Titanium dioxide nanoparticles Disrupt ultrastructure and function of Rat thyroid tissue via oxidative stress.

Nano-TiO2 is widely used in various fields such as industry, daily necessities, food and medicine. Previous studies have shown that it can enter mammalian tissues through the digestive tract or respiratory tract and have effects on various organs and systems. However, the effect of nano-TiO2 on the mammalian thyroid gland has not been reported. In this study, we fed SD rats with rutile nano-TiO2 at a dose of 5 mg/kg body weight for 3 weeks, and then examined the thyroid histology and thyroid function of the rats. In vitro experiments were conducted to determine the effects of nano-TiO2 on the viability, apoptosis, inflammatory factors, antioxidant enzymes, and oxidative stress of human thyroid follicular epithelial cells. Histological evidence showed abnormal morphology of rat thyroid follicles and organelle damage in follicular epithelial cells. Nano-TiO2 caused a decrease in the level of sodium/iodide symporter (NIS), an increase in the level of apoptotic protein cleaved-caspase 3, and an increase in the levels of pro-inflammatory factors IL-1ß and TNF-α in rat thyroid tissue. Nano-TiO2 also resulted in increased serum FT4 and TPO-Ab levels. In in vitro experiments, nano-TiO2 reduced the viability of human thyroid follicular cells, downregulated the levels and activities of antioxidant enzymes CAT, GPX1 and SOD, and increased the levels of ROS and MDA caused by oxidative stress. These results indicate that nano-TiO2 damages the structure and function of thyroid follicular epithelial cells through oxidative stress. Long-term exposure to nano-TiO2 could be a potential risk factor for thyroid dysfunction.

Transcriptomics and gut microbiome analysis of the edible herb Bidens pilosa as a functional feed additive to promote growth and metabolism in tilapia (Oreochromis spp.).

To reduce the use of antibiotics and chemicals in aquaculture, an edible herb, Bidens pilosa, has been selected as a multifunctional feed additive. Although there has been considerable research into the effects of B. pilosa on poultry, the wider effects of B. pilosa, particularly on the growth and gut microbiota of fish, remain largely unexplored. We aimed to investigate the interactive effects between the host on growth and the gut microbiota using transcriptomics and the gut microbiota in B. pilosa-fed tilapia. In this study, we added 0.5% and 1% B. pilosa to the diet and observed that the growth performance of tilapia significantly increased over 8 weeks of feeding. Comparative transcriptome analysis was performed on RNA sequence profiles obtained from liver and muscle tissues. Functional enrichment analysis revealed that B. pilosa regulates several pathways and genes involved in amino acid metabolism, lipid metabolism, carbohydrate metabolism, endocrine system, signal transduction, and metabolism of other amino acids. The expression of the selected growth-associated genes was validated by qRT-PCR. The qRT-PCR results indicated that B. pilosa may enhance growth performance by activating the expression of the liver igf1 and muscle igf1rb genes and inhibiting the expression of the muscle negative regulator mstnb. Both the enhancement of liver endocrine IGF1/IGF1Rb signaling and the suppression of muscle autocrine/paracrine MSTN signaling induced the expression of myogenic regulatory factors (MRFs), myod1, myog and mrf4 in muscle to promote muscle growth in tilapia. The predicted function of the gut microbiota showed several significantly different pathways that overlapped with the KEGG enrichment results of differentially expressed genes in the liver transcriptomes. This finding suggested that the gut microbiota may influence liver metabolism through the gut-liver axis in B. pilosa-fed tilapia. In conclusion, dietary B. pilosa can regulate endocrine IGF1 signaling and autocrine/paracrine MSTN signaling to activate the expression of MRFs to promote muscle growth and alter the composition of gut bacteria, which can then affect liver amino acid metabolism, carbohydrate metabolism, endocrine system, lipid metabolism, metabolism of other amino acids, and signal transduction in the host, ultimately enhancing growth performance. Our results suggest that B. pilosa has the potential to be a functional additive that can be used as an alternative to reduce antibiotic use as a growth promoter in aquaculture.

Elongatibacter sediminis gen. nov., sp. nov., isolated from intertidal sediment, and genomic comparison with all genera in the family Wenzhouxiangellaceae.

A novel slightly halophilic, aerobic, and Gram-stain-negative strain, designated as CH-27T, was isolated during a bacterial resource investigation of intertidal sediment collected from Xiaoshi Island in Weihai, PR China. Cells of strain CH-27T were rod-shaped with widths of 0.3-0.6 µm and lengths of 2.0-11.0 µm. Strain CH-27T grew optimally at 37 °C, pH 7.0 and with 2.0 % (w/v) NaCl. Catalase activity was weakly positive and oxidase activity was positive. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CH-27T was most related to Marinihelvus fidelis KCTC 92639T (93.6 %), followed by Wenzhouxiangella marina MCCC 1K00261T (92.0 %). Based on genome comparisons between strain CH-27T and M. fidelis KCTC 92639T, the average amino acid identity was 63.6 % and the percentage of conserved proteins was 48.3 %. The major cellular fatty acid of strain CH-27T (≥10 %) was iso-C15 : 0 and the sole respiratory quinone was quinone-8. The polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, and aminophospholipid. The DNA G+C content was 62.7 mol%. Based on comprehensive analysis of its phylogenetic, physiological, biochemical, and chemotaxonomic characteristics, strain CH-27T represents a novel species in a novel genus, for which the name Elongatibacter sediminis gen. nov., sp.nov. is proposed. The type strain is CH-27T (=MCCC 1H00480T=KCTC 8011T).

piRNA PROPER Suppresses DUSP1 Translation by Targeting N6-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer.

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.

The association between weight change patterns and obesity-related complex multimorbidity: evidence from NHANES.

Objective: Obesity is a major risk factor for non-communicable diseases (NCDs), which has been the leading cause of death nowadays. The aim of this study is to examine the association between total changes in body mass index (BMI) across adulthood and the risk of obesity-related complex multimorbidity in elderly, characterizing the capacity of BMI waves in predicting major chronic diseases. Methods: In this retrospective study, 15,520 participants were analyzed from the National Health and Nutrition Examination Survey (NHANES) from 1999 and 2018. BMI was categorized as obesity (≥30.0 kg/m²), overweight (25.0-29.9 kg/m²), normal weight (18.5-24.9 kg/m²), and underweight (<18.5 kg/m²). Odds ratios (ORs) with 95% confidence interval (CIs) for the relationship between BMI change patterns and major health outcomes included hypertension, cancer, chronic obstructive pulmonary disease, cardiovascular disease, and diabetes, and population attributable fractions (PAFs) of BMI were evaluated. Results: In comparison with participants who remained non-obese, those who are stable obese showed the highest risks of developing at least one chronic disease in later life, with odds ratios of 2.76 (95% CI: 2.20 to 3.45) from age 25 years to 10 years before baseline, 2.90 (2.28 to 3.68) from age 25 years to baseline, and 2.49 (2.11 to 2.95) in the 10-year period before baseline. Moving from non-obese to obese weight-change pattern in all periods (from age 25 years to 10 years before baseline: OR = 1.82; 95% CI, 1.57 to 2.11; from age 25 years to baseline: OR = 1.87; 95% CI, 1.59 to 2.19; from 10 years before baseline to baseline: OR = 1.62; 95% CI, 1.26 to 2.08) and moving from obese to non-obese, the 10-year period before baseline (OR = 1.89; 95% CI, 1.39 to 2.57) was associated with increased risk of chronic diseases. Midlife obesity status can explain the 8.6% risk of occurrence of the chronic diseases in elderly. Conclusions: Maintaining a stable healthy weight and losing weight in early adulthood and midlife are important for better life quality during the aging process. More effective strategies and policies to reduce the prevalence of obesity are needed.

Mitochondrial transfer between BMSCs and Müller promotes mitochondrial fusion and suppresses gliosis in degenerative retina.

Mitochondrial dysfunction and Müller cells gliosis are significant pathological characteristics of retinal degeneration (RD) and causing blinding. Stem cell therapy is a promising treatment for RD, the recently accepted therapeutic mechanism is cell fusion induced materials transfer. However, whether materials including mitochondrial transfer between grafted stem cells and recipient's cells contribute to suppressing gliosis and mechanism are unclear. In present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) transferred mitochondria to Müller cells by cell fusion and tunneling nanotubes. BMSCs-derived mitochondria (BMSCs-mito) were integrated into mitochondrial network of Müller cells, improving mitochondrial function, reducing oxidative stress and gliosis, which protected visual function partially in the degenerative rat retina. RNA sequencing analysis revealed that BMSCs-mito increased mitochondrial DNA (mtDNA) content and facilitated mitochondrial fusion in damaged Müller cells. It suggests that mitochondrial transfer from BMSCs remodels Müller cells metabolism and suppresses gliosis; thus, delaying the degenerative progression of RD.

EGFR Mutation and TKI Treatment Promote Secretion of Small Extracellular Vesicle PD-L1 and Contribute to Immunosuppression in NSCLC.

In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment followed by anti-PD-1 therapy, poor results were observed. The underlying mechanism remains unclear. We used high-resolution flow cytometry and ELISA to detect the circulating level of small extracellular vesicle (sEV) PD-L1 in NSCLC individuals with EGFR mutations before and after receiving TKIs. The secretion amount of sEV PD-L1 of lung cancer cell lines with EGFR mutations under TKI treatment or not were detected using high-resolution flow cytometry and Western blotting. The results revealed that patients harboring EGFR mutations exhibit increased levels of sEV PD-L1 in circulation, which inversely correlated with the presence of CD8+ T cells in tumor tissues. Furthermore, tumor cells carrying EGFR mutations secrete a higher quantity of PD-L1-positive sEVs. TKI treatment appeared to amplify the levels of PD-L1-positive sEVs in the bloodstream. Mutation-induced and TKI-induced sEVs substantially impaired the functionality of CD8+ T cells. Importantly, our findings indicated that EGFR mutations and TKI therapies promote secretion of PD-L1-positive sEVs via distinct molecular mechanisms, namely the HRS and ALIX pathways, respectively. In conclusion, the increased secretion of PD-L1-positive sEVs, prompted by genetic alterations and TKI administration, may contribute to the limited efficacy of immunotherapy observed in EGFR-mutant patients and patients who have received TKI treatment.

An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFß Signaling.

Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFß/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.

Oral pimonidazole unveils clinicopathologic and epigenetic features of hypoxic tumour aggressiveness in localized prostate cancer.

BACKGROUND: Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation. METHODS: A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets. RESULTS: Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types. CONCLUSIONS: Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.

Transcriptomic Insights and the Development of Microsatellite Markers to Assess Genetic Diversity in the Broodstock Management of Litopenaeus stylirostris.

The Pacific blue shrimp (Litopenaeus stylirostris) is a premium product in the international seafood market. However, intensified farming has increased disease incidence and reduced genetic diversity. In this study, we developed a transcriptome database for L. stylirostris and mined microsatellite markers to analyze their genetic diversity. Using the Illumina HiSeq 4000 platform, we identified 53,263 unigenes from muscle, hepatopancreas, the intestine, and lymphoid tissues. Microsatellite analysis identified 36,415 markers from 18,657 unigenes, predominantly dinucleotide repeats. Functional annotation highlighted key disease resistance pathways and enriched categories. The screening and PCR testing of 42 transcriptome-based and 58 literature-based markers identified 40 with successful amplification. The genotyping of 200 broodstock samples revealed that Na, Ho, He, PIC, and FIS values were 3, 0.54 ± 0.05, 0.43 ± 0.09, 0.41 ± 0.22, and 0.17 ± 0.27, respectively, indicating moderate genetic variability and significant inbreeding. Four universal microsatellite markers (CL1472.Contig13, CL517.Contig2, Unigene5692, and Unigene7147) were identified for precise diversity analysis in Pacific blue, Pacific white (Litopenaeus vannamei), and black tiger shrimps (Penaeus monodon). The transcriptome database supports the development of markers and functional gene analysis for selective breeding programs. Our findings underscore the need for an appropriate genetic management system to mitigate inbreeding depression, reduce disease susceptibility, and preserve genetic diversity in farmed shrimp populations.

Fullerenols Ameliorate Social Deficiency and Rescue Cognitive Dysfunction of BTBR T+Itpr3tf/J Autistic-Like Mice.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments. Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining. Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment. Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.

SNHG15-mediated feedback loop interplays with HNRNPA1/SLC7A11/GPX4 pathway to promote gastric cancer progression.

Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.

Quantifying Coloring Skills Among Preschoolers.

IMPORTANCE: Coloring is popular with preschool children and reveals their developmental state. However, interpreting coloring performances is challenging because descriptive and subjective evaluations are commonly used with large variations. OBJECTIVE: To develop a scoring method to objectively quantify children's coloring skills. DESIGN: Colored blank train templates were analyzed using four indicators (entropy, complexity, coloring outside the lines, and unexpected blank areas) to form a summed score. SETTING: Kindergarten in a urban city (Tainan, Taiwan). PARTICIPANTS: Two hundred thirty-nine typically developing children ages 3 to 6 yr. OUTCOME AND MEASURES: A newly developed method to assess coloring skill on the basis of a colored picture of a train. RESULTS: The summed score exhibited good internal consistency (Cronbach's α = .80), discriminative validity (p = .04), convergent validity (rs = .66 and .59 with age and visual-motor integration), and acceptable factorial validity (comparative fit index = .99, standardized root-mean-square residual = .04, and root-mean-square error of approximation = .13). Moreover, three coloring patterns (mature, transitional, and immature) were identified. CONCLUSIONS AND RELEVANCE: The new method provides objective, reliable, and valid scores representing coloring skills in typically developing children. In addition, the coloring patterns can be recognized. This method can be used to facilitate comparisons of children's coloring skills with peers and provide valuable insight into children's development. Plain-Language Summary: This study proposes a new method to objectively quantify children's coloring skills with sound reliability and validity in typically developing children. The method can be used to evaluate children's coloring skills and patterns to shed light on their developmental stages.

