Dataset Information

MiR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma.

ABSTRACT: The pathogenesis of the cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF), is unclear. MicroRNA (miRNA) are small noncoding RNAs that target mRNA leading to reduced mRNA translation. Recently, specific miRNA were shown to be altered in CTCL. We detected significantly reduced expression of miR-223 in early-stage MF skin, and further decreased levels of miR-223 in advanced-stage disease. CTCL peripheral blood mononuclear cells and cell lines also had reduced miR-223 as compared with controls. Elevated expression of miR-223 in these cell lines reduced cell growth and clonogenic potential, whereas inhibition of miR-223 increased cell numbers. Investigations into putative miR-223 targets with oncogenic function, including E2F1 and MEF2C, and the predicted miR-223 target, TOX, revealed that all three were targeted by miR-223 in CTCL. E2F1, MEF2C, and TOX proteins were decreased with miR-223 overexpression, whereas miR-223 inhibition led to increased protein levels in CTCL. In addition, we showed that the 3'-UTR of TOX mRNA was a genuine target of miR-223. Therefore, reduced levels of miR-223 in MF/CTCL lead to increased expression of E2F1, MEF2C, and TOX, which likely contributes to the development and/or progression of CTCL. Thus, miR-223 and its targets may be useful for the development of new therapeutics for MF/CTCL.

SUBMITTER: McGirt LY

PROVIDER: S-EPMC3961555 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

miR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma.

McGirt Laura Y LY Adams Clare M CM Baerenwald Devin A DA Zwerner Jeffrey P JP Zic John A JA Eischen Christine M CM

The Journal of investigative dermatology 20131107 4

The pathogenesis of the cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF), is unclear. MicroRNA (miRNA) are small noncoding RNAs that target mRNA leading to reduced mRNA translation. Recently, specific miRNA were shown to be altered in CTCL. We detected significantly reduced expression of miR-223 in early-stage MF skin, and further decreased levels of miR-223 in advanced-stage disease. CTCL peripheral blood mononuclear cells and cell lines also had reduced miR-223 as compared with control ...[more]

PMID: 24304814

Similar Datasets

Project description:BackgroundA prospective, observational, US-based study (PROVe) used three questionnaires (Pruritus-VAS, Skindex-29, MF/SS-CTCL QoL) to assess quality of life in patients diagnosed with mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL); however, none of these studies was provided with a preference-based algorithm yielding health state utility values (HSUVs).ObjectiveThis study aimed to assess the feasibility of deriving HSUVs from published mapping algorithms by comparing mapped utilities with the HSUVs reported in the MF-CTCL literature.MethodsWe searched PubMed, the School of Health and Related Research Health Utility Database (ScHARRHUD), and the Health Economics Research Centre (HERC) database of mapping studies (version 7.0) to identify any studies mapping Pruritus-VAS, Skindex-29, or MF/SS-CTCL QoL to a preference-based instrument (ideally, EQ-5D), and any studies assessing HSUVs in MF-CTCL. Two algorithms from a recent study that mapped Pruritus-VAS onto EQ-5D-3L were applied to the PROVe patient-level data. We performed multiple imputation to handle missing VAS data, calculated average mapped utilities in the whole sample, and compared them with relevant factors using the t-test and one-way analysis of variance (ANOVA).ResultsOverall, 298 patients provided 1441 Pruritus-VAS scores over a 2-year follow-up (1-21 visits per patient). The average mapped HSUVs ranged between 0.950 and 0.999 depending on the algorithm applied and imputation of missing data. In subgroup analysis, significant differences (p < 0.05) were observed according to age, race, and cancer stage. A few previous studies that collected HSUVs from MF-CTCL patients reported mean values of between 0.82 and 0.87 using time trade-off, 0.63 and 0.83 using EQ-5D, and 0.51 and 0.69 using the HUI3.ConclusionsThe HSUVs derived by applying published mapping algorithms to PROVe Pruritus-VAS data appeared largely overestimated if compared with the existing literature. More research is required to understand the applicability of existing mapping algorithms and to develop new mapping algorithms in MF-CTCL.

