Intraoperative radiotherapy during awake craniotomies: preliminary results of a single-center case series

Awake craniotomies are performed to avoid postoperative neurological deficits when resecting lesions in the eloquent cortex, especially the speech area. Intraoperative radiotherapy (IORT) has recently focused on optimizing the oncological treatment of primary malignant brain tumors and metastases. Herein, for the first time, we present preliminary results of IORT in the setting of awake craniotomies. From 2021 to 2022, all patients undergoing awake craniotomies for tumor resection combined with IORT were analyzed retrospectively. Demographical and clinical data, operative procedure, and treatment-related complications were evaluated. Five patients were identified (age (mean ± standard deviation (SD): 65 ± 13.5 years (y)). A solid left frontal metastasis was detected in the first patient (female, 49 y). The second patient (male, 72 y) presented with a solid metastasis on the left parietal lobe. The third patient (male, 52 y) was diagnosed with a left temporoparietal metastasis. Patient four (male, 74 y) was diagnosed with a high-grade glioma on the left frontal lobe. A metastasis on the left temporooccipital lobe was detected in the fifth patient (male, 78 y). After awake craniotomy and macroscopic complete tumor resection, intraoperative tumor bed irradiation was carried out with 50 kV x-rays and a total of 20 Gy for 16.7 ± 2.5 min. During a mean follow-up of 6.3 ± 2.6 months, none of the patients developed any surgery- or IORT-related complications or disabling permanent neurological deficits. Intraoperative radiotherapy in combination with awake craniotomy seems to be feasible and safe

Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years

<p>Abstract</p> <p>Background</p> <p>Early onset lung cancer shows some familial aggregation, pointing to a genetic predisposition. This study was set up to investigate the role of candidate genes in the susceptibility to lung cancer patients younger than 51 years at diagnosis.</p> <p>Methods</p> <p>246 patients with a primary, histologically or cytologically confirmed neoplasm, recruited from 2000 to 2003 in major lung clinics across Germany, were matched to 223 unrelated healthy controls. 11 single nucleotide polymorphisms of genes with reported associations to lung cancer have been genotyped.</p> <p>Results</p> <p>Genetic associations or gene-smoking interactions was found for <it>GPX1(Pro200Leu) </it>and <it>EPHX1(His113Tyr)</it>. Carriers of the Leu-allele of <it>GPX1(Pro200Leu) </it>showed a significant risk reduction of OR = 0.6 (95% CI: 0.4–0.8, p = 0.002) in general and of OR = 0.3 (95% CI:0.1–0.8, p = 0.012) within heavy smokers. We could also find a risk decreasing genetic effect for His-carriers of <it>EPHX1(His113Tyr) </it>for moderate smokers (OR = 0.2, 95% CI:0.1–0.7, p = 0.012). Considered both variants together, a monotone decrease of the OR was found for smokers (OR of 0.20; 95% CI: 0.07–0.60) for each protective allele.</p> <p>Conclusion</p> <p>Smoking is the most important risk factor for young lung cancer patients. However, this study provides some support for the T-Allel of <it>GPX1(Pro200Leu) </it>and the C-Allele of <it>EPHX1(His113Tyr) </it>to play a protective role in early onset lung cancer susceptibility.</p

Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms

Amyloid beta (Abeta) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. The mechanisms underlying such toxicity on synaptic functions are complex and not fully understood. Here, we provide the first evidence that these mechanisms involve protein phosphatase 1 (PP1). Using a novel transgenic mouse model expressing human APP with the Swedish and Arctic mutations that render Abeta more prone to form oligomers (arcAbeta mice), we show that the LTP impairment induced by Abeta oligomers can be fully reversed by PP1 inhibition in vitro. We further demonstrate that the genetic inhibition of endogenous PP1 in vivo confers resistance to Abeta oligomer-mediated toxicity and preserves LTP. Overall, these results reveal that PP1 is a key player in the mechanisms of AD pathology

Co-Localization of Reelin and Proteolytic AbetaPP Fragments in Hippocampal Plaques in Aged Wild-Type Mice

Reelin is a large extracellular glycoprotein required for proper neuronal positioning during development. In the adult brain, Reelin plays a crucial modulatory role in the induction of synaptic plasticity and successful formation of long-term memory. Recently, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). We previously reported that aging in several species is characterized by a decline in Reelin-expressing interneurons and concomitant accumulation in amyloid-like plaques in the hippocampal formation, significantly correlating with cognitive impairments. In transgenic AD mice, we detected Reelin in oligomeric amyloid-beta aggregates and in tight association with fibrillary plaques. Here, we used immunohistochemistry at the light and electron microscopy level to characterize further the morphology, temporal and spatial progression, as well as the potential of Reelin-positive plaques to sequester murine amyloid-beta peptides in wild-type mice across aging. We developed a new immunohistochemical protocol involving a stringent protease pretreatment which markedly enhanced Reelin-immunoreactivity and allowed specific detection of variable shapes of murine anti-amyloid-beta protein precursor-immunoreactivity in plaques in the hippocampus, likely representing N-terminal fragments and amyloid-beta species. Ultrastructural investigations confirmed the presence of Reelin in extracellular space, somata of interneurons in young and aged wild-type mice. In aged mice, Reelin- and amyloid-beta-immunoreactivity was detected in extracellular, spherical deposits, likely representing small intermediates or fragments of amyloid fibrils. Our results suggest that Reelin itself aggregates into abnormal oligomeric or protofibrillary deposits during aging, potentially creating a precursor condition for fibrillary amyloid-beta plaque formation

