Development of TiNbTaZrMo bio-high entropy alloy (BioHEA) super-solid solution by selective laser melting, and its improved mechanical property and biocompatibility

BioHEAs, specifically designed high entropy alloy (HEA) systems for biomedical applications, represent a new era for biometals. However, recent challenges are (1) the poor shape customizability, and (2) the inevitable severe segregation due to the intrinsic fact that HEA is an ultra-multicomponent alloy system. To achieve shape customization and suppression of elemental segregation simultaneously, we used an extremely high cooling rate (~107 K/s) of the selective laser melting (SLM) process. We, for the first time, developed pre-alloyed Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 BioHEA powders and SLM-built parts with low porosity, customizable shape, excellent yield stress, and good biocompatibility. The SLM-built specimens showed drastically suppressed elemental segregation compared to the cast counterpart, representing realization of a super-solid solution. As a result, the 0.2% proof stress reached 1690 ± 78 MPa, which is significantly higher than that of cast Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 (1140 MPa). The SLM-built Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 BioHEA is promising as a next-generation metallic material for biomedical applications.Ishimoto T., Ozasa R., Nakano K., et al. Development of TiNbTaZrMo bio-high entropy alloy (BioHEA) super-solid solution by selective laser melting, and its improved mechanical property and biocompatibility. Scripta Materialia, 194, 113658. https://doi.org/10.1016/j.scriptamat.2020.113658

Novel single crystalline-like non-equiatomic TiZrHfNbTaMo bio-high entropy alloy (BioHEA) developed by laser powder bed fusion

This study developed a non-equiatomic Ti28.33Zr28.33Hf28.33Nb6.74Ta6.74Mo1.55 super-solid solutionized BioHEA using laser powder bed fusion (LPBF) to reach the full potential as BioHEA. We succeeded in significant suppression of elemental segregation, thus, resulting in a single crystalline-like texture by activating layer-to-layer epitaxial growth. Relatively low Young’s modulus was achieved in the single crystalline-like BioHEA. Moreover, LPBF-fabricated BioHEA exhibited significantly higher yield stress (1355–1426 MPa) due to the effective solid solution hardening compared to as-cast counterpart with marked segregation (949 MPa), and good biocompatibility. This is first report achieving BioHEA with low modulus, excellent strength-ductility balance, and good biocompatibility via LPBF.Gokcekaya O., Ishimoto T., Nishikawa Y., et al. Novel single crystalline-like non-equiatomic TiZrHfNbTaMo bio-high entropy alloy (BioHEA) developed by laser powder bed fusion. Materials Research Letters 11, 274 (2023); https://doi.org/10.1080/21663831.2022.2147406

Generation of Leukaemia-Derived Dendritic Cells (DCleu) to improve anti-leukaemic activity in AML: selection of the most efficient response modifier combinations

Dendritic cells (DC) and leukaemia derived DC (DC(leu)) are potent stimulators of anti-leukaemic activity in acute myeloid leukaemia (AML) and can be generated from mononuclear cells in vitro following standard DC/DC(leu)-generating protocols. With respect to future clinical applications though, DC/DC(leu)-generating protocols specifically designed for application in a whole-blood-(WB)-environment must be established. Therefore, we developed ten new DC/DC(leu)-generating protocols (kits; Kit-A/-C/-D/-E/-F/-G/-H/-I/-K/-M) for the generation of DC/DC(leu) from leukaemic WB, containing calcium-ionophore, granulocyte-macrophage-colony-stimulating-factor (GM-CSF), tumour-necrosis-factor-alpha, prostaglandin-E(1) (PGE(1)), prostaglandin-E(2) (PGE(2)) and/or picibanil (OK-432). All protocols were evaluated regarding their performance in generating DC/DC(leu) using refined classification and/or ranking systems; DC/DC(leu) were evaluated regarding their performance in stimulating anti-leukaemic activity using a cytotoxicity fluorolysis assay. Overall, we found the new kits capable to generate (mature) DC/DC(leu) from leukaemic WB. Through refined classification and ranking systems, we were able to select Kit-I (GM-CSF + OK-432), -K (GM-CSF + PGE(2)) and -M (GM-CSF + PGE(1)) as the most efficient kits in generating (mature) DC/DC(leu), which are further competent to stimulate immunoreactive cells to show an improved anti-leukaemic cytotoxicity as well. This great performance of Kit-I, -K and -M in mediating DC/DC(leu)-based anti-leukaemic immunity in a WB-environment in vitro constitutes an important and directive step for translating DC/DC(leu)-based immunotherapy of AML into clinical application

