gap, using a sample of Chinese A-share listed companies in Shanghai and Shenzhen from 2011 to 2021, this article studies the impact of senior executives’ military experience on corporate green total factor productivity (GTFP). The results show that senior executives’ military experience has a significant positive impact on corporate GTFP. Further research shows that the positive impact of senior executives’ military experience on corporate GTFP is more significant in regions with imperfect formal institutions. The test of mechanism effect shows that R&D investment is an important channel for executives’ military experience to promote corporate GTFP. For the first time, this article examines the impact of informal institutions on corporate GTFP from the perspective of senior executives’ military experience. The research contributions of this study are as follows: it enriches the literature on the economic consequences of senior executives’ military experience and the influencing factors of corporate GTFP and has enlightenment and reference significance for improving the corporate GTFP.
Dynamics of the Missile Launch from the Very Short-Range Mobile Firing Unit
Authors: Fedaravičius Algimantas , Jasas Karolis , Gaidys Rimvydas , Pilkauskas Kęstutis
Published: April 2023

In this article, the results of research of dynamical processes during the first stage of a missile launch from very short-range mobile firing unit (MFU) are presented. The determined laws of motion of the system’s components enabled determining characteristic motions that need to be reconstructed by the launcher simulator intended to be developed for personnel training. The half-car approach is applied for modelling the unit which consists of a vehicle and is attached to its missile launcher. The combined system is represented by a lumped-parameter model. The mathematical model is derived by applying the principle of Lagrange differential equations. Motion laws of the components of the system as its response to excitation load generated during missile launch were determined.
Competitive Removal of Perchlorate Ions by Quaternary Amine Modified Reed in the Presence of Nitrate and Phosphate
Authors: Baidas Salem , Al-Deyain Khaled , Meng Xiaoguang , Gao Baoyu
Published: April 2023

We report a kinetic and equilibrium study in which we examined the removal of perchlorate anions from water by adsorption onto modified reed (MR), an adsorption material constituted by giant reed (GR) particles whose anion adsorption properties have been enhanced by quaternary amine (QA) crosslinking. In particular, we examined how MR adsorption of perchlorate interacts competitively with concomitant adsorption of agriculture-derived phosphate and nitrate contaminants. Equilibrium and pH experiments were first conducted in single-component systems, the results of which were best described by the Langmuir-Freundlich (L-F) isotherm. Subsequent analyses of competitive effects on adsorption showed that although MR had a higher adsorption capacity for perchlorate alone than for nitrate or phosphate alone, the addition of either phosphate or nitrate to a perchlorate solution had a diminishing effect on MR adsorption of perchlorate within a natural-water pH range, with phosphate having the stronger competitive effect. Perchlorate adsorption on MR varied inversely with competing ion concentrations, providing direct evidence of the perchlorate diminution effect being attributable to anion competition. Finally, we developed a multicomponent isotherm model that describes the binary adsorption of perchlorate in the presence of each of these competing anions. The results of this work provide perchlorate removal efficiency information that is directly applicable to the design of water treatment systems.
KCa3.1 Promotes Proinflammatory Exosome Secretion by Activating AKT/Rab27a in Atrial Myocytes during Rapid Pacing
Authors: Liu Dishiwen , Chen Huiyu , Fu Yuntao , Yao Yajun , He Shanqing , Wang Youcheng , Cao Zhen , Wang Xuewen , Yang Mei , Zhao Qingyan
Published: April 2023

Purpose. The aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes. Methods. Eighteen beagles were randomly divided into the sham group (

n
=
6

), pacing group (

n
=
6

), and pacing+TRAM-34 group (

n
=
6

). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson’s trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells. Results. Atrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion. Conclusions. KCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.
Glycated Hemoglobin is a Significant Predictor of Femoral, but Not of Carotid or Popliteal, Intima-Media Thickness in Adolescents with Type 1 Diabetes: A Case-Series Study
Authors: Ho Hung-Chi , Lo Fu-Sung , Lee Jen-Kuang , Tsai Wen-Yu , Su Ta-Chen
Published: April 2023

