LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis.

Hematopoietic transcription factor LIM domain only 2 (LMO2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL) patients. Here, we demonstrate that LMO2 is activated by deacetylation on lysine 74 and 78 via the nicotinamide phosphoribosyltransferase (NAMPT)/sirtuin 2 (SIRT2) pathway. LMO2 deacetylation enables LMO2 to interact with LIM domain binding 1 and activate the TAL1 complex. NAMPT/SIRT2-mediated activation of LMO2 by deacetylation appears to be important for hematopoietic differentiation of induced pluripotent stem cells and blood formation in zebrafish embryos. In T-ALL, deacetylated LMO2 induces expression of TAL1 complex target genes HHEX and NKX3.1 as well as LMO2 autoregulation. Consistent with this, inhibition of NAMPT or SIRT2 suppressed the in vitro growth and in vivo engraftment of T-ALL cells via diminished LMO2 deacetylation. This new molecular mechanism may provide new therapeutic possibilities in T-ALL and may contribute to the development of new methods for in vitro generation of blood cells.

Manufacture of endothelial colony-forming progenitor cells from steady-state peripheral blood leukapheresis using pooled human platelet lysate.

BACKGROUND: Endothelial colony-forming progenitor cells (ECFCs) are promising candidates for cell therapies. However, ECFC translation to the clinic requires optimized isolation and manufacture technologies according to good manufacturing practice (GMP). STUDY DESIGN AND METHODS: ECFCs were manufactured from steady-state peripheral blood (PB) leukapheresis (11 donors), using GMP-compliant technologies including pooled human platelet (PLT) lysate, and compared to human umbilical cord endothelial cells, human aortic endothelial cells, and human cerebral microvascular endothelial cells. Specific variables assessed were growth kinetics, phenotype, trophic factors production, stimulation of tube formation, and Dil-AcLDL uptake. RESULTS: ECFCs could be isolated from PB leukapheresis units with mean processed volume of 5411 mL and mean white blood cell (WBC) concentration factor of 8.74. The mean frequency was 1.44 × 10-8 ECFCs per WBC, corresponding to a mean of 177.8 ECFCs per apheresis unit. Expandable for up to 12 cumulative population doublings, calculated projection showed that approximately 730 × 103 ECFCs could be manufactured from 1 apheresis unit. ECFCs produced epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor (VEGF)-A, PLT-derived growth factor-B, interleukin-8, and monocyte chemoattractant protein-1, featured high potential for capillary-like tubes formation, and showed no telomerase activity. They were characterized by CD29, CD31, CD44, CD105, CD117, CD133, CD144, CD146, and VEGF-R2 expression, with the most common subpopulation CD34+CD117-CD133-. Compared to controls, ECFCs featured greater Dil-AcLDL uptake and higher expression of CD29, CD31, CD34, CD44, CD144, and VEGF-R2. CONCLUSIONS: Here we show that isolation of ECFCs with proangiogenic profile from steady-state PB leukapheresis is feasible, marking a first step toward ECFC product manufacture according to GMP.

A Revolution that never happened.

If we define scientific revolutions as changes of scientists' ontologies, types of causal explanation, and paradigmatic types of methods and instruments, Antoine-Laurent Lavoisier's contribution to chemistry did not amount to a scientific revolution. Contrary to the received view that Lavoisier initiated a "chemical revolution," which is accepted by Chang and Kusch, I argue that Lavoisier shared with the phlogistonists their "flat ontology" of chemical substance, established decades before the 1770s, their types of explaining chemical transformation, and their quantitative methods. Based on my historical reconstruction, I criticize Chang's argument that the late eighteenth-century phlogistic systems and Lavoisier's system belonged to two different theoretical traditions. As a consequence, I also question Chang's argument that the acceptance of Lavoisier's system can be explained in terms of dominance of "compositionism" over "principlism."

Chemical Expertise: Chemistry in the Royal Prussian Porcelain Manufactory.

Eighteenth-century chemists defined chemistry as both a "science and an art." By "chemical art" they meant not merely experimentation but also parts of certain arts and crafts. This raises the question of how to identify the "chemical parts" of the arts and crafts in eighteenth-century Europe. In this essay I tackle this question with respect to porcelain manufacture. My essay begins with a brief discussion of historiographical problems related to this question. It then analyzes practices involved in porcelain manufacture that can be reasonably identified as chemical practices or a chemical art. My analysis yields evidence for the argument that chemical experts and expertise fulfilled distinct technical functions in porcelain manufacture and, by extension, in eighteenth-century "big industry," along with its system of division of labor.

Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells.

