The potential role of thioredoxin 1 and CD30 systems as multiple pathway targets and biomarkers in tumor therapy

Our progress in understanding pathological disease mechanisms has led to the identification of biomarkers that have had a considerable impact on clinical practice. It is hoped that the move from generalized to stratified approaches, with the grouping of patients into clinical/therapeutic subgroups according to specific biomarkers, will lead to increasingly more effective clinical treatments in the near future. This success depends on the identification of biomarkers that reflect disease evolution and can be used to predict disease state and therapy response, or represent themselves a target for treatment. Biomarkers can be identified by studying relationships between serum, tissue, or tumor microenvironment parameters and clinical or therapeutic parameters at onset and during the progression of the disease, using systems biology. Given that multiple pathways, such as those responsible for redox and immune regulation, are deregulated or altered in tumors, the future of tumor therapy could lie in the simultaneous targeting of these pathways using extracellular and intracellular targets and biomarkers. With this aim in mind, we evaluated the role of thioredoxin 1, a key redox regulator, and CD30, a cell membrane receptor, in immune regulation. Our results lead us to suggest that the combined use of these biomarkers provides more detailed information concerning the multiple pathways affected in disease and hence the possibility of more effective treatment

Oncogeni e metastasi linfonodali in tumori primitivi del cavo orale

Sulla base di precedenti ricerche di biologia molecolare eseguite su alcuni oncogeni (p53, Ha e Ki-ras, cErb) mediante estrazione di DNA gnomico da tessuto neoplastico di carcinomi del distretto oro-maxillo-facciale, gli AA hanno intrapreso uno studio degli stessi oncogeni su DNA estratto da tessuto linfonodale metastatico di forme primitive del cavo orale. Gli AA sottolineano come per questa indagine, a differenza di quelle precedenti, si siano dovute affrontare notevoli problematiche di ordine operativo, cui peraltro è verosimilmente da attribuire la estrema povertà di specifiche segnalazioni in letteratura. Le difficoltà sono legate essenzialmente al pattern istopatologico della metastasi linfonodale che rende in taluni casi indaginoso l’allestimento di speciments validi ai fini dello studio. Ciò ha comportato la ricerca di un percorso metodologico peculiare. Vengono riportati e discussi i primi dati ricavati dall’analisi genetica del tessuto linfonodale metastatico. Gli AA ritengono che tale ricerca possa, con i necessari approfondimenti, rappresentare il presupposto per un eventuale più mirato approccio al trattamento delle metastasi linfonodali

CD30 antigen and multiple sclerosis: CD30, an important costimulatory molecule and marker of a regulatory subpopulation of dendritic cells, is involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. The role of IFNbeta-1a in the treatment of multiple sclerosis

Objectives: The immunological effect of CD30 on dendritic cells ( DCs) was examined in a comparative study of patients with relapsing- remitting multiple sclerosis ( RRMS). The patients were divided into two groups on the basis of interferon ( IFN)beta-1a treatment: IFN beta-1a-treated patients and untreated patients. We have already shown that CD30 is a marker of cells involved in the regulation of the balance between TH1 and TH2 immune responses and so the aim of this study was to confirm this role in DCs and, consequently, to clarify the immunopathological mechanisms of MS and the causes of immunosuppressive drug failure. Methods: We studied network interactions between soluble ( s) CD30 and TH1/ TH2 cytokines in the supernatants of CD14+- derived immature DC ( IDC) and DC cultures from treated and untreated patients. Network interactions between the sCD30 and cytokines in IDC and DC supernatants were also evaluated in relation to TH1/ TH2 cytokine serum levels. Results: Our overall results show that CD30 is expressed on IDCs and DCs, indicating an immunological role in resting and activated physiological conditions. This role would appear to be the regulation of the resting and activated physiological balance between the TH1/ TH2 immune functions as abnormal increases in sCD30 levels result in impaired regulation. Further studies are undoubtedly required to clarify this situation. IFN beta-1a treatment was found to determine a fall in sCD30 levels, leading to the restoration of the normal functional selection of IDCs from progenitor cells and the regulation of the TH1/ TH2 network balance. However, IFN beta- 1a treatment may also be responsible for the in vivo suppression of CD30- mediated TH1- DC functions in immune activation. TH1- DC functions are involved in the induction of T- regulatory cells for the physiological deletion of self-aggressive cells. Conclusion: We conclude that CD30 is an important costimulatory molecule and marker of a regulatory subpopulation of DCs which induces and modulates immune cells involved in the maintenance of the physiological balance between TH1/ TH2 immune responses and tolerance. Elucidating the mechanisms restoring DC and T- regulatory cell function could lead to more effective therapy and strategies for the prevention and treatment of immunopathological conditions such as autoimmunity, transplant rejection, allergy and tumors. Copyright (C) 2005 S. Karger AG, Basel

P53 and H-RAS genomic analysis in oral squamous cell carcinoma

We examined p53 gene that has been detected in many gastrointestinal tract neoplasms, in lO oral cancer patients. The study consisted of a primer-mediated enzymatic amplification (PCR) of two fragments (lll-319pb) included in the exon5-intron5-exon6 region, and of a successive digestion by two restriction enzymes, HhaI and Hae III. No p53 alteration was evident in any of the samples We also examined k-ras point mutations in codonl2. We agree with other authors who point out there is no evidence far alterations in the araI cavity, but these are often found in malignancies of the lower digestive tract. The absence of p53 gene modifications in oral squamous carcinomas suggests that other codon mutation or other genetic events are implicated in etiopathogenesi

Immunological study of IFNß-1a treated and untreated multiple sclerosis patients: clarifying IFNB mechanisms and establishing specific dendritic cell immunotherapy

Objectives: A comparative immunological evaluation of multiple sclerosis ( MS) patients receiving IFNbeta treatment and patients who are not receiving treatment may help clarify IFNbeta neurological mechanisms and lead the way to an effective dendritic cell ( DC) immunotherapy. This type of study helps clarify the pathological function of T cells and DCs within the TH1/TH2/TH3 network as well as the specific interactions between TH1/TH2/TH3 cytokines implicated in MS pathological mechanisms and determine the best way of reestablishing the TH1/TH2/TH3 network equilibrium. Methods: We studied network interactions between TH1/TH2/TH3 cytokine levels in serum and supernatants of whole blood and CD14+ monocyte-derived DCs in the remission phase of the disease and in correlation to the Expanded Disability Status Scale (EDSS). Results: We found that TH1 dysregulation results in a disruption of the maturation and activation of dendritic and T cells, and a lack of T-regulating cells for the induction of self-tolerance; IFNbeta mechanisms restore regulation by reestablishing the network balance but fail to resolve the disease completely due to in vivo IL12p70 network interactions leading to the deletion of self-aggressive cells. Conclusions: Our results indicate that a specific DC immunotherapy could cure rather than treat MS. The best point to reestablish the normal physiological cycle is at the immature DC stage which can be done in vitro with treated peripheral blood CD14+ cells and used in vivo to stimulate the expansion of specific regulatory T cells. Copyright (C) 2005 S. Karger AG, Basel

Soluble CD30: a biomarker for evaluating the clinical risk versus benefit of IFNß1A treatment in multiple sclerosis

Aberrant redox regulation occurs in immune and neurological pathologies, hence targeting the pathways involved in the regulation of the redox system could provide further insights into these diseases and open up new avenues for therapy. Soluble (s) CD30 is of key clinical importance in this respect, as its levels reflect the functionality of the CD30 receptor (CD30R), the specific lymphocyte receptor for thiol disulfide/oxidoreductase thioredoxin 1 (Trx1) which is known to regulate important immune and neurological processes. Increased levels of sCD30 appear to be a common element of oxidative stress, immunological alterations and neurological deficit, therefore these increases could be used as a clinical biomarker and target for therapy. We targeted sCD30 in our study of dendritic cell (DC) regulation of the T helper (Th) cell network in multiple sclerosis (MS) patients, as abnormalities in T regulatory (Treg)/Th1/Th17 pathways contribute to the pathogenesis of this immunological/neurological disease. DC profiles in Treg/Th1/Th2/Th17-types of cytokine production in culture supernatants were used as they determine the type of Th differentiation. Our results show that sCD30 levels increase significantly in MS patients, reflecting the disruption in the regulation of the Treg/Th1/Th17 cell network. A fall in the level of soluble CD30, induced by IFNbeta1a therapy, opposed the increase of neurological deficit through increasing IL10 and TGFbeta levels, thus re-establishing network homeostasis but only when this was accompanied by an increase in IL12p70 levels. Since IL12p70 cytokine production is regulated by Trx1, our results indicate that redox system alterations may be the cause of IFNbeta1a therapeutic inefficacy. We conclude that an increase in the level of IL10, TGFbeta and IL12p70 and a fall in the level of sCD30 represent a means of evaluating the clinical risk/benefit of IFNbeta1a treatment

Soluble CD30: A Biomarker for Evaluating the Clinical Risk versus Benefit of IFNβ1A Treatment in Multiple Sclerosis Patients

Aberrant redox regulation occurs in immune and neurological pathologies, hence targeting the pathways involved in the regulation of the redox system could provide further insights into these diseases and open up new avenues for therapy. Soluble (s) CD30 is of key clinical importance in this respect, as its levels reflect the functionality of the CD30 receptor (CD30R), the specific lymphocyte receptor for thiol disulfide/oxidoreductase thioredoxin 1 (Trx1) which is known to regulate important immune and neurological processes. Increased levels of sCD30 appear to be a common element of oxidative stress, immunological alterations and neurological deficit, therefore these increases could be used as a clinical biomarker and target for therapy. We targeted sCD30 in our study of dendritic cell (DC) regulation of the T helper (Th) cell network in multiple sclerosis (MS) patients, as abnormalities in T regulatory (Treg)/Th1/Th17 pathways contribute to the pathogenesis of this immunological/neurological disease. DC profiles in Treg/Th1/Th2/Th17-types of cytokine production in culture supernatants were used as they determine the type of Th differentiation. Our results show that sCD30 levels increase significantly in MS patients, reflecting the disruption in the regulation of the Treg/Th1/Th17 cell network. A fall in the level of soluble CD30, induced by IFNβ1a therapy, opposed the increase of neurological deficit through increasing IL10 and TGFβ levels, thus re-establishing network homeostasis but only when this was accompanied by an increase in IL12p70 levels. Since IL12p70 cytokine production is regulated by Trx1, our results indicate that redox system alterations may be the cause of IFNβ1a therapeutic inefficacy. We conclude that an increase in the level of IL10, TGFβ and IL12p70 and a fall in the level of sCD30 represent a means of evaluating the clinical risk/benefit of IFNβ1a treatment. </jats:p