Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions.

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions.

Potential and application of abortive transcripts as a novel molecular marker of cancers.

Abortive transcript (AT) is a 2-19 nt long non-coding RNA that is produced in the abortive initiation stage. Abortive initiation was found to be closely related to RNA polymerase through in vitro experiments. Therefore, the distribution of AT length and the scale of abortive initiation are correlated to the promoter, discriminator, and transcription initiation sequence, and can be affected by transcription elongation factors. AT plays an important role in the occurrence and development of various diseases. Here we summarize the discovery of AT, the factors responsible for AT formation, the detection methods and biological functions of AT, to provide new clues for finding potential targets in the early diagnosis and treatment of cancers.

Genome-wide characterization and functional analysis of the melon TGA gene family in disease resistance through ectopic overexpression in Arabidopsis thaliana.

TGA-binding (TGA) transcription factors, characterized by the basic region/leucine zipper motif (bZIP), have been recognized as pivotal regulators in plant growth, development, and stress responses through their binding to the as-1 element. In this study, the TGA gene families in melon, watermelon, cucumber, pumpkin, and zucchini were comprehensively characterized, encompassing analyses of gene/protein structures, phylogenetic relationships, gene duplication events, and cis-acting elements in gene promoters. Upon transient expression in Nicotiana benthamiana, the melon CmTGAs, with typical bZIP and DOG1 domains, were observed to localize within the nucleus. Biochemical investigation revealed specific interactions between CmTGA2/3/5/8/9 and CmNPR3 or CmNPR4. The CmTGA genes exhibited differential expression patterns in melon plants in response to different hormones like salicylic acid, methyl jasmonate, and ethylene, as well as a fungal pathogen, Stagonosporopsis cucurbitacearum that causes gummy stem blight in melon. The overexpression of CmTGA3, CmTGA8, and CmTGA9 in Arabidopsis plants resulted in the upregulation of AtPR1 and AtPR5 expression, thereby imparting enhanced resistance to Pseudomonas syringae pv. Tomato DC3000. In contrast, the overexpression of CmTGA7 or CmTGA9 resulted in a compromised resistance to Botrytis cinerea, coinciding with a concomitant reduction in the expression levels of AtPDF1.2 and AtMYC2 following infection with B. cinerea. These findings shed light on the important roles of specific CmTGA genes in plant immunity, suggesting that genetic manipulation of these genes could be a promising avenue for enhancing plant immune responses.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation.

NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.

NIR-II Conjugated Electrolytes as Biomimetics of Lipid Bilayers for In Vivo Liposome Tracking.

Liposomes serve as promising and versatile vehicles for drug delivery. Tracking these nanosized vesicles, particularly in vivo, is crucial for understanding their pharmacokinetics. This study introduces the design and synthesis of three new conjugated electrolyte (CE) molecules, which emit in the second near-infrared window (NIR-II), facilitating deeper tissue penetration. Additionally, these CEs, acting as biomimetics of lipid bilayers, demonstrate superior compatibility with lipid membranes compared to commonly used carbocyanine dyes like DiR. To counteract the aggregation-caused quenching effect, CEs employ a twisted backbone, as such their fluorescence intensities can effectively enhance after a fluorophore multimerization strategy. Notably, a "passive" method was employed to integrate CEs into liposomes during the liposome formation, and membrane incorporation efficiency was significantly promoted to nearly 100%. To validate the in vivo tracking capability, the CE-containing liposomes were functionalized with cyclic arginine-glycine-aspartic acid (cRGD) peptides, serving as tumor-targeting ligands. Clear fluorescent images visualizing tumor site in living mice were captured by collecting the NIR-II emission. Uniquely, these CEs exhibit additional emission peak in visible region, enabling in vitro subcellular analysis using routine confocal microscopy. These results underscore the potential of CEs as a new-generation of membrane-targeting probes to facilitate the liposome-based medicine research.

Re-analysis of single-cell transcriptomics reveals a critical role of macrophage-like smooth muscle cells in advanced atherosclerotic plaque.

Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis. Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque. Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism. Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche. A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque. At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling. Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.

Relationship between ischemic index, leakage index, and macular edema in branch retinal vein occlusion.

PURPOSE: To investigate the combined association of the ischemic index and leakage index with macular edema on ultra-widefield fluorescein angiography (UWFFA) in patients with branch retinal vein occlusion (BRVO). METHODS: Retrospective image analysis study. The leakage index and ischemic index were calculated using Fiji after aligning early and late UWFFA images. Differences in the ischemic index, leakage index, and central macular thickness (CMT) between ischemic and non-ischemic BRVO were compared. Moreover, the association between the ischemic index, leakage index, and macular edema was analyzed. RESULTS: Eighty-three patients with BRVO were enrolled, including 53 non-ischemic BRVO and 30 ischemic BRVO patients. No significant differences were observed in leakage index and CMT between ischemic BRVO and non-ischemic BRVO (all P > 0.05). In all included patients, CMT correlated with the panretina and all subregion leakage indexes (all P < 0.01), but not with the ischemic index (all P > 0.05). In the ischemic BRVO group, CMT showed a correlation with the leakage index in several regions, but not with the ischemic index. After adjusting for the ischemic index and other clinical features, CMT remained significantly correlated with the leakage index in all regions. CONCLUSION: The leakage index may be a more effective biomarker for monitoring BRVO-associated macular edema compared to the ischemic index. Further follow-up studies are warranted to validate these findings.

Long-term outcomes of pulmonary atresia with ventricular septal defect by different initial rehabilitative surgical age.

Background: There is a lack of evidence guiding the surgical timing selection in pulmonary atresia with ventricular septal defect. This study aims to compare the long-term outcomes of different initial rehabilitative surgical ages in patients with pulmonary atresia with ventricular septal defect (PAVSD). Methods: From January 2011 to December 2020, a total of 101 PAVSD patients undergoing the initial rehabilitative surgery at our center were retrospectively reviewed. Receiver-operator characteristics curve analysis was used to identify the cutoff age of 6.4 months and therefore to classify the patients into two groups. Competing risk models were used to identify risk factors associated with complete repair. The probability of survival and complete repair were compared between the two groups using the Kaplan-Meier curve and cumulative incidence curve, respectively. Results: The median duration of follow-up was 72.76 months. There were similar ΔMcGoon ratio and ΔNakata index between the two groups. Multivariate analysis showed that age ≤6.4 months (hazard ratio (HR) = 2.728; 95% confidence interval (CI):1.122-6.637; p = 0.027) and right ventricle-to-pulmonary artery connection (HR = 4.196; 95% CI = 1.782-9.883; p = 0.001) were associated with increased probability of complete repair. The cumulative incidence curve showed that the estimated complete repair rates were 64% ± 8% after 3 years and 69% ± 8%% after 5 years in the younger group, significantly higher than 28% ± 6% after 3 years and 33% ± 6% after 5 years in the elder group (p < 0.001). There was no significant difference regarding the estimated survival rate between the two groups. Conclusion: Compared with those undergoing the initial rehabilitative surgery at the age >6.4 months, PAVSD patients at the age ≤6.4 months had an equal pulmonary vasculature development, a similar probability of survival but an improved probability of complete repair.

A novel fluoropolymer as a protein delivery vector with robust adjuvant effect for cancer immunotherapy.

The inefficient treatment using protein-based nanovaccines is largely attributed to their inadequate immunogenicity. Herein, we developed a novel fluoropolymer (PF) via ring-opening polymerization and constructed a fluoropolymer-based nanovaccine for tumor immunotherapy. Due to the existence of fluoroalkyl chains, PF not only played a crucial role in tumor antigen delivery but also exhibited a remarkable adjuvant effect in enhancing the immunogenicity of nanovaccines. The nanovaccines formed by mixing PF with a model antigen ovalbumin (OVA) enhanced the uptake of antigen proteins by dendritic cells (DCs) and promoted the maturation and antigen presentation of DCs. Compared with free OVA, PF/OVA showed better efficacy in both pre-cancer prevention and tumor treatment. Furthermore, the proportion of CD4+ T and CD8+ T cells was significantly increased in lymph nodes and tumors of mice immunized with PF/OVA. Additionally, there was a great enhancement in the levels of key anti-tumor cytokines (TNF-α and IFN-γ) in the serum of the PF/OVA immunized mice. Our research has shown that fluoropolymer PF applied as a protein vector and adjuvant has great potential for the development of nanovaccines with robust immunogenicity.

The role of lactoferrin in bone remodeling: evaluation of its potential in targeted delivery and treatment of metabolic bone diseases and orthopedic conditions.

Lactoferrin (Lf) is a multifunctional protein that is synthesized endogenously and has various biological roles including immunological regulation, antibacterial, antiviral, and anticancer properties. Recently, research has uncovered Lf's critical functions in bone remodeling, where it regulates the function of osteoblasts, chondrocytes, osteoclasts, and mesenchymal stem cells. The signaling pathways involved in Lf's signaling in osteoblasts include (low density lipoprotein receptor-related protein - 1 (LRP-1), transforming growth factor ß (TGF-ß), and insulin-like growth factor - 1 (IGF-1), which activate downstream pathways such as ERK, PI3K/Akt, and NF-κB. These pathways collectively stimulate osteoblast proliferation, differentiation, and mineralization while inhibiting osteoclast differentiation and activity. Additionally, Lf's inhibitory effect on nuclear factor kappa B (NF-κB) suppresses the formation and activity of osteoclasts directly. Lf also promotes chondroprogenitor proliferation and differentiation to chondrocytes by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase/protein kinase B(PI3K/Akt)signaling pathways while inhibiting the expression of matrix-degrading enzymes through the suppression of the NF-κB pathway. Lf's ability to stimulate osteoblast and chondrocyte activity and inhibit osteoclast function accelerates fracture repair, as demonstrated by its effectiveness in animal models of critical-sized long bone defects. Moreover, studies have indicated that Lf can rescue dysregulated bone remodeling in osteoporotic conditions by stimulating bone formation and suppressing bone resorption. These beneficial effects of Lf on bone health have led to its exploration in nutraceutical and pharmaceutical applications. However, due to the large size of Lf, small bioactive peptides are preferred for pharmaceutical applications. These peptides have been shown to promote bone fracture repair and reverse osteoporosis in animal studies, indicating their potential as therapeutic agents for bone-related diseases. Nonetheless, the active concentration of Lf in serum may not be sufficient at the site requiring bone regeneration, necessitating the development of various delivery strategies to enhance Lf's bioavailability and target its active concentration to the site requiring bone regeneration. This review provides a critical discussion of the issues mentioned above, providing insight into the roles of Lf in bone remodeling and the potential use of Lf as a therapeutic target for bone disorders.

Attention-guided multi-scale context aggregation network for multi-modal brain glioma segmentation.

BACKGROUND: Accurate segmentation of brain glioma is a critical prerequisite for clinical diagnosis, surgical planning and treatment evaluation. In current clinical workflow, physicians typically perform delineation of brain tumor subregions slice-by-slice, which is more susceptible to variabilities in raters and also time-consuming. Besides, even though convolutional neural networks (CNNs) are driving progress, the performance of standard models still have some room for further improvement. PURPOSE: To deal with these issues, this paper proposes an attention-guided multi-scale context aggregation network (AMCA-Net) for the accurate segmentation of brain glioma in the magnetic resonance imaging (MRI) images with multi-modalities. METHODS: AMCA-Net extracts the multi-scale features from the MRI images and fuses the extracted discriminative features via a self-attention mechanism for brain glioma segmentation. The extraction is performed via a series of down-sampling, convolution layers, and the global context information guidance (GCIG) modules are developed to fuse the features extracted for contextual features. At the end of the down-sampling, a multi-scale fusion (MSF) module is designed to exploit and combine all the extracted multi-scale features. Each of the GCIG and MSF modules contain a channel attention (CA) module that can adaptively calibrate feature responses and emphasize the most relevant features. Finally, multiple predictions with different resolutions are fused through different weightings given by a multi-resolution adaptation (MRA) module instead of the use of averaging or max-pooling to improve the final segmentation results. RESULTS: Datasets used in this paper are publicly accessible, that is, the Multimodal Brain Tumor Segmentation Challenges 2018 (BraTS2018) and 2019 (BraTS2019). BraTS2018 contains 285 patient cases and BraTS2019 contains 335 cases. Simulations show that the AMCA-Net has better or comparable performance against that of the other state-of-the-art models. In terms of the Dice score and Hausdorff 95 for the BraTS2018 dataset, 90.4% and 10.2 mm for the whole tumor region (WT), 83.9% and 7.4 mm for the tumor core region (TC), 80.2% and 4.3 mm for the enhancing tumor region (ET), whereas the Dice score and Hausdorff 95 for the BraTS2019 dataset, 91.0% and 10.7 mm for the WT, 84.2% and 8.4 mm for the TC, 80.1% and 4.8 mm for the ET. CONCLUSIONS: The proposed AMCA-Net performs comparably well in comparison to several state-of-the-art neural net models in identifying the areas involving the peritumoral edema, enhancing tumor, and necrotic and non-enhancing tumor core of brain glioma, which has great potential for clinical practice. In future research, we will further explore the feasibility of applying AMCA-Net to other similar segmentation tasks.

