Variations in outcomes for Indigenous women with breast cancer in Australia: A systematic review.

This systematic review examines variations in outcomes along the breast cancer continuum for Australian women by Indigenous status. Multiple databases were systematically searched for peer-reviewed articles published from 1 January 1990 to 1 March 2015 focussing on adult female breast cancer patients in Australia and assessing survival, patient and tumour characteristics, diagnosis and treatment by Indigenous status. Sixteen quantitative studies were included with 12 rated high, 3 moderate and 1 as low quality. No eligible studies on referral, treatment choices, completion or follow-up were retrieved. Indigenous women had poorer survival most likely reflecting geographical isolation, advanced disease, patterns of care, comorbidities and disadvantage. They were also more likely to be diagnosed when younger, have advanced disease or comorbidities, reside in disadvantaged or remote areas, and less likely to undergo mammographic screening or surgery. Despite wide heterogeneity across studies, an overall pattern of poorer survival for Indigenous women and variations along the breast cancer continuum of care was evident. The predominance of state-specific studies and small numbers of included Indigenous women made forming a national perspective difficult. The review highlighted the need to improve Indigenous identification in cancer registries and administrative databases and identified key gaps notably the lack of qualitative studies in current literature.

A systematic review of inequalities in psychosocial outcomes for women with breast cancer according to residential location and Indigenous status in Australia.

BACKGROUND: The aim of this systematic review was to examine variations in psychosocial outcomes by residential location and Indigenous status in women diagnosed with breast cancer (BC) in Australia. METHODS: Systematic searches were undertaken using multiple databases covering articles between 1 January 1990 and 1 March 2015 focusing on adult women with BC in an Australian setting and measuring quality of life (QOL), psychological distress or psychosocial support. RESULTS: Thirteen quantitative and three qualitative articles were included. Two quantitative and one qualitative article were rated high quality, seven moderate and the remaining were low quality. No studies examining inequalities by Indigenous status were identified. Non-metropolitan women were more likely to record lower QOL relating to breast cancer-specific concerns and reported a lack of information and resources specific to their needs. Continuity of support, ongoing care and access to specialist and allied health professionals were major concerns for non-metropolitan women. Non-metropolitan women identified unmet needs in relation to travel, fear of cancer recurrence and lack of psychosocial support. CONCLUSIONS: Overall, there was a lack of evidence relating to variations in psychosocial outcomes for women with BC according to residential status or Indigenous status. While the review identified some specific concerns for non-metropolitan women with BC, it was limited by the lack of good quality studies using standardised measures. Copyright © 2016 John Wiley & Sons, Ltd.

Factors predictive of immediate breast reconstruction following mastectomy for invasive breast cancer in Australia.

PURPOSE: To investigate person, cancer and treatment determinants of immediate breast reconstruction (IBR) in Australia. METHODS: Bi-variable and multi-variable analyses of the Quality Audit database. RESULTS: Of 12,707 invasive cancers treated by mastectomy circa 1998-2010, 8% had IBR. This proportion increased over time and reduced from 29% in women below 30 years to approximately 1% in those aged 70 years or more. Multiple regression indicated that other IBR predictors included: high socio-economic status; private health insurance; being asymptomatic; a metropolitan rather than inner regional treatment centre; higher surgeon case load; small tumour size; negative nodal status, positive progesterone receptor status; more cancer foci; multiple affected breast quadrants; synchronous bilateral cancer; not having neo-adjuvant chemotherapy, adjuvant radiotherapy or adjuvant hormone therapy; and receiving ovarian ablation. CONCLUSIONS: Variations in access to specialty services and other possible causes of variations in IBR rates need further investigation.

Survival and degree of spread for female breast cancers in New South Wales from 1980 to 2003: implications for cancer control.

This study investigated associations of degree of spread at diagnosis of breast cancer and socio-demographic factors with the risk of death among NSW females diagnosed in 1980-2003. Trends by diagnostic period, socio-demographic differences, and the implications for cancer control were considered. NSW Central Cancer Registry data were analyzed using regression and rank-order tests to show predictors of death from breast cancer and trends in degree of spread. Compared with localized disease, case fatality was thrice and 14 times higher for cancers with regional spread and distant metastases, respectively. After adjusting for degree of spread and socio-demographic differences, the relative risk of death from breast cancer has declined in recent diagnostic periods compared with the 1980-1983 baseline, reaching a low of 0.38 (0.35, 0.40) for 1999-2003. Age-specific analyses indicated that relative risks were lower in 1999-2003 for 50-69 year olds (RR = 0.31) than younger (RR = 0.40), or older (RR = 0.46) females. Regional or distant disease at diagnosis was lowest in the older age groups, the highest socio-economic stratum and in more recent periods. Females born in non-English speaking countries presented with more advanced disease, as did metropolitan women with the highest access to health services. Degree of spread of cancer at diagnosis is a powerful predictor of case fatality. Case fatalities from breast cancer have declined by diagnostic period, after adjusting for degree of spread, which may reflect treatment and screening advances. Attention should be directed at reducing disparities by socio-economic status and encouraging migrant women to present earlier.

Use of complementary therapies by Australian women with breast cancer.

International research suggests complementary therapy usage is common in women with breast cancer. Comparable data do not exist for Australia. A self-completed questionnaire was used to survey Australian women with breast cancer about their usage of complementary therapies. The survey was mailed to members of two breast cancer consumer advocacy groups, and assessed type of therapy used, reasons for use, and sources of information about complementary therapies. Of 367 respondents with breast cancer, 87.5% had used complementary therapies, with many using four or more therapies. Most commonly used were vitamin supplements (54.2%), support groups (49.8%), massage (41.4%) and meditation (38.7%). Common reasons for use included improving physical (86.3%) and emotional (83.2%) wellbeing and boosting the immune system (68.8%). Women sought information about complementary therapies from a variety of sources. The range of therapies used and the diverse reasons for use emphasise the need for reliable, evidence-based information about complementary therapies for women and clinicians.

Investigating breast symptoms in primary care: enhancing concordance with current best advice.

The purpose of this study was to determine whether a targeted intervention could improve primary care practitioners' concordance with guidelines regarding management of women with breast symptoms. One hundred and twelve practitioners from randomly selected areas around Australia prospectively audited their investigations for each woman with a new breast symptom over two 12-week periods, before and five months after the release of national guidelines. Between the two audits, doctors received feedback on practice in relation to peers and attended one seminar in their local areas led by specialists from the Royal Australasian College of Physicians and the Royal Australasian College of Surgeons. For five recommendations, there were statistically significant improvements at the second audit in line with standard Investigation of a New Breast Symptom (INBS) guidelines. All these were for investigations of breast lumps. At first audit, there were seven recommendations where practitioners were already managing more than 80% of women in accordance with the INBS, and where there were no statistically significant increases in concordance at second audit. Another six recommendations had lower concordance with the recommendations prior to the release of the guidelines and did not significantly improve at second audit. These tended to be for less-common presentations and where clinical findings were not consistent with other test results. We concluded that a targeted intervention improved physician concordance with current best advice for investigating women who present with new breast symptoms in a primary care setting. Further educational programs are needed to improve investigations for rarer symptoms, and to enhance physicians' confidence in the results of their clinical examinations.

Bis[platinum(II)] and bis[platinum(IV)] complexes with optically active bis(vicinal-1,2-diamines) and their interaction with DNA.

Bis[platinum(II)] [Cl2Pt(LL)PtCl2] complexes 2,5 and 8 with chiral non-racemic ligands: 1a-c (LL = (R,R), (S,S) and (R,S) N,N'-bis(3,4-diaminobutyl)hexanediamide); 4a,b (LL = (R,R) and (S,S) N,N'-bis[3,4-bis(diaminobutyl)] urea); 7a-d (LL' = (R,R), (S,S), (R,S) and (S,R) 4,5-diamino-N-(3,4-diaminobutyl) pentanamide) and bis[platinum(IV)] complex 10-13 with ligands 1a,b and 4a,b have been prepared and characterized by IR, 1H, 13C and 195Pt NMR spectra. The interactions of 2a-c, 5a, 5b, 8a-d and 10a with dsDNA were investigated with the goal of examining whether the chirality, the nature of the spacer and the oxidation state have an influence on platinum-DNA binding properties. All the bis[platinum(II)] complexes form with dsDNA intra- and interstrand crosslinks and crosslinks over sticky ends, whereas the bis[platinum(IV)] complex 10a only forms intra- and interstrand crosslinks. The platinum-DNA coordination sites were determined by the T4 DNA polymerase footprinting method. The results show that all investigated bis(platinum) complexes have high preference towards distinct purines. All isomeric bis(amide) 2a-c and mono(amide) 8a-d complexes exhibit nearly the same binding pattern, whereas the ureide complexes 5a and 5b have other coordination sites with higher sequence preference. Interestingly, the ureides 5a and 5b differ in their coordination sites not only in comparison to the bis(amides) 2a-c and mono(amides) 8a-d, but also between each other. The bis[platinum(IV)] complex 10a also differs in coordination sites in comparison to all the bis[platinum(II)] compounds.

Synthesis of 1-(2-aminophenyl)isoquinolines and the biological activity of their cis-dichloro platinum(II) complexes.

The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and varying substitution of the phenyl ring is reported. These compounds constitute a new class of ligands for the synthesis of oligocyclic platinum(II) complexes. In vitro cytotoxicity tests indicate that the most basic amine ligands afford the most effective complexes. Two of the new complexes were more potent against L1210 murine leukemia cells than the well-established antitumor compound cisplatinum.

Molecular interaction of DNA with bisplatinum(II) complexes having bis(vicinal 1,2-diamines) as ligand.

The interaction of novel, tetrafunctional bisplatinum compounds with DNA was investigated. These compounds have bis(vicinal 1,2-diamines) as ligand. The reactions' efficiency, types of cross-links, alterations of the global DNA structure, and sequence selectivity differ significantly from the corresponding features of cisplatin. In particular, they form multiple complexes with dsDNA, which include intrastrand, interstrand and interhelical cross-links and cross-links over sticky ends. The novel compounds are able to untwist but not shorten dsDNA. The reactivity and adduct-forming efficiency of these compounds is, depending on the spacer length, 100-200-fold higher than that of cisplatin. As a consequence, interstrand cross-links are also formed to a higher extent. The chemical stability of the interstrand cross-links against cyanide ions, however, is weaker than that of interstrand cross-links formed by cisplatin, suggesting that each platinum sphere of a bisplatinum compound forms intrastrand cross-links. With dsDNA, they show a preference toward purines, particularly guanines, but they apparently are also coordinated to other nucleobases. Their sequence selectivity toward dsDNA is higher than that of cisplatin. Thus, the novel compounds extend the spectrum of alternative platinum-based compounds with chemical features different from cisplatin.

Active mammalian replication origins are associated with a high-density cluster of mCpG dinucleotides.

ori-beta is a well-characterized origin of bidirectional replication (OBR) located approximately 17 kb downstream of the dihydrofolate reductase gene in hamster cell chromosomes. The approximately 2-kb region of ori-beta that exhibits greatest replication initiation activity also contains 12 potential methylation sites in the form of CpG dinucleotides. To ascertain whether DNA methylation might play a role at mammalian replication origins, the methylation status of these sites was examined with bisulfite to chemically distinguish cytosine (C) from 5-methylcytosine (mC). All of the CpGs were methylated, and nine of them were located within 356 bp flanking the minimal OBR, creating a high-density cluster of mCpGs that was approximately 10 times greater than average for human DNA. However, the previously reported densely methylated island in which all cytosines were methylated regardless of their dinucleotide composition was not detected and appeared to be an experimental artifact. A second OBR, located at the 5' end of the RPS14 gene, exhibited a strikingly similar methylation pattern, and the organization of CpG dinucleotides at other mammalian origins revealed the potential for high-density CpG methylation. Moreover, analysis of bromodeoxyuridine-labeled nascent DNA confirmed that active replication origins were methylated. These results suggest that a high-density cluster of mCpG dinucleotides may play a role in either the establishment or the regulation of mammalian replication origins.

Organization of the alpha-globin promoter and possible role of nuclear factor I in an alpha-globin-inducible and a noninducible cell line.

Nuclear factor I (NFI) was suggested to be involved in the expression of the human alpha-globin gene. Two established cell lines, which express alpha-globin differentially, were therefore compared for differences in binding of NFI at the alpha-globin promoter in vivo. HeLa cells, in which alpha-globin is repressed, show a high density promoter occupation with several proteins associated with structurally distorted DNA. Cell line K562, which is inducible for alpha-globin, surprisingly was found to be heterogeneous consisting mainly of cells (approximately 95%) unable to express alpha-globin. However, the promoter of the nonexpressing K562 cells was clearly different from that of HeLa cells, being occupied only at basal transcriptional elements. Therefore, the alpha-globin gene in these K562 cells may not be truly repressed, but in an intermediate state between repression and active transcription. The NFI site of the alpha-globin promoter appeared occupied in HeLa but free of proteins in K562 cells. All cells of both cell lines produce NFI, but the composition and DNA binding affinity of NFI species differ significantly between the two cell lines. Therefore, distinct forms of NFI may repress alpha-globin transcription in HeLa cells. However, NFI is apparently not involved in establishing the latent transcriptional state of the majority of K562 cells.

A novel type of interaction between cruciform DNA and a cruciform binding protein from HeLa cells.

We recently identified and enriched a protein (CBP) from HeLa cells with binding specificity for cruciform-containing DNA. We have now studied the interaction of CBP with stable cruciform DNA molecules containing the 27 bp palindrome of SV40 on one strand and an unrelated 26 bp palindrome on the other strand by hydroxyl radical footprinting. The CBP-DNA interaction is localized to the four-way junction at the base of the cruciforms. CBP appears to interact with the elbows of the junctions in an asymmetric fashion. Upon CBP binding, structural distortions were observed in the cruciform stems and in a DNA region adjacent to the junction. These features distinguish CBP from other cruciform binding proteins, which bind symmetrically and display exclusively either contacts with the DNA backbone or structural alterations in the DNA.

Conserved high-affinity NF-kappa B binding site in the interferon regulatory factor-1 promoter is not occupied by NF-kappa B in vivo and is transcriptionally inactive.

The promoter of the interferon regulatory factor-1 (IRF-1) gene contains at position -47 to -38 an evolutionary conserved binding sequence for the inducible transcription factor NF-kappa B. This site is highly homologous to a transcriptionally active site from the MHC class I enhancer. In this study, we show by in vitro assays using purified NF-kappa B that the kappa B motif in the IRF-1 promoter binds the factor specifically and with high affinity, comparable to various other cis-acting kappa B elements. Two copies of the IRF-1 kappa B site fused to the heterologous c-fos promoter conferred induction of a chloramphenicol acetyl transferase (CAT) reported gene in response to stimulation of L929 fibroblasts with various NF-kappa B inducers, such as tumor necrosis factor alpha (TNF alpha) or phorbol 12-myristate 13-acetate (PMA). Mutation of the binding site completely abolished transcriptional inducibility of the heterologous promoter. Surprisingly, the same IRF-1 kappa B motif in context of the homologous IRF-1 promoter was transcriptionally inactive in CAT assays. The very weak induction of the IRF-1 promoter in response to TNF treatment or infection of fibroblasts with Newcastle disease virus (NDV) was barely affected by point mutation of the kappa B site or loss of the site by truncation of the promoter. Analysis of the occupational state of the chromosomal IRF-1 kappa B site by in vivo foot-printing revealed that no footprint was induced over the kappa B motif in the IRF-1 promoter after PMA treatment of L929 fibroblast cells, despite the simultaneous induction of IRF-1 mRNA and NF-kappa B binding activity. Constitutive footprints were detected at a CCAAT and GC-rich region in the promoter. This is the first example of a high-affinity NF-kappa B binding site within a promoter which may not participate in transcriptional regulation under conditions activating NF-kappa B DNA binding and gene expression.

