Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.

• MeSH
• Induced Pluripotent Stem Cells metabolism   MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Mutation MeSH
• Vesicular Transport Proteins * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Bacterial resistance has become a global concern for public health agencies. Various resistance mechanisms found in Staphylococcus aureus strains grant this bacterium resistance to a wide range of antibiotics, contributing to the rise in human mortality worldwide. Resistance mediated by efflux pumps is one of the most prevalent mechanisms in multi-resistant bacteria, which has aroused the interest of several researchers in the search for possible efflux pump inhibitors. In view of the aforementioned considerations, it is important that new strategies, such as the synthesis of chalcones, be made available as a viable strategy in antimicrobial therapy. In this study, the synthesized chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one was tested for its antibacterial activity, focusing on antibiotic modification and the inhibition of the MepA efflux pump present in S. aureus strain K2068. The broth microdilution method, using microdilution plates, was employed in microbiological tests to determine the minimum inhibitory concentration of the chalcone, antibiotics, and ethidium bromide. The results show that while the chalcone did not exhibit direct antibacterial activity, it synergistically enhanced the effects of ciprofloxacin and ethidium bromide, as evidenced by the reduction in MICs. In addition, computer simulations of molecular docking demonstrate that the tested chalcone acts on the same binding site as the efflux pump inhibitor chlorpromazine, interacting with essentially the same residues. These data suggest that the chalcone may act as a MepA inhibitor.

• MeSH
• Anti-Bacterial Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Bacterial Proteins * metabolism   genetics   chemistry   antagonists & inhibitors   MeSH
• Chalcone * pharmacology   chemistry   MeSH
• Chalcones * pharmacology   chemistry   MeSH
• Humans MeSH
• Membrane Transport Proteins * metabolism   genetics   chemistry   MeSH
• Microbial Sensitivity Tests MeSH
• Multidrug Resistance-Associated Proteins * metabolism   genetics   chemistry   MeSH
• Molecular Docking Simulation MeSH
• Staphylococcus aureus * drug effects   genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Inhibitory Janusových kináz (JAK) patří k novějším terapeutickým modalitám v léčbě zánětlivých revmatických onemocnění. Našly si své místo v terapii u nemocných s refrakterním onemocněním, u kterých došlo k selhání nejen konvenčních chorobu modifikujících léků, ale i biologik. Nitrobuněčná signalizace prostřednictvím JAK je aktivována navázáním celé řady cytokinů na odpovídající buněčné receptory a dochází k aktivaci transkripčních proteinů (signal transducer and activator of transcription protein, STAT) a v konečné fázi dochází k transkripci genů zapojených do imunitní odpovědi. Filgotinib je inhibitor JAK s pětinásobně vyšší selektivitu pro JAK1 než pro JAK2, JAK3 a TYK2. V současné době je schválen v České republice pro terapii revmatoidní artritidy a ulcerózní kolitidy.

Janus kinase (JAK) inhibition is a newer therapeutic approach for treating autoimmune inflammatory rheumatic diseases. It has found its place in the therapy of patients with refractory disease, in whom not only conventional disease-modifying drugs have failed, but also biologics. JAKs activate intracellular signaling by binding to cellular receptors and activating signal transducers and activator of transcription (STAT) proteins, which ultimately lead to the transcription of genes involved in the immune response. Filgotinib is a JAK inhibitor with fivefold higher selectivity for JAK1 than for JAK2, JAK3, and TYK2. It is currently approved in the Czech Republic for the treatment of rheumatoid arthritis and ulcerative colitis.

