PubMed Health⌕ Search

Biomedical subjects

M Hills

Publications and source records attributed to M Hills.

At least 19 recordsLinked to original sources
PubMed2006

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy.

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approximately 5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11-12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21-q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3-q4 and 18p11.31 and gains of 6p25.1-p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2-11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

Adult↗
PubMed2005

Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience.

De novo resistance to endocrine therapy is a near-universal feature of oestrogen receptor (ER)- negative breast cancer. Although many ER-positive breast cancers also show no response to tamoxifen or aromatase inhibitors on objective clinical grounds the large majority show reduced proliferation indicating that some oestrogen dependence is present in almost all ER-positive breast cancer. In neoadjuvant studies HER2 positivity is associated with poor response rates to tamoxifen but not aromatase inhibitors, consistent with preclinical models. Acquired resistance to tamoxifen is associated with decreases in ER positivity but most recurrent lesions remain ER-positive. A small proportion of these show increased HER2 expression and in these patients increased phospho-p38 may contribute to the tamoxifen-resistant phenotype. There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors.

Antineoplastic Agents, Hormonal↗
PubMed2004

High incidence of HER-2 positivity in inflammatory breast cancer.

HER-2 is over-expressed in around 25% of human breast cancers, and is associated with poor outcome. We examined the incidence of HER-2 status in inflammatory breast cancer (IBC). Forty-nine newly diagnosed IBCs were studied. Formalin-fixed paraffin-embedded pre-treatment tissue biopsies were examined immunohistochemically for the over-expression of the HER-2 protein and gene using the HercepTest and FISH assay. Clinical outcome was compared between the HER-2 positive (HercepTest score 3 + and FISH positive) and negative groups. Fifty-two per cent of the IBCs examined were HER-2 positive. The HER-2 positive group were demographically comparable to the HER-2 negative group. Ninety-six per cent of the HER-2 positive patients responded to primary chemotherapy compared to 76% of the HER-2 negative (P = 0.09). No significant differences in outcome emerged between the two groups. In conclusion, this study found the incidence of HER-2 protein over-expression in IBC is higher than previously reported in non-IBC. Early HER-2 directed therapy (such as the monoclonal antibody trastuzumab) as a part of multimodal treatment may improve outcome in this poor prognosis cancer.

Adult↗
PubMed2004

Anastrozole demonstrates clinical and biological effectiveness in oestrogen receptor-positive breast cancers, irrespective of the erbB2 status.

Overexpression of erbB2 in breast tumours can predict resistance to tamoxifen therapy. We conducted a small trial to determine if erbB2 status correlates with tumour response and biochemical changes in postmenopausal women receiving neoadjuvant therapy with the aromatase inhibitor, anastrozole. Twenty-four postmenopausal women with oestrogen receptor (ER)-rich, large, operable breast tumours received three months of neoadjuvant anastrozole, 1 or 10 mg daily, then surgery, followed by another five years of anastrozole 1 mg daily. Response to the treatment was based on changes in clinical and ultrasound measurements of tumour volume and changes in tumour proliferation and progesterone receptor (PgR) status. After follow-up for a median duration of four years therapy, there was no apparent difference between erbB2 0/1+ and erbB2 3+ tumours in clinical response or changes in proliferation and PgR expression. In conclusion, anastrozole appears to be an effective endocrine option in this patient population, irrespective of the erbB2 status.

Aged↗
PubMed2003

Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres.

Accurate diagnostic assessment of HER-2 is essential for the appropriate application of the humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) to the treatment of patients with metastatic breast cancer. The diagnostic test needs to be applicable to archival, fixed tissue removed at excision, in many cases several years earlier. We compared the assessment of HER-2 by immunohistochemistry (IHC; HercepTest) and fluorescence in situ hybridization (FISH) in 426 breast carcinomas from patients being considered for trastuzumab therapy. The tumours were tested in three reference centres having been sent in from 37 hospitals. Only 2/270 (0.7%) IHC 0/1+ tumours were FISH positive. Six of 102 (5.9%) IHC 3+ tumours were FISH negative. Five of the six had between 1.75 and 2.0 HER-2 gene copies per chromosome 17 and the sixth had multiple copies of chromosome 17. Thirteen per cent of tumours were IHC 2+ and overall 48% of these were FISH positive but this proportion varied markedly between the centres. Sixty IHC-stained slides selected to be enriched with 2+ cases were circulated between the three laboratories and scored. There were 20 cases in which there was some discordance in scoring. Consideration of the FISH score in these cases led to concordance in the designation of positivity/negativity in 19 of these 20 cases. These data support an algorithm in which FISH testing is restricted to IHC 2+ tumours in reference centres. The results may not extrapolate to laboratories with less experience or using different methodologies.

Algorithms↗
PubMed2001

HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer.

In experimental models, human epidermal growth factor receptor-2 (HER-2) amplification leads to estrogen independence and tamoxifen resistance in estrogen receptor (ER)-positive human breast cancer cells. Some but not all reports suggest an association between HER-2 positivity and hormone independence in breast cancer patients. This study aimed to evaluate the antiproliferative effects of endocrine therapy in HER-2-positive/ER-positive primary human breast cancer. The effect on proliferation (Ki67) of hormone therapy was assessed at 2 weeks and/or 12 weeks in biopsies from 115 primary breast cancers with ER-positive tumors. The patients took part in one of 3 neoadjuvant trials of hormonal therapy with a SERM (tamoxifen or idoxifene) or an aromatase inhibitor (anastrozole or vorozole). HER-2 status was assessed by immunocytochemistry and fluorescence in situ hybridization (FISH). Fifteen patients were defined as HER-2 positive by both immunohistochemistry and FISH, with the remaining 100 patients HER-2 negative. Geometric mean Ki67 levels were substantially higher in HER-2-positive than HER-2-negative tumors (27.7% versus 11.5%, respectively; P = 0.003). In HER-2-negative patients, Ki67 was reduced by 62 and 71% at 2 and 12 weeks, respectively (P < 0.0001 for both), but HER-2-positive patients showed no significant fall. The proportional change in Ki67 was significantly different between HER-2-positive and -negative patients (P = 0.014 at 2 weeks; P = 0.047 at 12 weeks). Mean ER levels were lower in the HER-2-positive patients (P = 0.06) but the change in Ki67 was impeded even in those with high ER. Apoptotic index was reduced by 30% at 2 weeks in the HER-2-negative group. However, there were no statistically significant differences in apoptotic index between the groups. It is concluded that ER-positive/HER-2-positive primary breast carcinomas show an impeded antiproliferative response to endocrine therapy that nonetheless may vary between individual treatments. This together with high baseline proliferation is likely to translate to poor clinical response.

Anastrozole↗
PubMed2001

Heat-labile proteases in molecular biology applications.

Thermolabile proteases were identified in three Gram-negative psychrotrophic bacteria. The protease from the psychrotrophic strain A9 was purified and its application to common molecular biology techniques was demonstrated. Heat-stable molecular biology enzymes (Taq polymerase and PvuII) were digested by a heat-labile protease, which was then inactivated by a mild heat treatment. The clear benefit of using heat-labile proteases arises in situations where further reactions may be accomplished without an intermediate purification step, thereby saving time and avoiding the possibility of product loss.

Cold Temperature↗
PubMed2001

The development of phonological awareness: effects of spoken language experience and orthography.

Phonological awareness, the ability to analyze spoken language into small sound units, has been shown to be affected by the individual's early orthographic experience (alphabetic vs. non-alphabetic). Past studies, however, have not differentiated the effect of script alphabeticity from that of spoken language experience, which covaries strongly with the phonological properties of the language. The present study compares younger, pre-reading to older, literate children from different linguistic backgrounds on their phonological awareness. Hong Kong and Guangzhou subjects both spoke Cantonese. The latter subjects had early experience with Pinyin (alphabetic) in addition to their logographic Chinese reading; the former read only logographic Chinese. New Zealand subjects spoke English and read the Roman alphabet. Results showed that: (1) the Hong Kong and Guangzhou pre-readers performed very similarly at all levels of phonological awareness; (2) the New Zealand pre-readers outperformed their Hong Kong and Guangzhou counterparts on onset, rime, and coda analyses; (3) the Guangzhou reading children outperformed their Hong Kong counterparts on onset and coda analyses. Whereas finding (3) reflects an effect of alphabeticity in the first learned script, finding (2) in combination with finding (1) indicates an effect of early spoken language experience independent of orthography. The fact that orthographic and spoken language experience both impact on the development of phonological skills implies a mediating function of phonological awareness in integrating sound information derived from reading and perceiving speech.

