bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of robustness and accuracy of many numerical schemes for phase-field simulations
Authors: Xu Jinchao , Xu Xiaofeng 
Published: April 2023

In this paper, we study the stability, accuracy and convergence behavior of various numerical schemes for phase-field modeling through a simple ODE model. Both theoretical analysis and numerical experiments are carried out on this ODE model to demonstrate the limitation of most numerical schemes that have been used in practice. One main conclusion is that the first-order fully implicit scheme is the only robust algorithm for phase-field simulations while all other schemes (that have been analyzed) may have convergence issue if the time step size is not exceedingly small. More specifically, by rigorous analysis in most cases, we have the following conclusions: (i) The first-order fully implicit scheme converges to the correct steady state solution for all time step sizes. In the case of multiple solutions, one of the solution branches always converges to the correct steady state solution. (ii) The first-order convex splitting scheme, which is equivalent to the first-order fully implicit scheme with a different time scaling, always converges to the correct steady state solution but may seriously lack numerical accuracy for transient solutions. (iii) For the second-order fully implicit and convex splitting schemes, for any time step size [Formula: see text], there exists an initial condition [Formula: see text], with [Formula: see text], such that the numerical solution converges to the wrong steady state solution. (iv) For [Formula: see text], all second-order schemes studied in this paper converge to the correct steady state solution although severe numerical oscillations occur for most of them if the time step size is not sufficiently small. (v) An unconditionally energy-stable scheme (such as the modified Crank–Nicolson scheme) is not necessarily better than a conditionally energy-stable scheme (such as the Crank–Nicolson scheme). Most, if not all, of the above conclusions are expected to be true for more general Allen–Cahn and other phase-field models.
Constrained Tiny Machine Learning for Predicting Gas Concentration with I4.0 Low-cost Sensors
Authors: El Adoui Mohammed , Herpoel Thomas , Frénay Benoît 
Published: April 2023

Low-cost gas sensors (LCS) often produce inaccurate measurements due to varying environmental conditions that are not consistent with laboratory settings, leading to inadequate productivity levels compared to high-quality sensors. To address this issue, we propose the use of Machine Learning (ML) to predict accurate concentrations of pollutant gases acquired by LCS integrated into an embedded Internet of Things platform. However, a key challenge is to optimize an accurate ML design under low memory and computation power constraints of microcontrollers (MCUs) while maintaining accurate ML scores.
After data analysis and pre-processing, we assess and analyze the performance of five ML algorithms to predict the concentration of pollutants gases from multiple specifications (weather, presence of other gases, etc.). To support the experiments, datasets from three sources are used: (1) VOCSens, (2) Belgian Interregional Environment Agency cell, and (3) Visual-Crossing. Once the best model was optimized and validated, multiple hard constraints were added to the selected ML structure to satisfy material and expert requirements. Trained models were ported to be implemented locally in a MCU after comparing several porting libraries. The assembled code obtained is evaluated based on two metrics: storage memory consumption and inference time, relative to the highest attainable capacities.
The improved random forest is the best ML model for the used dataset with an R2 score meeting of 0.72 and Root Means Square Error of 0.0028 ppm. The best generated Tiny-ML model needs 3% of RAM and 98% of Flash storage.
The empirical results prove that the developed ML algorithm applied to LCS provides high accuracy to predict pollutant gases. This algorithm can also be used to adjust the LCS systems to provide calibrated data in real time, even if the platform being used is not particularly advanced or powerful.
Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei 
Published: April 2023

Abstract

High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma.

Significance:
Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma.
See related commentary by Stouth et al., p. 2091
TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer
Authors: Khatpe Aditi S. , Dirks Rebecca , Bhat-Nakshatri Poornima , Mang Henry , Batic Katie , Swiezy Sarah , Olson Jacob , Rao Xi , Wang Yue , Tanaka Hiromi , Liu Sheng , Wan Jun , Chen Duojiao , Liu Yunlong , Fang Fang , Althouse Sandra , Hulsey Emily , Granatir Maggie M. , Addison Rebekah , Temm Constance J. , Sandusky George , Lee-Gosselin Audrey , Nephew Kenneth , Miller Kathy D. , Nakshatri Harikrishna 
Published: April 2023

AbstractStudy of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we used healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku-like, DNA repair protein) was identified as one of the earliest events during immortalization. TONSL, which is located on chromosome 8q24.3, was found to be amplified in approximately 20% of breast cancers. TONSL alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor–positive adenocarcinomas in mice. Analysis of a breast tumor microarray with approximately 600 tumors revealed poor overall and progression-free survival of patients with TONSL-overexpressing tumors. TONSL increased chromatin accessibility to pro-oncogenic transcription factors, including NF-κB and limited access to the tumor-suppressor p53. TONSL overexpression resulted in significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination (HR) and Fanconi anemia pathways. Consistent with these results, TONSL-overexpressing primary cells exhibited upregulated DNA repair via HR. Moreover, TONSL was essential for growth of TONSL-amplified breast cancer cell lines in vivo, and these cells were sensitive to TONSL–FACT complex inhibitor CBL0137. Together, these findings identify TONSL as a regulator of epithelial cell immortalization to facilitate cancer initiation and as a target for breast cancer therapy.Significance:The chr.8q24.3 amplicon-resident gene TONSL is upregulated during the initial steps of tumorigenesis to support neoplastic transformation by increasing DNA repair and represents a potential therapeutic target for treating breast cancer.
BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality
Authors: Murai Junko , Pommier Yves 
Published: April 2023

AbstractThe concept of “BRCAness” was first described in 2004 to define the situation in which a homologous recombination repair (HRR) defect in a tumor relates to and phenocopies BRCA1 or BRCA2 loss-of-function mutations. Soon after the discovery of synthetic lethality of PARP1/2 inhibitors in BRCA1- or BRCA2-deficient cells, McCabe and colleagues extended the concept of BRCAness to homologous recombination deficiency (HRD) by studying the sensitivity of cancer cells to PARP inhibitors. They genetically revealed that deficiency in HR-related genes (RAD51, RAD54, DSS1, and RPA1), DNA damage signaling genes (ATR, ATM, CHK1, CHK2, and NBS1), or Fanconi anemia–related genes (FANCD2, FANCA, and FANCC) conferred sensitivity to PARP inhibitors. Thus, cells acquire BRCAness either by genetic inactivation of the BRCA or HRD genes. Here, we briefly review how genomic profiling can identify BRCAness and deficiencies in HRD genes and the current difficulty to apply BRCAness/HRD in the clinic. We also discuss how BRCAness relates to HRD and the utility of evaluating BRCAness/HRD to select therapies with PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib, pamiparib, fuzuloparib), topoisomerase I (TOP1) inhibitors (irinotecan, topotecan, and tumor-targeted TOP1 inhibitors), and platinum derivatives (cisplatin and carboplatin).See related article by McCabe and colleagues, Cancer Res 2006;66:8109–15.
Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101)
Authors: Carmagnani Pestana Roberto , Moyers Justin T. , Roszik Jason , Sen Shiraj , Hong David S. , Naing Aung , Herzog Cynthia E. , Fu Siqing , Piha-Paul Sarina A. , Rodon Jordi , Yap Timothy A. , Karp Daniel D. , Tsimberidou Apostolia M. , Pant Shubham , Zarzour Maria A. , Ratan Ravin , Ravi Vinod , Benjamin Robert S. , Lazar Alexander J. , Wang Wei-Lien , Daw Najat , Gill Jonathan B. , Harrison Douglas J. , Lewis Valerae O. , Roland Christina L. , Patel Shreyaskumar R. , Livingston J. Andrew , Somaiah Neeta , Ludwig Joseph A. , Conley Anthony P. , Hamerschlak Nelson , Gorlick Richard , Meric-Bernstam Funda , Subbiah Vivek 
Published: April 2023

Abstract

Purpose:
Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.

Experimental Design:
In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021.

Results:
Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P &lt; 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P &lt; 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P &lt; 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P &lt; 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis.

Conclusions:
Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.
Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials
Authors: Antonarakis Emmanuel S. , Subudhi Sumit K. , Pieczonka Christopher M. , Karsh Lawrence I. , Quinn David I. , Hafron Jason M. , Wilfehrt Helen M. , Harmon Matthew , Sheikh Nadeem A. , Shore Neal D. , Petrylak Daniel P. 
Published: April 2023

Abstract

Purpose:
We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods:
Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival.

Results:
Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed.

Conclusions:
Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Abstract CT135: A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors
Authors: Bacha Jeffrey , Brown Dennis , Kanekal Sarath , Sankar Neil , Lopez Lorena , Yam Noymi , Wagner Lars , Geller James , Leggas Markos , Thompson Patrick , Osterheld Javier 
Published: April 2023

Abstract
Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan.
Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled.
Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented.
Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated.
Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date.
Citation Format: Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars Wagner, James Geller, Markos Leggas, Patrick Thompson, Javier Osterheld. A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT135.
Abstract LB013: Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma survival
Authors: Agrawal Praveen 
Published: April 2023

Abstract
Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma survival, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that alpha-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding alpha-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growth in vivo and in vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon alpha–2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that alpha-2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors.
Citation Format: Praveen Agrawal. Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB013.
Abstract LB037: Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene
Authors: Chen Jilong , Ma Yun 
Published: April 2023

Abstract
Chronic myeloid leukemia (CML) is a hematological malignancy mainly caused by the Bcr-Abl oncogene that results from the reciprocal translocation between human chromosome 9 and 22, and occurs in more than 90% of CML cases. Bcr-Abl oncogene is also involved in tumorigenesis of other leukemia such as acute lymphoid leukemia (ALL). Although progress has been made in the understanding of signal transduction in Abl-mediated transformation, the molecular mechanisms underlying Abl-induced tumorigenesis are still not fully understood. It is well known that imatinib treatment can greatly suppress Bcr-Abl-mediated development of leukemia, but intracellular molecules induced by imatinib and their roles in the tumorigenesis remain largely to be determined. On the other hand, the majority of human transcripts lack protein-coding capacity, which are defined as noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) play important roles in various vital biological processes. Notably, increasing number of lncRNAs have been linked to human diseases, including cancers. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. Here, we identified several imatinib-induced lncRNAs as critical regulator of Bcr-Abl-induced tumorigenesis. Most of these lncRNAs expressed in a very low levels in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, they could be significantly induced in Abl-positive leukemic cells treated by imatinib. Silencing these lncRNAs promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of particular lncRNAs sensitized the cells to apoptosis and suppressed tumor growth. In concert, knockout of some murine lncRNAs in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, some lncRNA deficient mice were generated, and we observed that knockout of particular murine lncRNAs facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA deficiency promoted Abl-transformed cell survival and development of leukemia in mice. In summary, these findings unveil an inhibitory role of several critical lncRNAs in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis.
Citation Format: Jilong Chen, Yun Ma. Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB037.