Quality of life (QoL) is a relevant end point and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an end point in cancer ...phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of under-reporting and delay of publication. All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about end points was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed. In total, 446 publications were eligible. In 210 (47.1%), QoL was not included among end points. QoL was not an end point in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory end point, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as end point or with missing QoL results was relevant in all tumor types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years, respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials. QoL is not included among end points in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant under-reporting and delay in publication.
Objectives
In our previous reports, we have demonstrated that extremely low‐frequency electromagnetic fields (ELF‐EMF) exposure enhances the proliferation of keratinocyte. The present study aimed to ...clarify effects of ELF‐EMF on wound healing and molecular mechanisms involved, using a scratch in vitro model.
Materials and methods
The wounded monolayer cultures of human immortalized keratinocytes (HaCaT), at different ELF‐EMF and Sham exposure times were monitored under an inverted microscope. The production and expression of IL‐1β, TNF‐α, IL‐18 and IL‐18BP were measured by enzyme‐linked immunosorbent assay and quantitative real‐time PCR. The activity and the expression of matrix metalloproteinases (MMP)‐2/9 was evaluated by zymography and Western blot analysis, respectively. Signal transduction proteins expression (Akt and ERK) was measured by Western blot.
Results
The results of wound healing in vitro assay revealed a significant reduction of cell‐free area time‐dependent in ELF‐EMF‐exposed cells compared to Sham condition. Gene expression and release of cytokines analysed were significantly increased in ELF‐EMF‐exposed cells. Our results further showed that ELF‐EMF exposure induced the activity and expressions of MMP‐9. Molecular data showed that effects of ELF‐EMF might be mediated via Akt and ERK signal pathway, as demonstrated using their specific inhibitors.
Conclusions
Our results highlight ability of ELF‐EMF to modulate inflammation mediators and keratinocyte proliferation/migration, playing an important role in wound repair. The ELF‐EMF accelerates wound healing modulating expression of the MMP‐9 via Akt/ERK pathway.
Sjögren’s syndrome (SS) or sicca syndrome was described by Swedish ophthalmologist Sjögren in the year 1933 for the first time. The etiology of the SS is multifunctional and includes a combination of ...genetic predisposition and environmental as well as epigenetic factors. It is an autoimmune disease characterized by features of systemic autoimmunity, dysfunction, and inflammation in the exocrine glands (mainly salivary and lacrimal glands) and lymphocytic infiltration of exocrine glands. In fact, the involvement of lacrimal and salivary glands results in the typical features of dry eye and salivary dysfunction (xerostomia). Only in one-third of the patients also present systemic extraglandular manifestations. T cells were originally considered to play the initiating role in the autoimmune process, while B cells were restricted to autoantibody production. In recent years, it is understood that the roles of B cells are multiple. Moreover, autoantibodies and blood B cell analysis are major contributors to a clinical diagnosis of Sjögren’s syndrome. Recently, there has been rising interest in microRNA implication in autoimmunity. Unfortunately, to date, there are only a few studies that have investigated their participation in SS etiopathogenesis. The purpose of this work is to gather the data present in the literature to clarify this complex topic.
Abstract Higher levels of proinflammatory cytokines are found in Parkinson’s disease (PD) patient’s brains and inflammation is thought to be a major contributor to the neurodegeneration. During the ...inflammatory process, microglial release of proinflammatory cytokines act on the endothelium of blood–brain barrier (BBB) cells to stimulate upregulation of adhesion molecules. Consequently, this upregulation leads to the recruitment of passing T cells and monocytes, which express the counter receptors, that then go on to release more cytokines Whitton, P.S., 2007. Inflammation as a causative factor in the aetiology of Parkinson’s disease, Br. J. Pharmacol. 50, 963–976; Kortekaas, R., Leenders, K.L., Van Oostrom, J.C., Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005. Blood–brain barrier dysfunction in parkinsonian midbrain in vivo , Ann. Neurol. 57, 176–179. In addition, a systemic inflammatory response results in the production of cytokines which circulate in the blood and communicate with neurons within the brain. Thus, a central inflammatory reaction interacts with peripheral blood mononuclear cells (PBMCs) modulating immune activity. The present study investigates levels of production and expression of cyto/chemokines by PBMCs in PD patients. Basal and LPS-induced levels of MCP-1, RANTES, MIP-1α, IL-8, IFNγ, IL-1β and TNFα were significantly higher in PD patients than in HC subjects ( p < 0.001), as determined by RT-PCR and Elisa methods. Cyto/chemokine levels were significantly correlated with UPDRS III and H/Y stage ( p < 0.001). The Pearson’s correlation coefficient ( R ) was also used to assess the strength of the relationship between NF-κBp65 levels and all studied cyto/chemokines and between NF-κBp65, UPDRS III and H/Y score in PD patients. The overall results strengthen and extend the knowledge of the peripheral dysregulation in the cytokine network associated with PD.
Purpose
There is no agreement on the most appropriate post-operative pathway for the management of positive margins after laser cordectomy for early stage glottic tumours (T1-2N0M0). This literature ...review and meta-analysis aim to evaluate the post-operative treatment with the best oncological results among follow-up, radiotherapy (RT) and surgical second look. The parameters utilized were incidence of recurrence, overall (OS), disease-specific (DSS) and disease-free (DFS) survival and larynx preservation (LP).
Methods
The articles were found through a string typed into PubMed from 2007 to 2022. The studies with detailed oncological results were selected according to inclusion criteria, and then the meta-analysis was carried out.
Results
Sixteen studies met the inclusion criteria for 2808 patients. The positive margin was found in 748 patients (26.6%), of which 416 were referred to follow-up, 89 to RT and 242 to a surgical second look. A false positive margin was found in 58/104 patients (56%). The recurrence rate in patients with positive margins was significantly higher (
p
= 0.003). In OS, DSS, DFS and LP, the odds ratio (OR) value was always greater than 1, assessing the role of the positive margin as a risk factor.
Conclusions
Prospective studies will be necessary to establish the role of positive margin as a prognostic factor. A surgical second look in case of positive margin seems to be the best option for the patient in terms of lower risk of recurrence and better oncological results. Better collaboration between surgeon and pathologist would be desirable to limit the real and false positive margins.
The diffuse distribution of nicotinic cholinergic receptors (nAChRs) in both brain and peripheral immune cells points out their involvement in several pathological conditions. Indeed, the deregulated ...function of the nAChR was previously correlated with cognitive decline and neuropsychiatric symptoms in Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB). The evaluation in peripheral immune cells of nAChR subtypes, which could reflect their expression in brain regions, is a prominent investigation area.
This study aims to evaluate the expression levels of both the nAChR subunits and the main known inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) of patients with DLB and AD to better characterize their involvement in these two diseases.
Higher gene expression levels of TNFα, IL6 and IL1β were observed in DLB and AD patients in comparison with healthy controls (HC). In our cohort, a reduction of nAChRα4, nAChRβ2 and nAChRβ4 was detected in both DLB and AD with respect to HC. Considering nAChR gene expressions in DLB and AD, significant differences were observed for nAChRα3, nAChRα4, nAChRβ2 and nAChRβ4 between the two groups. Moreover, the acetylcholine esterase (AChE) gene expression was significantly higher in DLB than in AD. Correlation analysis points out the relation between different nAChR subtype expressions in DLB (nAChRβ2 vs nAChRα3; nAChRα4 vs nAChRα3) and AD (nAChRα4 vs nAChRα3; nAChRα4 vs nAChRβ4; nAChRα7 vs nAChRα3; nAChRα7 vs nAChRα4).
Different gene expressions of both pro-inflammatory cytokines and nAChR subtypes may represent a peripheral link between inflammation and neurodegeneration. Inflammatory cytokines and different nAChRs should be valid and accurate peripheral markers for the clinical diagnosis of DLB and AD. However, although nAChRs show a great biological role in the regulation of inflammation, no significant correlation was detected between nAChR subtypes and the examined cytokines in our cohort of patients.
Summary
Background Extremely low frequency (ELF) electromagnetic fields (EMF) are known to produce a variety of biological effects. Clinical studies are ongoing using EMF in healing of bone ...fractures and skin wounds. However, little is known about the mechanisms of action of ELF‐EMF. Several studies have demonstrated that expression and regulation of nitric oxide synthase (NOS) and cyclooxygenase‐2 (COX‐2) are vital for wound healing; however, no reports have demonstrated a direct action of ELF‐EMF in the modulation of these inflammatory molecules in human keratinocytes.
