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Invasive breast cancer diagnosis and treatment planning require an accurate assessment of human epidermal growth factor receptor 2 (HER2) expression levels. While immunohistochemical techniques (IHC) are the gold standard for HER2 evaluation, their implementation can be resource-intensive and costly. To reduce these obstacles and expedite the procedure, we present an efficient deep-learning model that generates high-quality IHC-stained images directly from Hematoxylin and Eosin (H&E) stained images. We propose a new IHC-GAN that enhances the Pix2PixHD model into a dual generator module, improving its performance and simplifying its structure. Furthermore, to strengthen feature extraction for HE-stained image classification, we integrate MobileNetV3 as the backbone network. The extracted features are then merged with those generated by the generator to improve overall performance. Moreover, the decoder's performance is enhanced by providing the related features from the classified labels by incorporating the adaptive instance normalization technique. The proposed IHC-GAN was trained and validated on a comprehensive dataset comprising 4,870 registered image pairs, encompassing a spectrum of HER2 expression levels. Our findings demonstrate promising results in translating H&E images to IHC-equivalent representations, offering a potential solution to reduce the costs associated with traditional HER2 assessment methods. We extensively validate our model and the current dataset. We compare it with state-of-the-art techniques, achieving high performance using different evaluation metrics, showing 0.0927 FID, 22.87 PSNR, and 0.3735 SSIM. The proposed approach exhibits significant enhancements over current GAN models, including an 88% reduction in Frechet Inception Distance (FID), a 4% enhancement in Learned Perceptual Image Patch Similarity (LPIPS), a 10% increase in Peak Signal-to-Noise Ratio (PSNR), and a 45% reduction in Mean Squared Error (MSE). This advancement holds significant potential for enhancing efficiency, reducing manpower requirements, and facilitating timely treatment decisions in breast cancer care., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: We confirm that the manuscript represents our own work, is original, and has not been copyrighted, published, submitted, or accepted for publication elsewhere. We further confirm that we all have fully read the manuscript and give consent to be co-authors of the manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Lymph node involvement is one of the well-demonstrated prognostic factors in ampullary carcinoma. The aim of this study is to clarify the role of lymph nodes in predicting the survival outcome of ampullary carcinoma. Methods: A cohort of consecutive curative pancreaticoduodenectomies for ampullary carcinoma from 1999 to 2014 was retrospectively analyzed. The effect of node-associated variables, including lymph node status, positive lymph node number, total harvested lymph node (THLN) number, and lymph node ratio (LNR) was examined using univariate and multivariate analyses for survival outcome prediction. Results: In 194 evaluable patients, univariate analysis demonstrated that stage, cell differentiation, perineural invasion, and nodal status were significant conventional prognostic factors. Concerning the node-associated variables, positive nodal status, positive lymph node number ≥2, THLN number <14, and LNR ≥0.15 were significantly associated with poorer survival outcomes, with a 5-year survival rate of 20.3, 38.9, 25.4, and 18 %, respectively. By multivariate analysis, nodal status and THLN number were two independent predictors of survival. The most favorable 5-year survival rate was 84.4 % in patients with negative nodal involvement and THLN number ≥14, compared with the poorest 5-year survival rate of 16.1 % in those with positive nodal status and THLN number <14. Conclusions: Tumor biology reflected by lymph node status is the most important independent prognostic factor; nevertheless, surgical radicality based on THLN number also plays a significant role in the survival outcome for patients with ampullary carcinoma after curative pancreaticoduodenectomy. [ABSTRACT FROM AUTHOR]

Background Childhood-to-adult persistent asthma is usually considered to be an atopic disease. However gastroesophageal reflux may also play an important role in this phenotype of asthma, especially when it is refractory to pulmonary medicine. Methods Fifty-seven consecutive GERD patients who had decades of childhood-to-adult persistent asthmatic symptoms refractory to pulmonary medication were enrolled. GERD was assessed by a symptom questionnaire, endoscopy, reflux monitoring, and manometry, and treated by Stretta radiofrequency (SRF) or laparoscopic Nissen fundoplication (LNF). The outcomes were followed up with a questionnaire for an average of 3.3 ± 1.1 years. Results Upper esophageal sphincter hypotonia, lower esophageal sphincter (LES) hypotonia, shortened LES, and esophageal body dyskinesia were demonstrated by esophagus manometry in 50.9%, 43.9%, 35.1%, and 45.6% of the patients, respectively. The symptom scores for heartburn, regurgitation, coughing, wheezing, and chest tightness significantly decreased from 5.8 ± 2.0, 5.6 ± 2.0, 7.3 ± 1.6, 8.4 ± 1.2, and 8.1 ± 1.5, to 1.2 ± 1.8, 1.1 ± 1.6, 2.8 ± 2.5, 3.8 ± 2.7, and 3.9 ± 2.7, respectively, after anti-reflux treatment (P < 0.001). Conclusions Esophagus dysfunction is high in childhood-to-adult persistent asthmatic patients with GERD. SRF and LNF are both effective for esophagus symptoms as well as persistent asthmatic symptoms for these patients. GER may relate with asthmatic symptoms in some patients. Evaluating asthmatic patients for possible treatment of the underlying cause, such as GERD, may improve symptoms and prevent disease persistence. [ABSTRACT FROM AUTHOR]

Background: The role of histone modifications in the DNA damage response has been extensively studied in nonplant systems, including mammals and yeast. However, there is a lack of detailed evidence showing how chromatin dynamics, either an individual mark or combined chromatin states, participate in regulating differentially expressed genes in the plant DNA damage response. Results: In this study, we used RNA-seq and ChIP-seq to show that differentially expressed genes (DEGs), in response to ionizing radiation (IR), might be involved in different pathways responsible for the DNA damage response. Moreover, chromatin structures associated with promoters, exons and intergenic regions are significantly affected by IR. Most importantly, either an individual mark or a certain chromatin state was found to be highly correlated with the expression of up-regulated genes. In contrast, only the chromatin states, as opposed to any individual marks tested are related to the expression of the down-regulated genes. Conclusions: Our findings demonstrate that IR-related DEGs are modulated by distinct epigenetic mechanisms. Either chromatin states or distinct histone dynamics may act sequentially or in combination in regulating up-regulated genes, but the complex chromatin structure is mainly responsible for the expression of down-regulated genes. Thus, this study provides new insights into how up- and down-regulated genes are epigenetically regulated at the chromatin levels, thereby helping us to understand distinct epigenetic mechanisms that function in the plant DNA damage response. [ABSTRACT FROM AUTHOR]

Background: Gallbladder metastasis from renal cell carcinoma (RCC) is extremely rare. The purpose of this study is to clarify the characteristics of metastatic RCC to gallbladder.Methods: The pooled data for analysis were collected from the case of metastatic RCC to gallbladder encountered by our institution along with sporadic cases reported in literature from 1991 to 2015.Results: A total of 50 cases of metastatic RCC to gallbladder were recruited for study. Fifty-seven percentage of the primary RCC was from the right kidney and 43% from the left. The median interval between diagnoses of primary and metastatic RCC to gallbladder was 36 months, with the longest duration up to 324 months. Most (70%) were asymptomatic. The size of metastatic RCC to gallbladder ranged from 0.8 cm to 9 cm, with median of 2.6 cm. Majority (91%) of the metastatic RCCs presented as a polypoid mass with narrow stalk, and 82% were hypervascular lesion. The overall 1 year, 3 year and 5 year survival rate was 91.5%, 76.2% and 59.3% respectively, with a median of 26.5 months. Number of the metastatic site, timing of gallbladder metastasis, symptom, tumor size and operation type of cholecystectomy seemed to have no impact on survival.Conclusions: Metastatic RCC to the gallbladder should be taken into account for a gallbladder polypoid mass with narrow hypervascular stalk during the diagnosis and/or follow-up of primary RCC. Gallbladder metastasis from RCC is not necessarily to be an advanced stage with poor outcome, and cholecystectomy is recommended whenever possible. [ABSTRACT FROM AUTHOR]

Background: Bidirectional gene pairs are highly abundant and mostly co-regulated in eukaryotic genomes. The structural features of bidirectional promoters (BDPs) have been well studied in yeast, humans and plants. However, the underlying mechanisms responsible for the coexpression of BDPs remain understudied, especially in plants. Results: Here, we characterized chromatin features associated with rice BDPs. Several unique chromatin features were present in rice BDPs but were missing from unidirectional promoters (UDPs), including overrepresented active histone marks, canonical nucleosomes and underrepresented H3K27me3. In particular, overrepresented active marks (H3K4ac, H4K12ac, H4K16ac, H3K4me2 and H3K36me3) were truly overrepresented in type I BDPs but not in the other two BDPs, based on a Kolmogorov-Smirnov test. Conclusions: Our analyses indicate that active marks (H3K4ac, H4K12ac, H4K16ac, H3K4me3, H3K9ac and H3K27ac) may coordinate with repressive marks (H3K27me3 and H3K9me1/3) to build a unique chromatin structure that favors the coregulation of bidirectional gene pairs. Thus, our findings help to enhance the understanding of unique epigenetic mechanisms that regulate bidirectional gene pairs and may improve the manipulation of gene pairs for crop bioengineering. [ABSTRACT FROM AUTHOR]

Background: Hepatoid carcinoma of the pancreas is extremely rare. This article tries to summarize the clinical features and outcomes of pancreatic hepatoid carcinoma. Methods: The data pool for analysis includes the case we encountered with hepatoid carcinoma of the pancreas and the reported cases in the literature. Results: Twenty-three cases of hepatoid carcinoma of the pancreas were analyzed. This tumor occurred more frequently in male than in female patients (69.6 vs. 30.4 %). Tumor sizes range from 0.5 to 11.0 cm with median of 6.0 cm. The most common symptom was epigastric pain (36.4 %). When the tumor locates at pancreatic head, nausea/vomiting (62.5 %) is more common, followed by jaundice and epigastric pain (50.0 %). For those at pancreatic body-tail, 42.9 % of the patients presented no symptom. Alpha-fetoprotein (AFP) was abnormally elevated in 60 % of the cases. Hepatoid carcinoma in the pancreas could be either pure form or mixed form with other malignancy (40.9 %), with the most common coexisted pathology of malignant neuroendocrine tumor (22.7 %). Metastasis occurred in 36.4 % of the cases at the diagnosis of this tumor, including liver metastasis in 31.8 % and lymph node metastasis in 21.1 %. The overall 1-year survival rate was 71.1 % and 5-year 40.4 %, with a median of 13.0 months. Unresectability, hepatic, and lymph node metastases are associated with negative impact on survival outcome. Conclusions: Elevation of serum AFP may be a clue leading to the diagnosis of pancreatic hepatoid carcinoma. This tumor could be mixed form with other malignancy. Surgical resection should be the treatment of choice whenever possible. [ABSTRACT FROM AUTHOR]

Sheng-Chieh Lin, Yi-Chu Liao and Po-Ming Chen contributed equally to this work. Reference 1 Lin S-C, Liao Y-C, Chen P-M, Yang Y-Y, Wang Y-H, Tung S-L, Chuang C-M, Sung Y-W, Jang T-H, Chuang S-E, Wang L-H. Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF- B and TGF- 2 signaling. Correction: Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF- B and TGF- 2 signaling. [Extracted from the article]

Background: The cooperation between phorbol 12-myristate 13-acetate induced protein 1 (NOXA) and myeloid cell leukemia 1 (MCL1) is critical in the intrinsic apoptotic pathway. Human papillomavirus 16 (HPV16), by inducing p53 and pRb-E2F degradation, may play an essential role in development of squamous cell carcinoma of the head and neck (SCCHN) through NOXA-MCL1 axis-mediated apoptosis. Therefore, genetic variants of NOXA and MCL1 may modify the SCCHN risk associated with HPV16 seropositivity. Methods: HPV16 serology was obtained by immunoadsorption assay. Four functional SNPs in the promoter of NOXA (rs9957673, rs4558496) and MCL1 (rs9803935, rs3738485) were genotyped for 380 cases and 335 frequency-matched cancer-free controls of non-Hispanic whites. Results: Associations between the four polymorphisms and SCCHN risk were not significant, while we observed a significantly joint effect on SCCHN risk between the polymorphisms and HPV16 seropositivity. Notably, this effect modification was particularly pronounced for oropharyngeal cancer in subgroups including never smokers, never drinkers and younger subjects. Conclusions: Our results suggested that polymorphisms of NOXA and MCL1 may modify the risk of HPV16-associated oropharyngeal cancer. The further identification of population subgroups at higher risk provides evidence that HPV-targeting treatment may help benefit SCCHN. However, larger studies are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Background: Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN. Methods: We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population. Results: Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend = 0.046), particularly for non-oropharyngeal tumors (Ptrend = 0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR = 1.29, 95% CI = 1.01-1.64; AG/GG vs. AA: adjusted OR = 1.30, 95% CI = 1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR = 0.54, 95% CI = 0.34-0.86; TG/GG vs. TT: adjusted OR = 0.76, 95% CI = 0.61-0.95). Conclusions: Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers. [ABSTRACT FROM AUTHOR]

Background: Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving in carcinogenesis, including lung cancer. We hypothesized that VEGF polymorphisms may affect survival outcomes among locally advanced non-small cell lung cancer (LA-NSCLC) patients. Methods: We genotyped three potentially functional VEGF variants [-460 T > C (rs833061), -634 G > C (rs2010963), and +936 C > T (rs3025039)] and estimated haplotypes in 124 Caucasian patients with LA-NSCLC treated with definitive radiotherapy. We used Kaplan-Meier log-rank tests, and Cox proportional hazard models to evaluate the association between VEGF variants and overall survival (OS). Results: Gender, Karnofsky's performance scores (KPS) and clinical stage seemed to influence the OS. The variant C genotypes were independently associated with significantly improved OS (CT+CC vs. TT: adjusted hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.37-0.92, P = 0.022), compared with the VEGF -460 TT genotype. Conclusions: Our study suggests that VEGF -460 C genotypes may be associated with a better survival of LA-NSCLC patients after chemoradiotherapy. Large studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: Controversy exists regarding the reconstruction of bone defects in Enneking III. This study aimed to use the finite element analysis (FEA) method to clarify (1) the utility of reconstructing the pelvis Enneking III region and (2) the optimal approach for this reconstruction. Methods: FEA models were generated for three types of Enneking III defects in the pelvis, replacing all the defect areas in region III with a sizable solid box for topology optimization (TO). Based on the defect location and TO results, three reconstruction schemes were designed for each type of defect. We subsequently conducted simulations of static FEA under natural walking loads using ANSYS software (version 2022R1, Canonsburg, Pennsylvania, USA). Results: Compared with Scheme A, reconstruction of the Enneking III region (Schemes B and C) led to a more uniform stress distribution and lower peak stress in the pelvis. Moreover, prostheses and screws exhibit decreased peak stress and deformation, with complex reconstruction schemes (C) outperforming simpler ones (B). Conclusions: The FEA results suggest that reconstructing Enneking Zone III defects improves stress distribution and reduces peak stress in the pelvis compared to non-reconstruction, potentially enhancing stability and reducing fracture risks. Complex reconstruction schemes involving more contralateral pelvis regions demonstrate superior biomechanical performance. However, clinical decisions should be individualized, integrating biomechanical insights with comprehensive patient-specific factors. [ABSTRACT FROM AUTHOR]

