Prognostic value of coagulation markers in patients with colorectal caner: A prospective study.

Background and Aims: The occurrence, growth, and metastasis of colorectal cancer (CRC) are connected to the hypercoagulable state of blood (CRC). This study aimed to identify significant coagulation factors to predict metastasis and prognosis of CRC. Methods: Thrombomodulin (TM), thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC), and tissue plasminogen activator-inhibitor complex (t-PAIC) were detected by chemiluminescence immunoassay using Sysmex HISCL5000 automated analyzers. The Sysmex CS 5100 automatic blood coagulation analyzer was used to detect d-dimer (DD), fibrin degradation product (FDP), prothrombin time (PT), thrombin time (TT), international normalized ratio (INR), fibrinogen (Fbg), and activated partial thromboplastin time (APTT). Area under the curve (AUC) and the receiver operating characteristic curve (ROC) were used to assess the diagnostic efficacy of markers. Kaplan-Meier analysis was used to calculate survival probabilities. Independent prognostic factors and the nomogram were developed using single-factor and multifactor cox regression analysis model. Results: The following indicators (TM, TAT, PIC, t-PAIC, DD, FDP, PT, INR, APTT, and Fbg) were markedly higher in CRC patients than in healthy controls, and they were higher in the metastasis (M) group than in the nonmetastasis (NM) group. The combination "TAT + PIC + DD + FDP + Fbg" can distinguish M from NM with exceptional sensitivity and specificity. Patients with CRC who had high levels of TAT, PIC, DD, FDP, Fbg, TM, tPAIC, PT, and INR had significantly shorter survival. Conclusion: The prognosis of CRC patients can be predicted by coagulation indicators. The independent predictive variables for overall survival were found to be TM and DD. To forecast CRC patient survival, a nomogram was created.

Pseudolaric Acid A: A Promising Antifungal Agent Against Prevalent Non-albicans Candida Species.

Purpose: The non-albicans Candida (NAC) species have recently gained great importance worldwide due to the increasing proportion in candida causing bloodstream infections. This investigation aimed to explore the efficacy of Pseudolaric acid A (PAA, a diterpenoid derived from Pseudolarix kaempferi) and its synergistic effect with fluconazole (FLC) against NAC species, including C. tropicalis, C. parapsilosis complex, and C. glabrata. Methods: The microdilution checkerboard assay and time-killing curves were performed to detect the antifungal efficiency. To examine the integrity of cell walls and membranes, calcofluor white stain and propidium iodide stain were used. The changes of intracellular ultrastructure in Candida cells after treatment were observed using transmission electron microscopy. Changes in cell viability with the autophagy inhibitor 3-MA were assessed by the XTT method. Results: It was revealed that PAA alone is effective on C. tropicalis, C. parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis (MIC 8-128 µg/mL). Strong synergism against FLC-resistant C. tropicalis was observed (FICI 0.07-0.281), when PAA and FLC were combined. PAA had dose-dependently detrimental effects on C. tropicalis cell membranes. Moreover, increased vacuoles and autophagosome formation were found in C. tropicalis exposed to PAA. And the inhibitory effect of PAA against C. tropicalis can be relieved by autophagy inhibitor 3-MA in a certain concentration range. Ultrastructural alterations of C. tropicalis were more pronounced under the combination of PAA and FLC, including separation of the cell membrane from the cell wall, increased number of vacuoles, and degradation of organelles. Conclusion: These observations indicated that PAA and its combination with FLC could be a promising therapeutic candidate for treating infections caused by NAC species.

WITHDRAWN: Konjac Glucomannan, in Combination with Cisplatin, Suppresses Lymphoma Malignant Progression by Inducing Ferroptosis

The article has been withdrawn at the request of the authors.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham editorial policy on article withdrawal can be found at https://benthamscience.com/editorialpolicies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Interaction between aluminum exposure and ApoEε4 gene on cognitive function of in-service workers.

The occurrence and development of cognitive impairment, the early stage of AD, may be affected both by factors of environmental (aluminum exposure) and genetic (ApoEε4 gene). But whether there is an interaction between the two factors on cognitive function is still unknown. To explore the interaction between the two factors on cognitive function of in-service workers. A total of 1121 in-service workers in a large aluminum factory were investigated in Shanxi Province. Cognitive function was assessed by the Mini-mental State Examination (MMSE), the clock-drawing test (CDT), the Digit Span Test (DST, including DSFT and DSBT), the fuld object memory evaluation (FOM), and the verbal fluency task (VFT). The plasma-Al (p-Al) concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) as an internal exposure indicator, and the participants were divided into four Al exposure groups according to the quartile of p-Al concentrations, namely Q1, Q2, Q3, and Q4. ApoE genotype was determined by Ligase Detection Reaction (LDR). The multiplicative model was fitted using non-conditional logistic regression and additive model was fitted using crossover analysis to analyze the interaction between p-Al concentrations and the ApoEε4 gene. Finally, a dose-response relationship between p-Al concentrations and cognitive impairment was observed, with the p-Al concentrations increased, cognitive function performance gradually becomes worse (Ptrend＜0.05), and the risk of cognitive impairment gradually increases (Ptrend＜0.05), mainly in executive/visuospatial impairment, auditory memory impairment (particularly the working memory impairment). And ApoEε4 gene may be a risk factor for cognitive impairment, while no association between the ApoEε2 gene and cognitive impairment is observed. Additionally, an additive but no multiplicative interaction between p-Al concentrations and ApoEε4 gene is observed, and when the two factors work together, the risk of cognitive impairment further increased, of which 44.2% can be attributed to the interaction effect.

Synergistic Antibiofilm Effects of Pseudolaric Acid A Combined with Fluconazole against Candida albicans via Inhibition of Adhesion and Yeast-To-Hypha Transition.

Candida albicans biofilms are resistant to several clinical antifungal agents. Thus, it is necessary to develop new antibiofilm intervention measures. Pseudolaric acid A (PAA), a diterpenoid mainly derived from the pine bark of Pseudolarix kaempferi, has been reported to have an inhibitory effect on C. albicans. The primary aim of the current study was to investigate the antibiofilm effect of PAA when combined with fluconazole (FLC) and explore the underlying mechanisms. Biofilm activity was assessed by tetrazolium {XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt]} reduction assays. PAA (4 µg/mL) combined with FLC (0.5 µg/mL) significantly inhibited early, developmental, and mature biofilm formation compared with the effect of PAA or FLC alone (P < 0.05). Furthermore, PAA (4 µg/mL) combined with FLC (0.5 µg/mL) produced a 56% reduction in C. albicans biofilm adhesion. The combination of PAA (4 µg/mL) and FLC (0.5 µg/mL) also performed well in inhibiting yeast-to-hypha transition. Transcriptome analysis using RNA sequencing and quantitative reverse transcription PCR indicated that the PAA-FLC combination treatment produced a strong synergistic inhibitory effect on the expression of genes involved in adhesion (ALS1, ALS4, and ALS2) and yeast-to-hypha transition (ECE1, PRA1, and TEC1). Notably, PAA, rather than FLC, may have a primary role in suppressing the expression of ALS1. In conclusion, these findings demonstrate, for the first time, that the combination of PAA and FLC has an improved antibiofilm effect against the formation of C. albicans biofilms by inhibiting adhesion and yeast-to-hypha transition; this may provide a novel therapeutic strategy for treating C. albicans biofilm-associated infection. IMPORTANCE Biofilms are the primary cause of antibiotic-resistant candida infections associated with medical implants and devices worldwide. Treating biofilm-associated infections is a challenge for clinicians because these infections are intractable and persistent. Candida albicans readily forms extensive biofilms on the surface of medical implants and mucosa. In this study, we demonstrated, for the first time, an inhibitory effect of pseudolaric acid A alone and in combination with fluconazole on C. albicans biofilms. Moreover, pseudolaric acid A in combination with fluconazole exerted an antibiofilm effect through multiple pathways, including inhibition of yeast-to-hypha transition and adhesion. This research not only provides new insights into the synergistic mechanisms of antifungal drug combinations but also brings new possibilities for addressing C. albicans drug resistance.

Synergistic Effect of Pseudolaric Acid B with Fluconazole Against Resistant Isolates and Biofilm of Candida tropicalis.

PURPOSE: Candida tropicalis (C. tropicalis) has emerged as an important fungal pathogen due to its increasing resistance to conventional antifungal agents, especially fluconazole (FLC). Pseudolaric acid B (PAB), a herbal-originated diterpene acid from Pseudolarix kaempferi Gordon, has been reported to possess inhibitory activity against fungus. The present study aims to investigate the antifungal effect of PAB alone and in combination with FLC on planktonic and biofilm cells of C. tropicalis. METHODS: The antifungal activity of PAB against planktonic isolates was evaluated alone and in combination with FLC using the chequerboard microdilution method and growth curve assay. The anti-biofilm effects were quantified by tetrazolium (XTT) reduction assay, which were further confirmed by scanning electron microscopy (SEM) and fluorescent microscope to observe morphological changes of biofilm treated with PAB and FLC. RESULTS: It was revealed that PAB alone exhibited similar inhibitory activity against FLC-resistant and FLC-susceptible strains with median MIC ranging from 8 to 16 µg/mL. When administered in combination, synergism was observed in all (13/13) FLC-resistant and (2/9) FLC-susceptible strains with FICI ranging from 0.070 to 0.375. Moreover, the concomitant use of PAB and FLC exhibited a strong dose-dependent synergistic inhibitory effect on the early and mature biofilm, eliminating more than 80% biofilm formation. SEM found that PAB, different from azoles, could significantly inhibit spore germination and destroy the cell integrity causing cell deformation, swelling, collapse and outer membrane perforation. CONCLUSION: PAB was highly active against FLC-resistant isolates and biofilm of C. tropicalis, particularly when combined with FLC. These findings suggest that PAB may have potential as a novel antifungal agent with different targets from azole drugs.