bluuebunny/crossref_metadata_2025 huggingface dataset:
Voxel-Wise Medical Image Generalization for Eliminating Distribution Shift
Authors: Li Feifei , Wang Yuanbin , Beyan Oya , Schöneck Mirjam , Caldeira Liliana Lourenco
Published: January 2024

Currently, the medical field is witnessing an increase in the use of machine learning techniques. Supervised learning methods adopted in classification, prediction, and segmentation tasks for medical images always experience decreased performance when the training and testing datasets do not follow the independent and identically distributed assumption. These distribution shift situations seriously influence machine learning applications’ robustness, fairness, and trustworthiness in the medical domain. Hence, in this article, we adopt the CycleGAN (generative adversarial network) method to cycle train the computed tomography data from different scanners/manufacturers. It aims to eliminate the distribution shift from diverse data terminals based on our previous work [
14
]. However, due to the model collapse problem and generative mechanisms of the GAN-based model, the images we generated contained serious artifacts. To remove the boundary marks and artifacts, we adopt score-based diffusion generative models to refine the images voxel-wisely. This innovative combination of two generative models enhances the quality of data providers while maintaining significant features. Meanwhile, we use five paired patients’ medical images to deal with the evaluation experiments with structural similarity index measure metrics and the segmentation model’s performance comparison. We conclude that CycleGAN can be utilized as an efficient data augmentation technique rather than a distribution-shift-eliminating method. In contrast, the denoising diffusion the denoising diffusion model is more suitable for dealing with the distribution shift problem aroused by the different terminal modules. The limitation of generative methods applied in medical images is the difficulty in obtaining large and diverse datasets that accurately capture the complexity of biological structure and variability. In our following research, we plan to assess the initial and generated datasets to explore more possibilities to overcome the above limitation. We will also incorporate the generative methods into the federated learning architecture, which can maintain their advantages and resolve the distribution shift issue on a larger scale.
EPHA: An Energy-efficient Parallel Hybrid Architecture for ANNs and SNNs
Authors: Zhao Yunping , Ma Sheng , Liu Hengzhu , Huang Libo
Published: January 2024

Artificial neural networks (ANNs) and spiking neural networks (SNNs) are two general approaches to achieve artificial intelligence (AI). The former have been widely used in academia and industry fields; the latter, SNNs, are more similar to biological neural networks and can realize ultra-low power consumption, thus have received widespread research attention. However, due to their fundamental differences in computation formula and information coding, the two methods often require different and incompatible platforms. Alongside the development of AI, a general platform that can support both ANNs and SNNs is necessary. Moreover, there are some similarities between ANNs and SNNs, which leaves room to deploy different networks on the same architecture. However, there is little related research on this topic. Accordingly, this article presents an energy-efficient, scalable, and non-Von Neumann architecture (EPHA) for ANNs and SNNs. Our study combines device-, circuit-, architecture-, and algorithm-level innovations to achieve a parallel architecture with ultra-low power consumption. We use the compensated ferrimagnet to act as both synapses and neurons to store weights and perform dot-product operations, respectively. Moreover, we propose a novel computing flow to reduce the operations across multiple crossbar arrays, which enables our design to conduct large and complex tasks. On a suite of ANN and SNN workloads, the EPHA is 1.6× more power-efficient than a state-of-the-art design, NEBULA, in the ANN mode. In the SNN mode, our design is 4 orders of magnitude more than the Loihi in power efficiency.
Optimizing VLIW Instruction Scheduling via a Two-Dimensional Constrained Dynamic Programming
Authors: Deng Can , Chen Zhaoyun , Shi Yang , Ma Yimin , Wen Mei , Luo Lei
Published: January 2024

Typical embedded processors, such as Digital Signal Processors (DSPs), usually adopt Very Long Instruction Word (VLIW) architecture to improve computing efficiency. The performance of VLIW processors heavily relies on Instruction-Level Parallelism (ILP). Therefore, it is crucial to develop an efficient instruction scheduling algorithm to explore more ILP. While heuristic algorithms are widely used in modern compilers due to simple implementation and low computational cost, they have limitations in providing accurate solutions and are prone to local optima. On the other hand, exact algorithms can usually find the optimal solution, but their high time overhead makes them less suitable for large-scale problems. This article proposes a two-dimensional constrained dynamic programming (TDCDP) approach and a quantitative model for instruction scheduling. The TDCDP approach achieves near-optimal solutions within an acceptable time overhead. Furthermore, we integrate our TDCDP approach into mainstream compiler architecture, encompassing Pre- and Post-RA (register allocation) scheduling. We conduct a quantitative evaluation of TDCDP compared with four heuristic algorithms on a typical VLIW processor. Our approach achieves an efficiency improvement of up to 58.34% in final solutions compared with the heuristic algorithms. Additionally, the Post-RA Scheduling enhances programs with an average speedup of 14.04% than solely applying the Pre-RA Scheduling.
Biology, Ecology, and Management of Flea Beetles in Brassica Crops
Authors: Li Zhenyu , Costamagna Alejandro Carlos , Beran Franziska , You Minsheng
Published: January 2024

