DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response.

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation.

Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme.

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models.

Toward Complete, Candid, and Unbiased International Consensus Statements on Concussion in Sport.

Five international consensus statements on concussion in sports have been published. This commentary argues that there is a strong need for a new approach to them that foregrounds public health expertise and patient-centered guidance. Doing so will help players, parents and practitioners keep perspective about these potentially life-altering injuries especially when they recur.

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues.

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine.

Analysis of relative bacterial activity and lactate dehydrogenase gene expression of caries-associated bacteria in a site-specific natural biofilm: an ex vivo study.

Objectives: Detecting bacterial activity is considered a promising approach to monitor shifts from symbiosis to dysbiosis in oral microbiome. The present study aimed at investigating both the relative bacterial activity and the lactate dehydrogenase (ldh) gene expression of caries-associated bacteria in a site-specific natural biofilm.

Material And Methods: Sixty subjects (age, mean ± SE: 30.

High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Quantification of Glycosaminoglycans as Biomarkers of Mucopolysaccharidosis II.

We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a mouse model of mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we developed a plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to simultaneously measure heparan sulfate and dermatan sulfate derived disaccharides in tissue, cerebrospinal fluid (CSF) and individual cell populations isolated from mouse brain. The method offers ultra-high sensitivity enabling quantitation of specific GAG species in as low as 100,000 isolated neurons and a low volume of CSF.

Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys.

Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages.

Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice.

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies.

Retroperitoneal soft tissue sarcoma: low-dose neoadjuvant radiation therapy followed by surgery with or without intraoperative radiotherapy and adjuvant radiation therapy.

Background: We describe the clinical history, outcome, and toxicity of five patients with high-grade retroperitoneal soft tissue sarcoma (RSTS) who were treated with neoadjuvant low-dose radiotherapy (RT) followed by resection with or without intraoperative radiotherapy (IORT), followed by adjuvant RT. We aim to provide additional evidence for the various treatment options that exist for this rare tumor entity.

Methods: Most patients presented with mild abdominal symptoms.

Correlation between relative bacterial activity and lactate dehydrogenase gene expression of co-cultures in vitro.

Objectives: The present study aims at correlating the relative bacterial activity with the H concentration and the ldh expression of caries-associated bacteria in co-cultures.

Materials And Methods: Well plates were prepared with BHI medium and cultures of Lactobacillus paracasei and Fusobacterium nucleatum. Bacterial growth at 37 °C was measured using a microplate-photometer before and after adding sucrose to the samples.

Sex-specific differences in the occurrence of subspecies and in the oral cavity.

The periodontitis-associated species (FN) has been implicated in several extra-oral diseases, including preterm birth and colorectal cancer. Due to its genetic and phenotypic heterogeneity, FN is classified in four subspecies which may differ in their disease potential. Here we compared the prevalence of FN subspecies and the close relative (FP) via 16S rRNA gene analysis in saliva from 100 healthy individuals (60 females, and 40 males) from eleven countries spanning five continents.

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.

The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects.

is frequent among -negative isolates and in the human oral cavity, but highly virulent strains are uncommon.

is a new member of the Mitis group and is associated with infective endocarditis. Low and high virulent variants have been described. A search was made in the national reference collection of endocarditis isolates for -like strains by sequencing housekeeping genes (16S rRNA-gene, ).

Age-related changes in immune function (immune senescence) in caries and periodontal diseases: a systematic review.

Aim: To systematically review the evidence regarding immune senescence in the pathogenesis of periodontitis and dental caries.

Methods: A systematic search of electronic databases utilizing medical subject headings (MeSH terms) supplemented by screening of review articles and other relevant texts was undertaken.

Results: Seventy-three articles were included (43 for periodontitis, 30 for caries).

Trends in antibiotic use and microbial diagnostics in periodontal treatment: comparing surveys of German dentists in a ten-year period.

Objectives: The use of antibiotics and microbial tests in periodontal treatment among German dental practitioners was investigated in 2012-2013 and compared with 2002-2003 data.

Materials And Methods: One thousand four hundred representative German practitioners received a postal questionnaire requesting their prescribing habits concerning type, dose, frequency, and sequence of antibiotics adjunctive to mechanical debridement. Additionally, the use of local antimicrobials and microbial tests were recorded.

Analysis of Bacterial Activity in Sound and Cariogenic Biofilm: A Pilot in vivo Study.

Dental caries is a multifactorial disease with many associated microbial taxa, but only a few are notably contributing to acidogenicity. The ribosome number and the corresponding 16S ribosomal RNA (rRNA) concentration are considered a molecular indicator for general metabolic activity of bacteria, as they are elevated with increased anabolic and catabolic activities. We hypothesize that the activity of aciduric/acidogenic bacterial taxa, reflected by a rise in ribosomal counts, could resolve differences between plaque biofilm from sound surfaces and caries lesions.

Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430).

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays.

Customized treatment of recurrent gynaecological cancer--the need for intraoperative radiation therapy.

Objective: The objective of this retrospective study was to analyze the experience with intraoperative radiation therapy (IORT) at the present institution and to evaluate its contribution to the management of patients with recurrent gynecological cancer. Materials and

Methods: Retrospectively this study reviewed data of patients with a gynecological malignancy considered for treatment with IORT at Freiburg University Medical Center between 2005 and 2012. For this purpose, an analysis of medical records, radiation oncology records, operation reports, and follow-up data was conducted.

MRI and FDG-PET/CT imaging in gynecological malignancies: the radiation oncology perspective.

MRI and FDG-PET imaging plays an important role in diagnosis, monitoring and follow-up of gynecological cancer. The goal of this paper was to summarize data of the literature about sensitivity and specificity of MRI and FDG-PET/CT for detection of primary tumor, lymph nodes invasion and metastases in cervix and endometrial cancer and to discuss their implication for radiation treatment planning and monitoring.