Protein p53 plays an essential role in the induction of apoptosis by ionizing radiation in haemopoietic cells, the damage of which is the main reason for the development of bone marrow post-irradiation syndrome. p53 activation leads to an increase in the Bcl-2 family pro-apoptotic protein PUMA level. PUMA inhibits all the five anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-XL, Bcl-W and A1) and directly triggers apoptosis mediated by pro-apoptotic proteins Bax/Bak. In proliferating cells, knockout of p53 inhibits apoptosis on the one hand, but on the other disables the cellular division arrest moderated by p21Cip1/Waf1. The radioprotective effect of p53 inhibitor pifithrin was obvious at radiation doses causing the bone marrow syndrome. Knockout of PUMA also exerts its radioprotective effect through blocking the apoptosis induction, but the arrest of cells in the cell cycle through p21 induction is not abolished. PUMA -/- mice are radioresistant in terms of the development of post-irradiation syndrome after all radiation doses. Small molecules are being searched for that could prevent binding of PUMA with Bcl-2 family anti-apoptotic proteins. This would result in apoptosis inhibition and radioprotective or mitigating effects of these inhibitors.

• MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• myši MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• proteiny regulující apoptózu genetika   metabolismus   MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• toluen analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

OBJECTIVES: Epidemiological studies of underground miners have provided clear evidence that inhalation of radon decay products causes lung cancer. Moreover, these studies have served as a quantitative basis for estimation of radon-associated excess lung cancer risk. However, questions remain regarding the effects of exposure to the low levels of radon decay products typically encountered in contemporary occupational and environmental settings on the risk of lung cancer and other diseases, and on the modifiers of these associations. These issues are of central importance for estimation of risks associated with residential and occupational radon exposures. METHODS: The Pooled Uranium Miner Analysis (PUMA) assembles information on cohorts of uranium miners in North America and Europe. Data available include individual annual estimates of exposure to radon decay products, demographic and employment history information on each worker and information on vital status, date of death and cause of death. Some, but not all, cohorts also have individual information on cigarette smoking, external gamma radiation exposure and non-radiological occupational exposures. RESULTS: The PUMA study represents the largest study of uranium miners conducted to date, encompassing 124 507 miners, 4.51 million person-years at risk and 54 462 deaths, including 7825 deaths due to lung cancer. Planned research topics include analyses of associations between radon exposure and mortality due to lung cancer, cancers other than lung, non-malignant disease, modifiers of these associations and characterisation of overall relative mortality excesses and lifetime risks. CONCLUSION: PUMA provides opportunities to evaluate new research questions and to conduct analyses to assess potential health risks associated with uranium mining that have greater statistical power than can be achieved with any single cohort.

• MeSH
• hodnocení rizik MeSH
• horníci * MeSH
• kohortové studie MeSH
• kouření cigaret epidemiologie   MeSH
• lidé MeSH
• nádory plic epidemiologie   mortalita   MeSH
• nádory vyvolané zářením epidemiologie   mortalita   MeSH
• nemoci z povolání epidemiologie   MeSH
• pracovní expozice škodlivé účinky   MeSH
• radon škodlivé účinky   MeSH
• uran * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• Evropa MeSH
• Severní Amerika MeSH

This review summarizes recent progress in understanding the role of p53-upregulated mediator of apoptosis (PUMA) in molecular pathways with respect to its potential therapeutic applications. Particular emphasis is given to the PUMA´s role in ionizing radiation-induced signalling as radiotoxicity of normal tissue is mediated mostly via apoptosis. PUMA and its p53-dependent and p53- independent induction are described and potential use as a new target for the development of radioprotective agents is suggested. Further implications, including targeting PUMA to prevent and treat cardiovascular and neurodegenerative diseases, are also discussed together with an overview of other therapeutic applications. Finally, basic chemical structures for the development of novel PUMA modulators such as pifithrine derivatives, kinase inhibitors or modulators of Bcl-2 protein family are described.

• MeSH
• apoptóza účinky léků   genetika   MeSH
• cílená molekulární terapie metody   MeSH
• kardiovaskulární látky farmakologie   terapeutické užití   MeSH
• kardiovaskulární nemoci farmakoterapie   patologie   MeSH
• lidé MeSH
• nádorový supresorový protein p53 antagonisté a inhibitory   genetika   metabolismus   MeSH
• nádory genetika   radioterapie   MeSH
• neurodegenerativní nemoci farmakoterapie   patologie   MeSH
• neuroprotektivní látky farmakologie   terapeutické užití   MeSH
• poškození DNA účinky léků   účinky záření   MeSH
• proteiny regulující apoptózu antagonisté a inhibitory   metabolismus   MeSH
• protoonkogenní proteiny antagonisté a inhibitory   metabolismus   MeSH
• radiační poranění prevence a kontrola   MeSH
• radioprotektivní látky farmakologie   terapeutické užití   MeSH
• signální transdukce účinky léků   genetika   MeSH
• tolerance záření účinky léků   MeSH
• vazba proteinů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Using ITS2 gene sequences, the validity of the tapeworm Diphyllobothrium pacificum (Nybelin, 1931), infecting humans on the Pacific coast of South America and in Japan, was assessed. ITS2 sequences of this cestode differed markedly (sequence similarity 79.0-80.2%) from those of the most common human-infecting cestode, the broad fish tapeworm Diphyllobothrium latum (L.), as well as other four species of Diphyllobothrium, including potential human parasites (D. cordatum, D. dendriticum, and D. lanceolatum) and two species of Spirometra (sequence similarity 77.5-81.9%). Interspecific sequence similarity between all but one (D. pacificum) species was 86.1-99.6%, whereas individual isolates of D. dendriticum and D. ditremum exhibited intraspecific sequence similarity of 97.0-98.0% and 98.2-99.9%, respectively. Phylogenetic trees constructed from ITS2 sequences show a markedly distant position of D. pacificum from other species analyzed and also indicate the possible paraphyly of Spirometra.

• MeSH
• difylobotriáza parazitologie   MeSH
• Diphyllobothrium genetika   klasifikace   MeSH
• financování organizované MeSH
• fylogeneze MeSH
• Herpestidae MeSH
• lachtani rodu Arctocephalus a Callorhinus MeSH
• lidé MeSH
• mezerníky ribozomální DNA genetika   MeSH
• molekulární sekvence - údaje MeSH
• mroži MeSH
• Puma MeSH
• ryby MeSH
• sekvenční homologie nukleových kyselin MeSH
• zeměpis MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH
• Geografické názvy
• Jižní Amerika MeSH

Alpha-tomatine is a major glycoalkaloid found in the roots, leaves, stems and fruit of tomatoes Lycopersicon esculentum . Recently, alpha-tomatine has been recognized as a potential anticancer drug. In the present study, we identified the signaling cascades involved in the antitumor effect of alpha-tomatine on MOLT-4 leukemic cells. Alpha-tomatine inhibited the proliferation and decreased the viability of MOLT-4 cells in a dose-dependent manner. An increase in the activity of caspases 9 and 3/7 was not observed. However, an increase in the amount of p53 and its phosphorylation on serine 15, as well as an increased amount of mitochondrial protein PUMA was detected 4 and 24 h after exposure to alpha-tomatine at a concentration of 1–3 μmol/l. Inhibition of the proliferation of MOLT-4 cells by alpha-tomatine is also associated with an increase in p21 WAF1/CIP1 and the activation of Chk2. The comet assay did not detect significant amounts of single or double DNA strand breaks in cells treated with alpha-tomatine at concentrations of 0.1–9 μmol/l. Our results thus contribute to the understanding of the anticancer action of alpha-tomatine.

• Klíčová slova
• chk2, checkpoint kinase 2,
• MeSH
• apoptóza účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• kometový test MeSH
• leukemie T-buněčná * farmakoterapie   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 * analýza   metabolismus   účinky léků   MeSH
• onkogenní protein p21(ras) MeSH
• poškození DNA MeSH
• proliferace buněk účinky léků   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• protinádorové látky MeSH
• průtoková cytometrie MeSH
• Puma MeSH
• replikace DNA MeSH
• statistika jako téma MeSH
• techniky in vitro MeSH
• tomatin * analogy a deriváty   terapeutické užití   MeSH
• western blotting MeSH

BACKGROUND: The Pooled Uranium Miners Analysis (PUMA) study draws together information from cohorts of uranium miners from Canada, the Czech Republic, France, Germany and the USA. METHODS: Vital status and cause of death were ascertained and compared with expectations based upon national mortality rates by computing standardized mortality ratios (SMRs) overall and by categories of time since first hire, calendar period of first employment and duration of employment as a miner. RESULTS: There were 51 787 deaths observed among 118 329 male miners [SMR = 1.05; 95% confidence interval (CI): 1.04, 1.06]. The SMR was elevated for all cancers (n = 16 633, SMR = 1.23; 95% CI: 1.21, 1.25), due primarily to excess mortality from cancers of the lung (n = 7756, SMR = 1.90; 95% CI: 1.86, 1.94), liver and gallbladder (n = 549, SMR = 1.15; 95% CI: 1.06, 1.25), larynx (n = 229, SMR = 1.10; 95% CI: 0.97, 1.26), stomach (n = 1058, SMR = 1.08; 95% CI: 1.02, 1.15) and pleura (n = 39, SMR = 1.06; 95% CI: 0.75, 1.44). Lung-cancer SMRs increased with duration of employment, decreased with calendar period and persisted with time since first hire. Among non-malignant causes, the SMR was elevated for external causes (n = 3362, SMR = 1.41; 95% CI: 1.36, 1.46) and respiratory diseases (n = 4508, SMR = 1.32; 95% CI: 1.28, 1.36), most notably silicosis (n = 814, SMR = 13.56; 95% CI: 12.64, 14.52), but not chronic obstructive pulmonary disease (n = 1729, SMR = 0.98; 95% CI: 0.93, 1.02). CONCLUSIONS: Whereas there are important obstacles to the ability to detect adverse effects of occupational exposures via SMR analyses, PUMA provides evidence of excess mortality among uranium miners due to a range of categories of cause of death. The persistent elevation of SMRs with time since first hire as a uranium miner underscores the importance of long-term follow-up of these workers.

