High Score Group Research Articles

Evaluating the Prognostic Value of the Modified H2FPEF Score in Patients With Heart Failure With Preserved Ejection Fraction.

The H2FPEF score, a convenient tool developed for diagnosing heart failure with preserved ejection fraction (HFpEF), exhibited useful prognostic utility in HFpEF. However, the applicability and the prognostic value of the H2FPEF score in Chinese HFpEF patients have yet to be fully confirmed. The study aimed to evaluate the effect of modified H2FPEF score on the prognosis of Chinese HFpEF patients. In this retrospective study, we calculated the H2FPEF scores by body mass index (BMI) ≥ 25 kg/m2 and 30 kg/m2 respectively, for 497 consecutive HFpEF patients in China. Subjects were divided into low- (0 - 3 points), intermediate- (4 - 6 points), and high-score (7 - 9 points) groups. The primary and secondary endpoints were heart failure (HF)-related events and acute coronary syndrome (ACS), respectively. Cox proportional hazard models were applied to calculate hazard ratios (HRs). Receiver operating characteristic (ROC) curves and areas under the curve (AUC) were used to evaluate the prediction of the H2FPEF score for adverse outcomes. Over a mean follow-up of 40.46 ± 6.52 months, the primary and secondary endpoints occurred in 168 patients (33.8%) and 97 patients (19.5%), respectively. By the definition of obesity as BMI ≥ 25 kg/m2, a higher incidence of HF-related events and ACS was observed among those with a higher modified H2FPEF score. The modified H2FPEF significantly predicted HF-related events (AUC: 0.723; 95% confidence interval (CI): 0.676 - 0.770; P < 0.001) and ACS (AUC: 0.670; 95% CI: 0.608 - 0.731; P < 0.014) with higher power than the H2FPEF score calculated by BMI ≥ 30 kg/m2. The cutoff of the modified H2FPEF score was 6.5 for detecting HF-related events and ACS. The modified H2FPEF score, using BMI ≥ 25 kg/m2 to define obesity, could more effectively predict the occurrence of subsequent cardiovascular events in Chinese HFpEF patients. The modified H2FPEF score above 6.5 is a risk factor for adverse cardiovascular events in HFpEF patients.

Comprehensive analysis of NOTCH pathway with tumor environment in pancreatic adenocarcinoma

Abstract Objectives Pancreatic adenocarcinoma (PAAD) ranks among the most prevalent malignant neoplasms, and multiple pathways are involved in its pathogenesis, including the NOTCH pathway. However, the variable biological functions of the pathway in PAAD are controversial. Methods RNA-seq data for PAAD was analyzed using data from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Utilizing Kaplan-Meier survival curves and Cox regression analyses, we examined the prognostic significance. The tumor microenvironment and immunotherapy responses were investigated using ssGSEA, ESTIMATE, and TIDE models. Functional enrichment analysis was used to explore gene functions. Results We identified NOTCH2, JAG1, NOTCH4, and DLL3 as high-priority members of the NOTCH pathway that modulates PAAD. Elevated NOTCH2 and JAG1 levels were markedly linked to reduced overall survival (OS), while increased NOTCH4 and DLL3 levels were significantly related to extended OS. Immune analyses showed that NOTCH-based scores were closely related to the immune microenvironment. NOTCH scores were not only closely correlated with tumor-infiltrating immune cells, but also with immunologically activated and immune checkpoint gene expression. The high NOTCH score group had a higher proportion of tumor-infiltrating immune cells and had better responses to immune checkpoint inhibitor therapy. Conclusions These data indicate that NOTCH2, JAG1, NOTCH4, and DLL3 could function as efficient prognostic biomarkers and therapeutic targets in PAAD, and patients with a high NOTCH score may have a significant response to immune checkpoint inhibitor treatment.

