Innate immune receptor NOD2 mediates LGR5+ intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation

International audienceThe nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist muramyl dipeptide (MDP), a peptidoglycan motif common to all bacteria, supports leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)+ intestinal stem cell (ISC) survival through NOD2 activation upon an otherwise lethal oxidative stress-mediated signal. However, the underlying protective mechanisms remain unknown. Here, using irradiation as stressor and primarily murine-derived intestinal organoids as a model system, we show that MDP induced a significant reduction of total and mitochondrial reactive oxygen species (ROS) within ISCs, which was associated with mitophagy induction. ATG16L1 knockout (KO) and NOD2 KO organoids did not benefit from the MDP-induced cytoprotection. We confirmed the MDP-dependent induction of ISC mitophagy upon stress in vivo. These findings elucidate the NOD2-mediated mechanism of cytoprotection involving the clearance of the lethal excess of ROS molecules through mitophagy, triggered by the coordinated activation of NOD2 and ATG16L1 by a nuclear factor κB (NF-κB)-independent pathway

The Current Role of Whole Brain Radiation Therapy in Non–Small Cell Lung Cancer Patients

The incidence of brain metastases has increased in patients with NSCLC as a result of better systemic disease control and advances in imaging modalities. Whole brain radiotherapy (WBRT) has been the mainstay treatment of multiple symptomatic brain metastases for years. A number of recent publications have questioned its place in the absence of a survival and quality of life benefit and the possible risk for long-term neurotoxicity. Omission or deferral of WBRT and strategies consisting of stereotactic radiosurgery or delivery of systemic therapies alone are being proposed more and more. However, critical analysis of the literature shows that WBRT still has relevant indications in well-selected patients. Within this review, we discuss the place of WBRT in the modern management of patients with NSCLC. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.</p

Brain Radiation Necrosis: Current Management With a Focus on Non-small Cell Lung Cancer Patients

As the prognosis of metastatic non-small cell lung cancer (NSCLC) patients is constantly improving with advances in systemic therapies (immune checkpoint blockers and new generation of targeted molecular compounds), more attention should be paid to the diagnosis and management of treatments-related long-term secondary effects. Brain metastases (BM) occur frequently in the natural history of NSCLC and stereotactic radiation therapy (SRT) is one of the main efficient local non-invasive therapeutic methods. However, SRT may have some disabling side effects. Brain radiation necrosis (RN) represents one of the main limiting toxicities, generally occurring from 6 months to several years after treatment. The diagnosis of RN itself may be quite challenging, as conventional imaging is frequently not able to differentiate RN from BM recurrence. Retrospective studies have suggested increased incidence rates of RN in NSCLC patients with oncogenic driver mutations [epidermal growth factor receptor (EGFR) mutated or anaplastic lymphoma kinase (ALK) positive] or receiving tyrosine kinase inhibitors. The risk of immune checkpoint inhibitors in contributing to RN remains controversial. Treatment modalities for RN have not been prospectively compared. Those include surveillance, corticosteroids, bevacizumab and local interventions (minimally invasive laser interstitial thermal ablation or surgery). The aim of this review is to describe and discuss possible RN management options in the light of the newly available literature, with a particular focus on NSCLC patients

Black hole lasers, a mode analysis

We show that the black hole laser effect discovered by Corley & Jacobson should be described in terms of frequency eigenmodes that are spatially bound. The spectrum contains a discrete and finite set of complex frequency modes which appear in pairs and which encode the laser effect. In addition, it contains real frequency modes that form a continuous set when space is infinite, and which are only elastically scattered, i.e., not subject to any Bogoliubov transformation. The quantization is straightforward, but the calculation of the asymptotic fluxes is rather involved. When the number of complex frequency modes is small, our expressions differ from those given earlier. In particular, when the region between the horizons shrinks, there is a minimal distance under which no complex frequency mode exists, and no radiation is emitted. Finally, we relate this effect to other dynamical instabilities found for rotating black holes and in electric fields, and we give the conditions to get this type of instability.Comment: 19 pages, 3 figures, main changes: new figure and new Sec.6 `conditions for having a laser effect', final version accepted in PR

Higher Toxicity with 42 Gy in 10 Fractions as a Total Dose for 3D-Conformal Accelerated Partial Breast Irradiation: Results from a Dose Escalation Phase II Trial

Objective: Recent recommendations regarding indications of accelerated partial breast irradiation (APBI) have been put forward for selected breast cancer (BC) patients. However, some treatment planning parameters, such as total dose, are not yet well defined. The Institut Gustave Roussy has initiated a dose escalation trial at the 40 Gy/10 fractions/5 days and at a further step of total dose (TD) of 42 Gy/10 fractions/5 days. Here, we report early results of the latest step compared with the 40 Gy dose level. Methods and materials: From October 2007 to March 2010, a total of 48 pT1N0 BC patients were enrolled within this clinical trial: 17 patients at a TD of 42 Gy/10f/5d and 31 at a TD of 40 Gy/10f/5d. Median follow-up was 19 months (min-max, 12–26). All the patients were treated by APBI using a technique with 2 minitangents and an “enface” electrons delivering 20% of the total dose. Toxicities were systematically assessed at 1; 2; 6 months and then every 6 months. Results: Patients’ recruitment of 42 Gy step was ended owing to persistent grade 3 toxicity 6 months after APBI completion (n = 1). Early toxicities were statistically higher after a total dose of 42 Gy regarding grade ≥2 dry (p = 0.01) and moist (p = 0.05) skin desquamation. Breast pain was also statistically higher in the 42 Gy step compared to 40 Gy step (p = 0.02). Other late toxicities (grade ≥2 fibrosis and telangectasia) were not statistically different between 42 Gy and 40 Gy. Conclusions: Early toxicities were more severe and higher rates of late toxicities were observed after 42 Gy/10 fractions/5 days when compared to 40 Gy/10 fractions/5 days. This data suggest that 40 Gy/10 fractions/5 days could potentially be the maximum tolerance for PBI although longer follow-up is warranted to better assess late toxicities

Current management of limited-stage SCLC and CONVERT trial impact:Results of the EORTC Lung Cancer Group survey

Objectives: The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue tobe considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of theCONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting.Methods and materials: An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCGand to members of several European thoracic oncology societies between April and December 2018.Results: 198 responses were analysed. The majority of respondents (88%, n=174) were aware of the CONVERTtrial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the mostcommonly used regimen, however the use of concurrent BD radiotherapy increased after the publication ofCONVERT (n=59/186, 32% prior to and n=78/187, 42% after the publication, p=0.053). The main reasonsfor not implementing BD after the CONVERT publication were logistical issues (n=88, 44%), inconvenience forpatients (n=56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT(n=38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did notroutinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integratingnovel targeted therapies-immunotherapies (n=160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRIsurveillance (n=140, 71%) and, 3) biomarker driven trials (n=92, 46%).Conclusion: Once daily radiotherapy (60–66 Gy in 30–33 fractions) remains the most prescribed radiotherapyfractionation, despite the findings suggested by the CONVERT trial.info:eu-repo/semantics/publishe

The Johnsonian September 17, 1943

The Johnsonian is the weekly student newspaper of Winthrop University. It is published during fall and spring semesters with the exception of university holidays and exam periods. We have proudly served the Winthrop and Rock Hill community since 1923.https://digitalcommons.winthrop.edu/thejohnsonian1940s/1067/thumbnail.jp

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first‑line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment