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MELATONIN: A PLEIOTROPIC MOLECULE OF NATURAL ORIGIN. EVALUATION OF THE DIFFERENT THERAPEUTIC ACTIVITIES IN ANIMAL MODELS AND / OR HUMAN PATIENTS AND A STUDY OF THE METABOLIC-BIOCHEMICAL PATHWAYS RELATED TO THEM.
Full text link1.0. ABSTRACT
Background
Melatonin (MLT), a pineal gland hormone, seves as a bioclock and bio-calendar to mediate many receptor- or non-receptor functions. In addition to its immunomodulatory and neurological effects, MLT has a relevant oncostatic activity especially with respect to breast and prostate cancers, but the mechanism of action is still unclear. The growth of androgen-independent LNCaP prostate cancer cells has been demonstrated to be inhibited by MLT both in vitro and in vivo in a nude mice xenograft model. Clearly, the oncostatic effects of MLT may not be related to a single function, but rather to a complex interaction of several factors that involve the redox state, the immune system, the modulation of the endocrine system and membrane receptors.
MLT also increases sleepiness, decreases core temperature and increases peripheral temperature in humans. The role of MLT in the treatment of sleep disturbances, to prevent jet lag or as a part of the sepsis treatment is widely discussed; yet the role in critically ill patients still deserves further investigation. Critically ill patients suffer from severe sleep disturbances during their stay in an Intensive Care Unit (ICU). Moreover, these patients require high levels of antioxidants due to their critical illness.
Aims of the thesis
The main object of my PhD thesis was to confirm the pleiotropy of MLT molecule by testing its activity in two of the most promising clinical applications: the cure of prostate cancer and the regulation of the sleep/wake rhythm as adjuvant in the sedative therapy in critically ill patients.
Spcific Aims:
• To evaluate the oncostatic effect of MLT administered intraperitoneally (i.p.) by saline solution on human prostate tumor. To this purpose I have selected an in-vivo experimental model of nude mice (athymic), xenografted subcutaneously with tumor cells of a human prostatic line (LNCaP).
• Using the same animal model and the same administration route (i.p.) and treatment schedule of MLT administered in saline, to investigate the efficacy of a novel and promising pharmaceutical formulation: MLT included in a solid lipid nanoparticles system (SLN-MLT).
• Using the same mouse model of human prostate cancer, to test whether MLT can be administered efficiently using alternative ways that are more sustainable for prolonged treatments than i.p. MLT, e.g., transdermal delivery through the skin barrier directly onto the tumor via a novel and patented technique named cryoRx.
• To focus on the underlying action mechanism of MLT at the tumor cellular micro-environment and the possible influence on such a mechanism of the lipid nanocarrier employed.
• To evaluate in a cohort of ICU patients, if the circadian rhythm of MLT secretion is disrupted and to which extent MLT administration by different routes and different drug formulations (MLT as a tablet administered os, MLT encapsulated in SLN administered os as a suspension and MLT encapsulated in SLN applied transdermally as a suspension with the aid of a patch) is feasible in terms of absorption efficiency and adequacy in achieving and maintaining nocturnal peak plasma hormone.
• To evaluate if the restoration of the melatoninemia by the different ways of drug delivery in critically ill patients may be useful to restore the pleiotropic function of this hormone: facilitate the resolution of sleep-wake cycle disorders, improve the quality of sleep, reduce the number of episodes of anxiety, confusion and agitation, and reduce the amount of sedatives used, especially at night.
Materials and Methods
We used an in vivo model of human prostate tumor LNCaP cells xenografted into nude athymic mice. MLT has been administered i.p. as saline (n=13) and by SLN (n=13) or transdermally by cryoRx (n=14). For each treatment controls were also included. Each group received the same administration schedule: 3 treatments per week, for 6 week. At the end the animals were sacrificed and along the treatment period the mice weight were recorded as well as the tumor volume was measured. MLT concentration was assessed in plasma and tissues by ELISA test and tumors were evaluated for morphology, MLT content and HIF-1α expression.
The clinical effects of MLT administration as well as the pharmacokinetics profiles as a function of different administration ways (oral as MLT, oral as SLN and transdermal as SLN) have been studied in ICU patients. During the 2nd day of the ICU stay, serial withdrawal were taken to determine the endogenous MLT secretion, and then after MLT administration, additional plasma samples were obtained during the 3rd day to evaluate the exogenous plasma MLT content, for a total of 20 withdrawal for each patient. Each blood sample was centrifuged and the plasma stored at -20°C. To determine the MLT concentration we used an ELISA kit that includes a pre-purification of the sample by SPE (solid phase extraction) cartridges.
Results
Tumors developed slowly in all the MLT-treated (topical and i.p.) groups and at the end of the treatment, the mean volume was significantly lower vs control. Both tumoral and plasma MLT levels were significantly higher in treated (topical and i.p.) vs not-treated animals. Harvested tumor showed a strong inflammatory reaction which seemed to surround and infiltrate the tumor cells. In SLN-MLT treated animals, in addition to a strong lymphocyte infiltration, the tumor appeared limited also by the presence of fibroblast type cells. Preliminary results showed HIF-1α expression increased in both treatment groups (topical and i.p.) vs Ctrl.
In the clinical study, we have seen that MLT administration, is safe, reduces need for analgesic and sedative drugs restoring the normal circadian rhythm. In patients who received MLT or SLN-MLT by os, the absorption was rapid: the peak plasma concentration had a median of 30 min and after only 5 min, the MLT levels were significantly higher than physiological ones. The AUC of SLN-MLT was significantly higher than when MLT was administered by saline solution. SLN-MLT by transdermal route, presented a delayed peak plasma concentration (4 h) and a lower bioavailability but MLT plasma levels reached however the pharmacological concentration able to restore the pleiotropic function of this hormone and facilitate the resolution of sleep-wake cycle disorders.
Conclusions
We have confirmed the positive effects of MLT on tumor growth and we have focused on its effect on hypoxia. The possible role as anti-tumor drug candidate deserves to be further investigated. We demonstrated that different alternative and novel ways to deliver MLT are effective as well. This would accelerate the transferability of obtained data towards a therapy. on MLT oncostatic activity.
In the clinical study, we have proved that MLT is able to normalize the sleep-wake cycle, to ameliorate the sleep quality and to reduce the number of sedative drugs used in ICU pts. We proved also that transdermal administration by SLN is effective in rising plasma MLT levels as well as enteral administration and is more practicable in clinical setting
Melatonin : positive effects on high-risk patients with desynchronized sleep-wake rhythm
No full textBackground
Melatonin (MT), a pineal gland hormone, mediates many processes, including the biorhythmic regulation of the organism physiology. The role of MT in the treatment of sleep disturbances, to prevent jet lag or as a part of the sepsis treatment is widely discussed. Circadian rhythm of MT is desynchronized in critically ill pts in intensive care unit (ICU). The restoration of MT levels has been recently proved to be useful. The aims of the investigation are: to confirm that MT is a molecule active in the regulation of sleep/wake rhythm in ICU patients and to compare the differences in the MT pharmacokinetics using different administration route and drug formulation.
Methodology
The clinical effects of long term (5 days) administration of oral MT, as well as the pharmacokinetics profiles as a function of different administration ways (os, os by SLN (solid lipid nanoparticles), transdermal by SLN) have been studied in ICU pts. From the second day of the ICU stay, serial withdrawal were taken to determine both the endogenous and the exogenous plasma MT content, for a total of 20 withdrawal for each patient. Each blood sample was centrifuged and the plasma stored at -20°C. To determine the MT concentration we used an ELISA kit that includes a pre-purification of the sample by SPE (solid phase extraction) cartridges.
Results
In this study, we have seen that administration of oral MT, is safe, reduces need for analgesic and sedative drugs and shows better neurological status indicators, also restoring the normal circadian rhythm. In patients who have received oral MT, the absorption is rapid: the peak plasma concentration has a median of 30 minutes and after only 5 minutes the MT levels were significantly higher than physiological ones. The group treated with transdermal MT presents a delayed peak plasma concentration (4 h).
Conclusions
In this study, we have proved that MT is able to normalize the sleep-wake cycle, to ameliorate the sleep quality and to reduce the number of sedative drugs used in ICU pts. We proved also that transdermal administration by SLN is effective in rising plasma MT levels as well as enteral administration and is more practicable in clinical setting
Novel strategies to deliver melatonin (in SLN and by cryo-laser therapy) to prostate cancer cells
No full textBackground: Melatonin (MT) is a chemical signal of dark/light,
and serves as a bioclock and bio-calendar to mediate many
receptor- or non receptor-mediated functions. MT also has a
relevant oncostatic activity, especially with respect to prostate
cancers, recently related to hypoxia and sphingolipids signaling
pathways. The aims of the investigation are: to confirm that MT
is active in the cure of prostate cancer, to speculate on the
underlying mechanisms, to investigate the signaling pathways
involved and to assess whether alternative and novel ways to
deliver the drug may be competitive.
Methods: We used an in vivo model of human prostate tumor
LNCaP cells xenografted into nude athymic mice. MT has been
administered i.p. as saline (n=13) and by SLN (solid lipid
nanoparticles) (n=13) or transdermally by Cryopass therapy
(n=14). For each treatment controls were also included. Each
group received the same administration schedule: 3 treatments
per week, for 6 week. At the end the animals were sacrificed
and along the treatment period the mice weight were recorded
as well as the tumor volume was measured. MT concentration
was assessed in plasma and tissues by ELISA test and tumors
were evaluated for morphology, MT content and HIF-1a
expression.
Results: Tumors developed slowly in all the MT-treated (topical
and i.p.) groups and at the end of the treatment, the mean
volume was significantly lower vs control. Both tumor and
plasma levels were significantly higher in treated vs not-treated
animals. Harvested tumor showed a strong inflammatory
reaction which seemed to surround and infiltrate the tumor
cells. In SLN-MT treated animals, in addition to a strong
lymphocyte infiltration, the tumor appeared limited also by the
presence of fibroblast type cells. Preliminary results showed
HIF-1 expression increased in both treatment groups vs
control.
Conclusions: We have confirmed the positive effects of MT on
tumor growth and we have focused on its effect on hypoxia.
The possible role as anti-tumor drug candidate deserves to be
further investigated. We demonstrated that different alternative
and novel ways to deliver MT are effective as well. This would
accelerate the transferability of obtained data towards a
therapy. on MT oncostatic activity
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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