8 research outputs found
Cytoplasmic Intron Sequence-Retaining Transcripts Can Be Dendritically Targeted via ID Element Retrotransposons
SummaryRNA precursors give rise to mRNA after splicing of intronic sequences traditionally thought to occur in the nucleus. Here, we show that intron sequences are retained in a number of dendritically-targeted mRNAs, by using microarray and Illumina sequencing of isolated dendritic mRNA as well as in situ hybridization. Many of the retained introns contain ID elements, a class of SINE retrotransposon. A portion of these SINEs confers dendritic targeting to exogenous and endogenous transcripts showing the necessity of ID-mediated mechanisms for the targeting of different transcripts to dendrites. ID elements are capable of selectively altering the distribution of endogenous proteins, providing a link between intronic SINEs and protein function. As such, the ID element represents a common dendritic targeting element found across multiple RNAs. Retention of intronic sequence is a more general phenomenon than previously thought and plays a functional role in the biology of the neuron, partly mediated by co-opted repetitive sequences
Cytoplasmic BK\u3csub\u3eCa\u3c/sub\u3e channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons
High single-channel conductance K+ channels, which respond jointly to membrane depolarization and micromolar concentrations of intracellular Ca2+ ions, arise from extensive cell-specific alternative splicing of pore-forming α-subunit mRNAs. Here, we report the discovery of an endogenous BKCa channel α-subunit intron-containing mRNA in the cytoplasm of hippocampal neurons. This partially processed mRNA, which comprises ≈10% of the total BKCa channel α-subunit mRNAs, is distributed in a gradient throughout the somatodendritic space. We selectively reduced endogenous cytoplasmic levels of this intron-containing transcript by RNA interference without altering levels of the mature splice forms of the BKCa channel mRNAs. In doing so, we could demonstrate that changes in a unique BKCa channel α-subunit introncontaining splice variant mRNA can greatly impact the distribution of the BKCa channel protein to dendritic spines and intrinsic firing properties of hippocampal neurons. These data suggest a new regulatory mechanism for modulating the membrane properties and ion channel gradients of hippocampal neurons
Cytoplasmic Intron Sequence-Retaining Transcripts Can Be Dendritically Targeted via ID Element Retrotransposons
RNA Cargoes Associating with FMRP Reveal Deficits in Cellular Functioning in Fmr1 Null Mice
Treatment of early‐stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study*
BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) Study is a prospective analysis of an international database and here we examine front-line treatments and quality-of-life in patients with newly diagnosed Mycosis Fungoides (MF). OBJECTIVES: a) differences in first-line approach according to the TNMB staging; b) parameters related to a first-line systemic approach; c) response rates and quality of life (QoL) measures. PATIENTS AND METHODS: 395 newly diagnosed patients with early-stage MF (IA-IIA) were recruited from 41 centers in 17 countries between 1/1/2015–31/12/2018 following central clinicopathological review. RESULTS: First-line therapy was skin directed therapy (SDT) (81.6%) whilst a smaller percentage (44 cases;11.1%) received systemic therapy. Expectant observation was 7.3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA: 6%; IB: 14%; IIA:20%; IA-IB vs IIA: p10: 15%; <=10: 7%; p=0.01) and folliculotropic MF (FMF) (24% vs 12%; p=0.001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs T1a/T2a: OR: 3.07) and FMF (OR: 2.82). The overall response rate (ORR) to first-line SDT was 73% whilst the ORR to first-line systemic treatments was lower (57%) (p=0.027). Health related QoL improved significantly in both patients with responsive and stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices and that SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues
Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Study (PROCLIPI study).
BACKGROUND
The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) Study is a prospective analysis of an international database and here we examine front-line treatments and quality-of-life in patients with newly diagnosed Mycosis Fungoides (MF).
OBJECTIVES
a) differences in first-line approach according to the TNMB staging; b) parameters related to a first-line systemic approach; c) response rates and quality of life (QoL) measures.
PATIENTS AND METHODS
395 newly diagnosed patients with early-stage MF (IA-IIA) were recruited from 41 centers in 17 countries between 1/1/2015-31/12/2018 following central clinicopathological review.
RESULTS
First-line therapy was skin directed therapy (SDT) (81.6%) whilst a smaller percentage (44 cases;11.1%) received systemic therapy. Expectant observation was 7.3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA: 6%; IB: 14%; IIA:20%; IA-IB vs IIA: p10: 15%; <=10: 7%; p=0.01) and folliculotropic MF (FMF) (24% vs 12%; p=0.001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs T1a/T2a: OR: 3.07) and FMF (OR: 2.82). The overall response rate (ORR) to first-line SDT was 73% whilst the ORR to first-line systemic treatments was lower (57%) (p=0.027). Health related QoL improved significantly in both patients with responsive and stable disease.
CONCLUSIONS
Disease characteristics such as presence of plaques and FMF influence physician treatment choices and that SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues
Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study
Background The PROspective Cutaneous Lymphoma International Prognostic
Index (PROCLIPI) study is a prospective analysis of an international
database. Here we examine front-line treatments and quality of life
(QoL) in patients with newly diagnosed mycosis fungoides (MF).
Objectives To identify (i) differences in first-line approaches
according to tumour-nodes-metastasis-blood (TNMB) staging; (ii)
parameters related to a first-line systemic approach and (iii) response
rates and QoL measures.
Methods In total, 395 newly diagnosed patients with early-stage MF
(stage IA-IIA) were recruited from 41 centres in 17 countries between 1
January 2015 and 31 December 2018 following central clinicopathological
review.
Results The most common first-line therapy was skin-directed therapy
(SDT) (322 cases, 81 center dot 5%), while a smaller percentage (44
cases, 11 center dot 1%) received systemic therapy. Expectant
observation was used in 7 center dot 3%. In univariate analysis, the
use of systemic therapy was significantly associated with higher
clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0
center dot 001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0
center dot 001), higher modified Severity Weighted Assessment Tool (>
10, 15%; <= 10, 7%; P = 0 center dot 01) and folliculotropic MF (FMF)
(24% vs. 12%, P = 0 center dot 001). Multivariate analysis
demonstrated significant associations with the presence of plaques
(T1b/T2b vs. T1a/T2a, odds ratio 3 center dot 07) and FMF (odds ratio 2
center dot 83). The overall response rate (ORR) to first-line SDT was
73%, while the ORR to first-line systemic treatments was lower (57%)
(P = 0 center dot 027). Health-related QoL improved significantly both
in patients with responsive disease and in those with stable disease.
Conclusions Disease characteristics such as presence of plaques and FMF
influence physician treatment choices, and SDT was superior to systemic
therapy even in patients with such disease characteristics.
Consequently, future treatment guidelines for early-stage MF need to
address these issues