• MeSH
• kohortové studie MeSH
• lidé MeSH
• nádory plic * MeSH
• nemoci z povolání * MeSH
• pracovní expozice * škodlivé účinky   MeSH
• radon * MeSH
• uran * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• Evropa MeSH
• Francie MeSH
• Kanada MeSH
• Německo MeSH
• Severní Amerika MeSH

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

• MeSH
• dospělí MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory plic * epidemiologie   etiologie   MeSH
• nádory vyvolané zářením * epidemiologie   etiologie   MeSH
• nemoci z povolání * epidemiologie   MeSH
• pracovní expozice * škodlivé účinky   MeSH
• proteiny regulující apoptózu MeSH
• radon * škodlivé účinky   MeSH
• uran * škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: Radon is a ubiquitous occupational and environmental lung carcinogen. We aim to quantify the association between radon progeny and lung cancer mortality in the largest and most up-to-date pooled study of uranium miners. METHODS: The pooled uranium miners analysis combines 7 cohorts of male uranium miners with 7754 lung cancer deaths and 4.3 million person-years of follow-up. Vital status and lung cancer deaths were ascertained between 1946 and 2014. The association between cumulative radon exposure in working level months (WLM) and lung cancer was modelled as the excess relative rate (ERR) per 100 WLM using Poisson regression; variation in the association by temporal and exposure factors was examined. We also examined analyses restricted to miners first hired before 1960 and with <100 WLM cumulative exposure. RESULTS: In a model that allows for variation by attained age, time since exposure and annual exposure rate, the ERR/100 WLM was 4.68 (95% CI 2.88 to 6.96) among miners who were less than 55 years of age and were exposed in the prior 5 to <15 years at annual exposure rates of <0.5 WL. This association decreased with older attained age, longer time since exposure and higher annual exposure rate. In analyses restricted to men first hired before 1960, we observed similar patterns of association but a slightly lower estimate of the ERR/100 WLM. CONCLUSIONS: This new large, pooled study confirms and supports a linear exposure-response relationship between cumulative radon exposure and lung cancer mortality which is jointly modified by temporal and exposure factors.

• MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory plic * etiologie   MeSH
• nádory vyvolané zářením * epidemiologie   etiologie   MeSH
• nemoci z povolání * epidemiologie   etiologie   MeSH
• pracovní expozice * škodlivé účinky   MeSH
• proteiny regulující apoptózu MeSH
• radon * škodlivé účinky   MeSH
• uran * škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

• MeSH
• finanční podpora výzkumu jako téma MeSH
• kočky MeSH
• polymerázová řetězová reakce metody   MeSH
• proviry genetika   izolace a purifikace   MeSH
• virus kočičí imunodeficience genetika   izolace a purifikace   MeSH
• zvířata MeSH
• Check Tag
• kočky MeSH
• zvířata MeSH

Apoptosis in hair follicles often is studied under pathological conditions; little is known about apoptotic mechanisms during normal hair follicle formation and maintenance. We investigated proteins of intrinsic apoptotic pathway, Bim and Puma, during hair follicle development and the first catagen stage using immunofluorescence to describe their expression patterns and to correlate them with apoptosis as determined by TUNEL assay. Both proteins were found in developing follicles. Bim and Puma overlapped apoptosis only partially during physiological apoptotic stage and they were present in non-apoptotic parts of the follicles. Our findings suggest that these primary apoptotic molecules participate in postnatal development and maintenance of hair follicles.

• MeSH
• apoptóza fyziologie   MeSH
• barvení a značení metody   MeSH
• fluorescenční protilátková technika metody   MeSH
• koncové značení zlomů DNA in situ metody   MeSH
• membránové proteiny metabolismus   MeSH
• myši MeSH
• nádorové supresorové proteiny metabolismus   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• protoonkogenní proteiny metabolismus   MeSH
• vlasový folikul cytologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH