Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• autofagie * genetika   MeSH
• běloši genetika   MeSH
• duktální karcinom slinivky břišní * genetika   patologie   MeSH
• forkhead transkripční faktory MeSH
• genetická predispozice k nemoci * MeSH
• hepatocytární jaderný faktor 3-alfa genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé MeSH
• nádorové biomarkery * genetika   MeSH
• nádorové supresorové proteiny * genetika   MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.

• MeSH
• aktivátory chloridových kanálů terapeutické užití   farmakologie   MeSH
• aminofenoly * terapeutické užití   farmakologie   MeSH
• benzodioxoly * terapeutické užití   farmakologie   MeSH
• chinolony * farmakologie   terapeutické užití   MeSH
• cystická fibróza * genetika   farmakoterapie   MeSH
• fixní kombinace léků MeSH
• indoly * farmakologie   MeSH
• lidé MeSH
• organoidy * metabolismus   MeSH
• protein CFTR genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyridiny farmakologie   MeSH
• pyrrolidiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• stanovení celkové genové exprese metody   MeSH
• střeva účinky léků   MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pancreas is a vital gland of gastrointestinal system with exocrine and endocrine secretory functions, interweaved into essential metabolic circuitries of the human body. Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies, with a 5-year survival rate of 11%. This poor prognosis is primarily attributed to the absence of early symptoms, rapid metastatic dissemination, and the limited efficacy of current therapeutic interventions. Despite recent advancements in understanding the etiopathogenesis and treatment of PDAC, there remains a pressing need for improved individualized models, identification of novel molecular targets, and development of unbiased predictors of disease progression. Here we aim to explore the concept of precision medicine utilizing 3-dimensional, patient-specific cellular models of pancreatic tumors and discuss their potential applications in uncovering novel druggable molecular targets and predicting clinical parameters for individual patients.

• MeSH
• duktální karcinom slinivky břišní * patologie   genetika   metabolismus   MeSH
• individualizovaná medicína * metody   MeSH
• lidé MeSH
• nádory slinivky břišní * patologie   genetika   MeSH
• techniky 3D buněčné kultury metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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
• duktální karcinom slinivky břišní * etiologie   epidemiologie   patologie   MeSH
• expozom * MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• nádory slinivky břišní * etiologie   epidemiologie   patologie   MeSH
• rizikové faktory MeSH
• vystavení vlivu životního prostředí * škodlivé účinky   MeSH
• životní styl * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Automatické systémy pro dávkování inzulinu (AID) představují významný pokrok v léčbě diabetu, zejména pro pacienty s diabetem 1. typu (DM1T). Tyto uzavřené hybridní smyčky integrují technologii kontinuální monitorace glukózy (CGM) s léčbou inzulinovou pumpou (CSII). Napodobují fyziologickou funkci slinivky tím, že upravují dávku inzulinu v reakci na hladiny glukózy v reálném čase. Vývoj těchto systémů představuje zásadní milník v péči o diabetes a nabízí naději ke zlepšení kompenzace diabetu, snížení rizika hypoglykemie a zvýšení kvality života pacientů.

Automatic insulin delivery systems represent a significant advancement in the management of diabetes, particularly for individuals with type 1 diabetes. These systems, often referred to as hybrid closed-loop systems, integrate continuous glucose monitoring (CGM) technology with insulin pump therapy, aiming to imitate the physiological function of the pancreas by adjusting insulin delivery in response to real-time glucose levels. The development of these systems has been a critical milestone in diabetes care, offering the promise of improved glucose control, reduced risk of hypoglycemia, and enhanced quality of life for patients.

• MeSH
• diabetes mellitus 1. typu * farmakoterapie   MeSH
• inzulinové infuzní systémy MeSH
• lidé MeSH
• prospektivní studie MeSH
• regulace glykemie MeSH
• selfmonitoring glykemie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

AIM: Exposure to light at night and meal time misaligned with the light/dark (LD) cycle-typical features of daily life in modern 24/7 society-are associated with negative effects on health. To understand the mechanism, we developed a novel protocol of complex chronodisruption (CD) in which we exposed female rats to four weekly cycles consisting of 5-day intervals of constant light and 2-day intervals of food access restricted to the light phase of the 12:12 LD cycle. METHODS: We examined the effects of CD on behavior, estrous cycle, sleep patterns, glucose homeostasis and profiles of clock- and metabolism-related gene expression (using RT qPCR) and liver metabolome and lipidome (using untargeted metabolomic and lipidomic profiling). RESULTS: CD attenuated the rhythmic output of the central clock in the suprachiasmatic nucleus via Prok2 signaling, thereby disrupting locomotor activity, the estrous cycle, sleep patterns, and mutual phase relationship between the central and peripheral clocks. In the periphery, CD abolished Per1,2 expression rhythms in peripheral tissues (liver, pancreas, colon) and worsened glucose homeostasis. In the liver, it impaired the expression of NAD+, lipid, and cholesterol metabolism genes and abolished most of the high-amplitude rhythms of lipids and polar metabolites. Interestingly, CD abolished the circadian rhythm of Cpt1a expression and increased the levels of long-chain acylcarnitines (ACar 18:2, ACar 16:0), indicating enhanced fatty acid oxidation in mitochondria. CONCLUSION: Our data show the widespread effects of CD on metabolism and point to ACars as biomarkers for CD due to misaligned sleep and feeding patterns.

• MeSH
• cirkadiánní hodiny fyziologie   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• fotoperioda MeSH
• játra * metabolismus   MeSH
• karnitin * analogy a deriváty   metabolismus   MeSH
• krysa rodu rattus MeSH
• metabolom * MeSH
• nucleus suprachiasmaticus metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Objev inzulinu v roce 1921 znamenal revoluci v léčbě diabetes mellitus. Od počátečních intravenózních aplikací inzulinu se léčba přesunula k subkutánním injekcím a následně k využití inzulinových per. Významný pokrok přinesly inzulinové pumpy, které umožňují kontinuální subkutánní podávání inzulinu a tím napodobení fyziologické sekrece. Propojení inzulinových pump s kontinuální monitorací glukózy vedlo k vývoji hybridních uzavřených smyček. Tyto systémy využívají algoritmy pro automatickou úpravu dávek inzulinu na základě aktuálních a predikovaných hodnot glykemie. Výsledkem je zlepšení glykemické kontroly, snížení variability glykemie a snížení rizika jak hypoglykemických, tak hyperglykemických epizod.

The discovery of insulin in 1921 revolutionized the treatment of diabetes mellitus. From initial intravenous applications, treatment progressed to subcutaneous injections and subsequently to the use of insulin pens. Insulin pumps represented a significant advancement, enabling continuous subcutaneous insulin infusion and thus mimicking physiological secretion. The combination of insulin pumps with continuous glucose monitoring has led to the development of hybrid closed-loop systems. These systems utilize algorithms to automatically adjust insulin doses based on current and predicted glucose levels. The result is improved glycemic control, reduced glycemic variability, and decreased risk of both hypoglycemic and hyperglycemic episodes.

• MeSH
• diabetes mellitus 1. typu farmakoterapie   krev   prevence a kontrola   MeSH
• diabetes mellitus farmakoterapie   prevence a kontrola   MeSH
• hyperglykemie krev   prevence a kontrola   MeSH
• hypoglykemie krev   prevence a kontrola   MeSH
• inzulin aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• inzulinové infuzní systémy * MeSH
• kontinuální monitorování glukózy metody   přístrojové vybavení   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Slinivka břišní je životně důležitý orgán plnící jak exokrinní, tak endokrinní funkci. Exokrinní část je zodpovědná za produk- ci trávicích enzymů, které se uvolňují do duodena, zatímco endokrinní část zahrnuje ostrůvky Langerhansových buněk, které produkují hormony, jako je inzulin, glukagon a somatostatin. Ačkoli jsou tyto dvě části funkčně odlišné, existuje mezi nimi neustálá vzájemná interakce. Narušení této dráhy může vést k onemocněním. Nádory či záněty slinivky, traumata a chirurgické zákroky mohou vést k sekundárnímu diabetu. Pokud inzult zároveň poškodí aciny i ostrůvky pankreatu do- jde k rozvoji exokrinní i endokrinní insuficience. U pacientů s diabetem je pankreatická exokrinní insuficience velmi častá, přesto je málo známo o souvislostech vzniku mezi nimi. Cílem tohoto přehledového článku je poskytnout čtenáři přehled o fyziologii pankreatu, shrnout patofyziologii a diagnostiku pankreatické exokrinní nedostatečnosti a zaměřit se na možné vztahy mezi exokrinní pankreatickou insuficiencí a diabetem.

Pancreas is a vital organ fulfilling both exocrine and endocrine functions. The exocrine part is responsible for the production of digestive enzymes that are released into duodenum, while the endocrine part includes islets of Langerhans cells that produce hormones such as insulin, glucagon and somatostatin. Although these two parts are functionally distinct, there is a constant interaction between them. Disruption of this pathway can lead to a development of various diseases. Tumors or inflammation of the pancreas, trauma and surgery can lead to a secondary diabetes. If the insult simultaneously damages the acini and pancreatic islets, both exocrine and endocrine insufficiency will develop. Pancreatic exocrine insufficiency is very common in patients with diabetes, yet little is known about the association between these two units. The aim of this review article is to provide an overview of a pancreatic physiology, to summarize the pathophysiology and diagnostics of pancreatic exocrine insufficiency, and to focus on a possible relationships between exocrine pancreatic insufficiency and diabetes mellitus.

• MeSH
• chronická pankreatitida komplikace   terapie   MeSH
• diabetes mellitus MeSH
• exokrinní pankreatická insuficience * diagnóza   etiologie   farmakoterapie   MeSH
• Langerhansovy ostrůvky patologie   MeSH
• lidé MeSH
• pankreas fyziologie   patologie   MeSH
• Check Tag
• lidé MeSH

Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma (PDAC) initiation and progression. We also highlight some emerging gut microbiome editing techniques currently being investigated in the context of pancreatic disease. Notably, while the gut microbiome is significantly altered in PDAC and its precursor diseases, its utility as a diagnostic and prognostic tool is hindered by a lack of reproducibility and the potential for reverse causality in case-control cohorts. Future research should emphasise longitudinal and mechanistic studies as well as integrating lifestyle exposure and multi-omics data to unravel complex host-microbiome interactions. This will allow for deeper aetiologic and mechanistic insights that can inform treatments and guide public health recommendations.

• MeSH
• duktální karcinom slinivky břišní * mikrobiologie   metabolismus   patologie   MeSH
• lidé MeSH
• nádory slinivky břišní * metabolismus   mikrobiologie   patologie   etiologie   MeSH
• střevní mikroflóra * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below a level that allows normal digestion of nutrients. Pancreatic disease and pancreatic surgery are the main causes of PEI, but other conditions can affect the digestive function of the pancreas. METHODS: In collaboration with European Digestive Surgery (EDS), European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), European Society for Clinical Nutrition and Metabolism (ESPEN), European Society of Digestive Oncology (ESDO), and European Society of Primary Care Gastroenterology (ESPCG) the working group developed European guidelines for the diagnosis and therapy of PEI. United European Gastroenterology (UEG) provided both endorsement and financial support for the development of the guidelines. RESULTS: Recommendations covered topics related to the clinical management of PEI: concept, pathogenesis, clinical relevance, general diagnostic approach, general therapeutic approach, PEI secondary to chronic pancreatitis, PEI after acute pancreatitis, PEI associated with pancreatic cancer, PEI secondary to cystic fibrosis, PEI after pancreatic surgery, PEI after esophageal, gastric, and bariatric surgery, PEI in patients with type 1 and type 2 diabetes, and PEI in other conditions. CONCLUSIONS: The European guidelines for the diagnosis and therapy of PEI provide evidence-based recommendations concerning key aspects of the etiology, diagnosis, therapy, and follow-up, based on current available evidence. These recommendations should serve as a reference standard for existing management of PEI and as a guide for future clinical research. This article summarizes the recommendations and statements.

• MeSH
• exokrinní pankreatická insuficience * diagnóza   terapie   etiologie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• směrnice pro lékařskou praxi MeSH
• Geografické názvy
• Evropa MeSH