Dendritic/antigen presenting cell mediated provision of T-cell receptor gamma delta (TCRγδ) expressing cells contributes to improving antileukemic reactions ex vivo

T-cell receptor gamma delta (TCRγδ) expressing T-cells are known to mediate an MHC-independent immune response and could therefore qualify for immune therapies. We examined the influence of dendritic cells(DC)/antigen presenting cell (APC) generated from blast-containing whole blood (WB) samples from AML and MDS patients on the provision of (leukemia-specific) TCRγδ expressing T-cells after mixed lymphocyte culture (MLC). Kit-M (granulocyte-macrophage colony-stimulating factor (GM-CSF) + prostaglandin E1 (PGE1)) or Kit-I (GM-CSF + Picibanil) were used to generate leukemia derived APC/DC (DCleu)from WB, which were subsequently used to stimulate T-cell enriched MLC. Immune cell composition and functionality were analysed using degranulation- (DEG), intracellular cytokine- (INTCYT) and cytotoxicity fluorolysis- (CTX) assays. Flow cytometry was used for cell quantification. We found increased frequencies of APCs/DCs and their subtypes after Kit-treatment of healthy and patients´ WB compared to control, as well as an increased stimulation and activation of several types of immune reactive cells after MLC. Higher frequencies of TCRγδ expressing leukemia-specific degranulation and intracellularly cytokine producing T-cells were found. The effect of Kit-M-treatment on frequencies of TCRγδ expressing cells and their degranulation could be correlated with the Kit-M-mediated blast lysis compared to control. We also found higher frequencies of TCRγδ expressing T-cells in AML patients´ samples with an achieved remission (compared to blast persistence) after induction chemotherapy. This might point to APC/DC-mediated effects resulting in the provision of leukemia-specific TCRγδ expressing T-cells: Moreover a quantification of TCRγδ expressing T-cells might contribute to predict prognosis of AML/MDS patients

Polycomb Repressive Complex 2 (PRC2) Restricts Hematopoietic Stem Cell Activity

Polycomb group proteins are transcriptional repressors that play a central role in the establishment and maintenance of gene expression patterns during development. Using mice with an N-ethyl-N-nitrosourea (ENU)-induced mutation in Suppressor of Zeste 12 (Suz12), a core component of Polycomb Repressive Complex 2 (PRC2), we show here that loss of Suz12 function enhances hematopoietic stem cell (HSC) activity. In addition to these effects on a wild-type genetic background, mutations in Suz12 are sufficient to ameliorate the stem cell defect and thrombocytopenia present in mice that lack the thrombopoietin receptor (c-Mpl). To investigate the molecular targets of the PRC2 complex in the HSC compartment, we examined changes in global patterns of gene expression in cells deficient in Suz12. We identified a distinct set of genes that are regulated by Suz12 in hematopoietic cells, including eight genes that appear to be highly responsive to PRC2 function within this compartment. These data suggest that PRC2 is required to maintain a specific gene expression pattern in hematopoiesis that is indispensable to normal stem cell function

Prognostische Faktoren nach Leberteilresektion nicht-kolorektaler Lebermetastasen