Combined SNPs sequencing and allele specific proteomics capture reveal functional causality underpinning the 2p25 prostate cancer susceptibility locus.

Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, a novel oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.

Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Genome-wide analysis and expression profiling of the HD-ZIP gene family in kiwifruit.

The homeodomain-leucine zipper (HD-Zip) gene family plays a pivotal role in plant development and stress responses. Nevertheless, a comprehensive characterization of the HD-Zip gene family in kiwifruit has been lacking. In this study, we have systematically identified 70 HD-Zip genes in the Actinidia chinensis (Ac) genome and 55 in the Actinidia eriantha (Ae) genome. These genes have been categorized into four subfamilies (HD-Zip I, II, III, and IV) through rigorous phylogenetic analysis. Analysis of synteny patterns and selection pressures has provided insights into how whole-genome duplication (WGD) or segmental may have contributed to the divergence in gene numbers between these two kiwifruit species, with duplicated gene pairs undergoing purifying selection. Furthermore, our study has unveiled tissue-specific expression patterns among kiwifruit HD-Zip genes, with some genes identified as key regulators of kiwifruit responses to bacterial canker disease and postharvest processes. These findings not only offer valuable insights into the evolutionary and functional characteristics of kiwifruit HD-Zips but also shed light on their potential roles in plant growth and development.

Developing an Accumulative Assessment System of Upper Extremity Motor Function in Patients With Stroke Using Deep Learning.

OBJECTIVE: The Fugl-Meyer assessment for upper extremity (FMA-UE) is a measure for assessing upper extremity motor function in patients with stroke. However, the considerable administration time of the assessment decreases its feasibility. This study aimed to develop an accumulative assessment system of upper extremity motor function (AAS-UE) based on the FMA-UE to improve administrative efficiency while retaining sufficient psychometric properties. METHODS: The study used secondary data from 3 previous studies having FMA-UE datasets, including 2 follow-up studies for subacute stroke individuals and 1 test-retest study for individuals with chronic stroke. The AAS-UE adopted deep learning algorithms to use patients' prior information (ie, the FMA-UE scores in previous assessments, time interval of adjacent assessments, and chronicity of stroke) to select a short and personalized item set for the following assessment items and reproduce their FMA-UE scores. RESULTS: Our data included a total of 682 patients after stroke. The AAS-UE administered 10 different items for each patient. The AAS-UE demonstrated good concurrent validity (r = 0.97-0.99 with the FMA-UE), high test-retest reliability (intra-class correlation coefficient = 0.96), low random measurement error (percentage of minimal detectable change = 15.6%), good group-level responsiveness (standardized response mean = 0.65-1.07), and good individual-level responsiveness (30.5%-53.2% of patients showed significant improvement). These psychometric properties were comparable to those of the FMA-UE. CONCLUSION: The AAS-UE uses an innovative assessment method, which makes good use of patients' prior information to achieve administrative efficiency with good psychometric properties. IMPACT: This study demonstrates a new assessment method to improve administrative efficiency while retaining psychometric properties, especially individual-level responsiveness and random measurement error, by making good use of patients' basic information and medical records.

OCTA characteristics in non-arteritic central retinal artery occlusion and correlation with visual acuity.

