Understanding the earliest pathophysiological changes of Alzheimer's disease (AD) may aid in the search for timely diagnostic biomarkers and effective disease-modifying therapies. The p53 protein is ...mostly known for its role in tumor suppression. However, emerging evidence supports that dysregulated p53 activity may contribute to various peripheral and brain alterations during the earliest stages of AD. This review describes the mechanisms through which p53 dysregulation may exacerbate AD pathology and how this could be used as a potential peripheral biomarker for early detection of the disease. MAIN BODY: p53, known as the guardian of the genome, may underlie various compensation or defense mechanisms that prevent neurons from degeneration. These mechanisms include maintenance of redox homeostasis, regulation of inflammation, control of synaptic function, reduction of amyloid β peptides, and inhibition of neuronal cell cycle re-entry. Thereby, dysregulation of p53-dependent compensation mechanisms may contribute to neuronal dysfunction, thus leading to neurodegeneration. Interestingly, a conformational misfolded variant of p53, described in the literature as unfolded p53, which has lost its canonical structure and function, was observed in peripheral cells from mild cognitive impairment (MCI) and AD patients. In AD pathology, this peculiar conformational variant was caused by post-translational modifications rather than mutations as commonly observed in cancer. Although the presence of the conformational variant of p53 in the brain has yet to be formally demonstrated, the plethora of p53-dependent compensation mechanisms underscores that the guardian of the genome may not only be lost in the periphery during AD pathology.
These findings revisit the role of p53 in the early development and exacerbation of AD pathology, both in the brain and periphery. The conformational variant of p53 represents a potential peripheral biomarker that could detect AD at its earliest stages.
Our understanding of Alzheimer's disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses. More recently, the p53 protein, ...well-known as a genome guardian, has gained attention for its potential role in the early evolution of AD. This is due to the central involvement of p53's in the control of oxidative stress and potential involvement in the Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can affect brain processes, thus contributing to AD development. The following review will explore the impact of p53 PTMs on its function and consequential involvement in AD pathogenesis. The greater understanding of the role of p53 in the pathogenesis of AD could result in more targeted therapies benefiting the many patients of this debilitating disease.
Given the important role of adjuvants in prophylactic vaccines, identification and development of new adjuvants with enhanced efficacy and safety is necessary. The use of adjuvants with ...immunopotentiating properties that can direct the immune responses to humoral or cell-mediated immunity and can induce T-cell responses has made it possible to design more protective vaccines. Although current regulations focus on traditional adjuvants, notably aluminum and calcium salts, advances have been made in regulatory considerations. The regulatory agencies for the evaluation of medicinal products are actively drafting guidance on requirements for the evaluation of new adjuvants. This article briefly summarizes the most widely studied adjuvants in vaccination, including those licensed for human vaccines and the regulatory aspects relevant to adjuvant quality at development stages.
Endoplasmic Reticulum Stress BÁNHEGYI, GÁBOR; BAUMEISTER, PETER; BENEDETTI, ANGELO ...
Annals of the New York Academy of Sciences,
October 2007, Letnik:
1113, Številka:
1
Journal Article
Recenzirano
: Stress is the imbalance of homeostasis, which can be sensed even at the subcellular level. The stress‐sensing capability of various organelles including the endoplasmic reticulum (ER) has been ...described. It has become evident that acute or prolonged ER stress plays an important role in many human diseases; especially those involving organs/tissues specialized in protein secretion. This article summarizes the emerging role of ER stress in diverse human pathophysiological conditions such as carcinogenesis and tumor progression, cerebral ischemia, plasma cell maturation and apoptosis, obesity, insulin resistance, and type 2 diabetes. Certain components of the ER stress response machinery are identified as biomarkers of the diseases or as possible targets for therapeutic intervention.
In the last 20 years, novel non-seasonal influenza viruses have emerged, most of which have originated from birds. Despite their apparent inability to cause pandemics, with the exception of H1N1 ...swine influenza virus, these viruses still constitute a constant threat to public health. While general concern has decreased after the peak of the H5N1 virus, in recent years several novel reassorted influenza viruses (e.g., H7N9, H9N2, H10N8) have jumped the host-species barrier and are under surveillance by the scientific community and public health systems. It is still unclear whether these viruses can actually cause pandemics or just isolated episodes. The purpose of this review is to provide an overview of old and novel potential pandemic strains of recent decades.
Abstract To assess in Italy the pre-pandemic susceptibility of the general population to the 2009 A/H1N1v influenza virus, 587 serum samples collected in 2004 were analyzed using ...haemagglutination-inhibition (HI), single-radial-haemolysis (SRH) and microneutralisation (MN) assays. Serum samples were stratified by age group, gender, and geographic area. Overall, using HI assay, the proportion of subjects showing antibodies cross-reacting with 2009 A/H1N1v virus at seroprotection level (≥1:40) was estimated to be 6.7%, 12.4%, and 22.4% in individuals born between 2004 and 1949, 1948 and 1939, 1938 and 1909, respectively. With a HI antibody titre of ≥1:10, in the same birth cohort, the seroprotection levels were 13.5%, 19.2%, and 58.2%, respectively. The results suggest that the Italian population was not fully naïf to the current pandemic virus and that the possible previous exposure and immune response increases with age.
We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal ...challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and morbidity arising from infection with HPAI H5N1 virus.
N. meningitidis infections represent a global health problem that can lead to the development of serious permanent sequelae. Although the use of antibiotics and prevention via vaccination have ...reduced the incidence of meningococcal disease, our understanding regarding N. meningitidis pathogenesis is still limited, especially of those mechanisms responsible for IMD and fulminant or deadly septic shock. These severe clinical presentations occur in a limited number of subjects, whereas about 10% of healthy individuals are estimated to carry the bacteria as a commensal. Since TLR activation is involved in the defense against N. meningitidis, several studies have highlighted the association between host TLR SNPs and a higher susceptibility and severity of N. meningitidis infections. Moreover, TLR SNPs induced variations in immunological responses and in their persistence upon vaccination against meningococcal disease. In the absence of mass vaccination programs, the early identification of risk factors for meningococcal disease would be recommended in order to start immunization strategies and antibiotic treatment in those subjects carrying the risk variants. In addition, it could allow us to identify individuals with a higher risk for severe disease and sequelae in order to develop a personalized healthcare of high-risk subjects based on their genomic profile. In this review, we have illustrated important preliminary correlations between TLR variants and meningococcal susceptibility/severity and with vaccine-induced immune responses.
Background
Treatments for patients with Alzheimer’s Disease (AD) are now available, and are associated with certain risks. There is an increased need from providers, to have tools that will aid in ...clinical decision‐making.
Method
The AlzoSure® Predict test, is an IP‐LC‐MS/MS based method, to quantify the AZ284® peptide of an unfolded variant of the p53 protein (U‐p53AZ).
A dataset from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, with 479 participants, aged 60‐85, 237 being cognitively normal (CN), 98 with minimal cognitive impairment (MCI), 141 with dementia due to AD (ADD), and 3 with non‐AD dementia (OD), was used to validate the performance of AlzoSure® Predict to identify the risk individuals, to experience a significant cognitive deterioration (CN to MCI or ADD and MCI to ADD) and to stratify them according to the time frame, during which, this will occur (6 or 2 years).
Result
316 participants had a follow up of up to 6 years, and 294 had a follow up of up to 2 years.
The performance of AlzoSure® Predict, as measured by AUC, is high, regardless of the follow‐up time frame. For prediction of deterioration within 6 years, the obtained AUC is 0.9842 with DeLong 95% CI: 0.9727‐0.9956 (68 case, who experienced a deterioration, and 248 controls), ho didn’t and for prediction of deterioration within 24 months, it is 0.9891, with DeLong 95% CI: 0.9789‐0.9994 (46 cases, and 248 controls).
The cut‐off values of AlzoSure® Predict are defined to stratify individuals, at the time of testing, according to the time frame, during which they may experience a significant cognitive deterioration.
AlzoSure® Predict showed high performance to identify rapid progressors to AD within 2 y, with a PPV/ NPV >90%, Sens>80%, and Spec>95%
Conclusion
AlzoSure® Predict has the capability to identify individuals, who are at risk to experience a significant cognitive deterioration, and stratify this risk according to the time frame, even in a period within 2 years, during which this deterioration will occur.
AlzoSure® Predict can become a tool, to strengthen a personalized clinical decision‐making, with improved precision, to be used by providers, who care for patients with AD.
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