• MeSH
• dějiny 20. století MeSH
• lidé MeSH
• pohybové poruchy dějiny   MeSH
• poléková akatizie dějiny   MeSH
• psychiatrie dějiny   MeSH
• Check Tag
• dějiny 20. století MeSH
• lidé MeSH
• Publikační typ
• biografie MeSH
• časopisecké články MeSH
• historické články MeSH
• Geografické názvy
• Česká republika MeSH

• O autorovi
• Haskovec, L

The role of the nucleolus and autophagy in maintenance of nuclear integrity is poorly understood. In addition, the mechanisms of nuclear destruction in cancer cells senesced after conventional chemotherapy are unclear. In an attempt to elucidate these issues, we studied teratocarcinoma PA1 cells treated with Etoposide (ETO), focusing on the nucleolus. Following treatment, most cells enter G2 arrest, display persistent DNA damage and activate p53, senescence, and macroautophagy markers. 2-5 µm sized nucleolar aggresomes (NoA) containing fibrillarin (FIB) and damaged rDNA, colocalized with ubiquitin, pAMPK, and LC3-II emerge, accompanied by heterochromatin fragments, when translocated perinuclearly. Microscopic counts following application of specific inhibitors revealed that formation of FIB-NoA is dependent on deficiency of the ubiquitin proteasome system coupled to functional autophagy. In contrast, the accompanying NoAs release of pericentric heterochromatin, which exceeds their frequency, is favored by debilitation of autophagic flux. Potential survivors release NoA in the cytoplasm during rare mitoses, while exit of pericentric fragments often depleted of H3K9Me3, with or without encompassing by NoA, occurs through the nucleolar protrusions and defects of the nuclear envelope. Foci of LC3-II are accumulated in the nucleoli undergoing cessation of rDNA transcription. As an origin of heterochromatin fragmentation, the unscheduled DNA synthesis and circular DNAs were found in the perinucleolar heterochromatin shell, along with activation and retrotransposition of ALU elements, colocalized with 45S rDNA in NoAs. The data indicate coordination of the basic nucleolar function with autophagy regulation in maintenance of the integrity of the nucleolus associated domains secured by inactivity of retrotransposons.

• Klíčová slova
• ALU retrotransposition, LADs, NADs, aggresome, autophagy, cellular senescence, nucleolus, pericentric fragments, rRNA transcription, ubiquitin-proteasome,
• MeSH
• autofagie účinky léků   genetika   MeSH
• buněčné jadérko účinky léků   genetika   metabolismus   MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• etoposid toxicita   MeSH
• heterochromatin účinky léků   metabolismus   MeSH
• inhibitor p16 cyklin-dependentní kinasy metabolismus   MeSH
• kontrolní body buněčného cyklu účinky léků   genetika   MeSH
• lidé MeSH
• mutageny toxicita   MeSH
• nádorové buněčné linie MeSH
• poškození DNA MeSH
• retroelementy účinky léků   genetika   MeSH
• ribozomální DNA genetika   metabolismus   MeSH
• stárnutí buněk účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromozomální proteiny, nehistonové MeSH
• etoposid MeSH
• fibrillarin MeSH Prohlížeč
• heterochromatin MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• mutageny MeSH
• retroelementy MeSH
• ribozomální DNA MeSH

The nuclear lamina represents a multifunctional platform involved in such diverse yet interconnected processes as spatial organization of the genome, maintenance of mechanical stability of the nucleus, regulation of transcription and replication. Most of lamina activities are exerted through tethering of lamina-associated chromatin domains (LADs) to the nuclear periphery. Yet, the lamina is a dynamic structure demonstrating considerable expansion during the cell cycle to accommodate increased number of LADs formed during DNA replication. We analyzed dynamics of nuclear growth during interphase and changes in lamina structure as a function of cell cycle progression. The nuclear lamina demonstrates steady growth from G1 till G2, while quantitative analysis of lamina meshwork by super-resolution microscopy revealed that microdomain organization of the lamina is maintained, with lamin A and lamin B microdomain periodicity and interdomain gap sizes unchanged. FRAP analysis, in contrast, demonstrated differences in lamin A and B1 exchange rates; the latter showing higher recovery rate in S-phase cells. In order to further analyze the mechanism of lamina growth in interphase, we generated a lamina-free nuclear envelope in living interphase cells by reversible hypotonic shock. The nuclear envelope in nuclear buds formed after such a treatment initially lacked lamins, and analysis of lamina formation revealed striking difference in lamin A and B1 assembly: lamin A reassembled within 30 min post-treatment, whereas lamin B1 did not incorporate into the newly formed lamina at all. We suggest that in somatic cells lamin B1 meshwork growth is coordinated with replication of LADs, and lamin A meshwork assembly seems to be chromatin-independent process.

• Klíčová slova
• Cell cycle, DNA replication, Interphase, Microdomains, Nuclear lamina, Nucleus,
• MeSH
• Cricetulus MeSH
• interfáze * MeSH
• jaderná lamina chemie   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši MeSH
• prasata MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Anchoring of heterochromatin to the nuclear envelope appears to be an important process ensuring the spatial organization of the chromatin structure and genome function in eukaryotic nuclei. Proteins of the inner nuclear membrane (INM) mediating these interactions are able to recognize lamina-associated heterochromatin domains (termed LAD) and simultaneously bind either lamin A/C or lamin B1. One of these proteins is the lamin B receptor (LBR) that binds lamin B1 and tethers heterochromatin to the INM in embryonic and undifferentiated cells. It is replaced by lamin A/C with specific lamin A/C binding proteins at the beginning of cell differentiation and in differentiated cells. Our functional experiments in cancer cell lines show that heterochromatin in cancer cells is tethered to the INM by LBR, which is downregulated together with lamin B1 at the onset of cell transition to senescence. The downregulation of these proteins in senescent cells leads to the detachment of centromeric repetitive sequences from INM, their relocation to the nucleoplasm, and distension. In cells, the expression of LBR and LB1 is highly coordinated as evidenced by the reduction of both proteins in LBR shRNA lines. The loss of the constitutive heterochromatin structure containing LADs results in changes in chromatin architecture and genome function and can be the reason for the permanent loss of cell proliferation in senescence.

• Klíčová slova
• cellular senescence, centromere-specific satellite heterochromatin, constitutive heterochromatin, heterochromatin tether, lamin A/C, lamin B receptor, lamin B1,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Assessment of coronary flow is only performed during pharmacological tests. Supine bicycle tests permit the visualization of coronary flow assessments during exercise. PURPOSE: To assess the parameters of coronary flow in the left anterior descending artery (LAD) during exercise, which could be a sign of significant LAD narrowing. MATERIAL AND METHODS: A total of 253 patients were enrolled: Group 1, 186 non-selective participants before undergoing a coronary angiography; and Group 2, 67 controls without coronary artery disease (CAD). All the patients performed a supine bicycle echocardiography test. Coronary flow velocities and coronary flow velocity reserve (CFVR) were measured at the mid-segment of the LAD during exercise. Patients in Group 1 underwent a coronary angiography. RESULTS: In comparison with participants without significant LAD stenosis, patients with LAD lesions had a lower ΔV (16 ± 21 vs. 27 ± 20 cm/s, P < 0.04) and a lower CFVR (1.5 ± 0.8 vs. 2.0 ± 0.6, P < 0.004). In comparison with patients without significant proximal LAD stenosis, the patients with proximal LAD lesions had a lower flow velocity at the peak of exercise (49 ± 32 vs. 61 ± 19 cm/s, P < 0.02), a lower ΔV (13 ± 19 vs. 26 ± 22 cm/s, P < 0.004), and a lower CFVR (1.4 ± 0.6 vs. 1.9 ± 0.7, P < 0.0001). In comparison with the control group, the patients with LAD stenosis had a lower flow velocity at the peak of exercise, a lower ΔV, and a lower CFVR. CONCLUSION: Non-invasive CFVR measurement in the LAD could provide valuable additional information to a conventional echocardiography exercise test. In routine clinical practice, CFVR is sufficient for a diagnosis of severe stenosis.

• Klíčová slova
• Coronary flow reserve, LAD flow, coronary flow velocity, exercise echo, visualization of coronary artery,
• MeSH
• cyklistika fyziologie   MeSH
• koronární angiografie MeSH
• koronární cirkulace * MeSH
• koronární nemoc diagnostické zobrazování   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pulzní dopplerovská echokardiografie * MeSH
• rychlost toku krve * MeSH
• studie případů a kontrol MeSH
• zátěžová echokardiografie * MeSH
• zátěžový test * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

One of the key functions of nitric oxide (NO) in human is to dilate blood vessels. We tested glycerol trinitrate (GTN) and other well-known NO donors together with those bearing a >C=N-OH group for possible conversion to NO (or nitrites, respectively) by diaphorase (DP) and lipoamide dehydrogenase (LAD). Both, DP and LAD were unable to convert formamidoxime (FAM), acetone oxime (AC), acetohydroxamic acid (AHA) and Nomega-hydroxy-L-arginine (L-NOHA). On the other hand, we observed good conversion of GTN without the requirement of superoxide anion. However, superoxide anion participated to a varying extent in the conversion of other donors (formaldoxime (FAL), acetaldoxime (AO), nitroprusside (NP), S-nitrosoglutathione (SNOG), S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine (HA)). All DP- and LAD-mediated reactions were inhibited by diphenyleneiodonium chloride (DPI), (an inhibitor of flavine enzymes), in a concentration-dependent manner. For these inhibition reactions we determined Ki and IC50 values. In addition, we found that conversion of SNOG was significantly accelerated by glutathione reductase (GTR). Like with DP, 2-phenyl- 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) was reduced also by LAD and thioredoxin reductase (TRR). In summary, we found that LAD significantly accelerates the conversion of a defined subset of NO donors to NO, especially GTN, and eliminates the NO scavenging effect of PTIO.

• MeSH
• biokatalýza * MeSH
• Clostridium kluyveri enzymologie   MeSH
• cyklické N-oxidy metabolismus   MeSH
• dihydrolipoamiddehydrogenasa antagonisté a inhibitory   metabolismus   MeSH
• elektronová paramagnetická rezonance MeSH
• imidazoly metabolismus   MeSH
• kinetika MeSH
• oniové sloučeniny farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• oxidace-redukce MeSH
• scavengery volných radikálů metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide MeSH Prohlížeč
• cyklické N-oxidy MeSH
• dihydrolipoamiddehydrogenasa MeSH
• diphenyleneiodonium MeSH Prohlížeč
• imidazoly MeSH
• oniové sloučeniny MeSH
• oxid dusnatý MeSH
• scavengery volných radikálů MeSH

BACKGROUND: The relationship between culprit vessel, infarct size, and outcomes in non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unclear. In some reports, the left circumflex artery (LCX) was more often the culprit at angiography than the right coronary artery (RCA) or left anterior descending artery (LAD), and infarcts were larger with LCX culprits. METHODS: We determined culprit vessel frequency and initial patency (TIMI flow grade), median fold elevation of peak troponin above the upper limit of normal, and outcomes (30-day death or myocardial infarction [MI] and 1-year mortality) by culprit vessel in high-risk NSTE ACS patients in the EARLY ACS trial. RESULTS: Of 9406 patients, 2066 (22.0%) had angiographic core laboratory data. We evaluated 1774 patients for whom the culprit artery was not the left main, a bypass graft, or branch vessel. The culprit was the LCX in 560 (31.6%), LAD in 653 (36.8%), and RCA in 561 (31.6%) patients. There were fewer women (24.1%) and more prior MI (25.5%) among patients with a culprit LCX compared with those with a culprit LAD or RCA. Patients with LCX (21.2%) and RCA (27.5%) culprits more often had an occluded artery (TIMI 0/1) than did those with LAD (11.3%). Peak troponin elevation was significantly higher for LCX than RCA or LAD culprits. LCX culprit vessels were not associated with worse 30-day or 1-year outcomes in adjusted models. CONCLUSIONS: Among patients with NSTE ACS, the frequencies of LCX, LAD, and RCA culprits were similar. Although LCX lesions were associated with higher peak troponin levels, there was no difference in short- or intermediate-term outcomes by culprit artery.

• Klíčová slova
• Acute coronary syndromes, Infarct size, Left circumflex artery,
• MeSH
• akutní koronární syndrom diagnostické zobrazování   epidemiologie   terapie   MeSH
• časové faktory MeSH
• elektrokardiografie * MeSH
• eptifibatid MeSH
• incidence MeSH
• inhibitory agregace trombocytů aplikace a dávkování   MeSH
• intravenózní infuze MeSH
• koronární angiografie * MeSH
• koronární angioplastika metody   MeSH
• koronární cévy diagnostické zobrazování   chirurgie   MeSH
• lidé MeSH
• míra přežití trendy   MeSH
• peptidy aplikace a dávkování   MeSH
• prognóza MeSH
• rizikové faktory MeSH
• senioři MeSH
• trombocytový glykoproteinový komplex IIb-IIIa antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Nový Zéland epidemiologie   MeSH
• Spojené státy americké epidemiologie   MeSH
• Názvy látek
• eptifibatid MeSH
• inhibitory agregace trombocytů MeSH
• peptidy MeSH
• trombocytový glykoproteinový komplex IIb-IIIa MeSH

PURPOSE: To quantify mean heart dose (MHD) and doses to the left anterior descending artery (LAD) and left ventricle (LV) in a retrospective series of patients who underwent perioperative accelerated partial breast irradiation with multicatheter interstitial brachytherapy (MIB-APBI). METHODS: Sixty-eight patients with low-risk left breast cancer were treated with MIB-APBI at our institution between 2012 and 2017. Interstitial tubes were inserted during the tumorectomy and sentinel node biopsy and APBI was started 6 days later. The prescribed dose was 34 Gy in 10 fractions (twice a day) to the clinical target volume (CTV). The heart, LAD, and LV were contoured and the distance between each structure and the CTV was measured. The MHD, mean and maximum LAD doses (LAD mean/max), and mean LV doses (LV mean) were calculated and corrected to biologically equivalent doses in 2‑Gy fractionation (EQD2). We also evaluated the impact of the distance between the cardiac structures and the CTV and of the volume receiving the prescribed dose (V100) and high-dose volume (V150) on heart dosimetry. RESULTS: Mean EQD2 for MHD, LAD mean/max, and mean LV were 0.9 ± 0.4 Gy (range 0.3-2.2), 1.6 ± 1.1 Gy (range, 0.4-5.6), 2.6 ± 1.9 Gy (range, 0.7-9.2), and 1.3 ± 0.6 Gy (range, 0.5-3.4), respectively. MHD, LAD mean/max, and LV mean significantly correlated with the distance between the CTV and these structures, but all doses were below the recommended limits (German Society of Radiation Oncology; DEGRO). The MHD and LV mean were significantly dependent on V100. CONCLUSION: Perioperative MIB-APBI resulted in low cardiac doses in our study. This finding provides further support for the value of this technique in well-selected patients with early-stage left breast cancer.

• Klíčová slova
• APBI, Brachytherapy, Cardiac doses, Cardiotoxicity, Left breast irradiation, Radiotherapy,
• MeSH
• brachyterapie metody   MeSH
• celková dávka radioterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu radioterapie   MeSH
• prsy účinky záření   MeSH
• retrospektivní studie MeSH
• srdce účinky záření   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: We performed a retrospective analysis of patients treated with radical cystectomy and lymphadenectomy (LAD) for bladder cancer to assess the differential association of the extent of LAD with perioperative complications and re-hospitalization. MATERIALS AND METHODS: LAD templates were defined as limited (lLAD = external, internal iliac and obturator), extended (eLAD = up to crossing of ureter and presacral lymph nodes), and super-extended (sLAD = up to the inferior mesenteric artery). Logistic regression models investigated the association of LAD templates with intraoperative, 30- and 30-90-day postoperative complications, as well as re-hospitalizations within 30 and 30-90 days. RESULTS: A total of 284 patients were available for analysis. sLAD led to a higher lymph-node yield (median 39 vs 13 for lLAD and 31 for eLAD, p < 0.05) and N2/N3 status compared to lLAD and eLAD (p = 0.04). sLAD was associated with a blood loss of > 500 ml (OR 1.3, 95% CI 1.08-1.49, p = 0.003) but not with intraoperative transfusion, operation time, or length of hospital stay (p > 0.05). Overall, 11 (4%) patients were readmitted within 30 days and 50 (17.6%) within 30-90 days. The 30- and 30-90-day mortality rates were 2.8% and 1.4%, respectively. On logistic regression, LAD template was not associated with postoperative complications or re-hospitalization rates. CONCLUSIONS: sLAD leads to higher lymph-node yield and N2/N3 rate but not to higher complication rate compared to lLAD and eLAD. With the advent of novel adjuvant systemic therapies, precise nodal staging will have a crucial role in patients counseling and clinical decision making.

• Klíčová slova
• Bladder cancer, Complications, Lymphadenectomy, Radical cystectomy,
• MeSH
• cystektomie metody   MeSH
• incidence MeSH
• karcinom z přechodných buněk patologie   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfadenektomie škodlivé účinky   metody   MeSH
• lymfatické metastázy MeSH
• lymfatické uzliny patologie   MeSH
• nádory močového měchýře patologie   chirurgie   MeSH
• pánev MeSH
• pooperační komplikace epidemiologie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• staging nádorů MeSH
• znovupřijetí pacienta trendy   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Rakousko epidemiologie   MeSH

The purpose of this study was to compare the radiation dose to organs at risk for deep-inspiration breath hold (DIBH) and free-breathing (FB) radiotherapy in patients with lef-sided breast cancer undergoing adjuvant radiotherapy after partial mastectomy. Methods: One hundred patients with left-sided breast cancer underwent DIBH and FB planning computed tomography scans, and the 2 techniques were compared. Dose-volume histograms were analyzed for heart, left anterior descending coronary artery (LAD), and left lung. Results: Radiation dose to heart, LAD, and left lung was significantly lower for DIBH than for free breathing plans. The median mean heart dose for DIBH technique in comparison with FB was 1.21 Gy, and 3.22 Gy respectively; for LAD, 4.67 versus 24.71 Gy; and for left lung 8.32 Gy versus 9.99 Gy. Conclusion: DIBH is an effective technique to reduce cardiac and lung radiation exposure.

• Klíčová slova
• deep−inspiration breath hold radiotherapy−breast cancer−cardiovascular toxicity−adjuvant radiotherapy,
• MeSH
• celková dávka radioterapie MeSH
• jednostranný karcinom prsu * diagnostické zobrazování   radioterapie   chirurgie   MeSH
• lidé MeSH
• mastektomie MeSH
• nádory prsu * radioterapie   chirurgie   MeSH
• plánování radioterapie pomocí počítače MeSH
• segmentální mastektomie MeSH
• zadržování dechu MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH