Moderately HRT vs. CRT for localized prostate cancer using image-guided VMAT with SIB: evaluation of acute and late toxicities

Purpose: This retrospective study aims at investigating the effects of moderately hypofractionated radiation therapy (HRT) on acute and late toxicities as well as on early biochemical control and therapeutic efficiency compared to conventional radiation therapy (CRT) in prostate cancer. Patients and methods: We analyzed 55 HRT patients irradiated with the total dose of 60 Gy in 20 fractions delivered over 4 weeks. These patients were compared to a control group of 55 patients who received CRT with a total of <78 Gy in 37–39 fractions delivered over circa 8 weeks. External beam radiation therapy (EBRT) was conducted using daily image-guided (cone beam CT) volumetric modulated arc therapy (VMAT) and a simultaneously integrated boost (SIB) for both groups to protect the rectum. Acute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v5, whereas chronic toxicities were assessed in accordance with LENT-SOMA. Patient traits were compared by implementing t‑tests and Wilcoxon–Whitney tests for continuous variables, whereas discrete characteristics were evaluated by applying two-tailed Fisher’s exact tests. In addition, we calculated average treatment effects (ATE). Thereby, propensity score matching (PSM) based on nearest-neighbor matching considering age, comorbidities, and risk stratification as covariates was applied. The statistical analysis was conducted using Stata 14.2 (StataCorp LLC, TX, USA). Results: As confirmed by the descriptive tests, the ATE revealed that the intensity and occurrence of urinary frequency (p = 0.034) and proctitis (p = 0.027) significantly decreased for the HRT group, whereas all other acute toxicities did not differ significantly between the HRT and CRT groups. For late toxicities, neither statistical tests nor ATE estimation showed significant differences. Also, no significant difference was found regarding the decrease in prostate specific antigen (PSA) after a median follow-up of 13 months (range 2–28 months), which indicates biochemical freedom from progression. Conclusion: HRT offers several medical and economic advantages and should therefore be considered as a useful alternative to CRT

Fusoselect: cell-cell fusion activity engineered by directed evolution of a retroviral glycoprotein

Membrane fusion plays a key role in many biological processes including vesicle trafficking, synaptic transmission, fertilization or cell entry of enveloped viruses. As a common feature the fusion process is mediated by distinct membrane proteins. We describe here ‘Fusoselect', a universal procedure allowing the identification and engineering of molecular determinants for cell-cell fusion-activity by directed evolution. The system couples cell-cell fusion with the release of retroviral particles, but can principally be applied to membrane proteins of non-viral origin as well. As a model system, we chose a γ-retroviral envelope protein, which naturally becomes fusion-active through proteolytic processing by the viral protease. The selection process evolved variants that, in contrast to the parental protein, mediated cell-cell fusion in absence of the viral protease. Detailed analysis of the variants revealed molecular determinants for fusion competence in the cytoplasmic tail (CT) of retroviral Env proteins and demonstrated the power of Fusoselec

Fusoselect: cell–cell fusion activity engineered by directed evolution of a retroviral glycoprotein

Membrane fusion plays a key role in many biological processes including vesicle trafficking, synaptic transmission, fertilization or cell entry of enveloped viruses. As a common feature the fusion process is mediated by distinct membrane proteins. We describe here ‘Fusoselect’, a universal procedure allowing the identification and engineering of molecular determinants for cell–cell fusion-activity by directed evolution. The system couples cell–cell fusion with the release of retroviral particles, but can principally be applied to membrane proteins of non-viral origin as well. As a model system, we chose a γ-retroviral envelope protein, which naturally becomes fusion-active through proteolytic processing by the viral protease. The selection process evolved variants that, in contrast to the parental protein, mediated cell–cell fusion in absence of the viral protease. Detailed analysis of the variants revealed molecular determinants for fusion competence in the cytoplasmic tail (CT) of retroviral Env proteins and demonstrated the power of Fusoselect

Efficiency of moderately hypofractionated radiotherapy in NSCLC cell model

BackgroundThe current standard of radiotherapy for inoperable locally advanced NSCLCs with single fraction doses of 2.0 Gy, results in poor outcomes. Several fractionation schedules have been explored that developed over the past decades to increasingly more hypofractionated treatments. Moderate hypofractionated radiotherapy, as an alternative treatment, has gained clinical importance due to shorter duration and higher patient convenience. However, clinical trials show controversial results, adding to the need for pre-clinical radiobiological studies of this schedule.MethodsWe examined in comparative analysis the efficiency of moderate hypofractionation and normofractionation in four different NSCLC cell lines and fibroblasts using several molecular-biological approaches. Cells were daily irradiated with 24x2.75 Gy (moderate hypofractionation) or with 30x2 Gy (normofractionation), imitating the clinical situation. Proliferation and growth rate via direct counting of cell numbers, MTT assay and measurements of DNA-synthesizing cells (EdU assay), DNA repair efficiency via immunocytochemical staining of residual γH2AX/53BP1 foci and cell surviving via clonogenic assay (CSA) were experimentally evaluated.ResultsOverall, the four tumor cell lines and fibroblasts showed different sensitivity to both radiation regimes, indicating cell specificity of the effect. The absolute cell numbers and the CSA revealed significant differences between schedules (P &lt; 0.0001 for all employed cell lines and both assays) with a stronger effect of moderate hypofractionation.ConclusionOur results provide evidence for the similar effectiveness and toxicity of both regimes, with some favorable evidence towards a moderate hypofractionation. This indicates that increasing the dose per fraction may improve patient survival and therapy outcomes

Integration fluktuierender erneuerbarer Energien durch konvergente Nutzung von Strom- und Gasnetzen - Konvergenz Strom- und Gasnetze (KonStGas) - Abschlussbericht

Für die Energiewende in Deutschland ist zeitnah ein nennenswerter Ausbau der Stromnetze auf Transport- und Verteilnetzebene erforderlich. Mittel- bis langfristig werden für die Umstellung der Strom- und Energieversorgung auf erneuerbaren Energien (EE) zusätzlich große Speicherkapazitäten benötigt. Dabei sind kostengünstige und mit minimalen Energieverlusten verbundene Speicher- und Erzeugungstechnologien anzustreben. Lösungsansätze dafür werden bisher überwiegend auf der Stromseite diskutiert. Chancen, die sich aus der Kopplung von Strom- und Gasnetzen ergeben, werden kaum wahrgenommen. Das erhebliche Lösungspotential der vorhandenen Gasinfrastruktur und -Anwendungstechnologien mittels Power-to-Gas sowie die damit verbundenen Auswirkungen auf eine nachhaltige Gestaltung der Energiewende finden zu wenig Beachtung. Vor diesem Hintergrund hatte das Forschungsvorhaben "Integration fluktuierender erneuerbarer Energien durch konvergente Nutzung von Strom und Gasnetzen - Konvergenz Strom- und Gasnetze" zum Ziel, unter Berücksichtigung der Kopplung von Strom- und Gasnetzen, (1) die Potenziale zur Aufnahme, Speicherung und Verteilung von EE zu bestimmen, (2) die dynamischen Energieströme aus Angebot und Nachfrage in der gesamten Energieversorgungsstruktur zu modellieren, (3) die Kopplung volkswirtschaftlich zu analysieren und (4) Handlungsempfehlungen für den Ausbau der Netzinfrastrukturen und die Entwicklung eines zukünftigen Energiemarktes abzuleiten

Galactic Core-Collapse Supernovae at IceCube: “Fire Drill” Data Challenges and follow-up

The next Galactic core-collapse supernova (CCSN) presents a once-in-a-lifetime opportunity to make astrophysical measurements using neutrinos, gravitational waves, and electromagnetic radiation. CCSNe local to the Milky Way are extremely rare, so it is paramount that detectors are prepared to observe the signal when it arrives. The IceCube Neutrino Observatory, a gigaton water Cherenkov detector below the South Pole, is sensitive to the burst of neutrinos released by a Galactic CCSN at a level >10σ. This burst of neutrinos precedes optical emission by hours to days, enabling neutrinos to serve as an early warning for follow-up observation. IceCube\u27s detection capabilities make it a cornerstone of the global network of neutrino detectors monitoring for Galactic CCSNe, the SuperNova Early Warning System (SNEWS 2.0). In this contribution, we describe IceCube\u27s sensitivity to Galactic CCSNe and strategies for operational readiness, including "fire drill" data challenges. We also discuss coordination with SNEWS 2.0