Multiscale simulations reveal the driving forces of p53C phase separation accelerated by oncogenic mutations.

Liquid-Liquid phase separation (LLPS) of p53 to form liquid condensates has been implicated in cellular functions and dysfunctions. The p53 condensates may serve as amyloid fibril precursors to initiate p53 aggregation, which is associated with oncogenic gain-of-function and various human cancers. M237I and R249S mutations located in p53 core domain (p53C) have been detected respectively in glioblastomas and hepatocellular carcinoma. Interestingly, these p53C mutants can also undergo LLPS and liquid-to-solid phase transition, which are faster than wild type p53C. However, the underlying molecular basis governing the accelerated LLPS and liquid-to-solid transition of p53C remain poorly understood. Herein, we explore the M237I/R249S mutation-induced structural alterations and phase separation behavior of p53C by employing multiscale molecular dynamics simulations. All-atom simulations revealed conformational disruptions in the zinc-binding domain of the M237I mutant and in both loop3 and zinc-binding domain of the R249S mutant. The two mutations enhance hydrophobic exposure of those regions and attenuate intramolecular interactions, which may hasten the LLPS and aggregation of p53C. Martini 3 coarse-grained simulations demonstrated spontaneous phase separation of p53C and accelerated effects of M237I/R249S mutations on the phase separation of p53C. Importantly, we find that the regions with enhanced intermolecular interactions observed in coarse-grained simulations coincide with the disrupted regions with weakened intramolecular interactions observed in all-atom simulations, indicating that M237I/R249S mutation-induced local structural disruptions expedite the LLPS of p53C. This study unveils the molecular mechanisms underlying the two cancer-associated mutation-accelerated LLPS and aggregation of p53C, providing avenues for anticancer therapy by targeting the phase separation process.

Comparative analysis of the mutational landscape and evolutionary patterns of pancreatic ductal adenocarcinoma metastases in the liver or peritoneum.

Background: Pancreatic ductal adenocarcinoma (PDAC) often presents with liver or peritoneal metastases at diagnosis. Despite similar treatment approaches, patient outcomes vary between these metastatic sites. To improve targeted therapies for metastatic PDAC, a comprehensive analysis of the genetic profiles and evolutionary patterns at these distinct metastatic locations is essential. Methods: We performed whole exome sequencing on 44 tissue samples from 27 PDAC patients, including primary tumours and matched liver or peritoneal metastases. We analysed somatic mutation profiles, signatures, and affected pathways for each group, and examined clonal evolution using subclonal architectures and phylogenetic trees. Results: KRAS mutations remained the predominant driver alteration, with a prevalence of 89 % across all tumours. Notably, we observed site-specific differences in mutation frequencies, with KRAS alterations detected in 77.8 % (7/9) of peritoneal metastases and 87.5 % (7/8) of liver metastases. TP53 mutations exhibited a similar pattern, occurring in 55.6 % (5/9) of peritoneal and 37.5 % (3/8) of liver metastases. Intriguingly, we identified site-specific alterations in DNA repair pathway genes, including ATM and BRCA1, with distinct mutational profiles in liver versus peritoneal metastases. Furthermore, liver metastases demonstrated a significantly higher tumor mutational burden (TMB) compared to peritoneal metastases (median [IQR]: 2.14 [1.77-2.71] vs. 1.29 [1.21-1.69] mutations/Mb; P = 0.048). Conclusions: In conclusion, metastasis of pancreatic cancer may be influenced by variables other than KRAS mutations, such as TP53. PDAC peritoneal and liver metastases may differ in potential therapeutic biomarkers. Further inquiry is needed on the biological mechanisms underlying metastasis and the treatment of diverse metastases.

YAP inhibition overcomes adaptive resistance in HER2-positive gastric cancer treated with trastuzumab via the AKT/mTOR and ERK/mTOR axis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice. METHODS: In this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs. RESULTS: We revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways. CONCLUSION: These findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab.

Classification of congenital cataracts based on multidimensional phenotypes and its association with visual outcomes.

