Are molecular target therapies limited by cardiotoxicity — causes and symptoms of cardiovascular damage

  Since the introduction of new drugs, (commonly referred to as ‘Molecular Target Therapies’), into oncological clinical practice both the number of objective indicators/endpoints of achieved treatment response and cancer survival duration have increased. Nevertheless, the risk of cardiovascular complications has also risen. Optimistic reports on the relatively low cardiotoxicity of these drugs have been verified through experience. Routine clinical practice has witnessed growing numbers of new drug groups that have different molecular target points and also a varied cardiotoxicity. This paper presents the most important cardiovascular complications associated with the use of molecularly targeted drugs and includes their mechanisms of development

Are molecular target therapies limited by cardiotoxicity — causes and symptoms of cardiovascular damage

Since the introduction of new drugs, (commonly referred to as ‘Molecular Target Therapies’), into oncological clinical practice both the number of objective indicators/endpoints of achieved treatment response and cancer survival duration have increased. Nevertheless, the risk of cardiovascular complications has also risen. Optimistic reports on the relatively low cardiotoxicity of these drugs have been verified through experience. Routine clinical practice has witnessed growing numbers of new drug groups that have different molecular target points and also a varied cardiotoxicity.This paper presents the most important cardiovascular complications associated with the use of molecularly targeted drugs and includes their mechanisms of development

Tissue expression of S100 proteins in gallbladder mucosa of the patients with calculous cholecystitis

 Proteins of S100 group, produced by phagocytes represent endogenous activators of innate immune responses. Role of these proteins in the etiopathogenesis of cholelithiasis remains unknown. The studies aimed at the morphometric evaluation of S100A8 and S100A9 protein expression in gallbladder mucosa in patients with acute and chronic calculous cholecystitis (n = 71). The presence of proteins was detected by immunohistochemistry while quantitative analysis employed the spatial visualization technique. We found the immunopositive expression of the two studied S100 proteins in neutrophils and monocytes/macrophages of the gallbladder’s wall and a higher expression in acute cholecystitis. Quantitative study revealed higher immunoexpression of S100A9 over S100A8 in both studied groups of patients. Moreover, a reciprocal linear relationship between the expression of the studied proteins and a positive correlation between expression of either S100A8 or S100A9 and inflammatory activity (grading) in the gallbladder wall were found. The expression of S100A8 protein in the chronic cholecystitis group and in older patients correlated with leukocytosis, which suggests the role of S100A8 particularly at the chronic stage of cholecystitis. The obtained results indicated close relationship between S100A8 and S100A9 proteins in their proinflammatory functions. The increased expression of only one of them can be recognized as a useful index of local inflammatory activity in calculous cholecystitis.

Wyniki leczenia wemurafenibem chorych na zaawansowanego czerniaka w ramach programu lekowego w Polsce

Introduction. Melanoma is a heterogeneous group of tumours with poor prognosis if the disease is metastatic. More than half of patients with melanoma of the skin have detectable mutations in the BRAF gene. Vemurafenib is the BRAF kinase inhibitor used in the treatment of patients with advanced melanoma with the BRAF mutation. This improves time to progression-free survival and overall survival in patients with this diagnosis. The aim of the study was to analyse the results of treatment and safety of vemurafenib in patients treated during the Polish drug programme. Materials and methods .Between October 2013 and April 2015 a total of 189 patients were treated, 90 women and 99 men, who had previously been diagnosed with unresectable/metastatic melanoma with BRAF V600 mutation. Patients received vemurafenib in 960 mg dose twice per day. The estimated progression-free survival, overall survival and adverse events were assessed. For the survival analysis the Kaplan-Meier method and log-rank test (log-rank) for multi-factor analysis were used. Results. In the first evaluation of the effectiveness of treatment, 8 patients (4.3%) had a complete response, 75 patients (39.7%) partial response, 62 patients (32.8%) had stable disease, and 44 patients (23.2%) had progression of the disease. The disease was controlled in 76.7% of patients. After progression during the therapy with vemurafenib 27% of the patients received subsequent lines of systemic therapy. Twenty-eight patients received chemotherapy and 22 patients immunotherapy with ipilimumab. During the last analysis dated 5 September 2015, the median observation time for still living patients was 8 months (range 3–26). Median progression-free survival was 6.7 months. The median overall survival was 12 months. 146 patients (77%) had adverse events, mostly in the form of dermal toxicity of Grades 1 and 2. Thirty-two patients (17%) presented with side effects of the 3rd and 4th grades of toxicity. Two patients had to stop the treatment due to the toxicity. There were no deaths reported due to the toxicity of treatment. Conclusions. The multicentre analysis confirmed the efficacy and safety of vemurafenib in routine clinical practice in a heterogeneous group of advanced melanomas with BRAF mutation. We confirmed the importance of the known prognostic factors for overall survival in this group of patients, such as lactate dehydogenaze activity (LDH) and ECOG performance status. The current survival of patients with the metastatic melanomas with BRAF mutations are longer than those observed in historical groups.  Wstęp. Czerniak należy do heterogennej grupy nowotworów o bardzo złym rokowaniu w przypadku rozsiewu choroby. U ponad połowy chorych na czerniaka skóry stwierdza się obecność mutacji w obrębie genu BRAF. Wemurafenib jest inhibitorem kinazy BRAF stosowanym w leczeniu chorych na zaawansowanego czerniaka z mutacją BRAF, który poprawia u nich czas przeżycia wolny od progresji choroby oraz przeżycia całkowitego. Celem pracy jest analiza wyników leczenia oraz bezpieczeństwa terapii wemurafenibem u chorych leczonych w ramach programu lekowego w Polsce. Materiały i metody. W okresie od października 2013 do kwietnia 2015 roku leczonych było 189 chorych (90 kobiet i 99 mężczyzn) z rozpoznaniem nieresekcyjnego/przerzutowego czerniaka z mutacją BRAF V600. Chorzy otrzymywali wemurafenib w dawce wyjściowej 960 mg dwa razy na dobę. Oceniano czas wolny od progresji choroby, czas przeżycia całkowitego oraz monitorowano działania niepożądane. Do analizy przeżycia użyto metody Kaplana-Meiera oraz testu logarytmicznego rang (log-rank) dla analiz dwuczynnikowych. Wyniki. W pierwszej ocenie skuteczności leczenia u 8 chorych (4,3%) stwierdzono całkowitą odpowiedź, u 75 chorych (39,7%) częściową odpowiedź, u 62 chorych (32,8%) stabilizację choroby, a u 44 chorych (23,2%) progresję choroby. Kontrolę choroby wykazano u 76,7% chorych. Po progresji w trakcie terapii wemurafenibem 27% chorych otrzymało kolejne linie leczenia systemowego — 28 chorych chemioterapię, 22 chorych ipilimumab. Podczas ostatniej analizy z dnia 5 września 2015 mediana czasu obserwacji dla żyjących chorych wyniosła 8 miesięcy (zakres 3–26). Mediana przeżycia wolnego od progresji wyniosła 6,7 miesiąca. Mediana czasu całkowitego przeżycia wyniosła 12 miesięcy. U 146 chorych (77%) stwierdzono działania niepożądane, głównie pod postacią toksyczności skórnej w stopniu 1. i 2., u 32 chorych (17%) objawy uboczne w 3.–4. stopniu toksyczności. U dwóch chorych zakończono leczenie z powodu toksyczności. Nie było zgonów spowodowanych toksycznością leczenia. Wnioski. Przeprowadzona analiza wieloośrodkowa potwierdziła skuteczność i bezpieczeństwo leczenia wemurafenibem w rutynowej praktyce klinicznej w heterogennej grupie zaawansowanych czerniaków z obecnością mutacji BRAF. Potwierdzono wagę znanych czynników prognostycznych dla całkowitego przeżycia w tej grupie chorych, takich jak aktywność dehydrogenazy mleczanowej (LDH) i wyjściowy stan sprawności wg ECOG. Obecne przeżycia chorych w grupie przerzutowych czerniaków z mutacją BRAF są dłuższe niż obserwowane w próbach historycznych.

Two-site recognition of Staphylococcus aureus peptidoglycan by lysostaphin SH3b

Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore a therapeutic agent of choice to eradicate staphylococcal infections. The C-terminal SH3b domain of lysostaphin recognizes peptidoglycans containing a pentaglycine crossbridge and has been proposed to drive the preferential digestion of staphylococcal cell walls. Here we elucidate the molecular mechanism underpinning recognition of staphylococcal peptidoglycan by the lysostaphin SH3b domain. We show that the pentaglycine crossbridge and the peptide stem are recognized by two independent binding sites located on opposite sides of the SH3b domain, thereby inducing a clustering of SH3b domains. We propose that this unusual binding mechanism allows synergistic and structurally dynamic recognition of S. aureus peptidoglycan and underpins the potent bacteriolytic activity of this enzyme

”SMALL TOWNS IN POLISH CULTURAL SPACE” Conference in Cedynia, 20-22 May 2009

Aconference organised by the National Heritage Board of Poland with the cooperation of the West Pomeranian Voivodeship Conservator of Historical Monuments on 20-22 May 2009 in Cedynia was entitled ”Small Towns in Polish Cultural Space”. The event was attended by voivodeship conservators of monuments, representatives of the Department for the Protection of Historical Monuments at the Ministry of Culture and National Heritage and heads of the Regional Centres for the Documentation and Protection of Historical Monuments. The debates took place in the western wing of the Cistercian convent in Cedynia, rebuilt and adapted for a hotel. The participants spoke about, i. a. local spatial planning and its role in the protection of historical town planning complexes, the principles of formulating correct plans guaranteeing the execution of the law, an attempt at devising a strategy associated with the protection of small historical towns, and town documentation, i.e. an abbreviated historical town planning study. The conference was accompanied by a tour of the historical small towns of Western Pomerania, which enabled the participants to become acquainted with the state of the preservation of mediaeval sacral architecture and town fortifications, the prime threats and causes of damage, and the complex protection of historical town planning space. The topics broached at the conference were a mere foretaste of the extremely complicated protection of historical small towns. The proposal made by the head of the National Heritage Board to continue this theme by presenting its successive aspects met with full approval

The role of the Conservation Analyses Department in the performance of statutory tasks of the National Heritage Board of Poland

The Conservation Analyses Department was established by the order of the Director of the National Centre for Research and Documentation of Monuments dated 6 June 2010. The Department comprised the Team of Experts and the Conservation Policy Formation Workshop. The Department co-ordinates and supervises work connected with the preparation of opinions and expertises regarding the protection of non-movable and movable monuments for public administration authorities – the Ministry of Culture and National Heritage, Voivodeship Offices for Monument Protection and their branches and local government conservators. It carries out its tasks with the help of local divisions representing the National Heritage Board of Poland. The definite majority of issued opinions concerns the evaluation of the level of preservation of the value of historic objects or areas during administrative procedures being conducted by the Ministry of Culture and National Heritage with regard to deletions from the register of monuments. The Conservation Analyses Department co-ordinates the implementation of the procedure for acknowledgement of a historic object as a history monument and participates in work regarding the creation and dissemination of standards of documentation, research and conservation of historic objects. The activity of the Department in the field of protection of historic parks and gardens is particularly worth mentioning. It includes, among others, study and design works carried out in Branicki’s Garden in Białystok from 2006 till 2009 and the preparation of conservation requests and the resulting projects of regeneration of the palace park in Białowieża and the park in Trzebiny. The palace & park layout in Trzebiny is currently administered by the National Heritage Board of Poland – the Local Workshop in Trzebiny. An important task ordered by the Minister of Culture and National Heritage is the management of the regeneration of Muskau Park. Over 20 years’ period of regeneration works is a significant yet still fragmentary process of restoration of the full historical value of the park. The Institute is also responsible for the creation and putting into common use of standards of documentation, elaborations and manuals regarding the protection of cultural heritage that are addressed to a wide group of recipients, an example of which is the Methodological guide to the elaboration of communal monument care programmes. The international co-operation with Eastern states has been carried out by NHBP and its predecessors for many years, including the „Nieśwież Academy” Postgraduate Summer School and cooperation with the Trakai Historical National Park in Lithuania. All activities being handled by the Conservation Analyses Department of the National Heritage Board of Poland are subject and may become subject to modifications, depending on the orders of the Ministry of Culture and National Heritage, the needs of voivodeship monument conservators and other institutions and the emerging topics that must be solved urgently. Currently the Conservation Analyses Department employs 14 persons. They build an interdisciplinary team consisting of a group of historians of art, monument experts – conservators, landscape architects, an architect and a lawyer – persons with a large professional experience and significant achievements

KATARZYNA ZALASIŃSKA, ”THE PROTECTION Of HISTORICAL MONUMENTS. ADJUDICATION WITH A COMMENTARY”, LexisNexis, Warszawa 2010

At the beginning of this year the LexisNexis publishers issued a book, which excellently fills the gap that emerged from the time of the binding Statute of 23 July 2003 on the protection of historical monuments. This is the first book of its sort to render available, analyse and subject to a constructive assessment the accomplishments of the judicature as regards the range of the protection of historical monuments and adjudication pronounced upon the basis of the statue in force. The author, who presents the young generation of lawyers, is one of the few researchers dealing with the legal aspects of the protection of historical monuments. The book offers a lucid presentation of the mechanics of the impact of law, and allows the reader to understand the nature of law and the ways in which it should be deployed so that undertakings associated with the protection of historical monuments would be effective. The adjudication of administrative courts discussed in the book depicts essential problems linked with an interpretation of regulations upon the stage of their application. The cited examples contain important directives, which the conservation organs should follow while interpreting the regulations of material law and choosing suitable administrative procedure. The titular publication will certainly prove useful for lawyers and employees of government and self-government administration. Presumably, it will also meet with great interest among conservators not attached to the administration as well as the owners of historical monuments

Effect of cyclosporin A on immunological response in lungs of guinea pigs infected with Trichinella spiralis.

The effects of cyclosporin A (CsA), a potent immunosuppressive drug with antiparasitic activity, on the innate immunological response in guinea pig lungs during an early period (6th and 14th days) after T. spiralis infection were studied. CsA treatment of T. spiralis-infected guinea pigs caused a significant attenuation of immunological response in lungs by decreasing lymphocyte infiltration into pulmonary alveolar space, inhibiting alveolar macrophage superoxide anion production and lowering both the production of NO metabolites measured in bronchoalveolar lavage fluid and expression of the iNOS protein in lung homogenates, allowing us to speculate that the T. spiralis-dependent immunological response is dependent on lymphocyte T function. Interestingly, CsA itself had a pro-inflammatory effect, promoting leucocyte accumulation and macrophage superoxide production in guinea pig lungs. This observation may have a relevance to the situation in patients undergoing CsA therapy. Macrophage expression of the iNOS protein, evaluated by immunoblotting was not influenced by treatment of animals with CsA or anti-TGF-antibody, indicating different regulation of the guinea pig and murine enzymes