In healthy adults, the association between the glycated hemoglobin A1c (HbA1c) level and intima-media thickness (IMT) is stronger in the femoral artery than that in the carotid artery. However, whether this differential strength of association also applies to adolescents with type 1 diabetes (T1D) is unknown. Therefore, this study aimed to examine whether IMT increases in extracarotid arteries (specifically in the lower extremities) prior to the carotid artery. In total, 286 adolescents with T1D (15.9 ± 4.9 years; 42.0% male participants) were enrolled, and the B-mode ultrasonographic measurement of IMT in the carotid, femoral, and popliteal arteries was performed. Cardiovascular risk factors, including blood pressure (BP), body mass index, lipid levels, and glycemic parameters, were evaluated. To evaluate the site-dependent relationship between IMT and cardiovascular risk factors, a linear mixed-effects model was developed with repeated IMT measurements at various arterial sites as fixed effects and participants as random effects. Glycemic parameters, lipids, uric acid, high-sensitivity C-reactive protein, and advanced glycation end-products were some cardiovascular risk factors that worsened with increasing HbA1c levels. Patients with a higher HbA1c level (>10% vs. ≤10%) had thicker IMT in the femoral artery but not in the carotid or popliteal arteries. Patients with poorer diabetic control exhibited significant changes in certain cardiovascular functions, including central systolic BP, left ventricular (LV) ejection time, LV dp/dt max, stroke volume, and brachial artery compliance. A standard mediation analysis revealed that none of the aforementioned cardiovascular functions mediated the relationship between higher HbA1c level and greater femoral IMT. In adolescents with T1D, cardiovascular risk factors deteriorate with worsening blood glucose control. In the early stages of T1D, femoral IMT may serve as a more sensitive surrogate marker for hyperglycemia-induced subclinical atherosclerosis, an effect that may not be mediated by alterations in cardiovascular functions.
Analysis of Influence of Ultra-High Pressure Water Jet Cutting Pressure Sequence on Pressure Relief and Reflection Improvement of Coal Seam
Authors: Ma Shoulong
Published: April 2023

In order to explore the pressure relief effect of the two combined pressure relief and antireflection technologies of ultra-high pressure water jet cutting before pressure and pressure before cutting, theoretical analysis, numerical simulation, and field test were used to study the main control factors of the combined high-pressure water jet slit cutting and fracturing antireflection technology. This paper introduces the combined technology of ultra-high pressure hydraulic fracturing, and analyses the mechanism of pressure relief and transparency enhancement of the combination of cutting before pressure and pressure relief after cutting. The results show that the starting pressure of the coal seam with ultra-high pressure water jet cutting and pressure relief is 13 MPa, the influence radius of hydraulic fracturing is 45–55 m, the starting pressure of the coal seam with pressure cutting and pressure relief is 16 MPa, and the influence radius of hydraulic fracturing is 35–45 m. Compared with pressure cutting combined pressure relief and permeability enhancement technology, cutting pressure relief and permeability enhancement technology can improve the permeability of coal seams more evenly and effectively, and reduce the stress of coal seams near the hole. The ultra-high pressure cutting and pressure combined technology can make the pressure relief of coal body uniform and sufficient, and the overall permeability coefficient of the coal body is greatly improved. The drilling purity is 2.3 times of the extraction purity of the ordinary single hole drilling, and the extraction influence range is increased, and the extraction effect is significantly improved. At the same time, the stress of coal body is reduced after slitting, and the starting pressure of hydraulic fracturing is reduced. The research results provide a scientific basis for the coal seam pressure relief and permeability enhancement under similar conditions in the mining area and have a broad application prospect.
Evaluating Photopheresis Regimens for Advanced CTCL: The Role of the SARS‐CoV‐2 Pandemic—A Single‐Center Retrospective Study
Authors: Hardin Jori , Cohen Leah , Rook Alain , Kim Ellen
Published: April 2023

Extracorporeal photopheresis (ECP) is an established, safe, and effective treatment for cutaneous T‐cell lymphoma (CTCL). There is no published literature reviewing the clinical efficacy of ECP at varying frequencies or the ideal duration of therapy. The SARS‐CoV‐2 pandemic necessitated a reduced frequency of ECP for patients with CTCL at our center. We performed a retrospective chart review of patients with CTCL receiving ECP at the Penn Dermatology Photopheresis Service (PDPS) on March 1, 2020, and followed up their course until January 31, 2021. Our retrospective cohort study suggests that one day of ECP with extending duration between treatments can be considered an alternative maintenance regimen in appropriate patients with stable disease on concomitant multimodality immunomodulatory therapy.
Supplementary Figure Legend from Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma
Authors: Adelaiye-Ogala Remi , Damayanti Nur P. , Orillion Ashley R. , Arisa Sreevani , Chintala Sreenivasulu , Titus Mark A. , Kao Chinghai , Pili Roberto
Published: April 2023

Supplementary Figure Legend
Supplementary methods from Flightless-I Blocks p62-Mediated Recognition of LC3 to Impede Selective Autophagy and Promote Breast Cancer Progression
Authors: He Jian-Ping , Hou Pei-Pei , Chen Qi-Tao , Wang Wei-Jia , Sun Xiao-Yu , Yang Peng-Bo , Li Ying-Ping , Yao Lu-Ming , Li Xiaotong , Jiang Xin-Dong , Chien Kun-Yi , Zhang Zhi-Ming , Wu Qiu-Wan , Cowin Allison J. , Wu Qiao , Chen Hang-Zi
Published: April 2023

Supplementary materials and methods and supplementary figure legends.
Data from Prolonged Exposure to Reduced Levels of Androgen Accelerates Prostate Cancer Progression in Nkx3.1; Pten Mutant Mice
Authors: Banach-Petrosky Whitney , Jessen Walter J. , Ouyang Xuesong , Gao Hui , Rao Jayashree , Quinn John , Aronow Bruce J. , Abate-Shen Cory
Published: March 2023

Abstract
In this report, we have investigated the relationship between androgen levels and prostate tumorigenesis in Nkx3.1; Pten mutant mice, a genetically engineered mouse model of human prostate cancer. By experimentally manipulating serum levels of testosterone in these mice for an extended period (i.e., 7 months), we have found that prolonged exposure of Nkx3.1; Pten mutant mice to androgen levels that are 10-fold lower than normal (the “Low-T” group) resulted in a marked acceleration of prostate tumorigenesis compared with those exposed to androgen levels within the reference range (the “Normal-T” group). We found that prostate tumors from the Low-T mutant mice share a similar gene expression profile as androgen-independent prostate tumors from these mutant mice, which includes the deregulated expression of several genes that are up-regulated in human hormone-refractory prostate cancer, such as Vav3 and Runx1. We propose that exposure to reduced androgens may promote prostate tumorigenesis by selecting for molecular events that promote more aggressive, hormone-refractory tumors. [Cancer Res 2007;67(19):9089–96]
Data from Loss of MLL PHD Finger 3 Is Necessary for MLL-ENL–Induced Hematopoietic Stem Cell Immortalization
Authors: Chen Jing , Santillan Donna A. , Koonce Mark , Wei Wei , Luo Roger , Thirman Michael J. , Zeleznik-Le Nancy J. , Diaz Manuel O.
Published: March 2023

Abstract
Reciprocal chromosomal translocations at the MLL gene locus result in expression of novel fusion proteins, such as MLL-ENL, associated with leukemia. The three PHD finger cassette, one of the highly conserved domains in MLL, is absent in all fusion proteins. This domain has been shown to interact with Cyp33, a cyclophilin which enhances the recruitment of histone deacetylases (HDAC) to the MLL repression domain and mediates HOX gene repression. Insertion of the third PHD finger of MLL into MLL-ENL allows the recruitment of Cyp33 and, subsequently, HDAC1 to the fusion protein. Furthermore, expression of the fusion protein with the PHD finger insertion mediates the down-regulation of the HOXC8 gene expression in a Cyp33-dependent manner. Finally, the addition of the PHD finger domain or the third PHD finger alone into MLL-ENL blocks the hematopoietic stem cell immortalization potential of the fusion protein in serial plating colony assays. Insertion of only the first and second PHD fingers has no such effect. These data support the hypothesis that the binding of Cyp33 to the MLL third PHD finger switches the MLL function from transactivation to repression. In the immortalizing MLL fusion protein, the loss of the PHD fingers, in combination with the gain of the activation domain of ENL or of other partner proteins, makes the fusion protein a constitutive transactivator. This leads to constitutive overexpression of MLL target genes that block stem cell commitment and promote stem cell renewal, probably the first step in MLL-related leukemogenesis. [Cancer Res 2008;68(15):6199–207]
Data from Transforming Growth Factor β1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7–Infected Cervical Epithelial Cells
Authors: Deng Wen , Tsao Sai Wah , Kwok Yvonne K. , Wong Esther , Huang Xiao Ru , Liu Si , Tsang Chi M. , Ngan Hextan Y.S. , Cheung Annie N.Y. , Lan Hui Yao , Guan Xin-Yuan , Cheung Annie L.M.
Published: March 2023