AIM: To observe the retinal and choroidal circulations in patients with non-arteritic permanent central retinal artery occlusion (NA-CRAO) via optical coherence tomography angiography (OCTA) and analyze their correlation with visual acuity. METHODS: Sixty-two eyes with clinically confirmed acute NA-CRAO were included in the study and divided into: A type (mild n=29), B type (moderate n=27) and C type (severe n=6) based on the degree of visual loss, retinal edema, and arterial blood flow delay in fundus fluorescence angiography (FFA). Contralateral healthy eyes were used as the control group. Best-corrected visual acuity (BCVA), slit lamp microscopy, indirect ophthalmoscopy, fundus color photography, OCTA, and FFA were performed. Spearman's correlation analysis was used to determine the correlations between retinal and choroidal vessels and visual acuity. RESULTS: There were no statistically significant differences in age, gender, and intraocular pressure among the three types and the control group (P>0.05). Vessel density in deep capillary plexus (VD-DCP) significantly decreased (P<0.05) in all three types of NA-CRAO patients compared to the control group. Vessel density in superficial vascular plexus (VD-SVP) significantly decreased (P<0.05) in type A patients and choriocapillaris flow area significantly decreased (P<0.05) in type B and type C patients compared to the control group; while outer retinal flow areas significantly increased in the type A (P<0.05) and decreased in type C patients (P<0.05). The retinal thickness significantly increased in type C group (P<0.05). The VD-SVP at fovea in the type A was significantly lower than both of type B and C. The VD-SVP at nasal parafovea in type A and B was significantly lower than type C (P<0.05). The logMAR BCVA of type A was significantly better than that of type B and C groups (P<0.05). Spearman's correlation analysis showed that the logMAR BCVA was positively correlated with VD-SVP at fovea (r=0.679, P=0.031) and nasal parafovea (r=0.826, P=0.013). CONCLUSION: OCTA is valuable for assessing retinal ischemia, and evaluating visual impairment. Deep retinal vasculature is commonly affected in all NA-CRAO types. VD-SVPs at fovea and nasal parafovea can serve as reliable markers of visual impairment in NA-CRAO.

A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study.

Alternative polyadenylation plays an important role in cancer initiation and progression; however, current transcriptome-wide association studies mostly ignore alternative polyadenylation when identifying putative cancer susceptibility genes. Here, we perform a pan-cancer 3' untranslated region alternative polyadenylation transcriptome-wide association analysis by integrating 55 well-powered (n > 50,000) genome-wide association studies datasets across 22 major cancer types with alternative polyadenylation quantification from 23,955 RNA sequencing samples across 7,574 individuals. We find that genetic variants associated with alternative polyadenylation are co-localized with 28.57% of cancer loci and contribute a significant portion of cancer heritability. We further identify 642 significant cancer susceptibility genes predicted to modulate cancer risk via alternative polyadenylation, 62.46% of which have been overlooked by traditional expression- and splicing- studies. As proof of principle validation, we show that alternative alleles facilitate 3' untranslated region lengthening of CRLS1 gene leading to increased protein abundance and promoted proliferation of breast cancer cells. Together, our study highlights the significant role of alternative polyadenylation in discovering new cancer susceptibility genes and provides a strong foundational framework for enhancing our understanding of the etiology underlying human cancers.

Ligustilide inhibits Purkinje cell ferritinophagy via the ULK1/NCOA4 pathway to attenuate valproic acid-induced autistic features.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in which social impairment is the core symptom. Presently, there are no definitive medications to cure core symptoms of ASD, and most therapeutic strategies ameliorate ASD symptoms. Treatments with proven efficacy in autism are imminent. Ligustilide (LIG), an herbal monomer extracted from Angelica Sinensis and Chuanxiong, is mainly distributed in the cerebellum and widely used in treating neurological disorders. However, there are no studies on its effect on autistic-like phenotypes and its mechanism of action. PURPOSE: Investigate the efficacy and mechanism of LIG in treating ASD using two Valproic acid(VPA)-exposed and BTBR T + Itpr3tf/J (BTBR) mouse models of autism. METHODS: VPA-exposed mice and BTBR mice were given LIG for treatment, and its effect on autistic-like phenotype was detected by behavioral experiments, which included a three-chamber social test. Subsequently, RNA-Sequence(RNA-Seq) of the cerebellum was performed to observe the biological changes to search target pathways. The autophagy and ferroptosis pathways screened were verified by WB(Western Blot) assay, and the cerebellum was stained by immunofluorescence and examined by electron microscopy. To further explore the therapeutic mechanism, ULK1 agonist BL-918 was used to block the therapeutic effect of LIG to verify its target effect. RESULTS: Our work demonstrates that LIG administration from P12-P14 improved autism-related behaviors and motor dysfunction in VPA-exposed mice. Similarly, BTBR mice showed the same improvement. RNA-Seq data identified ULK1 as the target of LIG in regulating ferritinophagy in the cerebellum of VPA-exposed mice, as evidenced by activated autophagy, increased ferritin degradation, iron overload, and lipid peroxidation. We found that VPA exposure-induced ferritinophagy occurred in the Purkinje cells, with enhanced NCOA4 and Lc3B expressions. Notably, the therapeutic effect of LIG disappeared when ULK1 was activated. CONCLUSION: LIG treatment inhibits ferritinophagy in Purkinje cells via the ULK1/NCOA4-dependent pathway. Our study reveals for the first time that LIG treatment ameliorates autism symptoms in VPA-exposed mice by reducing aberrant Purkinje ferritinophagy. At the same time, our study complements the pathogenic mechanisms of autism and introduces new possibilities for its therapeutic options.