AIM: To establish a classification for congenital cataracts that can facilitate individualized treatment and help identify individuals with a high likelihood of different visual outcomes. METHODS: Consecutive patients diagnosed with congenital cataracts and undergoing surgery between January 2005 and November 2021 were recruited. Data on visual outcomes and the phenotypic characteristics of ocular biometry and the anterior and posterior segments were extracted from the patients' medical records. A hierarchical cluster analysis was performed. The main outcome measure was the identification of distinct clusters of eyes with congenital cataracts. RESULTS: A total of 164 children (299 eyes) were divided into two clusters based on their ocular features. Cluster 1 (96 eyes) had a shorter axial length (mean±SD, 19.44±1.68 mm), a low prevalence of macular abnormalities (1.04%), and no retinal abnormalities or posterior cataracts. Cluster 2 (203 eyes) had a greater axial length (mean±SD, 20.42±2.10 mm) and a higher prevalence of macular abnormalities (8.37%), retinal abnormalities (98.52%), and posterior cataracts (4.93%). Compared with the eyes in Cluster 2 (57.14%), those in Cluster 1 (71.88%) had a 2.2 times higher chance of good best-corrected visual acuity [<0.7 logMAR; OR (95%CI), 2.20 (1.25-3.81); P=0.006]. CONCLUSION: This retrospective study categorizes congenital cataracts into two distinct clusters, each associated with a different likelihood of visual outcomes. This innovative classification may enable the personalization and prioritization of early interventions for patients who may gain the greatest benefit, thereby making strides toward precision medicine in the field of congenital cataracts.

Association Between Preoperative Ocular Parameters and Myopic Shift in Children Undergoing Primary Intraocular Lens Implantation.

Purpose: To evaluate the association between preoperative ocular parameters and myopic shift following primary intraocular lens (IOL) implantation in pediatric cataracts. Methods: Eyes from pediatric patients undergoing bilateral cataract surgery with primary IOL implantation were included. Eyes were grouped by age at surgery and subdivided into three axial length (AL) subgroups and three keratometry subgroups. Mixed-effects linear regression was utilized to assess the trend in myopic shift among subgroups. Multivariable analysis was performed to determine factors associated with myopic shift. Results: A total of 222 eyes were included. The median age at surgery was 4.36 years (interquartile range [IQR], 3.16-6.00 years) and the median follow-up was 4.18 years (IQR, 3.48-4.64 years). As preoperative AL increased, a decreased trend was observed in myopic shift and rate of myopic shift (P = 0.008 and P = 0.003, respectively, in the 4 to <6 years old group; P = 0.002 and P < 0.001, respectively, in the ≥6 years old group). Greater myopic shift and rate of myopic shift were associated with younger age at surgery (P = 0.008 and P = 0.008, respectively). Both myopic shift and rate of myopic shift were negatively associated with AL. Conclusions: Age at surgery and preoperative AL were associated with myopic shift in pediatric cataracts following primary IOL implantation. Adjusting the target refraction based on preoperative AL could potentially improve patients' long-term refractive outcome. Translational Relevance: This study may help to guide the selection of postoperative target refraction according to age at surgery and preoperative ocular parameters for pediatric cataracts.

Melatonin improves influenza virus infection-induced acute exacerbation of COPD by suppressing macrophage M1 polarization and apoptosis.

BACKGROUND: Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. METHODS: COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. RESULTS: The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1ß attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1ß/STAT1 signaling via MTs. CONCLUSIONS: These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1ß/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD.

Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides.

Many RNA-binding proteins such as fused-in sarcoma (FUS) can self-assemble into reversible liquid droplets and fibrils through the self-association of their low-complexity (LC) domains. Recent experiments have revealed that SYG-rich segments in the FUS LC domains play critical roles in the reversible self-assembly behaviors of FUS. These FUS LC segments alone can self-assemble into reversible kinked fibrils, which are markedly different from the canonical irreversible steric zipper ß-sheet fibrils. However, the molecular determinants underlying the reversible and irreversible self-assembly are poorly understood. Herein we conducted extensive all-atom and coarse-grained molecular dynamics simulations of four representative hexapeptides: two low-complexity aromatic-rich kinked peptides from the amyotrophic lateral sclerosis-related FUS protein, FUS37-42 (SYSGYS) and FUS54-59 (SYSSYG); and two steric zipper peptides from Alzheimer's-associated Aß and Tau proteins, Aß16-21 (KLVFFA) and Tau306-311 (VQIVYK). We dissected their reversible and irreversible self-assembly dynamics, predicted their phase separation behaviors, and elucidated the underpinning molecular interactions. Our simulations showed that alternating stickers (Tyr) and spacers (Gly and Ser) in FUS37-42 and FUS54-59 facilitate the formation of highly dynamic coil-rich oligomers and lead to reversible self-assembly, while consecutive hydrophobic residues of LVFF in Aß16-21 and IVY in Tau306-311 act as hydrophobic patches, favoring the formation of stable ß-sheet-rich oligomers and driving the irreversible self-assembly. Intriguingly, we found that FUS37-42 and FUS54-59 peptides, possessing the same amino acid composition and the same number of sticker and spacer residues, display differential self-assembly propensities. This finding suggests that the self-assembly behaviors of FUS peptides are fine-tuned by the site-specific patterning of spacer residues (Ser and Gly). This study provides significant mechanistic insights into reversible and irreversible peptide self-assembly, which would be helpful for understanding the molecular mechanisms underlying the formation of biological liquid condensates and pathological solid amyloid fibrils.

Circ DENND4C inhibits pyroptosis and alleviates ischemia-reperfusion acute kidney injury by exosomes secreted from human urine-derived stem cells.

Acute kidney injury (AKI) is a disease characterised by acute onset, high mortality, and poor prognosis, and is mainly caused by ischemia-reperfusion (I/R). Human urine-derived stem cells (USCs) exhibit antioxidant, anti-inflammatory, and anti-apoptotic cytoprotective effects. Previously, we found that exosomes from USCs had the ability to inhibit apoptosis and protect kidneys from I/R injury. This study aimed to investigate the role of USC-derived exosomes (USC-Exos) in reducing pyroptosis and alleviating I/R-AKI. Models of HK-2 cells hypoxia-reoxygenation (H/R) and I/R kidney injury was established in Sprague Dawley rats to simulate AKI in vitro and in vivo. USC-Exos were isolated using ultracentrifugation and identified via electron microscopy and western blotting. USC-Exos were co-cultured with HK-2 cells and injected into rats via the tail vein. The expression of pyroptosis-related molecules (GSDMD, caspase-1, and NLRP-3) was verified using PCR and western blotting. Changes in renal function were reflected in the serum creatinine, urea, and cystatin C levels. The degree of renal injury was determined using haematoxylin and eosin and immunohistochemical staining. The levels of IL-1ß and IL-18 were detected using enzyme-linked immunosorbent assay (ELISA) to verify the role of USC-Exos in pyroptosis. Differentially expressed circRNAs in I/R rat kidneys were screened by transcriptome sequencing, and a dual-luciferase experiment was used to verify the interaction between upstream and downstream molecules. Ischemia-reperfusion resulted in significantly impaired renal function and expression of pyroptosis molecules, and significantly increased concentrations of inflammatory factors. These effects were reversed by injecting USC-Exos. Circ DENND4C was the most significantly decreased circRNA in I/R rat renal tissue, and knock-down of circ DENND4C can aggravate AKI in vivo and in vitro. DAVID(http://david.abcc.ncifcrf.gov) website showed that miR 138-5p/FOXO3a is a potential downstream target of circ DENND4C. Knock-down of circ DENND4C in HK-2 cells resulted in increased expression of miR 138-5p and increased miR 138-5p can reverse the regulation of FOXO3a. Dual-luciferase assay verified the reverse interaction between circ DENND4C, miR 138-5p, and FOXO3a. Exosomes promote cell proliferation and inhibit the activation of NLR family pyrin domain containing 3 through the circ DENND4C/miR 138-5p/FOXO3a pathway, thereby reducing pyroptosis and AKI. Circ DENND4C may be a potential therapeutic target for AKI.

