bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased let‐7d‐5p in non‐alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis
Authors: Infante‐Menéndez Jorge , López‐Pastor Andrea R. , González‐Illanes Tamara , González‐López Paula , Huertas‐Lárez Raquel , Rey Esther , González‐Rodríguez Águeda , García‐Monzón Carmelo , Patil Nikita P. , Vega de Céniga Melina , Baker Aaron B. , Gómez‐Hernández Almudena , Escribano Oscar 
Published: April 2023

AbstractBackground and AimsThe molecular mechanisms driving non‐alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let‐7d‐5p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker.MethodsWe evaluated let‐7d‐5p levels and its targets in liver biopsies from a cross‐sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let‐7d‐5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let‐7d‐5p in vitro to corroborate the results observed in vivo. Circulating let‐7d‐5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT‐qPCR.ResultsOur results demonstrate that hepatic let‐7d‐5p was significantly up‐regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin‐like growth factor 1 (IGF1), IGF‐I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let‐7d‐5p expression, and its overexpression decreased AKT, IGF‐IR and IR protein expression. Furthermore, let‐7d‐5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let‐7d‐5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker.ConclusionsOur results highlight the emerging role of let‐7d‐5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non‐invasive biomarker for NAFLD diagnosis.
Maternal obesity and offspring health: Adapting metabolic changes through autophagy and mitophagy
Authors: Wang Litao , O'Kane Aislinn M. , Zhang Yingmei , Ren Jun 
Published: April 2023

SummaryMaternal obesity leads to obstetric complications and a high prevalence of metabolic anomalies in the offspring. Among various contributing factors for maternal obesity‐evoked health sequelae, developmental programming is considered as one of the leading culprit factors for maternal obesity‐associated chronic comorbidities. Although a unified theory is still lacking to systematically address multiple unfavorable postnatal health sequelae, a cadre of etiological machineries have been put forward, including lipotoxicity, inflammation, oxidative stress, autophagy/mitophagy defect, and cell death. Hereinto, autophagy and mitophagy play an essential housekeeping role in the clearance of long‐lived, damaged, and unnecessary cell components to maintain and restore cellular homeostasis. Defective autophagy/mitophagy has been reported in maternal obesity and negatively impacts fetal development and postnatal health. This review will provide an update on metabolic disorders in fetal development and postnatal health issues evoked by maternal obesity and/or intrauterine overnutrition and discuss the possible contribution of autophagy/mitophagy in metabolic diseases. Moreover, relevant mechanisms and potential therapeutic strategies will be discussed in an effort to target autophagy/mitophagy and metabolic disturbances in maternal obesity.
Asymmetric impacts of ICT and energy intensity on agricultural productivity: Evidence from Asia‐Pacific region
Authors: Paul Arindam , Sahoo Dukhabandhu , Jena Amrita 
Published: April 2023

AbstractIn the contemporary times of rising food insecurity and malnutrition, the agricultural sector needs more attention. This study aims to investigate the asymmetric impacts of information and communication technologies (ICTs), energy intensity, urbanization, and inequality on agricultural productivity for 20 Asia‐Pacific countries from 1990 to 2020. To investigate asymmetric impacts, the study employs the panel nonlinear autoregressive distributed lag (NARDL) model. The estimated results revealed that positive and negative shocks in ICT, energy intensity, and urbanization have asymmetric impacts on agricultural productivity in the long run, whereas symmetry is observed in short‐run impacts. It is found that a 1% increase (decrease) in ICT and urbanization increases (decreases) agricultural productivity by 0.292% (0.662%) and 2.717% (2.759%), respectively, whereas a 1% increase (decrease) in energy intensity decreases (increases) agricultural productivity by 0.252% (0.216%) in the long run. Furthermore, the results of the Dumitrescu‐Hurlin panel causality test point out the existence of bi‐directional causality between agricultural productivity and the independent variables (ICT, energy intensity, urbanization, and inequality). Based on the findings, the study suggests that the Asia‐Pacific countries should increase the application of ICT and use energy more efficiently in agriculture to boost agricultural productivity.
Sports‐related dental injuries and oral health status among Malaysian para‐athletes: A cross‐sectional study
Authors: Othman Nurul Hanim , Rajali Aiemeeza , Zulkifeli Nik Rahayyu Nik , Shaharuddin Izzati Mohd , Hussein Kamarul Hashimy , Hassan Mohamed Ibrahim Abu 
Published: April 2023

AbstractBackgroundAthletes with disabilities may be at an even greater risk of orofacial trauma than their counterparts, and the risk may vary depending on the type of sports. This study aimed to assess the incidence of sports‐related dental injuries and oral health status among Malaysian para‐athletes.MethodsA questionnaire survey was conducted to assess self‐reported dental injuries and knowledge of their management. An intraoral examination was performed using the decayed, missing, and filled teeth (DMFT) index following the World Health Organization guidelines.ResultsA total of 61 para‐athletes (men = 90.16%, n = 55; women = 9.84%, n = 6) from different sports categories with different disabilities randomly participated in this study. The incidence of self‐reported dental injuries was 18.0% (n = 11), with the most common injury being crown tooth fracture (72.7%) and lip laceration (63.6%). However, the majority of the athletes (70.5%, n = 43) did nothing after experiencing dental trauma, and 82.0% (n = 50) were unaware of the immediate management of dental trauma. Based on the intraoral examination, only 9.8% (n = 6) of the athletes had perfectly sound teeth. The mean total DMFT index was 3.49 ± 2.371, while the mean DMFT index for decayed, missing, and filled teeth was 1.28 ± 1.293, 0.74 ± 0.705, and 1.48 ± 1.120, respectively. The mean DMFT index for decayed, missing, and filled teeth and total DMFT index significantly differed among the types of disabilities (P < .05) but not between the sexes (P > .05).ConclusionThe most commonly reported injuries among para‐athletes are crown tooth fractures and lip lacerations. The total DMFT index among para‐athletes is moderate, emphasising the need for improvements.
Synergistic actions of three MYB transcription factors underpins the high accumulation of myricetin in Morella rubra
Authors: Cao Yunlin , Zhang Ruining , Xing Mengyun , Ren Chuanhong , Li Jiajia , Qian Jiafei , Mei Yuyang , Yang Xiaochun , Sun Chongde , Grierson Donald , Chen Kunsong , Xu Changjie , Li Xian 
Published: April 2023

SUMMARYFlavonols are health‐promoting bioactive compounds important for human nutrition, health, and plant defense. The transcriptional regulation of kaempferol and quercetin biosynthesis has been studied extensively, while little is known about the regulatory mechanisms underlying myricetin biosynthesis, which has strong antioxidant, anticancer, antidiabetic, and anti‐inflammatory activities. In this study, the flavonol‐specific MrMYB12 in Morella rubra preferred activating the promoter of flavonol synthase 2 (MrFLS2) (6.4‐fold) rather than MrFLS1 (1.4‐fold) and upregulated quercetin biosynthesis. Furthermore, two SG44 R2R3‐MYB members, MrMYB5 and MrMYB5L, were identified by yeast one‐hybrid library screening using the promoter of flavonoid 3′,5′‐hydroxylase (MrF3′5′H), and transcript levels of these R2R3‐MYBs were correlated with accumulation of myricetin derivatives during leaf development. Dual‐luciferase and electrophoretic mobility shift assays demonstrated that both MrMYB5 and MrMYB5L could bind directly to MYB recognition sequence elements in promoters of MrF3′5′H or MrFLS1 and activate their expression. Protein–protein interactions of MrMYB5 or MrMYB5L with MrbHLH2 were confirmed by yeast two‐hybrid and bimolecular fluorescence complementation assays. MrMYB5L‐MrbHLH2 showed much higher synergistic activation of MrF3′5′H or MrFLS1 promoters than MrMYB5‐MrbHLH2. Studies with Arabidopsis thaliana homologs AtMYB5 and AtTT8 indicated that similar synergistic regulatory effects occur with promoters of MrF3′5′H or MrFLS1. Transient overexpression of MrMYB5L‐MrbHLH2 in Nicotiana benthamiana induced a higher accumulation of myricetin derivatives (57.70 μg g−1 FW) than MrMYB5‐MrbHLH2 (7.43 μg g−1 FW) when MrMYB12 was coexpressed with them. This study reveals a novel transcriptional mechanism regulating myricetin biosynthesis with the potential use for future metabolic engineering of health‐promoting flavonols.
Comparative Investigation of Expression of Glutamatergic and GABAergic Genes in the Rat Hippocampus after Focal Brain Ischemia and Central LPS Administration
Authors: Kalinina Tatyana S. , Shishkina Galina T. , Lanshakov Dmitriy A. , Sukhareva Ekaterina V. , Onufriev Mikhail V. , Moiseeva Yulia V. , Gulyaeva Natalia V. , Dygalo Nikolay N. 
Published: April 2023

Abstract
Among the responses in the early stages of stroke, activation of neurodegenerative and proinflammatory processes in the hippocampus is of key importance for the development of negative post-ischemic functional consequences. However, it remains unclear, what genes are involved in these processes. The aim of this work was a comparative study of the expression of genes encoding glutamate and GABA transporters and receptors, as well as inflammation markers in the hippocampus one day after two types of middle cerebral artery occlusion (according to Koizumi et al. method, MCAO-MK, and Longa et al. method, MCAO-ML), and direct pro-inflammatory activation by central administration of bacterial lipopolysaccharide (LPS). Differences and similarities in the effects of these challenges on gene expression were observed. Expression of a larger number of genes associated with activation of apoptosis and neuroinflammation, glutamate reception, and markers of the GABAergic system changed after the MCAO-ML and LPS administration than after the MCAO-MK. Compared with the MCAO-ML, the MCAO-MK and LPS challenges caused changes in the expression of more genes involved in glutamate transport. The most pronounced difference between the responses to different challenges was the changes in expression of calmodulin and calmodulin-dependent kinases genes observed after MCAO, especially MCAO-ML, but not after LPS. The revealed specific features of the hippocampal gene responses to the two types of ischemia and a pro-inflammatory stimulus could contribute to further understanding of the molecular mechanisms underlying diversity of the post-stroke consequences both in the model studies and in the clinic.
An In Vivo CRISPR Screen Identifies That SNRPC Promotes Triple-Negative Breast Cancer Progression
Authors: Lu Xun-Xi , Yang Wen-Xiao , Pei Yu-Chen , Luo Hong , Li Xiao-Guang , Wang Yun-Jin , Zhang Guo-Liang , Ling Hong , Shao Zhi-Ming , Hu Xin 
Published: April 2023

Abstract

Dysregulation of RNA-binding proteins (RBP) is one of the characteristics of cancer. Investigating the biological functions and molecular mechanisms of abnormal RBPs can help uncover new cancer biomarkers and treatment strategies. To identify oncogenic RBPs in triple-negative breast cancer (TNBC), we employed an in vivo CRISPR screen and a TNBC progression model, which revealed small nuclear ribonucleoprotein polypeptide C (SNRPC), a subunit of the U1 small nuclear ribonucleoprotein particle (U1 snRNP), as a key modulator of TNBC progression. SNRPC was frequently upregulated, which corresponded to poor prognosis in patients with TNBC. SNRPC ablation significantly impaired the proliferation, migration, and invasion of TNBC cells in vitro and in vivo. In addition, SNRPC was essential for the stability of U1 snRNP and contributed to the RNA Pol II–controlled transcriptional program. Knockdown of SNRPC decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, and CDK4) and reduced their expression levels. Furthermore, SNRPC deletion was confirmed to inhibit TNBC progression partially through regulation of the TNFAIP2-Rac1–β-catenin signaling pathway. Taken together, this data suggests that SNRPC plays an oncogenic role in TNBC, is a marker of poor prognosis, and may be a valuable therapeutic target for patients with intractable TNBC.

Significance:
A functional CRISPR screen identifies SNRPC as an RNA-binding protein that promotes the aggressiveness of breast cancer by facilitating Pol II–controlled transcription of oncogenes.
MMP9 Clears the Way for Metastatic Cell Penetration Across the Blood–Brain Barrier
Authors: McCarty Joseph H. 
Published: April 2023

AbstractAlthough brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood–brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence microcopy and serial reconstruction of ultrastructural sections to analyze BBB breach and subsequent colonization of the brain. They show that matrix metalloprotease 9 (MMP9) plays a central role in these events. Pharmacologic or genetic targeting of MMP9 significantly reduced penetration across the BBB and limited micrometastasis formation. Surprisingly, extravasation and brain colonization does not involve significant degradation of canonical MMP9 protein targets such as collagen and laminin in vascular basement membranes, indicating the requirement for other extracellular matrix (ECM) or non-ECM substrates for MMP9. Collectively, these new and important findings reveal cell–cell adhesion and signaling events between cerebral endothelial and metastatic cancer cells as well as identify potential therapeutic targets to prevent metastatic tumor cell dissemination in the brain.See related article by Karreman et al., p. 1299
Abstract CT060: ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma
Authors: Arrillaga-Romany Isabel , Lassman Andrew , McGovern Susan L. , Mueller Sabine , Nabors Louis B. , van den Bent Martin , Vogelbaum Michael , Allen Joshua E. , Melemed Allen S. , Tarapore Rohinton S. , Yang Dewen , Wen Patrick , Cloughsey Timothy 
Published: April 2023

Abstract
Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease.
Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.
Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [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 CT060.
Abstract CT137: ENLIGHTen-01: a phase 1 study of fluorescein-specific (FITC-E2)-car T cells in combination with folate-fluorescein (UB-TT170) for osteosarcoma
Authors: Albert Catherine M. , Pinto Navin R. , Taylor Mallory , Wilson Ashley , Rawlings-Rhea Stephanie , Narayanaswamy Prabha , Huang Wenjun , Seidel Kristy , Mgebroff Stephanie , Brown Christopher , Garcia Jacob , Teoh Jeffrey , Orentas Rimas J. , Gardner Rebecca A. , Jensen Michael C. , Park Julie R. 
Published: April 2023

Abstract
Background: Outcomes for relapsed osteosarcoma (OS) remain poor and there are no systemic therapies that have been shown to provide a survival benefit. Chimeric Antigen Receptor (CAR) T cell immunotherapy involves the adoptive transfer of T-lymphocytes that have been engineered to recognize tumor-specific antigens, resulting in targeted lysis of malignant cells. Folate receptors (FR) are membrane-bound surface proteins that bind folates with high affinity. FRs are overexpressed in OS and have very limited expression in normal tissue. UB-TT170 (Umoja Biopharma) is a small molecule bispecific “adapter” consisting of folate conjugated to fluorescein (FL). It penetrates tumors in minutes and is retained for long periods of time due to high affinity for the FR, while unbound UB-TT170 rapidly clears from the blood and from FR- tissues. We hypothesize that administration of fixed dosing anti-FL(FITC-E2) CAR T cells followed by escalating doses of UB-TT170 will deliver personalized immunotherapy to OS patients. In addition, this approach offers an attractive safety mechanism since administration of NaFL should reverse CAR T cell reactivity.
Methods: We designed a Phase I study for young adult (15-30 yr) patients with recurrent/refractory OS to examine the safety and feasibility of administering autologous, peripheral blood-derived T cells that have been genetically modified to express a 2nd generation FL-specific CAR in combination with intra-subject dose escalation of UB-TT170. The primary objective is to identify a recommended dose escalation sequence of UB-TT170 to move forward in clinical development. A 3+3 design will be used to investigate 3 possible dosing sequences. The trial opened in July 2022. As of January 5, 2023, 5 subjects have enrolled and one subject has been treated on dose regimen 1. T cell products have been successfully manufactured for all enrolled subjects. The trial remains open to enrollment. Clinical trial registration numbers: NCT05312411
Citation Format: Catherine M. Albert, Navin R. Pinto, Mallory Taylor, Ashley Wilson, Stephanie Rawlings-Rhea, Prabha Narayanaswamy, Wenjun Huang, Kristy Seidel, Stephanie Mgebroff, Christopher Brown, Jacob Garcia, Jeffrey Teoh, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. ENLIGHTen-01: a phase 1 study of fluorescein-specific (FITC-E2)-car T cells in combination with folate-fluorescein (UB-TT170) for osteosarcoma [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 CT137.