Age Factors↗
PubMed2001

Characterization of a novel plant acyl-coA synthetase that is expressed in lipogenic tissues of Brassica napus L.

A cDNA encoding a novel isoform of acyl-CoA synthetase (ACS6) was isolated from embryos of oilseed rape. Homology searches show it is most closely related to ACS4 from rat and human brain rather than the other oilseed rape ACSs. The ACS6 is strongly expressed in embryos and flowers, tissues of Brassica napus that synthesize lipids at high rates. The activity of recombinantly expressed ACS6 was recovered in the insoluble fraction (214,000 x g, 1 h pellet). CHAPS-solubilized recombinant ACS6 protein preferred utilising long-chain fatty acids that contained a cis-9 double bond, i.e. palmitoleic, oleic, linoleic and linolenic acids. Western blot analysis showed that the ACS6 protein is membrane-bound.

Amino Acid Sequence↗
PubMed2001

Non-communicable disease mortality rates using the verbal autopsy in a cohort of middle aged and older populations in Beirut during wartime, 1983-93.

STUDY OBJECTIVES: Health priorities in middle to low income countries, such as Lebanon, have traditionally been assumed to follow those of a "typical" developing country, with a focus on the young and on communicable diseases. This study was carried out to quantify the magnitude of communicable and non-communicable disease mortality and to examine mortality pattern among middle aged and older populations in an urban setting in Lebanon. DESIGN AND PARTICIPANTS: A representative cohort of 1567 men and women (>/=50 years) who had participated in a cross sectional multi-dimensional health survey in Beirut, Lebanon in 1983 and were followed up 10 years later. Vital status was ascertained and causes of death were obtained through verbal autopsy. RESULTS: Total mortality rates were estimated at 33.7 and 25.2/1000 person years among men and women respectively. In both sexes, the leading causes of death were non-communicable, mainly circulatory diseases (60%) and cancer (15%). For all cause mortality, men had significantly higher risk than women (age adjusted rate ratio, RR=1.42, 95% confidence intervals (CI) = 1.16, 1.72) especially at younger ages. Except for cerebrovascular diseases, renal problems and injuries attributable to falls and fractures, men were also at higher cause specific mortality risk than women, in particular, for ischaemic heart disease (RR = 2.24, 95% CI = 1.62, 3.12). Comparison with earlier death certificate data in Lebanon and current estimates from other regions in the world showed the magnitude of cardiovascular disease over time. CONCLUSIONS: The results from this first cohort study in the Arab region show, in contrast with popular perception, a mortality pattern more like a developed country than a developing one. Strategies of public health activities, in particular for countries in transition, need to be continuously re-assessed in light of empirical epidemiological data and other health indicators for evidence-based decision making.

Age Distribution↗
PubMed2000

Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer.

Idoxifene is a novel selective estrogen receptor modulator. It has reduced agonist activity on breast and uterine cells compared with tamoxifen and antiproliferative effects in tamoxifen-resistant breast cancer cells. Previous studies have shown that a short course of treatment with other antiestrogens prior to surgery caused a significant reduction of the growth fraction when measured by immunohistological staining using the mouse monoclonal antibody Ki67. In this study, we assessed the effect of idoxifene on biological markers of cell proliferation (Ki67) and apoptosis (TdT-mediated dUTP-biotin nick end labeling), and estrogen and progesterone receptor (ER/PR) expression was also evaluated. Core-cut biopsies were obtained in 77 postmenopausal patients with primary breast cancer at diagnosis. Patients were randomized to 40 mg/day idoxifene or placebo for 14-21 days prior to obtaining a second biopsy sample at surgical resection. The percentage of Ki67-positive cells fell from a mean 19.7 +/- 2.7% (SE) to 13.4 +/- 3.4% in idoxifene-treated ER-positive tumors (n = 30; P = 0.0043), but there was no significant effect in placebo-treated ER-positive tumors (n = 27). No effect was seen on ER-negative tumors in either group. Idoxifene had no significant effect on apoptotic index but produced a statistically significant fall in idoxifene-treated ER immunohistochemical score and a small increase in PR that did not reach statistical significance (0.05 < P < 0.10). Idoxifene was well tolerated in all patients. Idoxifene has an antiproliferative effect in ER-positive but not ER-negative breast cancers, and no significant effect on apoptosis in the short-term.

Aged↗
PubMed1999

Time-related effects of estrogen withdrawal on proliferation- and cell death-related events in MCF-7 xenografts.

Endocrine treatments for human breast cancer have been based largely upon the removal of estrogenic stimuli. The regression of tumors after estrogen deprivation has generally been characterized as being due to reduced proliferation but more recently has been recognized to also involve increased apoptosis. The aim of our experiments was to define the associated changes in certain proliferation- and cell death-related biological parameters after hormone withdrawal from estrogen-dependent MCF-7 xenografts in athymic nude mice using immunohistochemical techniques. The baseline estrogen receptor (ER) level of this MCF-7 xenograft was relatively low (average H score 23) but it was strongly Bcl-2-, PgR- and pS2-positive, indicating the functional integrity of estrogen signaling. Changes in proliferation (Ki-67), apoptosis, ER, progesterone receptor (PgR), cyclin D1, p27kip1, Bcl-2 and Bax expression were assessed during the 2 weeks after estrogen deprivation. ER levels rose markedly after estrogen ablation, whereas PgR levels fell to about 10% of baseline and pS2 levels halved. The proportion of Ki-67-positive cells was unchanged after 24 hr but by day 14 had reduced by about 80%. The normal levels of cyclin D1 also reduced after estrogen withdrawal in contrast to the rapid increase in levels of cyclin-dependent kinase inhibitor p27kip1. This latter increase appeared to occur in advance of the changes in Ki-67. The proportion of apoptotic cells increased from a mean 1.5% at baseline to 2.9% after 3 days and 4.7% after 14 days. There were reductions in both Bcl-2 and Bax staining but these appeared to be greater for Bcl-2, effectively decreasing the Bcl-2/Bax ratio. Our results provide a framework for the use of these parameters as intermediate markers in comparisons of hormonal agents for human breast cancer treatment.

Animals↗
PubMed1999

Transplacental transfer of measles and total IgG.

This study was conducted to evaluate factors affecting the levels of total IgG (tIgG) and measles specific IgG (mIgG) in mother and cord sera, and the efficiency of transplacental transport of tIgG and mIgG. The study was conducted in four hospitals in Oporto, Portugal, where 1539 women and their newborns were enrolled. Measles IgG levels were lower among vaccinated mothers and respective cord sera than among vaccinated counterparts. Cord mIgG was strongly correlated with maternal levels in both vaccinated and unvaccinated groups. Transplacental transport efficiency (TTE) of mIgG decreased with increasing maternal levels, although almost one third of the observed effect was due to measurement error. The TTE was not affected by vaccination status. Monitoring maternal measles antibody levels and maternal vaccination status could be useful to determine when the age for measles vaccination can be reduced.

Adolescent↗
PubMed1999

A story/dialogue method for health promotion knowledge development and evaluation.

Arguments have been made in favour of a constructivist or postpositivist approach to health promotion knowledge development and program evaluation, but little has been articulated about what such an approach would look like. This article describes a 'story/dialogue method' that was created with and for practitioners in response to their concerns that much of their practice did not lend itself to a positivist, or conventional, methodology. Derived from constructivist, feminist and critical pedagogical theory, and with roots in qualitative methods, the method structures group dialogue around case stories addressing particular generative practice themes. While intended for practitioner training, organizational development and evaluation, the method to date has been used primarily for training purposes. This article describes the method, provides an example of its application, and discusses its strengths, weaknesses and relevance to health promotion.

Anecdotes as Topic↗
PubMed1998

Student experiences of nursing health promotion practice in hospital settings.

It has become evident that the current approaches to health care are inadequate for the changing needs of the world. Health promotion has gained recognition as a preferred option and many nursing programmes throughout the world have reoriented their curricula to incorporate this approach. This paper describes a study that was conducted to explicate student experiences of the practice of health promotion. Twenty-four students participated in the study; qualitative methods, narrative accounts and reflective journals were used to collect the data and the data was analysed using van Manen's recommendations for thematic analysis. Three major themes emerged: the centrality of caring; empowerment--power, participation and partnerships; and the primacy of people. Student narratives are used to illustrate the themes.

Attitude of Health Personnel↗