Soluble Nanographene C222: Synthesis and Applications for Synergistic Photodynamic/Photothermal Therapy.

Nanographene C222, which consists of a planar graphenic plane containing 222 carbon atoms, holds the record as the largest planar nanographene synthesized to date. However, its complete insolubility makes the processing of C222 difficult. Here we addressed this issue by introducing peripheral substituents perpendicular to the graphene plane, effectively disrupting the interlayer stacking and endowing C222 with good solubility. We also found that the electron-withdrawing substituents played a crucial role in the cyclodehydrogenation process, converting the dendritic polyphenylene precursor to C222. After disrupting the interlayer stacking, the introduction of only a few peripheral carboxylic groups allowed C222 to dissolve in phosphate buffer saline, reaching a concentration of up to 0.5 mg/mL. Taking advantage of the good photosensitizing and photothermal properties of the inner C222 core, the resulting water-soluble C222 emerged as a single-component agent for both photothermal and photodynamic tumor therapy, exhibiting an impressive tumor inhibition rate of 96%.

Immunoneoadjuvant therapy with immune checkpoint inhibitors of gastric cancer: an emerging exemplification : Immunoneoadjuvant therapy of gastric cancer.

Advances in immune checkpoint inhibitors (ICIs) have enabled more effective treatment for individuals with various types of solid tumors. Given the improved survival benefit and acceptable safety profile of ICIs in advanced gastric cancer, there is plenty of interest in the use of ICIs in the neoadjuvant setting with curative intent. Theoretically, immunoneoadjuvant with ICIs could boost the levels of endogenous tumor antigen present in the tumor to enhance T-cell priming and further enhance systemic immunity. This systemic immune response may improve the detection and elimination of the disseminated micrometastatic tumors beyond the resected tumor, which are sources of postsurgical relapse. Numerous clinical studies have begun to explore the application of ICIs in neoadjuvant treatment of gastric cancer. This article reviews the progress in the use of ICI monotherapy and in combination with alternative therapies for the treatment of gastric cancer to aid in the development of gastric cancer immunoneoadjuvant therapy and improve the overall therapeutic benefit.

Trends in bronchopulmonary dysplasia and respiratory support among extremely preterm infants in China over a decade.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is one of the most serious complications affecting extremely preterm infants. We aimed to evaluate temporal trends in BPD and administration of respiratory support among extremely preterm infants in China over a decade. METHODS: This was a retrospective study using data from a multicenter database, which included infants born less than 28 weeks' gestation discharged from 68 tertiary neonatal care centers in China between 2010 and 2019. Changes in rates and severity of BPD, as well as modalities and duration of respiratory support, were evaluated. RESULTS: Among 4808 eligible infants with gestational age (GA) of 21+6/7  to 27+6/7 weeks and a mean (SD) birth weight of 980 (177) g, no significant change of median GA was found over time. Overall, 780 (16.2%) infants died before 36 weeks' postmenstrual age, 2415 (50.2%) were classified as having no BPD, 917 (19.1%) developed Grade 1 BPD, 578 (12.0%) developed Grade 2 BPD, and 118 (2.5%) developed Grade 3 BPD. The rate of BPD increased from 20.8% in 2010 to 40.7% in 2019 (aRR for trend, 1.081; 95% confidence interval, 1.062-1.099), especially for Grade 1 and Grade 2. Although survival to discharge improved over the decade, the overall survival without BPD did not change during the study period. The use of invasive mechanical ventilation (IMV) remained unchanged. However, the use of noninvasive ventilation (NIV) increased from 71.5% in 2010 to 89.8% in 2019. Moreover, the median duration of NIV increased over time, from 17.0 (4.8, 34.0) days in 2010 to 33.0 (21.0, 44.0) days in 2019, without significant change in the duration of IMV. CONCLUSIONS: Although survival increased over the decade and respiratory support practices changed significantly between 2010 and 2019 in China, with increased use and duration of NIV, there was an increased rate of BPD and survival without BPD has not improved.

Sintilimab plus fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as neoadjuvant therapy for resectable gastric cancer and biomarker exploration.

At present, preoperative chemotherapy is the standard of care for the neoadjuvant treatment of potentially resectable gastric cancer (GC). However, because the efficacy and prognosis are not ideal, curative effects for this population are unsatisfactory. With the development of immune checkpoint inhibitors, the results of a few encouraging early trials of immunotherapeutic agents as neoadjuvant therapies for resectable GC have been reported. However, markers of the efficacy of immune checkpoint inhibitors remain unclear. This prospective single-center, single-arm observational study was designed to evaluate the efficacy of sintilimab plus the fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as a neoadjuvant treatment for localized GC. More importantly, this work assesses multiple dimensions and include ctDNA, the immune microenvironment and intestinal microbiome to explore correlations between biomarkers and neoadjuvant therapeutic efficacy. Clinical trial registration: ChiCTR2200061629 (www.chictr.org.cn/index.aspx).

Gastrointestinal signet ring cell malignancy: current advancement and future prospects.

Globally, gastrointestinal cancer is the most widespread neoplastic disease and the primary contributor to cancer-associated fatalities. Gastrointestinal signet ring cell carcinoma (SRCC) exhibits unique distinguishing features in several aspects when compared to adenocarcinomas (ACs). The scarcity of signet ring cell carcinoma has resulted in a heightened significance of related clinical and molecular investigations. However, a comprehensive and systematic review of the clinical, molecular, therapeutic, and research aspects of this disease is currently absent. This review provides an overview of the latest developments in our understanding of the clinical and molecular features of gastrointestinal signet ring cell carcinoma (SRCC). Additionally, we have compiled a list of potential therapeutic targets or biomarkers, as well as an examination of the current treatment options and the possible mechanisms of formation.

Heterogeneous graph framework for predicting the association between lncRNA and disease and case on uterine fibroid.

Long non-coding RNAs (lncRNAs) play crucial regulatory roles in various cellular processes, including gene expression, chromatin remodeling, and protein localization. Dysregulation of lncRNAs has been linked to several diseases, making it essential to understand their functions in disease mechanisms and therapeutic strategies. However, traditional experimental methods for studying lncRNA function are time-consuming, expensive, and offer limited insights. In recent years, computational methods have emerged as valuable tools for predicting lncRNA functions and their associations with diseases. However, many existing methods focus on constructing separate networks for lncRNA and disease similarity, resulting in information loss and insufficient processing capacity for isolated nodes. To address this, we developed 'RGLD' by combining Random Walk with restarting (RWR), Graph Neural Network (GNN), and Graph Attention Networks (GAT) to predict lncRNA-disease associations in a heterogeneous network. RGLD achieved an impressive AUC of 0.88, outperforming other methods. It can also predict novel associations between lncRNAs and diseases. RGLD identified HOTAIR, MEG3, and PVT1 as lncRNAs associated with uterine fibroids. Biological experiments directly or indirectly verified the involvement of these three lncRNAs in uterine fibroids, validating the accuracy of RGLD's predictions. Furthermore, we extensively discussed the functions of the target genes regulated by these lncRNAs in uterine fibroids, providing evidence for their role in the development and progression of the disease.

The mutational landscape of a US Midwestern breast cancer cohort reveals subtype-specific cancer drivers and prognostic markers.

BACKGROUND: Female breast cancer remains the second leading cause of cancer-related death in the USA. The heterogeneity in the tumor morphology across the cohort and within patients can lead to unpredictable therapy resistance, metastasis, and clinical outcome. Hence, supplementing classic pathological markers with intrinsic tumor molecular markers can help identify novel molecular subtypes and the discovery of actionable biomarkers. METHODS: We conducted a large multi-institutional genomic analysis of paired normal and tumor samples from breast cancer patients to profile the complex genomic architecture of breast tumors. Long-term patient follow-up, therapeutic regimens, and treatment response for this cohort are documented using the Breast Cancer Collaborative Registry. The majority of the patients in this study were at tumor stage 1 (51.4%) and stage 2 (36.3%) at the time of diagnosis. Whole-exome sequencing data from 554 patients were used for mutational profiling and identifying cancer drivers. RESULTS: We identified 54 tumors having at least 1000 mutations and 185 tumors with less than 100 mutations. Tumor mutational burden varied across the classified subtypes, and the top ten mutated genes include MUC4, MUC16, PIK3CA, TTN, TP53, NBPF10, NBPF1, CDC27, AHNAK2, and MUC2. Patients were classified based on seven biological and tumor-specific parameters, including grade, stage, hormone receptor status, histological subtype, Ki67 expression, lymph node status, race, and mutational profiles compared across different subtypes. Mutual exclusion of mutations in PIK3CA and TP53 was pronounced across different tumor grades. Cancer drivers specific to each subtype include TP53, PIK3CA, CDC27, CDH1, STK39, CBFB, MAP3K1, and GATA3, and mutations associated with patient survival were identified in our cohort. CONCLUSIONS: This extensive study has revealed tumor burden, driver genes, co-occurrence, mutual exclusivity, and survival effects of mutations on a US Midwestern breast cancer cohort, paving the way for developing personalized therapeutic strategies.

JUN-induced super-enhancer RNA forms R-loop to promote nasopharyngeal carcinoma metastasis.

Oncogenic super-enhancers (SEs) generate noncoding enhancer/SE RNAs (eRNAs/seRNAs) that exert a critical function in malignancy through powerful regulation of target gene expression. Herein, we show that a JUN-mediated seRNA can form R-loop to regulate target genes to promote metastasis of nasopharyngeal carcinoma (NPC). A combination of global run-on sequencing, chromatin-immunoprecipitation sequencing, and RNA sequencing was used to screen seRNAs. A specific seRNA associated with NPC metastasis (seRNA-NPCM) was identified as a transcriptional regulator for N-myc downstream-regulated gene 1 (NDRG1). JUN was found to regulate seRNA-NPCM through motif binding. seRNA-NPCM was elevated in NPC cancer tissues and highly metastatic cell lines, and promoted the metastasis of NPC cells in vitro and in vivo. Mechanistically, the 3' end of seRNA-NPCM hybridizes with the SE region to form an R-loop, and the middle segment of seRNA-NPCM binds to heterogeneous nuclear ribonucleoprotein R (hnRNPR) at the promoter of distal gene NDRG1 and neighboring gene tribbles pseudokinase 1 (TRIB1). These structures promote chromatin looping and long-distance chromatin interactions between SEs and promoters, thus facilitating NDRG1 and TRIB1 transcription. Furthermore, the clinical analyses showed that seRNA-NPCM and NDRG1 were independent prognostic factors for NPC patients. seRNA-NPCM plays a critical role in orchestrating target gene transcription to promote NPC metastasis.

Facile preparation of Ru nanoassemblies for electrochemical immunoassay of carcinoembryonic antigen in clinical serum.

Abnormal expression of carcinoembryonic antigen (CEA) can be used for early diagnosis of various cancers (e.g. colorectal cancer, cervical carcinomas, and breast cancer). In this work, using l-cysteine-ferrocene-ruthenium nanocomposites (L-Cys-Fc-Ru) to immobilize secondary antibody (Ab2) and Au nanoparticles (NPs) as the substrate to ensure accurate capture of primary antibody (Ab1), a signal-on sandwich-like biosensor was constructed in the presence of CEA. Specifically, Ru nanoassemblies (NAs) were first prepared by a facile one-step solvothermal approach as signal amplifiers for the electrical signal of Fc. Based on specific immune recognition, as the increase of CEA concentration, the content of L-Cys-Fc-Ru-Ab2 captured on the electrode surface also increased, thus the signal of Fc gradually increased. Therefore, the quantitative detection of CEA can be realized according to the peak current of Fc. After a series of experiments, it was found that the biosensor has a wide detection range from 1.0 pg mL-1 to 100.0 ng mL-1 and a low detection limit down to 0.5 pg mL-1, as well as good selectivity, repeatability and stability. Furthermore, satisfactory results were also obtained for the determination of CEA in serums, which were comparable to commercial electrochemiluminescence (ECL) method. The developed biosensor shows great potential in clinical applications.

