Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.

• Klíčová slova
• ATR, R-loops, RNA:DNA hybrids, checkpoint activation, cleavage, gene gating, origin firing, polyadenylation, pre-mRNA processing, replication catastrophe, replication stress,
• MeSH
• aktivní transport - buněčné jádro MeSH
• DNA nádorová genetika   metabolismus   MeSH
• DNA vazebné proteiny MeSH
• HeLa buňky MeSH
• heteroduplexy nukleové kyseliny genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• nádory genetika   metabolismus   MeSH
• nestabilita genomu * MeSH
• polyadenylace MeSH
• poškození DNA * MeSH
• prekurzory RNA biosyntéza   genetika   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• proteiny vázající RNA MeSH
• regulace genové exprese u nádorů MeSH
• replikace DNA * MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• štěpení RNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA nádorová MeSH
• DNA vazebné proteiny MeSH
• heteroduplexy nukleové kyseliny MeSH
• jaderné proteiny MeSH
• messenger RNA MeSH
• prekurzory RNA MeSH
• proteiny buněčného cyklu MeSH
• proteiny vázající RNA MeSH
• RNA nádorová MeSH
• THOC1 protein, human MeSH Prohlížeč
• WDR33 protein, human MeSH Prohlížeč

• MeSH
• dítě MeSH
• juvenilní myelomonocytární leukemie genetika   metabolismus   patologie   MeSH
• lidé MeSH
• předškolní dítě MeSH
• regulace genové exprese u leukemie * MeSH
• RNA dlouhá nekódující biosyntéza   genetika   MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• RNA dlouhá nekódující MeSH
• RNA nádorová MeSH

• MeSH
• chronická lymfatická leukemie metabolismus   mortalita   patologie   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA biosyntéza   MeSH
• míra přežití MeSH
• následné studie MeSH
• přežití bez známek nemoci MeSH
• RNA nádorová biosyntéza   MeSH
• senioři nad 80 let MeSH
• senioři 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
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mikro RNA MeSH
• MIRN150 microRNA, human MeSH Prohlížeč
• MIRN155 microRNA, human MeSH Prohlížeč
• RNA nádorová MeSH

The MYB gene codes for the c-Myb transcription factor maintaining proliferation of colon epithelial progenitors, thus controlling colon development and homeostasis. This gene is overexpressed in early phases of colorectal cancer (CRC) tumorigenesis. The aim of this study was to examine the expression of c-Myb in CRC tissue samples both at the messenger RNA (mRNA) and protein levels and to evaluate their associations with clinicopathological characteristics in a group of 108 CRC patients. Statistically significant negative association was found between the frequency of the c-Myb-positive tumor cells assessed by immunohistochemistry and the presence of distant metastases (p < 0.01) but not tumor differentiation, tumor stage, lymph node involvement, vascular invasion, tumor localization, age, and gender of the patients. Although the c-Myb protein level in the tumor tissue correlated with its mRNA level, no significant association between MYB mRNA and any clinicopathological characteristics was observed. We conclude that albeit overexpression of c-Myb is considered as an important factor contributing to early phases of CRC tumorigenesis, it may later have negative effect on tumor cell dissemination as observed recently in breast cancer as well. Further studies are required to explain the role of c-Myb during formation of CRC distant metastases.

• Klíčová slova
• Colorectal cancer, Immunohistochemistry, Metastases, c-Myb, mRNA,
• MeSH
• adenokarcinom genetika   sekundární   MeSH
• buněčná diferenciace MeSH
• dospělí MeSH
• down regulace MeSH
• geny myb * MeSH
• invazivní růst nádoru MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• messenger RNA biosyntéza   MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• protoonkogenní proteiny c-myb biosyntéza   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• RNA nádorová biosyntéza   MeSH
• senioři nad 80 let MeSH
• senioři 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
• Názvy látek
• messenger RNA MeSH
• nádorové proteiny MeSH
• protoonkogenní proteiny c-myb MeSH
• RNA nádorová MeSH

AIM: In our pilot study, we used plasma samples as liquid biopsy to search for miRNA signatures in patients with acute myeloid leukemia (AML) at diagnosis and in remission achieved after standard chemotherapy before planned transplantation. MATERIAL AND METHODS: We examined 10 plasma samples from healthy volunteers and 8 paired samples from patients with AML at diagnosis and in remission using TaqMan MicroRNA Arrays. The results were validated using single-target qPCR reactions run in triplicates. RESULTS: We selected 6 miRNAs with expressions significantly sensitive to therapy: miR-199b-5p, miR-301b, miR-326, miR-361-5p, miR-625 and miR-655. All selected miRNAs were not or very weakly expressed in healthy individuals. They were abundant in plasma in patients at diagnosis but their levels decreased after chemotherapy. CONCLUSION: We detected a therapy sensitive miRNA signature in plasma of patients with AML.

• Klíčová slova
• Acute myeloid leukemia, Liquid biopsy, Plasma, Remission, Standard chemotherapy, miRNA signature,
• MeSH
• akutní myeloidní leukemie krev   farmakoterapie   genetika   MeSH
• cytarabin aplikace a dávkování   MeSH
• dospělí MeSH
• idarubicin aplikace a dávkování   MeSH
• indukce remise MeSH
• konsolidační chemoterapie MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA biosyntéza   krev   genetika   MeSH
• mitoxantron aplikace a dávkování   MeSH
• pilotní projekty MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• RNA nádorová biosyntéza   krev   genetika   MeSH
• transkriptom * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• validační studie MeSH
• Názvy látek
• cytarabin MeSH
• idarubicin MeSH
• mikro RNA MeSH
• mirn199 microRNA, human MeSH Prohlížeč
• MIRN301A microRNA, human MeSH Prohlížeč
• MIRN326 microRNA, human MeSH Prohlížeč
• MIRN361 microRNA, human MeSH Prohlížeč
• MIRN625 microRNA, human MeSH Prohlížeč
• MIRN655 microRNA, human MeSH Prohlížeč
• mitoxantron MeSH
• RNA nádorová MeSH

The transcription factor PU.1 and its inhibitory microRNA-155 (miR-155) are important regulators of B-cell differentiation. PU.1 downregulation coupled with oncogenic miR-155 upregulation has been reported in lymphoid malignancies; however, these data have not been studied across different subtypes in relation to clinical outcomes. We studied expression of miR-155 and PU.1 in the six most prevalent human B-cell lymphomas (n = 131) including aggressive (DLBCL, HL, MCL) and indolent (B-CLL/SLL, MZL, FL) types. Levels of miR-155 and PU.1 inversely correlated in DLBCL, B-CLL/SLL, and FL tumor tissues. In HL tissues, an exceptionally high level of miR-155 was found in patients with unfavorable responses to first-line therapy and those who had shorter survival times. PU.1 downregulation was noted in B-CLL/SLL samples positive for the adverse prognostic markers CD38 and ZAP-70. Upregulation of miR-155 and downregulation of PU.1 expression are integral aspects of lymphoma biology that could mark aggressive behavior of some, but not all, lymphoma types.

• Klíčová slova
• Lymphoma, PU.1, Prognosis, microRNA miR-155,
• MeSH
• antigeny CD38 metabolismus   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfom metabolismus   mortalita   MeSH
• mikro RNA biosyntéza   MeSH
• nádorové biomarkery biosyntéza   MeSH
• prevalence MeSH
• protein-tyrosinkináza ZAP-70 metabolismus   MeSH
• protoonkogenní proteiny biosyntéza   MeSH
• regulace genové exprese u nádorů * MeSH
• RNA nádorová biosyntéza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• trans-aktivátory biosyntéza   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
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD38 MeSH
• mikro RNA MeSH
• MIRN155 microRNA, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• protein-tyrosinkináza ZAP-70 MeSH
• proto-oncogene protein Spi-1 MeSH Prohlížeč
• protoonkogenní proteiny MeSH
• RNA nádorová MeSH
• trans-aktivátory MeSH
• ZAP70 protein, human MeSH Prohlížeč

Malignant gliomas are the most common type of primary malignant brain tumours, characterized by extreme proliferation and aggressive invasion. There is evidence for over-expression of the YKL40 gene in high-grade gliomas. The high serum levels of the glycoprotein are associated with poor prognosis of various inflammatory and tumour processes. We investigated the YKL40 mRNA level and protein expression in the tumour site and in the serum of high-grade glioma patients. The YKL-40 expression in 36 patients with glial tumours (astrocytoma grade III, glioblastoma) and 33 age-matched healthy persons was measured by gene analysis, immunohistochemistry and ELISA. YKL-40 serum levels in high-grade glioma patients compared to healthy subjects were significantly increased (P ≤ 0.05). A wide range of variability in YKL40 mRNA expression was found. YKL-40 staining in situ was more abundant in glioblastoma tissue than in anaplastic astrocytoma, with the lowest level in normal brain tissue. Our gene analysis revealed that in general, YKL40 mRNA in glioma patients was over-expressed versus normal brain. A significant correlation between YKL40 transcript and protein levels was observed (P ≤ 0.05). It could be speculated that the YKL-40 protein might contribute to glioblastomas' specific biological characteristics that distinguish them from grade III gliomas. A complex investigation of YKL40 expression was performed at the molecular and cellular levels in human high-grade gliomas. Serum YKL-40 concentrations increased with tumour grade and correlated positively with transcript rate, being the highest in glioblastoma. We provide evidence for a relationship between YKL40 expression and the malignancy of glial tumours.

• MeSH
• adipokiny biosyntéza   krev   genetika   MeSH
• astrocytom metabolismus   patologie   terapie   MeSH
• dospělí MeSH
• glioblastom metabolismus   patologie   terapie   MeSH
• gliom metabolismus   patologie   terapie   MeSH
• kombinovaná terapie MeSH
• lektiny biosyntéza   krev   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• nádorové proteiny biosyntéza   krev   genetika   MeSH
• nádory mozku metabolismus   patologie   terapie   MeSH
• prognóza MeSH
• protein CHI3L1 MeSH
• regulace genové exprese u nádorů MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• stupeň nádoru MeSH
• upregulace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adipokiny MeSH
• CHI3L1 protein, human MeSH Prohlížeč
• lektiny MeSH
• messenger RNA MeSH
• nádorové proteiny MeSH
• protein CHI3L1 MeSH
• RNA nádorová MeSH

BACKGROUND: Rectal cancer accounts for approximately one third of all colorectal cancers (CRC), which belong among leading causes of cancer deaths worldwide. Standard treatment for locally advanced rectal cancer (cT3/4 and/or cN+) includes neoadjuvant chemoradiotherapy with fluoropyrimidines (capecitabine or 5-fluorouracil) followed by radical surgical resection. Unfortunately, a significant proportion of tumors do not respond enough to the neoadjuvant treatment and these patients are at risk of relapse. MicroRNAs (miRNAs) are small non-coding RNAs playing significant roles in the pathogenesis of many cancers including rectal cancer. MiRNAs could present the new predictive biomarkers for rectal cancer patients. METHODS: We selected 20 patients who underwent neoadjuvant chemoradiotherapy for advanced rectal cancer and whose tumors were classified as most sensitive or resistant to the treatment. These two groups were compared using large-scale miRNA expression profiling. RESULTS: Expression levels of 8 miRNAs significantly differed between two groups. MiR-215, miR-190b and miR-29b-2* have been overexpressed in non-responders, and let-7e, miR-196b, miR-450a, miR-450b-5p and miR-99a* have shown higher expression levels in responders. Using these miRNAs 9 of 10 responders and 9 of 10 non-responders (p < 0.05) have been correctly classified. CONCLUSIONS: Our pilot study suggests that miRNAs are part of the mechanisms that are involved in response of rectal cancer to the chemoradiotherapy and that miRNAs may be promising predictive biomarkers for such patients. In most miRNAs we identified (miR-215, miR-99a*, miR-196b, miR-450b-5p and let-7e), the connection between their expression and radioresistance or chemoresistance to inhibitors of thymidylate synthetase was already established.

• MeSH
• adenokarcinom genetika   metabolismus   patologie   chirurgie   terapie   MeSH
• capecitabinum MeSH
• chemoradioterapie * MeSH
• chemorezistence genetika   MeSH
• deoxycytidin analogy a deriváty   farmakologie   terapeutické užití   MeSH
• dospělí MeSH
• fluoruracil analogy a deriváty   farmakologie   terapeutické užití   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA biosyntéza   genetika   MeSH
• nádorové proteiny antagonisté a inhibitory   fyziologie   MeSH
• nádory rekta genetika   metabolismus   patologie   chirurgie   terapie   MeSH
• neoadjuvantní terapie * MeSH
• pilotní projekty MeSH
• protinádorové antimetabolity farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů * MeSH
• retrospektivní studie MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• thymidylátsynthasa antagonisté a inhibitory   fyziologie   MeSH
• tolerance záření genetika   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• capecitabinum MeSH
• deoxycytidin MeSH
• fluoruracil MeSH
• mikro RNA MeSH
• nádorové proteiny MeSH
• protinádorové antimetabolity MeSH
• RNA nádorová MeSH
• thymidylátsynthasa MeSH

The platinum(II) dichlorido and oxalato complexes of the general formula cis-[PtCl(2)(nHaza)(2)] (1-3) [Pt(ox)(nHaza)(2)] (4-6) involving 7-azaindole halogeno-derivatives (nHaza) were prepared and thoroughly characterized. A single-crystal X-ray analysis of cis-[PtCl(2)(3ClHaza)(2)]·DMF (1·DMF; 3ClHaza symbolizes 3-chloro-7-azaindole) revealed a distorted square-planar arrangement with both the 3ClHaza molecules coordinated through their N7 atoms in a cis fashion. In vitro cytotoxicity of the complexes was evaluated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay against the HOS (osteosarcoma), MCF7 (breast adenocarcinoma) and LNCaP (prostate adenocarcinoma) human cancer cell lines. The dichlorido complexes 1-3 (IC(50)=3.8, 3.9, and 2.5 μM, respectively) showed significantly higher in vitro anticancer effect against HOS as compared with cisplatin, whose IC(50)=37.7 μM. The biological effect of cisplatin against MCF7 (IC(50)=24.5 μM) and LNCaP (IC(50)=3.8 μM) was also exceeded by 1-3 (except for 2 against LNCaP), but the difference can be classified as significant only in the case of 1 (IC(50)=3.4 μM) and 3 (IC(50)=2.0 μM) against MCF7. The molecular pharmacological studies (RNA synthesis by T7 RNA polymerase in vitro) proved that 1-3 bind to DNA in a similar manner as cisplatin, since the RNA synthesis products of 1-3 and cisplatin showed a similar sequence profile of major bands.

• MeSH
• cisplatina * analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• cytotoxiny * chemická syntéza   chemie   farmakologie   MeSH
• indoly chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   MeSH
• protinádorové látky * chemická syntéza   chemie   farmakologie   MeSH
• RNA nádorová biosyntéza   MeSH
• RNA biosyntéza   MeSH
• screeningové testy protinádorových léčiv metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-azaindole dimer MeSH Prohlížeč
• cisplatina * MeSH
• cytotoxiny * MeSH
• indoly MeSH
• protinádorové látky * MeSH
• RNA nádorová MeSH
• RNA MeSH

BACKGROUND: Nowadays we know that survival rates do not differ between repeated and single liver resections for colorectal liver metastases (CLM). To be able to determine patients prone to early recurrence, the use of different markers with a better prognostic value than the routinely employed tumor markers is required. AIM OF STUDY: The aim of our study was to assess mRNA expression of MMP-7, MMP-9, TIMP-1, TIMP-2 and CEA in tissue samples from CLM and their relationship to disease-free interval (DFI) and overall survival (OS). PATIENTS AND METHODS: The liver tumor biopsies were obtained from 40 patients suffering from CLM treated with radical surgery. mRNA expression levels of CEA, MMPs and TIMPs and a housekeeping gene (GAPDH) were quantified using RT-PCR. RESULTS: The increased expression of CEA, MMP-9 and TIMP-1 in CLM was associated with a short DFI and a high tendency to early CLM recurrence. Statistical analysis confirmed CEA, MMP-9 and TIMP-1 expression as prognostic factors of survival. CONCLUSION: This study demonstrated the importance of CEA, MMP-9 and TIMP-1 in the prognostication of DFI and OS.

• MeSH
• adenokarcinom genetika   metabolismus   mortalita   sekundární   chirurgie   MeSH
• analýza přežití MeSH
• dospělí MeSH
• karcinoembryonální antigen biosyntéza   genetika   MeSH
• kolorektální nádory mortalita   patologie   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• matrixová metaloproteinasa 7 biosyntéza   genetika   MeSH
• matrixová metaloproteinasa 9 biosyntéza   genetika   MeSH
• messenger RNA biosyntéza   MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• nádory jater genetika   metabolismus   mortalita   sekundární   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• RNA nádorová biosyntéza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tkáňový inhibitor metaloproteinasy 1 biosyntéza   genetika   MeSH
• tkáňový inhibitor metaloproteinasy 2 biosyntéza   genetika   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
• práce podpořená grantem MeSH
• Názvy látek
• karcinoembryonální antigen MeSH
• matrixová metaloproteinasa 7 MeSH
• matrixová metaloproteinasa 9 MeSH
• messenger RNA MeSH
• MMP7 protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• RNA nádorová MeSH
• tkáňový inhibitor metaloproteinasy 1 MeSH
• tkáňový inhibitor metaloproteinasy 2 MeSH