Abstract
Uterine cervical cancer, the second most frequently occurring cancer in women worldwide, is tightly associated with the expression of high-risk human papillomavirus [mainly human papillomavirus (HPV)-16 and HPV18] oncogenes E6 and E7 and characteristically exhibits chromosomal instability. However, the mechanisms underlying chromosomal instability in cervical cancer are still not fully understood. In this study, we observed that two of three human cervical epithelial cell lines expressing HPV16 E6E7 became immortalized without extensive chromosomal instability and crisis. The introduction of transforming growth factor (TGF)-β1, a multiple functional cytokine/growth factor, in the culture medium induced crisis, which was associated with massive chromosomal end-to-end fusions and other structural aberrations. The distributions of structural aberrations on individual chromosomes were significantly correlated with the profiles of telomere signal–free ends. The immortalized cells that emerged from the TGF-β1–induced crisis showed multiple clonal structural aberrations that were not observed in cells without TGF-β1 treatment. Overexpression of the catalytic subunit of telomerase (hTERT) abolished the effects of TGF-β1 on chromosomal instability. Interestingly, another HPV16 E6E7–expressing cervical cell line that experienced crisis and telomere dysfunction under ordinary culture condition had a higher level of autocrine TGF-β1 production than the other two crisis-free immortalized cell lines. Blocking the TGF-β1 pathway by an inhibitor of TGF-β1 receptor type I prevented the crisis and telomere-mediated chromosomal instability. In addition, more dramatic telomere shortening was observed in cervical intraepithelial neoplasias having higher expression of TGF-β1 in vivo. These results together suggest an important role of TGF-β1 in the early process of cervical carcinogenesis. [Cancer Res 2008;68(17):7200–9]
Data from Epithelial to Mesenchymal Transition in Human Breast Epithelial Cells Transformed by 17β-Estradiol
Authors: Huang Yong , Fernandez Sandra V. , Goodwin Shirlean , Russo Patricia A. , Russo Irma H. , Sutter Thomas R. , Russo Jose
Published: March 2023

Abstract
The estrogen dependence of breast cancer has long been recognized; however, the role of 17β-estradiol (E2) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E2 treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF > bcMCF >>> trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor β1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation. [Cancer Res 2007;67(23):11147–57]
Data from Chimeric NKG2D–Modified T Cells Inhibit Systemic T-Cell Lymphoma Growth in a Manner Involving Multiple Cytokines and Cytotoxic Pathways
Authors: Zhang Tong , Barber Amorette , Sentman Charles L.
Published: March 2023

Abstract
In this study, the efficacy and mechanisms of chimeric NKG2D receptor (chNKG2D)–modified T cells in eliminating NKG2D ligand–positive RMA/Rae1 lymphoma cells were evaluated. Intravenous injection of RMA/Rae1 cells led to significant tumor formation in spleens and lymph nodes within 2 weeks. Adoptive transfer of chNKG2D-modified T cells after tumor injection significantly reduced tumor burdens in both spleens and lymph nodes, and prolonged the survival of tumor-bearing mice. Multiple treatments with chNKG2D T cells resulted in long-term tumor-free survival. Moreover, these long-term survivors were resistant to rechallenge with RMA tumor cells (NKG2D ligand–negative), and their spleen and lymph node cells produced IFN-γ in response to RMA but not to other tumors in vitro, indicating immunity against RMA tumor antigens. ChNKG2D T cell–derived IFN-γ and granulocyte-macrophage colony–stimulating factor, but not perforin (Pfp), tumor necrosis factor–related apoptosis-inducing ligand, or Fas ligand (FasL) alone were critical for in vivo efficacy. T cells deficient in both Pfp and FasL did not kill NKG2D ligand–positive RMA cells in vitro. Adoptive transfer of Pfp−/−FasL−/− chNKG2D T cells had reduced in vivo efficacy, indicating that chNKG2D T cells used both mechanisms to attack RMA/Rae1 cells. Taken together, these results indicate that chNKG2D T-cell–mediated therapeutic effects are mediated by both cytokine-dependent and cytotoxic mechanisms in vivo. [Cancer Res 2007;67(22):11029–36]
Data from Genome-Wide Analysis of Aromatase Inhibitor-Resistant, Tamoxifen-Resistant, and Long-Term Estrogen-Deprived Cells Reveals a Role for Estrogen Receptor
Authors: Masri Selma , Phung Sheryl , Wang Xin , Wu Xiwei , Yuan Yate-Ching , Wagman Lawrence , Chen Shiuan
Published: March 2023

