EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations

To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation. Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity. Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists. Signals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible

Polyaniline/palladium nanohybrids for moisture and hydrogen detection.

Palladium nanoparticles display fascinating electronic, optical and catalytic properties, thus they can be used for various applications such as sensor fabrication. Conducting polymers such as polyaniline have also been widely used in sensor technology due to its cost effectiveness, versatility, and ease of synthesis. In this research, attention was given to unify the exceptional properties of these two materials and construct palladium nanoparticle coated polyaniline films to detect hydrogen and moisture. Electrochemical polymerization of aniline was carried out on gold sputtered epoxy resin boards. Polyaniline film was generated across a gap of 0.2 mm created by a scratch made on the gold coating prior to electrochemical polymerization. A palladium nanoparticle dispersion was prepared using sonochemical reduction method and coated on to polyaniline film using drop-drying technique. Polyaniline only films were also fabricated for comparative analysis. Sensitivity of films towards humidity and hydrogen was evaluated using impedance spectroscopy in the presence of the respective species. According to the results, polyaniline films exhibited an impedance drop in the presence of humidity and the response was significantly improved once palladium nanoparticles were incorporated. Interestingly, polyaniline only films did not respond to hydrogen. Nevertheless, palladium nanoparticle coated polyaniline films exhibited remarkable response towards hydrogen

Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1α-mediated apoptosis.

BACKGROUND: Clear cell renal cell carcinoma (CCRCC) is the commonest form of kidney cancer. Up to 91% have biallelic inactivation of VHL, resulting in stabilisation of HIF-α subunits. Factor inhibiting HIF-1 is an enzyme that hydroxylates HIF-α subunits and prevents recruitment of the co-activator CBP/P300. An important question is whether FIH-1 controls HIF activity in CCRCC. METHODS: Human VHL defective CCRCC lines RCC10, RCC4 and 786-O were used to determine the role of FIH-1 in modulating HIF activity, using small interfering RNA knockdown, retroviral gene expression, quantitative RT-PCR, western blot analysis, Annexin V and propidium iodide labelling. RESULTS: Although it was previously suggested that FIH-1 is suppressed in CCRCC, we found that FIH-1 mRNA and protein are actually present at similar levels in CCRCC and normal kidney. The FIH-1 inhibition or knockdown in the VHL defective CCRCC lines RCC10 and RCC4 (which express both HIF-1α and HIF-2α) resulted in increased expression of HIF target genes. In the 786-O CCRCC cell line, which expresses only HIF-2α, FIH-1 attenuation showed no significant effect on expression of these genes; introduction of HIF-1α resulted in sensitivity of HIF targets to FIH-1 knockdown. In RCC4 and RCC10, knockdown of FIH-1 increased apoptosis. Suppressing HIF-1α expression in RCC10 prevented FIH-1 knockdown from increasing apoptosis. CONCLUSION: Our results support a unifying model in which HIF-1α has a tumour suppressor action in CCRCC, held in check by FIH-1. Inhibiting FIH-1 in CCRCC could be used to bias the HIF response towards HIF-1α and decrease tumour cell viability

Metastatic epidural spinal cord compression: current concepts and treatment

Metastatic epidural spinal cord compression (MESCC) is a medical emergency complicating the course of 5–10% of patients with cancer [1]. When diagnosis and treatment is early with the patient ambulatory prognosis for continued ambulation is good [2]. If the patient is nonambulatory or paraplegic, prognosis for meaningful recovery of motor and bladder function is markedly decreased. In the last decade, significant advances in the understanding, management and treatment of metastatic epidural spinal cord compression have occurred.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45378/1/11060_2005_Article_BF01051052.pd

The epigenetic landscape of renal cancer

This is an accepted manuscript of an article published by Nature in Nature Reviews: Nephrology on 28/11/2016, available online: https://doi.org/10.1038/nrneph.2016.168 The accepted version of the publication may differ from the final published version.The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers