Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). This study investigates how PSC predisposes individuals to altered inflammatory immune responses compared with IBD alone. A case-control study was conducted with a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 controls. Serum bile acid profile, proteomic analysis, and immune-related gene expression in the colon tissue were examined. Colonic tissue from PSC patients exhibited up-regulation of immune regulation and inflammatory signaling mRNA markers, including LGR5, IL-8, CCL2, COX2, TWIST1, and SNAIL. Additionally, PSC patients displayed a distinct proinflammatory serum proteomic signature and moderate elevation of some bile acids, such as glycochenodeoxycholic acid (GCDCA). Co-incubation of human-derived monocytes with GCDCA partially replicated the inflammatory profile observed in PSC. These findings suggest that circulating bile acids modulate the peripheral immune system proinflammatory response, contributing to the unique PSC phenotype.

• MeSH
• Adult MeSH
• Inflammatory Bowel Diseases * immunology   complications   blood   genetics   MeSH
• Colon metabolism   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Monocytes immunology   metabolism   MeSH
• Proteomics methods   MeSH
• Cholangitis, Sclerosing * immunology   blood   complications   genetics   MeSH
• Case-Control Studies MeSH
• Bile Acids and Salts * blood   immunology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.

• MeSH
• Cholangiocarcinoma * pathology   etiology   genetics   MeSH
• Inflammatory Bowel Diseases * complications   pathology   MeSH
• Colorectal Neoplasms * pathology   etiology   genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Bile Duct Neoplasms * pathology   etiology   genetics   MeSH
• Cholangitis, Sclerosing * complications   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Kognitívna porucha (KP) po ischemickej cievnej mozgovej príhode (CMP) je častým fenoménom. U niektorých pacientov môže KP pretrvávať aj dlhý čas po prekonanej CMP, čo sa v anglickej literatúre označuje ako PCSI - post stroke cognitive impairment. Ide o osobitnú nozologickú jednotku, ktorú je potrebné začať diagnostikovať už počas hospitalizácie, no definitívnu diagnózu je možné vykonať až následne kontrolným vyšetrením kognitívnych funkcií s odstupom šesť mesiacov od CMP. Článok prináša aktuálny prehľad o diagnostike, predikcii a terapii PSCI ako osobitnej nozologickej jednotky.

Cognitive impairment (CI) after stroke is a frequent phenomenon. In some patients, CI can persist for a long time after overcoming stroke, which is referred to in the English literature as PCSI - post stroke cognitive impairment. It is a special nosological entity that needs to be diagnosed already during hospitalization, but a definitive diagnosis can only be made subsequently by a control examination of cognitive functions six months after stroke. The following article provides an up-to-date overview of the diagnosis, prediction and therapy of PSCI as a special nosological unit.

• MeSH
• Stroke * diagnosis   complications   physiopathology   MeSH
• Dementia diagnosis   etiology   MeSH
• Diagnosis, Differential MeSH
• Cognitive Dysfunction * diagnosis   etiology   drug therapy   physiopathology   MeSH
• Humans MeSH
• Disease Management MeSH
• Neuroimaging classification   methods   MeSH
• Mental Status and Dementia Tests MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

BACKGROUND: Ulcerative colitis (UC) with concomitant primary sclerosing cholangitis (PSC) represents a distinct disease entity (PSC-UC). Mayo endoscopic subscore (MES) is a standard tool for assessing disease activity in UC but its relevance in PSC-UC remains unclear. AIM: To assess the accuracy of MES in UC and PSC-UC patients, we performed histological scoring using Nancy histological index (NHI). METHODS: MES was assessed in 30 PSC-UC and 29 UC adult patients during endoscopy. NHI and inflammation were evaluated in biopsies from the cecum, rectum, and terminal ileum. In addition, perinuclear anti-neutrophil cytoplasmic antibodies, fecal calprotectin, body mass index, and other relevant clinical characteristics were collected. RESULTS: The median MES and NHI were similar for UC patients (MES grade 2 and NHI grade 2 in the rectum) but were different for PSC-UC patients (MES grade 0 and NHI grade 2 in the cecum). There was a correlation between MES and NHI for UC patients (Spearman's r = 0.40, P = 0.029) but not for PSC-UC patients. Histopathological examination revealed persistent microscopic inflammation in 88% of PSC-UC patients with MES grade 0 (46% of all PSC-UC patients). Moreover, MES overestimated the severity of active inflammation in an additional 11% of PSC-UC patients. CONCLUSION: MES insufficiently identifies microscopic inflammation in PSC-UC. This indicates that histological evaluation should become a routine procedure of the diagnostic and grading system in both PSC-UC and PSC.

• Publication type
• Journal Article MeSH

T lymfocyty s chimerickým antigenním receptorem (CAR) představují nejmodernější technologii v cílené buněčné terapii onkologických onemocnění. Slibné klinické výsledky byly publikovány v léčbě hemato-onkologických malignit, avšak výsledky v léčbě solidních nádorů nejsou zatím tak povzbudivé. V navrhovaném projektu se budeme věnovat validaci protokolů pro výrobu CAR T-lymfocytů proti solidním nádorům v režimu správné laboratorní praxe. Zaměříme se hlavně na cílové antigeny GD2, PSMA a PSCA. Standardní operační protokoly a analytické certifikáty budou předány Státnímu ústavu pro kontrolu léčiv ke schválení. Na projektu budou spolupracovat tři špičková výzkumná pracoviště: (i) Mezinárodní centrum klinického výzkumu Fakultní nemocnice u sv. Anny v Brně, (ii) Centrum analýzy biomedicínského obrazu na Masarykově Univerzitě v Brně (MU-CBIA) a (iii) Ústav hematologie a krevní transfuze v Praze (ÚHKT). Naším hlavním cílem je zavést technologii výroby CAR T-lymfocytů pro cílenou buněčnou terapii solidních tumorů a tím umožnit přenos do klinické praxe.; Chimeric antigen receptor (CAR) T-cell is a cutting edge technology for targeted cell therapy of oncologic diseases. Promising clinical results were reported for hematological malignancies, but the results in solid tumors are not that encouranging yet. Here we propose to validate protocols for the production of CAR T-cells against solid tumor antigens under cGMP rules. We will focus mainly on target antigens GD2, PSMA, and PSCA. Standard operation protocols and analytical certificates will be presented to the State Institute for Drug Control for their approval. The consortium of three prominent research facilities will participate on this project: (i) International Clinical Research Center of St. Anne's University Hospital Brno (FNUSA-ICRC), (ii) Centre for Biomedical Image Analysis at Masaryk University Brno (MU-CBIA), and (iii) Institute of Hematology and Blood Transfusion in Prague (UHKT). Our main aim is to establish production of CAR T-cells for anti-solid tumor therapy which can be translated into clinical applications.

• Keywords
• advanced therapy medicinal products, solid tumors, T-lymfocyty, T-cells, solidní tumory, Chimerický antigenní receptor, Správná laboratorní praxe, Přípravky moderní terapie, Chimeric antigen receptor, Current Good Manufacturing Practice,

• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosed with autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. METHODS: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. RESULTS: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. DISCUSSION: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD.

• MeSH
• B7-H1 Antigen MeSH
• Programmed Cell Death 1 Receptor MeSH
• Hepatitis, Autoimmune * drug therapy   MeSH
• Cholestasis * MeSH
• Immune Checkpoint Inhibitors adverse effects   MeSH
• Humans MeSH
• Neoplasms * MeSH
• Nivolumab adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

The acidic tumor microenvironment (TME) of pancreatic cancer affects the physiological function of pancreatic stellate cells (PSCs), which in turn promotes cancer progression. Acid-sensing ion channel 1a (ASIC1a) is responsible for acidosis-related physiopathological processes. In this study, we investigated the effect of acid exposure on the activation and autophagy of PSCs, and the role of ASIC1a in these events. The results showed that acidic medium upregulated the expression of ASIC1a, induced PSCs activation and autophagy, which can be suppressed by inhibiting ASIC1a using PcTx1 or ASIC1a knockdown, suggesting that ASIC1a involves these two processes. In addition, the acid-induced activation of PSCs was impaired after the application of autophagy inhibitor alone or in combination with ASIC1a siRNA, meaning a connection between autophagy and activation. Collectively, our study provides evidence for the involvement of ASIC1a in the acid-caused PSCs activation, which may be associated with autophagy induction.

• MeSH
• Autophagy MeSH
• Acid Sensing Ion Channels * genetics   metabolism   MeSH
• Rats MeSH
• Pancreatic Stellate Cells * metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The lack of physiological parity between 2D cell culture and in vivo culture has led to the development of more organotypic models, such as organoids. Organoid models have been developed for a number of tissues, including the liver. Current organoid protocols are characterized by a reliance on extracellular matrices (ECMs), patterning in 2D culture, costly growth factors and a lack of cellular diversity, structure, and organization. Current hepatic organoid models are generally simplistic and composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant compared to native tissue. We have developed an approach that does not require 2D patterning, is ECM independent, and employs small molecules to mimic embryonic liver development that produces large quantities of liver-like organoids. Using single-cell RNA sequencing and immunofluorescence, we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, and a population of resident macrophages: Kupffer cells. The organoids exhibit key liver functions, including drug metabolism, serum protein production, urea synthesis and coagulation factor production, with preserved post-translational modifications such as N-glycosylation and functionality. The organoids can be transplanted and maintained long term in mice producing human albumin. The organoids exhibit a complex cellular repertoire reflective of the organ and have de novo vascularization and liver-like function. These characteristics are a prerequisite for many applications from cellular therapy, tissue engineering, drug toxicity assessment, and disease modeling to basic developmental biology.

• MeSH
• Hepatocytes MeSH
• Liver * MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Mice MeSH
• Organoids * MeSH
• Tissue Engineering MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Primární sklerozující cholangitida (PSC) je chronické progresivní onemocnění žlučových cest. Mezi primární sklerozující cholangitidou dospělých a juvenilní formou existuje řada rozdílů. V dětském věku vídáme tuto diagnózu nejčastěji ve spojitosti se zánětlivým střevním onemocněním (IBD). Fenotyp IBD se u pacientů s PSC-IBD liší od těch bez souběžné diagnózy PSC. Obvykle bývá charakterizován mírnějším průběhem a nálezem pankolitidy, rectal sparingu a backwash ileitidy. U těchto pacientů může být častěji přítomná endoskopická aktivita IBD navzdory chybějícím symptomům. Průběh PSC spojené s Crohnovou nemocí je zpravidla méně závažný než u PSC spojené s ulcerózní kolitidou (PSC-UC). Na rozdíl od pacientů s izolovanou formou UC bývají pacienti s PSC-UC častěji léčeni monoterapií aminosalicyláty. Navíc bylo u pacientů s PSC-UC popsáno nižší riziko provedení kolektomie a potřeby kortikosteroidů, thiopurinů nebo biologické terapie než u klasické formy UC. Recentní práce naznačují, že žádná z aktuálně používaných léčebných modalit nedokáže zastavit progresi PSC, přičemž značná část pacientů dospěje do stadia jaterního selhání vyžadujícího transplantaci jater.

Primary sclerosing cholangitis is a chronic progressive disease of the biliary tract. There are many differences between adult primary sclerosing cholangitis and juvenile type. Major part of pediatric PSC patients will develop inflammatory bowel disease (IBD). The phenotype of IBD in patients with PSC-IBD differs from those without associated PSC and is characterized by a milder course and typical findings of pancolitis, rectal sparing and backwash ileitis. Endoscopic activity of the disease is more often present despite the absence of symptoms suggesting subclinical inflammation. The course of PSC associated with Crohn’s disease is usually less severe than that with ulcerative colitis (UC). Compared to patients with an isolated form of UC, patients with PSC-UC are more often treated with amino-salicylates monotherapy. Likewise, these patients have been reported to have a lower risk of undergoing colectomy or requiring steroids, thiopurines, or biologic therapy than patients without associated PSC. Recent data suggest that none of the current treatment modalities can stop the progression of PSC, and significant number of patients will end up with liver failure requiring a liver transplant.

• MeSH
• Child MeSH
• Inflammatory Bowel Diseases complications   MeSH
• Humans MeSH
• Cholangitis, Sclerosing * diagnosis   etiology   complications   therapy   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

Monografii je určená specialistům z oborů hepatologie, gastroenterologie a vnitřního lékařství, ale také pro obory chirurgické, infekční lékařství, odborníky z oblasti zobrazovacích metod, patology a odborníky z oblasti aplikovaného výzkumu.