Pancreatic cancer (PC), particularly pancreatic ductal adenocarcinoma (PDAC), is a significant global health issue with high mortality rates. PDAC, though only 3 % of cancer diagnoses, causes 7 % of cancer deaths due to its severity and asymptomatic early stages. Risk factors include lifestyle choices, environmental exposures, and genetic predispositions. Conditions like new-onset type 2 diabetes and chronic pancreatitis also contribute significantly. Modifiable risk factors include smoking, alcohol consumption, non-alcoholic fatty pancreatic disease (NAFPD), and obesity. Smoking and heavy alcohol consumption increase PC risk, while NAFPD and obesity, particularly central adiposity, contribute through chronic inflammation and insulin resistance. Refined sugar and sugar-sweetened beverages (SSBs) are also linked to increased PC risk, especially among younger individuals. Hormonal treatments and medications like statins, aspirin, and metformin have mixed results on PC risk, with some showing protective effects. The gut microbiome influences PC through the gut-pancreas axis, with disruptions leading to inflammation and carcinogenesis. Exposure to toxic substances, including heavy metals and chemicals, is associated with increased PC risk. Glycome changes, such as abnormal glycosylation patterns, are significant in PDAC development and offer potential for early diagnosis. Interactions between environmental and genetic factors are crucial in PDAC susceptibility. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) linked to PDAC, but gene-environment interactions remain largely unexplored. Future research should focus on polygenic risk scores (PRS) and large-scale studies to better understand these interactions and their impact on PDAC risk.

• MeSH
• Carcinoma, Pancreatic Ductal * etiology   epidemiology   pathology   MeSH
• Exposome * MeSH
• Genetic Predisposition to Disease MeSH
• Humans MeSH
• Pancreatic Neoplasms * etiology   epidemiology   pathology   MeSH
• Risk Factors MeSH
• Environmental Exposure * adverse effects   MeSH
• Life Style * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) causes/predisposes to advanced chronic liver disease. However, the role of the SERPINA1 Pi∗ZZ genotype in patients with decompensated cirrhosis is unclear. Thus, we evaluated the impact of the Pi∗ZZ genotype on the disease course after the first hepatic decompensation event. METHODS: We retrospectively included 59 adults with decompensated cirrhosis and severe AATD (Pi∗ZZ) from 12 European tertiary care centres. First decompensation was considered as baseline. To compare the course of AATD to other cirrhosis aetiologies, we applied propensity score matching for Child-Turcotte-Pugh (CTP) score as well as age/sex. Patients were followed until further decompensation, liver transplantation or liver-related death. RESULTS: Most patients were male (74.6%), with a mean age of 55 years. The most common type of first decompensation was ascites (n = 40; 67.8%), followed by variceal bleeding (n = 13; 22.0%) and overt hepatic encephalopathy (n = 6; 10.2%). Median CTP and MELD (model for end-stage liver disease) scores at first decompensation were 8 and 14, respectively. Median MELD scores were 16 and 20 points at listing and liver transplantation (median time on list: 2.9 [IQR 1.1-7.2] months), respectively. Patients with other aetiologies (subdistribution hazard ratio: steatotic liver disease: 0.62, 95% CI 0.44-0.88, p = 0.007; abstinent alcohol-associated liver disease: 0.50, 95% CI 0.35-0.71, p <0.001; hepatitis C virus-associated cirrhosis: 0.56, 95% CI 0.37-0.83, p = 0.004) had a significantly lower risk of further hepatic decompensation, liver transplantation, or liver-related death, compared to those with Pi∗ZZ. Exchanging further decompensation with acute-on-chronic liver failure yielded similar results. CONCLUSION: Our study defines the course of decompensated cirrhosis in patients with severe AATD (Pi∗ZZ), who are particularly prone to complications of cirrhosis and exhibit a more progressive disease course than those with cirrhosis of other aetiologies. IMPACT AND IMPLICATIONS: Alpha-1 antitrypsin deficiency is an inherited disease that affects the lung and the liver. Carrying two severely dysfunctional copies of the alpha-1 antitrypsin gene may cause advanced chronic liver disease/cirrhosis. Affected individuals with a first complication of cirrhosis are more prone to developing further liver-related events (including multiorgan dysfunction) and requiring liver transplantation (which cures the inherited liver disease) compared to patients who have similarly advanced liver disease. These findings should prompt the development of disease-modifying treatments and early listing for liver transplantation.

