Identifying biological markers to guide treatment decisions in first-episode psychosis (FEP) is essential for improving patient outcomes. This longitudinal study investigated DNA methylation (DNAm) patterns and DNAm-derived cell-type proportions (CTP) in blood and associated them with response to risperidone treatment, a second-generation antipsychotic drug, in antipsychotic-naïve FEP patients. We also explored longitudinal changes in DNAm associated with risperidone treatment. We profiled DNAm in 114 individuals before (anFEP) and after two months of risperidone treatment using microarrays. The main results were compared with 115 healthy controls and validated in an independent cohort of subjects with schizophrenia (n = 26) with one-month follow-up data. We identified 302 differentially methylated positions (DMPs) associated with treatment response, measured by changes in the Positive and Negative Syndrome Scale score, of which 16 were validated in the independent cohort. Sixteen differentially methylated regions (DMRs) were associated with response, with one (in SIPA1L3) being validated. A decrease in B-cell proportions was correlated with symptom improvement in both cohorts. Additionally, four DMPs associated with risperidone treatment were identified: two related to the psychotic state and two specifically to risperidone treatment. DNAm-derived CTP showed alterations in anFEP compared with controls, particularly in the neutrophil-to-lymphocyte ratio, which normalized after treatment. These findings suggest that DNAm, particularly in B-cells, may be a promising marker for monitoring response to risperidone treatment in schizophrenia. Our longitudinal study revealed novel and known genes that may be regulated by risperidone and could be used as response markers to improve prognosis in schizophrenia and FEP.
- MeSH
- Antipsychotic Agents * therapeutic use MeSH
- Adult MeSH
- Humans MeSH
- Longitudinal Studies MeSH
- DNA Methylation * drug effects MeSH
- Adolescent MeSH
- Young Adult MeSH
- Psychotic Disorders * drug therapy genetics blood MeSH
- Risperidone * therapeutic use pharmacology MeSH
- Schizophrenia * drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Virové bradavice jsou celosvětově časté onemocnění způsobené lidským papilomavirem, který má řadu genotypů. Mnoho z těchto virů je komenzálních a u imunokompetentních hostitelů nevyvolávají žádné projevy. Za vhodných podmínek některé způsobují klinické změny na kůži nebo na sliznicích v anogenitální či orofaryngeální oblasti. U dětí se nejčastěji setkáváme s verruca vulgaris, verruca plantaris a verruca plana. Řada těchto projevů samovolně vymizí, problémem jsou perzistentní či úporně recidivující bradavice. Léčbou se snažíme nejen zlikvidovat viditelné změny za minimalizace bolesti a bez jizvení, ale také o prevenci recidivy ať již v místě původní bradavice nebo kdekoli jinde na těle.
Viral warts are a common disease worldwide caused by the human papillomavirus, which has a number of genotypes. Many of these viruses are commensal and do not cause any symptoms in immunocompetent hosts. Under appropriate conditions, however, some cause clinical changes on the skin or mucous membranes in the anogenital or oropharyngeal part. Verruca vulgaris, verruca plantaris and verruca plana are most often encountered in children. Many of these manifestations disappear on their own, the problem is persistent or stubbornly recurring warts. With the treatment, we try not only to eliminate visible changes while minimizing pain and without scarring, but also to prevent recurrence, whether at the site of the original wart or anywhere else on the body.
- MeSH
- Warts * drug therapy therapy MeSH
- Child * MeSH
- Fluorouracil pharmacology therapeutic use MeSH
- Papillomavirus Infections transmission therapy MeSH
- Keratinocytes pathology MeSH
- Cryotherapy methods MeSH
- Salicylic Acid therapeutic use MeSH
- Trichloroacetic Acid therapeutic use MeSH
- Lasers MeSH
- Humans MeSH
- Podophyllin pharmacology therapeutic use MeSH
- Check Tag
- Child * MeSH
- Humans MeSH
The regulation of the pyrimidine biosynthetic pathway by pyrimidines was investigated in the biological control agent Pseudomonas aureofaciens ATCC 17418. Using succinate as a carbon source, orotic acid or uracil supplementation had a repressive effect in ATCC 17418 cells on dihydroorotate dehydrogenase or orotidine 5'- monophosphate decarboxylase activity but only orotic acid supplementation appeared to repress the level of orotate phosphoribosyltransferase activity. In glucose-grown ATCC 17418 cells, orotic acid supplementation appeared to repress the level of phosphoribosyltransferase or decarboxylase while uracil supplementation depressed the dihydroorotase, dehydrogenase, and decarboxylase activities. The pyrimidine auxotrophic mutant strain GW-2, isolated from ATCC 17418 using chemical mutagenesis and resistance to 5-fluoroorotic acid, was found to be deficient for orotidine 5'-monophosphate decarboxylase activity. Pyrimidine limitation of the succinate-grown mutant strain cells resulted in only a slight derepression of transcarbamoylase activity while pyrimidine limitation of glucose-grown mutant cells caused a derepression of the four active pyrimidine biosynthetic enzyme activities relative to their activities in the mutant cells grown with excess uracil. The control of the known regulatory enzyme aspartate transcarbamoylase was examined in P. aureofaciens ATCC 17418. Transcarbamoylase activity was shown to be inhibited by pyrophosphate, ATP, UTP, and ADP. It was concluded that the pyrimidine biosynthetic pathway in P. aureofaciens ATCC 17418 was subject to regulation at the transcriptional level and at the level of aspartate transcarbamoylase activity, which could be valuable in comprehending its nucleic acid metabolism as well as its taxonomic assignment to the Pseudomonas chlororaphis homology group.
- MeSH
- Aspartate Carbamoyltransferase metabolism MeSH
- Bacterial Proteins metabolism genetics MeSH
- Biosynthetic Pathways MeSH
- Dihydroorotate Dehydrogenase MeSH
- Glucose metabolism MeSH
- Succinic Acid metabolism MeSH
- Orotic Acid metabolism MeSH
- Orotate Phosphoribosyltransferase metabolism MeSH
- Orotidine-5'-Phosphate Decarboxylase metabolism genetics MeSH
- Oxidoreductases Acting on CH-CH Group Donors metabolism MeSH
- Pseudomonas * metabolism genetics enzymology MeSH
- Pyrimidines * biosynthesis MeSH
- Gene Expression Regulation, Bacterial * MeSH
- Uracil metabolism MeSH
- Publication type
- Journal Article MeSH
18letý chlapec s epilepsií a multifokální motorickou neuropatií po očkování proti chřipce byl přijat k hospitalizaci pro respirační infekci a stav po epileptickém paroxysmu. Při přijetí byl klinický nález až na chabou paraparézu dolních končetin jako reziduum multifokální neuropatie a faryngitidu chudý, laboratorně byla trombopenie a elevace zánětlivých markerů. Za 36 hodin od přijetí se rozvíjí kvalitativní porucha vědomí charakteru deliria s halucinacemi, bludy, poruchou paměti, výrazným motorickým neklidem a spánkovou inverzí. Chlapec byl následně přeložen na jednotku intenzivní péče. Bylo provedeno toxikologické a neurologické vyšetření s lumbální punkcí, MR i CT mozku, vše s negativním nálezem, psychiatrické vyšetření se závěrem organické delirium. Chlapec byl i přes vysoké dávky midazolamu, chlorpromazinu a risperidonu stále delirantní. Až po opakovaných rozhovorech chlapec přiznává abúzus alkoholu, zejména absintu, to potvrzuje i vysoká hladina CDT. Po nasazení klomethiazolu příznaky deliria rychle ustoupily.
An 18-year-old boy with epilepsy and multifocal motor neuropathy after influenza vaccination was admitted for respiratory infection and after an epileptic seizure. On admission, clinical findings were poor except for peripheral paraparesis as residual multifocal neuropathy and pharyngitis, with thrombopenia and elevation of inflammatory markers in the admission laboratory. Within 36 hours, he developed a qualitative disruption of consciousness in the nature of delirium with hallucinations, delusions, memory impairment, marked motor restlessness, and sleep inversion. The boy was subsequently transferred to the intensive care unit. Toxicological and neurological examination with lumbar puncture, MRI and CT of the brain were performed, all with negative findings, and psychiatric examination concluded organic delirium. The boy was still delirious despite high doses of midazolam, chlorpromazine and risperidone. Only after repeated interviews did the boy admit to alcohol abuse, especially absinthe, as confirmed by a high CDT level. After the administration of clomethiazole, the symptoms of delirium quickly subsided.
- MeSH
- Alcohol Withdrawal Delirium * etiology complications MeSH
- Chlorpromazine pharmacology therapeutic use MeSH
- Epilepsy drug therapy MeSH
- Respiratory Tract Infections drug therapy MeSH
- Carbohydrate Dehydrogenases analysis MeSH
- Humans MeSH
- Midazolam pharmacology therapeutic use MeSH
- Adolescent * MeSH
- Polyneuropathies etiology MeSH
- Consciousness Disorders etiology MeSH
- Risperidone pharmacology therapeutic use MeSH
- Seizures * etiology MeSH
- Check Tag
- Humans MeSH
- Adolescent * MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
Chemoresistance represents a major issue affecting cancer therapy efficacy. Because microRNAs (miRNAs) regulate gene expression on multiple levels, their role in chemoresistance development is reasonably certain. In our previous study, miR-122-5p and miR-142-5p were identified as diagnostic, prognostic, and predictive biomarkers for primary and metastatic rectal cancer. The aim of the present study was to investigate whether these miRNAs can also reflect the disease course of patients with colon cancer (CC). Further, we focused on a deeper understanding of their involvement in 5-fluorouracil (5-FU) chemoresistance development.