Study on psychological resilience and associated influencing factors in lung cancer patients with bone metastases

BACKGROUND Evaluating the psychological resilience of lung cancer (LC) patients helps understand their mental state and guides future treatment. However, there is limited research on the psychological resilience of LC patients with bone metastases. AIM To explore the psychological resilience of LC patients with bone metastases and identify factors that may influence psychological resilience. METHODS LC patients with bone metastases who met the inclusion criteria were screened from those admitted to the Third Affiliated Hospital of Wenzhou Medical University. The psychological scores of the enrolled patients were collected. They were then grouped based on the mean psychological score: Those with scores lower than the mean value were placed in the low-score group and those with scores equal to or greater than the mean value was placed in the high-score group. The baseline data (age, gender, education level, marital status, residence, monthly income, and religious beliefs), along with self-efficacy and medical coping mode scores, were compared. RESULTS This study included 142 LC patients with bone metastases admitted to our hospital from June 2022 to December 2023, with an average psychological resilience score of 63.24 ± 9.96 points. After grouping, the low-score group consisted of 69 patients, including 42 males and 27 females, with an average age of 67.38 ± 9.55 years. The high-score group consisted of 73 patients, including 49 males and 24 females, with a mean age of 61.97 ± 5.00 years. χ 2 analysis revealed significant differences between the two groups in education level (χ 2 = 6.604, P = 0.037), residence (χ 2 = 12.950, P = 0.002), monthly income (χ 2 = 9.375, P = 0.009), and medical coping modes (χ 2 = 19.150, P = 0.000). Independent sample t -test showed that the high-score group had significantly higher self-efficacy scores (t = 3.383, P = 0.001) and lower age than the low-score group (t = 4.256, P &lt; 0.001). Furthermore, multivariate logistic regression hazard analysis confirmed that self-efficacy is an independent protective factor for psychological resilience [odds ratio (OR) = 0.926, P = 0.035, 95% confidence interval (CI): 0.862-0.995], while age (OR = 1.099, P = 0.003, 95%CI: 1.034-1.169) and medical coping modes (avoidance vs confrontation: OR = 3.767, P = 0.012, 95%CI: 1.342-10.570; resignation vs confrontation: OR = 5.687, P = 0.001, 95%CI: 1.974-16.385) were identified as independent risk factors. A predictive model based on self-efficacy, age, and medical coping modes was developed. The receiver operating characteristic analysis showed an area under the curve value of 0.778 (95%CI: 0.701-0.856, P &lt; 0.001), indicating that the model has good predictive performance. CONCLUSION LC patients with bone metastases are less psychologically resilient than the general population. Factors such as self-efficacy, age, and medical coping modes influence their psychological resilience. Patients with low self-efficacy, old age, and avoidance/resignation coping modes should be closely observed.

Validation of a genome-based model for adjusting radiotherapy dose (GARD) in patients with locally advanced rectal cancer

