Bacterial-Infection-Triggered Release of Antibacterial Aldehyde from Triblock Copolyether Hydrogels.

Bacterial infections pose a significant threat to public health worldwide. Hydrogel-based biomaterials have proven to be particularly useful in addressing persistent bacterial infections due to their stimuli-responsive degradability, high biocompatibility, ability to release antibacterial agents on demand, and long-lasting antibacterial activity. Herein, we fabricated ABA-type triblock copolyether hydrogels, wherein, hexanal, a bioactive aldehyde with antibacterial activity, was affixed to the hydrophobic micellar core via acetal linkage. The hydrogel exhibited degradation under acidic environment via the hydrolysis of acetal linkages, leading to the concomitant release of hexanal to exhibit highly potent bactericidal activity against both Escherichia coli and Staphylococcus aureus. Furthermore, a dual-mode release of the model therapeutic agent Nile Red from the hydrophobic micellar core of the hydrogel in conjunction with hexanal was demonstrated using this system. We anticipate that this study will provide a new platform for the development of hydrogels with tailorable release profiles for biologically active compounds that are activated by the acidification triggered by bacterial infection.

2023 White Paper on Recent Issues in Bioanalysis: Deuterated Drugs; LNP; Tumor/FFPE Biopsy; Targeted Proteomics; Small Molecule Covalent Inhibitors; Chiral Bioanalysis; Remote Regulatory Assessments; Sample Reconciliation/Chain of Custody (PART 1A - Recommendations on Mass Spectrometry, Chromatography, Sample Preparation Latest Developments, Challenges, and Solutions and BMV/Regulated Bioanalysis PART 1B - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/IVD/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with this NEW Regulation" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication covers the recommendations on Mass Spectrometry Assays, Regulated Bioanalysis/BMV (Part 1A) and Regulatory Inputs (Part 1B). Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 7 and 8 (2024), respectively.

2022 White Paper on Recent Issues in Bioanalysis: ICH M10 BMV Guideline & Global Harmonization; Hybrid Assays; Oligonucleotides & ADC; Non-Liquid & Rare Matrices; Regulatory Inputs (Part 1A - Recommendations on Mass Spectrometry, Chromatography and Sample Preparation, Novel Technologies, Novel Modalities, and Novel Challenges, ICH M10 BMV Guideline & Global Harmonization Part 1B - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 16th Workshop on Recent Issues in Bioanalysis (16th WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on the ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1A) covers the recommendations on Mass Spectrometry and ICH M10. Part 1B covers the Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine. Part 2 (LBA, Biomarkers/CDx and Cytometry) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 15 of Bioanalysis, issues 15 and 14 (2023), respectively.

Potential lifetime effects caused by cellular uptake of nanoplastics: A review.

Plastics have been used for about 100 years, and daily-use products composed of plastics are now prevalent. As a result, humans are very easily exposed to the plastic particles generated from the daily-use plastics. However, studies on cellular uptake of nanoplastics in "human cells" have only recently begun to attract attention. In previous studies, definitions of nanoplastics and microplastics were vague, but recently, they have been considered to be different and are being studied separately. However, nanoplastics, unlike plastic particles of other sizes such as macro- and microplastics, can be absorbed by human cells, and thus can cause various risks such as cytotoxicity, inflammation, oxidative stress, and even diseases such as cancer82, 83. and diabetes (Fan et al., 2022; Wang et al., 2023). Thus, in this review, we defined microplastics and nanoplastics to be different and described the potential risks of nanoplastics to human caused by cellular uptake according to their diverse factors. In addition, during and following plastic product usage a substantial number of fragments of different sizes can be generated, including nanoplastics. Fragmentation of microplastics into nanoplastics may also occur during ingestion and inhalation, which can potentially cause long-term hazards to human health. However, there are still few in vivo studies conducted on the health effect of nanoplastics ingestion and inhalation.

Tackling Challenging Data Integrity Topics in 2020: Update on Good Clinical Practice Perspectives from the US FDA and MHRA UK.

With the globalization of clinical trials, regulators have increased collaboration to evaluate the adequacy of clinical trial conduct and to optimize regulatory oversight. The 2020 joint Good Clinical Practice (GCP) symposium of the US Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency provided the agencies' perspectives on the challenges in ensuring data quality in novel clinical trial designs and the importance of the management and documentation of protocol deviations, sponsor oversight of clinical trials, and use of electronic source data, including electronic health records. This paper summarizes considerations of both agencies on these topics, along with case examples. This paper touches upon considerations when using real-world data to support regulatory decisions. It also discusses the impact of the coronavirus disease 2019 (COVID-19) pandemic on clinical trial conduct and underscores the importance of well-designed, resilient, and adaptable systems for GCP compliance and data integrity.

