Sublingual immunotherapy vs placebo in the management of grass pollen-induced allergic rhinitis in adults: A systematic review and meta-analysis.

INTRODUCTION: Allergic rhinitis (AR) is a common inflammatory condition of the nasal mucosa affecting approximately 20% of the population worldwide. Current therapies include intranasal antihistamines, corticosteroids, subcutaneous and sublingual immunotherapy (SLIT). This review and meta-analysis assess the efficacy of SLIT in the management of grass pollen-induced AR in adults. METHODS: Ovid EMBASE, Ovid EBM Reviews, Cochrane Central Register of Controlled Trials, Ovid MedLine and PubMed were searched using the following terms: 'sublingual immunotherapy', 'SLIT', 'rhinitis', 'allergic rhinitis', 'rhinosinusitis' and 'rhino-conjunctivitis'. All included studies were double-blind, placebo-controlled and randomised trials. Primary outcome was symptom score and secondary outcome included quality of life and safety profile. Meta-analysis of symptom improvement was carried out. RESULTS: Six studies were identified with 979 subjects randomly allocated to SLIT and 992 to a placebo control. All studies reported an improvement in symptoms with SLIT, with five reaching statistical significance (P < .05). Four studies reported statistically significant improvement in quality of life (P < .05). Oral pruritus was the most common adverse event reported. The overall risk of bias was high in 50% of the studies. CONCLUSIONS: Sublingual immunotherapy was a safe and effective treatment for grass pollen-induced AR in adults, and therefore, consideration should be given to its use for moderate-to-severe disease in the UK-wide population.

The dREAM/Myb-MuvB complex and Grim are key regulators of the programmed death of neural precursor cells at the Drosophila posterior wing margin.

Successful development of a multicellular organism depends on the finely tuned orchestration of cell proliferation, differentiation and apoptosis from embryogenesis through adulthood. The MYB-gene family encodes sequence-specific DNA-binding transcription factors that have been implicated in the regulation of both normal and neoplastic growth. The Drosophila Myb protein, DMyb (and vertebrate B-Myb protein), has been shown to be part of the dREAM/MMB complex, a large multi-subunit complex, which in addition to four Myb-interacting proteins including Mip130, contains repressive E2F and pRB proteins. This complex has been implicated in the regulation of DNA replication within the context of chorion gene amplification and transcriptional regulation of a wide array of genes. Detailed phenotypic analysis of mutations in the Drosophila myb gene, Dm myb, has revealed a previously undiscovered function for the dREAM/MMB complex in regulating programmed cell death (PCD). In cooperation with the pro-apoptotic protein Grim and dREAM/MMB, DMyb promotes the PCD of specified sensory organ precursor daughter cells in at least two different settings in the peripheral nervous system: the pIIIb precursor of the neuron and sheath cells in the posterior wing margin and the glial cell in the thoracic microchaete lineage. Unlike previously analyzed settings, in which the main role of DMyb has been to antagonize the activities of other dREAM/MMB complex members, it appears to be the critical effector in promoting PCD. The finding that Dm myb and grim are both involved in regulating PCD in two distinct settings suggests that these two genes may often work together to mediate PCD.

Development of advanced conduction disturbances following balloon-expandable transcatheter aortic valve replacement leads to poorer clinical outcomes.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a reliable method of treating patients with severe aortic stenosis, but is associated with postprocedure conduction defects. OBJECTIVE: The purpose of this study was to compare clinical outcomes in patients who developed advanced conduction defects post-TAVR to those who did not. METHODS: We conducted a retrospective chart review of 243 patients who underwent balloon-expandable TAVR with the Edwards Sapien valve to determine the incidence of advanced conduction defects in our cohort. We compared clinical outcomes including overall mortality, improvement in symptomatology, and improvement in left ventricular ejection fraction. RESULTS: Among the 243 patients included in the study, 9.1% (22/243) required permanent pacemaker (PPM); 19.8% (48/243) developed left bundle branch block (LBBB), and 71.2% (173/243) did not develop any permanent advanced conduction defects. Overall 1-year mortality was similar across all three groups. There was significant improvement in New York Heart Association functional capacity of all groups post-TAVR, but this was much less in the PPM group (45.5% vs 68.8%, P = .04). Postprocedure from TAVR, patients with LBBB or PM were less likely to have improvement in their ejection fraction (net loss of -0.7% for LBBB and -5.7% for PPM compared to a net gain of 2.3% for no-LBBB/PM (P = .02). CONCLUSION: Patients who develop LBBB or require PM post-TAVR with Edwards Sapien valves are less likely to improve New York Heart Association functional capacity and more likely to have no improvement or deterioration of their pre-TAVR left ventricular ejection fraction.

MYB and CBP: physiological relevance of a biochemical interaction.

Drosophila melanogaster possesses a single gene, Dm myb, that is closely related to the vertebrate family of Myb genes, which encode transcription factors involved in regulatory decisions affecting cell proliferation, differentiation and apoptosis. In proliferating cells, the Dm myb gene product, DMyb, promotes both S-phase and M-phase, and acts to preserve diploidy by suppressing endoreduplication. The CBP and p300 proteins are transcriptional co-activators that interact with a multitude of transcription factors, including Myb. In transient transfection assays, transcriptional activation by DMyb is enhanced by co-expression of the Drosophila CBP protein, dCBP. Genetic interaction analysis reveals that these genes work together to promote mitosis, thereby demonstrating the physiological relevance of the biochemical interaction between the Myb and CBP proteins within a developing organism.

The DNA replication-related element-binding factor (DREF) is a transcriptional regulator of the Drosophila myb gene.

Drosophila melanogaster possesses a single gene, Dm myb, that is closely related to the vertebrate proto-oncogene c-Myb, and its other family members (A-Myb and B-Myb), all of which encode transcription factors. Dm myb is expressed in all proliferating cells throughout development, and previous studies demonstrate that Dm myb promotes both S-phase and M-phase in proliferating cells, while preserving diploidy by suppressing endoreduplication. We have initiated a characterization of the mechanisms that regulate Dm myb expression, and we report here that the transcriptional activator DREF (the DNA replication-related element binding factor) activates Dm myb transcription via two binding sites located in the 5' flanking region; that the Dm myb promoter lacks a prototypical TATA box sequence and instead appears to use an initiator/downstream promoter element (Inr/DPE) type promoter; and that Dm myb expression is regulated at the translational as well as transcriptional level.

Two components of the Myb complex, DMyb and Mip130, are specifically associated with euchromatin and degraded during prometaphase throughout development.

The Drosophila Myb protein, DMyb, is a transcription factor important for cell proliferation and development. Unlike the mRNAs produced by mammalian myb genes, Drosophila myb transcripts do not fluctuate substantially during the cell cycle. A comprehensive analysis of the localization and degradation of the DMyb protein has now revealed that DMyb is present in nuclei during S phase of all mitotically active tissues throughout embryogenesis and larval development. However, DMyb and Mip130, another member of the Myb complex, are not uniformly distributed throughout the nucleus. Instead, both proteins, which colocalize, appear to be specifically excluded from heterochromatic regions of chromosomes. Furthermore, DMyb and Mip130 are unstable proteins that are degraded during prometaphase of mitosis. The timing of their degradation is reminiscent of Cyclin A, but at least for DMyb, the mechanism differs; although DMyb degradation is dependent on core APC/C components, it does not depend on the Fizzy or Fizzy-related adaptor proteins. DMyb levels are also high in actively endoreplicating polyploid cells, but there is no indication of cyclical degradation. We conclude that cell cycle specific degradation of DMyb and Mip130 is likely to be utilized as a key regulatory mechanism in down-regulating their levels and the activity of the Myb complex.

Mutations in Drosophila myb lead to centrosome amplification and genomic instability.

We have previously established that the single myb gene in Drosophila melanogaster, Dm myb, which is related to the proto-oncogene Myb, is required for the G2/M transition of the cell cycle and for suppression of endoreduplication in pupal wing cells. We now report that studies of the abdominal phenotype in loss-of-function Dm myb mutants reveal additional roles for Dm myb in the cell cycle, specifically in mitosis. Abdominal epidermal cells that are mutant for Dm myb proliferate more slowly than wild-type controls throughout pupation, with particularly sluggish progression through the early stages of mitosis. Abnormal mitoses associated with multiple functional centrosomes, unequal chromosome segregation, formation of micronuclei, and/or failure to complete cell division are common in the later cell cycles of mutant cells. Resulting nuclei are often aneuploid and/or polyploid. Similar defects have also been observed in loss-of-function mutations of the tumor suppressor genes p53, Brca1 and Brca2. These data demonstrate that in abdominal epidermal cells, Dm myb is required to sustain the appropriate rate of proliferation, to suppress formation of supernumerary centrosomes, and to maintain genomic integrity.

Drosophila myb exerts opposing effects on S phase, promoting proliferation and suppressing endoreduplication.

Drosophila melanogaster possesses a single gene, Dm myb, that is closely related to the vertebrate family of Myb genes, which encode transcription factors that are involved in regulatory decisions affecting cell proliferation, differentiation and apoptosis. The vertebrate Myb genes have been specifically implicated in regulating the G(1)/S transition of the cell cycle. Dm myb is expressed in all proliferating tissues, but not at detectable levels in endoreduplicating cells. Analysis of loss-of-function mutations in Dm myb revealed a block at the G(2)/M transition and mitotic defects, but did not directly implicate Dm myb function in the G(1/)S transition. We have used the Gal4-UAS binary system of ectopic expression to further investigate the function of Dm myb. Our results demonstrate that depending upon the type of cell cycle, ectopic Dm myb activity can exert opposing effects on S phase: driving DNA replication and promoting proliferation in diploid cells, even when developmental signals normally dictate cell cycle arrest; but suppressing endoreduplication in endocycling cells, an effect that can be overcome by induction of E2F. We also show that a C-terminally truncated DMyb protein, which is similar to an oncogenic form of vertebrate Myb, has more potent effects than the full-length protein, especially in endoreduplicating tissues. This finding indicates that the C terminus acts as a negative regulatory domain, which can be differentially regulated in a tissue-specific manner. Our studies help to resolve previous discrepancies regarding myb gene function in Drosophila and vertebrates. We conclude that in proliferating cells, Dm myb has the dual function of promoting S phase and M phase, while preserving diploidy by suppressing endoreduplication.