Neoadjuvant radiotherapy is the standard care of locally advanced rectal cancer. Although a majority of patients received the same dose, the curative efficacy varies among individuals. In recent years, cancer treatment has entered the era of precise medical care, and how to identify patients for proper treatment by molecular signature is an important path of individualized therapy. This study aimed to establish and validate a genome-based model for adjusting radiation dose (GARD) for Chinese locally advanced rectal cancer through gene expression microarrays, and to evaluate the response of the GARD model in predicting the efficacy of neoadjuvant radiotherapy. Fresh-frozen primary tumor from 64 patients with locally advanced rectal cancer undergoing neoadjuvant radiotherapy from 2015 to 2018 were included. The gene expression profile was analyzed using Affymetrix 3000Dx gene-chip scanner. The radiosensitivity index (RSI) and GARD were calculated using the pGRT™ algorithm. Neoadjuvant rectal cancer score (NAR) was selected as efficacy evaluation indicators. Patients were divided into high and low NAR scoring groups, and two-sample t-test was used to analyze the differences in GARD values between different NAR subgroups. ROC curves were used to calculate the cut-off values and the area under the curve (AUC) for assessing the validity of the GARD models. The personalized radiation dose ( pGRT dose )can be computed using the formula nd = GARD / (α + βd). Among patients, 1.5% T2, 46.3% T3, and 52.2% T4. Wherein pCR (n = 10; 15.6%) and no pCR (n = 54; 84.4%). The median NAR is 8.43 (rang from 0 to 50.34, IQR 3.75–14.98). NAR > 8.43 (n = 27; 42.2%) and NAR ≤ 8.43 (n = 37; 57.8%), suggesting that there are significant individual differences in clinical efficacy of patients with similar tumor stages and under the same treatment conditions. The median RSI is 0.48 (rang from 0.22 to 0.92, IQR 0.41–0.55). Median GARD was 18.40 rang from (rang from 2.26 to 37.52, IQR 14.94–22.28) within tumor tissue, suggesting individual differences in the efficacy of radiation therapy. The RSI value was significantly lower in the NAR low group (NAR ≤ 8.43) than in NAR high group (NAR > 8.43) (0.44 vs. 0.54, p = 0.0003). The GARD value was significantly higher in the NAR low group (NAR ≤ 8.43) than in NAR high group (NAR > 8.43) (21.01 vs. 15.88, p = 0.0004). Using the Receiver Operating Characteristic (ROC) curve analysis, a GARD threshold of 17 was identified as optimal, covering 37.5% of the 64-patient sample, with an area under the curve (AUC) of 0.75. In the external validation cohort, the high GARD score group demonstrated superior DFS compared to the low GARD score group(p < 0.001). Only 17% of patients had pGRT dose within the guideline recommended dose (45–50 Gy). The differences in NAR values among LARC patients receiving standard neoadjuvant radiotherapy suggest significant individual differences in clinical outcomes among patients with similar tumor stage and the same treatment conditions. Patients with a GARD value exceeding 17 exhibit a more favorable prognosis. Our results suggest that the gene expression-based pGRT™ algorithm has good efficacy prediction performance in preoperative concurrent radiotherapy for locally advanced rectal cancer, suggesting the potential clinical application of this method to guide the designation of individualized radiotherapy doses.

Knowledge, attitudes, and behaviours about gender equality: a cross-sectional survey of adolescents from rural India.

Background: Gender equality is a fundamental human right and vital to accelerate global progress towards several Sustainable Development Goals (SDGs). Adolescents' involvement is essential to achieve such equality and SDGs to develop peaceful sustainable societies. However, there are limited data especially from developing countries such as India to plan gender equality related programmes targeted at adolescents. Methods: We conducted a cross-sectional survey to assess gender equality related knowledge, attitudes, and behaviours among 16 to 19 year-old adolescents from sixty villages of the Maharashtra state of India. Results: Data from 1306 respondents (667 females and 639 males) showed a mean score of 30 out of 44, suggesting an overall moderate gender equality score in rural adolescents. The majority of girls (68.3%) were in the high scoring group, whereas the majority of boys were in the moderate group (60.3%). Regression analysis showed that responses from boys were associated with lower scores compared to responses from girls by five points (adjusted β-coefficient: -4.99, 95%CI: -5.85 to -4.12, p<0.001). Conclusions: Our findings suggest that there is a need to involve adolescents with a major focus on boys to improve gender equality in rural areas of Maharashtra. This will help introduce concepts of equality from an early age to educate boys, empower girls, and address gender-based discrimination and violence against girls and women.

The controlling nutritional status score as a new prognostic predictor in patients with cervical cancer receiving radiotherapy: a propensity score matching analysis

BackgroundAs assessment tools of nutritional status, the controlling nutritional status (CONUT) and modified controlling nutritional status (mCONUT) score are associated with survival in various cancers. We aimed to investigate the association between the CONUT/mCONUT score’s prognostic value and survival time in patients with FIGO stage IIB–IIIB cervical cancer treated with radiotherapy.MethodsIn this retrospective study, 165 patients between September 2013 and September 2015 were analyzed, and the optimal CONUT/mCONUT score cut-off values were determined using receiver operating characteristic curves. Propensity score matching (PSM) was used to minimize selection bias. The Kaplan–Meier method and a Cox proportional hazard model were used to assess the CONUT/mCONUT score’s predictive value linked to survival time. Two nomograms were created to predict the overall survival (OS) and progression-free survival (PFS).ResultsThe cut-off values for CONUT and mCONUT score were both 2. Five-year OS and PFS rates were higher in a low CONUT score group than in a high CONUT score group (OS: 81.1% vs. 53.8%, respectively, P < 0.001; PFS: 76.4% vs. 48.2%, respectively; P < 0.001). A high CONUT score was associated with decreased OS (hazard ratio (HR) 2.93, 95% CI 1.54–5.56; P = 0.001) and PFS (HR 2.77, 95% CI 1.52–5.04; P < 0.001). High CONUT scores influenced OS in the PSM cohort. A high mCONUT score was not associated with decreased OS and PFS in Cox regression analysis.ConclusionThe CONUT score is a promising indicator for predicting survival in patients with cervical cancer receiving radiotherapy.

Liquid-liquid phase separation-related signature predicts prognosis and therapeutic response in esophageal adenocarcinoma

BackgroundEsophageal adenocarcinoma is a leading cause of mortality worldwide. New evidence indicates that liquid-liquid phase separation is related to malignancies. The current study aims at exploring the functions of liquid-liquid phase separation within esophageal adenocarcinoma. Patients within the TCGA dataset were classified using liquid–liquid phase separation-related genes. Significantly differentially expressed genes and prognostic factors for overall survival have been screened by Cox regression. Based on the liquid-liquid phase separation score, the construction of a prognostic model and liquid-liquid phase separation signature was constructed. Tumor mutation burden and drug sensitivity were analyzed in two groups: high liquid-liquid phase separation scores, and low liquid-liquid phase separation scores. According to liquid-liquid phase separation, some small-molecule compounds targeting esophageal adenocarcinoma were screened. The results were verified in vitro with an external cohort. Results87 samples are involved, and 61 liquid-liquid phase separation-related genes may influence esophageal adenocarcinoma by changing DNA conformation and metabolism. Meanwhile, based on a high liquid-liquid phase separation score and low score group including 43 patients, it is found that the result significantly lowered the 5-year overall survival to 32.6 %, compared to 64.8 % in the low-score group of 44 patients with p < 0.001. The high score group had an average TIDE score of 0.27 versus 0.14 in the low-score group, with p = 0.003. The median tumor mutation burden was 9.1 mutations/Mb in the high-score group versus 6.4 mutations/Mb in the low-score group, with p = 0.011. The predictive model worked very well, with area under the curve values of 0.82, 0.79, and 0.76 for 1-, 3-, and 5-year survival, respectively. Liquid-liquid phase separation has been validated as an effective prognostic biomarker and drug sensitivity predictor. SignificanceLiquid-liquid phase separation is potentially implicated in esophageal adenocarcinoma and works as a prognostic biomarker assessment of vulnerability to LLPS, which could help develop individualized therapies by showing how one is situated about various medications where responses vary across the body.

Intestinal flora and inflammatory bowel disease: Causal relationships and predictive models

BackgroundInflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is significantly influenced by intestinal flora. Understanding the genetic and microbiotic interplay is crucial for IBD prediction and treatment. MethodsWe used Mendelian randomization (MR), transcriptomic analysis, and machine learning techniques, integrating data from the MiBioGen Consortium and various GWAS datasets. SNPs associated with intestinal flora were mapped to genes, with LASSO regression refining gene selection. Differentially expressed genes (DEGs) and immune infiltration patterns were identified through transcriptomic analysis. Six machine learning models were used for predictive modeling. FindingsMR analysis identified 25 gut microbiota classifications causally related to IBD. SNP mapping and gene expression analysis highlighted 24 significant genes. Drug target MR and colocalization validated these genes' causal relationships with IBD. Key pathways identified included the PI3K-Akt signaling pathway and epithelial-mesenchymal transition. Immune infiltration analysis revealed distinct patterns between high and low LASSO score groups. Machine learning models demonstrated high predictive value, with soft voting enhancing reliability. InterpretationBy integrating MR, transcriptomic analysis, and sophisticated machine learning approaches, this study elucidates the causal relationships between intestinal flora and IBD. The application of machine learning not only enhanced predictive modeling but also offered new insights into IBD pathogenesis, highlighted potential therapeutic targets, and established a robust framework for predicting IBD onset.

