Discovery of Anthranilic Acid Derivatives as Antagonists of the Pro-Inflammatory Orphan G Protein-Coupled Receptor GPR17.

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds' potencies were evaluated in calcium mobilization and radioligand binding assays, and structure-activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3'-methoxy-[1,1'-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid (52, PSB-22269, Ki 8.91 nM) and its 3'-trifluoromethyl analog (54, PSB-24040, Ki 83.2 nM). Receptor-ligand docking studies revealed that the compounds' binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.

Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.

OBJECTIVE: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). METHODS: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan. RESULTS: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters. INTERPRETATION: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2024.

Antihypertensive Medication Category Prescriptions and Blood Pressure Control in African Surinamese and Ghanaian Migrants with Hypertension in Amsterdam, The Netherlands: The HELIUS Study.

West African (WA) migrants in Europe have higher hypertension rates than the host populations. For African migrants, guidelines recommend diuretics and/or calcium channel blockers (CCB) for primary cardiovascular disease prevention, but data on antihypertensive medication (AHM) prescription patterns or related hypertension control rates are lacking. We assessed AHM prescription patterns and its relation to hypertension control among hypertensive WA migrants in the Netherlands compared to the host population. Cross-sectional data from WA or Dutch origin participants from the HELIUS study were used. Participants with treated hypertension and without diabetes, cardiovascular disease, or microalbuminuria were selected. We used logistic and linear regression analyses to assess the association between AHM categories and hypertension control rates (systolic blood pressure (BP) ≤ 140 mmHg and diastolic BP ≤ 90 mmHg) and the systolic BP levels. We compared 999 WA participants and 314 Dutch participants. Hypertension control rates were lower in the WA origin compared to Dutch origin participants (44.3% versus 58.0%, p < 0.001). For WA participants, prescription rates for any AHM category were: CCB (54.8%), diuretics (18.5%) beta-blocking agents (27.3%) and renin-angiotensin system blockers (52.6%). Prescription rates were higher for CCB and similar for diuretics compared to the Dutch participants. Neither CCB nor diuretics were associated with better control rates. Compared to Dutch participants, West African participants had similar diuretic prescriptions but significantly higher prescriptions for CCB. However, neither medications was associated with better hypertension control. Future research should explore physician and patient factors to improve hypertension control.

Genetic Risk of Reticular Pseudodrusen in Age-Related Macular Degeneration: HTRA1 /lncRNA BX842242.1 dominates, with no evidence for Complement Cascade involvement.

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2,165 AMD+/RPD+ and 4,181 AMD+/RPD-compared to 7,660 control participants, both chromosomes 1 ( CFH ) and 10 ( ARMS2/HTRA1 ) major AMD risk loci were reidentified. However association was only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD-cases. The chromosome 1 locus was notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. BX842242.1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identified even stronger enrichment for the chromosome 10 risk genotype.

The impact of demoralization on the stability of personality traits in a clinical sample.

This study examined whether reductions in the severity of personality disorders (PD) mainly reflect changes in personality traits or rather an alleviation of a demoralized state involving nonspecific unpleasant affect. We used 4 years of longitudinal data from the Collaborative Longitudinal Personality Disorders Study, in which patients (N = 419) completed the Neuroticism-Extraversion-Openness Personality Inventory-Revised (NEO-PI-R) three times over 4 years (at baseline and at 6-month and 4-year follow-up assessments). We compared the NEO Demoralization scale with NEO-PI-R domain scales adjusted for demoralization-related items to determine whether changes in demoralization are more pronounced than changes in adjusted personality traits. Results showed that adjusted Neuroticism and Demoralization changed at similar rates and both changed more than other traits. These changes were most pronounced in the first 6 months and tapered thereafter. Rank-order correlations were somewhat lower for Demoralization than adjusted traits. Our findings suggest that decreases in PD symptoms over time have to do with reductions in negative affect and that Demoralization as assessed via a subset of NEO-PI-R items is limited in its ability to distinguish negative affect from trait Neuroticism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract.

