Serum metabolomics analysis of patients with chronic obstructive pulmonary disease and 'frequent exacerbator' phenotype.

Chronic obstructive pulmonary disease (COPD) exacerbations accelerate loss of lung function and increased mortality. The complex nature of COPD presents challenges in accurately predicting and understanding frequent exacerbations. The present study aimed to assess the metabolic characteristics of the frequent exacerbation of COPD (COPD­FE) phenotype, identify potential metabolic biomarkers associated with COPD­FE risk and evaluate the underlying pathogenic mechanisms. An internal cohort of 30 stable patients with COPD was recruited. A widely targeted metabolomics approach was used to detect and compare serum metabolite expression profiles between patients with COPD­FE and patients with non­frequent exacerbation of COPD (COPD­NE). Bioinformatics analysis was used for pathway enrichment analysis of the identified metabolites. Spearman's correlation analysis assessed the associations between metabolites and clinical indicators, while receiver operating characteristic (ROC) analysis evaluated the ability of metabolites to distinguish between two groups. An external cohort of 20 patients with COPD validated findings from the internal cohort. Out of the 484 detected metabolites, 25 exhibited significant differences between COPD­FE and COPD­NE. Metabolomic analysis revealed differences in lipid, energy, amino acid and immunity pathways. Spearman's correlation analysis demonstrated associations between metabolites and clinical indicators of acute exacerbation risk. ROC analysis demonstrated that the area under the curve (AUC) values for D­fructose 1,6­bisphosphate (AUC=0.871), arginine (AUC=0.836), L­2­hydroxyglutarate (L­2HG; AUC=0.849), diacylglycerol (DG) (16:0/20:5) (AUC=0.827), DG (16:0/20:4) (AUC=0.818) and carnitine­C18:2 (AUC=0.804) were >0.8, highlighting their discriminative capacity between the two groups. External validation results demonstrated that DG (16:0/20:5), DG (16:0/20:4), carnitine­C18:2 and L­2HG were significantly different between patients with COPD­FE and those with COPD­NE. In conclusion, the present study offers insights into early identification, mechanistic understanding and personalized management of the COPD­FE phenotype.

Diagnostic value of carbohydrate antigen 50 in biliary tract cancer: A large-scale multicenter study.

BACKGROUND: To date, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have been widely used for the screening, diagnosis and prediction of biliary tract cancer (BTC) patients. However, few studies with large sample sizes of carbohydrate antigen 50 (CA50) were reported in BTC patients. METHODS: A total of 1121 patients from the Liver Cancer Clin-Bio Databank of Anhui Hepatobiliary Surgery Union between January 2017 and December 2022 were included in this study (673 in the training cohort and 448 in the validation cohort): among them, 458 with BTC, 178 with hepatocellular carcinoma (HCC), 23 with combined hepatocellular-cholangiocarcinoma, and 462 with nontumor patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the diagnostic efficacy and clinical usefulness. RESULTS: ROC curves obtained by combining CA50, CA19-9, and AFP showed that the AUC value of the diagnostic MODEL 1 was 0.885 (95% CI 0.856-0.885, specificity 70.3%, and sensitivity 84.0%) in the training cohort and 0.879 (0.841-0.917, 76.7%, and 84.3%) in the validation cohort. In addition, comparing iCCA and HCC (235 in the training cohort, 157 in the validation cohort), the AUC values of the diagnostic MODEL 2 were 0.893 (95% CI 0.853-0.933, specificity 96%, and sensitivity 68.6%) in the training cohort and 0.872 (95% CI 0.818-0.927, 94.2%, and 64.6%) in the validation cohort. CONCLUSION: The model combining CA50, CA19-9, and AFP not only has good diagnostic value for BTC but also has good diagnostic value for distinguishing iCCA and HCC.

Tumour response following preoperative chemotherapy is affected by body mass index in patients with colorectal liver metastases.

BACKGROUND: Colorectal cancer is the third most prevalent malignancy globally and ranks second in cancer-related mortality, with the liver being the primary organ of metastasis. Preoperative chemotherapy is widely recommended for initially or potentially resectable colorectal liver metastases (CRLMs). Tumour pathological response serves as the most important and intuitive indicator for assessing the efficacy of chemotherapy. However, the postoperative pathological results reveal that a considerable number of patients exhibit a poor response to preoperative chemotherapy. Body mass index (BMI) is one of the factors affecting the tumorigenesis and progression of colorectal cancer as well as prognosis after various antitumour therapies. Several studies have indicated that overweight and obese patients with metastatic colorectal cancer experience worse prognoses than those with normal weight, particularly when receiving first-line chemotherapy regimens in combination with bevacizumab. AIM: To explore the predictive value of BMI regarding the pathologic response following preoperative chemotherapy for CRLMs. METHODS: A retrospective analysis was performed in 126 consecutive patients with CRLM who underwent hepatectomy following preoperative chemotherapy at four different hospitals from October 2019 to July 2023. Univariate and multivariate logistic regression models were applied to analyse potential predictors of tumour pathological response. The Kaplan-Meier method with log rank test was used to compare progression-free survival (PFS) between patients with high and low BMI. BMI < 24.0 kg/m2 was defined as low BMI, and tumour regression grade 1-2 was defined as complete tumour response. RESULTS: Low BMI was observed in 74 (58.7%) patients and complete tumour response was found in 27 (21.4%) patients. The rate of complete tumour response was significantly higher in patients with low BMI (29.7% vs 9.6%, P = 0.007). Multivariate analysis revealed that low BMI [odds ratio (OR) = 4.56, 95% confidence interval (CI): 1.42-14.63, P = 0.011], targeted therapy with bevacizumab (OR = 3.02, 95%CI: 1.10-8.33, P = 0.033), preoperative carcinoembryonic antigen level < 10 ng/mL (OR = 3.84, 95%CI: 1.19-12.44, P = 0.025) and severe sinusoidal dilatation (OR = 0.17, 95%CI: 0.03-0.90, P = 0.037) were independent predictive factors for complete tumour response. The low BMI group exhibited a significantly longer median PFS than the high BMI group (10.7 mo vs 4.7 mo, P = 0.011). CONCLUSION: In CRLM patients receiving preoperative chemotherapy, a low BMI may be associated with better tumour response and longer PFS.

Inhibition of Amyloid ß Aggregation and Cytotoxicity by Berbamine Hydrochloride.

Alzheimer's disease (AD) continues to be a major global health challenge, and the recent approval of Aduhelm and Leqembi has opened new avenues for its treatment. Small-molecule inhibitors targeting Aß aggregation hold promise as an alternative to monoclonal antibodies. In this study, we evaluated the ability of berbamine hydrochloride (BBMH), a member of the bisbenzylisoquinoline alkaloids, to reduce Aß aggregation and cytotoxicity. Thioflavin T kinetics, circular dichroism spectroscopy, and atomic force microscopy results indicated that BBMH effectively inhibited Aß aggregation. Surface plasmon resonance and molecular docking results further revealed that BBMH could bind to Aß fibrils, thereby hindering the aggregation process. This physical picture has been confirmed in a quantitative way by chemical kinetics analysis, which showed BBMH tends to bind with the fibril ends and thus prevents the transition from protofibrils to mature fibrils as well as the elongation process. Additionally, our MTT results showed that BBMH was able to reduce the cytotoxicity of Aß40 on N2a cells. Our results demonstrate, for the first time, the potential of BBMH to inhibit Aß aggregation and cytotoxicity, offering a promising direction for further research and drug development efforts in the fight against Alzheimer's disease.

Toxic effects of bisphenol AF on the embryonic development of marine medaka (Oryzias melastigma).

Bisphenol AF (BPAF), an emerging environmental endocrine disruptor, has been detected in surface waters worldwide and has adverse effects on aquatic organisms. The accumulation of BPAF in oceans and its potential toxic effect on marine organisms are important concerns. In this study, the effects of BPAF (10, 100, 1, and 5 mg/L) on marine medaka (Oryzias melastigma) were evaluated, including effects on the survival rate, heart rate, hatchability, morphology, and gene expression in embryos. The survival rate of marine medaka embryos was significantly lower after treatment with 5 mg/L BPAF than in the solvent control group. Exposure to 1 mg/L and 5 mg/L BPAF significantly reduced hatchability. Low-dose BPAF (10 µg/L) significantly accelerated the heart rate of embryos, while high-dose BPAF (5 mg/L) significantly decreased the heart rate. BPAF exposure also resulted in notochord curvature, pericardial edema, yolk sac cysts, cardiovascular bleeding, and caudal curvature in marine medaka. At the molecular level, BPAF exposure affected the transcript levels of genes involved in the thyroid system (dio1, dio3a, trhr2, tg, and thra), cardiovascular system (gata4, atp2a1, and cacna1da), nervous system (elavl3 and gap43), and antioxidant and inflammatory systems (sod, pparß, and il-8) in embryos. These results indicate that BPAF exposure can alter the expression of functional genes, induce abnormal development, and reduce the hatching and survival rates in marine medaka embryos. Overall, BPAF can adversely affect the survival and development of marine medaka embryos, and BPAF may not be an ideal substitute for BPA.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Clinical efficacy of avatrombopag and recombinant human thrombopoietin in the treatment of chronic liver disease-associated severe thrombocytopenia: A real-world study.

Purpose: To investigate the clinical efficacy of avatrombopag, an oral thrombopoietin receptor agonist, versus subcutaneous recombinant human thrombopoietin (rh-TPO) in the treatment of severe thrombocytopenia (TCP) associated with chronic liver disease (CLD). Methods: Clinical data of 250 patients with severe TCP associated with CLD were collected in a single hospital from January 2019 to January 2022. The main parameters measured were the therapeutic response rate, changes in platelets (PLTs), and adverse events. Propensity score matching (PSM) was used to avoid possible selection bias. Results: After PSM, a total of 154 patients were enrolled in the study: 77 in the avatrombopag group and 77 in the rh-TPO group. There was no statistically significant difference between the two groups in the effect of increasing the PLT count (Waldχ 2 = 1.659, p = 0.198; Waldχ 2 = 0.220, p = 0.639). In addition, no interaction between time and different medications was found (Waldχ 2 = 0.540, p = 0.910; Waldχ 2 = 1.273, p = 0.736). Interestingly, in the subgroup analysis, both before and after PSM, avatrombopag showed better clinical efficacy than rh-TPO in the treatment of TCP associated with CLD in Child‒Pugh Class A (88.89% vs. 63.41%, p =0.003; 81.33% vs. 61.76%, p = 0.043). Fewer patients reported dizziness in the avatrombopag group than in the rh-TPO group both before and after PSM (7.8% vs. 25.0%; 7.8% vs. 24.7%, p < 0.05). Conclusion: Both before and after PSM, avatrombopag showed better clinical efficacy than rh-TPO in the treatment of TCP associated with CLD in Child‒Pugh Class A and showed a lower incidence of dizziness in all patients.

Discovery of a wild, genetically pure Chinese giant salamander creates new conservation opportunities.

Effective conservation of threatened biota relies on accurate assessments and scientific guidance. As an unfortunate example, Chinese giant salamanders ( Andrias, CGS) remain critically endangered in nature. Misguided conservation efforts, e.g., commercial propagation and releasing of millions of likely non-indigenous or interspecific hybrids, have further compromised conservation initiatives. Limited information on wild populations of CGS poses a significant conservation challenge. Following 18-month long field monitoring, we now report the discovery of a wild population of CGS in a closed nature reserve in Jiangxi Province, China. Genomic assessments reveal its genetic distinctiveness and do not detect genetic admixture with other species. Based on morphological and molecular evidences, we describe this CGS as a new species Andrias jiangxiensis sp. nov. This is the only known species of CGS today with a genetically pure, reproducing, in situ population. This discovery emphasizes the important role that closed nature reserves play in protecting species, and the necessity of integrating long-term field monitoring and genetic assessments. It sets a new pathway for discovering and conserving endangered species, especially for those biotas that are similarly being extirpated by anthropogenic translocations and overexploitation.

Preoperative nutritional evaluation of prostate cancer patients undergoing laparoscopic radical prostatectomy.

BACKGROUND AND OBJECTIVE: Prostate cancer (PCa) is one of the most common malignant tumors in men. Geriatric Nutritional Risk Index (GNRI) is an objective index for evaluating nutritional status of elderly people over 65 years old. The aim of the current study was to explore the correlation and predictive value between GNRI and postoperative recovery and complications in PCa patients undergoing laparoscopic radical prostatectomy (LRP). METHODS: Taking 98 as the GNRI boundary value, 96 PCa patients (aged≥65 y) undergoing LRP in the Department of Urology, Affiliated Hospital of North Sichuan Medical College from January 2018 to December 2020 were grouped into malnutrition group (MNg, 34 patients, 35.4%) and normal nutrition group (NNg, 62 patients, 64.6%). Basic information, laboratory examination indexes, operation conditions, postoperative complications and postoperative recovery indexes of patients were recorded and retrospectively analyzed. Clavien-Dindo Classification System (CDCS) was used to assess postoperative complications. T-test was used to analyze differences between the two groups. ROC curve was generated to determine the predictive value of GNRI for postoperative complications. RESULTS: Percentage of complications was significantly higher in MNg group compared with that in NNg group (P < 0.01). The average grade based on CDCS was significantly lower in NNg group compared with that in MNg group (P < 0.01). Body weight, Body Mass Index (BMI), preoperative hemoglobin value (HGB), serum albumin (ALB) values of MNg and NNg were significantly positively correlated with GNRI (P<0.01). Incidence and severity of postoperative complications of MNg patients were significantly higher compared with those of NNg patients (P<0.05). Average hospitalization cost of MNg patients was higher in MNg patients compared with that of NNg patients (P<0.05). Duration of post-anesthesia care unit (PACU), duration of antibiotic use and duration of indwelling drainage tube were longer in MNg patients compared with those in NNg patients (P<0.05). Furthermore, volume of indwelling drainage tube was higher in MNg patients compared with that in NNg patients (P<0.05). CONCLUSION: GNRI is an effective and reliable tool for evaluation of preoperative nutritional status of prostate cancer patients. The findings showed that GNRI is correlated with postoperative recovery and complications, and is an effective predictive marker.

Disturbances of the Gut Microbiota, Sleep Architecture, and mTOR Signaling Pathway in Patients with Severe Obstructive Sleep Apnea-Associated Hypertension.

Intermittent hypoxia and sleep fragmentation are pathophysiological processes involved in obstructive sleep apnea (OSA) which affect gut microbiota, sleep architecture, and mTOR signaling pathway. However, the involvement of these elements in the pathogenesis mechanism of OSA-associated hypertension remains unclear. Therefore, this study investigated whether the OSA-associated hypertension mechanism is regulated by the gut microbiota and mTOR signaling pathway. Patients were diagnosed by polysomnography; their fecal samples were obtained and analyzed for their microbiome composition by 16S ribosomal RNA pyrosequencing and bioinformatics analysis. Transcript genes on fasting peripheral blood mononuclear cells (PBMCs) were examined using Illumina RNA-sequencing analysis. Totally, we enrolled 60 patients with severe OSA [without hypertension (n = 27) and with hypertension (n = 33)] and 12 controls (neither OSA nor hypertension). Results revealed that severe-OSA patients with hypertension had an altered gut microbiome, decreased short-chain fatty acid-producing bacteria (P < 0.05), and reduced arginine and proline metabolism pathways (P=0.001), compared with controls; also, they had increased stage N1 sleep and reduced stages N2 and N3 sleep accompanied by repeated arousals (P < 0.05). Analysis of PBMCs using the Kyoto Encyclopedia of Genes and Genomes database showed that the mTOR signaling pathway (P=0.006) was the most important differential gene-enriched pathway in severe-OSA patients with hypertension. Our findings extend prior work and suggest a possibility that the regulation of the mTOR signaling pathway is involved in developing OSA-associated hypertension through its interaction with the disturbance of the gut microbiome and sleep architecture.

Identification and Functional Investigation of Novel Heterozygous HELQ Mutations in Patients with Sertoli Cell-only Syndrome.

Background: Male infertility is a major health concern in couples of childbearing ages. Nonobstructive azoospermia (NOA) is an extreme form of male infertility that affects ∼1% of adult men, and the etiology remains unknown in most cases. Sertoli cell-only syndrome (SCOS) is the most severe type of NOA. Aims: To explore novel human candidate variants that cause SCOS. Methods: (1) Whole exome sequencing (WES) of 20 men with SCOS, (2) Sanger sequencing of the HELQ gene in an additional 163 men with SCOS, (3) in vitro functional assays, and (4) in vivo studies. Results: WES of 20 patients with SCOS led to the identification of two heterozygous missense mutations (M1 and M2) in two unrelated Chinese patients with infertility. Using subsequent Sanger sequencing covering all the coding regions of the HELQ gene for 163 additional SCOS cases, we identified four additional heterozygous mutations (M3-M6) in unrelated patients. In vitro functional analyses revealed that two of these mutations (M5, c.2538T > G and M6, c.2945G > T) might affect the function of the HELQ protein. Two heterozygous mutant mouse models with mutations similar to those of two patients (M5 and M6) did not show any considerable spermatogenic defects. Conclusion: Assuming that the mouse models accurately reflect the impact of the mutations, heterozygous HELQ variants alone did not lead to the development of the SCOS phenotype in mice. However, we cannot rule out the risk variants in Chinese or other human populations, and a larger dataset is needed to confirm the association between HELQ mutations with SCOS.

Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation.

Microtubules play crucial role in process of mitosis and cell proliferation, which have been considered as attractive drug targets for anticancer therapy. The aim of this study was to discover novel and chemically diverse tubulin inhibitors for treatment of cancer. In this investigation, the multilayer virtual screening methods, including common feature pharmacophore model, structure-based pharmacophore model and molecular docking, were developed to screen BioDiversity database with 30,000 compounds. A total of 102 compounds were obtained by the virtual screening, and further filtered by diverse chemical clusters with desired properties and PAINS analysis. Finally, 50 compounds were selected and submitted to the biological evaluation. Among these hits, hits 8 and 30 with novel scaffolds displayed stronger antiproliferative activity on four human tumor cells including Hela, A549, MCF-7, and HepG2. Moreover, the two hits were subsequently submitted to molecular dynamic simulations of 90 ns with the aim of exploring the stability of ligand-protein interactions into the binding pocket, and further probing the mechanism of the interaction between tubulin and hits. The molecular dynamic simulation results revealed there had stronger interactions between tubulin and hits in equilibrium state. Therefore, the hits 8 and 30 have been well characterized as lead compounds for developing new tubulin inhibitors with potential anticancer activity.

Why do we lack a specific magic anti-COVID-19 drug? Analyses and solutions.

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.

lncRNA MIR155HG Alleviates Depression-Like Behaviors in Mice by Regulating the miR-155/BDNF Axis.

Depression is one of most common psychiatric disorders, and the detailed molecular mechanism remains to be fully elucidated. Brain-derived neurotrophic factor (BDNF) is a critical neurotrophic factor that is decreased and closely involved in the development of depression. Noncoding RNAs are central regulators of cellular activities that modulate target genes. However, the roles of long noncoding RNA (lncRNA) MIR155HG and miRNA-155 (miR-155) in the pathophysiology of depression are unclear. In the present study, we aimed to explore the effects of lncRNA MIR155HG and miR-155 on the development of depression and uncover the underlying molecular mechanism. Real-time quantitative polymerase chain reaction was used to examine the expression of MIR155HG and miR-155. Western blotting was applied to measure the expression of BDNF. A luciferase reporter assay was utilized to determine the regulatory relationship between MIR155HG and miR-155. Our current work found that lncRNA MIR155HG and BDNF levels decreased while miR-155 levels increased in the hippocampal region of CUMS (chronic unpredictable mild stress) mice, a well-accepted mouse model of depression. Moreover, MIR155HG rescued while miR-155 exacerbated the depression-like behaviors of CUMS mice. Through bioinformatics analysis and luciferase reporter assays, we found that MIR155HG directly bound to and negatively modulated the expression of miR-155. Moreover, increased miR-155 was found to repress the expression of BDNF, a critical neurotrophic factor that has been reported to alleviate the depression-like behaviors of CUMS mice. Our present study revealed that lncRNA MIR155HG protected CUMS mice by regulating the miR-155/BDNF axis. Our study aimed to understand the pathophysiology of depression and provided potential therapeutic targets to diagnose and treat depression.

Developing novel computational prediction models for assessing chemical-induced neurotoxicity using naïve Bayes classifier technique.

Development of reliable and efficient alternative in vivo methods for evaluation of the chemicals with potential neurotoxicity is an urgent need in the early stages of drug design. In this investigation, the computational prediction models for drug-induced neurotoxicity were developed by using the classical naïve Bayes classifier. Eight molecular properties closely relevant to neurotoxicity were selected. Then, 110 classification models were developed with using the eight important molecular descriptors and 10 types of fingerprints with 11 different maximum diameters. Among these 110 prediction models, the prediction model (NB-03) based on eight molecular descriptors combined with ECFP_10 fingerprints showed the best prediction performance, which gave 90.5% overall prediction accuracy for the training set and 82.1% concordance for the external test set. In addition, compared to naïve Bayes classifier, the recursive partitioning classifier displayed worse predictive performance for neurotoxicity. Therefore, the established NB-03 prediction model can be used as a reliable virtual screening tool to predict neurotoxicity in the early stages of drug design. Moreover, some structure alerts for characterizing neurotoxicity were identified in this research, which could give an important guidance for the chemists in structural modification and optimization to reduce the chemicals with potential neurotoxicity.