Evolution and trends of childhood cataract research in the past 10 years: A scientometric analysis.

Purpose: To present a panoramic review of childhood cataract knowledge networks, hotspots and trends. Methods: The Web of Science Core Collection was used to retrieve the global literature on childhood cataract published between 2012 and 2021. Scientometric data were analyzed and visualized using VOSviewer and CiteSpace for metrics including publication count, citation count, country, journal, author, cited reference, subject category and their temporal trends. Results: A total of 3395 analyzed publications showed an inconsistent annual increasing trend. The USA (n = 939) was the leading contributor among countries. The Journal of American Association for Pediatric Ophthalmology and Strabismus (n = 113) had the highest number of publications among journals. Eight clusters of author collaboration network including 183 authors were identified. Gene mutation, cataract surgery management, intraocular lens implantation complications, prevalence, and glaucoma were identified as the research hotspots. Pediatric cataract surgery, new mutations, artificial intelligence, and cerebrotendinous xanthomatosis were identified as frontier research topics. "Biochemistry and molecular biology", "neurosciences", and "radiology, nuclear medicine and medical imaging" had the highest betweenness centrality values (0.38, 0.32, and 0.22). Multidisciplinary (burst years: 2020 to 2021; strength = 4.32) had the greatest strength as of 2021. Conclusions: Childhood cataract research intensely focuses on revealing the genetic background and pheno-spectrum of the diseases, innovating and/or optimizing surgical techniques, and preventing and treating postoperative complications. Artificial intelligence has shed light on the diagnosis and treatment of childhood cataracts. The advance in the research on molecular mechanisms of childhood cataracts depends on multidisciplinary cooperation.

High-throughput sequencing technology facilitates the discovery of novel biomarkers for antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis and/or morbid pregnancy, accompanied by persistent antiphospholipid antibody (aPL) positivity. However, due to the complex pathogenesis of APS and the large individual differences in the expression of aPL profiles of patients, the problem of APS diagnosis, prognosis judgment, and risk assessment may not be solved only from the antibody level. It is necessary to use new technologies and multiple dimensions to explore novel APS biomarkers. The application of next-generation sequencing (NGS) technology in diseases with a high incidence of somatic mutations, such as genetic diseases and tumors, has been very mature. Thus, we try to know the research and application progress of APS by NGS technology from genome, transcriptome, epigenome and other aspects. This review will describe the related research of NGS technology in APS and provide more reference for the deep understanding of APS-related screening markers and disease pathogenesis.

The Selective Trigeminal Nerve Motor Branching Transfer: an Preliminary Clinical Application for Facial Reanimation.

OBJECTIVE: To investigate the effectiveness and feasibility of selective trigeminal nerve motor branching in the repair of facial palsy. MATERIALS AND METHODS: The clinical data of patients with advanced facial palsy from 2016 to 2021 were retrospectively analyzed, including pictures and videos before and 18 months after surgery. The House-Brackmann grading system was used to evaluate facial nerve function before and after repair, and the symmetry scale of oral commissure at rest and Terzis' smile functional evaluation scale were used to qualitatively assess the symmetry of the mouth angle and smile function. The distance of oral commissure movement was assessed to evaluate the dynamic repair effect, and the FaCE facial muscle function scale was used to assess patients' subjective perception before and after surgery. RESULTS: A total of four patients were included in the study, all of whom showed signs of recovery of facial nerve function within six months. In all four cases, significant improvements were observed in House-Brackmann ratings, the smile function score and the symmetry scale of oral commissure at rest. Compared to the pre-operative period, the four patients demonstrated various degrees of eye-closing function recovery, and a significant improvement in oral commissure movement was observed ( P <0.001). FaCE scores also improved significantly after surgery ( P =0.019). CONCLUSION: Concurrent selective facial nerve repair with trigeminal branch-facial nerve anastomosis resulted in eye-closing function recovery while improving static and dynamic symmetry, yielding acceptable postoperative results.