Background: TGF-β1 is the most abundant cytokine in bone, in which it serves as a vital factor to interdict adipogenesis and osteogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, how TGF-β1 concurrently manipulates differentiation into these two distinct lineages remains elusive. Methods: Treatments with ligands or inhibitors followed by biochemical characterization, reporter assay, quantitative PCR and induced differentiation were applied to MSC line or primary BM-MSCs for signaling dissection. In vivo adipogenesis and ex vivo culture of bone explants were used to verify the functions of different SMAD complexes. Ingenuity Pathway Analysis, and analysis of transcriptomic datasets from human BM-MSCs in combination with hierarchical clustering and STRING assay were used to decipher the interplaying co-repressors. Mouse models of chronic and acute bone loss followed by biochemical assays and micro-computed tomography demonstrated the bone effects when functionally blocking the critical co-repressor HDAC1. Results: Distinct from the TGF-β1 inhibition on adipogenesis through canonical SMAD2/3 signaling, we clarified that TGF-β1 suppresses osteogenesis by inducing the formation of previously unidentified mixed SMADs mainly composed of SMAD1 and SMAD2, in which SMAD2 recruits more TGF-β1-induced co-repressors including HDAC1, TGIF1 and ATF3, whereas SMAD1 allows directing the whole transcriptional suppression complex to the cis-elements of osteogenic genes. Depletion of the cross-activation to the mixed SMADs dismantled specifically the TGF-β1 suppression on osteogenesis without affecting its inhibition on adipogenesis. Such phenomena can be reproduced via knockdown of co-repressors such as Hdac1 or addition of HDAC1 inhibitors in TGF-β1-treated MSCs. In either the chronic or the acute bone loss model, we demonstrated that the TGF-β signaling was augmented in the bone niche during osteolysis, whereas administration of HDAC1 inhibitors significantly improved bone quality. Conclusion: This study identifies a new signal valve through which TGF-β1 can inhibit osteogenesis specifically. Functional interruption of this valve can tilt the seesaw balance of BM-MSC differentiation towards osteogenesis, highlighting the interplaying co-repressors, such as HDAC1, as promising therapeutic targets to combat diverse degenerative orthopedic diseases. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested oxidative stress may play a key role in the pathogenesis of retinopathy, while evidence from observational studies directly linking oxidative biomarkers to clinically relevant outcomes has been limited. This study aims to investigate the association between oxidative balance score (OBS) and prevalence of retinopathy in a nationally representative sample of U.S. adults, including both those with and without diabetes. Methods: Data were obtained from the NHANES 2005–2008, including 3,287 participants. OBS was calculated from 16 dietary and 4 lifestyle components and categorized into tertiles. Weighted logistic regression was used to assess the association between OBS and retinopathy in the overall, diabetic, and non-diabetic populations, and Cox proportional hazards models evaluated the link between OBS and all-cause mortality in those with retinopathy. Restricted cubic spline (RCS) analysis explored the dose-response relationship between OBS and retinopathy. Subgroup analyses and interaction tests were conducted based on age, sex, race, BMI, education level, and diabetes status. Results: Participants in the highest OBS tertile had a 28% lower risk of retinopathy compared to those in the lowest tertile (OR 0.72, 95% CI 0.54–0.95, P = 0.023). RCS analysis showed a significant overall association between higher OBS and reduced retinopathy risk, without a nonlinear pattern. In participants with retinopathy, higher OBS was linked to a 60% reduction in all-cause mortality (HR 0.40, 95% CI 0.24–0.66, P < 0.001). Subgroup analysis revealed stronger inverse associations between OBS and retinopathy in younger individuals and those with higher education, with a significant interaction between OBS and age (P for interaction < 0.05). Conclusion: Our study provides evidence that higher cumulative antioxidant exposure assessed by OBS is associated with a reduced risk and severity of retinopathy and lower all-cause mortality in U.S. adults with retinopathy, highlighting the importance of maintaining a favorable oxidative balance in retinal health. [ABSTRACT FROM AUTHOR]

Fullerenols, a water-soluble polyhydroxy derivative of fullerene, hold promise in medical and materials science due to their unique properties. However, concerns about their potential embryotoxicity remain. Using a pregnancy mouse model and metabolomics analysis, our findings reveal that fullerenols exposure during pregnancy not only significantly reduced mice placental weight and villi thickness, but also altered the classes and concentrations of metabolites in the mouse placenta. Furthermore, we found that fullerenols exposure reduced the levels of CYP3A4, ERα and estriol (E3), while increasing the levels of estradiol (E2) and oxidative stress both in mouse placenta and placental trophoblast cells, and exogenous supplementation with E3 and ER agonists was effective in restoring these changes in vitro. Moreover, CYP3A4 inhibition was effective in decreasing intracellular E3 levels, whereas overexpression of CYP3A4 resisted the fullerenols-induced decrease in E3 expression Additionally, we synthesized glutathione-modified fullerenols (C60-(OH)n-GSH), which demonstrated improved biocompatibility and reduced embryotoxicity by enhancing intracellular glutathione levels and mitigating oxidative stress. In summary, our results demonstrated that fullerenols exposure decreased E3 synthesis by inhibiting CYP3A4 and exacerbated oxidative stress through downregulation of estrogen receptor activation and decreased glutathione levels. These findings highlight the risks of fullerenols exposure during pregnancy and offer strategies for safer nanomaterial development. [ABSTRACT FROM AUTHOR]

Background: Anxiety disorders in older adults have become a prominent public health problem due to their concomitant chronic conditions, reduced quality of life and even death. However, fewer studies have been conducted on differences in anxiety among older individuals in different aged-care models, and the interactive relationship between the influencing factors on anxiety remains unclear. The study aimed to examine the disparities in the prevalence of anxiety between community-dwelling and institutionalized older adults and related influencing factors. Methods: Data were collected from the Anhui Healthy Longevity Survey (AHLS) and the Anhui Elderly Caring Social Organizations Survey (AECSOS). Data on demographic variables, lifestyle factors and health-related variables in 6968 older adults were used for analysis. Anxiety symptoms were evaluated using the Generalized Anxiety Disorder Assessment Scale (GAD-7). Binary logistic regression models and a Classification and Regression Tree model (CART) were utilized to examine the relationship between variables. Results: The prevalence of anxiety were 24.3% and 16.7% among community-dwelling older adults and institutionalized older adults, respectively. Several factors including age, gender, residence, education, income level, live alone, and number of chronic diseases showed a linkage with anxiety among community-dwelling older adults. For the institutionalized older adults, gender, residence, source of income, and number of chronic diseases exhibited a significant association with anxiety. We noted the interactive effect, suggesting that community-dwelling female older adults with an income level of less than 6500 RMB per year and reported chronic disease comorbidities had the highest likelihood of anxiety, and institutionalized female older adults with income sources such as pension, subsidy, family providing, and resident in rural areas have the greatest risk of experiencing anxiety. Conclusions: This study has brought to light the higher risk of anxiety among community-dwelling older adults compared to institutionalized older adults. Targeted interventions are, therefore emphasized to address the negative impact of anxiety for populations at higher risk. [ABSTRACT FROM AUTHOR]

Background: As hypothermic circulatory arrest (HCA) is being more frequently induced in patients undergoing aortic arch surgery, its safety at different degrees has become a crucial area of study. The aim of this study was to assess the surgical outcomes of mild hypothermic circulatory arrest (MI-HCA) during aortic arch surgery. Methods: Acute type A aortic dissection (ATAAD) patients who underwent total arch replacement (TAR) and frozen elephant trunk (FET) surgery between January 2014 and December 2023 were enrolled in this study. The patients were divided into two groups according to the minimum nasopharyngeal temperature: the moderate hypothermic circulatory arrest (MHCA) group (20–28 °C) and the MI-HCA group (> 28 °C). The inverse probability of treatment weighting (IPTW) was used to balance differences in the baseline characteristics. Perioperative variables were analysed via pairwise comparisons, multivariable logistic regression, and subgroup forest plots to assess the impact of MI-HCA on surgical outcomes. Results: A total of 447 patients were included in this study, and the mean minimum nasopharyngeal temperature was 24.80 (23.98, 27.30) °C in the MHCA group and 30.10 (29.80, 30.70) °C in the MI-HCA group. The incidence of acute kidney injury (AKI) in the MI-HCA group was lower than that in the MHCA group (52% vs. 78%, p < 0.01). In the multivariable logistic regression analysis, MI-HCA was identified as an independent protective factor for AKI (OR = 0.354, 95% CI 0.177–0.689; p = 0.003). Additionally, compared with MHCA, MI-HCA was not associated with an increased incidence of stroke, spinal cord injury, or in-hospital mortality. After IPTW, the preoperative and intraoperative data of the patients were balanced, and the incidence of AKI in the MI-HCA group was still lower than that in the MHCA group (83.26% vs. 53.61%, p = 0.004). The subgroup forest plot also demonstrated that MI-HCA was a protective factor for postoperative AKI. Conclusions: The surgical outcomes of MI-HCA in ATAAD patients were satisfactory. Compared with MHCA, MI-HCA provided sufficient protection for distal organs, the brain, and the spinal cord, with a significantly lower incidence of AKI. These results indicate that MI-HCA could be a better approach for ATAAD surgery. [ABSTRACT FROM AUTHOR]

Background and objective: Accurate identification and prioritization of driver-mutations in cancer is critical for effective patient management. Despite the presence of numerous bioinformatic algorithms for estimating mutation pathogenicity, there is significant variation in their assessments. This inconsistency is evident even for well-established cancer driver mutations. This study aims to develop an ensemble machine learning approach to evaluate the performance (rank) of pathogenic and conservation scoring algorithms (PCSAs) based on their ability to distinguish pathogenic driver mutations from benign passenger (non-driver) mutations in head and neck squamous cell carcinoma (HNSC). Methods: The study used a dataset from 502 HNSC patients, classifying mutations based on 299 known high-confidence cancer driver genes. Missense somatic mutations in driver genes were treated as driver mutations, while non-driver mutations were randomly selected from other genes. Each mutation was annotated with 41 PCSAs. Three machine learning algorithms—logistic regression, random forest, and support vector machine—along with recursive feature elimination, were used to rank these PCSAs. The final ranking of the PCSAs was determined using rank-average-sort and rank-sum-sort methods. Results: The random forest algorithm emerged as the top performer among the three tested ML algorithms, with an AUC-ROC of 0.89, compared to 0.83 for the other two, in distinguishing pathogenic driver mutations from benign passenger mutations using all 41 PCSAs. The top 11 PCSAs were selected based on the first quintile cut-off from the final rank-sum distribution. Classifiers built using these top 11 PCSAs (DEOGEN2, Integrated_fitCons, MVP, etc.) demonstrated significantly higher performance (p-value < 2.22e-16) compared to those using the remaining 30 PCSAs across all three ML algorithms, in separating pathogenic driver from benign passenger mutations. The top PCSAs demonstrated strong performance on a validation cohort including independent HNSC and other cancer types: breast, lung, and colorectal - reflecting its consistency, robustness and generalizability. Conclusions: The ensemble machine learning approach effectively evaluates the performance of PCSAs based on their ability to differentiate pathogenic drivers from benign passenger mutations in HNSC and other cancer types. Notably, some well-known PCSAs performed poorly, underscoring the importance of data-driven selection over relying solely on popularity. [ABSTRACT FROM AUTHOR]

Background: Fourier transform infrared spectroscopy (FTIR) is an analytical technique increasingly applied in biological analysis. This study investigates the application of FTIR to identify early biochemical changes, particularly in lipid profiles, in individuals undergoing Roux-en-Y gastric bypass (RYGB). Methods: An observational study involving patients from a university hospital's Bariatric and Metabolic Surgery Program, with evaluations performed before (T0) and two months after (T1) RYGB. Biochemical parameters, anthropometric data, and body composition were assessed. FTIR spectra were pre-processed and analyzed using Principal Component Analysis and Partial Least Squares Discriminant Analysis. The normality of the data was evaluated using the Kolmogorov-Smirnov test, followed by paired T-tests or Wilcoxon tests as appropriate. Spearman correlation analysis of spectral information with biochemical parameters was also performed. A significance level of p < 0.05 was set for all tests. The university hospital's Research Ethics Committee approved the study (protocol CAAE 59075722.7.0000.5071). Results: The study evaluated 29 individuals (86.2% female) with a mean age of 41.2 ± 7.8 years. Significant differences were observed in anthropometric parameters and body composition (p < 0.001). Additionally, early improvements in the lipid profile were noted, with significant decreases in triglycerides, total cholesterol, and LDL cholesterol (p < 0.05) just two months post-surgery. FTIR identified correlations between biochemical parameters and specific spectral regions at T0 and T1. Notably, serum triglycerides showed a significant correlation with the lipid-specific spectral region (1796–1685 cm− 1) at both time points (p < 0.05). Conclusion: FTIR can effectively monitor biochemical changes in RYGB surgery patients. The spectral range associated with lipid functional groups (1796 –1675 cm⁻¹) showed a significant relationship with serum triglyceride levels before and after RYGB. Additionally, various biochemical parameters exhibited strong correlations with other spectral regions, implying that the serum spectral profile can indicate biochemical variations at different post-surgery stages. Trial registration: Brazilian Registry of Clinical Trials (Rebec), September 5, 2022, protocol RBR-26chs2g. [ABSTRACT FROM AUTHOR]

Over the past two decades, the study of sperm-borne small non-coding RNAs (sncRNAs) has garnered substantial growth. Once considered mere byproducts during germ cell maturation, these sncRNAs have now been recognized as crucial carriers of epigenetic information, playing a significant role in transmitting acquired traits from paternal to offspring, particularly under environmental influences. A growing body of evidence highlights the pivotal role of these sncRNAs in facilitating epigenetic inheritance across generations. However, the exact mechanisms through which these paternally supplied epigenetic carriers operate remain unclear and are under hot debate. This concise review presents the most extensive evidence to date on environmentally-responsive sperm-borne sncRNAs, encompassing brief summary of their origin, dynamics, compartmentalization, characteristics, as well as in-depth elaboration of their functional roles in epigenetic and transgenerational inheritance. Additionally, the review delves into the potential mechanisms by which sperm-delivered sncRNAs may acquire and transmit paternally acquired traits to offspring, modulating zygotic gene expression and influencing early embryonic development. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs often fail to provide long-term efficacy due to their lack of specificity and high toxicity. To enhance the biosafety and reduce the side effects of these drugs, various nanocarrier delivery systems have been developed. In this study, we loaded the anticancer drug doxorubicin (DOX) and an MRI contrast agent into silica nanoparticles, coating them with pH-responsive and tumor cell-targeting polymers. These polymers enable the carrier to achieve targeted delivery and controlled drug release in acidic environments. This integrated diagnostic and therapeutic strategy successfully achieved both the diagnosis and treatment of liver cancer. Additionally, we demonstrated that the nanocarrier inhibits autophagic flux in liver cancer cells by targeting the autophagy-lysosome pathway and regulating the nuclear translocation of TFEB, thereby promoting tumor cell death. This novel diagnostic-integrated nanocarrier is expected to be a promising tool for targeted liver cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Methods: Adult patients with mIDH1R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Results: Sixty-seven patients with R/R mIDH1R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event. Conclusions: Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy. Trial registration: NCT02719574. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the predictive accuracy of 11 intraocular lens (IOL) calculation formulas in eyes with an axial length (AL) less than 22.00 mm. Methods: New-generation formulas (Barrett Universal II [BUII], Emmetropia Verifying Optical [EVO] 2.0, Hill-Radial Basis Function [Hill-RBF] 3.0, Hoffer QST, K6, Kane, Pearl-DGS) and traditional formulas (Haigis, Hoffer Q, Holladay 1 and SRK/T) were evaluated for predictive accuracy. Subgroup analyses were performed based on AL and anterior chamber depth (ACD). Results: The study enrolled a total of 184 eyes from 184 patients. The BUII, Hoffer QST, Hoffer Q, Holladay 1, and SRK/T showed myopic shifts (-0.49 to -0.18 diopters [D], P < 0.05), whereas K6 displayed a hyperopic shift (0.11 D, P = 0.03). The Kane exhibited no systematic bias (-0.07 D), and yielded lower mean absolute error (MAE) (0.48 D, P < 0.05) and root mean square absolute error (RMSAE) (0.65 D, P < 0.01). For eyes with an AL ≤ 21.5 mm and an ACD > 2.5 mm, the Pearl-DGS displayed the smallest MAE (0.43 D) and lowest RMSAE (0.57 D), while other new-generation formulas showed relatively worse performance (MAE: 0.46 to 0.67 D; RMSAE: 0.60 to 0.84 D). Conclusion: The Kane formula showed the highest accuracy in short eyes, whereas the Pearl-DGS had superior performance in eyes with a relatively shorter AL and deeper ACD. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, a potential traumatic stressor, may be accompanied by positive changes, such as post-traumatic growth (PTG), which may allow patients to overcome this stressful event more easily. Our aim was to identify factors associated with PTG in breast cancer survivors (BCSs). Methods: We conducted a cross-sectional study in Seintinelles volunteers who answered online questionnaires. PTG was measured using the Post-Traumatic Growth Inventory (PTGI). Data on sociodemographic, health-related factors and lifestyle habits, fear of cancer recurrence, health locus of control, coping strategies, and time perspective were collected. Results: The study included 821 BCSs aged 26 to 79 years, one to 16 years after cancer diagnosis. Mean of PTG scores were: relating to others 20.27 ± 6.61; new possibilities 14.00 ± 5.44; personal strength 12.24 ± 4.32; spiritual change 2.95 ± 2.54; appreciation of life 10.59 ± 3.00 and total PTG 60.05 ± 18.11. Several factors were associated with PTG: health-related factors (satisfaction with one's own health, longer time since diagnosis), lifestyle habits (increasing physical activity level and stopping or reducing alcohol consumption after diagnosis), elements of locus of control (powerful others), coping strategies (positive thinking, seeking social support) and time perspective (present hedonistic), which were significantly positively associated with PTG. Chance locus of control and coping avoidance were inversely related to several PTG domains, even several years after diagnosis. Conclusions: PTG may be increased in BCSs by acting on its modifiable factors. This includes adopting healthy behaviours, such as increasing physical activity and stopping/reducing alcohol consumption, and developing locus of control elements, such as powerful others, and coping strategies, such as positive thinking and seeking social support, through targeted interventions. Further studies, especially longitudinal studies, are needed to confirm the observed associations between health behaviours, health locus of control, time perspective, and PTG scores. Other measures, such as post-traumatic stress, should be considered because of possible inferences with PTG. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence shows that small nucleolar RNA (snoRNA), a type of highly conserved non-coding RNA, is involved in tumorigenesis and aggressiveness. However, the roles of snoRNAs in regulating alternative splicing crucial for cancer progression remain elusive. Methods: High-throughput RNA sequencing and comprehensive analysis were performed to identify crucial snoRNAs and downstream alternative splicing events. Biotin-labeled RNA pull-down, mass spectrometry, cross-linking RNA immunoprecipitation, and in vitro binding assays were applied to explore interaction of snoRNAs with protein partners. Alternative splicing and gene expression was observed by real-time quantitative RT-PCR and western blot assays. In vitro and in vivo studies were performed to investigate biological effects of snoRNAs and their protein partners in gastric cancer. Survival analysis was undertaken by using Kaplan-Meier method and log-rank test. Results: SNORA37 was identified as an up-regulated snoRNA essential for tumorigenesis and aggressiveness of gastric cancer. Gain- and loss-of-function studies indicated that SNORA37 promoted the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, as an ELAV like RNA binding protein 1 (ELAVL1)-generated snoRNA, SNORA37 directly bound to cap methyltransferase 1 (CMTR1) to facilitate its interaction with ELAVL1, resulting in nuclear retention and activity of ELAVL1 in regulating alternative splicing of CD44. Rescue studies revealed that SNORA37 exerted oncogenic roles in gastric cancer progression via facilitating CMTR1-ELAVL1 interaction. In clinical gastric cancer cases, high levels of SNORA37, CMTR1, ELAVL1, or CD44 were associated with shorter survival and poor outcomes of patients. Conclusions: These results indicated that SNORA37/CMTR1/ELAVL1 feedback loop drives gastric cancer progression via facilitating CD44 alternative splicing. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy. This study aimed to investigate the expression and prognostic significance of a key epigenetic complex encompassing DNA methyltransferase-1 (DNMT1), the histone methyltransferase G9a, and the scaffold protein UHRF1 in PDAC. We also evaluated the therapeutic potential of an innovative inhibitor targeting these epigenetic effectors. Methods: Immunohistochemical analysis of DNMT1, G9a, and UHRF1 expression was conducted in human PDAC tissue samples. Staining was semi-quantitatively scored, and overexpression was defined as moderate to strong positivity. The prognostic impact was assessed by correlating protein expression with patient survival. The antitumoral effects of the dual DNMT1-G9a inhibitor CM272 were tested in PDAC cell lines, followed by transcriptomic analyses to identify underlying mechanisms. The in vivo antitumoral efficacy of CM272 was evaluated in PDAC xenograft and syngeneic mouse models, both alone and in combination with anti-PD1 immunotherapy. Results: DNMT1, G9a, and UHRF1 were significantly overexpressed in PDAC cells and stroma compared to normal pancreatic tissues. Simultaneous overexpression of the three proteins was associated with significantly reduced survival in resected PDAC patients. CM272 exhibited potent antiproliferative activity in PDAC cell lines, inducing apoptosis and altering key metabolic and cell cycle-related genes. CM272 also enhanced chemotherapy sensitivity and significantly inhibited tumor growth in vivo without detectable toxicity. Combination of CM272 with anti-PD1 therapy further improved antitumor responses and immune cell infiltration, particularly CD4 + and CD8 + T cells. Conclusions: The combined overexpression of DNMT1, G9a, and UHRF1 in PDAC is a strong predictor of poor prognosis. CM272, by targeting this epigenetic complex, shows promising therapeutic potential by inducing apoptosis, reprogramming metabolic pathways, and enhancing immune responses. The combination of CM272 with immunotherapy offers a novel, effective treatment strategy for PDAC. [ABSTRACT FROM AUTHOR]

Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences. In our institutional database, we identified 22 patients with targeted exome sequencing of pairs of initial and recurrent IDH-wildtype glioblastoma. Recurrences were classified as contiguous or discontiguous based on the presence or absence of T2 FLAIR signal connection to the initial site of disease on MRI. Exome analysis revealed shared driver and passenger mutations between discontiguous recurrences and initial tumors, supporting a common origin. Discontiguous recurrences were more likely to be hypermutated compared to contiguous recurrences (p = 0.038). Analysis of 2 glioblastoma cases with discontiguous recurrence at a collaborating institution also exhibited hypermutation. In conclusion, discontiguous glioblastoma recurrences share a common origin with the initial tumor and are more likely to be hypermutated than contiguous recurrences. [ABSTRACT FROM AUTHOR]

Background: Chlamydia is common among women of reproductive age and can cause serious health issues. This study aimed to examine the trends and factors linked to newly diagnosed and reported chlamydia cases in women aged 15–49 in Guangdong Province from 2006 to 2020. Methods: We included all newly diagnosed and reported chlamydia cases from January 1, 2006, to December 31, 2020. Data from 21 cities in Guangdong Province were sourced from the National Notifiable Infectious Disease Reporting Information System in China. Temporal trends were analyzed using Joinpoint regression models. City-level factors (population density, net migration rate, and male-to-female sex ratio) were derived from the Guangdong Statistical Yearbook and the Guangdong Health and Family Planning Statistical Yearbook. Quasi-Poisson regression models were used to explore the relationship between sociodemographic factors and chlamydia incidence. Results: From 2006 to 2020, 523,367 new chlamydia cases were reported among women of reproductive age in Guangdong. The mean reported rate was 122.6 per 100,000 population over 15 years, significantly increasing from 1.4 in 2006 to 179.7 in 2020 (average annual percent change [AAPC] = 47.4%, 95% CI: 42.8%-52.2%, P < 0.05). The highest rate was 196.8 per 100,000 population in 2019. Among older women, 9,045 cases were reported, with a mean reported rate of 4.9 per 100,000, rising significantly from 0.01 in 2006 to 9.6 in 2020 (AAPC = 52.6%, 95% CI: 30.3%-78.8%, P < 0.05). The reported rate among women of reproductive age correlated with the net migration rate (RR = 1.2; 95% CI: 1.2–1.3) and the ratio of those participating in child-bearing insurance to the permanent population (RR = 1.5; 95% CI: 1.4–1.6). Conclusion: The reported rate of new chlamydia cases among women of reproductive age was significantly higher than among older adults and increased markedly from 2006 to 2020. These findings underscore the urgent need for targeted prevention strategies for women of reproductive age. [ABSTRACT FROM AUTHOR]

Background: Environmental exposures such as airborne pollutant exposures and socio-economic indicators are increasingly recognized as important to consider when conducting clinical research using electronic health record (EHR) data or other sources of clinical data such as survey data. While numerous public sources of geospatial and spatiotemporal data are available to support such research, the data are challenging to work with due to inconsistencies in file formats and spatiotemporal resolutions, computational challenges with large file sizes, and a lack of tools for patient- or subject-level data integration. Results: We developed FHIR PIT (HL7® Fast Healthcare Interoperability Resources Patient data Integration Tool) as an open-source, modular, data-integration software pipeline that consumes EHR data in FHIR® format and integrates the data at the level of the patient or subject with environmental exposures data of varying spatiotemporal resolutions and file formats. We applied FHIR PIT to generate "integrated feature tables" containing patient- or subject-level EHR data integrated with environmental exposures data on two cohorts: one on patients with asthma and related common pulmonary disorders; and a second on patients with primary ciliary dyskinesia and related rare pulmonary disorders. The data were then exposed via the open Integrated Clinical and Environmental Exposures Service, which was then queried to explore relationships between exposures to two representative airborne pollutants (particulate matter and ozone) and annual emergency department or inpatient visits for respiratory issues. We found that hospitalizations for respiratory issues were more common among patients exposed to relatively high levels of particulate matter and ozone and were higher overall among patients with primary ciliary dyskinesia than among patients with asthma. Conclusions: Our manuscript describes a major release of FHIR PIT v1.0 and includes a technical demonstration use case and a clinical application on the use of FHIR PIT to support research on environmental exposures and health outcomes related to asthma and primary ciliary dyskinesia. For application of the tool to common data models (CDMs) other than FHIR, we offer open-source conversion tools to map from the PCORnet, i2b2, and OMOP CDMs to FHIR. [ABSTRACT FROM AUTHOR]

Background: Existing fall risk assessment tools in clinical settings often lack accuracy. Although an increasing number of fall risk prediction models have been developed for hospitalized older patients in recent years, it remains unclear how useful these models are for clinical practice and future research. Objectives: To systematically review published studies of fall risk prediction models for hospitalized older adults. Methods: A search was performed of the Web of Science, PubMed, Cochrane Library, CINAHL, MEDLINE, and Embase databases: to retrieve studies of predictive models related to falls in hospitalized older adults from their inception until January 11, 2024. Extraction of data from included studies, including study design, data sources, sample size, predictors, model development and performance, etc. Risk of bias and applicability were assessed using the Prediction Model Risk of Bias Assessment Tool (PROBAST) checklist. Results: A total of 8086 studies were retrieved, and after screening, 13 prediction models from 13 studies were included. Four models were externally validated. Eight models reported discrimination metrics and two models reported calibration metrics. The most common predictors of falls were mobility, fall history, medications, and psychiatric disorders. All studies indicated a high risk of bias, primarily due to inadequate study design and methodological flaws. The AUC values of 8 models ranged from 0.630 to 0.851. Conclusions: In the present study, all included studies had a high risk of bias, primarily due to the lack of prospective study design, inappropriate data analysis, and the absence of robust external validation. Future studies should prioritize the use of rigorous methodologies for the external validation of fall risk prediction models in hospitalized older adults. Trial registration: The study was registered in the International Database of Prospectively Registered Systematic Reviews (PROSPERO) CRD42024503718. [ABSTRACT FROM AUTHOR]

This review highlights recent progress in exosome-based drug delivery for cancer therapy, covering exosome biogenesis, cargo selection mechanisms, and their application across multiple cancer types. As small extracellular vesicles, exosomes exhibit high biocompatibility and low immunogenicity, making them ideal drug delivery vehicles capable of efficiently targeting cancer cells, minimizing off-target damage and side effects. This review aims to explore the potential of exosomes in cancer therapy, with a focus on applications in chemotherapy, gene therapy, and immunomodulation. Additionally, challenges related to exosome production and standardization are analyzed, highlighting the importance of addressing these issues for their clinical application. In conclusion, exosome-based drug delivery systems offer promising potential for future cancer therapies. Further research should aim to enhance production efficiency and facilitate clinical translation, paving the way for innovative cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) with a global prevalence of 30% is multifactorial and the involvement of gut bacteria has been recently proposed. However, finding robust bacterial signatures of NAFLD has been a great challenge, mainly due to its co-occurrence with other metabolic diseases. Results: Here, we collected public metagenomic data and integrated the taxonomy profiles with in silico generated community metabolic outputs, and detailed clinical data, of 1206 Chinese subjects w/wo metabolic diseases, including NAFLD (obese and lean), obesity, T2D, hypertension, and atherosclerosis. We identified highly specific microbiome signatures through building accurate machine learning models (accuracy = 0.845–0.917) for NAFLD with high portability (generalizable) and low prediction rate (specific) when applied to other metabolic diseases, as well as through a community approach involving differential co-abundance ecological networks. Moreover, using these signatures coupled with further mediation analysis and metabolic dependency modeling, we propose synergistic defined microbial consortia associated with NAFLD phenotype in overweight and lean individuals, respectively. Conclusion: Our study reveals robust and highly specific NAFLD signatures and offers a more realistic microbiome-therapeutics approach over individual species for this complex disease. E4koFqVmYng21Zwjp47efA Video Abstract [ABSTRACT FROM AUTHOR]

Background: A systematic appraisal of the comparative efficacy and safety profiles of naso-intestinal tube versus gastric tube feeding in the context of enteral nutrition for mechanically ventilated (MV) patients is imperative. Such an evaluation is essential to inform clinical practice, ensuring that the chosen method of nutritional support is both optimal and safe for this patient population. Methods: We executed an exhaustive search across PubMed et al. databases to identify randomized controlled trials (RCTs) that scrutinize the role of naso-intestinal and gastric tubes for mechanically ventilated (MV) patients up to May 30, 2024. The process of study selection, quality assessment, and data extraction was conducted independently by two researchers. RevMan 5.3 software was used for meta-analysis. Results: Our meta-analysis included 8 RCTs, published between 1992 and 2018, encompassing a total of 676 MV patients. The results indicated that naso-intestinal tube feeding, compared to gastric tube feeding, was associated with a significant reduction in the incidence of ventilator-associated pneumonia (VAP) [Risk Ratio (RR) = 0.69, 95% confidence interval (CI) (0.52, 0.92)] and gastric retention (RR = 0.11, 95% CI (0.04, 0.28)). No statistically significant differences were observed in the incidence of aspiration (RR = 0.93, 95% CI (0.35, 2.50)) vomiting (RR = 0.70, 95% CI (0.23, 2.08)), abdominal distension (RR = 0.87, 95% CI (0.29, 2.63)), or diarrhea (RR = 1.10, 95% CI (0.77, 1.55)). Conclusions: The current evidence indicates that naso-intestinal tube feeding is efficacious in lowering the incidence of VAP and gastric retention among MV patients, without a corresponding escalation in the risk of adverse events, including aspiration, vomiting, abdominal distension, and diarrhea. These insights significantly augment the existing corpus of knowledge pertaining to the optimization of enteral nutrition strategies for patients on mechanical ventilation. [ABSTRACT FROM AUTHOR]

Background: HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention. Methods: The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness. Results: CRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs. Conclusions: These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations. [ABSTRACT FROM AUTHOR]

Background: Polygalacturonase inhibiting proteins (PGIPs) play a pivotal role in plant defense against plant pathogens by inhibiting polygalacturonase (PG), an enzyme produced by pathogens to degrade plant cell wall pectin. PGIPs, also known as leucine-rich repeat pathogenesis-related (PR) proteins, activate the host's defense response upon interaction with PG, thereby reinforcing the host defense against plant pathogens attacks. In Egyptian or extra-long staple cotton (Gossypium barbadense), the interaction between PGIP and PG is one of the crucial steps in the defense mechanism against major pathogens such as Xanthomonas citri pv. malvacearum and Alternaria macrospora, which are responsible for bacterial leaf blight and leaf spot diseases, respectively. Results: To unravel the molecular mechanisms underlying these PR proteins, we conducted a comprehensive study involving molecular modeling, protein-protein docking, site-specific double mutation (E169G and F242K), and molecular dynamics simulations. Both wild-type and mutated cotton PGIPs were examined in the interaction with the PG enzyme of a bacterial and fungal pathogen. Our findings revealed that changes in conformations of double-mutated residues in the active site of PGIP lead to the inhibition of PG binding. The molecular dynamics simulation studies provide insights into the dynamic behaviour and stability of the PGIP-PG complexes, shedding light on the intricate details of the inhibitory and exhibitory mechanism against the major fungal and bacterial pathogens of G. barbadense, respectively. Conclusions: The findings of this study not only enhance our understanding of the molecular interactions between PGs of Xanthomonas citri pv. malvacearum and Alternaria macrospora and PGIP of G. barbadense but also present a potential strategy for developing the disease-resistant cotton varieties. By variations in the binding affinities of PGs through specific mutations in PGIP, this research offers promising avenues for the development of enhanced resistance to cotton plants against bacterial leaf blight and leaf spot diseases. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, characterized by its poor prognosis. Glycolipid metabolism is strongly associated with GBM development and malignant behavior. However, the precise functions of snoRNAs and ADARs in glycolipid metabolism within GBM cells remain elusive. The objective of the present study is to delve into the underlying mechanisms through which snoRNAs and ADARs exert regulatory effects on glycolipid metabolism in GBM cells. Methods: RNA immunoprecipitation and RNA pull-down experiments were conducted to verify the homodimerization of ADAR2 by SNORD113-3, and Sanger sequencing and Western blot experiments were used to detect the A-to-I RNA editing of PHKA2 mRNA by ADAR2. Furthermore, the phosphorylation of EBF1 was measured by in vitro kinase assay. Finally, in vivo studies using nude mice confirmed that SNORD113-3 and ADAR2 overexpression, along with PHKA2 knockdown, could suppress the formation of subcutaneous xenograft tumors and improve the outcome of tumor-bearing nude mice. Results: We found that PHKA2 in GBM significantly promoted glycolipid metabolism, while SNORD113-3, ADAR2, and EBF1 significantly inhibited glycolipid metabolism. SNORD113-3 promotes ADAR2 protein expression by promoting ADAR2 homodimer formation. ADAR2 mediates the A-to-I RNA editing of PHKA2 mRNA. Mass spectrometry analysis and in vitro kinase testing revealed that PHKA2 phosphorylates EBF1 on Y256, reducing the stability and expression of EBF1. Furthermore, direct binding of EBF1 to PKM2 and ACLY promoters was observed, suggesting the inhibition of their expression by EBF1. These findings suggest the existence of a SNORD113-3/ADAR2/PHKA2/EBF1 pathway that collectively regulates the metabolism of glycolipid and the growth of GBM cells. Finally, in vivo studies using nude mice confirmed that knockdown of PHKA2, along with overexpression of SNORD113-3 and ADAR2, could obviously suppress GBM subcutaneous xenograft tumor formation and improve the outcome of those tumor-bearing nude mice. Conclusions: Herein, we clarified the underlying mechanism involving the SNORD113-3/ADAR2/PHKA2/EBF1 pathway in the regulation of GBM cell growth and glycolipid metabolism. Our results provide a framework for the development of innovative therapeutic interventions to improve the prognosis of patients with GBM. [ABSTRACT FROM AUTHOR]

Background: The stability of soft and hard tissues surrounding the implant is not only a matter of aesthetics, but also affects the long-term stability of the implant. The present study was to explore the influence of buccal mucosa width/height (W/H) ratio, emergence profile and buccal bone width on peri-implant soft and hard tissue changes in the posterior region. Methods: Fifty-eight posterior implant restoration cases were recruited in this study. Evaluations were performed at the time of restoration placement (T0), and 1 year later (T1). Buccal mucosa width (BMW), buccal bone width (BBW), implant buccal inclination angle, and emergence angle were evaluated. The variables that may affect buccal mucosa recession (MR) as well as vertical bone loss (VBL) were analyzed. Results: The BMW at baseline was 2.93 ± 1.01 mm. The BBW at baseline was 1.50 ± 0.82 mm. The buccal mucosa W/H ratio at 1 year (1.23 ± 0.38) was significantly lower than that at baseline (1.42 ± 0.45). Buccal MR was − 0.22 ± 0.47 mm while VBL was 0.81 ± 0.80 mm. The correlation between MR and initial BMW (r=-0.381), initial W/H ratio (r=-0.422), BBW (r=-0.290) was statistically significant. The correlation between VBL and initial BMW (r=-0.421), initial W/H ratio (r=-0.305), implant buccal inclination angle (r = 0.507), BBW (r=-0.556) was statistically significant. Conclusions: Within the scope of this study, implant sites in the posterior region presenting a thin BMW, a thin BBW, and a small W/H ratio are more prone to exhibit buccal mucosa recession and vertical bone loss. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming. Key points: Refining the key regulatory factors and their mechanisms within the complex network of tumor metabolic reprogramming. Depicting the metabolic crosstalk between tumor cells, immune cells, and tumor stromal cells during tumor progression. Emphasizing the unresolved challenges of metabolic therapy in clinical translation and the advantages of personalized treatment. Providing theoretical support and research direction for new strategies for metabolic therapies. [ABSTRACT FROM AUTHOR]

Background: Natural language processing (NLP) enables the extraction of information embedded within unstructured texts, such as clinical case reports and trial eligibility criteria. By identifying relevant medical concepts, NLP facilitates the generation of structured and actionable data, supporting complex tasks like cohort identification and the analysis of clinical records. To accomplish those tasks, we introduce a deep learning-based and lexicon-based named entity recognition (NER) tool for texts in Spanish. It performs medical NER and normalization, medication information extraction and detection of temporal entities, negation and speculation, and temporality or experiencer attributes (Age, Contraindicated, Negated, Speculated, Hypothetical, Future, Family_member, Patient and Other). We built the tool with a dedicated lexicon and rules adapted from NegEx and HeidelTime. Using these resources, we annotated a corpus of 1200 texts, with high inter-annotator agreement (average F1 = 0.841% ± 0.045 for entities, and average F1 = 0.881% ± 0.032 for attributes). We used this corpus to train Transformer-based models (RoBERTa-based models, mBERT and mDeBERTa). We integrated them with the dictionary-based system in a hybrid tool, and distribute the models via the Hugging Face hub. For an internal validation, we used a held-out test set and conducted an error analysis. For an external validation, eight medical professionals evaluated the system by revising the annotation of 200 new texts not used in development. Results: In the internal validation, the models yielded F1 values up to 0.915. In the external validation with 100 clinical trials, the tool achieved an average F1 score of 0.858 (± 0.032); and in 100 anonymized clinical cases, it achieved an average F1 score of 0.910 (± 0.019). Conclusions: The tool is available at https://claramed.csic.es/medspaner. We also release the code (https://github.com/lcampillos/medspaner) and the annotated corpus to train the models. [ABSTRACT FROM AUTHOR]

The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy. Myeloid-derived suppressor cells (MDSCs), due to their potent immunosuppressive capabilities, emerged as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells. In addition to their immunosuppressive functions, MDSCs also promote tumor growth and metastasis through non-immunological mechanisms, such as angiogenesis and the formation of pre-metastatic niches. Consequently, MDSCs in the TME are key regulators of cancer immune responses and potential therapeutic targets in cancer treatment. This review describes the origins and phenotypes of MDSCs, their biological roles in tumor progression, and regulatory mechanisms, with a focus on current therapeutic approaches targeting tumor-associated MDSCs. Furthermore, the synergistic effects of targeting MDSCs in combination with immunotherapy are explored, aiming to provide new insights and directions for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Malaria incidence in the Greater Mekong Subregion has been on the decline, and most remaining malaria risk in the region is concentrated among hard-to-reach populations, especially those with exposure to forested areas. New vector control tools focused on outdoor protection in forest settings are needed for these populations. Methods: The delivery of a 'forest pack' containing a volatile pyrethroid spatial repellent (VPSR), a topical repellent, and pyrethroid treatment of clothing was evaluated in an operational study in Cambodia. Costs were collected using micro-costing approaches and the cost of distribution for the 'forest pack' was estimated using standard economic evaluation approaches and examined in sensitivity analyses. Results: The cost per eligible person (the target population) per malaria season for the whole pack was estimated to be 138 USD, which was nearly entirely driven by the cost of the products. Conclusions: Modifications to the 'forest pack' including adding a longer-lasting spatial repellent product or a reduced-cost topical repellent could significantly reduce the cost of pack distribution over the course of a malaria season. [ABSTRACT FROM AUTHOR]

Background: Parental migration plays a significant role in shaping the health outcomes of left-behind children. However, limited research has been conducted on how parental migration impacts the dental health of these children in China. To address this gap, this study aims to investigate the effects of parental migration on the dental health of left-behind children and explore the underlying mechanisms that contribute to these outcomes. Methods: This study utilized data from the first wave of the China Education Panel Survey (CEPS), which included a representative sample of 9,175 junior high school students. Dental caries, the most common dental issue among school-aged children, were employed as the primary indicator of oral health, focusing on both the presence of caries and their treatment. The analysis incorporated multiple methodologies, including the Ordinary Least Squares (OLS) model, instrumental variables approach, and the Propensity Score Matching (PSM) method, to assess the impact of parental migration on the dental health of left-behind children. Results: The findings indicated that parental migration did not increase the likelihood of left-behind children developing dental caries. However, it significantly reduced the probability of these children receiving treatment for dental caries. These results were consistent across various robustness tests. Mechanism analysis revealed no significant differences in the consumption of carbonated or sugary drinks between left-behind and non-left-behind children. However, left-behind children were less likely to identify their parents as their primary source of support and experienced lower levels of proactive communication from parents about their challenges compared to their peers. Conclusions: The study highlights that although parental migration does not increase the prevalence of dental caries among left-behind children, it contributes to inequities in their access to treatment. Given the serious implications of untreated dental caries, targeted efforts are needed to improve treatment rates among left-behind children. [ABSTRACT FROM AUTHOR]

Summary: Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes. Thus, the review delves into the mechanisms by which HIF-1 maintains its stability under normoxia including but not limited to giving insights into transcriptional, translational, as well as posttranslational regulation to underscore the pivotal role of HIF-1 in cellular adaptation and malignancy. Moreover, HIF-1 is extensively involved in cancer and cardiovascular diseases and potentially serves as a bridge between them. An overview of HIF-1-related drugs that are approved or in clinical trials is summarized, highlighting their potential capacity for targeting HIF-1 in cancer and cardiovascular toxicity related to cancer treatment. The review provides a comprehensive insight into HIF-1's regulatory mechanism and paves the way for future research and therapeutic development. [ABSTRACT FROM AUTHOR]

Background: The study aimed to was to investigate the relationship between miR-2861, miR-5011-5p, and colorectal carcinogenesis. Method: In the present study, it was isolated RNA from both the tumor and non-tumor tissue of a total of 80 CRC patients and after synthesizing the cDNA, it was performed qRT-PCR to determine the expression levels of miR‑2861 and miR‑5011-5p. In addition, it was predicted that dysregulated miRNAs targets, pathways and functional gene annotations that may be important in colorectal carcinogenesis using KEGG pathway and GO analysis. Results: The resulting data revealed that both expression levels of miR-2861 and miR-5011-5p were significantly decreased in tumor tissues compared with non-tumor tissues of CRC patients. The GO and KEGG pathway analysis showed that miR-2861 and miR-5011-5p may participate in multiple the biological process, cellular components, and molecular function subcategories such as mitotic cell cycle, regulation of small GTPase mediated signal transduction, cell death, and acid binding transcription factor activity. It was also revealed that target genes of miRNAs can be found in signaling pathways such as TGF-beta, Rap1, Ras, cAMP, Wnt, mTOR and, PI3K-Akt signaling pathways. Conclusion: These findings imply that miR-2861 and miR-5011-5p might function as tumor suppressors in the development of CRC. [ABSTRACT FROM AUTHOR]

Background and purpose: White matter hyperintensities in brain MRI are key indicators of various neurological conditions, and their accurate segmentation is essential for assessing disease progression. This study aims to evaluate the performance of a 3D convolutional neural network and a 3D Transformer-based model for white matter hyperintensities segmentation, focusing on their efficacy with limited datasets and similar computational resources. Materials and methods: We implemented a convolution-based model (3D ResNet-50 U-Net with spatial and channel squeeze & excitation) and a Transformer-based model (3D Swin Transformer with a convolutional stem). The models were evaluated on two clinical datasets from Kaohsiung Chang Gung Memorial Hospital and National Center for High-Performance Computing. Four metrics were used for evaluation: Dice similarity coefficient, lesion segmentation, lesion F1-Score, and lesion sensitivity. Results: The Transformer-based model, with appropriate adjustments, outperformed the well-established convolution-based model in foreground Dice similarity coefficient, lesion F1-Score, and sensitivity, demonstrating robust segmentation accuracy. DRLoc enhanced the Transformer's performance, achieving comparable results on internal and benchmark datasets despite limited data availability. Conclusion: With comparable computational overhead, a Transformer-based model can surpass a well-established convolution-based model in white matter hyperintensities segmentation on small datasets by capturing global context effectively, making them suitable for clinical applications where computational resources are constrained. [ABSTRACT FROM AUTHOR]

Background: In this work, we implement a data-driven approach using an aggregation of several analytical methods to study the characteristics of COVID-19 daily infection and death time series and identify correlations and characteristic trends that can be corroborated to the time evolution of this disease. The datasets cover twelve distinct countries across six continents, from January 22, 2020 till March 1, 2022. This time span is partitioned into three windows: (1) pre-vaccine, (2) post-vaccine and pre-omicron (BA.1 variant), and (3) post-vaccine including post-omicron variant. This study enables deriving insights into intriguing questions related to the science of system dynamics pertaining to COVID-19 evolution. Methods: We implement a set of several distinct analytical methods for: (a) statistical studies to estimate the skewness and kurtosis of the data distributions; (b) analyzing the stationarity properties of these time series using the Augmented Dickey-Fuller (ADF) tests; (c) examining co-integration properties for the non-stationary time series using the Phillips-Ouliaris (PO) tests; (d) calculating the Hurst exponent using the rescaled-range (R/S) analysis, along with the Detrended Fluctuation Analysis (DFA), for self-affinity studies of the evolving dynamical datasets. Results: We notably observe a significant asymmetry of distributions shows from skewness and the presence of heavy tails is noted from kurtosis. The daily infection and death data are, by and large, nonstationary, while their corresponding log return values render stationarity. The self-affinity studies through the Hurst exponents and DFA exhibit intriguing local changes over time. These changes can be attributed to the underlying dynamics of state transitions, especially from a random state to either mean-reversion or long-range memory/persistence states. Conclusions: We conduct systematic studies covering a widely diverse time series datasets of the daily infections and deaths during the evolution of the COVID-19 pandemic. We demonstrate the merit of a multiple analytics frameworks through systematically laying down a methodological structure for analyses and quantitatively examining the evolution of the daily COVID-19 infection and death cases. This methodology builds a capability for tracking dynamically evolving states pertaining to critical problems. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of mortality among individuals with noncommunicable diseases worldwide. Obesity is associated with an increased risk of developing cardiovascular disease (CVD). Mitochondria are integral to the cardiovascular system, and it has been reported that mitochondrial transfer is associated with the pathogenesis of multiple CVDs and obesity. This review offers a comprehensive examination of the relevance of mitochondrial transfer to cardiovascular health and disease, emphasizing the critical functions of mitochondria in energy metabolism and signal transduction within the cardiovascular system. This highlights how disruptions in mitochondrial transfer contribute to various CVDs, such as myocardial infarction, cardiomyopathies, and hypertension. Additionally, we provide an overview of the molecular mechanisms governing mitochondrial transfer and its potential implications for CVD treatment. This finding underscores the therapeutic potential of mitochondrial transfer and addresses the various mechanisms and challenges in its implementation. By delving into mitochondrial transfer and its targeted modulation, this review aims to advance our understanding of cardiovascular disease treatment, presenting new insights and potential therapeutic strategies in this evolving field. [ABSTRACT FROM AUTHOR]

Backgrounds: Due to the high mortality and hospitalization rate in chronic heart failure (HF), it is of great significance to study myocardial nutrition conditions. Amino acids (AAs) are essential nutrient metabolites for cell development and survival. This study aims to investigate the associations and prognostic value of plasma branched-chain amino acid/aromatic amino acid ratio (Fischer's ratio, FR) in patients with left ventricular ejection fraction (LVEF) ≤ 50%. Methods: The value of serum AAs was obtained from 441 cardiovascular patients by liquid chromatography-tandem, including 213 HF patients [all LVEF ≤ 50%, E/e'>14 (n = 101) and E/e'≤14 (n = 112)], and 228 controls without HF [(excluding HF with preserved ejection fraction (EF)]. Two-dimensional echocardiography and Doppler flow imaging determined LVEF and the ratio of early diastolic mitral inflow to mitral annular tissue velocities (E/e'). The abnormal LVEF (≤ 50%) refers to the definition of HF with reduced, mildly reduced, or improved EF. The logistic regression analysis was conducted to measure the FR index and the risk of cardiac dysfunction, and further confirmed by receiver-operating characteristic curves (ROC curve) analysis. In the prospective study, the 188 HF patients were followed up for a mean year (11.74 ± 1.44 months). The event-free HF endpoint or HF readmission was determined by Kaplan–Meier curves, and differences were assessed using log‐rank tests, respectively. Cox regression analysis was used to further assess the prognostic value of FR in HF. Results: FR index decreased gradually along with the control group, HF with E/e'≤14 group, and HF with E/e'>14 group (3.73 ± 1.20 vs. 3.45 ± 0.94 vs. 3.18 ± 0.83, respectively, P < 0.001). Low FR index was associated with HF after full adjustment in all patients [odds ratio (OR): 2.072; 95% confidence interval (CI): 1.546–2.776; P < 0.001]. Meanwhile, low FR index was the independent risk factor for E/e'>14 in HF patients (OR:1.659; 95% CI:1.125–2.446; P = 0.011). The area under the ROC curve for predicting abnormal E/e' was 0.762 (sensitivity 75.51%, specificity 65.05%) by multivariate logistic regression. Furthermore, the decreased FR values indicated poor HF endpoint or HF readmission in HF patients (all Log-rank P < 0.01). The Cox regression analysis showed that low FR tertiles remained correlated to the risk of HF endpoint [hazard ratio (HR): 1.949; 95% CI: 1.006–3.778; P = 0.048]. Conclusions: In all patients, low FR confers an increased risk for predicting HF. Decreased FR levels could also indicate increased left ventricular (LV) filling pressure in HF. In addition, a lower FR value was associated with higher HF endpoint events. Thus, FR can be a valuable indicator of heart function. [ABSTRACT FROM AUTHOR]