Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition

Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM

Cancer Stem Cell-Like Cells Derived from Malignant Peripheral Nerve Sheath Tumors

This study aims to examine whether or not cancer stem cells exist in malignant peripheral nerve sheath tumors (MPNST). Cells of established lines, primary cultures and freshly dissected tumors were cultured in serum free conditions supplemented with epidermal and fibroblast growth factors. From one established human MPNST cell line, S462, cells meeting the criteria for cancer stem cells were isolated. Clonal spheres were obtained, which could be passaged multiple times. Enrichment of stem cell-like cells in these spheres was also supported by increased expression of stem cell markers such as CD133, Oct4, Nestin and NGFR, and decreased expression of mature cell markers such as CD90 and NCAM. Furthermore, cells of these clonal S462 spheres differentiated into Schwann cells, smooth muscle/fibroblast and neurons-like cells under specific differentiation-inducing cultural conditions. Finally, subcutaneous injection of the spheres into immunodeficient nude mice led to tumor formation at a higher rate compared to the parental adherent cells (66% versus 10% at 2.5×105). These results provide evidence for the existence of cancer stem cell-like cells in malignant peripheral nerve sheath tumors

Results of Polish Adult Leukemia Study Group (PALG) project assessing TP53 mutations with next-generation sequencing technology in relapsed and refractory chronic lymphocytic leukemia patients — an 18-month update

Indtroduction and methods: In chronic lymphocytic leukemia (CLL), molecular and cytogenetic diagnostics are crucial for the determination of accurate prognosis and treatment choice. Among different genetic aberrations, del(17p13) or TP53 mutations constitute high-risk factors, and early identification of such defects is a high priority for CLL patients. While cytogenetic diagnostics is well-established and accessible for the majority of CLL patients in Poland, molecular diagnostics of TP53 mutations is performed only in a few ERIC-certified centers (eight as of September 2020), and only two of these employ next-generation sequencing (NGS) for routine analysis of TP53 status in CLL patients. Here we report the interim results of a project assessing TP53 mutations with NGS technology in relapsed or refractory CLL patients with confirmed negative del(17p13) status. 249 patients from 32 clinical centers were included in the study. Results: NGS analysis revealed TP53 mutations in 42/249 (17%) patients, half of whom (21/249, 8.5%) had subclonal mutations (VAF ≤10%). These results are in line with published data in relapsed/refractory CLL patients. Conclusions: The results of the project demonstrated the feasibility and accuracy of NGS testing in CLL patients despite several initial logistical and technical obstacles. Our study also proved that, with appropriate funding, CLL patients from any hematological center in Poland can have access to state-of-the-art molecular diagnostic

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Small cities as an element of cross-border landscape exemplified in the Pradziad euroregion

Krajobraz transgraniczny, oprócz cech środowiska biotycznego, abiotycznego i antropogenicznego, jest definiowany przez obecność linii granicznej. Artykuł określa najważniejsze elementy definiujące pojęcie krajobrazu transgranicznego. Na przykładzie czterech małych miast: Nysy, Prudnika, Jesenika i Bruntála, zlokalizowanych w przygranicznym fragmencie euroregionu Pradziad, artykuł prezentuje wybrane możliwości rozwojowe małych miast euroregionu w kontekście jego krajobrazu transgranicznego.A cross-border landscape may be defined not merely by the features of the biotic, nonbiotic and anthropogenic environment but also by the existing border. The text specifies the most important elements defining the notion of a cross-border landscape. It puts the examples of four small cities, i.e.: Nysa, Prudnik, Jasenik and Bruntál situated within the cross-border area of the ‘Pradziad’ Euroregion, into analysis. The article presents the short-listed development opportunities of the aforementioned small cities within the context of a cross-border landscape

Prevalence of comorbid depressive symptoms in rehabilitation: A cross-indication, nationwide observational study

Objective: Patients in rehabilitation with comorbid depressive disorders display increased morbidity, mortality and inability to work. The aim of this study is to determine the prevalence of comorbid depressive symptoms in rehabilitation. Methods: A total of 6,000 patients were contacted by post at the same time as receiving approval for their medical rehabilitation from German Federal Pension Insurance. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-2). Results were compared with prevalences in the general population by analysing the German Health Interview and Examination Survey for Adults (DEGS). Results: A total of 2,152 out of 5,891 patients participated in the study (response rate: 36.5%). The prevalence of self-reported depressive symptoms was 33.1% (women 34.1%, men 31.3%). In contrast, 7.8% of the German general population reported depressive symptoms (women 9.4%, men 6.2%). The highest prevalences were found in neurological (36.4%) and orthopaedic (35.6%) rehabilitation, the lowest in cancer rehabilitation (23.0%). Depressive symptoms were significantly associated with higher comorbidity and impairment due to pain, with lower social support and self-efficacy and with specific work-related problems. Conclusion: A short routine screening yielded a positive test result for depressive symptoms in a third of rehabilitation patients, thus approximately four times higher than in the general population. This is valuable information in order to better adjust treatment to patient needs.Hintergrund: Personen mit komorbiden depressiven Symptomen weisen eine erhöhte Morbidität, Mortalität und Arbeitsunfähigkeit auf. Ziel der Arbeit war daher die Bestimmung der Prävalenz komorbider depressiver Symptomatik in der Rehabilitation im Vergleich zur Allgemeinbevölkerung. Weiterhin wurde der Zusammenhang zu anderen Reha-relevanten Beeinträchtigungen und Ressourcen untersucht. Methoden: Insgesamt 6.000 Versicherte der DRV Bund wurden zum Zeitpunkt der Bewilligung ihrer Rehabilitationsmaßnahme im Heilverfahren postalisch kontaktiert und um Beantwortung eines umfangreichen Fragebogens gebeten. Depressive Symptomatik wurde mithilfe des Patient Health Questionnaire (PHQ-2) operationalisiert. Die Stichprobenziehung erfolgte geschichtet für die sechs häufigsten somatischen Diagnosegrundgruppen. Indikationsübergreifende Analysen wurden entsprechend der tatsächlichen Verteilung der Diagnosegrundgruppen bei der DRV Bund gewichtet. Zudem wurde die unterschiedliche Teilnahmebereitschaft von Frauen und Männern in die Gewichtung einbezogen. Ergebnisse aus der Rehabilitation wurden mit Prävalenzen in der Allgemeinbevölkerung anhand von Analysen des Scientific Use File des Deutschen Erwachsenen Gesundheitssurveys (DEGS) ebenfalls auf Basis des PHQ-2 verglichen (n=5.938). Ergebnisse: 2.152 von 5.891 postalisch erreichten Rehabilitanden nahmen an der Studie teil (Responsequote: 36,5%). Umfangreiche Non-Response-Analysen zeigten keine Hinweise für einen nennenswerten Selektionsbias. Die Prävalenz von selbstberichteten komorbiden depressiven Symptomen lag bei 33,1% (Frauen 34,1%, Männer 31,3%). Hingegen berichteten 7,8% der Allgemeinbevölkerung zwischen 18 und 64 Jahren depressive Symptome (Frauen 9,4%, Männer 6,2%). Die höchste Prävalenz wiesen neurologische (36,4%) und orthopädische Rehabilitanden (35,6%) auf, die niedrigste onkologische Rehabilitanden (23,0%). Depressive Symptome waren signifikant mit höherer Komorbidität und Beeinträchtigung durch Schmerzen, dem Vorliegen von besonderen beruflichen Problemlagen sowie mit niedrigerer sozialer Unterstützung und Selbstwirksamkeitserwartung assoziiert. Diskussion: Die Studie zeigte bei einem Drittel der Rehabilitanden das Vorliegen von selbstberichteter komorbider depressiver Symptomatik auf. Damit ist die Prävalenz in der somatischen Rehabilitation im Vergleich zur Allgemeinbevölkerung etwa um den Faktor 4 erhöht. Ein Routine-Kurzscreening auf depressive Symptomatik bei Antragstellern auf medizinische Rehabilitation könnte wertvolle Informationen zur Auswahl einer geeigneten Rehabilitationseinrichtung liefern. Eine differenzielle Zuweisung entsprechend des individuellen Beeinträchtigungsprofils des Antragstellers könnte zu einer passgenaueren und somit potenziell noch wirksameren Rehabilitation führen

Zabezpieczenie wzgórza zamkowego w Oświęcimiu

Niespotykane opady deszczu w maju 2010 r. spowodowały uaktywnienie się licznych osuwisk i spływów przypowierzchniowych ze skarp i nasypów. Jedno z tych zjawisk, mogące mieć fatalne skutki w przypadku pozostawienia go bez zabezpieczenia, miało miejsce w obrębie wzgórza zamkowego w Oświęcimiu