Bone marrow-derived mesenchymal stromal cells obstruct AML-targeting CD8+ clonal effector and CAR T-cell function while promoting a senescence-associated phenotype.

Bone marrow mesenchymal stromal cells (MSCs) have been described as potent regulators of T-cell function, though whether they could impede the effectiveness of immunotherapy against acute myeloid leukemia (AML) is still under investigation. We examine whether they could interfere with the activity of leukemia-specific clonal cytotoxic T-lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells, as well as whether the immunomodulatory properties of MSCs could be associated with the induction of T-cell senescence. Co-cultures of leukemia-associated Wilm's tumor protein 1 (WT1) and tyrosine-protein kinase transmembrane receptor 1 (ROR1)-reactive CTLs and of CD123-redirected switchable CAR T cells were prepared in the presence of MSCs and assessed for cytotoxic potential, cytokine secretion, and expansion. T-cell senescence within functional memory sub-compartments was investigated for the senescence-associated phenotype CD28-CD57+ using unmodified peripheral blood mononuclear cells. We describe inhibition of expansion of AML-redirected switchable CAR T cells by MSCs via indoleamine 2,3-dioxygenase 1 (IDO-1) activity, as well as reduction of interferon gamma (IFNγ) and interleukin-2 (IL-2) release. In addition, MSCs interfered with the secretory potential of leukemia-associated WT1- and ROR1-targeting CTL clones, inhibiting the release of IFNγ, tumor necrosis factor alpha, and IL-2. Abrogated T cells were shown to retain their cytolytic activity. Moreover, we demonstrate induction of a CD28loCD27loCD57+KLRG1+ senescent T-cell phenotype by MSCs. In summary, we show that MSCs are potent modulators of anti-leukemic T cells, and targeting their modes of action would likely be beneficial in a combinatorial approach with AML-directed immunotherapy.

[Career prospects of graduate Bachelor nursing degree programs - Results of a nationwide study in Germany]. / Berufsperspektiven von Absolventinnen und Absolventen grundständig qualifizierender Pflegestudiengänge − Ergebnisse einer bundesweiten Verbleibstudie.

Career prospects of graduate Bachelor nursing degree programs - Results of a nationwide study in Germany Abstract. BACKGROUND: Graduates of Bachelor nursing degree programs are available on the labour market for a few years. Currently, there is no empirical evidence or reports on different fields of these academically prepared nurses in Germany. AIM: Aim of this study was to assess the whereabouts of academically prepared nurses in the German labour market, their satisfaction with their current working conditions, and future prospects of the graduates. METHODS: A cross-sectional design was conducted using an online survey to assess whereabouts of academically prepared nurses (n = 273) after graduation from all German Bachelor nursing degree programs. RESULTS: The majority of 77.6 % of participating nurses worked in direct acute settings or in elderly care. Those, working in direct patient care appeared to be significantly more dissatisfied with their working conditions in comparison to those in extended nursing practice (p = 0.000). High satisfaction scores were reported for qualification-adjusted activities, and working conditions in general. Positive perspectives for personal growth and development see 81.3 %. However, 31.1 % of this sample were enrolled in Master programs or plan to enrol in a further education study program into the next future. CONCLUSIONS: In order to become implicit, the process of academic nursing education needs to continue in all practice settings. However, innovative human resources development strategies are needed to use the benefit and full scope of practice in academically prepared nurses in Germany.

Multiple off-axis fiber Bragg gratings for 3D shape sensing.

Point-by-point femtosecond laser processed fiber Bragg gratings are arranged around the edge of a standard single-mode optical fiber core. The relative amplitudes of at least three such fiber Bragg gratings are utilized to detect the central position of the mode field within the fiber core and calculate the local curvature of the fiber. An analytical approximation is given, and an experimental validation is performed.

TriFabs--Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery.

TriFabs are IgG-shaped bispecific antibodies (bsAbs) composed of two regular Fab arms fused via flexible linker peptides to one asymmetric third Fab-sized binding module. This third module replaces the IgG Fc region and is composed of the variable region of the heavy chain (VH) fused to CH3 with "knob"-mutations, and the variable region of the light chain (VL) fused to CH3 with matching "holes". The hinge region does not contain disulfides to facilitate antigen access to the third binding site. To compensate for the loss of hinge-disulfides between heavy chains, CH3 knob-hole heterodimers are linked by S354C-Y349C disulphides, and VH and VL of the stem region may be linked via VH44C-VL100C disulphides. TriFabs which bind one antigen bivalent in the same manner as IgGs and the second antigen monovalent "in between" these Fabs can be applied to simultaneously engage two antigens, or for targeted delivery of small and large (fluorescent or cytotoxic) payloads.

Induction of heat shock protein HSPA6 (HSP70B') upon HSP90 inhibition in cancer cell lines.

Genome-wide transcript profiling to elucidate responses to HSP90 inhibition revealed strong induction of HSPA6 in MCF-7 cells treated with 17-AAG. Time- and dose dependent induction of HSPA6 (confirmed by qPCR and Western Blots) occurred also upon treatment with Radicicol, another HSP90 inhibitor. HSPA6 was not detectable in untreated cells or cells treated with toxins that do not inhibit HSP90, or upon applying oxidative stress. Thus, HSPA6 induction is not a general response to cytotoxic insults. Modulation of HSPA6 levels by siRNA-mediated inhibition or recombinant expression did not influence 17-AAG mediated cell death. HSPA6 induction as a consequence of HSP90 inhibition occurs in various (but not all) cell lines and may be a more specific marker for HSP90 inhibition than induction of other HSP70 proteins.