182 research outputs found
Anticancer drugs repurposed for Alzheimer’s disease: a systematic review
Background: The relationship between cancer and dementia is triggering growing research interest. Several
preclinical studies have provided the biological rationale for the repurposing of specific anticancer agents in
Alzheimer’s disease (AD), and a growing number of research protocols are testing their efficacy and safety/
tolerability in patients with AD.
Methods: The aim of the present systematic review was to provide an overview on the repurposing of approved
anticancer drugs in clinical trials for AD by considering both ongoing and completed research protocols in all
phases. In parallel, a systematic literature review was conducted on PubMed, ISI Web, and the Cochrane Library to
identify published clinical studies on repurposed anticancer agents in AD.
Results: Based on a structured search on the ClinicalTrials.gov and the EudraCT databases, we identified 13 clinical
trials testing 11 different approved anticancer agents (five tyrosine kinase inhibitors, two retinoid X receptor
agonists, two immunomodulatory agents, one histone deacetylase inhibitor, and one monoclonal antibody) in the
AD continuum. The systematic literature search led to the identification of five published studies (one phase I, three
phase II, and one phase IIb/III) reporting the effects of antitumoral treatments in patients with mild cognitive
impairment or AD dementia. The clinical findings and the methodological characteristics of these studies are
described and discussed.
Conclusion: Anticancer agents are triggering growing interest in the context of repurposed therapies in AD.
Several clinical trials are underway, and data are expected to be available in the near future. To date, data emerging
from published clinical studies are controversial. The promising results emerging from preclinical studies and
identified research protocols should be confirmed and extended by larger, adequately designed, and high-quality
clinical trials
MEN1 Gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids
Context: MEN1 gene alterations have been implicated in lung carcinoids, but their effect on gene expression and disease outcome is unknown.
Objective: Our objective was to analyze MEN1 gene and expression anomalies in lung neuroendocrine neoplasms and their correlations with clinicopathologic data and disease outcome.
Design: We examined 74 lung neuroendocrine neoplasms including 58 carcinoids and 16 high-grade neuroendocrine carcinomas (HGNECs) for MEN1 mutations (n = 70) and allelic losses (n = 69), promoter hypermethylation (n = 65), and mRNA (n = 74) expression. Results were correlated with disease outcome.
Results: MEN1 mutations were found in 7 of 55 (13%) carcinoids and in 1 HGNEC, mostly associated with loss of the second allele. MEN1 decreased expression levels correlated with the presence of mutations (P = .0060) and was also lower in HGNECs than carcinoids (P = .0024). MEN1 methylation was not associated with mRNA expression levels. Patients with carcinoids harboring MEN1 mutation and loss had shorter overall survival (P = .039 and P = .035, respectively) and low MEN1 mRNA levels correlated with distant metastasis (P = .00010) and shorter survival (P = .0071). In multivariate analysis, stage and MEN1 allelic loss were independent predictors of prognosis.
Conclusion: Thirteen percent of pulmonary carcinoids harbor MEN1 mutation associated with reduced mRNA expression and poor prognosis. Also in mutation-negative tumors, low MEN1 gene expression correlates with an adverse disease outcome. Hypermethylation was excluded as the underlying mechanism
Oxidized Alginate Dopamine Conjugate: In Vitro Characterization for Nose‐to‐Brain Delivery Application
Background: The blood–brain barrier (BBB) bypass of dopamine (DA) is still a challenge for supplying it to the neurons of Substantia Nigra mainly affected by Parkinson disease. DA prodrugs have been studied to cross the BBB, overcoming the limitations of DA hydrophilicity. Therefore, the aim of this work is the synthesis and preliminary characterization of an oxidized alginate-dopamine (AlgOX-DA) conjugate conceived for DA nose-to-brain delivery. Methods: A Schiff base was designed to connect oxidized polymeric backbone to DA and both AlgOX and AlgOX-DA were characterized in terms of Raman, XPS, FT-IR, and 1H- NMR spectroscopies, as well as in vitro mucoadhesive and release tests. Results: Data demonstrated that AlgOX-DA was the most mucoadhesive material among the tested ones and it released the neurotransmitter in simulated nasal fluid and in low amounts in phosphate buffer saline. Results also demonstrated the capability of scanning near-field optical microscopy to study the structural and fluorescence properties of AlgOX, fluorescently labeled with fluorescein isothiocyanate microstructures. Interestingly, in SH-SY5Y neuroblastoma cell line up to 100 μg/mL, no toxic effect was derived from AlgOX and AlgOX-DA in 24 h. Conclusions: Overall, the in vitro performances of AlgOX and AlgOX-DA conjugates seem to encourage further ex vivo and in vivo studies in view of nose-to-brain administratio
The Bortoluzzi Mud Volcano (Ionian Sea, Italy) and its potential for tracking the seismic cycle of active faults
The Ionian Sea in southern Italy is at the center
of active interaction and convergence between the Eurasian
and African–Adriatic plates in the Mediterranean. This area
is seismically active with instrumentally and/or historically
recorded Mw > 7:0 earthquakes, and it is affected by recently
discovered long strike-slip faults across the active Calabrian
accretionary wedge. Many mud volcanoes occur on
top of the wedge. A recently discovered one (called the Bortoluzzi
Mud Volcano or BMV) was surveyed during the Seismofaults
2017 cruise (May 2017). Bathymetric backscatter
surveys, seismic reflection profiles, geochemical and earthquake
data, and a gravity core are used here to geologically,
geochemically, and geophysically characterize this structure.
