Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications.

Breast cancer is one of the most common malignancies that pose a serious threat to women's health. Reprogramming of energy metabolism is a major feature of the malignant transformation of breast cancer. Compared to normal cells, tumor cells reprogram metabolic processes more efficiently, converting nutrient supplies into glucose, amino acid and lipid required for malignant proliferation and progression. Non-coding RNAs(ncRNAs) are a class of functional RNA molecules that are not translated into proteins but regulate the expression of target genes. NcRNAs have been demonstrated to be involved in various aspects of energy metabolism, including glycolysis, glutaminolysis, and fatty acid synthesis. This review focuses on the metabolic regulatory mechanisms and clinical applications of metabolism-regulating ncRNAs involved in breast cancer. We summarize the vital roles played by metabolism-regulating ncRNAs for endocrine therapy, targeted therapy, chemotherapy, immunotherapy, and radiotherapy resistance in breast cancer, as well as their potential as therapeutic targets and biomarkers. Difficulties and perspectives of current targeted metabolism and non-coding RNA therapeutic strategies are discussed.

Yellow Petal locus GaYP promotes flavonol biosynthesis and yellow coloration in petals of Asiatic cotton (Gossypium arboreum).

KEY MESSAGE: Yellow Petal locus GaYP is located on chromosome 11 and encodes a Sg6 R2R3-MYB transcription factor, which promotes flavonol biosynthesis and yellow coloration in Asiatic cotton petals. Petal color is pivotal to ornamental value and reproduction of plants. Yellow coloration in plant petals is mainly attributed to colorants including carotenoids, aurones and some flavonols. To date, the genetic regulatory mechanism of flavonol biosynthesis in petals is still to be elucidated. Here, we employed Asiatic cottons with or without deep yellow coloration in petals to address this question. Multi-omic and biochemical analysis revealed significantly up-regulated transcription of flavonol structural genes and increased levels of flavonols, especially gossypetin and 6-hydroxykaempferol, in yellow petals of Asiatic cotton. Furthermore, the Yellow Petal gene (GaYP) was mapped on chromosome 11 by using a recombinant inbred line population. It was found that GaYP encoded a transcriptional factor belonging to Sg6 R2R3-MYB proteins. GaYP could bind to the promoter of flavonol synthase gene (GaFLS) and activate the transcription of downstream genes. Knocking out of GaYP or GaFLS homologs in upland cotton largely eliminated flavonol accumulation and pale yellow coloration in petals. Our results indicated that flavonol synthesis, up-regulated by the R2R3-MYB transcription activator GaYP, was the causative factor for yellow coloration of Asiatic cotton petals. In addition, knocking out of GaYP homologs also led to decrease in anthocyanin accumulation and petal size in upland cotton, suggesting that GaYP and its homologs might modulate developmental or physiological processes beyond flavonol biosynthesis.

Aptamer-based biosensors and application in tumor theranostics.

An aptamer is a short oligonucleotide chain that can specifically recognize targeting analytes. Due to its high specificity, low cost, and good biocompatibility, aptamers as the targeting elements of biosensors have been applied widely in non-invasive tumor imaging and treatment in situ to replace traditional methods. In this review, we will summarize recent advances in using aptamer-based biosensors in tumor diagnosis. After a brief introduction of the advantage of aptamers compared with enzyme sensors and immune sensors, the different sensing designs and mechanisms based on 3 signal transduction modes will be reviewed to cover different kinds of analytical methods, including: electrochemistry analysis, colorimetry analysis, and fluorescence analysis. Finally, the prospective advantages of aptamer-based biosensors in tumor theranostics and post-treatment monitoring are also evaluated in this review.

Genome resequencing-based high-density genetic map and QTL detection for yield and fiber quality traits in diploid Asiatic cotton (Gossypium arboreum).