• Publication type
• Journal Article MeSH

Genetika neurodegeneratívnych demencií je turbulentnou témou súčasnosti. Na jednej strane sa postupne zvyšuje množstvo génov zapojených do patogenézy neurodegeneratívnych procesov, na druhej strane vystupuje problém s interpretáciou dosiahnutých výsledkov. Alzheimerova choroba (AD) a demencia s Lewyho telieskami (DLB) predstavujú v súčasnosti dobre definované klinické jednotky. Alzheimerova choroba má jasne určené kauzálne gény (APP, PSEN1, PSEN2) a významný gén susceptibility (APOE). Popri nich sa postupne objavujú nové gény susceptibility, ktoré modifikujú klinický obraz, vek nástupu ochorenia a spolu s APOE vytvárajú komplikované genetické pozadie. Demencia s Lewyho telieskami je heterogénnejšou entitou ako Alzheimerova choroba z klinického aj genetického hľadiska. Génmi susceptibility DLB sú viaceré gény zdieľané s Alzheimerovou chorobou, Parkinsonovou chorobou (PD), frontotemporálnou demenciou (FTD) a inými neurodegeneráciami. V našom príspevku sa snažíme sumarizovať genetické pozadie AD a DLB, charakterizovať ich podobnosti a rozdiely a poukázať na komplexnosť neurodegeneratívneho ekosystému ("neurodegeneratómu").

The genetics of neurodegenerative dementias is a turbulent topic. On the one hand, the number of genes involved in the pathogenesis of neurodegenerative processes is gradually increasing, on the other hand, the problem of interpretation of the results is emerging. Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) represent currently well-defined clinical entities. AD has clearly defined causal genes (APP, PSEN1, PSEN2) and a major susceptibility gene (APOE). In addition to these, new susceptibi­lity genes are gradually emerging that modify the clinical picture, the age of onset and, together with APOE, create a complicated genetic background. Dementia with Lewy bodies (DLB) is a more heterogeneous entity than Alzheimer's disease, both clinically and genetically. DLB susceptibility genes are multiple genes shared with Alzheimer`s disease, Parkinson disease, frontotemporal dementia (FTD) and other neurodegenerations. In our paper, we aim to summarize the genetic background of both AD and DLB, to characterize their similarities and differences, and to highlight the complexity of the neurodegenerative ecosystem ("neurodegeneratome").

• MeSH
• Alzheimer Disease * diagnosis   genetics   MeSH
• Apolipoproteins metabolism   MeSH
• Lewy Body Disease * diagnosis   genetics   MeSH
• Epigenomics classification   MeSH
• Genetic Background MeSH
• Genetic Testing methods   MeSH
• Humans MeSH
• Neurodegenerative Diseases diagnosis   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Nonspecific structural chromosomal aberrations (CAs) are found in around 1% of circulating lymphocytes from healthy individuals but the frequency may be higher after exposure to carcinogenic chemicals or radiation. CAs have been used in the monitoring of persons exposed to genotoxic agents and radiation. Previous studies on occupationally exposed individuals have shown associations between the frequency of CAs in peripheral blood lymphocytes and subsequent cancer risk. The cause for CA formation is believed to be unrepaired or insufficiently repaired DNA double-strand breaks or other DNA damage, and additionally telomere shortening. CAs include chromosome (CSAs) and chromatid type aberrations (CTAs). In the present review, we first describe the types of CAs, the conventional techniques used for their detection and some aspects of interpreting the results. We then focus on germline genetic variation in the frequency and type of CAs measured in a genome-wide association study in healthy individuals in relation to occupational and smoking-related exposure compared to nonexposed referents. The associations (at P < 10-5) on 1473 healthy individuals were broadly classified in candidate genes from functional pathways related to DNA damage response/repair, including PSMA1, UBR5, RRM2B, PMS2P4, STAG3L4, BOD1, COPRS, and FTO; another group included genes related to apoptosis, cell proliferation, angiogenesis, and tumorigenesis, COPB1, NR2C1, COPRS, RHOT1, ITGB3, SYK, and SEMA6A; a third small group mapped to genes KLF7, SEMA5A and ITGB3 which were related to autistic traits, known to manifest frequent CAs. Dedicated studies on 153 DNA repair genes showed associations for some 30 genes, the expression of which could be modified by the implicated variants. We finally point out that monitoring of CAs is so far the only method of assessing cancer risk in healthy human populations, and the use of the technology should be made more attractive by developing automated performance steps and incorporating artificial intelligence methods into the scoring.

• MeSH
• Genome-Wide Association Study * MeSH
• Chromosome Aberrations * MeSH
• Gene-Environment Interaction MeSH
• Humans MeSH
• Lymphocytes metabolism   MeSH
• Neoplasms genetics   MeSH
• DNA Repair genetics   MeSH
• DNA Damage MeSH
• Occupational Exposure adverse effects   MeSH
• Environmental Exposure adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel-Lindau (VHL) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes VHL, PRCC, and PBRM1. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.

• MeSH
• DNA-Binding Proteins MeSH
• Epigenesis, Genetic * genetics   MeSH
• Epigenome * genetics   MeSH
• Carcinoma, Renal Cell * genetics   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosome Mapping methods   MeSH
• DNA Methylation * genetics   MeSH
• Von Hippel-Lindau Tumor Suppressor Protein genetics   MeSH
• Kidney Neoplasms * genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Transcription Factors MeSH
• DNA Copy Number Variations * genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Low levels of vitamin D have been associated with several autoimmune diseases. A growing body of evidence supports the association of vitamin D with skeletal muscle damage, regeneration, and energy and lipid metabolism. The aim was to analyse vitamin D and its receptor (VDR) in the muscle tissue of patients with idiopathic inflammatory myopathies (IIM) and to relate them to clinical parameters and muscle lipid and energy metabolism. METHODS: Forty-six patients with IIM and 67 healthy controls (HC) were included in the study. 27 IIM patients participated in a 24-week exercise intervention. Muscle biopsies were obtained from 7 IIM patients before/after training, 13 non-exercising IIM controls, and 21 HC. Circulating concentrations of 25(OH)D and 1,25(OH)D were measured. Gene expression of VDR and CYP27B1, the enzyme converting 25(OH)D to hormonally active 1,25(OH)D, was determined by qPCR in muscle tissue and primary muscle cells. Lipid oxidative metabolism was assessed in muscle tissue (mRNA, qPCR) and primary muscle cells (radioactive assays). RESULTS: Lower levels of active 1,25(OH)D were observed in IIM patients compared with HC (mean ± SD: 125.0 ± 45.4 vs. 164.7 ± 49.2 pmol/L; p < 0.0001). 25(OH)D was associated with CRP (r = -0.316, p = 0.037), MITAX (r = -0.311, p = 0.040) and HAQ (r = -0.390, p = 0.009) in IIM. After 24 weeks of training, active 1,25(OH)D was associated with MMT8 (r = 0.866, p < 0.0001), FI-2 (r = 0.608, p = 0.013) and HAQ (r = -0.537, p = 0.032). Gene expression of both VDR and CYP27B1 in primary muscle cells decreased after training (p = 0.031 and p = 0.078, respectively). Associations of VDR mRNA in muscle tissue with MMT-8 (IIM: r = -0.559, p = 0.013), serum CK (HC: r = 0.484, p = 0.031), myoglobin (IIM: r = 0.510, p = 0.026) and myostatin (IIM: r = -0.519, p = 0.023) were observed. The expression of VDR in differentiated muscle cells correlated negatively with the complete oxidation of palmitic acid (r = -0.532, p = 0.028). Muscle mRNA of carnitine palmitoyl transferase 1 (CPT1) (downregulated in IIM, p = 0.001) correlated positively with serum 1,25(OH) vitamin D (r = 0.410, p = 0.042). CONCLUSION: Reduced biologically active vitamin D in circulation suggests its impaired metabolism in IIM. Serum vitamin D levels and gene expression of its receptor and activating enzyme in muscle tissue were modified by regular exercise and associated with disease manifestations, physical fitness, and muscle lipid metabolism of IIM patients.

• MeSH
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase metabolism   MeSH
• Adult MeSH
• Muscle, Skeletal * metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipid Metabolism * physiology   MeSH
• Myositis * metabolism   MeSH
• Receptors, Calcitriol * metabolism   MeSH
• Aged MeSH
• Physical Fitness * physiology   MeSH
• Vitamin D * blood   metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

• MeSH
• Molecular Targeted Therapy * MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 * metabolism   genetics   antagonists & inhibitors   MeSH
• Neoplasms * drug therapy   metabolism   genetics   MeSH
• Antineoplastic Agents * therapeutic use   pharmacology   MeSH
• Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH