Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARγ, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARγ signaling could also play an anti-neoplastic role in several <it>in vitro </it>models, although conflicting results are reported from <it>in vivo </it>models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes.</p> <p>Methods</p> <p>A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs.</p> <p>Results</p> <p>In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, <it>P </it>= 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, <it>P </it>= 0.02), and among women (OR = 2.07, <it>P </it>= 0.01).</p> <p>Conclusion</p> <p>These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal.</p

Drosophila muscleblind Codes for Proteins with One and Two Tandem Zinc Finger Motifs

Muscleblind-like proteins, Muscleblind (Mbl) in Drosophila and MBNL1-3 in vertebrates, are regulators of alternative splicing. Human MBNL1 is a key factor in the etiology of myotonic dystrophy (DM), a muscle wasting disease caused by the occurrence of toxic RNA molecules containing CUG/CCUG repeats. MBNL1 binds to these RNAs and is sequestered in nuclear foci preventing it from exerting its normal function, which ultimately leads to mis-spliced mRNAs, a major cause of the disease. Muscleblind-proteins bind to RNAs via N-terminal zinc fingers of the Cys3-His type. These zinc fingers are arranged in one (invertebrates) or two (vertebrates) tandem zinc finger (TZF) motifs with both fingers targeting GC steps in the RNA molecule. Here I show that mbl genes in Drosophila and in other insects also encode proteins with two TZF motifs, highly similar to vertebrate MBNL proteins. In Drosophila the different protein isoforms have overlapping but possibly divergent functions in vivo, evident by their unequal capacities to rescue the splicing defects observed in mbl mutant embryos. In addition, using whole transcriptome analysis, I identified several new splicing targets for Mbl in Drosophila embryos. Two of these novel targets, kkv (krotzkopf-verkehrt, coding for Chitin Synthase 1) and cora (coracle, coding for the Drosophila homolog of Protein 4.1), are not muscle-specific but expressed mainly in epidermal cells, indicating a function for mbl not only in muscles and the nervous system

Expression of a Dominant Negative CELF Protein In Vivo Leads to Altered Muscle Organization, Fiber Size, and Subtype

CUG-BP and ETR-3-like factor (CELF) proteins regulate tissue- and developmental stage-specific alternative splicing in striated muscle. We previously demonstrated that heart muscle-specific expression of a nuclear dominant negative CELF protein in transgenic mice (MHC-CELFΔ) effectively disrupts endogenous CELF activity in the heart in vivo, resulting in impaired cardiac function. In this study, transgenic mice that express the dominant negative protein under a skeletal muscle-specific promoter (Myo-CELFΔ) were generated to investigate the role of CELF-mediated alternative splicing programs in normal skeletal muscle.Myo-CELFΔ mice exhibit modest changes in CELF-mediated alternative splicing in skeletal muscle, accompanied by a reduction of endomysial and perimysial spaces, an increase in fiber size variability, and an increase in slow twitch muscle fibers. Weight gain and mean body weight, total number of muscle fibers, and overall muscle strength were not affected.Although these findings demonstrate that CELF activity contributes to the normal alternative splicing of a subset of muscle transcripts in vivo, the mildness of the effects in Myo-CELFΔ muscles compared to those in MHC-CELFΔ hearts suggests CELF activity may be less determinative for alternative splicing in skeletal muscle than in heart muscle. Nonetheless, even these small changes in CELF-mediated splicing regulation were sufficient to alter muscle organization and muscle fiber properties affected in myotonic dystrophy. This lends further evidence to the hypothesis that dysregulation of CELF-mediated alternative splicing programs may be responsible for the disruption of these properties during muscle pathogenesis

Signaling Mechanisms of Vav3, a Guanine Nucleotide Exchange Factor and Androgen Receptor Coactivator, in Physiology and Prostate Cancer Progression

The Rho GTPase guanine nucleotide exchange factor (GEF) Vav3 is the third member of the Vavfamily of GEFS and is activated by tyrosine phosphorylation. Through stimulation of Rho GTPaseactivity, Vav3 promotes cell migration, invasion, and other cellular processes. Work from our laboratory first established that Vav3 is upregulated in models of castration-resistant prostate cancer progression and enhances androgen receptor as well as androgen receptor splice variant activity. Recent analysis of clinical specimens supports Vav3 as a potential biomarker of aggressive prostate cancer. Consistent with a role in promoting castration-­resistant disease, Vav3 is a versatile enhancer of androgen receptor by both ligand-dependent and ligand-independent mechanisms and as such impacts established pathways of androgen receptor reactivation in advanced prostate cancer. Distinct Vav3 domains and mechanisms participate in ligand-dependent and -independent androgen receptor coactivation. To provide a physiologic context, we review Vav3 actions elucidated by gene knockout studies. This chapter describes the pervasive role of Vav3 in progression of prostate cancer to castration resistance. We discuss the mechanisms by which prostate cancer cells exploit Vav3 signaling to promote androgen receptor activity under different hormonal milieus, which are relevant to clinical prostate cancer. Lastly, we review the data on the emerging role for Vav3 in other cancers ranging from leukemias to gliomas.https://nsuworks.nova.edu/hpd_medsci_faculty_books/1002/thumbnail.jp

A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60S Subunit Export

A systematic search for human ribosome biogenesis factors shows conservation of many aspects of eukaryotic ribosome synthesis with the well-studied process in yeast and identifies an export route of 60S subunits that is specific for higher eukaryotes

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8&nbsp;% in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat

Triplet Repeat–Derived siRNAs Enhance RNA–Mediated Toxicity in a Drosophila Model for Myotonic Dystrophy

More than 20 human neurological and neurodegenerative diseases are caused by simple DNA repeat expansions; among these, non-coding CTG repeat expansions are the basis of myotonic dystrophy (DM1). Recent work, however, has also revealed that many human genes have anti-sense transcripts, raising the possibility that human trinucleotide expansion diseases may be comprised of pathogenic activities due both to a sense expanded-repeat transcript and to an anti-sense expanded-repeat transcript. We established a Drosophila model for DM1 and tested the role of interactions between expanded CTG transcripts and expanded CAG repeat transcripts. These studies revealed dramatically enhanced toxicity in flies co-expressing CTG with CAG expanded repeats. Expression of the two transcripts led to novel pathogenesis with the generation of dcr-2 and ago2-dependent 21-nt triplet repeat-derived siRNAs. These small RNAs targeted the expression of CAG-containing genes, such as Ataxin-2 and TATA binding protein (TBP), which bear long CAG repeats in both fly and man. These findings indicate that the generation of triplet repeat-derived siRNAs may dramatically enhance toxicity in human repeat expansion diseases in which anti-sense transcription occurs