The BMV is a circular feature ' 22m high and ' 1100m in
diameter with steep slopes (up to a dip of 22 ). It sits atop
the Calabrian accretionary wedge and a system of flowerlike
oblique-slip faults that are probably seismically active as
demonstrated by earthquake hypocentral and focal data. Geochemistry
of water samples from the seawater column on top
of the BMV shows a significant contamination of the bottom
waters from saline (evaporite-type) CH4-dominated crustalderived
fluids similar to the fluids collected from a mud volcano
located on the Calabria mainland over the same accretionary
wedge. These results attest to the occurrence of open
crustal pathways for fluids through the BMV down to at least
the Messinian evaporites at about 3000 m. This evidence
is also substantiated by helium isotope ratios and by comparison
and contrast with different geochemical data from
three seawater columns located over other active faults in the
Ionian Sea area. One conclusion is that the BMV may be
useful for tracking the seismic cycle of active faults through
geochemical monitoring. Due to the widespread diffusion of
mud volcanoes in seismically active settings, this study contributes
to indicating a future path for the use of mud volcanoes
in the monitoring and mitigation of natural hazards.Published1-233SR TERREMOTI - Attività dei CentriJCR Journa
The cognitive and behavioural profile of Amyotrophic Lateral Sclerosis: Application of the consensus criteria
Abstract. OBJECTIVE: The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteri
MEN1 Gene Mutation and Reduced Expression Are Associated with Poor Prognosis in Pulmonary Carcinoids
Comparing long-acting antipsychotic discontinuation rates under ordinary clinical circumstances: a survival analysis from an observational, pragmatic study
Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network 'Depot Study' was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4-44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3-43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4-84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6-40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6-27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742-0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003-4.634; p = 0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation
A Systematic Review of the Biological Processes Involved in Deep-Brain Stimulation for Parkinson's disease: A Focus on the Potential Disease-Modifying Effects
Deep-Brain Stimulation (DBS) is an important treatment option for the management of Parkinson's disease (PD) and is a common symptomatic treatment. However, an increasing number of studies have examined the biological processes to assess if DBS can also modify the natural history of PD by acting on its pathophysiological mechanisms. Relevant literature published up to November 2020 was systematically searched on databases such as PubMed, ISI Web of Knowledge, Academic Search Index, and Science Citation Index. The following predefined inclusion criteria were applied to the full-text versions of the selected articles: i) recruiting and monitoring of PD subjects that were previously treated with DBS and ii) investigating the electrophysiological, biochemical, epigenetic, or neuroimaging effects of DBS. Studies focusing exclusively on motor and clinical changes were excluded. Reviews, case reports, studies on animal models, and computational studies were also not considered. Out of 2,960 records screened, 43 studies met the inclusion criteria. Only three studies described a potential disease-modifying effect of DBS. However, a wide heterogeneity was observed in the investigated biomarkers, and the design and methodological issues of several studies limited their ability to find potential disease-modifying features. Specifically, 60.4% of the trials followed-up subjects for no more than 1 year from the surgical intervention, and 67.4% observed patients with PD only once after DBS. Moreover, 64.2% of the studies enrolled late-stage PD patients. Most of the studies (88.4%) reported that DBS only had a symptomatic effect, with several of them showing some limitations in the study design and recruitment of patients. Further studies using shared biomarkers are encouraged to assess if and how DBS might affect the progression of PD. Based on the existing preclinical literature, prospective clinical trials examining the course of PD in early-stage patients are needed
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