BACKGROUND: Mesenchymal stromal cells (MSCs) are attractive for cell-based therapies ranging from regenerative medicine and tissue engineering to immunomodulation. However, clinical efficacy is variable and it is unclear how the phenotypes defining bone marrow (BM)-derived MSCs as well as donor characteristics affect their functional properties. METHODS: BM-MSCs were isolated from 53 (25 female, 28 male; age: 13 to 80 years) donors and analyzed by: (1) phenotype using flow cytometry and cell size measurement; (2) in vitro growth kinetics using population doubling time; (3) colony formation capacity and telomerase activity; and (4) function by in vitro differentiation capacity, suppression of T cell proliferation, cytokines and trophic factors secretion, and hormone and growth factor receptor expression. Additionally, expression of Oct4, Nanog, Prdm14 and SOX2 mRNA was compared to pluripotent stem cells. RESULTS: BM-MSCs from younger donors showed increased expression of MCAM, VCAM-1, ALCAM, PDGFRß, PDL-1, Thy1 and CD71, and led to lower IL-6 production when co-cultured with activated T cells. Female BM-MSCs showed increased expression of IFN-γR1 and IL-6ß, and were more potent in T cell proliferation suppression. High-clonogenic BM-MSCs were smaller, divided more rapidly and were more frequent in BM-MSC preparations from younger female donors. CD10, ß1integrin, HCAM, CD71, VCAM-1, IFN-γR1, MCAM, ALCAM, LNGFR and HLA ABC were correlated to BM-MSC preparations with high clonogenic potential and expression of IFN-γR1, MCAM and HLA ABC was associated with rapid growth of BM-MSCs. The mesodermal differentiation capacity of BM-MSCs was unaffected by donor age or gender but was affected by phenotype (CD10, IFN-γR1, GD2). BM-MSCs from female and male donors expressed androgen receptor and FGFR3, and secreted VEGF-A, HGF, LIF, Angiopoietin-1, basic fibroblast growth factor (bFGF) and NGFB. HGF secretion correlated negatively to the expression of CD71, CD140b and Galectin 1. The expression of Oct4, Nanog and Prdm14 mRNA in BM-MSCs was much lower compared to pluripotent stem cells and was not related to donor age or gender. Prdm14 mRNA expression correlated positively to the clonogenic potential of BM-MSCs. CONCLUSIONS: By identifying donor-related effects and assigning phenotypes of BM-MSC preparations to functional properties, we provide useful tools for assay development and production for clinical applications of BM-MSC preparations.

Recommending early integration of palliative care - does it work?

BACKGROUND: In 2006, our comprehensive cancer center decided to implement early integration (EI) of palliative care (PC) by (a) literally adopting the WHO definition of PC into cancer care guidelines and (b) providing a PC consulting team (PCST) to provide EI on in- and outpatient wards. The experience with this approach was assessed to identify shortcomings. METHODS: A retrospective systematic chart analysis of a 2-year period was performed. RESULTS: A total of 862 patients were treated (May 2006-April 2008). Many patients consulted by the PCST for the first time were already in a reduced performance status (ECOG 3 & 4: 40%) or experiencing burdening symptoms (i.e., dyspnoea 27%). After the first year (period A; "getting started"), the overall prevalence of symptoms identified on first PC contact decreased from seven to three, (p < 0.001) as well as surrogate measures for advanced disease (i.e., frailty: from 63% to 33%; CI: [-36%; -23%], p < 0.001). CONCLUSION: Surrogate measures (symptom burden, performance status) indicate that PC was integrated earlier in the course of the disease after a 1-year phase of "getting started" with EI. Yet, the WHO recommendation alone was too vague to successfully trigger EI of PC. Therefore, the authors advocate the provision of disease specific guidelines to institutionalize EI of PC. Such guidelines have been developed for 19 different malignancies and are presented separately.

Expression of blood group genes by mesenchymal stem cells.

Incompatible blood group antigens are highly immunogenic and can cause graft rejections. Focusing on distinct carbohydrate- and protein-based membrane structures, defined by blood group antigens, we investigated human bone marrow-derived mesenchymal stem cells (MSCs) cultured in human serum. The presence of H (CD173), ABO, RhD, RhCE, RhAG, Kell, urea transporter type B (SLC14A1, previously known as JK), and Duffy antigen receptor of chemokines (DARC) was evaluated at the levels of genome, transcriptome and antigen. Fucosyltransferase-1 (FUT1), RHCE, KEL, SLC14A1 (JK) and DARC mRNA were transcribed in MSCs. FUT1 mRNA transcription was lost during differentiation. The mRNA transcription of SLC14A1 (JK) decreased during chondrogenic differentiation, while that of DARC increased during adipogenic differentiation. All MSCs synthesized SLC14A1 (JK) but no DARC protein. However, none of the protein antigens tested occurred on the surface, indicating a lack of associated protein function in the membrane. As A and B antigens are neither expressed nor adsorbed, concerns of ABO compatibility with human serum supplements during culture are alleviated. The H antigen expression by GD2dim+ MSCs identified two distinct MSC subpopulations and enabled their isolation. We hypothesize that GD2(dim+) H(+) MSCs retain a better 'stemness'. Because immunogenic blood group antigens are lacking, they cannot affect MSC engraftment in vivo, which is promising for clinical applications.

[In process.] / Kuhns Theorie wissenschaftlicher Revolutionen in der neueren Wissenschaftsgeschichte.

The essay presents a critical analysis of KUHN's theory of the historical development of the sciences and of scientific revolutions from the perspective of the historiography of science. It focusses on KUHNS'S concept of structure, his intemalistic model of scientific change in history as well as his assumptions about the duration of scientific revolutions and the relation between continuity and discontinuity.

Savant officials in the Prussian mining administration.

In the second half of the eighteenth century, the Prussian State supported savants who combined learned inquiry into nature with technical work. Members of the physical and mathematical classes of the Royal Prussian Academy of Sciences were involved in State projects such as surveying for the construction of canals, chemical analysis of Silesian iron, production of porcelain and of beet sugar. Some of these men were truly 'hybrid' experts living both in the worlds of State-directed manufacture and academic natural inquiry. Among these savant experts there was a particular sub-group that is at the centre of this paper: mining officials who were also recognized as mineralogists, geologists and chemists. The paper describes and analyses the training and the varied technical and scientific activities of these 'savant officials'. At the centre of attention are the travels of inspection of the mineralogist and mining official Carl Abraham Gerhard (1738-1821) in the late 1760s. I argue that Gerhard's travels of inspection were at the same time geological travels and that savant officials like Gerhard made a significant contribution to the fledgling science of geology.

Integrating Palliative Medicine into Comprehensive Breast Cancer Therapy - a Pilot Project.

BACKGROUND: To comply with the World Health Organization (WHO) recommendations, our institution's administrative directives were adopted to advocate the provision of palliative care (PC) early in the disease trajectory of breast cancer (BC). To assess the outcome of this recommendation, this study evaluated the effects of this approach. METHODS: A retrospective systematic chart analysis of a 2-year period was performed. The first PC consultation of patients was analyzed according to (a) physical condition, (b) symptom burden of the patients, and (c) reasons for PC consultation. RESULTS: Many patients were already in a reduced physical state and experienced burdening symptoms when first counselled by PC. After a 1-year experience with PC consultations, the number of burdening symptoms identified at first PC consultation decreased and senologists increasingly requested PC support also for non-somatic issues. CONCLUSIONS: A development towards a better understanding of PC competencies after a 1-year initiation period could be demonstrated, but BC patients continued to be in late stages of the disease at the time of first PC contact. Disease-specific guidelines may facilitate and optimize the integration of PC into breast cancer therapy.

Implementing WHO recommendations for palliative care into routine lung cancer therapy: a feasibility project.

BACKGROUND: The World Health Organization (WHO) explicitly recommends the integration of palliative care (PC) early in the disease trajectory as part of the WHO definition of PC. Our comprehensive cancer centre decided to include this recommendation in the administrative directives for principles of cancer care. The aim of this study was to assess, for patients with lung cancer, (a) at what point in the disease trajectory the patients were first provided PC and (b) whether - over one year - an earlier integration of PC could be achieved. OBJECTIVE: A retrospective systematic chart analysis of a two year period was performed. We assumed that seeing patients relatively early during the course of the illness would be reflected by seeing patients that would be not already (i) in a reduced performance status, (ii) experiencing symptoms that are indicators for advanced disease (e.g., dyspnoea and pain) and (iii) close to death. Therefore, the first PC consultation for every lung cancer patient was analyzed to assess in what physical condition patients receive first PC consultation, what burdening symptoms they already experienced and how long the patients lived after their first consultations. RESULTS: Most patients were already in a reduced physical state, were experiencing burdening symptoms and many died shortly after the first PC consultation. After a one year period, the number of burdening symptoms identified at first PC consultation and the admissions to the in-patient PC was decreased while non-PC physicians increasingly requested PC support for psychosocial interventions. CONCLUSION: Though some degree of development towards a better understanding of PC competencies and the "early integration" approach could be demonstrated, the adoption of the WHO recommendation alone did not suffice to integrate PC into routine cancer care early in the course of the illness. Therefore, the development of disease specific guidelines is advocated by our working group.