A TrkB Antibody Agonist Promotes Plasticity after Cervical Spinal Cord Injury in Adult Rats.

After spinal cord injury (SCI) in mammals, there is only limited repair and, consequently, only moderate recovery. One mechanism frequently discussed to be involved in this recovery is plasticity (i.e., adaptations in spared neuronal circuitries). In the current study, we tested the effect of an intrathecal application of the TrkB agonist antibody, 29D7, on plasticity after cervical SCI in adult rats. Treatment with 29D7 for 4 weeks resulted in an ∼50% increase in collateral sprouting of severed corticospinal tract fibers above the lesion compared to the control group and enhanced branching in the gray matter rostral to the injury. Growth-associated protein 43 immunoreactivity in the spinal cord rostral to the level of the injury as well as contralateral to the lesion was also increased. These indications of enhanced plasticity by 29D7 were paralleled by improved performances of the mildly affected paw, as assessed by Montoya and tray reaching tasks. The reaching behaviors of the paw ipsilateral to the side of severe injury to the cortico- and rubrospinal tract were not altered by the treatment. The present study suggests that 29D7 may be a potential candidate to promote plasticity and functional recovery, especially after moderate SCI. Future studies confirming these results, along with a potential combinatory therapy including rehabilitative training, will be needed to evaluate the clinical value of such a treatment.

Data Integrity in Global Clinical Trials: Discussions From Joint US Food and Drug Administration and UK Medicines and Healthcare Products Regulatory Agency Good Clinical Practice Workshop.

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials. Regulatory agencies conduct GCP inspections to verify the integrity of data generated in clinical trials and to assure the protection of human research subjects, in addition to ensuring that clinical trials are conducted according to the applicable regulations. The first joint GCP workshop of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA-UK) was held in October 2018 and provided the agencies' perspectives on the importance of data quality management practices on data integrity. Regulatory perspectives on data blinding to minimize introduction of bias, and the role of audit trails in assessing data integrity in global clinical trials were discussed. This paper summarizes considerations of both agencies on these topics, along with case examples.

2019 White Paper On Recent Issues in Bioanalysis: FDA BMV Guidance, ICH M10 BMV Guideline and Regulatory Inputs (Part 2 - Recommendations on 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and Regulatory Agencies' Input on Bioanalysis, Biomarkers and Immunogenicity).

The 2019 13th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1-5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of Bioanalysis, issues 22 and 24 (2019), respectively.

2018 White Paper on Recent Issues in Bioanalysis: 'A global bioanalytical community perspective on last decade of incurred samples reanalysis (ISR)' (Part 1 - small molecule regulated bioanalysis, small molecule biomarkers, peptides & oligonucleotide bioanalysis).

The 2018 12th Workshop on Recent Issues in Bioanalysis (12th WRIB) took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day full immersion in bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LC-MS, hybrid ligand binding assay (LBA)/LC-MS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for LC-MS for small molecules, peptides, oligonucleotides and small molecule biomarkers. Part 2 (hybrid LBA/LC-MS for biotherapeutics and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis, biomarkers and immunogenicity using LBA and cell-based assays) are published in volume 10 of Bioanalysis, issues 23 and 24 (2018), respectively.

2018 White Paper on Recent Issues in Bioanalysis: focus on immunogenicity assays by hybrid LBA/LCMS and regulatory feedback (Part 2 - PK, PD & ADA assays by hybrid LBA/LCMS & regulatory agencies' inputs on bioanalysis, biomarkers and immunogenicity).

The 2018 12th Workshop on Recent Issues in Bioanalysis took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for PK, PD and ADA assays by hybrid LBA/LCMS and regulatory agencies' input. Part 1 (LCMS for small molecules, peptides, oligonucleotides and small molecule biomarkers) and Part 3 (LBA/cell-based assays: immunogenicity, biomarkers and PK assays) are published in volume 10 of Bioanalysis, issues 22 and 24 (2018), respectively.

2017 White Paper: rise of hybrid LBA/LCMS immunogenicity assays (Part 2: hybrid LBA/LCMS biotherapeutics, biomarkers & immunogenicity assays and regulatory agencies' inputs).

The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California on 3-7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid ligand binding assay (LBA)/LCMS and LBA approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for biotherapeutics, biomarkers and immunogenicity assays using hybrid LBA/LCMS and regulatory agencies' inputs. Part 1 (LCMS for small molecules, peptides and small molecule biomarkers) and Part 3 (LBA: immunogenicity, biomarkers and pharmacokinetic assays) are published in Volume 9 of Bioanalysis, issues 22 and 24 (2017), respectively.

2017 White Paper on recent issues in bioanalysis: a global perspective on immunogenicity guidelines & biomarker assay performance (Part 3 - LBA: immunogenicity, biomarkers and PK assays).

The 2017 11th Workshop on Recent Issues in Bioanalysis took place in Los Angeles/Universal City, California, on 3-7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule analysis involving LC-MS, hybrid ligand-binding assay (LBA)/LC-MS and LBA approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for large-molecule bioanalysis, biomarkers and immunogenicity using LBA. Part 1 (LC-MS for small molecules, peptides and small molecule biomarkers) and Part 2 (hybrid LBA/LC-MS for biotherapeutics and regulatory agencies' inputs) are published in volume 9 of Bioanalysis, issues 22 and 23 (2017), respectively.

2017 White Paper on recent issues in bioanalysis: aren't BMV guidance/guidelines 'Scientific'? (Part 1 - LCMS: small molecules, peptides and small molecule biomarkers).

The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand-binding assay (LBA) approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for Small Molecules, Peptides and Small Molecule Biomarkers using LCMS. Part 2 (Biotherapeutics, Biomarkers and Immunogenicity Assays using Hybrid LBA/LCMS and Regulatory Agencies' Inputs) and Part 3 (LBA: Immunogenicity, Biomarkers and PK Assays) are published in volume 9 of Bioanalysis, issues 23 and 24 (2017), respectively.

A single-chip 32-channel analog beamformer with 4-ns delay resolution and 768-ns maximum delay range for ultrasound medical imaging with a linear array transducer.

A single-chip 32-channel analog beamformer is proposed. It achieves a delay resolution of 4 ns and a maximum delay range of 768 ns. It has a focal-point based architecture, which consists of 7 sub-analog beamformers (sub-ABF). Each sub-ABF performs a RX focusing operation for a single focal point. Seven sub-ABFs perform a time-interleaving operation to achieve the maximum delay range of 768 ns. Phase interpolators are used in sub-ABFs to generate sampling clocks with the delay resolution of 4 ns from a low frequency system clock of 5 MHz. Each sub-ABF samples 32 echo signals at different times into sampling capacitors, which work as analog memory cells. The sampled 32 echo signals of each sub-ABF are originated from one target focal point at one instance. They are summed at one instance in a sub-ABF to perform the RX focusing for the target focal point. The proposed ABF chip has been fabricated in a 0.13- µ m CMOS process with an active area of 16 mm (2). The total power consumption is 287 mW. In measurement, the digital echo signals from a commercial ultrasound medical imaging machine were applied to the fabricated chip through commercial DAC chips. Due to the speed limitation of the DAC chips, the delay resolution was relaxed to 10 ns for the real-time measurement. A linear array transducer with no steering operation is used in this work.

An analog-digital hybrid RX beamformer chip with non-uniform sampling for ultrasound medical imaging with 2D CMUT array.

To reduce the memory area, a two-stage RX beamformer (BF) chip with 64 channels is proposed for the ultrasound medical imaging with a 2D CMUT array. The chip retrieved successfully two B-mode phantom images with a steering angle from -45 (°) to +45 (°), the maximum delay range of 8 µs, and the delay resolution of 6.25 ns. An analog-digital hybrid BF (HBF) is chosen for the proposed chip to utilize the easy beamforming operation in the digital domain and also to reduce chip area by minimizing the number of ADCs. The chip consists of eight analog beamformers (ABF) for the 1st-stage and a digital beamformer (DBF) for the 2nd-stage. The two-stage architecture reduces the memory area of both ABF and DBF by around four times. The DBF circuit is divided into three steps to further reduce the digital FIFO memory area by around twice. Coupled with the non-uniform sampling scheme, the proposed two-stage HBF chip reduces the total memory area by around 40 times compared to the uniform-sampling single-stage BF chip. The chip fabricated in a 0.13- µm CMOS process occupies the area of 19.4 mm(2), and dissipates 1.14 W with the analog supply of 3.3 V and the digital supply of 1.2 V.

TrkB agonist antibody pretreatment enhances neuronal survival and long-term sensory motor function following hypoxic ischemic injury in neonatal rats.

Perinatal hypoxic ischemia (H-I) causes brain damage and long-term neurological impairments, leading to motor dysfunctions and cerebral palsy. Many studies have demonstrated that the TrkB-ERK1/2 signaling pathway plays a key role in mediating the protective effect of brain-derived neurotrophic factor (BDNF) following perinatal H-I brain injury in experimental animals. In the present study, we explored the neuroprotective effects of the TrkB-specific agonist monoclonal antibody 29D7 on H-I brain injury in neonatal rats. First, we found that intracerebroventricular (icv) administration of 29D7 in normal P7 rats markedly increased the levels of phosphorylated ERK1/2 and phosphorylated AKT in neurons up to 24 h. Second, P7 rats received icv administration of 29D7 and subjected to H-I injury induced by unilateral carotid artery ligation and exposure to hypoxia (8% oxygen). We found that 29D7, to a similar extent to BDNF, significantly inhibited activation of caspase-3, a biochemical hallmark of apoptosis, following H-I injury. Third, we found that this 29D7-mediated neuroprotective action persisted at least up to 5 weeks post-H-I injury as assessed by brain tissue loss, implicating long-term neurotrophic effects rather than an acute delay of cell death. Moreover, the long-term neuroprotective effect of 29D7 was tightly correlated with sensorimotor functional recovery as assessed by a tape-removal test, while 29D7 did not significantly improve rotarod performance. Taken together, these findings demonstrate that pretreatment with the TrkB-selective agonist 29D7 significantly increases neuronal survival and behavioral recovery following neonatal hypoxic-ischemic brain injury.

Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer's disease.

Amyloid plaques associated with Alzheimer's disease (AD) induce inflammatory responses associated with activated microglia and reactive astrocytes, which exacerbate neurodegeneration through release of inflammatory cytokines, reactive oxygen species, and other factors. Inflammation contributes to neurodegeneration at later stages of AD, but it may also play a role in early disease pathogenesis. We found that before plaque deposition, amyloid precursor protein (APP)/presenilin 1 (PSEN1) transgenic mice (PSAPP mice), a well-characterized model of AD, exhibit evidence of cerebrovascular inflammation. Expression of the endothelial cell-specific antigen MECA-32 (mouse endothelial cell antigen-32) was upregulated in the cerebrovasculature of young PSAPP mice (3 months old) and was similar to that observed in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis characterized by neuroinflammation. MECA-32 is normally expressed in central and peripheral vasculature throughout development, but expression in the cerebrovasculature is downregulated on establishment of the blood-brain barrier (BBB). However, CNS inflammation triggers re-expression of MECA-32 in compromised cerebrovasculature. Our study indicates that MECA-32 may be a robust marker of cerebrovascular inflammation and compromised BBB integrity, triggered by soluble amyloid-ß early in disease pathogenesis.

Geriatric drug evaluation: where are we now and where should we be in the future?

The older population is currently the fastest growing age group in the United States, and this trend is expected to continue for several decades. Older individuals, in general, have a higher disease burden compared with younger adults and are the major users of medications, yet premarketing drug clinical trials have often excluded them even for the drugs that have high utility in this age group. Extrapolation of clinical results from younger to older individuals does not provide adequate benefit-risk estimation, and the frequent need for dose adjustment in older patients from initially approved doses exemplifies the current lack of adequate clinical data in the elderly. Herein, we discuss the information gap for older individuals and the need for a better understanding of the effect of aging on drug responses. We also present cases for future directions, urging the implementation of improved clinical trial designs using new and emerging pharmacokinetic and pharmacodynamic methods to allow the provision of evidence-based individualized treatment to this high drug use group.

Identification of anti-inflammatory targets for Huntington's disease using a brain slice-based screening assay.

Huntington's disease (HD) is a late-onset, neurodegenerative disease for which there are currently no cures nor disease-modifying treatments. Here we report the identification of several potential anti-inflammatory targets for HD using an ex vivo model of HD that involves the acute transfection of human mutant huntingtin-based constructs into rat brain slices. This model recapitulates key components of the human disease, including the formation of intracellular huntingtin protein (HTT)-containing inclusions and the progressive neurodegeneration of striatal neurons-both occurring within the native tissue context of these neurons. Using this "high-throughput biology" screening platform, we conducted a hypothesis-neutral screen of a collection of drug-like compounds which identified several anti-inflammatory targets that provided neuroprotection against HTT fragment-induced neurodegeneration. The nature of these targets provide further support for non-cell autonomous mechanisms mediating significant aspects of neuropathogenesis induced by mutant HTT fragment proteins.