In der vorliegenden Untersuchung wurden die im Zeitraum von 1984 bis 2006 an der Universitätsklinik Frankfurt am Main aufgrund von nicht-kolorektalen Lebermetastasen durchgeführten Leberteilresektionen untersucht. Ziele dieser Arbeit sind die Darstellung des Patientenkollektivs einschließlich der operativen Faktoren der Lebermetastasenresektion, die Ermittlung von Langzeitergebnissen nach der Resektion und die Feststellung von Prognosefaktoren im Hinblick auf das postoperative Überleben dieser Patienten. Das untersuchte Patientenkollektiv (n = 69) umfasste 31 Männer und 38 Frauen mit einem medianen Alter von 52 Jahren zum Zeitpunkt der Leberresektion. Am häufigsten waren folgende Primärtumore vertreten: Magenkarzinom, Mammakarzinom, Malignes Melanom, Neuroendokriner Tumor und Nierenzellkarzinom. Der größte Anteil der Primärtumore wurde als mäßig differenziert (G2) eingestuft. 55,1 % der Patienten zeigten eine solitäre Lebermetastasierung. Der mediane Tumordurchmesser betrug 5 cm. Bei 14,5 % der Patienten wurden bilobäre und bei 85,5 % unilobäre Lebermetastasen festgestellt. 20,3 % der Patienten präsentierten sich mit einer synchronen und 73,9 % mit einer metachronen Metastasierung (unbekannt: 5,8 %). Zur Resektion der Metastasen wurden atypische Segmentektomien (n = 25), typische Segmentektomien (n = 22) und (erweiterte) Hemihepatektomien (n = 22) durchgeführt. Bei einer medianen Operationsdauer von 195 min erfolgte bei 69,6 % der Patienten ein zusätzlicher Eingriff. Der mediane Sicherheitsabstand zum Resektionsrand lag bei 10 mm. Die Liegedauer auf der Intensivstation betrug im Median einen Tag. Bei 39 Patienten traten postoperative Komplikationen auf. Ein Fortschreiten der Tumorerkrankung war bei 30 Patienten dokumentiert. Das mediane tumorspezifische Überleben nach Resektion nicht-kolorektaler Lebermetastasen lag bei 4,3 Jahren. Die dazugehörigen 1-, 5- und 10-JahresÜberlebensraten betrugen 80,1 %, 47,9 % und 35,5 %. Die mediane tumorspezifische Überlebenszeit nach Resektion nicht-kolorektaler, nicht-neuroendokriner Metastasen stellte sich mit 2,0 Jahren und folgenden 1-, 5- und 10-Jahres-Überlebensraten dar: 76,8 %, 43,1 % und 27,9 %. Nach der Leberresektion aufgrund von Metastasen eines Magenkarzinoms ergaben sich tumorspezifische 1-, 5- und 10-Jahres-Überlebensraten von 80,8 %, 23,1 % und 11,5 % (mediane ÜLZ: 18 Monate). Die 1-, 5- und 10-Jahres-Überlebensraten nach der Resektion von Filiae eines Mammakarzinoms betrugen 74,6 %, 51,1 % und erneut 51,1 %. Die mediane Überlebenszeit nach Operation von Metastasen eines Malignen Melanoms lag bei 22 Monaten: 1-JÜR: 66,7 %, 5-JÜR: 33,3 %, 10-JÜR: 0,0 %. Nach der Resektion von Filiae eines Neuroendokrinen Tumors betrug die 1- 5- und 10-Jahres-Überlebensrate 100,0 %, 80,0 % und erneut 80,0 %. Bei Patienten mit primärem Nierenzellkarzinom ergab sich nach der Resektion eine mediane Überlebenszeit von 44 Monaten und die dazugehörige 1-Jahres-Überlebensrate lag bei 75,0 %. Die folgenden Faktoren zeigten sich in den Resultaten der univariaten Analyse als signifikante Prädiktoren für das tumorspezifische Überleben der Patienten: Primärtumorgruppe8, Grading des Primärtumors, zusätzliche Eingriffe neben der Leberresektion und Sicherheitsabstand zum Resektionsrand. In der multivariaten, tumorspezifischen Analyse wurden zwei Determinanten als unabhängige Prognosefaktoren für das Überleben nach der Leberresektion identifiziert: Der kleinste Sicherheitsabstand der Leberfiliae zum Resektionsrand und die Durchführung eines zusätzlichen Eingriffs neben der Leberresektion. Bei Durchführung eines solchen Eingriffs war das Risiko für die Patienten, an der Tumorerkrankung zu versterben, 3,5mal so groß im Vergleich zu Patienten, bei denen kein zusätzlicher Eingriff erfolgt ist. Bei Annahme eines Sicherheitsabstandes von mindestens 10 mm als Referenz, errechnete sich im Vergleich dazu für Patienten, bei denen kein Sicherheitsabstand eingehalten werden konnte, ein 6,3mal so großes Risiko an der Tumorerkrankung zu versterben. Bei Einhaltung eines kleinen Abstandes zum Resektionsrand (0,1 mm - 9,9 mm) war das entsprechende Risiko für die Patienten 4,9mal so groß. Die Resektion nicht-kolorektaler Lebermetastasen erscheint in ausgewählten Fällen sinnvoll. Um die Prognose der operierten Patienten zu verbessern, sollte entsprechend den Ergebnissen der vorliegenden Arbeit ein Sicherheitsabstand von mindestens einem Zentimeter angestrebt werden.This dissertation examines liver resections for hepatic metastases from noncolorectal cancers. The patients in this study underwent hepatic resection between 1984 and 2006 at the University Hospital in Frankfurt Main. The aims of this dissertation are to describe the patient population and the operative factors, to determine long-term survival rates after liver resection and to identify prognostic factors associated with cancer-specific survival. Hepatic resections for non-colorectal metastases were performed on 31 men and 38 women. The median age was 52 years. The most prevalent primary tumour types were gastric cancer, breast cancer, malignant melanoma, neuroendocrine tumours and renal cell cancer. The biggest part of them was classified as moderately differentiated (G2). 55.1% of the patients presented with a solitary metastasis. The median maximum diameter of the metastases measured 5 centimeters. Metastases in one lobe of the liver were observed in 59 patients and in 10 patients both lobes were affected. 20.3% of the patients presented synchronous lesions, whereas 73.9% had metachronous lesions (unknown: 5,8%). 25 out of 69 patients underwent atypical segmentectomy, 22 received typical segmentectomy and 22 underwent (extended) hemihepatectomy. The median duration of surgery was 195 minutes. An additional intervention was performed on 69.6% of the patients. The median width of the resection margin measured 10 millimetres. Furthermore the median stay on intensive care unit was one day. Postoperative complications occured in 39 cases. Recurrent disease was documented for 30 patientes. The median cancer-specific survival after hepatic resection for non-colorectal metastases was 4.3 years. The corresponding survival rates after 1, 5 and 10 years were 80.1%, 47.9% and 35.5%. After liver resection from non-colorectal non-neuroendocrine metastases the median cancer-specific survival was two years. Moreover the 1-, 5- and 10-year survival rates were 76.8%, 43.1% and 27.9%. Hepatic resection for gastric metastases showed cancer-specific survival rates of 80.8% after 1 year, 23.1% after 5 years and 11.5% after 10 years (median survival: 18 months). The 1-, 5- and 10-year survival rates for patients with metastases from breast cancer were 74.6%, 51.1% and 51.1%. The median survival after hepatic resection as treatment for malignant melanoma liver metastases was 22 months, showing 1- 5- and 10-year survival rates of 66.7%, 33.3% and 0.0%. Following liver resection for neuroendocrine tumour metastases cancer-specific survival was 100.0% at 1 year, 80.0% at 5 years and 80.0% again at 10 years. Patients who developed liver metastases from a renal cell cancer had a median survival of 44 months after hepatic resection. These patients showed a 1-year survival rate of 75,0%. According to the results of the univariate cancer-specific analysis the following factors were significant predictors of survival: primary tumour group, grading of the primary tumour, additional surgical intervention and margin status. By means of multivariate analysis two variables were identified to be independent prognostic factors for cancer-specific survival after hepatic resection: the shortest distance from the edge of the tumour to the line of transection and the enforcement of an additional intervention beyond liver resection. If an additional intervention was performed, the odds-ratio to die due to the tumour was 3.5 compared with patients who did not undergo an additional surgical intervention. When taking a safety margin of 10 millimetres as reference, the odds-ratio to die was 6.3 with a positive margin status and 4.9 with a negative margin status ranging from 0.1 millimetre to 9.9 millimetres. Hepatic resection for non-colorectal liver metastases seems to be reasonable for selected cases. According to the results of this study, a resection margin of at least 1 centimetre should be achieved in these patients in order to improve their prognosis

