Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.

Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9-3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells.

The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.

Compact low resolution spectrograph, an imaging and long slit spectrograph for robotic telescopes.

The COmpact LOw REsolution Spectrograph (COLORES) is a compact and lightweight (13 kg) f/8 imaging spectrograph designed for robotic telescopes, now installed and operating on the TELMA, a rapid-slewing 60 cm telescope of the BOOTES-2 observatory in Málaga (Spain). COLORES is a multi-mode instrument that enables the observer to seamlessly switch between low-dispersion spectroscopy and direct imaging modes during an observation. In this paper, we describe the instrument and its development, from the initial scientific requirements through the optical design process to final configuration with theoretical performance calculations. The mechanical and electronic design is described, methods of calibration are discussed and early laboratory and scientific results are shown.

Consumption of three strong opioids (morphine, oxycodone and fentanyl) in seven European countries during seven years (2003-2009).

PURPOSE: The aim was to analyse the consumption of selected strong opioid analgesics during a seven-year period of 2003-2009 in order to compare Slovak consumption with that in six other European countries and to determine our position. METHODS: Drug consumption data from the State Institute for Drug Control in Slovak Republic were used. As to the data from other countries, annual health statistics published on websites were used in comparison. RESULTS: Obviously the consumption of one of studied opioid drugs with transdermal aplication route, particularly fentanyl, tended to increase in all countries during the observed period. Oxycodone tends to yield a rapid increase in consumption as well. As opposed to the latter drugs, the consumption of morphine was decreasing throughout the observed period. The consumption of these drugs in Slovakia remains low (except for that of fentanyl). CONCLUSION: Our analysis confirmed a clear shift from oral to transdermal therapy as well as usage of newer drugs. Drug consumption data are a relatively new source of information for health research. Our analysis showed increasing trends in fentanyl (patch opioid) consumption in all compared countries as well as an increasing consumption of oxycodone and decreasing consumption of morphine (Fig. 3, Ref. 17).

A commentary on a decrease in consumption of selective COX-2 inhibitors (coxibs) Comparison between Slovakia and Nordic countries.

PURPOSE: The aim of our work was to analyze utilization patterns in Slovakia and Nordic countries and to determine coxib risk perception among medical professionals. METHODS: The consumption of coxibs in Slovakia during 1999-2009 was analyzed. Data were obtained from the State Institute for Drug Control in SR. Obtained results were compared to data based on annual health statistics in Denmark, Finland and Norway. General Practitioners were asked on a perceived risk. RESULTS: We observed an increase of consumption in first years, followed with a marked decrease after year 2004. Slovak consumption was very small. Coxibs represented in Slovakia only a small part of totally prescribed non-steroidal anti-inflammatory drugs. They constituted only 1.44 % in the year 2003, whereas in Norway 41.2 %. 14 % of respondents (n=570) marked coxibs to be the safest analgesic drug. CONCLUSION: Published data show that consumption of coxibs (rofecoxib was linked with serious thrombotic cardiovascular adverse effect) fall down markedly. Consumption data from 1999 until 2009 from Slovakia and three Nordic countries showed significant differences (p<0.001). During the observed period, the utilization of coxibs in Slovakia was very small - a possible explanation is new drug, higher prize, doctor's habits (Tab. 2, Fig. 1, Ref. 11).

Consumption of three most widely used analgesics in six European countries.

WHAT IS KNOWN AND OBJECTIVE: Analgesics are among the most widely used drugs and there is wide intercountry variability in the rates of consumption of different analgesics. Our objective is to determine and compare patterns of analgesic consumption in the Slovak Republic and a number of other European countries. METHODS: We undertook a drug utilization study using WHO ATC/defined daily doses (DDD) methodology. Wholesale analgesic data collected by the Slovak State Institute for Drug Control were used. Utilization was calculated as DDD per 1000 inhabitants per day. Comparison with wholesale data from Czech Republic, Estonia, Finland, Norway and Denmark, published on the Internet, was made. RESULTS AND DISCUSSION: Paracetamol/acetaminophen consumption varied only a little in Slovak Republic and Czech Republic, whereas consumption in Nordic countries was significantly higher (P < 0.05) and in Estonia significantly lower. Ibuprofen consumption was significantly higher in Czech Republic and Finland. Significantly lower consumption was in Norway. The lowest consumption of ASA/aspirin was in Denmark and in Norway. The highest consumption was in Finland. WHAT IS NEW AND CONCLUSION: Effective therapy needs good prescribing and well-informed prescribers and patients. Our study highlights wide differences in analgesic consumption even among similar European countries. The basis of these differences and their potential clinical impact require further investigation.

Comments to regional problems of analgesic risk perception.

OBJECTIVES: The aim of our study was to analyse analgesic risk perception and then to compare analgesic drug choice among general practitioners. METHOD: The structured questionnaire was used and completed during continuous medical education lectures. Series of targeted open or close questions and visual analog scale (VAS) to determine drug risk perception were used. Slovak general practitioners attending continuous medical education lectures during 2004-2005 were invited to participate in the study. Group 1 consisted of respodents from Bratislava (capital city of Slovakia, n = 245) and group 2 consisted of general practitioners from 3 other cities (middle and eastern Slovakia, n = 325). Data were compared to reported adverse drug reactions. RESULTS: Quarter of doctors 25.3% (n = 62), (25.2% (n = 82) respectively), considered non-steroidal anti-inflammatory drugs to be the safest group of analgesics. Gastrointestinal damage in general was perceived as most common adverse drug reaction. 72.41% (75.94% respectively) of respondents considered analgesics as exactly or probably danger. Perceived drug risk labeled on VAS was 4.23 (SD 1.52), (3.22 (SD 2.19) respectively) (p < 0.05). Total number of reported adverse drug reactions in years 1998-2002 was 3249, 412 were related to analgesic use. Specific organotoxic adverse drug reactions (nephrotoxicity, etc.) were reported rarely. CONCLUSION: The actual perception of analgesic risk in Slovakia seems to be generally inadequate. We found only a low support of spontaneous adverse drug reactions reporting to the national monitoring system (Tab. 1, Fig. 2, Ref. 11).

5 most consumpted opioid analgesics in Slovakia in the year 2006--comparison to five other countries (Finland, Norway, Denmark, Spain, Australia).

INTRODUCTION: Opioid analgesics are drugs of choice in the treatment of moderate and severe malignant or noncancer pain. Consumption data helps us to evaluate the status of country's public health. METHODS: We analysed the consumption of opioid analgesics from ATC class N02A in Slovakia in the year 2006 and compared it with five other countries -- Finland, Norway, Denmark, Spain and Australia. We then calculated drugs that accounted for 90% of the total volume of DDDs in the year 2006. RESULTS: Slovakia showed a dominance of tramadol consumption that constituted three quarters of the total group consumption. Tramadol is the commonest consumed opioid analgesic in all observed countries (in Norway it constituted only 35% of total group consumption, whereas in Slovakia it was 72%). DISCUSSION: Opioid consumption in Slovakia is increasing, but comparison with the Nordic countries, Spain and Australia showed a significantly lower consumption. Exception is tramadol with the highest consumption in Slovakia. CONCLUSION: Observed trends in consumption indicate a well known accent of the Nordic countries on treatment of pain. Opiod consumption in Slovakia continues to stay low (Tab. 1, Fig. 1, Ref. 10). Full Text (Free, PDF) www.bmj.sk.

Modified problem-based learning in pharmacology.

OBJECTIVE: The aim of this study was to determine differences between PBL as compared to modified PBL with special focus on acquiring EBM principles. METHODS: Two groups consisted of total 152 students (139 respectively). The use of EBM principles means integrating individual expertise with the best available external clinical evidence by using available data sources and national guidelines. CONCLUSION: Our findings suggest that modified PBL with extended EBM approach could be superior to "classical" PBL (Fig. 3, Ref. 29). Full Text (Free, PDF) www.bmj.sk.

Comparison of NSAID consumption in Slovakia, Finland and Norway.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) belong to most frequently used drugs worldwide. NSAIDs belong to the family of drugs that represent the biggest drug risk as to the number of adverse drug reactions (ADRs), as well as to the number of deregistered drugs. METHODS: We analysed the whole consumption of NSAIDs from ATC class M01 in Slovakia during 1996-2007. RESULTS: Most frequently used NSAIDs in Slovakia were ibuprofen and diclofenac. There was a marked increasing trend in piroxicam, meloxicam, ibuprofen and especially nimesulide medicines. CONCLUSION: Prescription habits of doctors in Slovakia reflect the drug risk only partially, nevertheless the total consumption of dangerous medicines is decreasing and substances with safer profile remain being more used. In the prescribing process the patients' risk factors together with the differences in drug characteristics should be considered. Nevertheless some of these drugs are OTC, and their consumption is strongly influenced by pharmacists and advertisement (Tab. 2, Fig. 1, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Flares from a candidate Galactic magnetar suggest a missing link to dim isolated neutron stars.

Magnetars are young neutron stars with very strong magnetic fields of the order of 10(14)-10(15) G. They are detected in our Galaxy either as soft gamma-ray repeaters or anomalous X-ray pulsars. Soft gamma-ray repeaters are a rare type of gamma-ray transient sources that are occasionally detected as bursters in the high-energy sky. No optical counterpart to the gamma-ray flares or the quiescent source has yet been identified. Here we report multi-wavelength observations of a puzzling source, SWIFT J195509+261406. We detected more than 40 flaring episodes in the optical band over a time span of three days, and a faint infrared flare 11 days later, after which the source returned to quiescence. Our radio observations confirm a Galactic nature and establish a lower distance limit of approximately 3.7 kpc. We suggest that SWIFT J195509+261406 could be an isolated magnetar whose bursting activity has been detected at optical wavelengths, and for which the long-term X-ray emission is short-lived. In this case, a new manifestation of magnetar activity has been recorded and we can consider SWIFT J195509+261406 to be a link between the 'persistent' soft gamma-ray repeaters/anomalous X-ray pulsars and dim isolated neutron stars.

A photometric redshift of z = 6.39 +/- 0.12 for GRB 050904.

Gamma-ray bursts (GRBs) and their afterglows are the most brilliant transient events in the Universe. Both the bursts themselves and their afterglows have been predicted to be visible out to redshifts of z approximately 20, and therefore to be powerful probes of the early Universe. The burst GRB 000131, at z = 4.50, was hitherto the most distant such event identified. Here we report the discovery of the bright near-infrared afterglow of GRB 050904 (ref. 4). From our measurements of the near-infrared afterglow, and our failure to detect the optical afterglow, we determine the photometric redshift of the burst to be z = 6.39 - 0.12 + 0.11 (refs 5-7). Subsequently, it was measured spectroscopically to be z = 6.29 +/- 0.01, in agreement with our photometric estimate. These results demonstrate that GRBs can be used to trace the star formation, metallicity, and reionization histories of the early Universe.

Experience with problem oriented teaching in pharmacology.

Pharmacology is one of the core subjects for further graduation in both preclinical and clinical area. Medical education is being performed either in the "classical" way (lecture based learning--LBL) or in a more advanced form, such as problem based learning (PBL). According to the Medline database, the interest in PBL is still increasing. At our department, the PBL has been introduced using the knowledge obtained at the the Mac Master University and University of Groningen. PBL in pharmacology requires well-qualified staff with clinical experience. A common character of PBL is the use of selected clinical cases as models and starting points to study certain topics with a student centred approach. In an interview we made on a sample of 88 students of our medical faculty in the last study year, 65.5% of them found the amount of information concerning pharmacotherapy not sufficient for their future clinical practice and 83.3% did not feel able to use the knowledge obtained. More than 90% of students did not see enough opportunities for pharmacotherapy training during clinical subject courses. These results are in support of our orientation of teaching towards the PBL. This type of teaching forces students to be active, trains their skills in communication and selection of knowledge, which is believed to enhance the long-term knowledge retention. By using the hybrid PBL-LBL model at our department we respect the principal proposal of medical education and attempt to improve skills in decision making in training of future medical doctors. (Tab. 3, Fig. 2, Ref. 13.)

The Slovak Drug Information (Druginfo) Centre during the period 1997-2004.

OBJECTIVES: The aim of the presented study was to evaluate the profile of users, the number and character of questions which were received during the period May 1997-December 2004. BACKGROUND: The drug information centre (Druginfo) has been established in Slovak Republic at the Department of Pharmacology in May 1997. Since 2002 Druginfo is a member of International Register of Drug Information Services of the Society of Hospital Pharmacists of Australia. Druginfo provides voluntarily free of charge drug information for healthcare professionals. METHOD: Druginfo receives questions addressed via phone, fax and e-mail. The questions were replied by consulting pharmacologists on duty. The data for this study were obtained from records which include list the received questions and the basic information about the questioners. RESULTS: The Druginfo received 495 questions during the period May 1997-December 2004. Questions were mostly from hospital physicians, followed by outpatient physicians and employees of the Faculty of Medicine. The most frequent specializations of the asking physicians were internal medicine, gynaecology-obstetrics, clinical pharmacology and general medicine. The most common topic was basic information about drugs, followed by questions concerning the use of drugs in pregnancy and lactation. According to the ATC classification the questions were most often related to antiinfective drugs, cardiovascular drugs and psychiatric drugs. CONCLUSION: The existence of Druginfo in Slovak Republic represents a possibility of an open access to independent drug information. (Fig. 3, Ref. 11.)