Cotton is the most important fiber crop in the world. Asiatic cotton (Gossypium arboreum, genome A2) is a diploid cotton species producing spinnable fibers and important germplasm for cotton breeding and a significant model for fiber biology. However, the genetic map of Asiatic cotton has been lagging behind tetraploid cottons, as well as other stable crops. This study aimed to construct a high-density SNP genetic map and to map QTLs for important yield and fiber quality traits. Using a recombinant inbred line (RIL) population and genome resequencing technology, we constructed a high-density genetic map that covered 1980.17 cM with an average distance of 0.61 cM between adjacent markers. QTL analysis revealed a total of 297 QTLs for 13 yield and fiber quality traits in three environments, explaining 5.0-37.4% of the phenotypic variance, among which 75 were stably detected in two or three environments. Besides, 47 QTL clusters, comprising 131 QTLs for representative traits, were identified. Our works laid solid foundation for fine mapping and cloning of QTL for yield and fiber quality traits in Asiatic cotton.

Clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles.

OBJECTIVE: This study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype-genotype correlations in these patients. METHODS: This was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes. RESULTS: Sixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure. CONCLUSIONS: The novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype-genotype correlations were established because of the diversity of the clinical characteristics of these patients.

A Potential Mechanism of Neurological Impairment in Children With Infantile Spasm: Based on Microanatomic Structure Analysis Employing Voxel-Based Morphometry and Surface-Based Morphometry.

BACKGROUND: Infantile epileptic spasms syndrome (IESS) would accompany with severe neurological impairment. Our study aimed to explore the potential mechanism by employing voxel-based and surface-based morphometry to detect brain microwould accompany with severe neurological impairment. Our study aimed to explore the potential mechanism by employing voxel-based and surface-based morphometry to detect brain microanatomic structure alteration. METHODS: The IESS group had 21 males and 13 females (mean age: 17.7 ± 15.6 months), whereas the healthy controls group had 22 males and 10 females (mean age: 29.4 ± 18.7 months). High-resolution 3D T1WI was performed. Computational Anatomy Toolbox implemented in Statistical Parametric Mapping 12 was used to measure the gray matter and white matter volume, and the cortical thickness separately. Independent sample t test was used to assess between-group differences. IESS group was assessed using the Bayley Scales of Infant Development. RESULTS: The IESS group showed a significantly decreased volume of gray matter in right middle temporal gyrus, inferior temporal gyrus, superior temporal gyrus, right fusiform, and bilateral precuneus (P < 0.001). There were no significant between-group differences with respect to white matter volume or cortical thickness (P > 0.001). The results of Bayley Scales of Infant Development showed that the Mental Development Index (MDI) and Psychomotor Development Index scores of children with IESS were almost concentrated in the range of <70. MDI score showed a positive correlation with gray matter reduction area in IESS group. CONCLUSION: Children with IESS had impaired cognitive and delayed motor development. And the decreased gray matter in the right temporal lobe, fusiform, and bilateral precuneus could be the potential anatomic basis for impaired function, such as hearing, visual, and language.

To explore the potential mechanisms of cognitive impairment in children with MRI-negative pharmacoresistant epilepsy due to focal cortical dysplasia: A pilot study from gray matter structure view.

Objectives: To investigate the characteristics of brain structure in children with focal cortical dysplasia (FCD)-induced pharmacoresistant epilepsy, and explore the potential mechanisms of cognitive impairment from the view of gray matter alteration. Methods: 25 pharmacoresistant pediatric patients with pathologically confirmed focal cortical dysplasia (FCD), and 25 gender-matched healthy controls were included in this study. 3.0T MRI data and intelligence tests using the Wechsler Intelligence Scale for Children-Forth Edition (WISC-IV) were generated for all subjects. Voxel-based morphometry (VBM)-diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) and surface-based morphometry (SBM) analyses were performed to analyze gray matter volume and cortical structure. Two-sample t-tests were used to compare the differences in gray matter volume (P＜0.05, FWE) and cortical thickness (P＜0.001, FWE) between the two groups. Also, the Spearman rank correlation analyses were employed to determine the relationship between structural alterations and neuropsychological results. Results: The WISC-IV scores of the FCD group were significantly lower than those of the HC group in terms of full-scale intelligence quotient (FSIQ), verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), and processing speed index (PSI) (all P＜0.01). Compared with the HC group, in the FCD group, the gray matter volume (GMV) reduced significantly in the left cerebellum_8, cerebellum_Crus2, and bilateral thalamus (P＜0.05, FWE); the GMV increased in the bilateral medial frontal gyrus, right precuneus, and left inferior temporal gyrus (P＜0.05, FWE), and the cortical thickness increased in the bilateral frontal, parietal, and temporal areas (P＜0.001, FWE). Correlation analyses showed that the age of seizure onset had positive correlations with the WISC-IV scores significantly. Meanwhile, the cortex thicknesses of the left pars opercularis gyrus, left middle temporal gyrus, and right inferior temporal gyrus had negative correlations with the WISC-IV scores significantly. Conclusion: FCD patients showed subtle structural abnormalities in multiple brain regions, with significant involvement of the primary visual cortex and language function cortex. And we also demonstrated a crucial correlation between gray matter structural alteration and cognitive impairment.