Around 180 genes have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in mice, and represent promising novel candidate genes for human CAKUT. In whole-exome sequencing data of two siblings with genetically unresolved multicystic dysplastic kidneys (MCDK), prioritizing variants in murine CAKUT-associated genes yielded a rare variant in the teashirt zinc finger homeobox 3 (TSHZ3) gene. Therefore, the role of TSHZ3 in human CAKUT was assessed. Twelve CAKUT patients from 9/301 (3%) families carried five different rare heterozygous TSHZ3 missense variants predicted to be deleterious. CAKUT patients with versus without TSHZ3 variants were more likely to present with hydronephrosis, hydroureter, ureteropelvic junction obstruction, MCDK, and with genital anomalies, developmental delay, overlapping with the previously described phenotypes in Tshz3-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the TSHZ3 locus. Comparable with Tshz3-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a TSHZ3 variant carrier compared to controls. TSHZ3 was expressed in the human fetal kidney, and strongly at embryonic day 11.5-14.5 in mesenchymal compartments of the murine ureter, kidney, and bladder. TSHZ3 variants in a 5' region were more frequent in CAKUT patients than in gnomAD samples (p < 0.001). Mutant TSHZ3 harboring N-terminal variants showed significantly altered SOX9 and/or myocardin binding, possibly adversely affecting smooth muscle differentiation. Our results provide evidence that heterozygous TSHZ3 variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.

Perceptions, barriers and facilitators regarding nutritional care for patients with chronic limb threatening ischemia: a focus group study among healthcare professionals.

BACKGROUND: Nutrition and nutritional care are essential for optimal outcomes, and, therefore of importance for patients with chronic limb threatening ischemia (CLTI) given their high risk of complications. However, insight is lacking in how healthcare professionals directly involved in the care of patients with CLTI perceive nutritional care, as well as in the perceived barriers and facilitators regarding optimal nutritional care. METHODS: In this qualitative study with a phenomenological approach, three online focus groups were conducted with various healthcare professionals directly involved in the care of patients with CLTI. Sample size was guided by information power. Focus group recordings were transcribed verbatim, and reflexive thematic analysis was performed. RESULTS: Seventeen healthcare professionals participated, including vascular surgeons, fellows in vascular surgery, a medical doctor and researcher, nurse specialized in wound care, general nurse, physical therapists, dietitians, and nutrition assistants. Four themes were generated: (1) nutritional care is crucial for optimal clinical outcomes and a healthy life, (2) insufficient attention to undernutrition and nutritional care by healthcare professionals, (3) patient-related factors challenge healthcare professionals in providing nutritional care, and (4) need for optimizing the organizational process related to nutritional care. Perceived barriers regarding nutritional care included knowledge deficits, nutritional care not being part of the healthcare professionals' routine, missing tools to identify undernutrition, patient-related factors, and time constraints. Facilitators regarding nutritional care included more scientific evidence regarding the effect of nutritional care on clinical outcomes and optimization of organizational processes related to nutritional care. CONCLUSION: Healthcare professionals perceive nutritional care as important for optimal outcomes, but nutritional care is not routinely implemented in the care of patients with CLTI. This lack of implementation of nutritional care may be due to the barriers perceived in various domains. The findings of this study stress the need to optimize nutritional care, with the aim of improving outcomes in the CLTI population.

Rapid on-site histology of lung and pleural biopsies using higher harmonic generation microscopy and artificial intelligence analysis.

Lung cancer is both one of the most prevalent and lethal cancers. To improve health outcomes while reducing the healthcare burden, it becomes crucial to move towards early detection and cost-effective workflows. Currently there is no method for on-site rapid histological feedback on biopsies taken in diagnostic endoscopic or surgical procedures. Higher harmonic generation (HHG) microscopy is a laser-based technique that provides images of unprocessed tissue. Here, we report the feasibility of a HHG portable microscope in the clinical workflow in terms of acquisition time, image quality and diagnostic accuracy in suspected pulmonary and pleural malignancy. 109 biopsies of 47 patients were imaged and a biopsy overview image was provided within a median of 6 minutes after excision. The assessment by pathologists and an artificial intelligence (AI) algorithm showed that image quality was sufficient for a malignancy or non-malignancy diagnosis in 97% of the biopsies, and 87% of the HHG images were correctly scored by the pathologists. HHG is therefore an excellent candidate to provide rapid pathology outcome on biopsy samples enabling immediate diagnosis and (local) treatment.

Quantification Approaches in Non-Target LC/ESI/HRMS Analysis: An Interlaboratory Comparison.

Nontargeted screening (NTS) utilizing liquid chromatography electrospray ionization high-resolution mass spectrometry (LC/ESI/HRMS) is increasingly used to identify environmental contaminants. Major differences in the ionization efficiency of compounds in ESI/HRMS result in widely varying responses and complicate quantitative analysis. Despite an increasing number of methods for quantification without authentic standards in NTS, the approaches are evaluated on limited and diverse data sets with varying chemical coverage collected on different instruments, complicating an unbiased comparison. In this interlaboratory comparison, organized by the NORMAN Network, we evaluated the accuracy and performance variability of five quantification approaches across 41 NTS methods from 37 laboratories. Three approaches are based on surrogate standard quantification (parent-transformation product, structurally similar or close eluting) and two on predicted ionization efficiencies (RandFor-IE and MLR-IE). Shortly, HPLC grade water, tap water, and surface water spiked with 45 compounds at 2 concentration levels were analyzed together with 41 calibrants at 6 known concentrations by the laboratories using in-house NTS workflows. The accuracy of the approaches was evaluated by comparing the estimated and spiked concentrations across quantification approaches, instrumentation, and laboratories. The RandFor-IE approach performed best with a reported mean prediction error of 15× and over 83% of compounds quantified within 10× error. Despite different instrumentation and workflows, the performance was stable across laboratories and did not depend on the complexity of water matrices.

The clinical and genetic spectrum of paediatric speech and language disorders.

Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52 143 individuals, reconstructing clinical histories using a large-scale data-mining approach of the electronic medical records from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of 26 broad speech and language diagnoses. We used natural language processing to assess the degree to which clinical diagnoses in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be retrieved easily through ICD-10 diagnosis codes, whereas stuttering as a speech phenotype was coded in only 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and, to a lesser degree, with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our analysis of electronic medical records were STXBP1 (n = 21), PTEN (n = 20) and CACNA1A (n = 18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of STXBP1 and aphasia (P = 8.57 × 10-7, 95% confidence interval = 18.62-130.39) and MYO7A with speech and language development delay attributable to hearing loss (P = 1.24 × 10-5, 95% confidence interval = 17.46-infinity). Finally, in a sub-cohort of 726 individuals with whole-exome sequencing data, we identified an enrichment of rare variants in neuronal receptor pathways, in addition to associations of UQCRC1 and KIF17 with expressive aphasia, MROH8 and BCHE with poor speech, and USP37, SLC22A9 and UMODL1 with aphasia. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.

Quantitation of the DNA-dependent protein kinase inhibitor peposertib (M3814) and metabolite in human plasma by LC-MS/MS.

The DNA-dependent protein kinase (DNA-PK) is an abundant nuclear protein that mediates DNA double-strand break repair by nonhomologous end joining (NHEJ). As such, DNA-PK is critical for V(D)J recombination in lymphocytes and for survival in cells exposed to ionizing radiation and clastogens. Peposertib (M3814) is a small molecule DNA-PK inhibitor currently in preclinical and clinical development for cancer treatment. We have developed a high-performance liquid chromatography-mass spectrometry method for quantitating peposertib and its metabolite in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex Synergi polar reverse phase (4 µm, 2 × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000 with electrospray, positive-mode ionization. The assay was linear from 10 to 3000 ng/mL for peposertib and 1-300 ng/mL for the metabolite and proved to be both accurate (97.3%-103.7%) and precise (<8.9%CV) fulfilling criteria from the Food and Drug Administration (FDA) guidance on bioanalytical method validation. This liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay will support several ongoing clinical studies by defining peposertib pharmacokinetics.

Granulomas in Common Variable Immunodeficiency Display Different Histopathological Features Compared to Other Granulomatous Diseases.

Granulomatous disease affects up to 20% of patients with Common Variable Immunodeficiency (CVID). Granulomas are comprised of highly activated immune cells, and emerge in response to antigenic triggers. In CVID granulomas however, the underlying pathophysiology is unclear and the specific trigger remains unknown. Granuloma formation in CVID is often compared to sarcoidosis, although clinical context and prognosis differ, suggesting a different pathogenesis. The aim of this study was to investigate if the cellular organization and proteomics of granulomas in CVID is different from other granulomatous diseases. Therefore, tissue slides from formaldehyde fixed paraffin embedded biopsies obtained from patients with CVID, sarcoidosis, tuberculosis and foreign-material induced pseudo-sarcoidosis were stained with hematoxylin and eosin and assessed for histopathological characteristics. Targeted spatial protein analysis was performed, and immune fluorescent multiplex assays were used to analyze the cellular organization. Histological analysis revealed that CVID granulomas were smaller, less circumscribed, with fewer multinucleated giant cells and minimal fibrosis compared to the other granulomatous diseases. Spatial protein analysis showed that granulomas in all diseases expressed CD68, CD11c, CD44, CD127, and PD-L1. However in CVID, reduced expression of the fibrosis-related protein fibronectin, but enrichment of CD163, CD3 and FAPα inside CVID granulomas was observed. Immunofluorescence analysis conformed a different cellular organization in CVID granulomas with increased influx of neutrophils, macrophages, T and B lymphocytes. In conclusion, granulomas in CVID display a different histological and cellular organization with increased influx of myeloid and lymphoid cells, compared to sarcoidosis, tuberculosis and pseudo-sarcoidosis, indicating a distinct pathogenesis underlying granuloma formation.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections. METHODS: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (109 cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score. RESULTS: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes. CONCLUSIONS: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.

The future of algal blooms in lakes globally is in our hands.

Lakes are fundamental to society and nature, yet they are currently exposed to excessive nutrients and climate change, resulting in algal blooms. In the future, this may change, but how and where still needs more scientific attention. Here, we explore future trends in algal blooms in lakes globally for >3500 'representative lakes' for the year 2050, considering the attribution of both nutrient and climate factors. We soft-coupled a process-based lake ecosystem model (PCLake+) with a watershed nutrient model (MARINA-Multi) to assess trends in algal blooms in terms of the Trophic State Index for chlorophyll-a (TSI-Chla). Globally between 2010 and 2050, we show a rising trend in algal blooms under fossil-fuelled development (TSI-Chla increase in 91 % of lakes) and a declining trend under sustainable development (TSI-Chla decrease in 63 % of lakes). These changes are significantly attributed to nutrients. While not always significant, climate change attributions point to being unfavourable for lakes in 2050, exacerbating lake water quality. Our study stresses prioritising responsible nutrient and climate management on policy agendas. This implies that the future of algal blooms in lakes is in our hands.

Rbm3 deficiency leads to transcriptome-wide splicing alterations.

Rbm3 (RNA-binding motif protein 3) is a stress responsive gene, which maintains cellular homeostasis and promotes survival upon various harmful cellular stimuli. Rbm3 protein shows conserved structural and molecular similarities to heterogeneous nuclear ribonucleoproteins (hnRNPs), which regulate all steps of the mRNA metabolism. Growing evidence is pointing towards a broader role of Rbm3 in various steps of gene expression. Here, we demonstrate that Rbm3 deficiency is linked to transcriptome-wide pre-mRNA splicing alterations, which can be reversed through Rbm3 co-expression from a cDNA. Using an MS2 tethering assay, we show that Rbm3 regulates splice site selection similar to other hnRNP proteins when recruited between two competing 5 ' splice sites. Furthermore, we show that the N-terminal part of Rbm3 encompassing the RNA recognition motif (RRM), is sufficient to elicit changes in splice site selection. On the basis of these findings, we propose a novel, undescribed function of Rbm3 in RNA splicing that contributes to the preservation of transcriptome integrity.

The Effects of Colchicine on Lipoprotein(a) and Oxidized Phospholipid Associated Cardiovascular Disease Risk.

AIMS: Inflammatory lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPLs) on lipoproteins convey residual cardiovascular disease risk. The LoDoCo2 (low-dose colchicine 2) trial showed that colchicine reduced the risk for cardiovascular events occurring on standard therapies in patients with chronic coronary disease (CCS). We explored the effects of colchicine on Lp(a) and oxidized lipoprotein associated risk in a LoDoCo2 biomarker subpopulation. METHODS: Lp(a), OxPLs on apolipoprotein(a) [OxPL-apo(a)] and apolipoprotein B (OxPL-apoB) levels were determined in the biomarker population of the LoDoCo2 trial (n = 1777). Cox regression analysis was used to compare the risk for the primary endpoint, consisting of myocardial infarction, ischemic stroke, or ischemia-driven revascularization by biomarker levels. Interactions between treatment, Lp(a) and OxPL levels were evaluated. RESULTS: Lp(a), OxPL-apo(a) and OxPL-apoB levels were similar between the colchicine and placebo groups. Consistent risk reduction by colchicine was observed in those with Lp(a) <125 nmol/L and ≥125 nmol/L, and the highest OxPL-apo(a) tertile compared to the lowest (Pinteraction=0.92 and 0.66). The absolute risk reduction for those with Lp(a) ≥125 nmol/L appeared higher compared to those with Lp(a) <125 nmol/L (4.4% vs 2.4%). A treatment interaction for colchicine was found in those with the highest OxPL-apoB tertile vs the lowest (Pinteraction=0.04). CONCLUSION: In patients with CCS, colchicine reduces cardiovascular disease risk in those with and without elevated Lp(a) but absolute benefits appeared higher in those with Lp(a) ≥125 nmol/L. Patients with higher levels of OxPL-apoB experienced greater benefit of colchicine, suggesting colchicine may be more effective in subjects with heightened oxidation-driven inflammation.

Oxidized circulating particles containing lipids and proteins (lipoproteins), including lipoprotein(a), are inflammatory and increase the risk for heart disease. Colchicine, an anti-inflammatory agent, reduces heart disease risk in patients with elevated levels of lipoprotein(a).Colchicine was more effective at reducing heart disease risk in patients with high levels of oxidized apoB containing lipoproteins compared to those with lower levels.

Exploring the Impact of the ß-Catenin Mutations in Hepatocellular Carcinoma: An In-Depth Review.

Liver cancer, primarily hepatocellular carcinoma, represents a major global health issue with significant clinical, economic, and psychological impacts. Its incidence continues to rise, driven by risk factors such as hepatitis B and C infections, nonalcoholic steatohepatitis, and various environmental influences. The Wnt/ß-Catenin signaling pathway, frequently dysregulated in HCC, emerges as a promising therapeutic target. Critical genetic alterations, particularly in the CTNNB1 gene, involve mutations at key phosphorylation sites on ß-catenin's N-terminal domain (S33, S37, T41, and S45) and in armadillo repeat domains (K335I and N387 K). These mutations impede ß-catenin degradation, enhancing its oncogenic potential. In addition to genetic alterations, molecular and epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNAs, further influence ß-catenin signaling and tumor progression. However, ß-catenin activation alone is insufficient for hepatocarcinogenesis; additional genetic "hits" are required for tumor initiation. Mutations or alterations in genes such as Ras, c-Met, NRF2, and LKB1, when combined with ß-catenin activation, significantly contribute to HCC development and progression. Understanding these cooperative mutations provides crucial insights into the disease and reveals potential therapeutic strategies. The complex interplay between genetic variations and the tumor microenvironment, coupled with novel therapeutic approaches targeting the Wnt/ß-Catenin pathway, offers promise for improved treatment of HCC. Despite advances, translating preclinical findings into clinical practice remains a challenge. Future research should focus on elucidating how specific ß-catenin mutations and additional genetic alterations contribute to HCC pathogenesis, leveraging genetically clengineered mouse models to explore distinct signaling impacts, and identifying downstream targets. Relevant clinical trials will be essential for advancing personalized therapies and enhancing patient outcomes. This review provides a comprehensive analysis of ß-Catenin signaling in HCC, highlighting its role in pathogenesis, diagnosis, and therapeutic targeting, and identifies key research directions to improve understanding and clinical outcomes.

Comprehensive two-dimensional gas chromatography as a tool for targeted and non-targeted analysis of contaminants of emerging concern in wastewater.

Wastewater is a major reservoir for chemical contaminants, both anthropogenic and biogenic. Recent chemical and toxicological analysis reveals the abundance and impact of these compounds, often termed contaminants of emerging concern (CECs). Concurrently, incomplete removal of these compounds in wastewater treatment plants sets a precedent for detailed characterisation and monitoring of such substances. Although liquid chromatography (LC) is frequently used for analysis of CECs in wastewater, gas chromatography (GC) maintains its significance for non-polar to mid-polar analytes. GC offers advantages such as increased separation efficiency, fewer matrix effects, and greater availability and reliability of reference mass spectra compared to LC. Comprehensive two-dimensional gas chromatography (GC × GC) delivers unmatched peak capacity and separational capabilities, critical in the resolution of diverse compound groups present within wastewater. When coupled with high resolution mass spectrometry, it provides a powerful identification tool with spectral databases and both 1st and 2nd dimensional retention indices, and has allowed for the separation, reliable annotation and characterisation of diverse CECs within wastewater in recent years. Herein, on the basis of recent studies from the last fifteen years, we outline cutting-edge methodologies and strategies for wastewater analysis using GC × GC. This includes sample preparation, derivatization of polar analytes, instrumental setup, and data analysis, ultimately providing the reader a framework for future non-targeted analysis of wastewater and other complex environmental matrices.