Small heat shock proteins are induced during multiple sclerosis lesion development in white but not grey matter

INTRODUCTION: The important protective role of small heat-shock proteins (HSPs) in regulating cellular survival and migration, counteracting protein aggregation, preventing apoptosis, and regulating inflammation in the central nervous system is now well-recognized. Yet, their role in the neuroinflammatory disorder multiple sclerosis (MS) is largely undocumented. With the exception of alpha B-crystallin (HSPB5), little is known about the roles of small HSPs in disease. RESULTS: Here, we examined the expression of four small HSPs during lesion development in MS, focussing on their cellular distribution, and regional differences between white matter (WM) and grey matter (GM). It is well known that MS lesions in these areas differ markedly in their pathology, with substantially more intense blood-brain barrier damage, leukocyte infiltration and microglial activation typifying WM but not GM lesions. We analysed transcript levels and protein distribution profiles for HSPB1, HSPB6, HSPB8 and HSPB11 in MS lesions at different stages, comparing them with normal-appearing brain tissue from MS patients and non-neurological controls. During active stages of demyelination in WM, and especially the centre of chronic active MS lesions, we found significantly increased expression of HSPB1, HSPB6 and HSPB8, but not HSPB11. When induced, small HSPs were exclusively found in astrocytes but not in oligodendrocytes, microglia or neurons. Surprisingly, while the numbers of astrocytes displaying high expression of small HSPs were markedly increased in actively demyelinating lesions in WM, no such induction was observed in GM lesions. This difference was particularly obvious in leukocortical lesions covering both WM and GM areas. CONCLUSIONS: Since induction of small HSPs in astrocytes is apparently a secondary response to damage, their differential expression between WM and GM likely reflects differences in mediators that accompany demyelination in either WM or GM during MS. Our findings also suggest that during MS, cortical structures fail to benefit from the protective actions of small HSPs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0267-2) contains supplementary material, which is available to authorized users

Axonal abnormalities in vanishing white matter

ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. ResultsIn the corpus callosum of Eif2b5-mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5-mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5-mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention

Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer’s disease pathology

Background Alzheimer’s disease (AD) is the most common neurodegenerative disease. In addition to the occurrence of amyloid deposits and widespread tau pathology, AD is associated with a neuroinflammatory response characterized by the activation of microglia and astrocytes. Protein kinase 2 (CK2, former casein kinase II) is involved in a wide variety of cellular processes. Previous studies on CK2 in AD showed controversial results, and the involvement of CK2 in neuroinflammation in AD remains elusive. Methods In this study, we used immunohistochemical and immunofluorescent staining methods to investigate the localization of CK2 in the hippocampus and temporal cortex of patients with AD and non-demented controls. We compared protein levels with Western blotting analysis, and we investigated CK2 activity in human U373 astrocytoma cells and human primary adult astrocytes stimulated with IL-1β or TNF-α. Results We report increased levels of CK2 in the hippocampus and temporal cortex of AD patients compared to non-demented controls. Immunohistochemical analysis shows CK2 immunoreactivity in astrocytes in AD and control cases. In AD, the presence of CK2 immunoreactive astrocytes is increased. CK2 immunopositive astrocytes are associated with amyloid deposits, suggesting an involvement of CK2 in the neuroinflammatory response. In U373 cells and human primary astrocytes, the selective CK2 inhibitor CX-4945 shows a dose-dependent reduction of the IL-1β or TNF-α induced MCP-1 and IL-6 secretion. Conclusions This data suggests that CK2 in astrocytes is involved in the neuroinflammatory response in AD. The reduction in pro-inflammatory cytokine secretion by human astrocytes using the selective CK2 inhibitor CX-4945 indicates that CK2 could be a potential target to modulate neuroinflammation in AD

Lutetium-177-PSMA-I&T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting. Methods & design: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC. Trial registration: Clinicaltrials.gov identifier: NCT04443062

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer:the BULLSEYE trial

Background: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration: ClinicalTrials.gov NCT04443062. First posted: June 23, 2020

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Cholinergic imbalance in the multiple sclerosis hippocampus

Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this diseas

Optimizing the concrete load-bearing structure of high-rise buildings: Combining the ground structure method with a recursive resizing algorithm on a case study

Theshortage in housing and office spaces, combined with the desire of people tolive in densely populated cities results in a lack of space. A proposedsolution can be found in the usage of high-rise buildings. Nowadays there ismore awareness for the environment, thus this research tries to reduce theenvironmental impact of a high-rise building by optimizing the material used inload-bearing structures. This research aims to give designers and engineersmore insight into the added value of structural optimization; in particular forthe material usage in the load-bearing structure of high-rise buildings. Theresearch objective is formulated as follows: What is the optimal topology for a reinforced concrete load-bearingstructure, situated at the perimeter of a high-rise building when optimizingthe material use?  A building isclassified as high-rise building when its roof is 70 m or more above groundlevel and accommodates work and/or living space. In literature the distinctionis made between three sorts of optimization: size, shape and topologyoptimization. Topology optimization has the most freedom, therefore it is morelikely to find a novel structure which minimizes the material use as much aspossible. In specific the Ground Structure Method (GSM) is used. The initialground structure is constructed by creating members between all nodes (fullconnectivity) which are located in the design space. The cross-sectional areasof the bars are the design variables in the optimization. An option is that thevariables turn to zero, thus elements are deleted resulting in less material.The conventional GSM starts with the full connectivity as initial groundstructure, deletes elements and calculates the new load distribution until athreshold is reached. In the end the load-bearing structure will consist ofcolumns, braces and beams, which are located at the perimeter of the floorplan. Literature indicates that (high-rise) buildings which are mainly loadedby horizontal loads would be optimal if they contain arches in the load-bearingstructure, or resemble the so-called Michell truss. However, the influence ofthe vertical load is often not taken into account, therefore this isinvestigated with the help of a parametric study. To compare the results withreality, a case study (Boston &amp; Seattle, Rotterdam) is investigated.   The core of the research is the furtherdevelopment of the optimization code, based on the GSM, written by He et al.,where multiple load cases and demands for the material strengths are implemented.In contrast to deleting elements, the code uses an adaptive ‘member adding’scheme, which is firstly proposed by Gilbert and Tyas. This scheme solvesproblems faster than the conventional GSM, up to 8 times, and is able to solvelarge problems. This code is extended during this research with new functionswhich implement demands for fire, second-order, buildability, flexural bucklingand stiffness. Also it is possible to add self-weight to the optimization. Thestiffness is implemented by adding a constraint to the displacement of the topof the building, wherefore a recursive resizing algorithm is written based onthe article of Chan. Thus the extended code exists of two optimizations, firsta strength optimization and afterwards a stiffness optimization. The code iswritten in Python and for the purpose of post-processing exporting the data toExcel and Abaqus is possible.  With thehelp of the extended code, two design spaces are investigated. One design spaceis smaller, such that the computational time is low and many variations can beexamined during the parametric study on the total vertical to total horizontalload ratio (v/h-ratio). The other is based on a case study for comparison witha realistic situation. The verification of the code shows that the extrafunctions work properly for the investigated problems. If the functionsconcerning the stiffness optimization, inclusion of self-weight, fire,buildability and second-order are used, the extended code becomes unstable andthe computation time increases enormously when optimizing the case study.Therefore it is chosen not to include during obtaining the results. The resultsof the parametric study shows an expected pattern for the load-bearingstructure, for a v/h-ratio below 4. The pattern consist of arches, originatingfrom the Michell truss. The optimization of the case study, subjected to onerealistic load combination, showed no clear pattern for the load-bearingstructure. Post-processing steps, based on engineering judgement, are taken toclarify the solutions, which showed that the columns above the supports shouldbe large in comparison to the other elements and that the arches are the mostoptimal structure. Therefore an “optimized” load-bearing structure consistingof arches is proposed. The analysis of the “optimized” load-bearing structureshows us that most of the elements meet the strength requirements. To find theoptimal solution an iterative process would be needed, because increasing thecross-section of an element will decrease the stress but increase thestiffness, thus attracting more load.   Thedifference between the optimized load-bearing structure and the originalload-bearing structure of the case study is that the optimized uses archesinstead of (punched) structural walls and uses less material (±3%). From thepost-processing of the results it is concluded that increasing the strengthratio (compression to tensile) to 1.0, decreasing the total v/h-ratio orignoring the rigid-diaphragm working of the floor help clarify the results ofthe optimization.   This research extendsthe current literature with extra insights in the use of the Ground StructureMethod in an optimization code. Also, it confirms that the arches (originatingfrom Michel Truss) is an efficient manner to transfer the loads to thesupports. However, more research in the influence of the supports, the designspace and the material type on the clearness of the optimal solution is needed.  The advice for designers and engineersis to see what the possibilities are for arches to use in their load-bearingstructure, because these are efficient in transferring the loads so materialcan be saved. The current version of the code needs to be made more userfriendly, stabler and faster before it is recommended to be used by designersand engineers. The extended code is a first attempt to implement multiple rulesfrom the Eurocode in a optimization code.  Related dataset 4TU.ResearchData https://doi.org/10.4121/uuid:d5a42352-a417-4082-aa0f-87047812bfedCivil Engineering | Structural Engineering | Structural Mechanic