There is no correlation between c-Myc mRNA expression and telomerase activity in human breast cancer

Background Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. The hTERT (human telomerase reverse transcriptase) subunit seems to be the rate-limiting determinant of telomerase and knowledge of factors controlling hTERT transcription may be useful in therapeutic strategies. The hTERT promoter contains binding sites for c-Myc and there is experimental and in vitro evidence that c-Myc may increase hTERT expression. Materials and methods RNA was extracted from 18 breast carcinomas and c-Myc mRNA expression was estimated by quantitative reverse transcriptase-PCR (RT-PCR) with Taqman methodology. These tumours had already been analysed for ER and PgR status using ligand-binding assays and had had their DNA ploidy and S-phase fractions measured by flow cytometry. Telomerase activity had already been determined by using a modified telomeric repeat and amplification protocol (TRAP) assay. Results Telomerase activity ranged from 0 to 246 units of Total Protein Generated (TPG), where one unit of TPG was equal to 600 molecules of telomerase substrate primers extended by at least three telomeric repeats. Median levels of TPG were 60 and mean levels 81. There was no significant correlation between levels of c-Myc mRNA expression, telomerase activity, S phase fraction or PgR. There was a significant negative correlation with ER status. Conclusion Although the hTERT promoter contains potential binding sites for c-Myc oncoprotein, we have found no correlation between c-Myc mRNA levels and telomerase activity

The mRNA expression of hTERT in human breast carcinomas correlates with VEGF expression

Background Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase) is the rate-limiting determinant of telomerase reactivation. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any correlation between hTERT and the negative prognostic indicators VEGF and PCNA by quantitatively measuring the mRNA expression of these genes in human breast cancer and in adjacent non-cancerous tissue (ANCT). Materials and methods RNA was extracted from 38 breast carcinomas and 40 ANCT. hTERT and VEGF165, VEGF189 and PCNA mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR) and Taqman methodology. Results The level of expression of VEGF-165 and PCNA was significantly higher in carcinoma tissue than ANCT (p = 0.02). The ratio of VEGF165/189 expression was significantly higher in breast carcinoma than ANCT (p = 0.025). hTERT mRNA expression correlated with VEGF-189 mRNA (p = 0.008) and VEGF165 (p = 0.07). Conclusions hTERT mRNA expression is associated with the expression of the VEGF189 and 165 isoforms. This could explain the poorer prognosis reported in breast tumours expressing high levels of hTERT. The relative expression of the VEGF isoforms is significantly different in breast tumour to ANCT, and this may be important in breast carcinogenesis

Is telomerase reactivation associated with the down-regulatoin of TGFβ receptor-II expression in human breast cancer?

Background Telomerase is a ribonucleoprotein that synthesizes telomeres and plays an important role in chromosomal stability and cellular immortalisation. Telomerase activity is detectable in most human cancers but not in normal somatic cells. TGF beta (transforming growth factor beta) is a member of a family of cytokines that are essential for cell survival and seems to be down-regulated in human cancer. Recent in vitro work using human breast cancer cell lines has suggested that TGF beta down-regulates the expression of hTERT (human telomerase reverse transcriptase) : the catalytic subunit of telomerase. We have therefore hypothesised that telomerase reactivation is associated with reduced immunohisto-chemical expression of TGF beta type II receptor (RII) in human breast cancer. Methods TGF beta RII immunohistochemical expression was determined in 24 infiltrating breast carcinomas with known telomerase activity (17 telomerase-positive and 7 telomerase-negative). Immunohistochemical expression of TGF beta RII was determined by a breast pathologist who was blinded to telomerase data. Results TGF beta RII was detected in all lesions. The percentage of stained cells ranged from 1–100%. The difference in TGF beta RII expression between telomerase positive and negative tumours was not statistically significant (p = 1.0). Conclusion The results of this pilot study suggest that there is no significant association between telomerase reactivation and TGF-beta RII down-regulation in human breast cancer

Optimal Geo-Indistinguishable Mechanisms for Location Privacy

We consider the geo-indistinguishability approach to location privacy, and the trade-off with respect to utility. We show that, given a desired degree of geo-indistinguishability, it is possible to construct a mechanism that minimizes the service quality loss, using linear programming techniques. In addition we show that, under certain conditions, such mechanism also provides optimal privacy in the sense of Shokri et al. Furthermore, we propose a method to reduce the number of constraints of the linear program from cubic to quadratic, maintaining the privacy guarantees and without affecting significantly the utility of the generated mechanism. This reduces considerably the time required to solve the linear program, thus enlarging significantly the location sets for which the optimal mechanisms can be computed.Comment: 13 page

Screening mammography in women aged 40–49: Is it time to change?

There is little doubt that significant benefits can accrue from carrying out screening mammography of women aged 40–49 in the setting of a highly quality assured service delivery. This will best be achieved using digital mammography to maximise detection rates and trained and high volume reading expert radiologists to apply economic cushions of optimising specificity as well as sensitivity in addition to utilising modern and accurate assessment and tissue sampling techniques that have evolved

Does mammary ductoscopy have a role in clinical practice?

BACKGROUND: Mammary ductoscopy (MD) is a newly developed endoscopic technique that allows direct visualisation of the mammary ductal epithelium using sub-millimetre fiberoptic microendoscopes inserted through the ductal opening onto the nipple surface. These scopes also provide working channels for insufflation, irrigation, ductal lavage, and possible therapeutic intervention. MD can be performed under local anaesthesia in the office setting. The objective of this study is to assess the technical feasibility of mammary ductoscopy, and examine its role in guiding ductal excision surgery and the early diagnosis of malignancy. METHODS: Mammary ductoscopy (MD) was performed using a 1 mm fiberoptic microendoscope (Mastascope TM) in 26 patients (age range: 14–73 years): 13 patients undergoing mastectomy (n = 12) or lumpectomy (n = 1) for ductal carcinoma (including 12 cases of DCIS and one case of infiltrating ductal carcinoma) and 13 patients with pathological nipple discharge (PND) and benign breast imaging and simple discharge cytology. Of the latter group: 10 procedures were performed under local anaesthesia (LA) in the office setting and 3 procedures were carried out under general anaesthesia (GA) to guide duct excision surgery. The ductoscopic appearances in this group were graded between 0 and 5 (D0–D5) according to the degree of suspicion. RESULTS: Intraoperative MD was accomplished in 11 (84.6%) of 13 patients undergoing surgery for DCIS. MD was unsuccessful in 2 cases: one patient (aged 73 years) had sclerosis of the nipple and one patient had preoperative vital blue injection in the subareolar region as part of the sentinel node biopsy thus resulting in inadequate visualisation. Intraductal pathology was visualised in 8 (80%) of the 10 cases undergoing mastectomy but ductoscopic cytology was positive for malignancy in only 2 cases (sensitivity = 16%, specificity = 100%). In the office setting, MD was accomplished in 9 (90%) out of 10 patients with PND and was well tolerated (mean pain score = 3.8 out of 10: range 0–7). Of these 10 patients; MD was inadequate (D0) in one patient due to complete occlusion of lumen by the lesion, showed a papilloma in 3 patients (D3), duct ectasia (D2) in 3 patients, irregular thickening of the lumen suspicious of DCIS (D4) in one patient and non-specific benign findings (D2) in 2 patients. Three women with benign ductoscopy and ductoscopy-assisted cytology were reassured and treated conservatively. The remaining 7 patients had ductoscopy-guided duct excision which revealed DCIS in one, papilloma in 4 and benign breast disease in 2 patients. Adequate cellular yield was obtained in 7(70%) out of 10 cases (benign cytology). The three patients who had MD under GA during microdochectomy had benign endoscopic appearances and final histology (one papilloma and 2 cases of duct ectasia). CONCLUSION: MD is technically feasible in most patients and has a potential in the early detection of breast cancer. The procedure can be performed safely in the office setting and should be considered in all patients presenting with a single duct PND. MD has the potential to reduce the number of duct excision procedures and minimise the extent of surgical resection. Ductoscopic cytology is not sufficiently sensitive for the diagnosis of malignancy and the development of a biopsy tool that obtains tissue under direct visualisation is required

Skin and fat necrosis of the breast following methylene blue dye injection for sentinel node biopsy in a patient with breast cancer

Sentinel lymph node biopsy (SLNB) is a simple technique that uses subdermal or peri-tumoral injection of vital blue dye and/or radioactive isotope to identify the first lymph node(s) draining the primary tumor. It has been shown to accurately predict axillary node status in patients with clinically node negative breast cancer. The SLNB is emerging as a new standard of care in patients with early breast cancer. However, the use of methylene blue (MB) dye can be associated with a number of local complications due to its tissue reactive properties. We report a rare case of skin and fat necrosis followed by a dry gangrene of the skin in a female patient with breast cancer who underwent SLNB localization using peri-tumoral injection of MB dye in another institution. This case and literature review suggest that the use of MB dye for SLNB identification should be avoided and replaced with alternative types of blue dye such as Patent Blue V preferably in conjunction with a radioactive isotope tracer

Pharmacogenomics of Medically Important Adverse Drug Effects

Introduction: Medicines with high toxicity profiles have a heightened risk of causing serious and fatal adverse drug effects (ADEs). General Practice (GP) is key in identifying and potentially preventing ADEs. While the use of genomic information has the potential to reduce ADEs, the robustness and reproducibility of genetic research findings are questionable. Hence, separating true positives from false positives and minimising the overabundance of false-positive signals is vital. Aim: To assess the current state of the art in pharmacogenomics (PGx) of adverse drug effects and analyse whether variants previously reported to be associated with medically important adverse effects (MIADEs) replicate in the UK Biobank (UKBB). Methods and Materials :Three separate systematic reviews of the literature were conducted to identify relevant studies. To identify high-risk medicines, data on serious and fatal ADEs from the UK pharmacovigilance was mapped onto GP prescription data in England. Previously described associations between variants and MIADEs related to high-risk medicines in GP and endocrine drugs for breast cancer were interrogated in UKBB. Results: I created a list of variants associated with ADEs and further generated a set of variant–drug pairs significantly associated with MIADEs. I identified medicines with high toxicity profiles in GP and created comparative safety charts to support evidence-based decision-making around formulary choices. No statistically significant genotype-treatment interactions were found for either baseline measurements or incident MIADEs in UKBB. This included MIADEs related to statins, NSAIDs, antipsychotics and endocrine therapy. Conclusions: None of the PGx findings tested were replicated in UKBB. This included associations between variants and MIADEs related to high-risk medicines in GP and endocrine agents, in relation to neither baseline measurements nor incident MIADEs. These variants are not accurate at identifying those who are at risk of developing MIADEs in patients receiving these treatments and therefore should not be considered for personalised recommendations

The evolving role of the dynamic thermal analysis in the early detection of breast cancer

It is now recognised that the breast exhibits a circadian rhythm which reflects its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian and that a circadian to ultradian shift may be a general correlation to neoplasia. Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development. The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer. This article focuses on dynamic thermal analysis as an evolving method in breast cancer detection in pre-menopausal women with dense breast tissue. Prospective multi-centre trials are required to validate this promising modality in screening. The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy