The CDK inhibitors in cancer research and therapy

Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in different human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the specific purpose of their research. For this purpose, the targets, commercial availability and IC50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitor

Politinio spektaklio konstravimas posovietinėje erdvėje

Straipsnyje, remiantis žiniasklaidos teoretikų darbais, analizuojami procesai, vykę žiniasklaidoje posovietinio perėjimo laikotarpiu, taip pat aiškinamasi, kaip dėl šių procesų keitėsi Murray Edelmano aprašytas politinio spektaklio konstravimas.Suirus Sovietų Sąjungai, nepriklausomybę išsikovojusiose valstybėse atsirado galimybė formuotis naujoms žiniasklaidos sistemoms, kurios dėl savitų aplinkybių skiriasi nuo išsamiai aprašytų joms analogiškų Vakarų Europoje ir JAV. Įvairūs žiniasklaidos tyrinėtojai aprašo, kaip skirtingomis aplinkybėmis vykstant posovietinio perėjimo procesui, susidėjusiam iš trijų etapų (proveržio, reformavimo ir stabilizacijos), susiformavo du skirtingi žiniasklaidos modeliai, besiskiriantys santykiu tarp žiniasklaidos ir politinės valdžios. Straipsnyje šie modeliai vadinami laisvuoju ir subordinaciniu. Laisvojo modelio valstybėse žiniasklaidai labiausiai orientuojantis į pelną suprastėjo jos kokybė ir pasitikėjimas ja, dėl to kuriamas politinis spektaklis buvo ne toks efektyvus. Subordinacinio modelio valstybėse žiniasklaidos pagrindu tapo jos turima galia, dėl to žiniasklaidos krizės požymiai buvo menkesni, atsirado galimybė efektyviau kurti politinį spektaklį.Esminiai žodžiai: posovietinė erdvė, politinis spektaklis, žiniasklaida, posovietinis perėjimas

Užslėptas tapatybių konfliktas: LDK paveldo diskursai Lietuvos ir Baltarusijos interneto žiniasklaidoje 2013–2014 metais

[full article and abstract in Lithuanian; abstract in English] This article is aimed at presenting an insight into national identities as constructed on the basis of the heritage of the Grand Duchy of Lithuania (GDL) in the major Lithuanian and Belarusian news sites (2013–2014). By performing content analysis, it was revealed that in the vast majority of news publications, either Lithuania or Belarus, respectively by country of publishing, was considered as the main or only successor of the GDL, although this narrative was not elaborated upon and was seen as self-explanatory. The neighboring state was rarely criticized and its narrative mostly considered as frivolous and not worthy of attention. A lack of contact, discussion and mutual explanation between the Lithuanian and Belarusian narratives in the public sphere means that a conflict between both national identities can be seen as hidden or potential.[straipsnis ir santrauka lietuvių kalba; santrauka anglų kalba] Straipsnyje analizuojama LDK paveldo reprezentacija kaip tautinės tapatybės konstravimo būdas popu­liariausiuose Lietuvos ir Baltarusijos naujienų portaluose 2013–2014 metais. Diskurso analizės metu nustatyta, kad daugumoje interneto žiniasklaidos publikacijų sava valstybė laikyta pagrindine arba vienintele LDK paveldėtoja, tačiau toks požiūris neakcentuotas ir laikytas savaime suprantamu. Kaimyninė valstybė tokiose publikacijose kritikuota retai, o joje vyraujantis naratyvas laikytas nerimtu, nepagrįstu ir nevertu dėmesio. Viešojoje erdvėje sąlyčio taškų tarp vienos ir kitos šalies naratyvų nėra, nė vienoje valstybėje kitos valstybės naratyvai nėra paaiškinami ir su jais nėra diskutuojama, todėl konfliktinė situacija tarp lietuvių ir baltarusių tapatybių gali būti laikoma užslėpta arba potencialia

Attitudes toward preventive services and lifestyle : the views of primary care patients in Europe. The EUROPREVIEW patient study

Background: For preventive interventions in general practice to succeed, patients' points of view must be taken into account in addition to those of GPs. Objective: To explore patients' views and beliefs about the importance of lifestyle and preventive interventions, to assess their readiness to make changes to their lifestyle and their willingness to receive support from GPs. Methods: Cross-sectional survey conducted by EUROPREV in primary care practices in 22 European countries. Patients were consecutively selected and interviewed from September 2008 to September 2009. Results: Seven thousand nine hundred and forty-seven participants, 52.2% females. Only 30.5% of risky drinkers think they need to change, as opposed to 64% of smokers, 73.5% of patients with unhealthy eating habits and 73% with lack of physical activity. Risky drinkers reported that GPs initiated a discussion on alcohol consumption less often (42%) than on smoking (63%), eating habits (59%) or physical activity (55%). Seventy-five per cent, 66% and 63% of patients without hypertension, diabetes or hypercholesterolaemia, respectively, think blood pressure, blood sugar and serum cholesterol should be checked yearly. Women (80%) think they should be screened with the cervical smear test and 72.8% of women aged 30-49 years with mammography, yearly or every 2 years. Conclusions: A high proportion of patients attending primary care with unhealthy lifestyles (especially risky drinkers) do not perceive the need to change their habits, and about half the patients reported not having had any discussion on healthy lifestyles with their GPs. Patients overestimate their need to be screened for cardiovascular risk factors and for cancer.peer-reviewe

Mycobacteria produce proteins involved in biofilm formation and growth-affecting processes

The aim of this study was to determine the effect of mycobacterial proteins on mycobacterial biofilm formation and growth processes. We separated growth-affecting proteins (GEPs) from wild type of Mycobacterium bovis and ATCC strain of Mycobacterium avium subsp. avium. Our results showed that these mycobacteria-secreted GEPs are involved in biofilm formation, growth stimulatory, and inhibitory processes. Our findings suggest that GEP stimulated M. avium subsp. avium growth in vitro. Stimulation process was observed in mycobacteria affected with GEP extracted from M. avium subsp. avium. We found that both GEPs inhibited the growth of the M. bovis. Optical density measurement and visual analysis confirm that GEP plays an important role in biofilm formation process. Most of M. bovis GEP are associated with the type VII secretion and general secretion pathways. Our results contribute to a better understanding of the mechanisms underlying mycobacterial biofilm formation and growth-affecting processes and better characterization of mycobacterial proteins and their functions. It is noteworthy that this finding represents the first demonstration of GEP-mediated growth effects on a solid and liquid medium

Additive Effects of PDGF Receptor β Signaling Pathways in Vascular Smooth Muscle Cell Development

The platelet-derived growth factor β receptor (PDGFRβ) is known to activate many molecules involved in signal transduction and has been a paradigm for receptor tyrosine kinase signaling for many years. We have sought to determine the role of individual signaling components downstream of this receptor in vivo by analyzing an allelic series of tyrosine–phenylalanine mutations that prevent binding of specific signal transduction components. Here we show that the incidence of vascular smooth muscle cells/pericytes (v/p), a PDGFRβ-dependent cell type, can be correlated to the amount of receptor expressed and the number of activated signal transduction pathways. A decrease in either receptor expression levels or disruption of multiple downstream signaling pathways lead to a significant reduction in v/p. Conversely, loss of RasGAP binding leads to an increase in this same cell population, implicating a potential role for this effector in attenuating the PDGFRβ signal. The combined in vivo and biochemical data suggest that the summation of pathways associated with the PDGFRβ signal transduction determines the expansion of developing v/p cells

The future prospects of Lithuanian family physicians: a 10-year forecasting study

BACKGROUND: When health care reform was started in 1991, the physician workforce in Lithuania was dominated by specialists, and the specialty of family physician (FP) did not exist at all. During fifteen years of Lithuania's independence this specialty evolved rapidly and over 1,900 FPs were trained or retrained. Since 2003, the Lithuanian health care sector has undergone restructuring to optimize the network of health care institutions as well as the delivery of services; specific attention has been paid to the development of services provided by FPs, with more health care services shifted from the hospital level to the primary health care level. In this paper we analyze if an adequate workforce of FPs will be available in the future to take over new emerging tasks. METHODS: A computer spreadsheet simulation model was used to project the supply of FPs in 2006–2015. The supply was projected according to three scenarios, which took into account different rates of retirement, migration and drop out from training. In addition different population projections and enrolment numbers in residency programs were also considered. Three requirement scenarios were made using different approaches. In the first scenario we used the requirement estimated by a panel of experts using the Delphi technique. The second scenario was based on the number of visits to FPs in 2003 and took into account the goal to increase the number of visits. The third scenario was based on the determination that one FP should serve no more than 2,000 inhabitants. The three scenarios for the projection of supply were compared with the three requirement scenarios. RESULTS: The supply of family physicians will be higher in 2015 compared to 2005 according to all projection scenarios. The largest differences in the supply scenarios were caused by different migration rates, enrolment numbers to training programs and the retirement age. The second supply scenario, which took into account 1.1% annual migration rate, stable enrolment to residency programs and later retirement, appears to be the most probable. The first requirement scenario, which was based on the opinion of well-informed key experts in the field, appears to be the best reflection of FP requirements; however none of the supply scenarios considered would satisfy these requirements. CONCLUSION: Despite the rapid expansion of the FP workforce during the last fifteen years, ten-year forecasts of supply and requirement indicate that the number of FPs in 2015 will not be sufficient. The annual enrolment in residency training programs should be increased by at least 20% for the next three years. Accurate year-by-year monitoring of the workforce is crucial in order to prevent future shortages and to maintain the desired family physician workforce

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events