Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer’s disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico, in vitro, and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics

Iron in a Cage: Fixation of a Fe(II)tpy2_{2} Complex by Fourfold Interlinking

The coordination sphere of the Fe(II) terpyridine complex 1 is rigidified by fourfold interlinking of both terpyridine ligands. Profiting from an octa‐aldehyde precursor complex, the ideal dimensions of the interlinking structures are determined by reversible Schiff‐base formation, before irreversible Wittig olefination provided the rigidified complex. Reversed‐phase HPLC enables the isolation of the all‐trans isomer of the Fe(II) terpyridine complex 1, which is fully characterized. While temperature independent low‐spin states were recorded with superconducting quantum interference device (SQUID) measurements for both, the open precursor 8 and the interlinked complex 1, evidence of the increased rigidity of the ligand sphere in 1 was provided by proton T$_{2}$ relaxation NMR experiments. The ligand sphere fixation in the macrocyclized complex 1 even reaches a level resisting substantial deformation upon deposition on an Au(111) surface, as demonstrated by its pristine form in a low temperature ultra‐high vacuum scanning tunneling microscope experiment

Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma

Small non-coding RNAs, in particular microRNAs(miRNAs), regulate fine-tuning of gene expression and can act as oncogenes or tumor suppressor genes. Differential miRNA expression has been reported to be of functional relevance for tumor biology. Using next-generation sequencing, the unbiased and absolute quantification of the small RNA transcriptome is now feasible. Neuroblastoma(NB) is an embryonal tumor with highly variable clinical course. We analyzed the small RNA transcriptomes of five favorable and five unfavorable NBs using SOLiD next-generation sequencing, generating a total of >188 000 000 reads. MiRNA expression profiles obtained by deep sequencing correlated well with real-time PCR data. Cluster analysis differentiated between favorable and unfavorable NBs, and the miRNA transcriptomes of these two groups were significantly different. Oncogenic miRNAs of the miR17-92 cluster and the miR-181 family were overexpressed in unfavorable NBs. In contrast, the putative tumor suppressive microRNAs, miR-542-5p and miR-628, were expressed in favorable NBs and virtually absent in unfavorable NBs. In-depth sequence analysis revealed extensive post-transcriptional miRNA editing. Of 13 identified novel miRNAs, three were further analyzed, and expression could be confirmed in a cohort of 70 NBs

RNA Sequencing of Collecting Duct Renal Cell Carcinoma Suggests an Interaction between miRNA and Target Genes and a Predominance of Deregulated Solute Carrier Genes

Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight normal tissues of renal cell carcinoma patients. At a threshold of |log2fold-change| ≥1, 3349 genes were upregulated and 1947 genes were downregulated in CDCs compared to the normal samples. Pathway analysis of the deregulated genes revealed that cancer pathways and cell cycle pathways were most prominent in CDCs. The most upregulated gene was keratin 17, and the most downregulated gene was cubilin. Among the most downregulated genes were four solute carrier genes (SLC3A1, SLC9A3, SLC26A7, and SLC47A1). The strongest negative correlations between miRNAs and mRNAs were found between the downregulated miR-374b-5p and its upregulated target genes HIST1H3B, HK2, and SLC7A11 and between upregulated miR-26b-5p and its downregulated target genes PPARGC1A, ALDH6A1, and MARC2. An upregulation of HK2 and a downregulation of PPARGC1A, ALDH6A1, and MARC2 were observed at the protein level. Survival analysis of the cancer genome atlas (TCGA) dataset showed for the first time that low gene expression of MARC2, cubilin, and SLC47A1 and high gene expression of KRT17 are associated with poor overall survival in clear cell renal cell carcinoma patients. Altogether, we identified dysregulated protein-coding genes, potential miRNA-target interactions, and prognostic markers that could be associated with CDC

Fabrication, workflow and delivery of reconstruction: Summary and consensus statements of group 4. The 6th EAO Consensus Conference 2021.

Objectives: To report assessments of four systematic reviews (SRs) on (i) clinical outcomes of all-ceramic implant-supported crowns (iSCs), (ii) production time, effectiveness, and costs of computer-assisted manufacturing (CAM), (iii) computer-assisted implant planning and surgery (CAIPS) time and costs, and (iv) patient-reported outcome measures (PROMS). Material and methods: An author group consisting of experienced clinicians and content experts discussed and evaluated the SRs and formulated consensus on the main findings, statements, clinical recommendations, and need for future research. Results: All four SRs were conducted and reported according to PRISMA and detailed comprehensive search strategies in at least three bibliometric databases and hand searching. The search strategies were deemed reproducible. Variation was noted regarding language restrictions and inclusion of grey literature, but the search comprehensiveness appeared persuasive. The SRs included bias risk assessments of the primary studies, and their study methodology impacted the interpretations of the extracted data. Conclusions: (i) There is limited evidence (49 NRCT) showing that veneered and monolithic all-ceramic iSCs have excellent outcomes observed up to 3 years. (ii) There is no evidence evaluating production time and effectiveness comparing subtractive and additive CAM of implant models, abutments and crowns. (iii) There is limited evidence (4 RCT) that CAIPS involves more time and costs when considering the entire workflow and for diagnostics, manufacturing, and insertion of the restoration. Time seems to be the decisive factor for higher costs. (iv) Patients' comfort increases when optical compared to conventional impressions are used for fabricating iSCs and short-span FPDs (2 RCT, 5 NRCT)

a clinical study protocol

Introduction The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, ‘small molecule’-mediated Rho inhibition after acute SCI warrants clinical investigation. Methods and analysis Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. Ethics and dissemination The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. Trial registration number NCT02096913; Pre-results

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (Ntotal = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families

The LabTogo-Project

A joint project between West African Science Service Center on Climate Change and Adapted Land Use (WASCAL), the University of Lomé and the German Biomass Research Center (Deutsches Biomasseforschungszentrum; DBFZ) was initiated in 2020. The project aims at evaluating alternative and regenerative energy sources for rural areas and creating the basis for successful implementation. In three different work packages, therefore, biomass potentials should be quantified, technologies should be examined with regard to their suitability and - in the case of biogas application - a research structure, pilot biogas laboratory, should be created that is necessary to enable the sustainable implementation of technologies

Immediate versus postponed intervention for infected necrotizing pancreatitis

BACKGROUND Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, −1; 95% confidence interval [CI], −12 to 10; P=0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions