The integration of artificial intelligence, notably the generative language model ChatGPT, into precision medicine precedes a paradigm shift in healthcare. This Review explores the capabilities of ChatGPT to process large data sets, understand contextual details, and generate human-like responses, making it a transformative tool for various applications in precision medicine. By analyzing the genetic sequences, identifying biomarkers, and predicting disease risks, ChatGPT facilitates earlier diagnosis and intervention. Moreover, its natural language processing capabilities enhance patient communication and engagement by elucidating complex medical concepts. This Review further examines ChatGPT's role in streamlining research, augmenting clinical trial recruitment, and supporting healthcare professionals through access to updated information and skill assessment. While acknowledging the complexities and potential concerns regarding reliance on publicly sourced data, this Review highlights ChatGPT's substantial capacity to optimize patient prognoses and enhance the operational efficacy of the healthcare delivery system.

Osteoporosis poses a significant threat to human health. Long non-coding RNAs (LncRNAs) have been deemed as crucial regulators in the pathogenesis of osteoporosis. However, the accuracy and efficiency of LncRNA-mediated regulation of bone formation require further improvement. Our previous study identified a repeat sequence in the human-derived LncRNA CTD-2555A7.2, suggesting its potential role in osteoporosis regulation. To investigate this hypothesis, we conducted systematic functional analyses of CTD-2555A7.2 in osteogenesis and explored its mechanisms and potential therapeutic applications. Through over-expression, siRNA silencing and repeat sequence over-expression in vitro and in vivo, our research demonstrate that CTD-2555A7.2 enhances bone formation by sequestering multiple miR-381-3p molecules through its repeat sequence. Through Western blot, siRNA silencing and luciferase reporter assay, we illuminated miR-381-3p suppresses osteogenic differentiation by concurrently targeting four essential genes of the Wnt signaling pathway: Apc, Lef1, wnt5a, and Lrp6. Notably, the mRNA of CTD-2555A7.2 repeat sequence exhibited pronounced therapeutic efficacy in ovariectomy osteoporosis models. Taken together, we identified a dual-amplification osteogenic axis (CTD-2555A7.2-miR-381-Wnt) that demonstrates significant regulatory effects on osteoporosis. This study has established an important theoretical framework for understanding osteogenic LncRNA mechanisms and provides novel insights for developing targeted therapeutics against osteoporosis.

Histone demethylation in cardiac hypertrophy is poorly understood. This study aims to determine the role of the histone demethylase LSD1 in pathological cardiac hypertrophy. Both isoprenaline (ISO)-treated and transverse aortic constriction (TAC)-treated rats developed hypertrophic hearts. LSD1 was significantly decreased; the histone marks mono- and dimethyl H3K4 and H3K9 (H3K4me1/2 and H3K9me1/2) were significantly up-regulated in the hypertrophic heart tissue, as well as the expression of the ANP, α-HMC and MLV-2v genes. An LSD1 inhibitor, OG-L002 could also induce cardiac hypertrophy and enhance the induction of cardiac hypertrophy by ISO. Overexpressed LSD1 abolished ISO-induced cardiac hypertrophy and downregulated H3K4me1/2 and H3K9me1/2 expression. Overexpression of LSD1 also reduced the expression of ANP, α-HMC and MLV-2v. In addition, we have reported isoprenaline (ISO) as one of the histone demethylase LSD1 inhibitors. This was confirmed by molecular docking, molecular dynamic studies and a histone demethylation assay. The H3K4me1/2 expression increases with the incubation of ISO in HEK 293T and HELA cells. CaMKII could be significantly activated by the LSD1 inhibitor OG-L002 as well as by ISO in rats. In summary, we have identified a novel role for LSD1 in initiating and maintaining cardiac hypertrophy.

Purpose:Apolipoprotein A1 (APOA1) is a potential crucial protein and treatment goal for pathological myopia in humans. This study set out to discover the function of APOA1 in scleral remodeling in myopia and its underlying mechanisms. Methods:A myopic cell model was induced using hypoxia. Following loss- and gain-of function experiments, the expression of the myofibroblast transdifferentiation-related and collagen production-related factors Forkhead box M1 (FOXM1), APOA1, and methyltransferase-like 3 (METTL3) in the myopic cell model was examined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. The proliferation and apoptosis were determined by Cell Counting Kit-8 assay and flow cytometry, respectively. Chromatin immunoprecipitation (ChIP) was employed to examine FOXM1 enrichment in the METTL3 promoter, methylated RNA immunoprecipitation (Me-RIP) to examine the N6-methyladenosine (m6A) modification level of APOA1, and photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to examine the binding between METTL3 and APOA1. Results:Hypoxia-induced human scleral fibroblasts (HSFs) had high APOA1 and FOXM1 expression and low METTL3 expression. FOXM1 knockdown elevated METTL3 expression and downregulated APOA1 expression. FOXM1 was enriched in METTL3 promoter. APOA1 or FOXM1 knockdown or METTL3 overexpression reversed the hypoxia-induced elevation in vinculin, paxillin, and α-smooth muscle actin (α-SMA) levels and apoptosis and the reduction in collagen, type I, alpha 1 (COL1A1) level and cell proliferation in HSFs. METTL3 or YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) knockdown or APOA1 overexpression reversed the impacts of FOXM1 knockdown on vinculin, paxillin, α-SMA, and COL1A1 expression and cell proliferation and apoptosis. Conclusions:FOXM1 elevated the m6A methylation level of APOA1 by repressing METTL3 transcription and enhanced APOA1 mRNA stability and transcription by reducing the YTHDF2-recognized m6A methylated transcripts.

Clozapine-resistant treatment-refractory schizophrenia (CR-TRS) patients face significant clinical challenges. While links between metabolic syndrome (MetS) and inflammatory cytokines in schizophrenia have been established, the relationship between MetS and cytokine levels in CR-TRS patients remains unexplored. This study aimed to investigate the relationship between cytokines levels, clinical symptoms and cognitive impairments in CR-TRS patients, both with and without MetS. The study included 69 CR-TRS patients (31with MetS and 38 without MetS) and 84 healthy controls. The levels of IL-2, IL-6, TNF-α and routine biochemical parameters were measured. Psychopathological symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. We found that CR-TRS patients with MetS displayed lower cognitive function scores compared to those without MetS, even when accounting for potential confounders. TNF-α levels were significantly higher in CRTRS patients with MetS compared to those without MetS, demonstrating substantial pathophysiological potential for CR-TRS patients with MetS via receiver operating characteristic curve (ROC). In CR-TRS patients without MetS, IL-2 independently contributed to the total score and general psychopathology subscore of PANSS. Additionally, IL-6 exhibited an independent contribution to the positive subscore of PANSS. In terms of cognition function, IL-6 independently contributed to the delayed memory of RBANS in CR-TRS patients without MetS. TNF-α could potentially serve as a predictive marker for distinguishing between CR-TRS patients with/without MetS, while IL-2 and IL-6 could independently contribute to psychopathological symptoms or cognitive function in CRTRS patients without MetS. Our study provided insights into the potential interplay between cytokines, clinical symptoms and cognitive impairments in CR-TRS patients with/without MetS.

In this work, near-infrared light responsive upconversion nanoparticles TiO2/(Ca,Y)F-2:Tm,Yb were hydrothermally prepared for tumor control. Moreover, femtosecond laser was adopted to reduce particle size and aggregation of TiO2/(Ca,Y)F-2:Tm,Yb, as a strategy to enhance its dispersity. In vitro studies of the biocompatibility and tumor control efficacy of TiO2/(Ca,Y)F-2:Tm,Yb were carried out via co-culturing human pancreatic carcinoma cells (CFPAC-1). It was found in the absence of near-infrared light, TiO2/(Ca,Y)F-2:Tm,Yb showed no toxicity to CFPAC-1 cells. On contrast, when exposed to near-infrared light, particles exhibited irradiation time, irradiation interval and particle concentration dependent suppression of CFPAC-1 cells proliferation along with portion of S phase cells increase. A nude mouse model with CFPAC-1 cells injection was established and TiO2/(Ca,Y)F-2:Tm,Yb was subsequently applied for in vivo tumor control. A 15 days tracking confirmed the antitumor capability of near-infrared light excited TiO2/(Ca,Y)F-2:Tm,Yb. Overall, we anticipate that the here-introduced TiO2/(Ca,Y)F-2:Tm,Yb can serve as an effective agent for photodynamic antitumor therapy.

PurposeBreast cancer (BC) is one of the biggest threats to women's health. LncRNA HOTAIR is related to the recurrence and metastasis of BC. Whether HOTAIR can serve as an effective biomarker to distinguish BC patients with different prognosis need to be further studied.MethodsThe miRNA and mRNA expression profile data of BC patients were downloaded from TCGA database. Univariate Cox regression was used to screen differential expression genes (DEGs). The miRcode database and miRWalk database were used to predict miRNA binding to HOTAIR and binding sites of miRNAs, respectively. Kaplan-Meier (KM) analysis was used to estimate the overall survival rate of BC patients. Finally, qRT-PCR and western blot were applied to evaluate the expression level of HOTAIR and mRNAs between BC cells and normal mammary cells.ResultsThe patients with high HOTAIR expression had poor prognosis in BC. Totally 10 genes correlated with BC prognosis were identified from 170 DEGs, among which PAX7, IYD, ZIC2, MS4A1, TPRXL, CD24, LHX1 were positively correlated with HOTAIR, while CHAD, NPY1R, TPRG1 were opposite. The levels of IYD, ZIC2, CD24 mRNA and protein were increased in BC tissues and BC cells. In BC cells, the levels of IYD, ZIC2 and CD24 mRNA and protein were significantly increased in HOTAIR overexpressed group. HOTAIR had the strongest interaction with hsa-miR-129-5p, followed by hsa-miR-107.ConclusionHOTAIR regulated the expression of downstream genes by interacting with 8 miRNAs and ultimately affected the prognosis of BC patients.

Objective: Pulmonary complications could badly affect the recovery of neurological function and neurological prognosis of neurological critically ill patients. This study evaluated the effect of high-flow nasal cannula (HFNC) therapy on decreasing pulmonary complications in neurologically critically ill patients. Patients and Methods: The patients admitted to the intensive care unit (ICU) with serious neurological disease and receiving oxygen therapy were retrospectively reviewed (Ethical No. IRB2021-YX-001). Patients were divided into the HFNC group and the conventional oxygen therapy (COT) group. We analyzed the data within these two groups, including patients' baseline data, short-term outcomes of respiratory complications, general outcomes including hospital stay, ICU stay and mortality, and neurological functions. To analyze the relevant factors, we performed multivariable logistic regression analysis. Results: A total of 283 patients met the criteria, including 164 cases in the HFNC group and 119 cases in the COT group. The HFNC group had remarkably less mechanical ventilation requirement with lower phlegm viscosity. Even more, ICU stay and total hospital stay were significantly shortened in the HNFC group. Conclusion: HFNC decreased pulmonary complications in neurologically critically ill patients and improved recovery of neurological function and neurological prognosis.

BACKGROUND:Hepatocellular carcinoma (HCC) is a frequent primary liver cancer, and it is one of the leading cause of cancer-related deaths. Hepatitis B virus (HBV) infection is a crucial risk factor for HCC. Thus, this study aimed to explore the prognostic role of HBV-positive HCC related specific genes in HCC.METHODS:The HCC related data were downloaded from three databases, including The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO). Univariate Cox regression analysis and LASSO Cox regression analysis were conducted to build the Risk score. Multivariate Cox regression analysis and survival analysis determined the independent prognostic indicators.RESULTS:After cross analysis of differentially expressed genes (DEGs), we have identified 106 overlapped DEGs, which were probably HBV-positive HCC related specific genes. These 106 DEGs were significantly enriched in 213 GO terms and 8 KEGG pathways. Among that, 11 optimal genes were selected to build a Risk score, and Risk score was an independent prognostic factor for HCC. High risk HCC patients had worse OS. Moreover, five kinds of immune cells were differentially infiltrated between high and low risk HCC patients.CONCLUSION:The prognostic signature, based on HMMR, MCM6, TPX2, KIF20A, CCL20, RGS2, NUSAP1, FABP5, FZD6, PBK, and STK39, is conducive to distinguish different prognosis of HCC patients.

Simple summary:Studies have shown that about 30% of kidney cancer patients will have metastasis, and lymph node metastasis (LNM) may be related to a poor prognosis. Our retrospective study aims to provide a reliable machine learning-based model to predict the occurrence of LNM in kidney cancer. We screened the pathological grade, liver metastasis, M staging, primary site, T staging, and tumor size from the training group (n=39016) formed by the SEER database and the validation group (n=771) formed by the medical center. Independent predictors of LNM in cancer patients. Using six different algorithms to build a prediction model, it is found that the prediction performance of the XGB model in the training group and the validation group is significantly better than any other machine learning model. The results show that prediction tools based on machine learning can accurately predict the probability of LNM in patients with kidney cancer and have satisfactory clinical application prospects.Background:Lymph node metastasis (LNM) is associated with the prognosis of patients with kidney cancer. This study aimed to provide reliable machine learning-based (ML-based) models to predict the probability of LNM in kidney cancer.Methods:Data on patients diagnosed with kidney cancer were extracted from the Surveillance, Epidemiology and Outcomes (SEER) database from 2010 to 2017, and variables were filtered by least absolute shrinkage and selection operator (LASSO), univariate and multivariate logistic regression analyses. Statistically significant risk factors were used to build predictive models. We used 10-fold cross-validation in the validation of the model. The area under the receiver operating characteristic curve (AUC) was used to assess the performance of the model. Correlation heat maps were used to investigate the correlation of features using permutation analysis to assess the importance of predictors. Probability density functions (PDFs) and clinical utility curves (CUCs) were used to determine clinical utility thresholds.Results:The training cohort of this study included 39,016 patients, and the validation cohort included 771 patients. In the two cohorts, 2544 (6.5%) and 66 (8.1%) patients had LNM, respectively. Pathological grade, liver metastasis, M stage, primary site, T stage, and tumor size were independent predictive factors of LNM. In both model validation, the XGB model significantly outperformed any of the machine learning models with an AUC value of 0.916.A web calculator (https://share.streamlit.io/liuwencai4/renal_lnm/main/renal_lnm.py) were built based on the XGB model. Based on the PDF and CUC, we suggested 54.6% as a threshold probability for guiding the diagnosis of LNM, which could distinguish about 89% of LNM patients.Conclusions:The predictive tool based on machine learning can precisely indicate the probability of LNM in kidney cancer patients and has a satisfying application prospect in clinical practice.

Objectives This research aimed to dissect the function of TYRP1 and PMEL in glaucomatous animal and cell models. Methods A chronic ocular hypertension (COH) rat model was induced in the right eyes of rats through the electrocoagulation of superficial iris veins. In addition, an oxygen-glucose deprivation (OGD)-retinal ganglion cell (RGC) model was constructed through OGD. TYRP1 and PMEL expression was altered in the animal and cell models to explore their effects. Results TYRP1 and PMEL expression was poor in glaucoma patients, COH rats, and OGD-RGCs. Mechanistically, TYRP1 interacted with PMEL to upregulate PMEL in OGD-RGCs. TYRP1 overexpression enhanced viability and diminished apoptosis and oxidative stress of OGD-RGCs, which was abolished by PMEL knockdown. TYRP1 upregulation reduced intraocular pressure, RGC apoptosis, and oxidative stress in COH rats, which was reversed by PMEL knockdown. Conclusions TYRP1 elevates PMEL expression to reduce RGC apoptosis and oxidative stress in vivo and in vitro.

OBJECTIVE:The present study was intended to investigate the role of embryonic stem cell-derived exosomes (ESC-Exos) in Müller cell retrodifferentiation and their specific mechanism.METHODS:Following co-incubation of the extracted ESC-Exos and Müller cells, their effects on the retrodifferentiation and proliferation of Müller cells were measured by EdU staining, immunofluorescence, and western blot. ESCs transfected with small interfering RNA of BDNF were co-incubated with Müller cells to determine Müller cell proliferation and retrodifferentiation. β-catenin expression in the nucleus and GSK-3β phosphorylation were measured to determine the role of the Wnt pathway in Müller cells. The function of the retina in RCS rats was observed using flash electroretinogram.RESULTS:Co-incubation of ESCs with Müller cells or overexpression of BDNF contributed to Müller cell retrodifferentiation and proliferation, as evidenced by increased cell proliferation, fluorescence intensities of proliferation markers and retinal stem cell markers, and expression of BDNF and β-catenin, and suppressed GSK-3β phosphorylation. However, co-incubation with ESCs silencing BDNF or treatment with GW4869 inhibited the proliferation and retrodifferentiation of retinal Müller cells. In addition, exosome injection increased BDNF, BrdU, PH3, SOX2, and Pax6 expression, enhanced β-catenin expression in the nucleus, diminished GSK-3β, and improved retinal degeneration in RCS rats.CONCLUSION:ESC-Exos accelerated Müller cell retrodifferentiation and proliferation through Wnt pathway activation by delivering BDNF protein to Müller cells.

Background: Glioblastoma (GBM) represents the most malignant glioma among astrocytomas and is a lethal form of brain cancer. Many RAB genes are involved in different cancers but RAB42 (Ras-associated binding 42) is seldom studied in GBM. Our study aimed to explore the role of RAB42 expression in the development and prognosis of GBM. Methods: All GBM patient data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The relevance of RAB42 expression to the clinicopathologic characteristics of GBM patients was analyzed. The overall survival (OS) significance was determined using log-rank. Significantly enriched KEGG pathways were screened using gene set enrichment analysis (GSEA). Results: High expression of RAB42 was observed in GBM specimens compared with normal samples, which was also verified in cell lines and tissue samples. Elevated RAB42 expression was correlated with higher GBM histological grade. The prognosis of GBM patients with high RAB42 expression was worse than those with lower RAB42. A total of 35 pathways, such as the P53 pathway, were significantly activated in highly RAB42-expressed GBM samples. Conclusions: High RAB42 expression is related to the development of GBM, and RAB42 is a probable prognostic marker for GBM.

The thiophene [2,3-d]pyrimidine structure-like small molecules were discovered from structure-based virtual screening of 1 billion compounds. Base on enzyme activity assay results, a SHP2-specific molecule inhibitor Comp#2 with IC50 of 1.174 mu M, 85-fold more selective for SHP2 than the highly related SHP1 (IC50 > 100 mu M). The compound can effectively inhibit SHP2-mediated cell signaling and cancer cell proliferation, including cervix cancer, human pancreatic cancer, large cell lung cancer, and mouse glioma cell. Moreover, the in vivo assay indicated that Comp#2 could inhibit cervix cancer tumors growth in BABL/c mice. This work has shown the specific SHP2 inhibitor can inhibit glioblastoma growth in vivo.

Previous studies have shown that lysine-specific demethylase 1 (LSD1) could regulate cell cycle progression through demethylation. The 3'domain of HOX transcript antisense RNA (Hotair) combined with the LSD1/CoREST/REST complex helps LSD1 target the corresponding gene. However, its role in mice's myocardial regeneration is still unclear. The heart from neonatal mice shows strong myocardial regeneration ability, but this ability disappears 7 days after birth. Our study shows that the myocardial tissue highly expresses Hotair and Lsd1 within 1 week after birth, consistent with the myocardial regeneration time window. Knockdown Lsd1 or Hotair expression by RNA interference could inhibit myocardial regeneration and cardiomyocyte proliferation. Our results suggest that Hotair-mediated demethylation of LSD1 may play an important role in myocardial regeneration in neonatal mice.

Nuclear factor erythroid 2-related factor 2 (NRF2) functions as a transcription factor and regulates a wide array of antioxidant and stress-responsive genes. NRF2 has been widely implicated in different types of cancers, but only limited studies concerning the relationship between NRF2 expression and tumour invasion or prognosis in lung cancer. Therefore, we conducted a meta-analysis to determine the prognostic value of NRF2 in patients with non-small cell lung cancer (NSCLC). The relationship between NRF2 expression in NSCLC patients and clinicopathological features was also investigated. Overall survival (OS) and treatment response rate were evaluated using STATA software. Twenty eligible articles with 2530 lung cancer patients were included in this meta-analysis. The results revealed that high expression level of NRF2 was associated with pathologic distant metastasis (odds ratio (OR) = 2.64, 95% confidence interval (CI) 1.62-4.31; P < 0.001), lymph node metastasis (OR = 2.14, 95% CI: 1.53-3.00; P < 0.001), and tumour node metastasis (TNM) stage (OR = 1.95, 95% CI: 1.52-2.49, P < 0.001). High NRF2 expression was associated with low treatment response rate in platinum-based chemotherapy (HR = 0.11, 95% CI 0.02-0.51; P = 0.005). High expression level of NRF2 is predictive for poor overall survival rate (HR = 1.86, 95% CI 1.44-2.41, P < 0.001) and poor progression-free survival (PFS) (HR = 2.27, 95% CI 1.26-4.09, P = 0.006). Compared to patients with a low level of NRF2 expression, patients with high NRF2 expression levels were associated with worse OS and PFS when given the chemotherapy or EGFR-TKI. Together, our meta-analysis results suggest that NRF2 can act as a potential indicator of NSCLC tumour aggressiveness and help the prognosis and design of a better treatment strategy for NSCLC patients.

Mounting evidence shows that long noncoding RNAs play important roles in human diseases and radioresistance could be an important factor for tumor recurrence. We observed that HOX antisense intergenic RNA (HOTAIR) expression increased in invasive ductal carcinoma (IDC) tissue. The irradiation effect of HOTAIR was detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, cell cycle and apoptosis analysis, and xenografts in nude mice. Western blot, RNA pulldown assay, and RNA immunoprecipitation were used for mechanistic studies. HOTAIR, upregulated in IDC of breast cancer tissue, could promote breast cancer cell proliferation by regulating cell cycle and apoptosis. Overexpression of HOTAIR promoted DNA damage repair factors KU70, KU80, DNA-PKs, and ATM expression, and these could be impeded by small molecular inhibitors of enhancer of zeste homolog 2 (EZH2). Meanwhile, we found that HOTAIR could facilitate recruitment of EZH2 to the Avian Myelocytomatosis Viral Oncogene Homolog (MYC) promoter. HOTAIR is an important modulator not only to the prognostic of breast cancer, but also a good marker for radiotherapy.

•This manuscript first reported pyridine derivatives as SHP2 inhibitors.•In this manuscript, multiple SHP2 inhibitors with development value were obtained.•Molecular docking study investigated the binding pocket of protein and ligand.