Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.</p

Functional and neurochemical contribution of the medial prefrontal-thalamus-hippocampus network in episodic memory

Contains fulltext : 201138.pdf (publisher's version ) (Open Access)The present work addressed the contribution of the mPFC-thalamus-hippocampus network in episodic memory and functional as well neurochemical alterations due to disease and aging. We show that the thalamus mediates between the hippocampus and mPFC when human memorize and remember episodic memory content and that these processes are related to changes in neurotransmitter concentration. Regarding aging, we showed that aerobic activity in the healthy elderly is associated with lower systemic inflammation which was associated with increased “communication” within the mPFC-thalamus-hippocampus network during learning of episodic memory content. Moreover, elderly that suffer from type 2 diabetes have increased inhibitory neurotransmitter concentration within the mPFC-thalamus-hippocampus network that was associated with decreased episodic memory performance. Together, we revealed new evidence regarding the function of the mPFC-thalamus-hippocampus network in episodic memory and determine functional as well neurochemical modifications due to aging and disease.Radboud University, 28 februari 2019Promotores : Tendolkar, I., Norris, D.G.148 p

Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice

Contains fulltext : 155182.pdf (publisher's version ) (Open Access)INTRODUCTION: Systemic lupus erythematosus is associated with a persistent circulation of modified autoantigen-containing apoptotic debris that might be capable of breaking tolerance. We aimed to evaluate apoptotic microvesicles obtained from lupus or control mice for the presence of apoptosis-associated chromatin modifications and for their capacity to stimulate dendritic cells (DC) from lupus and control mice. METHOD: Apoptotic microvesicles were in vitro generated from splenocytes, and ex vivo isolated from plasma of both MRL/lpr lupus mice and normal BALB/c mice. Microvesicles were analyzed using flow cytometry. Bone marrow-derived (BM)-DC cultured from MRL/lpr or BALB/c mice were incubated with microvesicles and CD40 expression and cytokine production were determined as measure of activation. RESULTS: Microvesicles derived from apoptotic splenocytes or plasma of MRL/lpr mice contained more modified chromatin compared to microvesicles of BALB/c mice, and showed enhanced activation of DC, either from MRL/lpr or BALB/c mice, and consecutively an enhanced DC-mediated activation of splenocytes. The content of apoptosis-modified chromatin in microvesicles of apoptotic splenocytes correlated with their potency to induce interleukin-6 (IL-6) production by DC. Microvesicle-activated MRL/lpr DC showed a significant higher production of IL-6 and tumor growth factor-beta (TGF-beta) compared to BALB/c DC, and were more potent in the activation of splenocytes. CONCLUSION: Apoptotic microvesicles from MRL/lpr mice are more potent activators of DC, and DC from MRL/lpr mice appear relatively more sensitive to activation by apoptotic microvesicles. Our findings indicate that aberrations at the level of apoptotic microvesicles and possibly DC contribute to the autoimmune response against chromatin in MRL/lpr mice

Transient relay function of midline thalamic nuclei during long-term memory consolidation in humans

Contains fulltext : 154335.pdf (Publisher’s version ) (Open Access)To test the hypothesis that thalamic midline nuclei play a transient role in memory consolidation, we reanalyzed a prospective functional MRI study, contrasting recent and progressively more remote memory retrieval. We revealed a transient thalamic connectivity increase with the hippocampus, the medial prefrontal cortex (mPFC), and a parahippocampal area, which decreased with time. In turn, mPFC-parahippocampal connectivity increased progressively. These findings support a model in which thalamic midline nuclei serve as a hub linking hippocampus, mPFC, and posterior representational areas during memory retrieval at an early (2 h) stage of consolidation, extending classical systems consolidation models by attributing a transient role to midline thalamic nuclei.5 p

A comparison of sLASER and MEGA-sLASER using simultaneous interleaved acquisition for measuring GABA in the human brain at 7T

Contains fulltext : 215671.pdf (publisher's version ) (Open Access

Implications of the magnetic susceptibility difference between grey and white matter for single-voxel proton spectroscopy at 7 T

Contains fulltext : 199479.pdf (publisher's version ) (Closed access

Effect of linewidth on estimation of metabolic concentration when using water lineshape spectral model fitting for single voxel proton spectroscopy at 7 T

Contains fulltext : 204427.pdf (publisher's version ) (Closed access)9 p

Determination of Genes Involved in Hygienic Behavior in the Honey Bee, Apis mellifera

Honeybees are an integral part of the agricultural industry, especially in the Midwestern United States. Honeybees serve as pollinators of crops, an invaluable job of honeybees, as well as producers of honey. Diseases that kill members of the colony threaten honeybee colonies, and there are few options available to treat these diseases. Some honeybees exhibit a behavior—termed hygienic behavior—in which the bees clean out diseased brood from the hive, thus conferring a natural resistance to three diseases of bees: American foulbrood, chalkbrood, and varroa mite. However, it is not found in all colonies and only a certain number of honeybees contain this behavior in a given colony. This desirable behavior can be traced to genetics—meaning hygienic honeybees exhibit this behavior partly due to information they carry in their DNA (genetic material). We have undertaken a large genetic screen in cooperation with Dr. Marla Spivak of the Entomology department at the University of Minnesota. We have identified differences between genes in brains from hygienic honeybees vs. non-hygienic honeybees using a technique called microarray, and are now validating these differences using a secondary biochemical technique. Identifying specific genes that allow these bees to protect their colonies is a critical step towards implementing this behavior in unprotected honeybee colonies