Brassica vegetable and oilseed crops are attacked by several different flea beetle species (Chrysomelidae: Alticini). Over the past decades, most research has focused on two Phyllotreta species, Phyllotreta striolata and Phyllotreta cruciferae, which are major pests of oilseed rape in North America. More recently, and especially after the ban of neonicotinoids in the European Union, the cabbage stem flea beetle, Psylliodes chrysocephala, has become greatly important and is now considered to be the major pest of winter oilseed rape in Europe. The major challenges to flea beetle control are the prediction of population dynamics in the field, differential susceptibility to insecticides, and the lack of resistant plant cultivars and other economically viable alternative management strategies. At the same time, many fundamental aspects of flea beetle biology and ecology, which may be relevant for the development of sustainable control strategies, are not well understood. This review focuses on the interactions between flea beetles and plants and summarizes the literature on current management strategies with an emphasis on the potential for biological control in flea beetle management.
Wheat Sourdough Breadmaking: A Scoping Review
Authors: De Bondt Yamina , Verdonck Celine , Brandt Markus J. , De Vuyst Luc , Gänzle Michael G. , Gobbetti Marco , Zannini Emanuele , Courtin Christophe M.
Published: January 2024

Using sourdough in breadmaking can enhance bread's shelf-life and flavor compared to exclusive baker's yeast use and is believed to increase its nutritional quality and healthiness. Previous research established insight into the microbial ecology of sourdough, but the link between leavening agent use, processing, and bread quality remains elusive. However, such knowledge is key for standardization, research on the health benefits, and the definition of sourdough bread. In this systematic scoping review, we analyzed 253 studies and identified large variations in the type and amount of leavening agent, fermentation conditions, and bread quality (specific loaf volume and acidification). The interrelation between these elements and their effect on the extent of fermentation is discussed, together with issues preventing proper comparison of breadmaking procedures. With this review, we want to contribute to the dialogue concerning the definition of sourdough-type bread products and the research into the health benefits attributed to them.
A comparison of two learning approach inventories and their utility in predicting examination performance and study habits
Authors: Thompson Andrew R.
Published: January 2024

Although learning approach inventories have been used extensively in education research, there has been no direct comparison of how student classification differs between instruments or how classification influences the interpretation of how learning approach impacts student performance. This is especially relevant in light of recent research questioning the validity of the Study Process Questionnaire (LoGiudice AB, Norman GR, Manzoor S, Monteiro S. Adv Health Sci Educ Theory Pract 28: 47–63, 2023; Johnson SN, Gallagher ED, Vagnozzi AM. PLoS One 16: e0250600, 2021).
Signal-correction errors in the EasyOne Pro LAB multiple-breath washout device significantly impact outcomes in children and adults
Authors: Oestreich Marc-Alexander , Wyler Florian , Buess Christian , Etter Blaise , Ramsey Kathryn A. , Latzin Philipp
Published: January 2024

We investigated the accuracy of the molar mass (MM) and CO2 sensors of a commercial multiple-breath washout device (ndd Medizintechnik AG, Switzerland). We identified humidity and respiratory exchange ratio-dependent errors that in most measurements resulted in an overestimation of expired nitrogen concentrations, and consequently, MBW results. Functional residual capacity and lung clearance index decreased by 6.6% and 9.9%, respectively. Despite improved signal accuracy, the difference in FRC between the EOPL and body plethysmography increased.
The vascular response to acute sauna heating is similar in young and middle-aged adults
Authors: Leach Olivia K. , Strong Kaitlyn , Mack Gary W. , Gifford Jayson R.
Published: January 2024

Sauna therapy has been shown to improve cardiovascular health and function in older adults and individuals with cardiovascular disease risk factors. Specifically, improvements in vascular function have been reported and have been attributed to the increased hemodynamic stimuli on the vasculature associated with thermal stress. The present study quantified this hemodynamic response to a sauna protocol associated with improved cardiovascular health across the lifespan. Our data show that middle-aged adults have the same shear rate and blood flow response to sauna as young adults.
Use of Virtual Reality in Physical Therapy as an Intervention and Diagnostic Tool
Authors: Bateni Hamid , Carruthers Jenna , Mohan Rebecca , Pishva Seyedamirhossein
Published: January 2024

Within the past decade, the integration of computer-generated virtual realities (VRs) has witnessed a significant rise in the field of healthcare, particularly in diagnosis and treatment applications. These VR systems have found extensive use in physical therapy, rehabilitation, research, and assessment. This narrative review article is aimed at providing a comprehensive overview of the literature regarding the implementation of VR in the physical therapy profession. The primary objective of this review is to provide information to clinicians about the diverse applications of VR and its potential advantages in intervening across various patient populations and diagnoses during rehabilitation therapy. Through in-depth discussions with experts and a thorough review of pertinent literature, several significant aspects of the topic were identified. Subsequently, we carried out an online search to investigate the prevalent utilization of VR systems within healthcare, both as assessment tools and for therapeutic interventions. Our examination encompassed a total of 56 articles, with supplementary references incorporated as required.
Optimization of Growth Conditions for Chlorpyrifos-Degrading Bacteria in Farm Soils in Nakuru County, Kenya
Authors: Wepukhulu Miriam , Wachira Peter , Huria Nderitu , Sifuna Paul , Essuman Suliman , Asamba Micah
Published: January 2024

Chlorpyrifos (CP) is a chlorinated organophosphate pesticide. In Kenya, it is commonly used as an acaricide, particularly in dairy farming, leading to soil and water contamination. The study is aimed at isolating bacteria with CP-degrading potential and optimizing their growth conditions, including temperature, pH, and CP concentration. The enrichment culture technique was used, with minimal salt medium (MSM) supplemented with commercial grade CP. A multilevel factorial design was used to investigate the interactions of temperature, pH, and CP concentration. According to the findings, seven bacterial strains with potential to degrade CP were characterized and identified as Alcaligenes faecalis, Bacillus weihenstephanensis, Bacillus toyonensis, Alcaligenes sp. strain SCAU23, Pseudomonas sp. strain PB845W, Brevundimonas diminuta, and uncultured bacterium clone 99. Growth and biodegradation of bacteria differed significantly among the isolates across pH value, temperature, and concentrations (P≤0.05). The optimum conditions for growth were pH 7, temperature of 25°C, and 25mg/l chlorpyrifos concentration, while optimum degradation conditions were pH 5, temp 25°C, and CP conc. 25mg/l. The Pearson correlation between optimum growth and degradation showed a weak positive relationship (R=0.1144) for pH and strong positive relationship for temperature and concentration of chlorpyrifos. Other than pH, the study shows that there could be other cofactors facilitating the chlorpyrifos degradation process. The findings show that an efficient consortium, at 25°C and pH 5, can include Bacillus toyonensis 20SBZ2B and Alcaligenes sp. SCAU23 as they showed high optical density (OD) values under these conditions. These results indicate the potential for these bacteria to be employed in chlorpyrifos-contaminated ecosystem detoxification efforts upon manipulation of natural growth conditions. The findings of this study offer a potential foundation for future research into the reconstitution of a consortium. Based on the optimum conditions identified, the isolated bacterial strains could be further developed into a consortium to effectively degrade CP in both laboratory and field conditions. Dairy farmers can utilize the isolated strains and the consortia to decontaminate farm soils.
Phonon DOS‐Based Machine Learning Model for Designing High‐Performance Solid Electrolytes in Li‐Ion Batteries
Authors: Jaafreh Russlan , Pereznieto Santiago , Jeong Seonghun , Widiantara I. Putu , Oh Jeong Moo , Kang Jee-Hyun , Mun Junyoung , Ko Young Gun , Kim Jung-Gu , Hamad Kotiba
Published: January 2024

In the present work, a machine learning (ML) model was built to design solid electrolytes with improved ionic conductivity for Li‐ion batteries (LIBs), and the model was based on the phonon density of states (PhDOS). Compounds with PhDOS calculations were collected from the Materials Project (MP) and processed to obtain frequencies and PhDOS to calculate the total phonon band center, a proxy for ionic conductivity. Total phonon band centers were involved in a learning process using four ML algorithms (extra random trees (XT), gradient boosting (GB), extreme gradient boosting (XGB), and decision trees (DT)). The cross‐validation results from the algorithms showed that the performance of the XT‐model was superior and confirmed through density functional theory‐ (DFT‐) based phonon calculations conducted on LiYO3, Li4CO4, LiNiO3, LiGeO3, and LiSiO3. The XT‐model was then used to predict the total phonon band centers of new compounds where these had no phonon calculations beforehand. Experimental validation of the XT‐model involved electrochemical impedance spectroscopy (EIS) measurements on two compounds: Li2CO3 from the high range and Li6PS5Cl from the low range. Additionally, LiBiO2 that is predicted to have low total phonon band center, according to the XT‐model, was considered further to estimate its potential as solid electrolyte in LIBs.
Excellent Bifunctional Water Electrolysis Activities of α‐MoO3/AC Nanocomposites
Authors: Sekar Sankar , Yun Ji-Seop , Park Seoyeon , Kim Deuk Young , Lee Youngmin , Lee Sejoon
Published: January 2024

Electrocatalytic water splitting is a cost‐effective and environment‐friendly technique for producing oxygen and hydrogen through the oxygen/hydrogen evolution reaction (OER/HER). Developing the highly active and stable electrocatalyst, particularly for bifunctional water electrolysis (i.e., both OER and HER), is still a formidable challenge. Herein, we demonstrated the enhanced bifunctional water splitting activities by utilizing the molybdenum trioxide‐anchored activated carbon (MoO3/AC) nanocomposites. The MoO3/AC samples were fabricated by the ultrasonication method using sol‐gel synthesized MoO3 and biomass‐derived AC, and they displayed a nanostreusel‐like morphology with spherical MoO3 nanoparticle‐decorated AC nanosheets. For the water electrolysis test, the MoO3/AC nanocomposites exhibited the excellent bifunctional electrocatalytic OER and HER performances with low overpotential and small Tafel slope values. Through analyzing the material characteristics and the electrochemical properties of MoO3/AC, it was found that the superb bifunctional OER‐HER activities were attributed to the synergistic effects from the hybridization of highly conductive AC and electrochemically active α‐MoO3. The results pronounce that the MoO3/AC nanocomposites possess an aptitude as a superb bifunctional OER/HER electrocatalyst for high‐performance water electrolysis.
Parodontgel® on Wound Healing and Patient‐Reported Outcome Measures (PROMs) after Tunneled Coronally Advanced Flap (TCAF)
Authors: Mancini Leonardo , Mancini Vincenzo
Published: January 2024

The adjunctive use of healing gels following periodontal plastic surgery is not common in clinical practice, and no definitive benefits have yet been demonstrated. Case Presentation. A 33‐year‐old male patient with a central lower incisor class RT1 recession sought treatment due to sensitivity and dissatisfaction with the appearance of his smile. The patient had no history of periodontal disease; however, he was under orthodontic treatment contributing to the gingival recession and irregular gum contours. Treatment. The patient underwent two sequential surgical procedures. Initially, an apically repositioned flap (APF) was performed to correct the frenulum reducing flap tension and improving the gum line aesthetics. Subsequently, after 8 weeks, a tunneled coronally advanced flap (TCAF) was executed to further refine the gum contours and achieve root coverage. Postoperative Healing Protocol. To enhance the healing process and alleviate postoperative discomfort, a healing gel containing hyaluronic acid as the active molecule was applied to the surgical sites. The gel was expected to reduce pain perception and minimize the need for painkiller intake during the critical first week of recovery. The patient was asked to fill a pain chart for the initial 7 days, recording pain levels on a visual analogue scale (VAS 0‐10) and the number of paracetamol tablets taken as painkillers. Results. After both the APF and TCAF surgeries, the patient reported pain levels with a mean VAS score of 4.33 and 4.25, respectively. The painkiller intake during the first week was noted to be 3 tablets for the APF and 2 tablets for the TCAF. Notably, the application of the healing gel with hyaluronic acid did not cause any adverse reactions, indicating its potential safety and efficacy in this context. Conclusion. The application of a healing gel containing hyaluronic acid after periodontal plastic surgery showed promising results in reducing postoperative pain and the need for painkillers during the initial week of recovery. However, further investigations through randomized clinical trials are required to establish the potential benefits and broader applicability of such healing gel applications in the context of periodontal plastic surgery.
VB-Based Gaussian Sum Cubature Kalman Filter for Adaptive Estimation of Unknown Delay and Loss Probability
Authors: Wang Ruipeng , Wang Xiaogang , Zhang Haojie
Published: January 2024

The traditional Kalman filter assumes that all measurements can be obtained in real time, which is invalid in practical engineering. Therefore, a variational Bayesian- (VB-) based Gaussian sum cubature Kalman filter is proposed to solve the nonlinear tracking problem of multistep random measurement delay and loss (MRMDL) with unknown probability. First, the measurement model with MRMDL is modified by Bernoulli random variables. Then, the expression of the likelihood function is reformulated as a mixture of multiple Gaussian distributions, and the cubature rule is used to improve the estimation accuracy under the framework of Gaussian sum filter in the process of time update. Finally, by constructing a hierarchical Gaussian model, the unknown and time-varying measurement delay and loss probability are estimated in real time with the state jointly using the VB method in the measurement update stage. The algorithm does not need to calculate the equivalent noise covariance matrix so as to avoid the possible division by zero operation, which improves the stability of the algorithm. Simulation results for a target tracking problem show that the proposed algorithm has a better performance in the presence of MRMDL and can estimate the unknown measurement delay and loss probability accurately.
Luteolin Is a Potential Immunomodulating Natural Compound against Pulpal Inflammation
Authors: Kawakami Kentaro , Fukuda Takao , Toyoda Masaaki , Nakao Yuki , Hayashi Chikako , Watanabe Yukari , Aoki Tsukasa , Shinjo Takanori , Iwashita Misaki , Yamashita Akiko , Shida Miyu , Sanui Terukazu , Uchiumi Takeshi , Nishimura Fusanori
Published: January 2024

Aim. The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n=6). Periodontal bone resorption volumes were calculated for each group (nonligated–ligated), and the ratio of bone volume to tissue volume was measured. Results. Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion. Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation.
Realization of a Wide Stopband Filter Using the Weakest Electric Field Method and Electromagnetic Hybrid Coupling Method
Authors: Yan Xiaohei , Guo Minjie
Published: January 2024

To enhance filter performance in terms of stopband, we propose a wide-stopband substrate-integrated waveguide filter based on the rejection of higher-order modes. The filter establishes the inner and outer coupling windows at the mode’s weakest electric field to achieve mode suppression. Simultaneously, we employ the electromagnetic hybrid coupling theory to analyze the electromagnetic distribution of the particular modes and determine the dimensions of the coupling circular apertures and slits based on the extracted coupling coefficients to attain suppression of the specific modes. The filter successfully suppresses all higher-order modes having resonant frequencies below that of the TE150 mode, as demonstrated by simulation results. We conducted measurements and found that the filter has a center frequency of 4.78 GHz, a bandwidth of 100 MHz with a -3 dB attenuation, and a stopband of -25 dB that extends up to 16.62 GHz (i.e., 3.48 times the center frequency). Simulation and measurement results demonstrate a good correlation. This method, compared to other SIW filters, is easy to design, has a wider stopband range, can be readily applied to practical microwave communication systems, and has potential applications.
Analysis of Wheel Wear and Wheel‐Rail Dynamic Characteristics of High‐Speed Trains under Braking Conditions
Authors: Song Rui , Lu Chenxu , Sun Lixia , Zhang Zhongkai , Chen Dilai , Shen Gang
Published: January 2024

When high‐speed trains operate under braking conditions, the wheel‐rail interaction increases significantly, which can lead to more serious wear problems. To analyze the evolution of wheel wear and the dynamic characteristics of wheel‐rail under braking conditions, this paper first carries out long‐term monitoring of the service state of wheel‐rail during the operation period. The study analyzed the matching characteristics of the measured wheel‐rail profile and calibrated the wear model by using the collected data. The resulting wear prediction model was then used to examine the wheel wear characteristics under braking conditions. The research results indicate that during the operation period, the wheel experiences tread concave wear within a range of ±20 mm of the rolling circle, at a rate of approximately 0.05 mm per 10,000 km. Meanwhile, the rail experiences top surface wear at a natural rate of about 0.09 mm per year. Concave wear causes the contact point of the wheel‐rail to appear in two zones, resulting in a sudden change of contact geometric parameters. The concave worn wheel and rail with a 60 N profile have better matching compared to the 60 rail profile. Increasing the braking torque and wheel‐rail friction coefficient will significantly increase the wheel wear depth on straight sections. On small‐radius curve sections, rail side lubrication can significantly reduce high rail side wheel flange wear. A worn concave wheel can lead to unfavorable wheel‐rail contact geometry characteristics and increase low‐frequency components in the vehicle’s lateral dynamic response.
Subclonal Cancer Driver Mutations Are Prevalent in the Unresected Peritumoral Edema of Adult Diffuse Gliomas
Authors: Underhill Hunter R. , Karsy Michael , Davidson Christian J. , Hellwig Sabine , Stevenson Samuel , Goold Eric A. , Vincenti Sydney , Sellers Drew L. , Dean Charlie , Harrison Brion E. , Bronner Mary P. , Colman Howard , Jensen Randy L.
Published: January 2024

Adult diffuse gliomas commonly recur regardless of therapy. As recurrence typically arises from the peritumoral edema adjacent to the resected bulk tumor, the profiling of somatic mutations from infiltrative malignant cells within this critical, unresected region could provide important insights into residual disease. A key obstacle has been the inability to distinguish between next-generation sequencing (NGS) noise and the true but weak signal from tumor cells hidden among the noncancerous brain tissue of the peritumoral edema. Here, we developed and validated True2 sequencing to reduce NGS-associated errors to <1 false positive/100 kb panel positions while detecting 97.6% of somatic mutations with an allele frequency ≥0.1%. True2 was then used to study the tumor and peritumoral edema of 22 adult diffuse gliomas including glioblastoma, astrocytoma, oligodendroglioma, and NF1-related low-grade neuroglioma. The tumor and peritumoral edema displayed a similar mutation burden, indicating that surgery debulks these cancers physically but not molecularly. Moreover, variants in the peritumoral edema included unique cancer driver mutations absent in the bulk tumor. Finally, analysis of multiple samples from each patient revealed multiple subclones with unique mutations in the same gene in 17 of 22 patients, supporting the occurrence of convergent evolution in response to patient-specific selective pressures in the tumor microenvironment that may form the molecular foundation of recurrent disease. Collectively, True2 enables the detection of ultralow frequency mutations during molecular analyses of adult diffuse gliomas, which is necessary to understand cancer evolution, recurrence, and individual response to therapy.

Significance:

True2 is a next-generation sequencing workflow that facilitates unbiased discovery of somatic mutations across the full range of variant allele frequencies, which could help identify residual disease vulnerabilities for targeted adjuvant therapies.
Risk of Clinically Significant Prostate Cancer after a Nonsuspicious Prostate MRI—A Comparison with the General Population
Authors: Pylväläinen Juho , Hoffström Jaakko , Kenttämies Anu , Auvinen Anssi , Mirtti Tuomas , Rannikko Antti
Published: January 2024

Background:

We compare the risk of clinically significant (csPCa; ISUP Grade Group ≥ 2) and insignificant prostate cancer (isPCa; ISUP Grade Group 1) in men with a nonsuspicious prostate MRI (nMRI; PI-RADS ≤ 2) with the general population, and assess the value of PSA density (PSAD) in stratification.

Methods:

In this retrospective population-based cohort study we identified 1,682 50–79-year-old men, who underwent nMRI at HUS (2016–2019). We compared their age-standardized incidence rates (IR) of csPCa and the odds of isPCa to a local age- and sex-matched general population (n = 230,458) during a six-year follow-up. Comparisons were performed by calculating incidence rate ratios (IRR) and ORs with 95% confidence intervals (CI). We repeated the comparison for the 920 men with nMRI and PSAD < 0.15 ng/mL/cm3.

Results:

Compared with the general population, the IR of csPCa was significantly higher after nMRI [1,852 vs. 552 per 100,000 person-years; IRR 3.4 (95% CI, 2.8–4.1)]. However, the IR was substantially lower if PSAD was low [778 per 100,000 person-years; IRR 1.4 (95% CI, 0.9–2.0)]. ORs for isPCa were 2.4 (95% CI, 1.7–3.5) for all men with nMRI and 5.0 (95% CI, 2.8–9.1) if PSAD was low.

Conclusions:

Compared with the general population, the risk of csPCa is not negligible after nMRI. However, men with nMRI and PSAD <0.15 ng/mL/cm3 have worse harm-benefit balance than men in the general population.

Impact:

Prostate biopsies for men with nMRI should be reserved for cases indicated by additional risk stratification.

See related In the Spotlight, p. 641
The Associations between Intakes of One-Carbon Metabolism–Related Vitamins and Breast Density among Young Women
Authors: Han Eunyoung , Van Horn Linda , Snetselaar Linda , Shepherd John A. , Park Yoon Jung , Kim Hyesook , Jung Seungyoun , Dorgan Joanne F.
Published: January 2024

Background:

Folate is the primary methyl donor and B vitamins are cofactors for one-carbon metabolism that maintain DNA integrity and epigenetic signatures implicated in carcinogenesis. Breast tissue is particularly susceptible to stimuli in early life. Only limited data are available on associations of one-carbon metabolism–related vitamin intake during youth and young adulthood with breast density, a strong risk factor for breast cancer.

Methods:

Over 18 years in the DISC and DISC06 Follow-up Study, diets of 182 young women were assessed by three 24-hour recalls on five occasions at ages 8 to 18 years and once at 25 to 29 years. Multivariable-adjusted linear mixed-effects regression was used to examine associations of intakes of one-carbon metabolism-related vitamins with MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at ages 25 to 29 years.

Results:

Folate intake in youth was inversely associated with %DBV (Ptrend = 0.006) and ADBV (Ptrend = 0.02). These inverse associations were observed with intake during post-, though not premenarche. In contrast, premenarche vitamin B2 intake was positively associated with ADBV (Ptrend < 0.001). Young adult folate and vitamin B6 intakes were inversely associated with %DBV (all Ptrend ≤ 0.04), whereas vitamins B6 and B12 were inversely associated with ADBV (all Ptrend ≤ 0.04).

Conclusions:

Among these DISC participants intakes of one-carbon metabolism-related vitamins were associated with breast density. Larger prospective studies among diverse populations are needed to replicate these findings.

Impact:

Our results suggest the importance of one-carbon metabolism-related vitamin intakes early in life with development of breast density and thereby potentially breast cancer risk later in life.
Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors
Authors: Roy Chaudhuri Tista , Lin Qingxiang , Stachowiak Ewa K. , Rosario Spencer R. , Spernyak Joseph A. , Ma Wen Wee , Stachowiak Michal K. , Greene Michelle K. , Quinn Gerard P. , McDade Simon S. , Clynes Martin , Scott Christopher J. , Straubinger Robert M.
Published: January 2024

Purpose:

Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters.

Experimental Design:

Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction.

Results:

Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect.

Conclusions:

This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification.
Data from Whole Transcriptome Sequencing Reveals Extensive Unspliced mRNA in Metastatic Castration-Resistant Prostate Cancer
Authors: Sowalsky Adam G. , Xia Zheng , Wang Liguo , Zhao Hao , Chen Shaoyong , Bubley Glenn J. , Balk Steven P. , Li Wei
Published: January 2024

Abstract
Men with metastatic prostate cancer who are treated with androgen deprivation therapies (ADT) usually relapse within 2 to 3 years with disease that is termed castration-resistant prostate cancer (CRPC). To identify the mechanism that drives these advanced tumors, paired-end RNA-sequencing (RNA-seq) was performed on a panel of CRPC bone marrow biopsy specimens. From this genome-wide approach, mutations were found in a series of genes with prostate cancer relevance, including AR, NCOR1, KDM3A, KDM4A, CHD1, SETD5, SETD7, INPP4B, RASGRP3, RASA1, TP53BP1, and CDH1, and a novel SND1:BRAF gene fusion. Among the most highly expressed transcripts were 10 noncoding RNAs (ncRNAs), including MALAT1 and PABPC1, which are involved in RNA processing. Notably, a high percentage of sequence reads mapped to introns, which were determined to be the result of incomplete splicing at canonical splice junctions. Using quantitative PCR (qPCR), a series of genes (AR, KLK2, KLK3, STEAP2, CPSF6, and CDK19) were confirmed to have a greater proportion of unspliced RNA in CRPC specimens than in normal prostate epithelium, untreated primary prostate cancer, and cultured prostate cancer cells. This inefficient coupling of transcription and mRNA splicing suggests an overall increase in transcription or defect in splicing.

Implications: Inefficient splicing in advanced prostate cancer provides a selective advantage through effects on microRNA networks but may render tumors vulnerable to agents that suppress rate-limiting steps in splicing. Mol Cancer Res; 13(1); 98–106. ©2014 AACR.
Data from The lncRNA PCAT29 Inhibits Oncogenic Phenotypes in Prostate Cancer
Authors: Malik Rohit , Patel Lalit , Prensner John R. , Shi Yang , Iyer Matthew K. , Subramaniyan Shruthi , Carley Alexander , Niknafs Yashar S. , Sahu Anirban , Han Sumin , Ma Teng , Liu Meilan , Asangani Irfan A. , Jing Xiaojun , Cao Xuhong , Dhanasekaran Saravana M. , Robinson Dan R. , Feng Felix Y. , Chinnaiyan Arul M.
Published: January 2024

Abstract
Long noncoding RNAs (lncRNA) have recently been associated with the development and progression of a variety of human cancers. However, to date, the interplay between known oncogenic or tumor-suppressive events and lncRNAs has not been well described. Here, the novel lncRNA, prostate cancer–associated transcript 29 (PCAT29), is characterized along with its relationship to the androgen receptor. PCAT29 is suppressed by DHT and upregulated upon castration therapy in a prostate cancer xenograft model. PCAT29 knockdown significantly increased proliferation and migration of prostate cancer cells, whereas PCAT29 overexpression conferred the opposite effect and suppressed growth and metastases of prostate tumors in chick chorioallantoic membrane assays. Finally, in prostate cancer patient specimens, low PCAT29 expression correlated with poor prognostic outcomes. Taken together, these data expose PCAT29 as an androgen-regulated tumor suppressor in prostate cancer.

Implications: This study identifies PCAT29 as the first androgen receptor–repressed lncRNA that functions as a tumor suppressor and that its loss may identify a subset of patients at higher risk for disease recurrence.

Visual Overview: http://mcr.aacrjournals.org/content/early/2014/07/31/1541-7786.MCR-14-0257/F1.large.jpg. Mol Cancer Res; 12(8); 1081–7. ©2014 AACR.
Data from Clinically Relevant microRNAs in Ovarian Cancer
Authors: Zhang Shu , Lu Zhen , Unruh Anna K. , Ivan Cristina , Baggerly Keith A. , Calin George A. , Li Zongfang , Bast Robert C. , Le Xiao-Feng
Published: January 2024

Abstract
microRNAs (miRNAs/miRs) belong to a class of small noncoding RNAs that can negatively regulate messenger RNA (mRNA) expression of target genes. miRNAs are involved in multiple aspects of ovarian cancer cell dysfunction and the phenotype of ovarian cancer cells can be modified by targeting miRNA expression. miRNA profiling has detected a number of candidate miRNAs with the potential to regulate many important biologic functions in ovarian cancer, but their role still needs to be clarified, given the remarkable heterogeneity among ovarian cancers and the context-dependent role of miRNAs. This review summarizes the data collected from The Cancer Genome Atlas (TCGA) and several other genome-wide projects to identify dysregulated miRNAs in ovarian cancers. Copy number variations (CNVs), epigenetic alterations, and oncogenic mutations are also discussed that affect miRNA levels in ovarian disease. Emphasis is given to the role of particular miRNAs in altering expression of genes in human ovarian cancers with the potential to provide diagnostic, prognostic, and therapeutic targets. Particular attention has been given to TP53, BRCA1/2, CA125 (MUC16), HE4 (WFDC2), and imprinted genes such as ARHI (DIRAS3). A better understanding of the abnormalities in miRNA expression and downstream transcriptional and biologic consequences will provide leads for more effective biomarkers and translational approaches in the management of ovarian cancer. Mol Cancer Res; 13(3); 393–401. ©2014 AACR.
Data from Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma
Authors: Newman Erika A. , Lu Fujia , Bashllari Daniela , Wang Li , Opipari Anthony W. , Castle Valerie P.
Published: January 2024

Abstract
In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIα (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival.

Implications: These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets. Mol Cancer Res; 13(3); 470–82. ©2015 AACR.
Supplementary Data 5 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

GSEA of genes associated with BATF expression in CoMMpass
Supplementary Data 3 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

Differential Accessible Regions in JJN3 and KMS11
Figure S4 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: January 2024

TAp73 significance in HBZ pathogenesis and its effect on cellular metabolism.
Data from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

Abstract
Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.
Significance:
These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM.

See related article by Neri, Barwick, et al., p. 56.

See related commentary by Yun and Cleveland, p. 5.

This article is featured in Selected Articles from This Issue, p. 4