Improved arteriogenesis with simultaneous skeletal muscle repair in ischemic tissue by SCL plus multipotent adult progenitor cell clones from peripheral blood

Background: The CD34- murine stem cell line RM26 cloned from peripheral blood mononuclear cells has been shown to generate hematopoietic progeny in lethally irradiated animals. The peripheral blood-derived cell clones expresses a variety of mesodermal and erythroid/myeloid transcription factors suggesting a multipotent differentiation potential like the bone marrow-derived `multipotent adult progenitor cells' (MAP-C). Methods: SCL+ CD34- RM26 cells were transfused intravenously into mice suffering from chronic hind-limb ischemia, evaluating the effect of stem cells on collateral artery growth and simultaneous skeletal muscle repair. Results: RM26 cells are capable of differentiating in vitro into endothelial cells when cultured on the appropriate collagen matrix. Activation of the SCL stem cell enhancer (SCL+) is mediated through the binding to two Ets and one GATA site and cells start to express milieu- and growth condition-dependent levels of the endothelial markers CD31 (PECAM) and Flt-1 (VEGF-R1). Intravenously infused RM26 cells significantly improved the collateral blood flow (arteriogenesis) and neo-angiogenesis formation in a murine hind-limb ischemia transplant model. Although transplanted RM26 cells did not integrate into the growing collateral arteries, cells were found adjacent to local arteriogenesis, but instead integrated into the ischemic skeletal muscle exclusively in the affected limb for simultaneous tissue repair. Conclusion: These data suggest that molecularly primed hem-/mesangioblast-type adult progenitor cells can circulate in the peripheral blood improving perfusion of tissues with chronic ischemia and extending beyond the vascular compartment. Copyright (C) 2004 S. Karger AG, Basel

Improved arteriogenesis with simultaneous skeletal muscle repair in ischemic tissue by SCL plus multipotent adult progenitor cell clones from peripheral blood

Background: The CD34- murine stem cell line RM26 cloned from peripheral blood mononuclear cells has been shown to generate hematopoietic progeny in lethally irradiated animals. The peripheral blood-derived cell clones expresses a variety of mesodermal and erythroid/myeloid transcription factors suggesting a multipotent differentiation potential like the bone marrow-derived `multipotent adult progenitor cells' (MAP-C). Methods: SCL+ CD34- RM26 cells were transfused intravenously into mice suffering from chronic hind-limb ischemia, evaluating the effect of stem cells on collateral artery growth and simultaneous skeletal muscle repair. Results: RM26 cells are capable of differentiating in vitro into endothelial cells when cultured on the appropriate collagen matrix. Activation of the SCL stem cell enhancer (SCL+) is mediated through the binding to two Ets and one GATA site and cells start to express milieu- and growth condition-dependent levels of the endothelial markers CD31 (PECAM) and Flt-1 (VEGF-R1). Intravenously infused RM26 cells significantly improved the collateral blood flow (arteriogenesis) and neo-angiogenesis formation in a murine hind-limb ischemia transplant model. Although transplanted RM26 cells did not integrate into the growing collateral arteries, cells were found adjacent to local arteriogenesis, but instead integrated into the ischemic skeletal muscle exclusively in the affected limb for simultaneous tissue repair. Conclusion: These data suggest that molecularly primed hem-/mesangioblast-type adult progenitor cells can circulate in the peripheral blood improving perfusion of tissues with chronic ischemia and extending beyond the vascular compartment. Copyright (C) 2004 S. Karger AG, Basel

Bendamustine: Safety and Efficacy in the Management of Indolent Non-Hodgkins Lymphoma

Bendamustine (Treanda, Ribomustin) was recently approved by the US Food and Drug Administration (FDA) for treatment of patients with rituximab refractory indolent lymphoma and is expected to turn into a frontline therapy option for indolent lymphoma. This compound with amphoteric properties was designed in the former Germany Democratic Republic in 1960s and re-discovered in 1990s with multiple successive well-designed studies. Bendamustine possesses a unique mechanism of action with potential antimetabolite properties, and only partial cross-resistance with other alkylators. Used in combination with rituximab in vitro, bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. In clinical studies, bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23–24 months. The optimal dosing and schedule of bendamustine administration is largely undecided and varies among studies. Results of ongoing trials and dose-finding studies will help to further help ascertain the optimal place of bendamustine in the management of indolent NHL

Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages

Antibody-dependent cellular phagocytosis (ADCP) by macrophages, an important effector function of tumor targeting antibodies, is hampered by ‘Don´t Eat Me!’ signals such as CD47 expressed by cancer cells. Yet, human leukocyte antigen (HLA) class I expression may also impair ADCP by engaging leukocyte immunoglobulin-like receptor subfamily B (LILRB) member 1 (LILRB1) or LILRB2. Analysis of different lymphoma cell lines revealed that the ratio of CD20 to HLA class I cell surface molecules determined the sensitivity to ADCP by the combination of rituximab and an Fc-silent variant of the CD47 antibody magrolimab (CD47-IgGσ). To boost ADCP, Fc-silent antibodies against LILRB1 and LILRB2 were generated (LILRB1-IgGσ and LILRB2-IgGσ, respectively). While LILRB2-IgGσ was not effective, LILRB1-IgGσ significantly enhanced ADCP of lymphoma cell lines when combined with both rituximab and CD47-IgGσ. LILRB1-IgGσ promoted serial engulfment of lymphoma cells and potentiated ADCP by non-polarized M0 as well as polarized M1 and M2 macrophages, but required CD47 co-blockade and the presence of the CD20 antibody. Importantly, complementing rituximab and CD47-IgGσ, LILRB1-IgGσ increased ADCP of chronic lymphocytic leukemia (CLL) or lymphoma cells isolated from patients. Thus, dual checkpoint blockade of CD47 and LILRB1 may be promising to improve antibody therapy of CLL and lymphomas through enhancing ADCP by macrophages

Characterization of human background rhythms with functional magnetic resonance imaging

Diese Dissertation zeigt, dass Hintergrundrhythmen mit Hilfe der gleichzeitigen Messung von EEG und fMRI Signalen untersucht werden können. Die Methodik dieses Ansatzes wurde durch den Einsatz einer speziellen fMRI Sequenz weiterentwickelt, und die Signalqualität durch visuell evozierte Potentiale überprüft. Der prominente okzipitale Alpha-Rhythmus und die vergleichsweise schwächeren rolandischen Rhythmen konnten in der elektromagnetisch störenden Umgebung des Magnetresonanztomografen, auch und gerade während der funktionellen Messsequenzen identifiziert werden. Durch den Einsatz der in dieser Arbeit vorgestellten Nachverarbeitungsmethoden kann die simultane Aufnahme von EEG und fMRI Signalen wertvolle Informationen über die neuronale Grundlage von Hirnrhythmen und ihrer hemodynamischer Korrelate liefern. Die hier vorgestellten Daten bekräftigen die Hypothese, dass die Amplitude der Hintergrundrhythmen mit spezifischen Deaktivierungen in sensorischen Hirnarealen einhergehen. Eine erhöhte Amplitude aller untersuchter Rhythmen war mit einem negativen BOLD Signal in sensorischen kortikalen Arealen verknüpft, was auf einen erniedrigten Energieverbrauch in Arealen mit höherer Synchronizität schliessen lässt. Der posteriore Alpha Rhythmus, ist invers mit dem hemodynamischen Signal in primären visuellen Arealen gekoppelt, während hämodynamische Korrelate der rolandischen Alpha und Beta Rhythmen in somatomotorischen Arealen lokalisiert wurden. Für den rolandischen Alpha und Beta Rhythmus wurden unterschiedliche regionale Netzwerke gefunden. Der rolandische Beta Rhythmus ist mit dem Motornetzwerk, während der rolandische Alpha Rhythmus mit einen somatosensorischen bzw. Assoziationsnetzwerk assoziert ist, was eine fundamentale Eigenschaft des Somatomotorischen Systems zu sein scheint. Die rolandischen Rhythmen könnten dadurch somatomotorische Areale während der Erhaltung oder Planung von Bewegungsabläufen funktional koppeln [Brovelli, et al., 2004]. Desweiteren wurde gezeigt, dass thalamische und cinguläre Strukturen mögliche Generatoren oder Modulatoren der hier untersuchten Hintergrundrhythmen sind. Die experimentellen Daten der hier vorgestellten Studien legen nahe, dass eine inverse Beziehung der Stärke eines Hintergrundrhythmus mit regional kortikalem Metabolismus und gleichzeitig eine „antagonistische“, positive Beziehung mit thalamischen oder cingulären Struktuen ein gernerelles orgnaisatorisches Prinzip des Gehirns zu sein scheint. Der Begriff der Grundaktivität des Gehirns [Gusnard, et al., 2001] müsste daher in verschiedene Netzwerke der Grundaktivität unterteilt werden, die elektrophysiologisch durch Hintergrundrhythmen definiert wären.The data provided by this thesis show that imaging of brain rhythms can be achieved by simultaneous EEG-fMRI recordings. This methodology was developed further by implementing an adapted MR sequence and the EEG-fMRI signal quality was confirmed by means of visual evoked potentials. Together with the post processing methods applied in this work, simultaneous EEG-fMRI recordings can thus provide valuable information about the neuronal basis of brain rhythms and their regional hemodynamic correlates. The data further substantiate the hypothesis that ‘idling’ rhythms indicate distinct deactivated sensory cortical areas. Increased power of all examined rhythms was associated with negative BOLD signal in sensory cortical areas, indicating less energy consumption in those areas with higher synchronicity. The posterior alpha or so-called Berger rhythm is coupled inversely to the hemodynamics in primary visual areas, whereas rolandic alpha and beta rhythm could be localized to somatomotor areas. Different networks were found for rolandic alpha and beta rhythms. The rolandic beta rhythm is more associated with a motor-network whereas the rolandic alpha rhythm is more associated with a sensory and association network which represents a fundamental characteristic of the sensorimotor system. The rolandic oscillations may bind sensorimotor areas into a functional loop during pre-movement motor maintenance behaviour [Brovelli, et al., 2004]. Furthermore thalamic and cingulate structures were shown to be possible generative or modulatory structures for the brain rhythms examined in this study. The experimental data obtained in this work suggest that the inverse correlation of an ‘idling’ rhythm’s strength with the metabolism in ‘its cortical areas’, and the positive correlation with cingulate or thalamic areas are both general organizational principles. The notion of a default mode of the brain [Gusnard, et al., 2001] may perhaps be further subdivided into different networks with a “default mode”, each of them electro-physiologically defined by its “idle rhythm”