Abstract
Acquired resistance to either tamoxifen or aromatase inhibitors (AI) develops after prolonged treatment in a majority of hormone-responsive breast cancers. In an attempt to further elucidate mechanisms of acquired resistance to AIs, MCF-7aro cells resistant to letrozole (T+LET R), anastrozole (T+ANA R), and exemestane (T+EXE R), as well as long-term estrogen deprived (LTEDaro) and tamoxifen-resistant (T+TAM R) lines were generated. This is the first complete panel of endocrine therapy–resistant cell lines, which were generated as multiple independent biological replicates for unbiased genome-wide analysis using affymetrix microarrays. Although similarities are apparent, microarray results clearly show gene signatures unique to AI-resistance were inherently different from LTEDaro and T+TAM R gene expression profiles. Based on hierarchical clustering, unique estrogen-responsive gene signatures vary depending on cell line, with some genes up-regulated in all lines versus other genes up-regulated only in the AI-resistant lines. Characterization of these resistant lines showed that LTEDaro, T+LET R, and T+ANA R cells contained a constitutively active estrogen receptor (ER)α that does not require estrogen for activation. This ligand-independent activation of ER was not observed in the parental cells, as well as T+EXE R and T+TAM R cells. Further characterization of these resistant lines was performed using cell cycle analysis, immunofluorescence experiments to visualize ER subcellular localization, as well as cross-resistance studies to determine second-line inhibitor response. Using this well-defined model system, our studies provide important information regarding differences in resistance mechanisms to AIs, TAM, and LTEDaro, which are critical in overcoming resistance when treating hormone-responsive breast cancers. [Cancer Res 2008;68(12):4910–8]
Data from Direct Evidence for Epithelial-Mesenchymal Transitions in Breast Cancer
Authors: Trimboli Anthony J. , Fukino Koichi , de Bruin Alain , Wei Guo , Shen Lei , Tanner Stephan M. , Creasap Nicholas , Rosol Thomas J. , Robinson Michael L. , Eng Charis , Ostrowski Michael C. , Leone Gustavo
Published: March 2023

Abstract
We developed stromal- and epithelial-specific cre-transgenic mice to directly visualize epithelial-mesenchymal transition (EMT) during cancer progression in vivo. Using three different oncogene-driven mouse mammary tumor models and cell-fate mapping strategies, we show in vivo evidence for the existence of EMT in breast cancer and show that myc can specifically elicit this process. Hierarchical cluster analysis of genome-wide loss of heterozygosity reveals that the incidence of EMT in invasive human breast carcinomas is rare, but when it occurs it is associated with the amplification of MYC. These data provide the first direct evidence for EMT in breast cancer and suggest that its development is favored by myc-initiated events. [Cancer Res 2008;68(3):937–45]
Data from Identification of Hypoxia-Inducible Factor-1α as a Novel Target for miR-17-92 MicroRNA Cluster
Authors: Taguchi Ayumu , Yanagisawa Kiyoshi , Tanaka Masaharu , Cao Ke , Matsuyama Yasushi , Goto Hidemi , Takahashi Takashi
Published: March 2023

Abstract
MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs that posttranscriptionally repress expression of target genes through imperfect base pairing with the 3′ untranslated region. We previously reported amplification and overexpression of the miR-17-92 miRNA cluster at 13q31.3 in lung cancers, as well as growth inhibition by treatment with antisense oligonucleotides against miR-17-5p and miR-20a, constituents of miR-17-92, specifically in miR-17-92–overexpressing lung cancer cell lines. Although these findings clearly suggested important roles of miR-17-92 overexpression in lung cancers, only a few targets for the miR-17-92 cluster have been identified thus far. In this study, we identified hypoxia-inducible factor (HIF)-1α as a novel direct target for miR-17-92 through global expression profiling by mass spectrometric analysis using an isobaric tagging reagent, iTRAQ, combined with bioinformatic target prediction. This is the first report to describe negative regulation of HIF-1α by miRNA, which seemed to occur without disrupting the induction of HIF-1α for cellular adaptation to hypoxia. In addition, overexpression of c-myc led to down-regulation of HIF-1α and induction of miR-17-92, the latter of which was previously reported to be a transcriptional activation activity, suggesting that the induction of miR-17-92 may play a role at least in part in c-myc–mediated repression of HIF-1α. Together with previous reports on the functional negative regulation of c-myc by HIF-1α, our findings suggest the possible existence of an intricate and finely tuned circuit involving c-myc, miR-17-92, and HIF-1α that may play a role in cancer cell proliferation under normoxia in a cellular context–dependent manner. [Cancer Res 2008;68(14):5540–5]
Data from BAF180 Is a Critical Regulator of p21 Induction and a Tumor Suppressor Mutated in Breast Cancer
Authors: Xia Wei , Nagase Satoru , Montia Amy Gerstein , Kalachikov Sergey M. , Keniry Megan , Su Tao , Memeo Lorenzo , Hibshoosh Hanina , Parsons Ramon
Published: March 2023

Abstract
Screening for tumor suppressor genes in breast cancer revealed multiple truncating mutations of PB1, which encodes the BAF180 subunit of the PBAF chromatin remodeling complex. Mutation was associated with loss of heterozygosity of the wild-type allele. BAF180 complementation of BAF180-mutant tumor cells caused G1 arrest that was dependent on increased expression of the cyclin/cyclin-dependent kinase inhibitor p21/WAF1/CIP1. Endogenous wild-type BAF180 bound to the p21 promoter and was required for proper p21 expression and G1 arrest after transforming growth factor-β and γ-radiation treatment. BAF180 thus functions on two tumor suppressor signaling pathways as a physiologic mediator of p21 expression. We conclude that BAF180 suppresses tumorigenesis, at least in part, through its ability to regulate p21. [Cancer Res 2008;68(6):1667–74]
Data from The HER4/4ICD Estrogen Receptor Coactivator and BH3-Only Protein Is an Effector of Tamoxifen-Induced Apoptosis
Authors: Naresh Anjali , Thor Ann D. , Edgerton Susan M. , Torkko Kathleen C. , Kumar Rakesh , Jones Frank E.
Published: March 2023

Abstract
Greater than 40% of breast cancer patients treated with tamoxifen exhibit de novo or acquired tumor resistance. Recent clinical evidence indicates that loss of expression of HER4 is an independent marker for tamoxifen resistance. In direct corroboration with clinical observations, suppression of HER4 expression in the tamoxifen-sensitive MCF-7 and T47D breast tumor cell lines resulted in resistance to tamoxifen-induced apoptosis. Furthermore, HER4 expression was lost in three independent MCF-7 models of acquired tamoxifen resistance. The HER4 intracellular domain (4ICD) is an independently signaling nuclear protein that functions as a potent ERα coactivator. In addition, mitochondrial 4ICD functions as a proapoptotic BH3-only protein. Tamoxifen disrupts an estrogen-driven interaction between ERα and 4ICD while promoting mitochondrial accumulation of the 4ICD BH3-only protein. BCL-2 inhibition of tamoxifen-induced apoptosis and tamoxifen activation of BAK, independent of BAX, further supports a role for 4ICD during tamoxifen-induced apoptosis. Finally, reintroduction of HER4, but not HER4 with a mutated BH3 domain, restores tamoxifen sensitivity to tamoxifen-resistant TamR cells in a xenograft model. Clinically, breast cancer patients with tumor expression of nuclear 4ICD responded to tamoxifen therapy with no clinical failures reported after 14 years of follow-up, whereas 20% of patients lacking nuclear 4ICD expression succumbed to their disease within 10 years of diagnosis. Our identification of the HER4/4ICD BH3-only protein as a critical mediator of tamoxifen action provides a clinically important role for 4ICD in human cancer and reveals a potential tumor marker to predict patient response to tamoxifen therapy. [Cancer Res 2008;68(15):6387–95]