The future is now: Model-based clinical trial design for Alzheimer's disease

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease.1 CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)

Multimodal Imaging Nanoparticles Derived from Hyaluronic Acid for Integrated Preoperative and Intraoperative Cancer Imaging

Surgical resection remains the most promising treatment strategy for many types of cancer. Residual malignant tissue after surgery, a consequence in part due to positive margins, contributes to high mortality and disease recurrence. In this study, multimodal contrast agents for integrated preoperative magnetic resonance imaging (MRI) and intraoperative fluorescence image-guided surgery (FIGS) are developed. Self-assembled multimodal imaging nanoparticles (SAMINs) were developed as a mixed micelle formulation using amphiphilic HA polymers functionalized with either GdDTPA for T1 contrast-enhanced MRI or Cy7.5, a near infrared fluorophore. To evaluate the relationship between MR and fluorescence signal from SAMINs, we employed simulated surgical phantoms that are routinely used to evaluate the depth at which near infrared (NIR) imaging agents can be detected by FIGS. Finally, imaging agent efficacy was evaluated in a human breast tumor xenograft model in nude mice, which demonstrated contrast in both fluorescence and magnetic resonance imaging

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

Near Infrared Fluorescent Nanoparticles Derived from Hyaluronic Acid Improve Tumor Contrast for Image-Guided Surgery.

Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or covalently conjugated Cy7.5. Using orthotopic human breast cancer MDA-MB-231 xenografts in nude mice we identified two lead formulations. One, NanoICGPBA, with physicochemically entrapped ICG, showed 2.3-fold greater tumor contrast than ICG alone at 24 h (p \u3c 0.01), and another, NanoCy7.5100-H, with covalently conjugated Cy7.5, showed 74-fold greater tumor contrast than Cy7.5 alone at 24 h (p \u3c 0.0001). These two lead formulations were then tested in immune competent BALB/c mice bearing orthotopic 4T1 breast cancer tumors. NanoICGPBA showed 2.2-fold greater contrast than ICG alone (p \u3c 0.0001), and NanoCy7.5100-H showed 14.8-fold greater contrast than Cy7.5 alone (p \u3c 0.0001). Furthermore, both NanoICGPBA and NanoCy7.5100-H provided strong tumor enhancement using image-guided surgery in mice bearing 4T1 tumors. These studies demonstrate the efficacy of a panel of HA-derived NPs in delineating tumors in vivo, and identifies promising formulations that can be used for future in vivo tumor removal efficacy studies

Small-scale, homelike facilities versus regular psychogeriatric nursing home wards: a cross-sectional study into residents' characteristics

<p>Abstract</p> <p>Background</p> <p>Nursing home care for people with dementia is increasingly organized in small-scale and homelike care settings, in which normal daily life is emphasized. Despite this increase, relatively little is known about residents' characteristics and whether these differ from residents in traditional nursing homes. This study explored and compared characteristics of residents with dementia living in small-scale, homelike facilities and regular psychogeriatric wards in nursing homes, focusing on functional status and cognition.</p> <p>Methods</p> <p>A cross-sectional study was conducted, including 769 residents with dementia requiring an intensive level of nursing home care: 586 from regular psychogeriatric wards and 183 residents from small-scale living facilities. Functional status and cognition were assessed using two subscales from the Resident Assessment Instrument Minimum Data Set (RAI-MDS): the Activities of Daily Living-Hierarchy scale (ADL-H) and the Cognitive Performance Scale (CPS). In addition, care dependency was measured using Dutch Care Severity Packages (DCSP). Finally, gender, age, living condition prior to admission and length of stay were recorded. Descriptive analyses, including independent samples t- tests and chi-square tests, were used. To analyze data in more detail, multivariate logistic regression analyses were performed.</p> <p>Results</p> <p>Residents living in small-scale, homelike facilities had a significantly higher functional status and cognitive performance compared with residents in regular psychogeriatric wards. In addition, they had a shorter length of stay, were less frequently admitted from home and were more often female than residents in regular wards. No differences were found in age and care dependency. While controlling for demographic variables, the association between dementia care setting and functional status and cognition remained.</p> <p>Conclusions</p> <p>Although residents require a similar intensive level of nursing home care, their characteristics differ among small-scale living facilities and regular psychogeriatric wards. These differences may limit research into effects and feasibility of various types of dementia care settings. Therefore, these studies should take resident characteristics into account in their design, for example by using a matching procedure.</p

The Beta-decay Paul Trap Mk IV: Design and commissioning

The Beta-decay Paul Trap is an open-geometry, linear trap used to measure the decays of $^8$Li and $^8$B to search for a tensor contribution to the weak interaction. In the latest $^8$Li measurement of Burkey et al. (2022), $\beta$ scattering was the dominant experimental systematic uncertainty. The Beta-decay Paul Trap Mk IV reduces the prevalence of $\beta$ scattering by a factor of 4 through a redesigned electrode geometry and the use of glassy carbon and graphite as electrode materials. The trap has been constructed and successfully commissioned with $^8$Li in a new data campaign that collected 2.6 million triple coincidence events, an increase in statistics by 30% with 4 times less $\beta$ scattering compared to the previous $^8$Li data set.Comment: 17 pages, 7 figure

Biodegradable core crosslinked star polymer nanoparticles as 19F MRI contrast agents for selective imaging

With the aim of developing stimuli-responsive imaging agents, we report here the synthesis of core crosslinked star (CCS) polymers and their evaluation as pH-sensitive 19F magnetic resonance imaging (19F MRI) contrast agents. Block copolymers consisting of poly(ethylene glycol)methyl ether methacrylate (PPEGMA) as the first block and a copolymer of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,2-trifluoroethyl methacrylate (TFEMA) as the second block were synthesised using RAFT polymerisation. The polymerisation kinetics were studied in detail. The block copolymers were then used as arm precursors for the arm-first synthesis of CCS polymers through RAFT dispersion polymerisation. The synthetic conditions were investigated and optimised. CCS polymers with a degradable core were also synthesised and evaluated as 19F MRI contrast agents. The degradation of the core was confirmed by treatment with various reducing agents. The particle size, 19F NMR signal and relaxation times as well as 19F MRI imaging performance of the CCS polymers were studied at a range of value of solution pH. Significant enhancement of the image intensity was observed when the pH was decreased from 8 to 5, indicating that the CCS nanoparticles could be used as 19F MRI contrast agents for the detection of the acidic environment within tumour tissue