Air–water interface of submerged superhydrophobic surfaces imaged by atomic force microscopy

Underwater air retention of superhydrophobic hierarchically structured surfaces is of increasing interest for technical applications. Persistent air layers (the Salvinia effect) are known from biological species, for example, the floating fern Salvinia or the backswimmer Notonecta. The use of this concept opens up new possibilities for biomimetic technical applications in the fields of drag reduction, antifouling, anticorrosion and under water sensing. Current knowledge regarding the shape of the air–water interface is insufficient, although it plays a crucial role with regards to stability in terms of diffusion and dynamic conditions. Optical methods for imaging the interface have been limited to the micrometer regime. In this work, we utilized a nondynamic and nondestructive atomic force microscopy (AFM) method to image the interface of submerged superhydrophobic structures with nanometer resolution. Up to now, only the interfaces of nanobubbles (acting almost like solids) have been characterized by AFM at these dimensions. In this study, we show for the first time that it is possible to image the air–water interface of submerged hierarchically structured (micro-pillars) surfaces by AFM in contact mode. By scanning with zero resulting force applied, we were able to determine the shape of the interface and thereby the depth of the water penetrating into the underlying structures. This approach is complemented by a second method: the interface was scanned with different applied force loads and the height for zero force was determined by linear regression. These methods open new possibilities for the investigation of air-retaining surfaces, specifically in terms of measuring contact area and in comparing different coatings, and thus will lead to the development of new applications

Air–water interface of submerged superhydrophobic surfaces imaged by atomic force microscopy

Underwater air retention of superhydrophobic hierarchically structured surfaces is of increasing interest for technical applications. Persistent air layers (the Salvinia effect) are known from biological species, for example, the floating fern Salvinia or the backswimmer Notonecta. The use of this concept opens up new possibilities for biomimetic technical applications in the fields of drag reduction, antifouling, anticorrosion and under water sensing. Current knowledge regarding the shape of the air–water interface is insufficient, although it plays a crucial role with regards to stability in terms of diffusion and dynamic conditions. Optical methods for imaging the interface have been limited to the micrometer regime. In this work, we utilized a nondynamic and nondestructive atomic force microscopy (AFM) method to image the interface of submerged superhydrophobic structures with nanometer resolution. Up to now, only the interfaces of nanobubbles (acting almost like solids) have been characterized by AFM at these dimensions. In this study, we show for the first time that it is possible to image the air–water interface of submerged hierarchically structured (micro-pillars) surfaces by AFM in contact mode. By scanning with zero resulting force applied, we were able to determine the shape of the interface and thereby the depth of the water penetrating into the underlying structures. This approach is complemented by a second method: the interface was scanned with different applied force loads and the height for zero force was determined by linear regression. These methods open new possibilities for the investigation of air-retaining surfaces, specifically in terms of measuring contact area and in comparing different coatings, and thus will lead to the development of new applications

Coincidental SARS-CoV-2 infection and mRNA vaccination: a case report addressing the most important clinical questions

The case describes the coincidental mRNA vaccination and SARS-CoV-2 infection of a 31-year-old physician addressing the theoretical considerations and recommendations for further actions in such a particular constellation that we will expect more often in the near future