From brain connectivity to cognitive function: Dissecting the salience network in pediatric BECTS-ESES.

BACKGROUND: Benign childhood epilepsy with centrotemporal spikes (BECTS), a common pediatric epilepsy, may lead to cognitive decline when compounded by Electrical Status Epilepticus during Sleep (ESES). Emerging evidence suggests that disruptions in the Salience Network (SN) contribute significantly to the cognitive deficits observed in BECTS-ESES. Our study rigorously investigates the dynamic functional connectivity (dFC) within the SN and its correlation with cognitive impairments in BECTS-ESES, employing advanced neuroimaging and neuropsychological assessments. METHODS: In this research, 45 patients diagnosed with BECTS-ESES and 55 age-matched healthy controls (HCs) participated. We utilized resting-state functional magnetic resonance imaging (fMRI) and Independent Component Analysis (ICA) to identify three fundamental SN nodes: the right Anterior Insula (rAI), left Anterior Insula (lAI), and the Anterior Cingulate Cortex (ACC). A two-sample t-test facilitated the comparison of dFC between these pivotal regions and other brain areas. RESULTS: Significantly, the BECTS-ESES group demonstrated increased dFC, particularly between the ACC and the right Middle Occipital Gyrus, and from the rAI to the right Superior Parietal Gyrus and Cerebellum, and from the lAI to the left Postcentral Gyrus. Such dFC augmentations provide neural insights potentially explaining the neuropsychological deficits in BECTS-ESES children. Employing comprehensive neuropsychological evaluations, we mapped these dFC disruptions to specific cognitive impairments encompassing memory, executive functioning, language, and attention. Through multiple regression analysis and path analysis, a preliminary but compelling association was discovered linking dFC disturbances directly to cognitive impairments. These findings underscore the critical role of SN disruptions in BECTS-ESES cognitive dysfunctions. LIMITATION: Our cross-sectional design and analytic methods preclude definitive mediation models and causal inferences, leaving the precise nature of dFC's mediating role and its direct impact by BECTS-ESES partially unresolved. Future longitudinal and confirmatory studies are needed to comprehensively delineate these associations. CONCLUSION: Our study heralds dFC within the SN as a vital biomarker for cognitive impairment in pediatric epilepsy, advocating for targeted cognitive-specific interventions in managing BECTS-ESES. The preliminary nature of our findings invites further studies to substantiate these associations, offering profound implications for the prognosis and therapeutic strategies in BECTS-ESES, thereby underlining the importance of this research in the field of pediatric neurology and epilepsy management.

Prognostic analysis in children with focal cortical dysplasia II undergoing epilepsy surgery: Clinical and radiological factors.

Objective: The aim of this study was to investigate the value of clinical profiles and radiological findings in assessing postsurgical outcomes in children with focal cortical dysplasia (FCD) II while exploring prognostic predictors of this disease. Methods: We retrospectively reviewed 50 patients with postoperative pathologically confirmed FCD II from January 2016 to June 2021. The clinical profiles and preoperative radiological findings were measured and analyzed. The patients were classified into four classes based on the Engel Class Outcome System at the last follow-up. For the analysis, the patients were divided into two categories based on Engel I and Engel II-IV, namely, seizure-free and non-seizure-free groups. Qualitative and quantitative factors were subsequently compared by groups using comparative statistics. Receiver operating characteristic (ROC) curves were used to identify the predictors of prognosis in children with FCD II. Results: Thirty-seven patients (74%) had Engel class I outcomes. The minimum postsurgical follow-up was 1 year. At the epilepsy onset, patients who attained seizure freedom were older and less likely to have no apparent lesions on the preoperative MRI ("MRI-negative"). The non-seizure-free group exhibited a higher gray matter signal intensity ratio (GR) on 3D T1-MPRAGE images (p = 0.006), with a lower GR on T2WI images (p = 0.003) and FLAIR images (p = 0.032). The ROC curve indicated that the model that combined the GR value of all MRI sequences (AUC, 0.87; 95% CI, 0.77-0.97; p < 0.001; 86% sensitivity, 85% specificity) was able to predict prognosis accurately. Conclusion: A lower age at the onset or the MRI-negative finding of FCD lesions suggests a poor prognosis for children with FCD II. The model consisting of GR values from three MRI sequences facilitates the prognostic assessment of FCD II patients with subtle MRI abnormalities to prevent worse outcomes.

Activation Map Reveals Language Impairment in Children with Benign Epilepsy with Centrotemporal Spikes (BECTS).

Objective: Neuropsychological evidence revealed language impairment in children with benign epilepsy with centrotemporal spikes (BECTS). This study investigates language function using task-activated fMRI. Methods: We conducted a language task fMRI study on three groups on a 3.0T MRI scanner, including a new onset drug naïve group (NODN-BECTS, n=11, age=9.6±1.6), an established epilepsy with medication-treated group (Med-BECTS, n=17, age=10.7±2.2) and a healthy control group (HC, n=18, age=10.8±1.7). We use MATLAB14 and SPM12 to pre-process and analyze the data. A one-sample t-test was used to identify task-related brain activation changes in each group, based on the general linear model (GLM). And, then two sample t-test was performed to compare different activated regions between groups. In addition, scores on the most recent Mandarin school exams were acquired to examine and contrast extra-scanner language performance. Results: Statistical results show that some language-related brain regions (such as the left superior frontal gyrus and cerebellar vermis) were additionally activated in the NODN-BECTS group compared with the HC group. Compared with NODN-BECTS and HC groups, decreased activations were found in language-related regions in the Med-BECTS group, including the left insula, superior and middle frontal gyri, and bilateral middle occipital gyri. On the Mandarin school exams, the average score for HC was 87.3±8.2, NODN was 84.8±7.8, and Med was 78.2±13.2. There was a trend toward statistical significance between the Med and the HC (p = 0.074) as well as NODN (p = 0.092) groups. No statistically significant differences were found between the HC and the NODN-BECTS groups. Significance: Language task fMRI reveals additional areas of activation in new onset BECTS compared to healthy controls which may be compensatory in nature. Antiseizure medications (ASMs) and/or longer duration of BECTS additionally appears to affect language-related regions and reduce their functional ability.

Role of SNAP-25 MnlI variant in impaired working memory and brain functions in attention deficit/hyperactivity disorder.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is a hereditary neurodevelopmental disorder characterized by working memory (WM) deficits. The MnlI variant (rs3746544) of the synaptosomal-associated protein 25 (SNAP-25) gene is associated with ADHD. In this study, we investigated the role and underlying mechanism of SNAP-25 MnlI variant in cognitive impairment and brain functions in boys with ADHD. METHOD: We performed WM capacity tests using the fourth version of the Wechsler Intelligence Scale for Children (WISC-IV) and regional homogeneity (ReHo) analysis for the resting-state functional magnetic resonance imaging data of 56 boys with ADHD divided into two genotypic groups (TT homozygotes and G-allele carriers). Next, Spearman's rank correlation analysis between the obtained ReHo values and the WM index (WMI) calculated for each participant. RESULTS: Compared with G-allele carrier group, there were higher ReHo values for the left medial prefrontal cortex (mPFC) and higher WM capacity in TT homozygote group. Contrary to TT homozygote group, the WM capacity was negatively correlated with the peak ReHo value for the left mPFC in G-allele carrier group. CONCLUSION: These findings suggest that SNAP-25 MnlI variant may underlie cognitive and brain function impairments in boys with ADHD, thus suggesting its potential as a new target for ADHD treatment.