Risk factors for perioperative acute heart failure in older hip fracture patients and establishment of a nomogram predictive model.

AIM: This study aims to explore the risk factors for perioperative acute heart failure in older patients with hip fracture and establish a nomogram prediction model. METHODS: The present study was a retrospective study. From January 2020 to December 2021, patients who underwent surgical treatment for hip fracture at the Third Hospital of Hebei Medical University were included. Heart failure was confirmed by discharge diagnosis or medical records. The samples were randomly divided into modeling and validation cohorts in a ratio of 7:3. Relevant demographic and clinic data of patients were collected. IBM SPSS Statistics 26.0 performed univariate and multivariate logistic regression analysis, to obtain the risk factors of acute heart failure. The R software was used to construct the nomogram prediction model. RESULTS: A total of 751 older patients with hip fracture were enrolled in this study, of which 138 patients (18.37%, 138/751) developed acute heart failure. Heart failure was confirmed by discharge diagnosis or medical records. Respiratory disease (odd ratio 7.68; 95% confidence interval 3.82-15.43; value of P 0.001), history of heart disease (chronic heart failure excluded) (odd ratio 2.21, 95% confidence interval 1.18-4.12; value of P 0.010), ASA ≥ 3 (odd ratio 14.46, 95% confidence interval 7.78-26.87; value of P 0.001), and preoperative waiting time ≤ 2 days (odd ratio 3.32, 95% confidence interval 1.33-8.30; value of P 0.010) were independent risk factors of perioperative acute heart failure in older patients with hip fracture. The area under the curve (AUC) of the prediction model based on these factors was calculated to be 0.877 (95% confidence interval 0.836-0.918). The sensitivity and specificity were 82.8% and 80.9%, respectively, and the fitting degree of the model was good. In the internal validation group, the AUC was 0.910, and the 95% confidence interval was 0.869-0.950. CONCLUSIONS: Several risk factors are identified for acute heart failure in older patients, based on which pragmatic nomogram prediction model is developed, facilitating detection of patients at risk early.

Delineation of clinical target volume and organs at risk in cervical cancer radiotherapy by deep learning networks.

PURPOSE: Delineation of the clinical target volume (CTV) and organs-at-risk (OARs) is important in cervical cancer radiotherapy. But it is generally labor-intensive, time-consuming, and subjective. This paper proposes a parallel-path attention fusion network (PPAF-net) to overcome these disadvantages in the delineation task. METHODS: The PPAF-net utilizes both the texture and structure information of CTV and OARs by employing a U-Net network to capture the high-level texture information, and an up-sampling and down-sampling (USDS) network to capture the low-level structure information to accentuate the boundaries of CTV and OARs. Multi-level features extracted from both networks are then fused together through an attention module to generate the delineation result. RESULTS: The dataset contains 276 computed tomography (CT) scans of patients with cervical cancer of staging IB-IIA. The images are provided by the West China Hospital of Sichuan University. Simulation results demonstrate that PPAF-net performs favorably on the delineation of the CTV and OARs (e.g., rectum, bladder and etc.) and achieves the state-of-the-art delineation accuracy, respectively, for the CTV and OARs. In terms of the Dice Similarity Coefficient (DSC) and the Hausdorff Distance (HD), 88.61% and 2.25 cm for the CTV, 92.27% and 0.73 cm for the rectum, 96.74% and 0.68 cm for the bladder, 96.38% and 0.65 cm for the left kidney, 96.79% and 0.63 cm for the right kidney, 93.42% and 0.52 cm for the left femoral head, 93.69% and 0.51 cm for the right femoral head, 87.53% and 1.07 cm for the small intestine, and 91.50% and 0.84 cm for the spinal cord. CONCLUSIONS: The proposed automatic delineation network PPAF-net performs well on CTV and OARs segmentation tasks, which has great potential for reducing the burden of radiation oncologists and increasing the accuracy of delineation. In future, radiation oncologists from the West China Hospital of Sichuan University will further evaluate the results of network delineation, making this method helpful in clinical practice.

