ABSTRACT
INTRODUCTION: In October 2018, the Substance Abuse and Mental Health Services Administration funded 21 sites throughout the USA to develop, implement and evaluate specialised care programmes for individuals at clinical high risk for developing a psychotic disorder (CHR-P). Per the funding requirements, such programmes were required to provide 'step-based care'-a model in which individuals are initially provided with low-intensity, non-psychosis-specific and more benign (ie, least side effects) interventions and only progress onto higher-intensity, psychosis-specific interventions with a greater risk of more severe side effects should they not meet a priori criteria for clinical response to such lower-intensity interventions. Here, we outline the evaluation component of the step-based care programme for individuals at CHR-P at The Ohio State University Early Psychosis Intervention Center (EPICENTER). METHODS AND ANALYSES: The EPICENTER CHR-P programme provides a step-based care model comprising psychotherapy, medication management, family support/education, peer support and vocational/educational support. All participants who opt to receive care at the EPICENTER will complete a standardised assessment battery as part of usual care. This battery will be administered on enrolment and will be re-administered at 6-month intervals throughout individuals' participation in EPICENTER clinical services. Participants will have the opportunity to allow for data from these usual care assessments to be used as part of an evaluation project for this new clinical service. The primary outcome for this evaluation project is time to remission of symptomatic and functional deficits commonly experienced by individuals at CHR-P. Participants will also have the opportunity to participate in a supplemental research project designed to further evaluate treatment outcomes and patient characteristics among individuals participating in EPICENTER clinical services. ETHICS AND DISSEMINATION: This project was approved by The Ohio State University Institutional Review Board. Results from this project will be disseminated through publications and presentations. TRIAL REGISTRATION NUMBER: NCT03970005; Pre-results.
Subject(s)
Mental Health Services/organization & administration , Psychotic Disorders/therapy , Adolescent , Adult , Antipsychotic Agents/therapeutic use , Child , Family/psychology , Female , Humans , Male , Ohio , Parents/education , Peer Group , Psychotherapy/organization & administration , Research Design , Risk Factors , Universities , Vocational Education/organization & administration , Young AdultABSTRACT
HTLV-I-associated adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I (HTLV-I)-negative peripheral T-cell lymphomas carry poor prognosis mainly because of acquired resistance to chemotherapy. We have shown that this disease is responsive to the combination of zidovudine and interferon-α. However, long-term maintenance therapy with this combination is associated with side effects affecting patient quality of life and hence more tolerated alternatives are needed. In this submission, we explored the effect of the mammalian target of rapamycin (mTOR) complex-1 (mTORC1) inhibitor everolimus (RAD001) on ATL and HTLV-negative malignant T-cell lines. We demonstrate that, at clinically achievable concentrations, long-term treatment with everolimus resulted in a dramatic inhibitory effect on the growth of HTLV-I-positive and -negative malignant T-cells, while normal resting or activated T-lymphocytes were resistant. Everolimus specifically induced oncoprotein Tax degradation and senescence in ATL cells and cell cycle arrest and apoptosis in HTLV-I-negative malignant T-cells. Everolimus-mediated apoptosis was also associated with an upregulation of p53 upregulated modulator of apoptosis (PUMA-α) proteins, an increase in Bax proteins and downregulation of Bcl-x(L) proteins in all tested HTLV-I-positive and -negative malignant cell lines. These results support a therapeutic role for everolimus, particularly as long-term maintenance therapy in patients with ATL and other HTLV-I-negative peripheral T-cell lymphomas.
Subject(s)
Apoptosis/drug effects , Cellular Senescence , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Lymphoma, T-Cell, Peripheral/drug therapy , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Apoptosis Regulatory Proteins/metabolism , Cells, Cultured , Everolimus , G1 Phase/drug effects , Human T-lymphotropic virus 1/metabolism , Humans , Leukemia-Lymphoma, Adult T-Cell/metabolism , Leukemia-Lymphoma, Adult T-Cell/pathology , Lymphoma, T-Cell, Peripheral/metabolism , Lymphoma, T-Cell, Peripheral/pathology , Proto-Oncogene Proteins/metabolism , Signal Transduction/drug effects , Sirolimus/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
Many of the best-selling anticancer drugs are plant-derived. We tested for the anticancer properties of extracts isolated from Centaurea ainetensis, a plant species endemic to Lebanon and which is often used in folk medicine. We performed bioassay-guided fractionation of Centaurea ainetensis extracts using a panel of normal and neoplastic murine cells to identify a component that is associated with antitumor activities. Among several compounds that were fractionated, the sesquiterpene lactone, Salograviolide A, was identified and found to exert the most significant growth inhibitory effects on neoplastic cells. At concentrations that were non-cytotoxic to primary keratinocytes, Centaurea ainetensis crude extract and Salograviolide A preferentially inhibited the proliferation of papilloma and squamous cell carcinoma (SCC) cell lines without significantly affecting the growth of normal cells. Flow cytometric analysis of DNA content indicated that the inhibition of cell proliferation by Centaurea ainetensis crude extract and Salograviolide A was due to G0/G1 cell cycle arrest and increased pre-G0/G1, respectively. The increase in pre-G0/G1, and presumably apoptosis induction, in Salograviolide A-treated keratinocytes was confirmed by DNA Hoechst staining. Western blot analysis and electrophoretic mobility shift assay showed that both the crude extract and the isolated molecule differentially modulated key cell cycle and apoptotic regulators as well as NF-kappaB signaling. Salograviolide A-induced growth inhibition in neoplastic cells was mediated by the accumulation of reactive oxygen species (ROS) highlighting a potent oxidant role of this molecule. These studies suggest the potential therapeutic effects of Centaurea ainetensis, and its component, Salograviolide A, against epidermal squamous cell carcinogenesis.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Centaurea/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Keratinocytes/drug effects , Skin Neoplasms/drug therapy , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Cycle/drug effects , Cells, Cultured , Heterocyclic Compounds, 3-Ring/isolation & purification , Keratinocytes/pathology , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Plant Extracts/pharmacology , Reactive Oxygen Species/metabolism , Skin Neoplasms/pathologyABSTRACT
Treatment with the synthetic retinoid HPR [N-(4-hydroxyphenyl)-retinamide] causes growth arrest and apoptosis in HTLV-I (human T-cell lymphotropic virus type-I)-positive and HTLV-I-negative malignant T-cells. It was observed that HPR-mediated growth inhibition was associated with ceramide accumulation only in HTLV-I-negative cells. The aim of the present study was to investigate the mechanism by which HPR differentially regulates ceramide metabolism in HTLV-I-negative and HTLV-I-positive malignant T-cells. Clinically achievable concentrations of HPR caused early dose-dependent increases in ceramide levels only in HTLV-I-negative cells and preceded HPR-induced growth suppression. HPR induced de novo synthesis of ceramide in HTLV-I-negative, but not in HTLV-I-positive, cells. Blocking ceramide glucosylation in HTLV-I-positive cells, which leads to accumulation of endogenous ceramide, rendered these cells more sensitive to HPR. Exogenous cell-permeant ceramides that function partially by generating endogenous ceramide induced growth suppression in all tested malignant lymphocytes, were consistently found to be less effective in HTLV-I-positive cells confirming their defect in de novo ceramide synthesis. Owing to its multipotent activities, the HTLV-I-encoded Tax protein was suspected to inhibit ceramide synthesis. Tax-transfected Molt-4 and HELA cells were less sensitive to HPR and C6-ceramide mediated growth inhibition respectively and produced lower levels of endogenous ceramide. Together, these results indicate that HTLV-I-positive cells are defective in de novo synthesis of ceramide and that therapeutic modalities that bypass this defect are more likely to be successful.
Subject(s)
CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Ceramides/biosynthesis , Fenretinide/pharmacology , Human T-lymphotropic virus 1/physiology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , Cell Death/drug effects , Cell Line, Transformed , Gene Products, tax/metabolism , Glucosyltransferases/antagonists & inhibitors , Humans , Morpholines/pharmacologyABSTRACT
The main cause of skin cancer and photo-aging is chronic exposure to ultraviolet B (UVB) radiation. Such damage can be ameliorated by retinoid treatment. UVB-radiation-induced skin carcinogenesis is associated with the induction of activator protein 1 (AP1) signaling and factors, namely FOS and JUN family members. We investigated the effects of several retinoids, all-trans-retinoic acid (tRA), 9-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl)-retinamide (HPR), on UVB-induced damage in primary mouse keratinocytes. In addition, the interplay between UVB radiation, retinoid receptors, and AP1 signaling was assessed using Western blot analysis and ribonuclease protection and gene reporter assays. Exposure of keratinocytes to UVB radiation caused a down-regulation of the retinoid receptor protein levels in a proteasome-mediated manner. In contrast, FOS and JUN proteins were transiently induced shortly after exposure to UVB radiation. Retinoid treatment caused a dose-dependent reduction in the levels of retinoid receptor proteins. When irradiated cells were treated with retinoids, no significant effects on AP1 protein expression were noted. Interestingly, pretreatments with tRA and cRA, but not HPR, suppressed UVB-radiation-induced AP1 activity by more than 50%, whereas post-treatment failed to produce similar effects. Our findings indicate that the inhibition of AP1 activity by retinoids explains, at least in part, the chemopreventive potential of retinoids in UV-radiation-associated epidermal damage.
Subject(s)
Keratinocytes/cytology , Keratinocytes/radiation effects , Transcription Factor AP-1/metabolism , Ultraviolet Rays , Animals , Antineoplastic Agents/pharmacology , Blotting, Western , Cell Line , Dose-Response Relationship, Radiation , Down-Regulation , Epidermis/metabolism , Fenretinide/pharmacology , Gene Expression Regulation , Genes, Reporter , Keratinocytes/metabolism , Luciferases/metabolism , Mice , Proteasome Endopeptidase Complex/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Retinoids/metabolism , Signal Transduction , Skin Neoplasms/etiology , Time Factors , Transfection , Tretinoin/metabolismABSTRACT
Squamous cell carcinoma (SCC) is the most prevalent form of epithelial cancer. SCC results when normal epithelial cells undergo multiple neoplastic changes that culminate in the evolution of an invasive cancer. Retinoids are commonly used as chemopreventive and treatment agents in skin cancer; however, SCC progression is accompanied by a gradual loss of retinoid responsiveness. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) has shown promising anti-neoplastic activity in a variety of tumor cells, including those that are resistant to all-trans retinoic acid (t-RA). We investigated the effect of HPR on growth and apoptosis of squamous cells at different stages of carcinogenesis. We then determined if retinoic acid receptor (RAR) overexpression affected the outcome of HPR treatment. To model SCC malignant progression, we used a panel of murine keratinocytes representing different stages of squamous cell carcinogenesis. This panel consisted of primary keratinocytes, SP1 and 308 papilloma cell lines, the PAM-212 squamous carcinoma cell line, and the spindle I7 cell line. With the exception of the primary keratinocytes, all cells were unresponsive to t-RA treatment. Pharmacological concentrations of HPR were non-cytotoxic to all keratinocytes tested and HPR sensitivity was stage-dependent, with the papilloma cell lines being the most sensitive, and the spindle cells being the most resistant. Overexpression of RARgamma in SP1 papilloma cells enhanced growth suppression and apoptosis induction by HPR. HPR-induced growth suppression was accompanied by a simultaneous block in the G(1) phase of the cell cycle in RAR-transduced and control SP1 cells and differential regulation of cell cycle and apoptotic mediators.