bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fertility, pregnancy and childbirth in women with multiple sclerosis: a population-based study from 2018 to 2020
Authors: Moccia Marcello , Affinito Giuseppina , Fumo Maria Grazia , Giordana Roberta , Di Gennaro Massimo , Mercogliano Michelangelo , Carotenuto Antonio , Petracca Maria , Lanzillo Roberta , Triassi Maria , Brescia Morra Vincenzo , Palladino Raffaele 
Published: April 2023

BackgroundWe aim to evaluate whether fertility, pregnancy, delivery and breastfeeding have been actually improving in women with multiple sclerosis (MS), compared with general population, and in relation to treatment features.MethodsWe included 2018–2020 population-level healthcare data on women with MS living in the Campania region (Italy). Fertility, pregnancy and delivery outcomes were obtained from Certificate of Delivery Assistance; breastfeeding was collected up to 6 months after delivery by trained personnel.ResultsOut of 2748 women with MS in childbearing age, 151 women delivered 156 babies. Fertility rate was 0.58 live births per woman with MS, compared with 1.29 in Campania region and 1.25 in Italy. Disease-modifying treatment (DMT) continuation during pregnancy was associated with lower birth weight (coeff −107.09; 95% CI –207.91 to –6.26; p=0.03). Exposure to DMTs with unknown/negative effects on pregnancy was associated with birth defects (OR 8.88; 95% CI 1.35 to 58.41; p=0.02). Birth defects occurred in pregnancies exposed to dimethyl fumarate (2/21 exposed pregnancies), fingolimod (1/11 exposed pregnancies) and natalizumab (2/30 exposed pregnancies). After delivery, 18.8% of women with MS were escalated of DMT efficacy, while 50.7% started on same/similar-efficacy DMTs, and 30.5% did not receive DMT. The probability of breastfeeding was higher in women who were treated with breastfeeding-safe DMTs (OR 5.57; 95% CI 1.09 to 28.55; p=0.03).ConclusionsFertility rate in women with MS remains below the general population. Family planning and subsequent DMT decisions should aim to achieve successful pregnancy, delivery and breastfeeding outcomes, while controlling disease activity.
Asthma hospitalisations and heat exposure in England: a case–crossover study during 2002–2019
Authors: Konstantinoudis Garyfallos , Minelli Cosetta , Lam Holly Ching Yu , Fuertes Elaine , Ballester Joan , Davies Bethan , Vicedo-Cabrera Ana Maria , Gasparrini Antonio , Blangiardo Marta 
Published: April 2023

BackgroundPrevious studies have reported an association between warm temperature and asthma hospitalisation. They have reported different sex-related and age-related vulnerabilities; nevertheless, little is known about how this effect has changed over time and how it varies in space. This study aims to evaluate the association between asthma hospitalisation and warm temperature and investigate vulnerabilities by age, sex, time and space.MethodsWe retrieved individual-level data on summer asthma hospitalisation at high temporal (daily) and spatial (postcodes) resolutions during 2002–2019 in England from the NHS Digital. Daily mean temperature at 1 km×1 km resolution was retrieved from the UK Met Office. We focused on lag 0–3 days. We employed a case–crossover study design and fitted Bayesian hierarchical Poisson models accounting for possible confounders (rainfall, relative humidity, wind speed and national holidays).ResultsAfter accounting for confounding, we found an increase of 1.11% (95% credible interval: 0.88% to 1.34%) in the asthma hospitalisation risk for every 1°C increase in the ambient summer temperature. The effect was highest for males aged 16–64 (2.10%, 1.59% to 2.61%) and during the early years of our analysis. We also found evidence of a decreasing linear trend of the effect over time. Populations in Yorkshire and the Humber and East and West Midlands were the most vulnerable.ConclusionThis study provides evidence of an association between warm temperature and hospital admission for asthma. The effect has decreased over time with potential explanations including temporal differences in patterns of heat exposure, adaptive mechanisms, asthma management, lifestyle, comorbidities and occupation.
Identifying the potential transcriptional regulatory network in Hirschsprung disease by integrated analysis of microarray datasets
Authors: Xu Wenyao , Yu Hui , Chen Dian , Pan Weikang , Yang Weili , Miao Jing , Jia Wanying , Zheng Baijun , Liu Yong , Chen Xinlin , Gao Ya , Tian Donghao 
Published: April 2023

ObjectiveHirschsprung disease (HSCR) is one of the common neurocristopathies in children, which is associated with at least 20 genes and involves a complex regulatory mechanism. Transcriptional regulatory network (TRN) has been commonly reported in regulating gene expression and enteric nervous system development but remains to be investigated in HSCR. This study aimed to identify the potential TRN implicated in the pathogenesis and diagnosis of HSCR.MethodsBased on three microarray datasets from the Gene Expression Omnibus database, the multiMiR package was used to investigate the microRNA (miRNA)–target interactions, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Then, we collected transcription factors (TFs) from the TransmiR database to construct the TF–miRNA–mRNA regulatory network and used cytoHubba to identify the key modules. Finally, the receiver operating characteristic (ROC) curve was determined and the integrated diagnostic models were established based on machine learning by the support vector machine method.ResultsWe identified 58 hub differentially expressed microRNAs (DEMis) and 16 differentially expressed mRNAs (DEMs). The robust target genes of DEMis and DEMs mainly enriched in several GO/KEGG terms, including neurogenesis, cell–substrate adhesion, PI3K–Akt, Ras/mitogen-activated protein kinase and Rho/ROCK signaling. Moreover, 2 TFs (TP53andTWIST1), 4 miRNAs (has-miR-107,has-miR-10b-5p,has-miR-659-3p, andhas-miR-371a-5p), and 4 mRNAs (PIM3,CHUK,F2RL1, andCA1) were identified to construct the TF–miRNA–mRNA regulatory network. ROC analysis revealed a strong diagnostic value of the key TRN regulons (all area under the curve values were more than 0.8).ConclusionThis study suggests a potential role of the TF–miRNA–mRNA network that can help enrich the connotation of HSCR pathogenesis and diagnosis and provide new horizons for treatment.
Cluster of electric thrusters for astronautic and robotic INPPS flagship space flights to Mars and Europa moon
Authors: Jansen Frank , Andreussi Tommaso , Cesarretti Giovanni , Ehresmann Manfred , Grill Julia , Herdrich Georg , Funaki Ikkoh , Girard Nathalie , Grundmann Jan Thimo , Krejci David , Leiter Hans , Masson Frederic , Maiwald Volker , Misuri Tommaso , Oriol Stephane , Piragino Antonio , Reissner Alexander , Schanz Lars 
Published: April 2023

AbstractThis review deals with the selection of the electric propulsion system (EPS) for the internationally developed and designed, primary nuclear-electric space tug International Nuclear Power and Propulsion System (INPPS). INPPS is scheduled for interplanetary missions to Mars and Jupiter moon Europa missions by the end of decade 2020. Regarding specific technical and mission parameters preselected electric thruster (ET) types, developed by international companies and institutions, are analysed, evaluated and investigated for a possible application as propulsion system (PS), the so-called CET (Cluster of Electric Thrusters). It is analysed whether solely electric thrusters, combined in an adequate CET, enable the envisaged interplanetary missions—robotic and astronautic/crewed with the INPPS flagship.Thruster clusters with strategic consortium considerations are analysed as a feasible PS of the INPPS. The studied CET consists of the following: (a) only European ETs, (b) combination of German and European ETs, (c) Japanese and European ETs or at least (d) Japanese, European and US thrusters. The main results are (1) Robotic and crewed INPPS mission to Mars/Europa are realizable with EPS only (no chemical propulsion is needed), (2) that every CET, except (c) of only Japanese and part of European thrusters, is capable to perform the main part of envisaged INPPS flagship mission orbit to Mars, back to Earth and to Jupiter/Europa moon.
Optimal Incentives in a Limit Order Book: A SPDE Control Approach
Authors: Baldacci Bastien , Bergault Philippe 
Published: April 2023

With the fragmentation of electronic markets, exchanges are now competing in order to attract trading activity on their platform. Consequently, they developed several regulatory tools to control liquidity provision/consumption on their liquidity pool. In this paper, we study the problem of an exchange using incentives in order to increase market liquidity. We model the limit order book as the solution of a stochastic partial differential equation (SPDE) as in [R. Cont and M. S. Müller, 2021, A stochastic partial differential equation model for limit order book dynamics, SIAM Journal on Financial Mathematics 12(2), 744–787]. The incentives proposed to the market participants are functions of the time and the distance of their limit order to the mid-price. We formulate the control problem of the exchange who wishes to modify the shape of the order book by increasing the volume at specific limits. Due to the particular nature of the SPDE control problem, we are able to characterize the solution with a classic Feynman–Kac representation theorem. Moreover, when studying the asymptotic behavior of the solution, a specific penalty function enables the exchange to obtain closed-form incentives at each limit of the order book. We study numerically the form of the incentives and their impact on the shape of the order book, and analyze the sensitivity of the incentives to the market parameters.
Abstract CT238: Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor
Authors: Yoo Stephen Sunghan , Lee Soohyeon , Shin Sangjoon , Jung Hyunjin , Hong David S. 
Published: April 2023

Abstract
A Phase I clinical trial is currently underway to test Nelmastobart (hSTC810), an antibody targeting butyrophilin 1A1 (BTN1A1), a novel immune checkpoint protein. This Phase I clinical trial is using a standard 3 + 3 escalation design to (i) explore safety, tolerability, dose-limiting toxicities, and pharmacokinetics, (ii) define a recommended Phase II dose, and (iii) evaluate preliminary efficacy in patients with advanced solid tumors. The current dose range for the clinical trial is 0.3 mg/kg to 15 mg/kg. Currently, all the dose levels have been completed without any dose-limiting toxicity having been observed. Here, we provide an update on the clinical trial data shown previously. First, we provide the results of the pharmacokinetics study of these patients for the selected doses and dosing intervals, including the peak plasma concentration (Cmax), the time to reach Cmax (tmax), and the average plasma concentration of hSTC810 over the dosing interval in steady state (Cavg). The change in cytokine expression and immune cell concentrations in patient blood samples were also analyzed. Specifically, a panel of cytokines was measured including IFN- γ, IL-2, IL-4, IL-6, IL-10, TNF-α, MCP-1, and TGF- β, while flow cytometry was used to detect a panel of immunological marker proteins including CD3, CD4, CD8, CD19, CD14, CD16, CD56, CD25, CD45. For pharmacokinetic studies, the concentrations of hSTC810 and anti-hSTC810 antibodies were quantified. Immunohistochemistry was performed on patient tumor biopsies that were stained for PD-L1, CD3, CD4, CD8, and BTN1A1 expression. The resultant slides were analyzed for PD-L1 tumor proportional score (TPS), PD-L1 combined positive score (CPS), BTN1A1 scoring, the percentage of CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, tumor-infiltrating lymphocytes, and necrosis.
Citation Format: Stephen Sunghan Yoo, Soohyeon Lee, Sangjoon Shin, Hyunjin Jung, David S. Hong. Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor [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 CT238.
Abstract LB032: Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2
Authors: Naderinezhad Samira , Zhang Guoliang , Wang Zheng , Zheng Dayong , Lian Junwei , Li Wenliang 
Published: April 2023

Abstract
Treatment-related neuroendocrine prostate cancer (t-NEPC, here as NEPC) is an aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% of lethal CRPC. The mechanisms underlying the progression of prostate cancer to NEPC are largely unclear, and new drug targets are desperately needed. NEPC is known to be highly vascularized. Elevated expression of NE markers and increased angiogenesis are two prominent phenotypes of NEPC, and thus are expected to be linked. However, direct molecular links between these two phenotypes are still elusive, whose elucidation will substantially expand our knowledge in NEPC and enable the development of effective treatments for NEPC. Through RNAi & cDNA screening and functional validations, we previously discovered that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. The mechanisms of GRK3 in prostate cancer progression were mostly unknown.
Our new data indicate that GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in NEPC. GRK3 promotes both angiogenesis and neuroendocrine differentiation in prostate cancer cells, indicating that it is a key missing link for these two phenotypes. Mechanistically, GRK3 enhances the epigenetic repressor activity of histone deacetylase 2 (HDAC2) to suppress key repressors of angiogenesis or NE phenotype. Through compound library screening, we have identified several compounds that block kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could substantially reduce angiogenesis and NE marker expression, as well as significantly inhibit NEPC cell growth in culture and in mouse xenografts.
In summary, kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression. Its mechanism of actions is at least in part through enhancing HDAC2’s epigenetic activity. Results based on our novel GRK3 inhibitors suggest that GRK3 is a valuable new drug target for aggressive prostate cancer.
Citation Format: Samira Naderinezhad, Guoliang Zhang, Zheng Wang, Dayong Zheng, Junwei Lian, Wenliang Li. Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2 [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 LB032.
Abstract LB085: Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer
Authors: van Dyk Dewald , Zanvit Peter , Fazenbaker Christine , McGlinchey Kelly , Luo Weichuan , Pezold Jessica , Meekin John , Chang Chien-ying , Clark Benjamin , Martin Philip L. , Hoover Clare , Tu Eric , Gilbreth Ryan , Cobbold Mark , Moody Gordon , Bosco Emily E. 
Published: April 2023

Abstract
Prostate cancer is traditionally considered an immunologically “cold” tumor type rendering patients insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent anti tumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumors are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a sub-optimal therapeutic index. Our target discovery and validation efforts identified STEAP2 as a superior prostate antigen for therapeutic targeting. Importantly, STEAP2 is a highly prevalent prostate cancer antigen displaying high, homogeneous cell surface expression across all stages of disease. A novel lead generation approach facilitated the development of a potent and specific armored STEAP2 CAR-T therapeutic candidate, AZD0754. This second generation CAR-T product is armored with a dominant-negative TGFβRII, thereby bolstering activity in the TGFβ-rich immunosuppressive environment of prostate cancer. Armored STEAP2 CAR-T cells demonstrate favorable in vitro properties, robust dose dependent in vivo efficacy in STEAP2 expressing cell line- and patient derived- mouse xenograft models and encouraging preclinical safety. Taken together, this data builds confidence in the specificity and potency of this potential first in class STEAP2 targeted CAR-T therapy and supports future clinical development.
Citation Format: Dewald van Dyk, Peter Zanvit, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica Pezold, John Meekin, Chien-ying Chang, Benjamin Clark, Philip L. Martin, Clare Hoover, Eric Tu, Ryan Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco. Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer [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 LB085.
Abstract LB115: Simultaneous whole-body ultrasound contrast imaging: a novel high throughput preclinical platform for targeted molecular imaging studies
Authors: Natarajan Arutselvan , Tabesh Farbod , Hyun Dongwoon , Paulmurugan Ramasamy , Dahl Jeremy 
Published: April 2023

Abstract
Ultrasound contrast agent (UCA) based molecular imaging is a rapidly growing field in biomedical research. Ultrasound (US) is a non-radiative imaging modality that is frequently used to investigate various human diseases in the clinic. US molecular imaging is a novel imaging modality that utilizes targeted contrast agents to add molecular information about the imaging target, including vascular biomarkers of cancer. Pre-clinical animal models are commonly used to evaluate and validate targeted contrast agents before extending them for FDA-approval. Key impediments in the preclinical evaluations are the short in vivo half-life of microbubbles (MBs) (less than 30 minutes), limited transducer scanning area, and focusing one target at a time, which all make this strategy low throughput. Moreover, whole-body imaging strategy is not available for US imaging compared to other imaging modalities, such as PET, CT, and MRI. To overcome these imitations, we have developed a multi-mouse US imaging platform using an Automated Breast Volume Scanner (ABVS) system. In addition, we have synthesized a novel breast cancer vascular-specific B7-H3 targeted microbubbles (TMBs) using a microfluidic device. We tested these TMBs in a genetically engineered transgenic mice model [FVB/N-Tg (MMTV-PyMT)634Mul/J] (n=32) that develops breast cancer in the mammary fat pad. The US imaging results of conventional Vevo 2100 system indicated that B7-H3-TMBs could provide target specific contrast signals in the tumor vasculature compared to control MBs. We used this MBs for whole-body imaging using an ABVS system with two mice simultaneously in a stage. We imaged multiple tumors (10 tumors/mouse, 2 mice per scan, n=20 tumors) with a single bolus injection of TMBs per mouse. The results successfully showed tumor specific contrast signals from tumors independent of tumor size. Introduction of this whole-body scanner, and its ability to scan multiple mice simultaneously allows rapid imaging of multiple tumors with 3D quantification of tumor size by administering a single TMB injection enabling without significant contrast loss. Our approach makes this US-MI as high throughput and can be used to test multiple contrast agents for investigating different aspects of biological problems including screening of vascular biomarkers of human diseases.
Citation Format: Arutselvan Natarajan, Farbod Tabesh, Dongwoon Hyun, Ramasamy Paulmurugan, Jeremy Dahl. Simultaneous whole-body ultrasound contrast imaging: a novel high throughput preclinical platform for targeted molecular imaging studies [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 LB115.
Abstract LB119: Recurrence score for recurrence over survival outcome in the landmark TAILORx trial
Authors: Yang Sherry X. , Yu John , Wang Molin 
Published: April 2023

Abstract
Overall survival is the most relevant endpoint in clinical research and patient care. Nonetheless, cancer recurrence has been frequently utilized as a surrogate endpoint, particularly in the context of multi-gene assays and molecular signatures. The 21-gene recurrence score (RS) was originally established against distant recurrence for prognosis in breast cancer. However, it is unclear whether RS has a weight for the recurrence over survival prognosis. We investigated RS on the choice of clinical endpoints in the Trial Assigning Individualized Options for Treatment (TAILORx), which had OS, invasive disease-free survival (DFS), and recurrence-free interval (RFI) in addition to distant recurrence-free interval as the clinical endpoints. Both midrange (11-25) and high-range (26-100) scores were associated with RFI, high-range only with DFS, but not significantly associated with OS in the multivariable Cox proportional-hazards regression models. Of 462 death events, 33.1% (153 events) were ascribed to breast cancer and 91.8% (424) were due to DFS-related events that included 24.5% other cancers, 34.2% unknown and 33.1% breast cancer. It is DFS that was wound up as the most representative surrogate endpoint for survival. The lack of survival significance was probably due to the nature of 21-gene assay weighted for recurrence rather than not having enough event numbers in the TAILORx clinical trial. The data call for establishing biomarkers directly towards OS or DFS to increase survival with more precision.
Citation Format: Sherry X. Yang, John Yu, Molin Wang. Recurrence score for recurrence over survival outcome in the landmark TAILORx trial [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 LB119.