Challenging the diagnosis of Cystic Fibrosis in a patient carrying the 186-8T/C allelic variant in the CF Transmembrane Conductance Regulator gene

BACKGROUND: This report describe for the first time a clinical case with a CFTR allelic variant 186-8T/C (c.54-8 T/C) in intron 1 of CFTR and underline the importance of applying a combination of genetic and functional tests to establish or exclude a diagnosis of Cystic Fibrosis. In this case the diagnostic algorithm proposed for CF has been successfully applied at our Center and previous CF diagnosis assigned in a different Center was not confirmed.Case report: A 38 year-old Italian woman had been treated as affected by CF since 2010, following diagnosis based on sweat tests (reported values of 73 and 57 mEq/L) and a clinical history consistent with CF. No mutations were identified by first level of genetic analysis. Afterwards the patient referred to our center for assessing the relevance of these findings. The genetic variant 186-8T/C (c.54-8 T/C) in intron 1 of the CFTR gene was detected by sequencing. Low-level interstitial-alveolar infiltration was recorded by high-resolution computerized tomography. Lung function was normal and sputum and Broncho Alveolar Lavage cultures resulted bacteriologically negative. Sweat chloride levels was re-assessed and resulted with values of 57 and 35 mEq/L, with a borderline range between 40 and 60 mEq/L. Nasal Potential Difference measurements resulted in three reliable measurements consistent with a non-CF phenotype. Differential diagnosis with ciliary dyskinesia was excluded, as was exon 2 skipping of CFTR gene that might have caused a CFTR functional defect. Furthermore, single cell fluorescence analysis in response to cAMP agonists performed in patient's monocytes overlapped those obtained in healthy donors. CONCLUSION: We concluded that this patient was not affected by CF. This case highlights the need for referrals to highly specialized centers and the importance of combined functional and genetic tests in making a correct diagnosis. Moreover, we confirmed a correlation between NPD tracings and cell depolarization in monocytes providing a rationale for proposing the use of leukocytes as a potential support for CF diagnosis

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism

Lessons from non-canonical splicing

Recent improvements in experimental and computational techniques that are used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies

Growth and reproduction in the Antarctic brooding bivalve Adacnarca nitens (Philobryidae) from the Ross Sea

We present information on the reproductive biology, population structure, and growth of the brooding Antarctic bivalve Adacnarca nitens Pelseneer 1903, from the Ross Sea, Antarctica. Individuals ranging from 0.85 - 6.00 mm were found attached to a hydrozoan colony. This species shows low fecundity and large egg size, common to other brooding species. The minimum size at which oogenesis was detected was 2.3 mm and the minimum size at which brooding was evident was 3.9 mm. Embryos of a full range of developmental stages were brooded simultaneously in females. The population showed a log-normal distribution and results suggest non-periodic reproduction with continuous embryonic development. The reproductive traits of A. nitens are discussed in the context of circum-Antarctic species distribution and limitations to dispersal in brooding benthic invertebrates

Targeting the hypoxia pathway to treat pancreatic cancer

Lori A Erickson,1 W Edward Highsmith Jr,1 Peiwen Fei,2 Jun Zhang1 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; 2University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA Abstract: The correlation between hypoxia and pancreatic cancer has long been discussed. Hao’s research team made many efforts on revealing the oncogenic function of hypoxic inducible factor-1 (HIF-1) in pancreatic cancer progression and development in recent years. Based on their research, they linked micro-environmental regulation of pancreatic cancer and its clinical significance. Hao’s research team suggests it is a promising approach to target HIF-1 for the management of pancreatic cancer progression and invasion. Keywords: hypoxia, HIF-1, pancreatic cance

Bioerosion rates of the sponge Cliona orientalis Thiele, 1900: Spatial variation over short distances

We studied bioerosion rates and tissue growth of the sponge Cliona orientalis Thiele, 1900. Experimental blocks grafted with sponge tissue were deployed at three sites in Moreton Bay, QLD, Australia, which have different environmental conditions. Bioerosion rates varied between 4, 5, and 10 kg m year when related to final tissue area and between 4, 7, and 16 kg m year when related to initial tissue area of the graft, which supports findings of earlier studies. Comparing results between the sites, eutrophication appeared to have the most stimulating effect and is most likely to have caused the measured differences. However, slight differences between shading and current speeds may also have played a role. Variation may have masked spatial differences of sponge growth, which were insignificant between study sites. Growth and bioerosion nevertheless followed the same trend and were weakly correlated. Habitat quality itself had no influence. Overall, the twofold difference in sponge bioerosion over a distance as short as 10 km suggests that when estimating bioerosion rates, subsamples should be tested at different locations