Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells

Background: Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. Materials and methods: MCF-7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal-stripped serum with 10-8 M 17-oestradiol and 10 g/ml insulin (stock 1), 10-8 M 17-oestradiol (stock 2), 10 g/ml insulin (stock 3) or no addition (stock 4). Results: Loss of growth response to oestrogen was observed only in stock 4 cells. Long-term maintenance with insulin in the absence of oestradiol (stock 3) resulted in raised oestrogen receptor alpha (ERlevels (measured by western immunoblotting) and development of hypersensitivity (assayed by oestrogen-responsive reporter gene induction and dose response to oestradiol for proliferation under serum-free conditions), but with no loss of growth response to oestrogen. Conclusion: Hypersensitivity can develop without any growth adaptation and therefore is not a prerequisite for loss of growth response in MCF-7 cells.

Attacking human implants: a new generation of cybercrime

Human ICT implants, such as RFID implants, cochlear implants, cardiac pacemakers, Deep Brain Stimulation, bionic limbs connected to the nervous system, and networked cognitive prostheses, are becoming increasingly complex. With ever-growing data processing functionalities in these implants, privacy and security become vital concerns. Electronic attacks on human ICT implants can cause significant harm, both to implant subjects and to their environment. This paper explores the vulnerabilities which human implants pose to crime victimisation in light of recent technological developments, and analyses how the law can deal with emerging challenges of what may well become the next generation of cybercrime: attacks targeted at technology implanted in the human body. After a state-of-the-art description of relevant types of human implants and a discussion how these implants challenge existing perceptions of the human body, we describe how various modes of attacks, such as sniffing, hacking, data interference, and denial of service, can be committed against implants. Subsequently, we analyse how these attacks can be assessed under current substantive and procedural criminal law, drawing on examples from UK and Dutch law. The possibilities and limitations of cybercrime provisions (eg, unlawful access, system interference) and bodily integrity provisions (eg, battery, assault, causing bodily harm) to deal with human-implant attacks are analysed. Based on this assessment, the paper concludes that attacks on human implants are not only a new generation in the evolution of cybercrime, but also raise fundamental questions on how criminal law conceives of attacks. Traditional distinctions between physical and non-physical modes of attack, between human bodies and things, between exterior and interior of the body need to be re-interpreted in light of developments in human implants. As the human body and technology become increasingly intertwined, cybercrime legislation and body-integrity crime legislation will also become intertwined, posing a new puzzle that legislators and practitioners will sooner or later have to solve.

Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro

Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. Since proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen-responsive human breast cancer cell lines (MCF-7, T-47-D, ZR-75-1). Cells were maintained short-term (1 week) or long-term (20±2 weeks) in phenol-red-free medium containing 5% charcoal-stripped serum with no addition, 10-8M 17-oestradiol, 1-5x10-4M methylparaben, 10-5M n-propylparaben or 10-5M n-butylparaben. Long-term exposure (20±2 weeks) of MCF-7 cells to methylparaben, n-propylparaben or n-butylparaben increased migration as measured using a scratch assay, time-lapse microscopy and xCELLigence technology: invasive properties were found to increase in matrix degradation assays and migration through matrigel on xCELLigence. Western immunoblotting showed an associated downregulation of E-cadherin and -catenin in the long-term paraben-exposed cells which could be consistent with a mechanism involving epithelial to mesenchymal transition. Increased migratory activity was demonstrated also in long-term paraben-exposed T-47-D and ZR-75-1 cells using a scratch assay and time-lapse microscopy. This is the first report that in vitro, parabens can influence not only proliferation but also migratory and invasive properties of human breast cancer cells.

Efficient wireless power delivery for biomedical implants

Power delivery for biomedical implants is a major consideration in their design for both measurement and stimulation. When performed by a wireless technique, transmission efficiency is critically important not only because of the costs associated with any losses but also because of the nature of those losses, for example, excessive heat can be uncomfortable for the individual involved. In this study, a method and means of wireless power transmission suitable for biomedical implants are both discussed and experimentally evaluated. The procedure initiated is comparable in size and simplicity to those methods already employed; however, some of Tesla’s fundamental ideas have been incorporated in order to obtain a significant improvement in efficiency. This study contains a theoretical basis for the approach taken; however, the emphasis here is on practical experimental analysis.

Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status

A framework for understanding the complexity of cancer development was established by Hanahan and Weinberg in their definition of the hallmarks of cancer. In this review, we consider the evidence that parabens can enable development in human breast epithelial cells of 4/6 of the basic hallmarks, 1/2 of the emerging hallmarks and 1/2 of the enabling characteristics. Hallmark 1: parabens have been measured as present in 99% of human breast tissue samples, possess oestrogenic activity and can stimulate sustained proliferation of human breast cancer cells at concentrations measurable in the breast. Hallmark 2: parabens can inhibit the suppression of breast cancer cell growth by hydroxytamoxifen, and through binding to the oestrogen-related receptor gamma (ERR) may prevent its deactivation by growth inhibitors. Hallmark 3: in the 10nM to 1M range, parabens give a dose-dependent evasion of apoptosis in high-risk donor breast epithelial cells. Hallmark 4: long-term exposure (>20weeks) to parabens leads to increased migratory and invasive activity in human breast cancer cells, properties which are linked to the metastatic process. Emerging hallmark: methylparaben has been shown in human breast epithelial cells to increase mTOR, a key regulator of energy metabolism. Enabling characteristic: parabens can cause DNA damage at high concentrations in the short term but more work is needed to investigate long-term low-doses of mixtures. The ability of parabens to enable multiple cancer hallmarks in human breast epithelial cells provides grounds for regulatory review of the implications of the presence of parabens in human breast tissue.

Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone de-acetylation

The health benefits of garlic have been proven by epidemiological and experimental studies. Diallyl disulphide (DADS), the major organosulfur compound found in garlic oil, is known to lower the incidence of breast cancer both in vitro and in vivo. The studies reported here demonstrate that DADS induces apoptosis in the MCF-7 breast-cancer cell line through interfering with cell-cycle growth phases in a way that increases the sub-G0 population and substantially halts DNA synthesis. DADS also induces phosphatidylserine (PS) translocation from the inner to the outer leaflet of the plasma membrane and activates caspase-3. Further studies revealed that DADS modulates the cellular levels of Bax, Bcl-2, Bcl-xL and Bcl-w in a dose-dependent manner, suggesting the involvement of Bcl-2 family proteins in DADS induced apoptosis. Histone deacetylation inhibitors (HDACi) are known to suppress cancer growth and induce apoptosis in cancer cells. Here it is shown that DADS has HDACi properties in MCF-7 cells as it lowers the removal of an acetyl group from an acetylated substrate and induces histone-4 (H4) hyper-acetylation. The data thus indicate that the HDACi properties of DADS may be responsible for the induction of apoptosis in breast cancer cells.

Sensory enhancement, a pilot perceptual study of subdermal magnetic implants

Subdermal magnetic implants originated as an art form in the world of body modification. To date an in depth scientific analysis of the benefits of this implant has yet to be established. This research explores the concept of sensory extension of the tactile sense utilising this form of implantation. This relatively simple procedure enables the tactile sense to respond to static and alternating magnetic fields. This is not to say that the underlying biology of the system has changed; i.e. the concept does not increase our tactile frequency response range or sensitivity to pressure, but now does invoke a perceptual response to a stimulus that is not innately available to humans. Within this research two social surveys have been conducted in order to ascertain one, the social acceptance of the general notion of human enhancement, and two the perceptual experiences of individuals with the magnetic implants themselves. In terms of acceptance to the notion of sensory improvement (via implantation) ~39% of the general population questioned responded positively with a further ~25% of the respondents answering with the indecisive response. Thus with careful dissemination a large proportion of individuals may adopt this technology much like this if it were to become available for consumers. Interestingly of the responses collected from the magnetic implants survey ~60% of the respondents actually underwent the implant for magnetic vision purposes. The main contribution of this research however comes from a series of psychophysical testing. In which 7 subjects with subdermal magnetic implants, were cross compared with 7 subjects that had similar magnets superficially attached to their dermis. The experimentation examined multiple psychometric thresholds of the candidates including intensity, frequency and temporal. Whilst relatively simple, the experimental setup for the perceptual experimentation conducted was novel in that custom hardware and protocols were created in order to determine the subjective thresholds of the individuals. Abstract iv The overall purpose of this research is to utilise this concept in high stress scenarios, such as driving or piloting; whereby alerts and warnings could be relayed to an operator without intruding upon their other (typically overloaded) exterior senses (i.e. the auditory and visual senses). Hence each of the thresholding experiments were designed with the intention of utilising the results in the design of signals for information transfer. The findings from the study show that the implanted group of subjects significantly outperformed the superficial group in the absolute intensity threshold experiment, i.e. the implanted group required significantly less force than the superficial group in order to perceive the stimulus. The results for the frequency difference threshold showed no significant difference in the two groups tested. Interestingly however at low frequencies, i.e. 20 and 50 Hz, the ability of the subjects tested to discriminate frequencies significantly increased with more complex waveforms i.e. square and sawtooth, when compared against the typically used sinewave. Furthermore a novel protocol for establishing the temporal gap detection threshold during a temporal numerosity study has been established in this thesis. This experiment measured the subjects’ capability to correctly determine the number of concatenated signals presented to them whilst the time between the signals, referred to as pulses, tended to zero. A significant finding was that when altering the length of, the frequency of, and the number of cycles of the pulses, the time between pulses for correct recognition altered. This finding will ultimately aid in the design of the tactile alerts for this method of information transfer. Preliminary development work for the use of this method of input to the body, in an automotive scenario, is also presented within this thesis in the form of a driving simulation. The overall goal of which is to present warning alerts to a driver, such as rear-to-end collision, or excessive speeds on roads, in order to prevent incidents and penalties from occurring. Discussion on the broader utility of this implant has been presented, reflecting on its potential use as a basis for vibrotactile, and sensory substitution, devices. This discussion furthers with postulations on its use as a human machine interface, as well as how a similar implant could be used within the ear as a hearing aid device.

The accuracy of HADS and GHQ-12 in detecting psychiatric morbidity in breast cancer patients

Objective: Psychological problems should be identified in breast cancer patients proactively if doctors and nurses are to help them cope with the challenges imposed by their illness. Screening is one possible way to identify emotional problems proactively. Self-report questionnaires can be useful alternatives to carrying out psychiatric interviews during screening, because interviewing a large number of patients can be impractical due to limited resources. Two such measures are the Hospital Anxiety and Depression Scale (HADS) and the General Health Questionnaire-12 (GHQ-12). Method: The present study aimed to compare the performance of the GHQ-12, and the HADS Unitary Scale and its subscales to that of the Schedule for Affective Disorders and Schizophrenia (SADS) in identifying patients with affective disorders, including DSM major depression and generalized anxiety disorder. The sample consisted of 296 female breast cancer patients who underwent surgery for breast cancer a year previously. Results: A small number of patients (11%) were identified as having DSM major depression or generalized anxiety disorder based on SADS score. The findings indicate that the optimal thresholds in detecting generalized anxiety disorder and DSM major depression with the HADS anxiety and depression subscales were ≥ 8 and ≥ 7, with 93.3% and 77.3% sensitivity, respectively, and 77.9% and 87.1% specificity, respectively. They also had a 21% and 36% positive predictive value, respectively. Using the HADS Unitary Scale the optimal threshold for detecting affective disorders was ≥ 12, with 88.9% sensitivity, 80.7% specificity, and a 35% positive predictive value. In detecting affective disorders, the optimal threshold on the GHQ-12 was ≥ 2, with 77.8% sensitivity and 70.2% specificity. This scale also had a 24% positive predictive value. In detecting generalized anxiety disorder and DSM major depression, the optimal thresholds on the GHQ-12 were ≥ 2 and ≥ 4 with 73.3% and 77.3% sensitivity, respectively, and 67.5% and 82% specificity, respectively. The scale also had 12% and 29% positive predictive values, respectively. Conclusion: The HADS Unitary Scale and its subscales were effective in identifying affective disorders. They can be used as screening measures in breast cancer patients. The GHQ-12 was less accurate in detecting affective disorders than the HADS, but it can also be used as a screening instrument to detect affective disorders, generalized anxiety disorder, and DSM major depression.

Sexual abuse in childhood and postoperative depression in women with breast cancer who opt for immediate reconstruction after mastectomy

INTRODUCTION Breast reconstruction is routinely offered to women who undergo mastectomy for breast cancer. However, patient-reported outcomes are mixed. Child abuse has enduring effects on adults’ well-being and body image. As part of a study into damaging effects of abuse on adjustment to breast cancer, we examined: (i) whether women with history of abuse would be more likely than other women to opt for reconstruction; and (ii) whether mood problems in women opting for reconstruction can be explained by greater prevalence of abuse. PATIENTS AND METHODS We recruited 355 women within 2-4 days after surgery for primary breast cancer; 104 had mastectomy alone and 29 opted for reconstruction. Using standardised questionnaires, women self-reported emotional distress and recollections of childhood sexual abuse. Self-report of distress was repeated 12 months later. RESULTS Women who had reconstruction were younger than those who did not. Controlling for this, they reported greater prevalence of abuse and more distress than those having mastectomy alone. They were also more depressed postoperatively, and this effect remained significant after controlling for abuse. CONCLUSIONS One interpretation of these findings is that history of abuse influences women's decisions about responding to the threat of mastectomy, but it is premature to draw inferences for practice until the findings are replicated. If they are replicated, it will be important to recognise increased vulnerability of some patients who choose reconstruction. Studying the characteristics and needs of women who opt for immediate reconstruction and examining the implications for women's adjustment should be a priority for research.

Predictors of onset of depression and anxiety in the year after diagnosis of breast cancer

Background Depression and anxiety are common after diagnosis of breast cancer. We examined to what extent these are recurrences of previous disorder and, controlling for this, whether shame, self-blame and low social support after diagnosis predicted onset of depression and anxiety subsequently. Method Women with primary breast cancer who had been treated surgically self-reported shame, self-blame, social support and emotional distress post-operatively. Psychiatric interview 12 months later identified those with adult lifetime episodes of major depression (MD) or generalized anxiety disorder (GAD) before diagnosis and onset over the subsequent year. Statistical analysis examined predictors of each disorder in that year. Results Of the patients, two-thirds with episodes of MD and 40% with episodes of GAD during the year after diagnosis were experiencing recurrence of previous disorder. Although low social support, self-blame and shame were each associated with both MD and GAD after diagnosis, they did not mediate the relationship of disorder after diagnosis with previous disorder. Low social support, but not shame or self-blame, predicted recurrence after controlling for previous disorder. Conclusions Anxiety and depression during the first year after diagnosis of breast cancer are often the recurrence of previous disorder. In predicting disorder following diagnosis, self-blame and shame are merely markers of previous disorder. Low social support is an independent predictor and therefore may have a causal role.

The perception of support received from breast care nurses by depressed patients following a diagnosis of breast cancer

INTRODUCTION Due to their specialist training, breast care nurses (BCNs) should be able to detect emotional distress and offer support to breast cancer patients. However, patients who are most distressed after diagnosis generally experience least support from care staff. To test whether BCNs overcome this potential barrier, we compared the support experienced by depressed and non-depressed patients from their BCNs and the other main professionals involved in their care: surgeons and ward nurses. PATIENTS AND METHODS Women with primary breast cancer (n = 355) 2–4 days after mastectomy or wide local excision, self-reported perceived professional support and current depression. Analysis of variance compared support ratings of depressed and non-depressed patients across staff types. RESULTS There was evidence of depression in 31 (9%) patients. Depressed patients recorded less surgeon and ward nurse support than those who were not depressed but the support received by patients from the BCN was high, whether or not patients were depressed. CONCLUSIONS BCNs were able to provide as much support to depressed patients as to non-depressed patients, whereas depressed patients felt less supported by surgeons and ward nurses than did non-depressed patients. Future research should examine the basis of BCNs' ability to overcome barriers to support in depressed patients. Our findings confirm the importance of maintaining the special role of the BCN.

Effect of aluminium on migration of oestrogen unresponsive MDA-MB-231 human breast cancer cells in culture

Aluminium (Al) has been measured in human breast tissue, and may be a contributory factor in breast cancer development. At the 10th Keele meeting, we reported that long-term exposure to Al could increase migratory properties of oestrogen-responsive MCF-7 human breast cancer cells suggesting a role for Al in the metastatic process. We now report that long-term exposure (20–25 weeks) to Al chloride or Al chlorohydrate at 10−4 M or 10−5Mconcentrations can also increase themigration of oestrogen unresponsiveMDA-MB-231 human breast cancer cells as measured using time-lapse microscopy and xCELLigence technology. In parallel, Al exposure was found to give rise to increased secretion of active matrixmetalloproteinaseMMP9 as measured by zymography, and increased intracellular levels of activated MMP14 as measured by western immunoblotting. These results demonstrate that Al can increase migration of human breast cancer cells irrespective of their oestrogen responsiveness, and implicate alterations to MMPs as a potential mechanism worthy of further study.