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Quotes are great source of knowledge, wisdom and insight. They help us to learn through forerunners and pathfinders who pioneered certain paths in life that we are yet to travel. They are great tools to reinforce and reaffirm what we already know but do not understand, or what we do and react to in our daily basis but do not make a philosophy out of it. It is such ignored realities or less attended to histories and discoveries which when they become words uttered by famous or successful people they become quotes, references and philosophy enough to help us accept it, or an idea, we apply it and see transformations in our lives. Quotes discover a philosophy, strengthen a belief or ideology, create a driving force in people to pursue their dreams. They are an effective weapon to uphold or dismiss certain philosophies in our midst. They are sophisticated way or simple art of using few words to mean a lot. A Case of Love and Hate is a book to give you insights, uphold and dismiss certain philosophies or notions in our midst, be it politically, socially and economically. To achieve this complex task, difficult and great piece of art, the author Cecil Jones Myondela (Chenjerai Mhondera) committed himself to intense focus, long term diligence, and effort. Success in every field requires a definite goal, burning desire to go after it and determination to do whatever it takes in order to succeed. The book of Quotes themed A Case of Love and Hate, Volume 1 is a product of such a bitter struggle, endurance and resilience by the author- on ground and in world of literature. To understand Mugabe, this is the book! To understand Zimbabwe, this is the book! To understand Africa, this is the book! Do not resist your chance to understand and keep in line with a Revolution in Africa!
The aim of this study is to provide a systematic assessment of the influence of the position on the arterial input function (AIF) for perfusion quantification. In 39 patients with a wide range of left ventricular function the AIF was determined using a diluted contrast bolus of a cardiac magnetic resonance imaging in three left ventricular levels (basal, mid, apex) as well as aortic sinus (AoS). Time to peak signal intensities, baseline corrected peak signal intensity and upslopes were determined and compared to those obtained in the AoS. The error induced by sampling the AIF in a position different to the AoS was determined by Fermi deconvolution. The time to peak signal intensity was strongly correlated (r2 > 0.9) for all positions with a systematic earlier arrival in the basal (− 2153 ± 818 ms), the mid (− 1429 ± 928 ms) and the apical slice (− 450 ± 739 ms) relative to the AoS (all p < 0.001). Peak signal intensity as well as upslopes were strongly correlated (r2 > 0.9 for both) for all positions with a systematic overestimation in all positions relative to the AoS (all p < 0.001 and all p < 0.05). Differences between the positions were more pronounced for patients with reduced ejection fraction. The error of averaged MBF quantification was 8%, 13% and 27% for the base, mid and apex. The location of the AIF significantly influences core parameters for perfusion quantification with a systematic and ejection fraction dependent error. Full quantification should be based on obtaining the AIF as close as possible to the myocardium to minimize these errors.
In Philadelphia Chromosome (Ph) positive ALL and CML the fusion between BCR and ABL leads to the BCR/ABL fusion proteins, which induces the leukemic phenotype because of the constitutive activation of multiple signaling pathways down-stream to the aberrant BCR/ABL fusion tyrosine kinase. Targeted inhibition of BCR/ABL by ABL-kinase inhibitors induces apoptosis in BCR/ABL transformed cells and leads to complete remission in Ph positive leukemia patients. However, a large portion of patients with advanced Ph+ leukemia relapse and acquire resistance. Kinase domain (KD) mutations interfering with inhibitor binding represent the major mechanism of acquired resistance in patients with Ph+ leukemia. Tetramerization of BCR/ABL through the N-terminal coiled-coil region (CC) of BCR is essential for the ABL-kinase activation. Targeting the CC-domain forces BCR/ABL into a monomeric conformation, reduces its kinase activity and increases the sensitivity for Imatinib. Here we show that i.) targeting the tetramerization by a peptide representing the Helix-2 of the CC efficiently reduced the autophosphorylation of both WT BCR/ABL and its mutants; ii.) Helix-2 inhibited the transformation potential of BCR/ABL independently of the presence of mutations; iii.) Helix-2 efficiently cooperated with Imatinib as revealed by their effects on the transformation potential and the factor-independence related to BCR/ABL with the exception of mutant T315I. These findings suggest that BCR/ABL harboring the T315I mutation have a transformation potential which is at least partially independent from its kinase activity. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. We definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the Helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable Helix-2 peptide (MPH-2) by fusing the Helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model. The T315I mutation confers resistance against all actually approved ABL-kinase inhibitors and competitive peptides. It seems not only to decrease affinity for kinase inhibitors but to confer additional features to the leukemogenic potential of BCR/ABL. To determine the role of T315I in resistance to the inhibition of oligomerization and in the leukemogenic potential of BCR/ABL, we investigated its influence on loss-of-function mutants with regard to the capacity to mediate factor-independence. Thus we studied the effects of T315I on BCR/ABL mutants lacking functional domains in the BCR portion indispensable for the oncogenic activity of BCR/ABL such as the N-terminal coiled coil (CC), the tyrosine phosphorylation site Y177 and the serine/threonine kinase domain (ST), as well as on the ABL portion of BCR/ABL (#ABL-T315I) with or without the inhibitory SH3 (delta SH3-ABL) domain. Here we report that i.) T315I restored the capacity to mediate factor independence of oligomerization_deficient p185BCR/ABL; ii.) resistance of p185-T315I against inhibition of the oligomerization depends on the phosphorylation at Y177; iii.) autophosphorylation at Y177 is not affected by the oligomerization inhibition, but phosphorylation at Y177 of endogenous BCR parallels the effects of T315I; iv.) the effects of T315I are associated with an intact ABL_kinase activity; v.) the presence of T315I is associated with an increased ABL_kinase activity also in mutants unable to induce Y177 phosphorylation of endogenous BCR; vi.) there is no direct relationship between the ABL-kinase activity and the capacity to mediate factor_independence induced by T315I as revealed by the #ABL-T315I mutant, which was unable to induce Y177 phosphorylation of BCR only in the presence of the SH3 domain. In contrast to its physiological counterpart c-ABL, the BCR/ABL kinase is constitutively activated, inducing the leukemic phenotype. The N-terminus of c-ABL (Cap region) contributes to the regulation of its kinase function. It is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain known as the myristoyl binding pocket in a process called “capping”, which results in an auto-inhibited conformation. Because the cap region is replaced by the N-terminus of BCR, BCR/ABL “escapes” this auto-inhibition. Allosteric inhibition by myristate “mimics”, such as GNF-2, is able to inhibit unmutated BCR/ABL, but not the BCR/ABL that harbors the “gatekeeper” mutation T315I. Here we investigated the possibility of increasing the efficacy of allosteric inhibition by blocking BCR/ABL oligomerization. We demonstrate that inhibition of oligomerization was able not only to increase the efficacy of GNF-2 on unmutated BCR/ABL, but also to overcome the resistance of BCR/ABL-T315I to allosteric inhibition. These results strongly suggest that the response to allosteric inhibition by GNF-2 is inversely related to the degree of oligomerization of BCR/ABL. Taken together these data suggest that the inhibition of tetramerization inhibits BCR/ABL-mediated transformation and can contribute to overcome Imatinib-resistance. The study provides the first evidence that an efficient peptide transduction system facilitates the employ-ment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo. Further the data show that T315I confers additional leukemogenic activity to BCR/ABL, which might explain the clinical behavior of patients with BCR/ABL -T315I-positive blasts. In summary, our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants represented by the combination of oligomerization and allosteric inhibitors.
Background: Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.
Methods: The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.
Results: Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.
Conclusions: Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.
Background: The t(9;22) translocation leads to the formation of the chimeric breakpoint cluster region/c-abl oncogene 1 (BCR/ABL) fusion gene on der22, the Philadelphia chromosome. The p185(BCR/ABL) or the p210(BCR/ABL) fusion proteins are encoded as a result of the translocation, depending on whether a "minor" or "major" breakpoint occurs, respectively. Both p185(BCR/ABL) and p210(BCR/ABL) exhibit constitutively activated ABL kinase activity. Through fusion to BCR the ABL kinase in p185(BCR/ABL) and p210(BCR/ABL) "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. A novel class of compounds including GNF-2 restores allosteric inhibition of the kinase activity and the transformation potential of BCR/ABL. Here we investigated whether there are differences between p185(BCR/ABL) and p210(BCR/ABL) regarding their sensitivity towards allosteric inhibition by GNF-2 in models of Philadelphia chromosome-positive acute lymphatic leukemia.
Design and methods: We investigated the anti-proliferative activity of GNF-2 in different Philadelphia chromosome-positive acute lymphatic leukemia models, such as cell lines, patient-derived long-term cultures and factor-dependent lymphatic Ba/F3 cells expressing either p185(BCR/ABL) or p210(BCR/ABL) and their resistance mutants.
Results: The inhibitory effects of GNF-2 differed constantly between p185(BCR/ABL) and p210(BCR/ABL) expressing cells. In all three Philadelphia chromosome-positive acute lymphatic leukemia models, p210(BCR/ABL)-transformed cells were more sensitive to GNF-2 than were p185BCR/ABL-positive cells. Similar results were obtained for p185(BCR/ABL) and the p210(BCR/ABL) harboring resistance mutations.
Conclusions: Our data provide the first evidence of a differential response of p185(BCR/ABL)- and p210(BCR/ABL)- transformed cells to allosteric inhibition by GNF-2, which is of importance for the treatment of patients with Philadelphia chromosome-positive acute lymphatic leukemia.
The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. The constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. Recently, we definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide (MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model.
This study provides the first evidence that an efficient peptide transduction system facilitates the employment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo.
Seit den Anfängen der Implantologie hat sich diese zu einer Wissenschaft entwickelt, die einer stetigen und lebhaften Entwicklung unterliegt. Die Einführung zweigeteilter Implantatsysteme stellte ein Novum dar, welches dem Behandler vielfältige Freiheiten in seiner Therapieplanung ermöglichte. Zu Beginn noch unbeachtet, sollte sich zeigen, dass die Existenz der Fügefläche zwischen Implantat und Abutment mit dem Rückgang des Implantatumgebenden Knochens vergesellschaftet ist. In der Literatur werden mehrere Ursachen für den Gewebsverlust diskutiert. Dazu zählen der Einfluss des Einheilmodus, das chirurgische Vorgehen, die Mundhygiene des Patienten, allgemeine Risikofaktoren, Überbelastung, Beweglichkeit der Bauteile zueinander oder eine mikrobielle Besiedelung des Implantatinneren. Implantate die seit längerem in Funktion stehen, zeigen nach deren Demontage mitunter eine herstellerabhängige Akkumulation mikrobieller Plaque im Inneren. In diesem Zusammenhang stellte sich die Frage, ob die Verbindung zwischen Implantat und Abutment das Eindringen von oralen Mikroorganismen erlaubt und diese dort dauerhaft überlebensfähig sind. Der Vorsatz der Studie bestand somit in der Entwicklung, Konstruktion und Fertigung eines Prüfsystems zur Untersuchung eines bakterienrelevanten Lecks an Implantat-Abutment-Verbindungen und dessen Nachweis. Die Anordnung sollte den klinischen Besiedlungsweg während einer Kausimulation nachahmen und eine Echtzeitanalyse der Dichtigkeit an der Fügefläche erlauben. Zur Probengewinnung aus dem Inneren wurden 20 aktuelle Implantatsysteme (konische Verbindungen, stoßende Verbindungen, andersartige Verbindungen) mit Bohrungen auf Höhe des ersten Hohlraumes unterhalb der Implantat-Abutment-Verbindung versehen. Der so präparierte und in eine Einbettmasse, mit knochenähnlichen, mechanischen Eigenschaften, eingegossene Prüfkörper befindet sich schulterwärts unmittelbar in einer Bakterienmischkultur aus S. mutans, S. sanguinis, A. viscosus, F. nucleatum und V. parvula versenkt, deren Spiegel das Implantat-Abutment-Interface übersteigt. Angeschlossen an den Prüfkörper ist vorangestellt eine perfusorartige Spritzenpumpe und nachgestellt eine Auffangautomatik zur Sammlung einzelner Spülproben. Das eingespannte Implantat und dessen verschraubter Aufbau erfahren in einer zweidimensionalen Kausimulation im „Frankfurter Kausimulator“ eine zyklischkippende Wechselbelastung. Das simulierte Intervall entspricht klinisch etwa einer Mahlzeit. Schon zu Versuchsbeginn und nach jeder Belastungsstufe (beginnend mit Fmin=0N und endend bei Fmax=200N in 25N-Schritten) wird das Implantatinnere mit physiologischer Kochsalzlösung aus der Spritzenpumpe gespült. Die aufgefangenen Proben wurden mittels des Tod-Lebend-Färbekits LIVE/DEAD®-BacLightTM (Farbstoff: SYTO 9 und PJ) für die fluoreszenzmikroskopische Untersuchung versetzt und in einer Thoma-Zählkammer ausgezählt. Zur Validierung der Anordnung wurde das Dichtigkeitsverhalten von den 20 Implantatsystemen (je n=5) untersucht und hinsichtlich ihrer Verbindungsgeometrie (Konus/Stoß/andersartig) verglichen. Das entwickelte Prüfverfahren ermöglicht die Betrachtung einer potentiellen, mikrobiell-relevanten Spaltbildung an den Fügeflächen von Implantat und Abutment. Von den untersuchten Konus-Verbindungen zeigte nur das Osstem® Co. Ltd. GS II eine Keiminvasion in den Innenraum. Bei den Stoß-Verbindungen wiesen das Camlog® J-Serie und das Friadent® Xive S plus ein mikrobielles Leck auf. Beide andersartigen Verbindungen, BPI® BSL und Heraeus® IQ:Nect, wurden ebenfalls während der Kurzzeitsimulation undicht. Die Ergebnisse verdeutlichen, dass systemimmanent eine bakterienrelevante Undichtigkeit schon sehr früh bei fabrikneuen Implantaten einsetzen kann. Die Durchlässigkeit der undichten Implantat-Abutment-Verbindungen spiegelt die Vermischung zweier Flüssigkeiten (innen/außen) wider und lässt auf eine dauerhafte Spaltbildung und Pumpwirkung an der betreffenden Ankopplung schließen. Es ist aufgrund der angewandten Methodik davon auszugehen, dass die eingedrungenen Keime auch über längere Zeit lebensfähig bleiben und sich den Mundhygienemaßnahmen des Patienten effektiv entziehen können. Im Vergleich mit den Beobachtungen der vorangegangenen Literatur und den erzielten Ergebnissen dieser Studie ist anzunehmen, dass konisch zulaufende Abutments zu einer geringeren Ausbildung von Kippbewegungen und somit zu einer weniger ausgeprägten Spaltbildung als stoßende oder andersartige Fügungen neigen. Daraus folgt eine ausgeprägtere, mikrobielle Barrierefunktion der konischen Verbindungen gegenüber anderen Ankopplungen. Ausschlaggebend für eine bakterielle Kolonisation des Lumens ist demzufolge die Art und Ausführung der mechanischen Anbindung zwischen der enossalen und der prothetischen Komponente eines Implantatsystems. Die unter diesen Gegebenheiten als undurchlässig zu betrachtenden Systeme haben ihre anhaltende Bakteriendichtigkeit in noch folgenden Langzeitversuchen unter Beweis zu stellen.
Vegetation structure and floristics of granite landforms in the South-west Slopes of New South Wales
(2012)
We describe the natural vegetation structure and floristics of 44 small-sized granite outcrops (inselbergs) in agricultural landscapes in the South-west Slopes (SWS) bioregion of New South Wales (35º 26’ S, 147º 23’ E to 35º 58’ S, 146º 59’E) and their relationships with geomorphology. We provide a list of 196 species (117 natives and 79 exotics). We found that structurally complex outcrops supported a greater diversity of native ground cover species and fewer exotic species than structurally simple outcrops. Tor landforms lacked vegetation structural complexity and were deficient in native shrubs, mid-storey and over-storey species but typically supported exotic grasses and broadleaved exotic weeds. Floristic composition differed among landforms and cluster analysis revealed highly dissimilar native plant communities among outcrops. Our study highlights the need to rehabilitate tor landforms and manage a broad spectrum of outcrops to conserve floristic diversity in agricultural landscapes. Selecting genetically diverse species for replanting, considering the density and spatial arrangement of plantings, and controlling invasive plants and feral herbivorous animals are fundamental issues in restoring granite outcrop vegetation in the SWS bioregion.
Standard monitoring of heart rate, blood pressure and arterial oxygen saturation during endoscopy is recommended by current guidelines on procedural sedation. A number of studies indicated a reduction of hypoxic (art. oxygenation < 90% for > 15 s) and severe hypoxic events (art. oxygenation < 85%) by additional use of capnography. Therefore, U.S. and the European guidelines comment that additional capnography monitoring can be considered in long or deep sedation. Integrated Pulmonary Index® (IPI) is an algorithm-based monitoring parameter that combines oxygenation measured by pulse oximetry (art. oxygenation, heart rate) and ventilation measured by capnography (respiratory rate, apnea > 10 s, partial pressure of end-tidal carbon dioxide [PetCO2]). The aim of this paper was to analyze the value of IPI as parameter to monitor the respiratory status in patients receiving propofol sedation during PEG-procedure. Patients reporting for PEG-placement under sedation were randomized 1:1 in either standard monitoring group (SM) or capnography monitoring group including IPI (IM). Heart rate, blood pressure and arterial oxygen saturation were monitored in SM. In IM additional monitoring was performed measuring PetCO2, respiratory rate and IPI. Capnography and IPI values were recorded for all patients but were only visible to the endoscopic team for the IM-group. IPI values range between 1 and 10 (10 = normal; 8–9 = within normal range; 7 = close to normal range, requires attention; 5–6 = requires attention and may require intervention; 3–4 = requires intervention; 1–2 requires immediate intervention). Results on capnography versus standard monitoring of the same study population was published previously. A total of 147 patients (74 in SM and 73 in IM) were included in the present study. Hypoxic events occurred in 62 patients (42%) and severe hypoxic events in 44 patients (29%), respectively. Baseline characteristics were equally distributed in both groups. IPI = 1, IPI < 7 as well as the parameters PetCO2 = 0 mmHg and apnea > 10 s had a high sensitivity for hypoxic and severe hypoxic events, respectively (IPI = 1: 81%/81% [hypoxic/severe hypoxic event], IPI < 7: 82%/88%, PetCO2: 69%/68%, apnea > 10 s: 84%/84%). All four parameters had a low specificity for both hypoxic and severe hypoxic events (IPI = 1: 13%/12%, IPI < 7: 7%/7%, PetCO2: 29%/27%, apnea > 10 s: 7%/7%). In multivariate analysis, only SM and PetCO2 = 0 mmHg were independent risk factors for hypoxia. IPI (IPI = 1 and IPI < 7) as well as the individual parameters PetCO2 = 0 mmHg and apnea > 10 s allow a fast and convenient conclusion on patients’ respiratory status in a morbid patient population. Sensitivity is good for most parameters, but specificity is poor. In conclusion, IPI can be a useful metric to assess respiratory status during propofol-sedation in PEG-placement. However, IPI was not superior to PetCO2 and apnea > 10 s.