- MeSH
- Drug Resistance, Neoplasm * genetics MeSH
- Fluorouracil * therapeutic use pharmacology MeSH
- Middle Aged MeSH
- Humans MeSH
- MicroRNAs * genetics blood MeSH
- Biomarkers, Tumor genetics blood MeSH
- Colonic Neoplasms * genetics drug therapy blood pathology MeSH
- Prognosis MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: To validate the prognostic value of the PAncreatic NeoAdjuvant MAssachusetts (PANAMA) score and to determine its predictive ability for survival benefit derived from adjuvant treatment in patients after resection of pancreatic ductal adenocarcinoma (PDAC) following neoadjuvant FOLFIRINOX. BACKGROUND: The PANAMA score was developed to guide prognostication in patients after neoadjuvant therapy and resection for PDAC. As this score focuses on the risk for residual disease after resection, it might also be able to select patients who benefit from adjuvant after neoadjuvant therapy. METHODS: This retrospective international multicenter study is endorsed by the European-African Hepato-Pancreato-Biliary Association. Patients with PDAC who underwent resection after neoadjuvant FOLFIRINOX were included. Mantel-Cox regression with interaction analysis was performed to assess the impact of adjuvant chemotherapy. RESULTS: Overall, 383 patients after resection of PDAC following neoadjuvant FOLFIRINOX were included of whom 187 (49%), 137 (36%), and 59 (15%) had a low-risk, intermediate-risk, and high-risk PANAMA-score, respectively. Discrimination in median overall survival (OS) was observed stratified by risk groups (48.5, 27.6, and 22.3 months, log-rank Plow-intermediate = 0.004, log-rank Pintermediate-high = 0.027). Adjuvant therapy was not associated with an OS difference in the low-risk group [hazard ratio (HR): 1.50, 95% CI: 0.92-2.50], whereas improved OS was observed in the intermediate (HR: 0.58, 95% CI: 0.34-0.97) and high-risk groups (HR: 0.47, 95% CI: 0.24-0.94; P interaction = 0.008). CONCLUSIONS: The PANAMA 3-tier risk groups (low-risk, intermediate-risk, and high-risk, available through pancreascalculator.com) correspond with differential survival in patients with resected PDAC following neoadjuvant FOLFIRINOX. The risk groups also differentiate between survival benefits associated with adjuvant treatment, with only the intermediate- and high-risk groups associated with improved OS.
- MeSH
- Chemotherapy, Adjuvant MeSH
- Adult MeSH
- Carcinoma, Pancreatic Ductal * mortality therapy drug therapy surgery MeSH
- Fluorouracil therapeutic use MeSH
- Risk Assessment MeSH
- Irinotecan therapeutic use MeSH
- Leucovorin therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Survival Rate MeSH
- Pancreatic Neoplasms * mortality therapy drug therapy surgery MeSH
- Neoadjuvant Therapy MeSH
- Oxaliplatin therapeutic use MeSH
- Pancreatectomy * MeSH
- Prognosis MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Validation Study MeSH
Mismatched nucleobase uracil is commonly repaired through the base excision repair initiated by DNA uracil glycosylases. The data presented in this study strongly indicate that the nuclear uracil-N-glycosylase activity and nuclear protein content in human cell lines is highest in the S phase of the cell cycle and that its distribution kinetics partially reflect the DNA replication activity in replication foci. In this respect, the data demonstrate structural changes of the replication focus related to the uracil-N-glycosylase distribution several dozens of minutes before end of its replication. The analysis also showed that very popular synchronisation protocols based on the double thymidine block can result in changes in the UNG2 content and uracil excision rate. In response, we propose a new method for the description of the changes of the content and the activity of different cell components during cell cycle without the necessity to use synchronisation protocols.
- MeSH
- Cell Nucleus metabolism MeSH
- Cell Cycle MeSH
- Kinetics MeSH
- Humans MeSH
- DNA Repair MeSH
- DNA Replication * MeSH
- S Phase MeSH
- Uracil-DNA Glycosidase * metabolism MeSH
- Uracil metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Colorectal Neoplasms drug therapy MeSH
- Drug Therapy, Combination MeSH
- Communication MeSH
- Quality of Life MeSH
- Humans MeSH
- Neoplasms * drug therapy MeSH
- Palliative Care methods MeSH
- Prognosis MeSH
- Pyrrolidines therapeutic use MeSH
- Truth Disclosure MeSH
- Thymine therapeutic use MeSH
- Trifluridine therapeutic use MeSH
- Physician-Patient Relations * MeSH
- Patient Participation psychology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
- MeSH
- Keratosis, Actinic * drug therapy pathology therapy MeSH
- Fluorouracil * administration & dosage pharmacology adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
