MUC13, a transmembrane mucin glycoprotein, is overexpressed in colorectal cancer (CRC), however, its regulation and functions are not fully understood. It has been shown that MUC13 protects colonic epithelial cells from apoptosis. Therefore, studying MUC13 and MUC13-regulated pathways may reveal promising therapeutic approaches for CRC treatment. Growing evidence suggests that microRNAs (miRs) are involved in the development and progression of CRC. In the present study, the MUC13-miR-4647 axis was addressed in association with survival of patients. miR-4647 is predicted in silico to bind to the MUC13 gene and was analyzed by RT-qPCR in 187 tumors and their adjacent non-malignant mucosa of patients with CRC. The impact of previously mentioned genes on survival and migration abilities of cancer cells was validated in vitro. Significantly upregulated MUC13 (P=0.02) in was observed tumor tissues compared with non-malignant adjacent mucosa, while miR-4647 (P=0.05) showed an opposite trend. Higher expression levels of MUC13 (log-rank P=0.05) were associated with worse patient's survival. The ectopic overexpression of studied miR resulted in decreased migratory abilities and worse survival of cells. Attenuated MUC13 expression levels confirmed the suppression of colony forming of CRC cells. In summary, the present data suggested the essential role of MUC13-miR-4647 in patients' survival, and this axis may serve as a novel therapeutic target. It is anticipated MUC13 may hold significant potential in the screening, diagnosis and treatment of CRC.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Selenium manifests its biological effects through its incorporation into selenoproteins, which play several roles in countering oxidative and inflammatory responses implicated in colorectal carcinogenesis. Selenoprotein genetic variants may contribute to colorectal cancer (CRC) development, as we previously observed for SNP variants in a large European prospective study and a Czech case-control cohort. METHODS: We tested if significantly associated selenoprotein gene SNPs from these studies were also associated with CRC risk in case-control studies from Ireland (colorectal neoplasia, i.e., cancer and adenoma cases: 450, controls: 461) and the Czech Republic (CRC cases: 718, controls: 646). Genotyping of 23 SNPs (20 in the Irish and 13 in the Czechs) was performed by competitive specific allele-specific PCR (KASPar). Multivariable adjusted logistic regression was used to assess the associations with CRC development. RESULTS: We found significant associations with an increased CRC risk for rs5859 (SELENOF) and rs2972994 (SELENOP) in the Irish cohort but only with rs4802034 (SELENOV) in the Czechs. Significant associations were observed for rs5859 (SELENOF), rs4659382 (SELENON), rs2972994 (SELENOP), rs34713741 (SELENOS), and the related Se metabolism gene variant rs2275129 (SEPHS1) with advanced colorectal neoplasia development. However, none of these findings retained significance after multiple testing corrections. CONCLUSIONS: Several SNPs previously associated with CRC risk were also associated with CRC or colorectal neoplasia development in either the Irish or Czech cohorts. Selenoprotein gene variation may modify CRC risk across diverse European populations, although the specific variants may differ.
- MeSH
- adenom * epidemiologie genetika MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * epidemiologie genetika MeSH
- lidé MeSH
- prospektivní studie MeSH
- selenoprotein P metabolismus MeSH
- selenoproteiny genetika metabolismus MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
The liquid biopsy has the potential to improve current clinical practice in oncology by providing real-time personalized information about a patient's disease status and response to treatment. In this study, we evaluated 161 peripheral blood (PB) samples that were collected around surgical resection from 47 metastatic colorectal cancer (mCRC) patients using the High-Definition Single Cell Assay (HDSCA) workflow. In conjunction with the standard circulating tumor cell (CTC) enumeration, cellular morphology and kinetics between time-points of collection were considered in the survival analysis. CTCs, CTC-Apoptotic, and CTC clusters were found to indicate poor survival with an increase in cell count from pre-resection to post-resection. This study demonstrates that CTC subcategorization based on morphological differences leads to nuanced results between the subtypes, emphasizing the heterogeneity within the CTC classification. Furthermore, we show that factoring in the time-point of each blood collection is critical, both for its static enumeration and for the change in cell populations between draws. By integrating morphology and time-based analysis alongside standard CTC enumeration, liquid biopsy platforms can provide greater insight into the pathophysiology of mCRC by highlighting the complexity of the disease across a patient's treatment.
- Publikační typ
- časopisecké články MeSH
Cíl: Cílem studie bylo posoudit, zda přidání výpočtu frakce arteriálního sycení (arterial enhancement fraction - AEF) k hodnocení vícefázové výpočetní tomografie (CT) zlepší detekci viabilní nádorové tkáně po lokální léčbě nádoru jater u různě zkušených hodnotitelů. Metodika: Dva mladí radiologové s rozdílně dlouhou praxí v CT diagnostice (3 a 1 rok) hodnotili nezávisle CT obrazy pacientů, kteří splnili kritéria studie. CT dokumentace byla hodnocena nejprve samostatně a poté v kombinaci s barevnými mapami AEF. Hodnotitelé posuzovali přítomnost rezidua viabilní nádorové tkáně, při pozitivním nálezu měřili jeho velikost. Stejnou obrazovou dokumentaci hodnotili dva zkušení radiologové (s praxí více než 10 let). Jeden z nich provedl shodné hodnocení jako mladí radiologové, druhý hodnotil pouze CT s AEF a přihlížel ke klinickému obrazu a dalšímu vývoji onemocnění. Oba zkušení hodnotitelé srovnali výsledky svého hodnocení a z jejich shody vzešla referenční hodnota, s níž byly porovnány nálezy mladých radiologů. Výsledky byly statisticky analyzovány. Výsledky: Hodnocena byla dokumentace 70 pacientů. Reziduum nádorové tkáně po prodělané lokální léčbě bylo detekováno u 40 osob. Přidání AEF ke standardní CT dokumentaci mírně zvýšilo senzitivitu pro detekci viabilní nádorové tkáně u obou mladších hodnotitelů, signifikantně však zvýšilo specificitu nálezu, u radiologa s tříletou praxí (z 56,6 % na 96,6 %, p = 0,0004) a začátečníka (z 36,7 % na 73,7 %, p = 0,0089). Podobně se zvýšila přesnost měření velikosti tumoru. Závěr: Použití AEF jako součásti hodnocení CT dokumentace zvyšuje schopnost detekovat přítomnost rezidua po lokální léčbě jaterních nádorů a zvyšuje přesnost jeho měření. Největší efekt byl patrný u nejméně zkušeného hodnotitele. Výpočet AEF lze provést z vícefázového CT bez výrazného navýšení radiační dávky.
Objectives: We investigated whether the use of arterial enhancement fraction (AEF) during the evaluation of multiphasic contrast-enhanced computed tomography (CECT) improves the assessment of viable tumor tissue after locoregional therapy in liver tumors. We tested how the use of the AEF influences the accuracy of tumor residue detection in differently experienced evaluators. Methods: Two differently experienced radiologists independently evaluated CT images of patients who met the criteria of our study. CT documentation was evaluated first separately and then in combination with AEF color maps. The evaluators assessed the presence of a residue of viable tumor tissue, and measured it, in case of a positive finding. The same documentation was evaluated by two experienced radiologists (with more than 10 years of experience). One of them performed the same evaluation as young radiologists, the other evaluated only CT with AEF and took into account the clinical information and further development of the disease. Both experienced evaluators compared the results of their evaluation and their agreement resulted in a reference value to which the findings of young radiologists were compared. The results were statistically analyzed. Results: The documentation of 70 patients was evaluated. Viable tumor tissue was detected in 40 of them. The addition of AEF to the standard CT documentation slightly increased the sensitivity in both young evaluators, but significantly increased the specificity in intermedialy experienced radiologist (from 56.6% to 96.6%, p = 0.0004) in novice (36.7% to 73,7%, p = 0.0089). Similarly, the precision of tumor size measurement has improved significantly for both. Conclusion: Using AEF as a part of CECT in monitoring after locoregional treatment of liver tumor increases the detection capability and accuracy of viable tumor tissue measurement. The greatest effect was seen in a low-experienced radiologist. AEF is calculated from triphasic CECT examination without increasing radiation dose and its assesment is not time-consuming.
In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.
BACKGROUND/AIM: Colorectal cancer is currently the third leading cause of cancer-related deaths and recently, alternative splicing has risen as its important regulator and potential treatment target. In the present study, we analyzed gene expression of the MBNL family of regulators of alternative splicing in various stages of colorectal cancer development, together with the MBNL-target splicing events in FOXP1 and EPB41L3 genes and tumor-related CD44 variants. MATERIALS AND METHODS: Samples of tumor tissue and non-malignant mucosa from 108 patients were collected. After RNA isolation and reverse transcription, the relative gene expression of a selected gene panel was tested by quantitative real-time PCR, followed by statistical analysis. RESULTS: MBNL expression was decreased in tumor tissue compared to non-tumor mucosa. In addition, lower expression was observed for the variants of FOXP1 and EPB41L3, while higher expression in tumor tissue was detected both for total CD44 and its cancer-related variants 3 and 6. Transcript levels of the MBNL genes were not found to be related to any of the studied clinicopathological characteristics. Multiple significant associations were identified in the target gene panel, including higher transcript levels of FOXP1 and CD44v3 in patients with distant metastases and connections between recurrence-free survival and altered levels of FOXP1 and CD44v3. CONCLUSION: Our results identified for the first-time deregulation of MBNL genes in colorectal cancer. Down-regulation of their transcripts in tumor tissue compared to matched non-tumor mucosa can lead to transition of alternative splicing patterns towards a less differentiated phenotype, which highlights the importance of alternative splicing regulation for tumor growth and propagation.
- MeSH
- alternativní sestřih MeSH
- buněčná diferenciace fyziologie MeSH
- dospělí MeSH
- kolorektální nádory genetika metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- proteiny vázající RNA biosyntéza genetika MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND/AIM: MicroRNAs (miRs) play an important role in the regulation of cancer-related processes and are promising candidates for cancer biomarkers. The aim of the study was to evaluate the association of response to anti-EGFR monoclonal antibodies (mAbs) with selected miR expression profiles, including miR-125b, let-7c, miR-99a, miR-17, miR-143 and miR-145 in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: This retrospective study included 46 patients with mCRC harbouring wild-type RAS gene treated with cetuximab or panitumumab combined with chemotherapy in first- or second-line therapy. The miR expression was assessed using qRT-PCR. RESULTS: Down-regulation of miR-125b and let-7c and up-regulation of miR-17 were found in the tumour tissue (p=0.0226, p=0.0040, p<0.0001). Objective response rate (ORR) was associated with up-regulation of miR-125b (p=0.0005). Disease control rate (DCR) was associated with up-regulation of miR-125b and let-7c (p=0.0383 and p=0.0255) and down-regulation of miR-17 (p=0.0464). MiR-125b showed correlation with progression-free and overall survival (p=0.055 and p=0.006). CONCLUSION: The results show that up-regulation of miR-125b is associated with higher ORR and DCR and longer survival; let-7c up-regulation and miR-17 down-regulation are associated with higher DCR in mCRC patients treated with anti-EGFR mAbs.
- MeSH
- cetuximab farmakologie terapeutické užití MeSH
- chemorezistence genetika MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- down regulace MeSH
- erbB receptory antagonisté a inhibitory genetika MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- kolorektální nádory farmakoterapie genetika mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA metabolismus MeSH
- nádorové biomarkery metabolismus MeSH
- panitumumab farmakologie terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití MeSH
- regulace genové exprese u nádorů MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- upregulace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND/AIM: Portal vein embolization (PVE) with autologous stem cells application (aHSC) is a method for future liver remnant volume (FLRV) increase. The aim of the study was to evaluate the positivite and negativite aspects of the method in clinical practice. PATIENTS AND METHODS: PVE with aHSC application was used in 32 patients with colorectal liver metastases and insufficient FLRV. Preoperative number of colorectal liver metastases (CLMs) was 5.2±3.6, CLMs volume 70.1±102.3 mm3 Results: FLRV growth occurred after 2-3 weeks in 31 (96.9%) patients, with volume increase from 528.2±170.5 to 715.4±143.3 ml (p=0.0001). Postoperative thirty days mortality, morbidity was 0% and 3.1%, respectively. Insufficient FLRV growth occurred in one patient. R0 liver resection was performed in 27(87.1%) patients. CLMs volume progression was in 5 (15.6%) patients from 680.0±59.4 to 723.1±57.1 ml (p=0.01). One and two-year overall survival were 88% and 62.9% respectively. Six and twelve-month recurrence-free survival rates were 50.7% and 39.6% respectively. CONCLUSION: PVE with aHSC application is a safe and useful method for FLRV growth. It significantly increases secondary CLMs resectability. However, it can cause CLMs progression. Liver resection should, therefore, be performed as soon as possible after achieving optimal increase of FLRV.
ATP-binding cassette (ABC) and solute carrier (SLC) transporters translocate diverse substances across cellular membranes and their deregulation may cause drug resistance of cancers. This study investigated significance of protein expression and cellular localization of the previously suggested putative prognostic markers ABCC2 and SLC22A3 in pancreatic cancer patients. Protein localization and brush border staining intensity of ABCC2 and SLC22A3 was assessed in tumor tissue blocks of 65 pancreatic cancer patients and associated with clinical data and survival of patients with regard to therapy. Negative SLC22A3 brush border staining in pancreatic tumors significantly increased the risk of both disease progression and patient´s death in univariate analyses. Multivariate analyses confirmed the association of SLC22A3 expression with progression-free survival of patients. A subgroup analysis of patients treated with regimens based on nucleoside analogs suggested that patients with negative brush border staining or apical localization of SLC22A3 in tumor cells have worse overall survival. The combination of positive ABCC2 and negative SLC22A3 brush border staining predicted worst overall survival and patients with positive brush border staining of both proteins had best overall and progression-free survival. The present study shows for the first time that the protein presence and to some extent also localization of SLC22A3 significantly associate with prognosis of pancreatic cancer in both unstratified and chemotherapy-treated patients. The combination of ABCC2 and SLC22A3 brush border staining also needs further attention in this regard.
- MeSH
- adenokarcinom * metabolismus mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- nádorové proteiny biosyntéza MeSH
- nádory slinivky břišní * metabolismus mortalita patologie MeSH
- přežití bez známek nemoci MeSH
- proteiny přenášející organické kationty biosyntéza MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům biosyntéza MeSH
- regulace genové exprese u nádorů * MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
Úvod: Resekce jater pro jaterní metastázy kolorektálního karcinomu (JMKRK) je jedinou radikální léčbou, nicméně jen 20−30 % JMKRK je radikálně resekabilních. U těchto nemocných je radiofrekvenční ablace (RFA) jednou z možných metod paliativní léčby. Metody: Od 1. 1. 2001 do 31. 12. 2018 byla RFA provedena u 381 nemocných s JMKRK, z toho otevřenou, laparotomickou cestou u 238 (62,5 %), transkutánním přístupem pod navigací výpočetní tomografií (CT) u 143 (37,5 %) nemocných. Průměrný věk nemocných léčených RFA byl 65,2±8,7 roku. Poměr mužů a žen byl 2:1. Indikací pro RFA byly JMKRK o průměru <5 cm (obvykle <3 cm). Z 381 nemocných jsme použili RFA jako jedinou léčbu u 334 (87,6 %), v kombinaci s resekcí u 36 (9,4 %) a v rámci etapového výkonu u 11 (3 %) nemocných. U 170 nemocných (44,6 %) jsme provedli ablaci jednoho ložiska, u zbývajících 211 nemocných (55,4 %) pak 2−5 ložisek. U každého nemocného bylo provedeno do 48 hod. po výkonu kontrolní CT. Výsledky: 30denní pooperační mortalita byla nulová. 30denní pooperační komplikace se vyskytly u 4,8 % transkutánních a 14,2 % otevřených výkonů. Jedno-, tří-, pěti- a desetileté celkové přežívání bylo u nemocných s RFA 94,8; 66,8; 43,9 a 16,6 %, u nemocných s resekcí jater pak 90,6; 69,1; 52,8, resp. 39,2 %. Ve stejných intervalech bylo bezpříznakové přežívání u nemocných s RFA 63,2; 30,1; 18,4, resp. 13,1 %, u nemocných s resekcí jater pak 71,1; 33,3; 22,8, resp. 15,5 %. Závěr: RFA je paliativní termoablační metoda, která je součástí léčebných možností u nemocných s radikálně neresekabilními JMKRK. RFA je vhodná zejména u neresekabilních, nebo resekabilních (ale za cenu velké jaterní resekce) solitárních JMKRK o průměru <3cm a při řešení recidiv JMKRK. RFA je součástí víceetapových výkonů.
Introduction: Radical liver resection is the only method for the treatment of patients with colorectal liver metastases (CLM); however, only 20-30% of patients with CLMs can be radically treated. Radiofrequency ablation (RFA) is one of the possible methods of palliative treatment in such patients. Methods: RFA was performed in 381 patients with CLMs between 01 Jan 2001 and 31 Dec 2018. The mean age of the patients was 65.2 ±8.7 years. The male to female ratio was 2:1. Open laparotomy was done in 238 (62.5%) patients and the CT-navigated transcutaneous approach was used in 143 (37.5%) patients. CLMs <5 cm (usually <3 cm) in diameter were the indication for RFA. We used RFA as the only method in 334 (87.6%) patients; RFA in combination with resection was used in 36 (9.4%), and with multi-stage resection in 11 (3%) patients. We performed RFA in a solitary CLM in 170 (44.6%) patients, and in 2-5 CLMs in 211 (55.6%) patients. We performed computed tomography in each patient 48 hours after procedure. Results: The 30-day postoperative mortality was zero. Complications were present in 4.8% of transcutaneous and in 14.2% of open procedures, respectively, in the 30-day postoperative period. One-, 3-, 5- and 10-year overall survival rates were 94.8, 66.8, 43.9 and 16.6%, respectively, in patients undergoing RFA, and 90.6, 69.1, 52.8 and 39.2%, respectively, in patients with liver resections. Disease free survival was 63.2, 30.1, 18.4 and 13.1%, respectively, in the same patients after RFA, and 71.1, 33.3, 22.8 and 15.5%, respectively, after liver resections. Conclusion: RFA is a palliative thermal ablation method, which is one of therapeutic options in patients with radically non-resectable CLMs. RFA is useful especially in a non-resectable, or resectable (but for the price of large liver resection) solitary CLM < 3 cm in diameter and in CLM relapses. RFA is also part of multi-stage liver procedures.
- MeSH
- analýza přežití MeSH
- kolorektální nádory * MeSH
- lidé MeSH
- metastázy nádorů * terapie MeSH
- nádory jater chirurgie sekundární terapie MeSH
- paliativní péče MeSH
- radiofrekvenční ablace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