Selective voluntary motor control influences knee joint torque, work and power in children with spastic cerebral palsy

BackgroundChildren with spastic cerebral palsy (CP) have damage to the corticospinal tracts that are responsible for selective motor control (SMC). Force, velocity and timing of joint movement are related biomechanical features controlled by the corticospinal tracts (CSTs) that are important for skilled movement. Research QuestionDoes SMC influence knee joint biomechanics in spastic CP? Methods: In this prospective study, relationships between SMC and knee biomechanics (peak torque, total work, average power) across a range of velocities (0–300 deg/s) were assessed using an isokinetic dynamometer in 23 children with spastic CP. SMC was assessed using Selective Control Assessment of the Lower Extremity (SCALE). Logistic and linear regression models were used to evaluate relationships between SCALE and biomechanical measures. ResultsThe ability to produce knee torque diminished with increasing velocity for both Low (0–4 points) and High (5–10 points) SCALE limb score groups (p < 0.01). More knees in the High group produced extension torque at 300 deg/s (p < 0.05) and flexion torque at 30, 90,180, 240 and 300 deg/s (p < 0.05). The ability to produce torque markedly decreased above 180 deg/s for Low group flexion. For knees that produced torque, significant positive correlations between SCALE limb scores and joint torque (0 and 120 deg/s), work (120 deg/s) and power (120 deg/s) were found (p < 0.05). Greater knee torque, work and power for the High group was found for the extensors at most velocities and the flexors for up to 120 deg/s (p < 0.05). Few Low group participants generated knee flexor torque above 120 deg/s limiting comparisons. SignificanceBiomechanical impairments found for children with low SMC are concerning as skilled movements during gait, play and sport activities occur at high velocities. Differences in SMC should be considered when designing individualized assessments and interventions.

The prognostic utility of Lactate/Albumin*Age score in septic patient with normal lactate level

BackgroundA previous study has shown that the lactate/albumin*age (LAA) score is useful for predicting mortality in patients with sepsis admitted to the ICU. We aimed to evaluate the clinical significance of the LAA score in patients with sepsis who presented to the emergency department (ED) MethodsThis retrospective observational study used data from the Korean Shock Society Registry collected between January 2017 and December 2021. The prognostic performance of the LAA score for predicting the 28-day mortality was evaluated. Lactate and albumin levels were measured immediately after arrival to the ED. ResultsOf the 5346 patients with sepsis, data from 3240 were analyzed. The area under the receiver operating characteristic curve (AUROC) of the LAA score (0.737, 95 % confidence interval (CI) 0.716–0.757), was higher than that of lactate (0.699, 95 % CI 0.677–0.720, p < 0.001), lactate/albumin (LA) ratio (0.730, 95 % CI 0.709–0.751, p = 0.016), and Sequential Organ Failure Assessment (SOFA) score (0.698, 95 % confidence interval 0.676–0.720, p = 0. 004), and Acute Physiology and Chronic Health Evaluation (APACHE) II scores (0.672; 95 % confidence interval 0.649–0.694, p < 0.001). The optimal cut-off value for the LAA score was 119.9. In the Kaplan-Meier analysis according to the optimal cutoff value, the 28-day mortality rates were higher in the high LAA score group (log-rank test, p < 0.001). The LAA score was independently associated with 28-day mortality in the multivariate Cox proportional hazards model (adjusted hazard ratio 2.07, 95 % CI 1.76–2.43, p < 0.001). In the normal (<2 mmol/L) lactate group, the AUROC value for LAA score was higher than LA ratio (normal group 0.674 vs 0.634, p < 0.004). In patients over 65 years old, LAA score (0.731) showed a higher AUROC value than LA ratio (0.725). (p < 0.001) ConclusionThe LAA score may be used as an independent predictor of mortality in patients with sepsis in the emergency department. Our results show that it performs better than serum lactate alone, LA ratio, and SOFA and APACHE II scores. While this suggests that the LAA could provide clinicians with a useful tool for timely early intervention and care planning in patients with a poor prognosis, further validation in large multicenter prospective studies are necessary to confirm its reliability and practicality as a readily available and objective biomarker.

A Novel Cuproptosis-Related Gene Signature Predicts Prognosis in Papillary Thyroid Carcinoma Patients.

Cuproptosis, a novel form of cell death mediated by protein lipoylation, is intricately linked to mitochondrial metabolism. However, the clinical association of cuproptosis- related genes (CRGs) in thyroid cancer remains unclear. In this study, we performed a systematic investigation on the differential expression and genetic alterations of CRGs in papillary thyroid cancer (PTC) and constructed a CRG signature to predict the prognosis of PTC patients. We integrated the data of The Cancer Genome Atlas (TCGA) database and analyzed the expression of 10 CRGs in PTC. CRG signature was constructed using univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) Cox regression. In addition, the signature-related molecular features were validated by a combination of functional enrichment, Cox regression, and immune infiltration analysis. Independent validation cohort and quantitative real-time polymerase chain reaction (qRT-PCR) were used to validate the expression of differentially expressed CRG (CDKN2A). Thyroid cancer patients could be divided into two subtypes (high and low CRG score groups). We found that the overall survival (OS) of patients was lower in the high CRG score group (HCSG) than in the low CRG score group (LCSG) (P < 0.001). The area under the curve (AUC) values for 3 years, 5 years, and 8 years were 0.872, 0.941, and 0.976, respectively. Cox regression analysis indicated that the CRG score could serve as an independent prognostic indicator for PTC. Functional enrichment analysis indicated that the CRG prognostic signature was also associated with the tumor immune microenvironment. In HCSG, the immune suppression cell score was significantly higher than in LCSG. In addition, we identified the expression of CRG (CDKN2A) by qRT-PCR, and the results aligned with the TCGA database. Our CRG signature demonstrates excellent predictive capabilities for the prognosis of PTC patients. CRGs may play an important role in tumorigenesis and could be used to predict the immunotherapy efficacy of PTC.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

Integration of Bioinformatics and Machine Learning to Identify CD8+ T Cell-Related Prognostic Signature to Predict Clinical Outcomes and Treatment Response in Breast Cancer Patients.

We assessed the abundance of CD8+ T cells in the TCGA and METABRIC datasets and obtained CTRGs through WGCNA. Subsequently, a prognostic signature (CTR score) was constructed from CTRGs screened by seven machine learning algorithms, and the relationship between the CTR score and TME, immunotherapy, and drug sensitivity was analyzed. Additionally, CTRGs' expression in different cells within TME was identified through single-cell analysis and spatial transcriptomics. Finally, the expression of CTRGs in clinical tissues was verified via RT-PCR. The CD8+ T cell-related prognostic signature consists of two CTRGs. In the TCGA and METABRIC datasets, the CTR score appeared to be negatively linked to the abundance of CD8+ T cells, and BC patients with higher risk score show a worse prognosis. The low CTR score group exhibits higher immune infiltration levels, closely associated with inhibiting the tumor microenvironment. Compared with the high CTR score group, the low CTR score group shows better responses to chemotherapy and immune checkpoint therapy. Single-cell analysis and spatial transcriptomics reveal the heterogeneity of two CTRGs in different cells. Compared with the adjacent tissues, CD163L1 and KLRB1 mRNA are downregulated in tumor tissues. This study establishes a robust CD8+ T cell-related prognostic signature, providing new insights for predicting the clinical outcomes and treatment responses of breast cancer patients.

Copper metabolism–related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer

ObjectivesTo comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism. MethodsCopper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays. ResultsFour copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration. ConclusionThe identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure

BackgroundHeart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown.MethodsWe comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored.ResultsSingle-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics.ConclusionOur study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

Associations of prenatal exposure to individual and mixed organophosphate esters with ADHD symptom trajectories in preschool children: The modifying effects of maternal Vitamin D

BackgroundOrganophosphate esters (OPEs) are a class of environmental chemicals with endocrine-disrupting properties. Epidemiologic studies have demonstrated that prenatal OPEs exposure is associated with neurodevelopmental disorders in offspring. However, studies assessing the effects of prenatal OPEs exposure on the dynamic changes in attention deficit hyperactivity disorder (ADHD) symptoms in preschoolers are scarce. Since vitamin D has been demonstrated to have a "neuroprotective" effect, the modifying effects of maternal vitamin D were estimated. MethodsThe present study included 2410 pregnant women from the Ma'anshan Birth Cohort. The levels of OPEs in the mothers' urine were examined in the three trimesters. The Chinese version of the Conners Abbreviated Symptom Questionnaire was used to examine preschoolers' ADHD symptoms at 3, 5, and 6 years of age. ADHD symptom trajectories were fitted via group-based trajectory modeling. We used multinomial logistic regression, Bayesian kernel machine regression, quantile-based g-computation, and generalized linear models to assess individual and mixed relationships between OPEs during pregnancy and preschoolers' ADHD symptoms and trajectories. ResultsPreschoolers' ADHD symptom scores were fitted to 3 trajectories, including the low-score, moderate-score, and high-score groups. First-trimester dibutyl phosphate (DBP), second-trimester bis(2-butoxyethyl) phosphate (BBOEP), and third-trimester diphenyl phosphate (DPHP) were associated with an increased risk in the high-score group (p < 0.05). BBOEP in the third trimester was associated with decreased risk in the moderate-score group (OR = 0.89, 95% CI: 0.79, 1.00). For mothers with 25(OH)D deficiency, a positive relationship was observed between OPEs during pregnancy and symptom trajectories. Our results did not reveal any mixed effects of OPEs on ADHD symptom trajectories. ConclusionPrenatal exposure to OPEs had heterogeneous associations with ADHD symptom trajectories in preschoolers. Additionally, the effect of individual OPEs on symptom trajectories was intensified by vitamin D deficiency.

Endoscopic program with a scoring system for surveillance of metachronous esophageal cell carcinoma for older patients considering risk factors after endoscopic resection

BackgroundThis study evaluated the association between the risk factors and prognosis for metachronous esophageal squamous cell carcinoma (ESCC) after endoscopic resection (ER) of esophageal cancer in older patients.MethodsWe conducted a retrospective observational study of 127 patients with ESCC who underwent ER from 2015 to 2020. Patients were classified as non-older (≤ 64 years), early older (65–74 years), and late older (≥ 75 years). We analyzed factors associated with poor overall survival and metachronous ESCC after ER using multivariate Cox regression analysis. A metachronous ESCC prediction scoring system was examined to validate the surveillance endoscopy program.ResultsBody mass index (BMI) and Charlson Comorbidity Index (CCI) were significant risk factors for poor overall survival in the multivariate analysis (p = 0.050 and p = 0.037, respectively). Multivariate analysis revealed that age of < 64 years, Lugol-voiding lesions (grade B/C), and head and neck cancer were significantly related to metachronous ESCC (p = 0.035, p = 0.035, and p = 0.014, respectively). In the development cohort, BMI < 18.5 kg/m2, CCI > 2, age < 64 years, Lugol-voiding lesions (grade B/C), and head and neck cancer were significantly related to metachronous ESCC, and each case was assigned 1 point. Patients were classified into low (0, 1, and 2) and high (> 3) score groups based on total scores. According to Kaplan–Meier curves, the 3-year overall survival was significantly lower in the high-score group than in the low-score group (91.5% vs. 100%, p = 0.012).ConclusionsWe proposed an endoscopic surveillance scoring system for metachronous ESCC considering BMI and CCI in older patients.

