Performance of Different Diagnostic PD-L1 Clones in Head and Neck Squamous Cell Carcinoma

Background: The approval of immune checkpoint inhibitors in combination with specific diagnostic biomarkers presents new challenges to pathologists as tumor tissue needs to be tested for expression of programmed death-ligand 1 (PD-L1) for a variety of indications. As there is currently no requirement to use companion diagnostic assays for PD-L1 testing in Germany different clones are used in daily routine. While the correlation of staining results has been tested in various entities, there is no data for head and neck squamous cell carcinomas (HNSCC) so far. Methods: We tested five different PD-L1 clones (SP263, SP142, E1L3N, 22-8, 22C3) on primary HNSCC tumor tissue of 75 patients in the form of tissue microarrays. Stainings of both immune and tumor cells were then assessed and quantified by pathologists to simulate real-world routine diagnostics. The results were analyzed descriptively and the resulting staining pattern across patients was further investigated by principal component analysis and non-negative matrix factorization clustering. Results: Percentages of positive immune and tumor cells varied greatly. Both the resulting combined positive score as well as the eligibility for certain checkpoint inhibitor regimens was therefore strongly dependent on the choice of the antibody. No relevant co-clustering and low similarity of relative staining patterns across patients was found for the different antibodies. Conclusions: Performance of different diagnostic anti PD-L1 antibody clones in HNSCC is less robust and interchangeable compared to reported data from other tumor entities. Determination of PD-L1 expression is critical for therapeutic decision making and may be aided by back-to-back testing of different PD-L1 clones

The development of study-specific self-efficacy during grammar school.(Zur Entwicklung der studienspezifischen Selbstwirksamkeit in der Oberstufe)

Article is in German. Even if more and more German adolescents acquire a university entrance qualification, not all of them finally enrol at a university. In particular, the transition from school to university strongly depends on parent’s education. Even with the same marks in school, adolescents from non-academic households are less likely to enrol in universities than adolescents from academic housholds. One important reason is their lower belief to master a university study. This study analyses a specific intervention in grammar school to improve study-specific self- efficacy, the belief in one’s capabilities to master a university study, using a longitudinal design. We apply a difference-in-difference framework and show that programme participation significantly improves the study-specific self-efficacy for puplis from non- academic families but not for those from academic families. Hence, such a programme could reduce social disparities between both groups

Specific induction of pp125 focal adhesion kinase in human breast cancer

The pp125 focal adhesion kinase (FAK) is involved in integrin-mediated cell signalling and overexpressed in a variety of solid tumours. Focal adhesion kinase expression has been correlated to invasion and metastasis, but the data on breast cancer are inconclusive. We analysed FAK mRNA, protein levels and expression patterns in primary breast cancer and normal breast tissue. FAK expression on the functional protein level and mRNA was determined in 55 matched pairs of breast cancer and corresponding normal tissue by Western blot, immunohistochemistry and RT–PCR. Using a score ranging from 0 to +5 for Western blots, we determined in normal breast tissue a score of 1.51±0.84 (mean±standard deviation), which was strongly induced to 2.91 (±1.22) in breast cancers (P<0.001). Overall, 45 out of 55 tissue pairs (81.8%) showed this upregulation of FAK protein in tumours in comparison to normal tissue. Immunohistochemistry confirmed these findings with a significant higher score for tumours vs physiological tissue (1.0±0.63 vs 2.27±0.91; P=0.001). Interestingly, no overall significant difference in the mRNA levels (P=0.359) was observed. In conclusion, expression levels of the FAK protein are specifically upregulated in breast cancer in comparison to matched normal breast tissue supporting its pivotal role in neoplastic signal transduction and representing a potential marker for malignant transformation

β1-integrins signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer

Consistent with their essential role in cell adhesion to the extracellular matrix, integrins and their associated signaling pathways have been shown to be involved in cell proliferation, migration, invasion and survival, processes required in both tumorigenesis and metastasis. β1-integrins represent the predominantly expressed integrins in mammary epithelial cells and have been proven crucial for mammary gland development and differentiation. Here we provide an overview of the studies that have used transgenic mouse models of mammary tumorigenesis to establish β1-integrin as a critical mediator of breast cancer progression and thereby as a potential therapeutic target for the development of new anticancer strategies

The dynamic cusp at low altitudes: a case study utilizing Viking, DMSP-F7, and Sondrestrom incoherent scatter radar observations

Coincident multi-instrument magnetospheric and ionospheric observations have made it possible to determine the position of the ionospheric footprint of the magnetospheric cusp and to monitor its evolution over time. The data used include charged particle and magnetic field measurements from the Earth-orbiting Viking and DMSP-F7 satellites, electric field measurements from Viking, interplanetary magnetic field and plasma data from IMP-8, and Sondrestrom incoherent scatter radar observations of the ionospheric plasma density, temperature, and convection. Viking detected cusp precipitation poleward of 75.5° invariant latitude. The ionospheric response to the observed electron precipitation was simulated using an auroral model. It predicts enhanced plasma density and elevated electron temperature in the upper E- and F-regions. Sondrestrom radar observations are in agreement with the predictions. The radar detected a cusp signature on each of five consecutive antenna elevation scans covering 1.2 h local time. The cusp appeared to be about 2° invariant latitude wide, and its ionospheric footprint shifted equatorward by nearly 2° during this time, possibly influenced by an overall decrease in the IMF Bz component. The radar plasma drift data and the Viking magnetic and electric field data suggest that the cusp was associated with a continuous, rather than a patchy, merging between the IMF and the geomagnetic field

Coordinated cluster and ground-based instrument observation of transient changes in the magnetopause boundary layer during an interval of predominantly northward IMF: Relation to reconnection pulses and FTE signatures

We study a series of transient entries into the low-latitude boundary layer (LLBL) of all four Cluster spacecraft during an outbound pass through the mid-afternoon magnetopause ([XGSM,YGSM,ZGSM] ≈ [2,7,9]RE). The events take place during an interval of northward IMF, as seen in the data from the ACE satellite and lagged by a propagation delay of 75 min that is well-defined by two separate studies: (1) the magnetospheric variations prior to the northward turning (Lockwood et al., 2001, this issue) and (2) the field clock angle seen by Cluster after it had emerged into the magnetosheath (Opgenoorth et al., 2001, this issue). With an additional lag of 16.5 min, the transient LLBL events correlate well with swings of the IMF clock angle (in GSM) to near 90 deg. Most of this additional lag is explained by ground-based observations, which reveal signatures of transient reconnection in the pre-noon sector that then take 10–15 min to propagate eastward to 15 MLT, where they are observed by Cluster. The eastward phase speed of these signatures agrees very well with the motion deduced by the cross-correlation of the signatures seen on the four Cluster spacecraft. The evidence that these events are reconnection pulses includes: transient erosion of the noon 630 nm (cusp/cleft) aurora to lower latitudes; transient and travelling enhancements of the flow into the polar cap, imaged by the AMIE technique; and poleward-moving events moving into the polar cap, seen by the EISCAT Svalbard Radar (ESR). A pass of the DMSP-F15 satellite reveals that the open field lines near noon have been opened for some time: the more recently opened field lines were found closer to dusk where the flow transient and the poleward-moving event intersected the satellite pass. The events at Cluster have ion and electron characteristics predicted and observed by Lockwood and Hapgood (1998) for a Flux Transfer Event (FTE), with allowance for magnetospheric ion reflection at Alfvenic disturbances in the magnetopause reconnection layer. Like FTEs, the events are about 1 RE in their direction of motion and show a rise in the magnetic field strength, but unlike FTEs, in general, they show no pressure excess in their core and hence, no characteristic bipolar signature in the boundary-normal component. However, most of the events were observed when the magnetic field was southward, i.e. on the edge of the interior magnetic cusp, or when the field was parallel to the magnetic equatorial plane. Only when the satellite begins to emerge from the exterior boundary (when the field was northward), do the events start to show a pressure excess in their core and the consequent bipolar signature. We identify the events as the first observations of FTEs at middle altitudes