Project description:BackgroundAlthough the quality of life (QoL) plays an important role in treatment decision making and clinical management of mycosis fungoides (MF) or Sézary syndrome (SS) subtypes of cutaneous T-cell lymphomas (MF/SS-CTCLs), an MF- or SS-specific measure of QoL does not exist.ObjectiveThe objective of this research was to develop and validate the first QoL instrument for MF/SS-CTCL using a patient-centered approach.MethodsA conceptual framework for the MF/SS-CTCL QoL was developed through a literature review and interviews with key opinion leaders. Concept elicitation with patients was utilized to refine the conceptual model and generate preliminary items. The items were then revised based on qualitative and quantitative feedback obtained through cognitive debriefing surveys and interviews with patients. Next, participants (N=126) completed the preliminary MF/SS-CTCL QoL and a comparator measure of health-related QoL (Skindex-29) through the PatientsLikeMe Open Research Exchange. The MF/SS-CTCL QoL was completed again 5 days later by 66 participants for the purposes of evaluating test-retest reliability. The MF/SS-CTCL QoL was finalized based on results from an empirical evaluation, which included both classical and modern test theory approaches. Specifically, this included evaluation of (1) the optimal item response theory measurement model; (2) item fit; (3) unidimensionality; (4) rating scale performance; (5) reliability; (6) test information (precision); (7) person-to-item map; (8) convergent and discriminant validity; and (9) presence of bias via differential item function.ResultsResults from the comprehensive psychometric evaluation utilizing a Rasch-Grouped Rating Scale model yielded a final 12-item instrument. The rating scale functioned as expected, and the instrument exhibited adequate person reliability (.87), good to excellent test-retest reliability (r=.89, P<.001), high levels of measurement precision, and good person-to-item targeting. The correlation between the MF/SS-CTCL QoL and the Skindex-29 (r=.852, P<.001) was significantly greater than the correlation between the MF/SS-CTCL QoL and syndrome stage (r=.260, P<.001), providing support for convergent and discriminant validity. Items did not show significant bias based on gender, age, or race. Rasch scores were converted to scaled scores with qualitative descriptive categories for ease of interpretation.ConclusionsEmpirical evaluation demonstrated strong evidence of excellent psychometric properties. Utilizing a patient-centered measure development approach ensures that this QoL instrument captures the information that is most meaningful and clinically relevant to patients.

Project description:ObjectivesTo evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions.DesignOpen-label, dose-escalation, phase I trial.SettingDermatology outpatient clinic and clinical research unit at a university teaching hospital.PatientsA total of 21 adult patients (11 male, 10 female)with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine.InterventionTreatment once every 2 weeks with 120 mg/m(2) intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity.Main outcome measuresClinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens.ResultsA minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyltransferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzylguanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P=.02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P=.01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55-0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug.ConclusionO6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses.

Project description:Mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) is a rare lymphoma localized in the skin. Due to its indolent nature and similarity to other skin conditions, diagnosis is often delayed or incorrect. Consequently, accurate calculations of incidence and prevalence are difficult to make. The treatment pathway taken by MF-CTCL patients can differ depending upon local healthcare systems, clinical policies and guidelines. This study aims to (1) provide an estimate for the prevalence of treated MF-CTCL patients in Spain, (2) describe the Spanish patient treatment pathways for MF-CTCL, including quantification of the distribution of patients between primary, secondary and tertiary care institutions, and (3) investigate and quantify the treatment preferences of physicians. This study employed primary market research methodologies to facilitate the collection of patient numbers and treatment practices from healthcare professionals (HCPs) and patients. Poor diagnosis of MF-CTCL may mean that actual prevalence levels in the broader population are higher than those estimated by this analysis of treated patients. This study was reliant upon accurate reporting by HCPs of patient numbers and their personal treatment practices. The rarity of the condition means the patient sample size is relatively small and limits possible accuracy of the quantitative analyses of patient-derived data, although this is supplemented by HCP-derived data in the analysis. Around 75% of MF-CTCL patients in Spain report that the initial diagnosis by their general practitioner is incorrect. This is usually due to underestimation of severity or type of skin disease. Once they have been correctly diagnosed (usually by a dermatologist) in secondary care, the management of MF-CTCL is led by dermatologists. In 39% of patients, shared care teams are also involved in patient management. Following diagnosis, the majority of patient management is conducted by secondary or tertiary care centers. Incidence rates have increased in recent years, and possible reasons for this include improving levels of diagnosis. Survival in MF-CTCL has also increased over the last few decades. This trend appears to be reflected in the prevalence reported in this study, which is higher than suggested by some other estimates. However, it is still likely that there are further undiagnosed MF-CTCL patients in Spain due to the challenges of diagnosis at the primary care level.

Dataset Information

MiR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma.

Publications

miR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets