Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

Expression of AEG-1 and p53 and their clinicopathological significance in malignant lesions of renal cell carcinomas: a microarray study.

The aim of this study was to investigate the relationship of AEG-1 and p53 with the prognostic parameters of renal cell carcinoma (RCC). In this study, 50 paraffin blocks were histopathologically diagnosed at the Department of Pathology of the Medical Hospital of Duzce University, between 2005 and 2011. The cases consisted of 24 clear cell (CC) and 26 non-clear cell (NCC) RCC subtypes as follows: 24 (48%) clear cell RCC, 12 (24%) papillary RCC, 4 (8%) multilocular cystic RCC and 10 (20%) chromophobe RCC; none had sarcomatoid changes. By immunohistochemical analysis we investigated AEG-1 and p53 expression in carcinomas of the kidney, and by statistical analysis determined their relationship with clinicopathological parameters. Significant relationships were found between increasing tumor diameter and the increase of p53 (p = 0.028). In addition, p53 was significantly related to renal sinus invasion (p = 0.05) and Fuhrman grade (p = 0.026). There was a significant relationship between increased AEG-1 staining scores and CC and NCC carcinoma subtypes (p = 0.032), tumor capsule invasion (p = 0.01) and lymphovascular invasion (p = 0.015). There was also a significant correlation between tumor size and capsule and lymphovascular invasion (p = 0.02). We concluded that high AEG-1 and p53 expression correlates with the prognostic parameters in RCC patients, and in addition may be associated with tumor progression.

Relationship among expression of basic-fibroblast growth factor, MTDH/astrocyte elevated gene-1, adenomatous polyposis coli, matrix metalloproteinase 9,and COX-2 markers with prognostic factors in prostate carcinomas.

BACKGROUND: The etiopathogenesis of prostate cancer (PC) is still not clear, but hormonal, genetic, and environmental factors are thought to play a role in the tumor pathogenesis. Astrocyte elevated gene-1(AEG-1) as a novel transmembrane protein is predominantly located in the perinuclear region and endoplasmic reticulum. It has been found that AEG-1 upregulation increases the invasive ability of glioma and prostate cancer. Basic fibroblast growth factor (bFGF), matrix metalloproteinase-9 (MMP-9), cyclooxygenases-2 (COX-2), and adenomatous polyposis coli (APC) are very important in tumor progression as well. MATERIALS AND METHODS: This study included 97 radical prostatectomy specimens. IHC stains for bFGF, MMP-9, COX-2, APC, and AEG-1 were performed on the tissue microarray using standard procedures. For each patient, the age, Gleason score, tumor volume, lymphovascular invasion, lymph node metastasis, surgical margin, and the invasion of vesiculoseminalis areas were assessed. Analyses were performed using the statistical PASW (ver. 18). RESULTS: Statistically significant positive relationships were found MMP-9 and COX-2 (r = 0.242 and P = 0.017), between MMP-9 and APC (r = 0.207 and P = 0.043), and between bFGF and AEG-1 (r = 0.295 and P = 0.004). However, the relationships between age and staining results and tumor volume and staining results were not found to be significant. Although a positive correlation was found between the Gleason score and tumor volume and the Gleason score and age (r = 0.415 and P = 0.0001; r = 0.246 and P = 0.015, respectively), we did not find a statistically significant relationship between other stains and other prognostic parameters (lymphovascular invasion, lymph node metastasis, surgical margin, or vesiculoseminalis invasion). CONCLUSION: The relationships we found between MMP-9 and COX-2, between MMP-9, and APC and between bFGF and AEG-1 as independent prognostic parameters could be helpful in the development of new therapeutic procedures.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Dosimetric and kinetic investigations of γ-irradiated sodium tartrate dihydrate.

Effects of gamma radiation on solid sodium tartrate dihydrate (NaTA) were studied using electron spin resonance (ESR) spectroscopy. One main singlet located at g = 2.0034 and many weak lines located at low and high magnetic field sides were found in the irradiated samples. Dosimetric and kinetic features of the radical species responsible for the experimental ESR spectra were explored through the variations in the signal intensities with respect to applied microwave power, temperature and storage time. Activation energies of the involved radical species were also determined using data derived from annealing studies.

Mast cells numbers and peritumoral microvessel density of the prostatic adenocarcinomas and correlation with prognostic parameters.

AIM: To determine the utility of mast cell numbers and microvascular density (MVD) in evaluating acinar type of prostatic adenocarcinoma (PCa), and to ascertain a relationship between the number of mast cells with prognostic parameters (larger tumor volume, high Gleason score, lymphovascular, perineural, seminal vesicles invasion, metastatic lymph node). METHODS: The study comprised 97 radical prostatectomy specimens. The paraffin sections were stained with anti-CD31, anti- CD34 and Toluidine Blue. The numbers of positive staining of cells and microvessels in 10 high-power fields were counted systematically. RESULTS: A statistically significant relationship was found between MVDn and number of MC (r=0.218 and p=0. 032). There was no correlation between age and MC and MVD (p=0.406 and p=0.671, respectively). CONCLUSION: A correlation between mast cell number and microvascular density cannot depend on tumor angiogenesis or this relationship can be an independent parameter. More comprehensive studies could reveal relationship with prognostic parameters.

Functional and morphological effects of fotemustine on the auditory system of the rat.

OBJECTIVE: This study aimed to elucidate the potential inner-ear effects of fotemustine, a chemotherapeutic agent which crosses the blood-brain barrier and is used in the treatment of primary and metastatic brain tumours and metastatic melanoma. METHODS: This study utilised distortion product otoacoustic emissions and transmission electron microscopy in order to conduct electrophysiological and morphological assessments, using a rat experimental model. Twelve ears of six male rats were examined two months following intraperitoneal slow infusion of fotemustine (100 mg/m2 or 7.4 mg/kg). Pre- and post-treatment measurements were compared. Finally, electron microscopy was performed on three rat temporal bones. RESULTS: After infusion of fotemustine, distortion product otoacoustic emissions revealed a significant reduction in signal-to-noise ratios only at 3600 Hz (from 11.95 +/- 7.52 to -0.26 +/- 9.45 dB) and at 3961 Hz (from 18.09 +/- 7.49 to 6.74 +/- 12.11 dB) (referenced to 2f1 - f2). Transmission electron microscopy of the temporal bone revealed ultrastructural changes in the outer hair cells, stria vascularis and cochlear ganglion at the cochlear basal turn. The ganglion cell perikarya were unaffected. CONCLUSIONS: Fotemustine was administered via intraperitoneal slow infusion in a rat experimental model. Twelve ears of six survivors, from 10 rats, were evaluated at the second month. Fotemustine was determined to have a potential for ototoxicity at 3600 and 3961 Hz. Three randomly chosen rats underwent electron microscopy for morphological analysis. Morphological effects in the cochlear basal turn were observed. Oedematous intracytoplasmic spaces and perivascular areas of the stria vascularis, as well as distorted chromatin content, were detected, thereby suggesting potential ototoxic effects for this agent. Further experimental and clinical studies are required in order to determine whether the effect seen in this pilot study is reversible, and to analyse effects in humans.