LncRNA SNHG14/miR-497a-5p/BACE1 axis modulates obesity-induced adipocyte inflammation and endoplasmic reticulum stress.

Obesity is a metabolic disease with excess weight. LncRNA SNHG14 is abnormally expressed in numerous diseases. This research aimed to enucleate the lncRNA SNHG14 role in obesity. Adipocytes were treated with free fatty acid (FFA) to establish an in vitro model for obesity. Mice were fed a high-fat diet to construct an in vivo model. Gene levels were determined using quantitative real-time PCR (RT-PCR). The protein level was checked by western blot. The lncRNA SNHG14 role in obesity was assessed using western blot and enzyme-linked immunosorbent assay. The mechanism was estimated by Starbase, dual-luciferase reporter gene assay, and RNA pull-down. LncRNA SNHG14 function in obesity was estimated using mouse xenograft models, RT-PCR, western blot, and enzyme-linked immunosorbent assay. LncRNA SNHG14 and BACE1 levels were increased, but the miR-497a-5p level was decreased in FFA-induced adipocytes. Interference with lncRNA SNHG14 reduced endoplasmic reticulum (ER) stress-related molecules GRP78 and CHOP expressions in FFA-induced adipocytes, and decreased IL-1ß, IL-6, and TNF-α expressions, indicating that lncRNA SNHG14 knockdown mitigated FFA-induced ER stress and inflammation in adipocytes. Mechanistically, lncRNA SNHG14 combined with miR-497a-5p, and miR-497a-5p targeted BACE1. Meanwhile, lncRNA SNHG14 knockdown reduced levels of GRP78, CHOP, IL-1ß, IL-6, and TNF-α, while cotransfection with anti-miR-497a-5p or pcDNA-BACE1 abolished these trends. Rescue assays illustrated that lncRNA SNHG14 knockdown relieved FFA-induced adipocyte ER stress and inflammation through miR-497a-5p/BACE1. Meanwhile, lncRNA SNHG14 knockdown restrained adipose inflammation and ER stress caused by obesity in vivo. LncRNA SNHG14 mediated obesity-induced adipose inflammation and ER stress through miR-497a-5p/BACE1.

Incidence, Causes, and Risk Factors of Unplanned Readmissions in Elderly Patients Undergoing Hip Fracture Surgery: An Observational Study.

Aim: The purpose of this study was to examine the incidence and cause of unplanned readmission after Surgically Treated Hip Fractures in Elderly Patients and identify the associated risk factors. Methods: This study retrospectively collected the data on elderly patients who underwent hip fracture surgery at two institutions from January 2020 to December 2021, and identified those who were readmitted within 12 months postoperatively. Based on the presence or not of postoperative readmission, they were divided into readmission and non-readmission groups. Demographics, surgery-related variables, and laboratory parameters were compared between groups. The specific causes for documented readmission were collected and summarized. Multivariate logistic regression analysis was performed to identify the associated risk factors. Results: There were 930 patients including 76 (8.2%) patients who were readmitted within 12 months postoperatively. Overall, cardiac and respiratory complications and new-onset fractures were the first three common causes of readmission, taking an overwhelming proportion of 53.9% (41/76). Over 60% (61.8%, 47/76) of readmissions occurred within 30 days after surgery, with medical complications taking a predominance (89.4%, 42/47). New-onset fractures accounted for a proportion of 18.4% (14/76), occurring at different time points; especially, at 90-365 days, it accounted for 44.4% (8/18). Multivariate analysis revealed that age ≥80 years (OR, 1.0, 95% CI, 1.0 to 1.1; P=0.032), preoperative albumin level ≤21.5 g/L (OR, 1.1, 95% CI, 1.0 to 1.2; P=0.009), the postoperative occurrence of DVT (OR, 4.2, 95% CI, 2.5 to 7.2; P=0.001), and local anesthesia (OR, 2.1, 95% CI, 1.1 to 4.0; P=0.029) were independent risk factors for unplanned readmissions. Conclusion: This study identified several risk factors for unplanned readmissions after elderly hip fractures, and provided detailed information about unplanned readmissions.

Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma.

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.

Tissue-specific metabolomic profiling after cardiopulmonary bypass in fetal sheep.

Objective: Fetal cardiopulmonary bypass (CPB) is essential to fetal heart surgery, while its development is limited by vital organ dysfunction after CPB. Studying organ metabolism may help to solve this problem. The objective of this study was to describe the tissue-specific metabolic fingerprints of fetal sheep under CPB and to associate them with organ functions. Methods: Ten pregnant ewes at 90-120 days of gestation were randomly divided into two groups. The bypass group underwent a 1-h fetal CPB, whereas the control group underwent only a fetal sternotomy. During bypass, echocardiography, blood gases, and blood biochemistry were measured. After bypass, lambs were sacrificed, and tissues of the heart, liver, brain, kidney, and placenta were harvested. The metabolites extracted from these tissues were analyzed using non-targeted metabolomics based on liquid chromatography-mass spectrometry techniques. Results: All tissues except the placenta displayed significant metabolic changes, and the fetal heart displayed obvious functional changes. Fetal sheep that underwent CPB had common and tissue-specific metabolic signatures. These changes can be attributed to dysregulated lipid metabolism, altered amino acid metabolism, and the accumulation of plasticizer metabolism. Conclusion: Fetal CPB causes tissue-specific metabolic changes in fetal sheep. Studying these metabolic changes, especially cardiac metabolism, is of great significance for the study of fetal CPB.

LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.

RATIONALE: Vascular smooth muscle cells (VSMCs) phenotype switch from contractile to proliferative phenotype is a pathological hallmark in various cardiovascular diseases. Recently, a subset of long noncoding RNAs was identified to produce functional polypeptides. However, the functional impact and regulatory mechanisms of long noncoding RNAs in VSMCs phenotype switching remain to be fully elucidated. OBJECTIVES: To illustrate the biological function and mechanism of a VSMC-enriched long noncoding RNA and its encoded peptide in VSMC phenotype switching and vascular remodeling. RESULTS: We identified a VSMC-enriched transcript encoded by a previously uncharacterized gene, which we called phenotype switching regulator (PSR), which was markedly upregulated during vascular remodeling. Although PSR was annotated as a long noncoding RNA, we demonstrated that the lncPSR (PSR transcript) also encoded a protein, which we named arteridin. In VSMCs, both arteridin and lncPSR were necessary and sufficient to induce phenotype switching. Mechanistically, arteridin and lncPSR regulate downstream genes by directly interacting with a transcription factor YBX1 (Y-box binding protein 1) and modulating its nuclear translocation and chromatin targeting. Intriguingly, the PSR transcription was also robustly induced by arteridin. More importantly, the loss of PSR gene or arteridin protein significantly attenuated the vascular remodeling induced by carotid arterial injury. In addition, VSMC-specific inhibition of lncPSR using adeno-associated virus attenuated Ang II (angiotensin II)-induced hypertensive vascular remodeling. CONCLUSIONS: PSR is a VSMC-enriched gene, and its transcript IncPSR and encoded protein (arteridin) coordinately regulate transcriptional reprogramming through a shared interacting partner, YBX1. This is a previously uncharacterized regulatory circuit in VSMC phenotype switching during vascular remodeling, with lncPSR/arteridin as potential therapeutic targets for the treatment of VSMC phenotype switching-related vascular remodeling.