Humboldt University of Berlin

About: Humboldt University of Berlin is a education organization based out in Berlin, Germany. It is known for research contribution in the topics: Population & Medicine. The organization has 33671 authors who have published 61781 publications receiving 1908102 citations. The organization is also known as: Humboldt-Universität zu Berlin & Universitas Humboldtiana Berolinensis.

Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct

Abstract: Certain bispecific antibodies exhibit an extraordinary potency and efficacy for target cell lysis by eliciting a polyclonal T-cell response. One example is a CD19-/CD3-bispecific single-chain antibody construct (bscCD19xCD3), which at femtomolar concentrations can redirect cytotoxic T cells to eliminate human B lymphocytes, B lymphoma cell lines and patient-derived malignant B cells. Here we have further explored the basis for this high potency. Using video-assisted microscopy, bscCD19xCD3 was found to alter the motility and activity of T cells from a scanning to a killing mode. Individual T cells could eliminate multiple target cells within a 9 hr time period, resulting in nuclear fragmentation and membrane blebbing of target cells. Complete target cell elimination was observed within 24 hr at effector-to-target cell ratios as low as 1:5. Under optimal conditions, cell killing started within minutes after addition of bscCD19xCD3, suggesting that the rate of serial killing was mostly determined by T-cell movement and target cell scanning and lysis. At all times, T cells remained highly motile, and no clusters of T and target cells were induced by the bispecific antibody. Bystanding target-negative cells were not detectably affected. Repeated target cell lysis by bscCD19xCD3-activated T cells increased the proportion of CD19/CD3 double-positive T cells, which was most likely a consequence of transfer of CD19 from B to T cells during cytolytic synapse formation. To our knowledge, this is the first study showing that a bispecific antibody can sustain multiple rounds of target cell lysis by T cells.

Noninvasive coronary angiography by 320-row computed tomography with lower radiation exposure and maintained diagnostic accuracy: comparison of results with cardiac catheterization in a head-to-head pilot investigation.

Abstract: Background— Noninvasive coronary angiography with the use of multislice computed tomography (CT) scanners is feasible with high sensitivity and negative predictive value; however, the radiation exposure associated with this technique is rather high. We evaluated coronary angiography using whole-heart 320-row CT, which avoids exposure-intensive overscanning and overranging. Methods and Results— A total of 30 consecutive patients with suspected coronary artery disease referred for clinically indicated conventional coronary angiography (CCA) were included in this prospective intention-to-diagnose study. CT was performed with the use of up to 320 simultaneous detector rows before same-day CCA, which, together with quantitative analysis, served as the reference standard. The per-patient sensitivity and specificity for CT compared with CCA were 100% (95% confidence interval [CI], 72 to 100) and 94% (95% CI, 73 to 100), respectively. Per-vessel versus per-segment sensitivity and specificity were 89% (95% CI, 62 ...

Constitutive Activation of Hypoxia-inducible Genes Related to Overexpression of Hypoxia-inducible Factor-1α in Clear Cell Renal Carcinomas

Abstract: The transcription factor hypoxia-inducible factor (HIF)-1 is an important mediator of hypoxic adaptation of tumor cells and controls several genes that have been implicated in tumor growth. Oxygen-dependent degradation of HIF-1alpha, the regulatory subunit, requires binding to the von Hippel Lindau (VHL) protein. Because functional inactivation of the VHL tumor suppressor gene occurs in up to 70% of clear cell renal carcinomas, we investigated whether this results in overexpression of HIF-1alpha and its target genes. Immunoblotting revealed increased expression of HIF-1alpha in 24 of 32 (75%) clear cell renal carcinomas but only 3 of 8 non-clear cell renal tumors. Somatic mutations of the VHL gene were detected only in clear cell renal carcinomas that overexpressed HIF-1alpha. None of the HIF-1alpha-negative tumors displayed a VHL mutation. The level of HIF-1alpha mRNA was not different between tumors and adjacent kidney tissue. Immunohistochemistry revealed distinct patterns of nuclear staining for HIF-1alpha, depending on histological type and overall abundance of HIF-1alpha. In those clear cell renal carcinomas that showed increased expression on immunoblots, HIF-1alpha was expressed in almost all cells. In the remaining clear cell and in non-clear cell tumors, staining was focal; these different patterns thus were compatible with genetic stabilization in contrast to microenvironmental stimulation of HIF-1alpha as the primary mechanism. The mRNA expression of two known target genes of HIF-1alpha, vascular endothelial growth factor and glucose transporter 1, increased progressively with increasing amounts of HIF-1alpha in tumor extracts. In addition, glucose transporter 1 protein levels correlated with HIF-1alpha abundance. In conclusion, the data provide in vivo evidence for a constitutive up-regulation of HIF-1alpha in the majority of clear cell renal carcinomas, which leads to more widespread accumulation of this transcription factor than hypoxic stimulation. These observations are most likely linked to functional inactivation of the VHL gene product. Increased expression of HIF-1alpha is associated with alterations in gene expression patterns that are likely to contribute to tumor phenotype and progression.

Explaining Women's Success: Technological Change and the Skill Content of Women's Work

Abstract: The closing of the gender wage gap is an ongoing phenomenon in industrialized countries. However, research has been limited in its ability to understand the causes of these changes, due in part to an inability to directly compare the work of women to that of men. In this study, we use a new approach for analyzing changes in the gender pay gap that uses direct measures of job tasks and gives a comprehensive characterization of how work for men and women has changed in recent decades. Using data from West Germany, we find that women have witnessed relative increases in non-routine analytic tasks and non-routine interactive tasks, which are associated with higher skill levels. The most notable difference between the genders is, however, the pronounced relative decline in routine task inputs among women with little change for men. These relative task changes explain a substantial fraction of the closing of the gender wage gap. Our evidence suggests that these task changes are driven, at least in part, by technological change. We also show that these task changes are related to the recent polarization of employment between low and high skilled occupations that we observed in the 1990s.