Addressing the design-implementation gap of sustainable business models by prototyping: A tool for planning and executing small-scale pilots

Next to the redesign of industrial products and processes, sustainable business model innovation is a strategic approach to integrate environmental and social concerns into the objectives and operations of organizations. One of the major challenges of this approach is that many promising business model ideas fail to reach the market, which is needed to achieve impact. In the literature, the issue is referred to as a design-implementation gap. This paper explores how that critical gap may be bridged. In doing so, we contribute to sustainable business model innovation theory and practice. We contribute to theory by connecting sustainable business model innovation with business experimentation and strategic design, two innovation approaches that leverage prototyping as a way to iteratively implement business ideas early on. Using a design science research methodology, we combine theoretical insights from these three literatures into a tool for setting up small-scale pilots of sustainable business models. We apply, evaluate, and improve our tool through a rigorous process by working with nine startups and one multinational company. As a result, we provide normative theory in terms of the sustainable business model innovation process, explaining that piloting a prototype forces organizations to simultaneously consider the desirability (i.e., what users want), feasibility (i.e., what is technically achievable), viability (i.e., what is financially possible), and sustainability (i.e., what is economically, socially and environmentally acceptable) of a new business model. Doing so early on is functional to bridge the design-implementation gap of sustainable business models. We contribute to practice with the tool itself, which organizations can use to translate sustainable business model ideas defined on paper into small-scale pilots as a first implementation step. We encourage future research building on the limitations of this exploratory study by working with a larg

Visualization and quantification of APP intracellular domain-mediated nuclear signaling by bimolecular fluorescence complementation

BACKGROUND: The amyloid precursor protein (APP) intracellular domain (AICD) is released from full-length APP upon sequential cleavage by either α- or β-secretase followed by γ-secretase. Together with the adaptor protein Fe65 and the histone acetyltransferase Tip60, AICD forms nuclear multiprotein complexes (AFT complexes) that function in transcriptional regulation. OBJECTIVE: To develop a medium-throughput machine-based assay for visualization and quantification of AFT complex formation in cultured cells. METHODS: We used cotransfection of bimolecular fluorescence complementation (BiFC) fusion constructs of APP and Tip60 for analysis of subcellular localization by confocal microscopy and quantification by flow cytometry (FC). RESULTS: Our novel BiFC-constructs show a nuclear localization of AFT complexes that is identical to conventional fluorescence-tagged constructs. Production of the BiFC signal is dependent on the adaptor protein Fe65 resulting in fluorescence complementation only after Fe65-mediated nuclear translocation of AICD and interaction with Tip60. We applied the AFT-BiFC system to show that the Swedish APP familial Alzheimer's disease mutation increases AFT complex formation, consistent with the notion that AICD mediated nuclear signaling mainly occurs following APP processing through the amyloidogenic β-secretase pathway. Next, we studied the impact of posttranslational modifications of AICD on AFT complex formation. Mutation of tyrosine 682 in the YENPTY motif of AICD to phenylalanine prevents phosphorylation resulting in increased nuclear AFT-BiFC signals. This is consistent with the negative impact of tyrosine phosphorylation on Fe65 binding to AICD. Finally, we studied the effect of oxidative stress. Our data shows that oxidative stress, at a level that also causes cell death, leads to a reduction in AFT-BiFC signals. CONCLUSION: We established a new method for visualization and FC quantification of the interaction between AICD, Fe65 and Tip60 in the nucleus based on BiFC. It enables flow cytometric analysis of AICD nuclear signaling and is characterized by scalability and low background fluorescence

APP Binds to the EGFR Ligands HB-EGF and EGF, Acting Synergistically with EGF to Promote ERK Signaling and Neuritogenesis

The amyloid precursor protein (APP) is a transmembrane glycoprotein central to Alzheimer's disease (AD) with functions in brain development and plasticity, including in neurogenesis and neurite outgrowth. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are well-described neurotrophic and neuromodulator EGFR ligands, both implicated in neurological disorders, including AD. Pro-HB-EGF arose as a putative novel APP interactor in a human brain cDNA library yeast two-hybrid screen. Based on their structural and functional similarities, we first aimed to verify if APP could bind to (HB-)EGF proforms. Here, we show that APP interacts with these two EGFR ligands, and further characterized the effects of APP-EGF interaction in ERK activation and neuritogenesis. Yeast co-transformation and co-immunoprecipitation assays confirmed APP interaction with HB-EGF. Co-immunoprecipitation also revealed that APP binds to cellular pro-EGF. Overexpression of HB-EGF in HeLa cells, or exposure of SH-SY5Y cells to EGF, both resulted in increased APP protein levels. EGF and APP were observed to synergistically activate the ERK pathway, crucial for neuronal differentiation. Immunofluorescence analysis of cellular neuritogenesis in APP overexpression and EGF exposure conditions confirmed a synergistic effect in promoting the number and the mean length of neurite-like processes. Synergistic ERK activation and neuritogenic effects were completely blocked by the EGFR inhibitor PD 168393, implying APP/EGF-induced activation of EGFR as part of the mechanism. This work shows novel APP protein interactors and provides a major insight into the APP/EGF-driven mechanisms underlying neurite outgrowth and neuronal differentiation, with potential relevance for AD and for adult neuroregeneration