Trends in consumption of opioid analgesics in Slovak Republic during 1998-2002.

OBJECTIVE: To describe the patterns of consumption in an opioid analgesic group in Slovakia between 1998 and 2002, to determine prescription habits, and to compare the results with those from selected countries. METHODS: A drug utilization study using WHO methodology [Anatomical-Therapeutic-Chemical classification/defined daily doses (ATC/DDD)] was made. The wholesale data from the State Institute of Drug Control in the Slovak Republic and drug safety reports from the National Centre for Supervision of Adverse Drug Reaction were collected. Utilization was calculated as the DDDs per 1000 inhabitants per day. RESULTS: Consumption of opioid analgesics (ATC class N02AA-N02AX) in Slovakia was still growing during the study with dominance of tramadol. In comparison with other countries in 2001, consumption of morphine (as a representative of analyzed ATC class) in Slovakia (0.17 DDD/1000 inhabitants per day) is still very low, in contrast with Denmark, Austria or Canada (1.80, 1.61 and 1.58 DDD/1000 inhabitants per day, respectively). The collected safety reports contained only a few reported adverse reactions to the opioid analgesics. CONCLUSION: Despite recent increases, the consumption of opioid analgesics in the Slovak republic remains low. We have tried to present an overall picture of prescription of opioid analgesics in Slovakia and to focus attention on this topic.

[Antibiotics in ambulatory practice in Slovakia 1999-2001]. / Antibiotiká v ambulantnej praxi na Slovensku v rokoch 1999-2001.

Evaluation of the consumption of antimicrobial drugs is an important component of antibiotic policy and provides a picture of rationality of treatment. In the present paper, the authors analyzed the consumption of antibacterial agents of the ATC group J01 for systemic use in out-patient practice in Slovakia in 1999-2001. The data were taken from materials of all Slovak insurance companies provided by the Ministry of Health of the Slovak Republic. The paper evaluated the total out-patient consumption of antimicrobial agents and the financial costs of antibiotic therapy, analyzed the consumption of the individual groups of antibiotics and the consumption of individual agents, and compared the found out-patient consumption with that of Finland. The DDD values in the period under study gave evidence of a high but stable consumption of antibiotics. The analysis according to the groups of antibiotics revealed the dominance of penicillins with wider spectra, penicillins sensitive to beta-lactamases, and macrolides. The evaluation of individual antimicrobial agents showed a positive tendency of the growth of amoxicillin consumption, compensated by a decrease in the consumption of less advantageous ampicillin. The comparison of the Slovak and Finnish consumptions of macrolide antibiotics showed a prevailing consumption of roxitromycin and klaritromycin in Slovakia, and azitromycin in Finland. As far as cephalosporins are concerned, the preparations of the first generation dominated in Finland, and those of the second generation in Slovakia.

Decay of the GRB 990123 optical afterglow: implications for the fireball model

Broad-band (ultraviolet to near-infrared) observations of the intense gamma ray burst GRB 990123 started approximately 8.5 hours after the event and continued until 18 February 1999. When combined with other data, in particular from the Robotic Telescope and Transient Source Experiment (ROTSE) and the Hubble Space Telescope (HST), evidence emerges for a smoothly declining light curve, suggesting some color dependence that could be related to a cooling break passing the ultraviolet-optical band at about 1 day after the high-energy event. The steeper decline rate seen after 1.5 to 2 days may be evidence for a collimated jet pointing toward the observer.

Grazing incidence replica optics for astronomical and laboratory applications.

Replica technology was developed for manufacturing numerous low-cost grazing incidence x-ray mirrors for both laboratory and astrophysical experiments. About forty mirrors with apertures between 1.7 and 24 cm have so far been made. The results of tests both at optical and x-ray wavelengths indicate that replica optics is well suited for space and laboratory uses.

[Behavior of copper and manganese in serum in hemodialysis]. / Das Verhalten des Kupfers und Mangans im Serum unter der Hämodialyse.

The extent to which chronic dialysis alters the serum copper and manganese content was examined. The copper content was not significantly altered, whereas the level of manganese in the blood rose highly significantly. This manganese originates from the dialysis fluid. The behaviour of the manganese level during dialysis treatment suggests that the element is deposited in the body. Its transport is clearly connected with protein, since the manganese is not found in the ultrafiltrate. The is no fear of manganese intoxication.