Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats.

Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer's disease (AD). While it is known that vascular fibrillar amyloid ß (Aß) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-ß1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-ß1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.

First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.

BACKGROUND: Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. METHODS: This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10 min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. RESULTS: Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1ß (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. CONCLUSIONS: Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions.

A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment.

BACKGROUND: The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. METHODS: The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. RESULTS: In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68-1.00) for patient response prediction. CONCLUSIONS: The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.

Identification of common mechanisms and biomarkers of atrial fibrillation and heart failure based on machine learning.

AIMS: Atrial fibrillation (AF) is the most common arrhythmia. Heart failure (HF) is a disease caused by heart dysfunction. The prevalence of AF and HF were progressively increasing over time. The co-existence of AF and HF presents a significant therapeutic challenge. In order to provide new ideas for the diagnosis of AF and HF, it is necessary to carry out biomarker related studies. METHODS AND RESULTS: The training set and validation set data of AF and HF patient samples were downloaded from the GEO database, 'limma' was used to compare the differences in gene expression levels between the disease group and the normal group to screen for differentially expressed genes (DEGs). Weighted correlation network analysis (WGCNA) identified the modules with the highest positive correlation with AF and HF. Functional enrichment and PPI network construction of key genes were carried out. Biomarkers were screened by machine learning. The infiltration of immune cells in AF and HF groups was evaluated by R-packet 'CIBERSORT'. The miRNA network was constructed and potential therapeutic agents for biomarker genes were predicted through the drugbank database. Through WGCNA analysis, it was found that the modules most positively correlated with AF and HF were MEturquoise (r = 0.21, P value = 0.09) and MEbrown (r = 0.62, P value = 8e-12), respectively. We screened 25 genes that were highly correlated with both AF and HF. Lasso regression analysis results showed 7 and 20 core genes in AF and HF groups, respectively. The top 20 important genes in AF and HF groups were obtained as core genes by RF model analysis. Four biomarkers were obtained after the intersection of core genes in four groups, namely, GLUL, NCF2, S100A12, and SRGN. The diagnostic efficacy of four genes in AF validation sets was good (AUC: GLUL 0.76, NCF2 0.64, S100A12 0.68, and SRGN 0.76), as well as in the HF validation set (AUC: GLUL 0.76, NCF2 0.84, S100A12 0.92, and SRGN 0.68). The highest correlation with neutrophils was observed for GLUL, NCF2, and S100A12, while SRGN exhibited the strongest correlation with T cells CD4 memory resting in the AF group. GLUL, NCF2, S100A12, and SRGN were most associated with neutrophils in the HF group. A total of 101 miRNAs were predicted by four genes, and GLUL, NCF2, and S100A12 predicted a total of 10 potential therapeutic agents. CONCLUSIONS: We identified four biological markers that are highly correlated with AF and HF, namely, GLUL, NCF2, S100A12, and SRGN. Our findings provide theoretical basis for the clinical diagnosis and treatment of AF and HF.

Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

OPINION STATEMENT: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

Increased [18F]fluorodeoxyglucose uptake in the left pallidum in military Veterans with blast-related mild traumatic brain injury: potential as an imaging biomarker and mediation with executive dysfunction and cognitive impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p<0.0001; q=3.29 x 10-9 (Cohen's d, 1.38, 95% CI (.96, 1.79)). The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2=0.22; p<0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a Receiver Operator Characteristic Area Under the Curve of 0.859 (p<0.0001) and likelihood ratio of 21.19 (threshold:SUVR≥0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared to controls, p<0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum mediated executive function impairments, adjusted causal mediation estimate p=0.021; total effect estimate, p=0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p<0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared to controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum, however the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions via basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. While confirmation of our results by single-subject-to-cohort analyses will be required prior to clinical deployment, this study provides proof-of-concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Validation of mitochondrial biomarkers and immune dynamics in polycystic ovary syndrome.

PROBLEM: Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, presents considerable therapeutic challenges due to its complex and elusive pathophysiology. METHOD OF STUDY: We employed three machine learning algorithms to identify potential biomarkers within a training dataset, comprising GSE138518, GSE155489, and GSE193123. The diagnostic accuracy of these biomarkers was rigorously evaluated using a validation dataset using area under the curve (AUC) metrics. Further validation in clinical samples was conducted using PCR and immunofluorescence techniques. Additionally, we investigate the complex interplay among immune cells in PCOS using CIBERSORT to uncover the relationships between the identified biomarkers and various immune cell types. RESULTS: Our analysis identified ACSS2, LPIN1, and NR4A1 as key mitochondria-related biomarkers associated with PCOS. A notable difference was observed in the immune microenvironment between PCOS patients and healthy controls. In particular, LPIN1 exhibited a positive correlation with resting mast cells, whereas NR4A1 demonstrated a negative correlation with monocytes in PCOS patients. CONCLUSION: ACSS2, LPIN1, and NR4A1 emerge as PCOS-related diagnostic biomarkers and potential intervention targets, opening new avenues for the diagnosis and management of PCOS.

Precision medicine in colorectal cancer: Leveraging multi-omics, spatial omics, and artificial intelligence.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Recent advancements in genomic technologies and analytical approaches have revolutionized CRC research, enabling precision medicine. This review highlights the integration of multi-omics, spatial omics, and artificial intelligence (AI) in advancing precision medicine for CRC. Multi-omics approaches have uncovered molecular mechanisms driving CRC progression, while spatial omics have provided insights into the spatial heterogeneity of gene expression in CRC tissues. AI techniques have been utilized to analyze complex datasets, identify new treatment targets, and enhance diagnosis and prognosis. Despite the tumor's heterogeneity and genetic and epigenetic complexity, the fusion of multi-omics, spatial omics, and AI shows the potential to overcome these challenges and advance precision medicine in CRC. The future lies in integrating these technologies to provide deeper insights and enable personalized therapies for CRC patients.

Screening of lung cancer serum biomarkers based on Boruta-shap and RFC-RFECV algorithms.

OBJECTIVE: This study aimed to identify a set of serum miRNAs as potential biomarkers for lung cancer diagnosis using algorithmic approaches. METHODS: Serum miRNA expression data from lung cancer patients and non-tumor controls were obtained. The top six miRNAs were selected using Boruta-shap and RFC-RFECV algorithms. A Gaussian Naive Bayes (NB) classifier was trained and evaluated using cross-validation, ROC curve analysis, and evaluation metrics. RESULTS: Six miRNAs (hsa-miRNA-144, hsa-miRNA-107, hsa-miRNA-484, hsa-miRNA-103, hsa-miRNA-26b, and hsa-miRNA-641) were identified as feature genes. The NB classifier achieved an area under curve (AUC) of 0.8966 and a mean AUC of 0.88 in cross-validation. Accuracy, recall, and F1 scores exhibited promising results, with an accuracy of 82%. In the validation set, the AUC values for the NB and SVC classifiers were 0.9345 and 0.9423, respectively, with a mean AUC of 0.95 in cross-validation. The classifiers demonstrated an accuracy of 89% in diagnosing lung cancer. CONCLUSION: This study identified a panel of six serum miRNAs with potential as non-invasive biomarkers for lung cancer diagnosis. These miRNAs show promise in providing sensitive and specific tools for detecting lung cancer. SIGNIFICANCE: Lung cancer is one of the top cancers worldwide, threatening the health and lives of tens of thousands of people. miRNA is a biomarker, which can be used as a potential clinical tool for diagnosis and prognosis of cancer patients. Therefore, the use of multiple miRNAs to construct diagnostic models may be one of the future methods of accurate diagnosis of lung cancer. In this study, we used the Boruta-shap and RFC-RFECV algorithms to automatically identify and extract characteristic miRNAs highly associated with lung cancer, thereby establishing an accurate classifier for the diagnosis of lung cancer with characteristic miRNAs.

Biopesticide Spinosad: unraveling ecotoxicological effects on zebrafish, Danio rerio.

Biopesticides are natural compounds considered more safe and sustainable for the environment. Spinosad (SPI) is a bioinsecticide used in marketed worldwide, to eradicate a variety of pests. This study aimed to assess the impacts of the SPI on the non-target organism zebrafish (Danio rerio). Several concentrations of SPI were tested to evaluate the acute (0.07-1.0mg/L) and chronic (0.006-0.100mg/L) ecotoxicological effects. To evaluate sub-individual effects, antioxidant defense, lipid peroxidation, energy sources, and cholinergic biomarkers were quantified. In both exposures, SPI induced significant effects on antioxidant defense indicating oxidative stress, disrupting energy pathways, and exhibiting neurotoxic effects, under environmentally relevant conditions. Integrated Biomarker Response (IBRv2) showed that with increasing SPI concentrations, an increase in impacts on organisms was recorded. This study demonstrates the vulnerability of a non-target organism to SPI, a bioinsecticide considered environmentally safe. Further research is essential to fully understand the implications of spinosad to aquatic biota.

Chronic cypermethrin induced toxicity and molecular fate assessment within common carp (Cyprinus carpio) using multiple biomarkers approach and its novel therapeutic detoxification.