In vivo footprinting of the IRF-1 promoter: inducible occupation of a GAS element next to a persistent structural alteration of the DNA.

GAS (gamma activated sequence) and GAS-like elements are found in a rapidly growing number of genes. Data from EMSA (electromobility shift assay) and transient transfection assays using heterologous promoter systems do not necessarily reflect transcriptional involvement and protein occupation of a binding site in vivo. This has been shown recently by in vivo footprinting of the NF-kappa B site at -40 in the interferon regulatory factor-1 (IRF-1) promoter. Here we show by in vivo footprinting using dimethylsulfate (DMS) that the GAS of the IRF-1 promoter, which also contains an overlapping putative NF-kappa B site, is occupied upon treatment with gamma-interferon (IFN gamma) but not with phorbol 12-myristate 13-acetate (PMA). Irrespective of induction, we detect a very strong DMS hypersensitivity at a guanosine just adjacent to GAS and a less persistent minor DMS hypersensitivity at a central cytosine. Our data confirm the crucial role of GAS in transcriptional activation by IFN gamma and are consistent with induced binding of p91 to GAS. In addition, our data suggest a major conformational distortion of the DNA at the GAS element of the IRF-1 promoter and that this GAS element is not involved in transcriptional activation by PMA.

Vigilin is a cytoplasmic protein. A study on its expression in primary cells and in established cell lines of different species.

A fusion protein composed of about two vigilin domains and beta-galactosidase was used to raise polyclonal antibodies which were affinity-purified and employed for immunoblotting and immunohistochemistry. A protein of an apparent molecular mass of 155 kDa could be stained in extracts of a variety of cells from different species and organs. Immunohistological studies on single cells showed that vigilin is accumulated in the cytoplasm. During in vitro maintenance of primary cell cultures, as well as of a growth-factor-dependent cell line, vigilin expression decreases and ceases in senescent cells. In contrast, vigilin is constitutively expressed in all other transformed cell lines of various origin studies so far. Vigilin expression can be induced in peripheral blood lymphocytes by mitogen stimulation. These observations suggest an involvement of vigilin in processes of cell activation. Immunoblot experiments demonstrating the presence of vigilin in a broad range of eukaryotes, indicate a high degree of evolutionary conservation.

Hydroxyl radical footprints reveal novel structural features around the NF I binding site in adenovirus DNA.

We have identified a number of as yet unknown structural abnormalities of the NF I-DNA binding site within the inverted terminal repetition of adenovirus DNA by probing it with a hydroxyl radical footprinting technique. NF I binding alters the accessibility of the deoxyribose moieties to hydroxyl radicals both at the 3' and at the 5' side of the recognition sequence 5'-TGG(N)6GCCAA-3'. A smooth bend at the 5' side of the binding sequence is already present in naked linear DNA and it is further enhanced by protein binding. This could be demonstrated not only by hydroxyl radical footprinting but also by studying the temperature dependent mobility during gel electrophoresis of DNA fragments carrying the NF I binding site at circularly permutated positions. We propose that the bent conformation at this site is responsible for facilitating protein/DNA interactions.