CD105: tumor diagnosis, prognostic marker and future tumor therapeutic target.

Cancer is one of the diseases with the highest morbidity and mortality rates worldwide, and its therapeutic options are inadequate. The endothelial glycoprotein, also known as CD105, is a type I transmembrane glycoprotein located on the surface of the cell membranes and it is one of the transforming growth factor-ß (TGF-ß) receptor complexes. It regulates the responses associated with binding to transforming growth factor ß1 egg (Activin-A), bone morphogenetic protein 2 (BMP-2), and bone morphogenetic protein 7 (BMP-7). Additionally, it is involved in the regulation of angiogenesis. This glycoprotein is indispensable in the treatment of tumor angiogenesis, and it also plays a leading role in tumor angiogenesis therapy. Therefore, CD105 is considered to be a novel therapeutic target. In this study, we explored the significance of CD105 in the diagnosis, treatment and prognosis of various tumors, and provided evidence for the effect and mechanism of CD105 on tumors.

Abnormal Insular Dynamic Functional Connectivity and Its Relation to Social Dysfunctioning in Children With Attention Deficit/Hyperactivity Disorder.

Anomalies in large-scale cognitive control networks impacting social attention abilities are hypothesized to be the cause of attention deficit hyperactivity disorder (ADHD). The precise nature of abnormal brain functional connectivity (FC) dynamics including other regions, on the other hand, is unknown. The concept that insular dynamic FC (dFC) among distinct brain regions is dysregulated in children with ADHD was evaluated using Insular subregions, and we studied how these dysregulations lead to social dysfunctioning. Data from 30 children with ADHD and 28 healthy controls (HCs) were evaluated using dynamic resting state functional magnetic resonance imaging (rs-fMRI). We evaluated the dFC within six subdivisions, namely both left and right dorsal anterior insula (dAI), ventral anterior insula (vAI), and posterior insula (PI). Using the insular sub-regions as seeds, we performed group comparison between the two groups. To do so, two sample t-tests were used, followed by post-hoc t-tests. Compared to the HCs, patients with ADHD exhibited decreased dFC values between right dAI and the left middle frontal gyrus, left postcentral gyrus and right of cerebellum crus, respectively. Results also showed a decreased dFC between left dAI and thalamus, left vAI and left precuneus and left PI with temporal pole. From the standpoint of the dynamic functional connectivity of insular subregions, our findings add to the growing body of evidence on brain dysfunction in ADHD. This research adds to our understanding of the neurocognitive mechanisms behind social functioning deficits in ADHD. Future ADHD research could benefit from merging the dFC approach with task-related fMRI and non-invasive brain stimulation, which could aid in the diagnosis and treatment of the disorder.

Oncolytic viral vectors in the era of diversified cancer therapy: from preclinical to clinical.

With the in-depth research and wide application of immunotherapy recently, new therapies based on oncolytic viruses are expected to create new prospects for cancer treatment via eliminating the suppression of the immune system by tumors. Currently, an increasing number of viruses are developed and engineered, and various virus vectors based on effectively stimulating human immune system to kill tumor cells have been approved for clinical treatment. Although the virus can retard the proliferation of tumor cells, the choice of oncolytic viruses in biological cancer therapy is equally critical given their therapeutic efficacy, safety and adverse effects. Moreover, previously known oncolytic viruses have not been systematically classified. Therefore, in this review, we summarized and distinguished the characteristics of several common types of oncolytic viruses: herpes simplex virus, adenovirus, measles virus, Newcastle disease virus, reovirus and respiratory syncytial virus. Subsequently, we outlined that these oncolytic viral vectors have been transformed from preclinical studies in combination with immunotherapy, radiotherapy, chemotherapy, and nanoparticles into clinical therapeutic strategies for various advanced solid malignancies or circulatory system cancers.