Analyse der Darstellungsmöglichkeiten einer gezielten Auswahl von Investitions-und Finanzierungsmodellenin Excel

Die moderne Betrachtungsweise von Investitions- und Finanzierungsmethoden beruht nicht mehr auf der Aufgabe der Hilfsfunktion, sondern auf einer entscheidungsorientierten Bewertung. Die vorliegende Thesis untersucht die Darstellungsmöglichkeiten von Investitions- und Finanzierungsmodellen auf Basis von Excel-Funktionen. Für statische und dynamische Investitionsverfahren sowie für externe Finanzierungsformen wie Beteiligungen, Kapitalerhöhungen oder Fremdfinanzierungen ist der Aufbau eines Prototyps sehr gut umsetzbar, da diese eine eindeutige Struktur aufweisen und aus den Modellen Entscheidungen zutreffend ableitbar sind. Das Durchspielen verschiedener Szenarien optimiert den Entscheidungsprozess. Die Aussagekraft eines Modells hängt jedoch immer von dessen Input-Daten ab. Datenaufbereitung sowie die Planung diverser Verlaufsmöglichkeiten des Vorhabens, sind grundlegende Prozesse bei der Modellierung. Excel-Modelle stoßen an ihre Grenzen, wenn Wahrscheinlichkeiten angegeben oder potentielle Risikofaktoren gewichtet werden sollen. Subjektivität kann hierbei nicht vermieden werden, da die Bemessung der Vorteilhaftigkeit eines Projekts immer quantitative und qualitative Faktoren umschließt. Gegenseitige Abhängigkeiten einzelner Parameter erschweren es zusätzlich Vergleiche zwischen Handlungsmöglichkeiten anzustellen. Lösungen hierfür könnten weitere Modelle mit komplexen Zielsystemen liefern. Eine detailliertere Kalkulation erfordere allerdings auch einen größeren Aufwand bei der Datenbeschaffung sowie -verarbeitung.Modern approaches of investing and financing methods are not based any more on an auxiliary function, but rather on a decision oriented valuation. This bachelor thesis analyses the possibilities of how to illustrate investing and financing models that are based on Excel functions. Prototypes for static and dynamic investing methods as well as for external financing models can be constructed quite easily, as they possess a clear structure and appropriate decisions can be deduced. By running through different scenarios the decision-making process can be optimised. However, the significance of a model always depends on its input data. Processing data and planning for diverse possible developments of the project are essential in the modelling process. Models in Excel reach their limits when it comes to defining probabilities or weighting potential risk factors. Subjectivity cannot be avoided, as the evaluation of the profitability of a project always includes quantitative and qualitative factors. Moreover reciprocal dependencies of individual parameters make it difficult to compare options. Further models with complex solution finding systems could resolve some of these problems. But more detailed calculations would certainly have higher requirements for collecting and processing input data

Laser beam powder bed fusion of novel biomedical titanium/niobium/tantalum alloys: Powder synthesis, microstructure evolution and mechanical properties

The synthesis of spherical titanium/niobium/tantalum (TNT) alloy powders, namely Ti-20Nb-6Ta, Ti-27Nb-6Ta, Ti-35Nb-6Ta, and Ti-22Nb-19Ta (in wt-%) by electrode induction melting gas atomization is reported. The powder materials are characterized in detail using X-ray diffraction and scanning electron microscopy. Their processability via laser beam powder bed fusion (PBF-LB/M) is proven, and microstructure as well as mechanical properties of the additively manufactured specimens are assessed. All powders feature a dendrite-type microstructure with Nb/Ta-rich dendritic and Ti-rich inter-dendritic phases. Crystal structures of the powders are strongly composition-dependent. Nb- and Ta-rich Ti-35Nb-6Ta and Ti-22Nb-19Ta feature a body-centered cubic lattice, whereas Ti-rich Ti-20Nb-6Ta and Ti-27Nb-6Ta powders are characterized by multi-phase microstructures, consisting of non-equilibrium martensitic phases. Processing by PBF-LB/M causes significant changes in their microstructures: the dendrite-type morphologies vanish, and the formation of microstructures with a homogeneous element distribution can be observed in all additively manufactured parts. Ultimate tensile strength (UTS) as well as elongation at fracture are assessed by tensile testing. UTS values are found to be in a range from 651 MPa (Ti-35Nb-6Ta) to 802 MPa (Ti-20Nb-6Ta); strain-to-failure is between 21.3 % (Ti-35Nb-6Ta) and 31.7 % (Ti-22Nb-19Ta). Ductile fracture behavior is seen for all TNT alloys investigated