Elevated expression of N-myc downstream regulated gene 1 protein in glioblastomas reflects tumor angiogenesis and poor patient prognosis.

N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis.

The optimal measurement method considering reliability and validity in the anterior knee laxity of anterior cruciate ligament tears.

To seek an optimal measurement method with high reliability and high validity for evaluation of the anterior knee laxity on stress radiographs and comparing the translation values to those of KT-2000 arthrometer. Anterior knee laxity in 77 patients was measured preoperatively using the TelosTM and the KT-2000 arthrometer. Side-to-side difference measurements were taken using three conventional measuring methods and one proposed method (Modified Lateral). The knee position on the stress radiograph was evaluated and scored based on the stress radiograph qualifying criteria depending on stress film correctiveness. Intraclass correlation coefficients were analyzed to evaluate the reliability of the measurement methods and were compared between high (Group H) and low (Group L) radiograph quality score groups for each method. Validity was assessed by comparing the KT-2000 and the TelosTM using Pearson correlation (r value). The Modified Lateral method showed the best Intraclass Correlation Coefficients (ICCs), followed by Center to Center, and Medial to Medial and Lateral to Lateral methods without considering the quality of Telos. In the comparison between groups based on Telos quality for intra-rater reliability, the Medial to Medial (MM) method demonstrated the best reliability in both groups (MM: ICCs, Group H = 0.942, Group L = 0.917, P = 0.693). As for inter-rater reliability, the Modified Lateral (ML) method exhibited the best reliability in both groups (ML: ICCs, Group H = 0.923, Group L = 0.882, P = 0.547). The value measured using the ML method in Telos showed the highest correlation coefficient with the KT-2000 measured value in both groups H and L. There were no statistically significant differences among the correlation coefficient values. The Modified Lateral method is recommended for its high reliability, taking into account the differences in bilateral knee positions and anatomical discriminability on stress radiographs when evaluating anterior knee translation with Telos. It also best reflected the KT-2000 arthrometer. Case Series, Level IV.

Intracranial artery calcification: Frequency, determinants, and modification of outcomes from endovascular thrombectomy

IntroductionIntracranial artery calcification (ICAC) is a common finding on computed tomography (CT) in patients presenting with large vessel occlusion acute ischemic stroke (LVO-AIS) and could serve as a useful biomarker of intracranial atherosclerosis and altered intracranial vessel pliability in patients undergoing endovascular thrombectomy (EVT). MethodsThis was a retrospective cohort study analyzing consecutive patients undergoing CT head prior to EVT between 2016 and 2020. Extent of ICAC proximal to the target vessel was scored using a validated grading scale examining thickness and circumferential extent of calcifications. The relationship between 3 levels of ICAC burden and procedural, clinical, and safety outcomes was analyzed. ResultsAmong 86 patients meeting inclusion criteria, ICAC of any degree was present in 72.1 %. Median ICAC score was 3 [IQR 0-4]. There was a U-shaped association between ICAC score and successful reperfusion: 90.9 %, 65.7 %, and 94.4 % in the low, intermediate, and high ICAC score groups, respectively (p = 0.008). Use of rescue intervention, most often angioplasty and stenting, was greatest in the high ICAC score group: 3.0 % vs. 5.7 % vs. 22.2 % (p = 0.05). Functional independence at 90 days did not differ significantly among groups (41.7 % vs. 31.0 % vs. 15.4 %, p = 0.26), nor did rates of symptomatic intracranial hemorrhage (15.2 % vs. 14.3 % vs. 16.7 %, p = 0.97). ConclusionsICAC is seen on CT in nearly three-quarters of patients with LVO-AIS. Extent of ICAC has a U-shaped association with successful reperfusion, in part due to more frequent use of rescue interventions in patients with extensive ICAC.