Objectives The present study analysed the effect of ELF‐EMF on the human keratinocyte cell line HaCaT in order to assess the mechanisms of action of ELF‐EMF and to provide further support for their therapeutic use in wound healing.
Methods Exposed HaCaT cells were compared with unexposed control cells. At different exposure times, expression of inducible NOS (iNOS), endothelial NOS (eNOS) and COX‐2 was evaluated by Western blot analysis. Modulation of iNOS and eNOS was monitored by evaluation of NOS activities, production of nitric oxide (NO) and O2− and expression of activator protein 1 (AP‐1). In addition, catalase activity and prostaglandin (PG) E2 production were determined. Effects of ELF‐EMF on cell growth and viability were monitored.
Results The exposure of HaCaT cells to ELF‐EMF increased iNOS and eNOS expression levels. These ELF‐EMF‐dependent increased expression levels were paralled by increased NOS activities, and increased NO production. In addition, higher levels of AP‐1 expression as well as a higher cell proliferation rate were associated with ELF‐EMF exposure. In contrast, ELF‐EMF decreased COX‐2 expression, PGE2 production, catalase activity and O2− production.
Conclusions Mediators of inflammation, such as reactive nitrogen and PGE2, and keratinocyte proliferation are critical for the tissue regenerative processes. The ability of ELF‐EMF to upmodulate NOS activities, thus nitrogen intermediates, as well as cell proliferation, and to downregulate COX‐2 expression and the downstream intermediate PGE2, highlights the potential therapeutic role of ELF‐EMF in wound healing processes.
Low frequency (LF) electromagnetic fields (EMFs) are abundantly present in modern society and in the last 20years the interest about the possible effect of extremely low frequency (ELF) EMFs on human ...health has increased progressively. Epidemiological studies, designed to verify whether EMF exposure may be a potential risk factor for health, have led to controversial results. The possible association between EMFs and an increased incidence of childhood leukemia, brain tumors or neurodegenerative diseases was not fully elucidated. On the other hand, EMFs are widely used, in neurology, psychiatry, rheumatology, orthopedics and dermatology, both in diagnosis and in therapy.
In vitro studies may help to evaluate the mechanism by which LF-EMFs affect biological systems.
Invitro model of wound healing used keratinocytes (HaCaT), neuroblastoma cell line (SH-SY5Y) as a model for analysis of differentiation, metabolism and functions related to neurodegenerative processes, and monocytic cell line (THP-1) was used as a model for inflammation and cytokines production, while leukemic cell line (K562) was used as a model for hematopoietic differentiation.
MCP-1, a chemokine that regulates the migration and infiltration of memory T cells, natural killer (NK), monocytes and epithelial cells, has been demonstrated to be induced and involved in various diseases.
Since, varying the parameters of EMFs different effects may be observed, we have studied MCP-1 expression in HaCaT, SH-SY5Y, THP-1 and K562 exposed to a sinusoidal EMF at 50Hz frequency with a flux density of 1mT (rms).
Our preliminary results showed that EMF-exposure differently modifies the expression of MCP-1 in different cell types. Thus, the MCP-1 expression needs to be better determined, with additional studies, with different parameters and times of exposure to ELF-EMF.
An adaptation of the
oscars
algorithm for bound constrained global optimization is presented, and numerically tested. The algorithm is a stochastic direct search method, and has low overheads which ...are constant per sample point. Some sample points are drawn randomly in the feasible region from time to time, ensuring global convergence almost surely under mild conditions. Additional sample points are preferentially placed near previous good sample points to improve the rate of convergence. Connections with partitioning strategies are explored for
oscars
and the new method, showing these methods have a reduced risk of sample point redundancy. Numerical testing shows that the method is viable in practice, and is substantially faster than
oscars
in 4 or more dimensions. Comparison with other methods shows good performance in moderately high dimensions. A power law test for identifying and avoiding proper local minima is presented and shown to give modest improvement.
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