Cypermethrin (CYP) is a chemical of emerging concern which has persistent and bioaccumulating impacts as it can be found extensively in freshwater ecosystem and agricultural products. It has exposure risk and toxic effects over human edible fish, as common carp. Four groups were designed for toxicity assessment and detoxification approach: control group (CL), CYP exposure group (CYP), CYP + 10% M. oleifera leaves and 10% M. oleifera seeds (CMO group), 10% M. oleifera leaves and 10% M. oleifera seeds (MO group). Trial period was forty days during which cohort of 240 fish in CYP and CMO group was exposed to 1/5 of 96h LC50 of CYP (0.1612 µg/L). CYP-exposed carp exhibited lower growth parameters, but carp fed with 10% M. oleifera seeds and leaves showed significant improvement in growth rate (SGR, RGR) and weight gain (WG) as compared to the control group. CYP exposure negatively affected haemato-biochemical parameters. Moreover, CYP exposure also led to oxidative stress, damaged immunological parameters, genotoxicity and histopathological damage in liver and intestinal cells. Whereas, M. oleifera supplementation has ameliorated these conditions. Thereby, supplementation with M. oleifera is potential and novel therapeutic detoxication approach for common carp and human health against persistent and bioaccumulating emerging chemicals.

Association of a dietary inflammatory index with cardiometabolic, endocrine, liver, renal and bones biomarkers: cross-sectional analysis of the UK Biobank study.

BACKGROUND AND AIMS: Research into the relationship between an Energy-adjusted Diet-Inflammatory Index (E-DII) and a wider health-related biomarkers profile is limited. Much of the existing evidence centers on traditional metabolic biomarkers in populations with chronic diseases, with scarce data on healthy individuals. Thus, this study aims to investigate the association between an E-DII score and 30 biomarkers spanning metabolic health, endocrine, bone health, liver function, cardiovascular, and renal functions, in healthy individuals. METHODS AND RESULTS: 66,978 healthy UK Biobank participants, the overall mean age was 55.3 (7.9) years were included in this cross-sectional study. E-DII scores, based on 18 food parameters, were categorised as anti-inflammatory (E-DII < -1), neutral (-1 to 1), and pro-inflammatory (>1). Regression analyses, adjusted for confounding factors, were conducted to investigate the association of 30 biomarkers with E-DII. Compared to those with an anti-inflammatory diet, individuals with a pro-inflammatory diet had increased levels of 16 biomarkers, including six cardiometabolic, five liver, and four renal markers. The concentration difference ranged from 0.27 SD for creatinine to 0.03 SD for total cholesterol. Conversely, those on a pro-inflammatory diet had decreased concentrations in six biomarkers, including two for endocrine and cardiometabolic. The association range varied from -0.04 for IGF-1 to -0.23 for SHBG. CONCLUSION: This study highlighted that a pro-inflammatory diet was associated with an adverse profile of biomarkers linked to cardiometabolic health, endocrine, liver function, and renal health.

Reproductive physiology of the boar: What defines the potential fertility of an ejaculate?

Despite decades of research and handling of semen for use in artificial insemination (AI) and other assisted reproductive technologies, 5-10% of selected boar sires are still considered sub-fertile, escaping current assessment methods for sperm quality and resilience to preservation. As end-product, the ejaculate (emitted spermatozoa sequentially exposed to the composite seminal plasma, the SP) ought to define the homeostasis of the testes, the epididymis, and the accessory sexual glands. Yet, linking findings in the ejaculate to sperm production biology and fertility is suboptimal. The present essay critically reviews how the ejaculate of a fertile boar can help us to diagnose both reproductive health and resilience to semen handling, focusing on methods -available and under development- to identify suitable biomarkers for cryotolerance and fertility. Bulk SP, semen proteins and microRNAs (miRNAs) have, albeit linked to sperm function and fertility after AI, failed to enhance reproductive outcomes at commercial level, perhaps for just being components of a complex functional pathway. Hence, focus is now on the interaction sperm-SP, comparing in vivo with ex vivo, and regarding nano-sized lipid bilayer seminal extracellular vesicles (sEVs) as priority. sEVs transport fragile molecules (lipids, proteins, nucleic acids) which, shielded from degradation, mediate cell-to-cell communication with spermatozoa and the female internal genital tract. Such interaction modulates essential reproductive processes, from sperm homeostasis to immunological female tolerance. sEVs can be harvested, characterized, stored, and manipulated, e.g. can be used for andrological diagnosis, selection of breeders, and alternatively be used as additives to improve cryosurvival and fertility.

Analysis of differential metabolites in serum metabolomics of patients with aortic dissection.

BACKGROUND: Pathogenesis and diagnostic biomarkers of aortic dissection (AD) can be categorized through the analysis of differential metabolites in serum. Analysis of differential metabolites in serum provides new methods for exploring the early diagnosis and treatment of aortic dissection. OBJECTIVES: This study examined affected metabolic pathways to assess the diagnostic value of metabolomics biomarkers in clients with AD. METHOD: The serum from 30 patients with AD and 30 healthy people was collected. The most diagnostic metabolite markers were determined using metabolomic analysis and related metabolic pathways were explored. RESULTS: In total, 71 differential metabolites were identified. The altered metabolic pathways included reduced phospholipid catabolism and four different metabolites considered of most diagnostic value including N2-gamma-glutamylglutamine, PC(phocholines) (20:4(5Z,8Z,11Z,14Z)/15:0), propionyl carnitine, and taurine. These four predictive metabolic biomarkers accurately classified AD patient and healthy control (HC) samples with an area under the curve (AUC) of 0.9875. Based on the value of the four different metabolites, a formula was created to calculate the risk of aortic dissection. Risk score = (N2-gamma-glutamylglutamine × -0.684) + (PC (20:4(5Z,8Z,11Z,14Z)/15:0) × 0.427) + (propionyl carnitine × 0.523) + (taurine × -1.242). An additional metabolic pathways model related to aortic dissection was explored. CONCLUSION: Metabolomics can assist in investigating the metabolic disorders associated with AD and facilitate a more in-depth search for potential metabolic biomarkers.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men.

BACKGROUND: Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. METHODS: We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. RESULTS: After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. CONCLUSIONS: These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Renal implications of pneumoperitoneum in laparoscopic surgery: mechanisms, risk factors, and preventive strategies.

Pneumoperitoneum, which is established for laparoscopic surgery, has systemic implications on the renal system and may contribute to acute kidney injury or postoperative renal dysfunction. Specifically, when the pressure exceeds 10 mmHg, pneumoperitoneum decreases renal blood flow, leading to renal dysfunction and temporary oliguria. The renal effects of pneumoperitoneum stem from both the direct effects of increased intra-abdominal pressure and indirect factors such as carbon dioxide absorption, neuroendocrine influences, and tissue damage resulting from oxidative stress. While pneumoperitoneum can exacerbate renal dysfunction in patients with pre-existing kidney issues, preserving the function of the remaining kidney is crucial in certain procedures such as laparoscopic live donor nephrectomy. However, available evidence on the effects of pneumoperitoneum on renal function is limited and of moderate quality. This review focuses on exploring the pathophysiological hypotheses underlying kidney damage, mechanisms leading to oliguria and kidney damage, and fluid management strategies for surgical patients during pneumoperitoneum.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Bioanalysis of Stress Biomarkers through Sensitive HILIC-MS/MS Method: A Stride toward Accurate Quantification of MDA, ACR, and CTA.

Quantifying reactive aldehyde biomarkers, such as malondialdehyde, acrolein, and crotonaldehyde, is the most preferred approach to determine oxidative stress. However, reported analytical methods lack specificity for accurately quantifying these aldehydes as certain methodologies may produce false positive results due to harsh experimental conditions. Thus, in this research work, a novel HILIC-MS/MS method with endogenous histidine derivatization is developed, which proves to have higher specificity and reproducibility in quantifying these aldehydes from the biological matrix. To overcome the reactivity of aldehyde, endogenous histidine is used for its derivatization. The generated adduct is orthogonally characterized by NMR and LC-HRMS. The method employed a hydrophilic HILIC column and multiple reaction monitoring (MRM) to accurately quantify these reactive aldehydes. The developed method is an unequivocal solution for quantifying stress in in vivo and in vitro studies.

Metabolomic analysis reveals the changing trend and differential markers of volatile and nonvolatile components of Artemisiae argyi with different aging years.

INTRODUCTION: Artemisia argyi Folium (AAF) is a traditional medicinal herb and edible plant. Analyzing the differential metabolites that affect the efficacy of AAF with different aging years is necessary. OBJECTIVE: The aim of the study was to investigate the changing trend and differential markers of volatile and nonvolatile metabolites of AAF from different aging years, which are necessary for application in clinical medicine. METHODOLOGY: Metabolites were analyzed using a widely targeted metabolomic approach based on ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS). RESULTS: A total of 153 volatile metabolites and 159 nonvolatile metabolites were identified. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) could clearly distinguish AAF aged for 1 year (AF-1), 3 years (AF-3), and 5 years (AF-5). Seven flavonoids and nine terpenoids were identified as biomarkers for tracking the aging years. CONCLUSIONS: The metabolomic method provided an effective strategy for tracking and identifying biomarkers of AAF from different aging years. This study laid the foundation for analysis of the biological activity of Artemisia argyi with different aging years.