Fibroblast growth factor receptor inhibition synergizes with paclitaxel and doxorubicin in endometrial cancer cells

OBJECTIVE: The fibroblast growth factor (FGF) family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas. Given the identification of activating mutations in the FGF receptor 2 (FGFR2) receptor tyrosine kinase in a subset of endometrial tumors, agents with activity against FGFRs are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Here, we evaluated the effect of FGFR inhibition on the in vitro efficacy of chemotherapy in endometrial cancer cell lines. METHODS: Human endometrial cancer cell lines with wild-type or activating FGFR2 mutations were used to determine any synergism with concurrent use of the pan-FGFR inhibitor, PD173074, and the chemotherapeutics, doxorubicin and paclitaxel, on cell proliferation and apoptosis. RESULTS: FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with paclitaxel or doxorubicin showed synergistic activity in the 3 FGFR2 mutant cell lines evaluated. In addition, although nonmutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the cytostatic effect of paclitaxel and doxorubicin in a subset of FGFR2 wild-type endometrial cancer cell lines. CONCLUSIONS: Together these data suggest a potential therapeutic benefit to combining an FGFR inhibitor with standard chemotherapeutic agents in endometrial cancer therapy particularly in patients with FGFR2 mutation positive tumors.

The interactions between insulin and androgens in progression to castrate resistant prostate cancer

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

Targeting aurora kinases : a novel approach to curb the growth and chemoresistance of androgen refractory prostate cancer

Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.

Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand

Overexpression of the receptor tyrosine kinase EphB4 is common in epithelial cancers and linked to tumor progression by promoting angiogenesis, increasing survival and facilitating invasion and migration. However, other studies have reported loss of EphB4 suggesting a tumor suppressor function in some cancers. These opposing roles may be regulated by (i) the presence of the primary ligand ephrin-B2 that regulates pathways involved in tumor suppression or (ii) the absence of ephrin-B2 that allows EphB4 signaling via ligand-independent pathways that contribute to tumor promotion. To explore this theory, EphB4 was overexpressed in the prostate cancer cell line 22Rv1 and the mammary epithelial cell line MCF-10A. Overexpressed EphB4 localized to lipid-rich regions of the plasma membrane and confirmed to be ligand-responsive as demonstrated by increased phosphorylation of ERK1/2 and internalization. EphB4 overexpressing cells demonstrated enhanced anchorage-independent growth, migration and invasion, all characteristics associated with an aggressive phenotype, and therefore supporting the hypothesis that overexpressed EphB4 facilitates tumor promotion. Importantly, these effects were reversed in the presence of ephrin-B2 which led to a reduction in EphB4 protein levels, demonstrating that ligand-dependent signaling is tumor suppressive. Furthermore, extended ligand stimulation caused a significant decrease in proliferation that correlated with a rise in caspase-3/7 and -8 activities. Together, these results demonstrate that overexpression of EphB4 confers a transformed phenotype in the case of MCF-10A cells and an increased metastatic phenotype in the case of 22Rv1 cancer cells and that both phenotypes can be restrained by stimulation with ephrin-B2, in part by reducing EphB4 levels.

A case-control study of ambient heat exposure and urolithiasis among outdoor workers in a shipbuilding company, Guangzhou, China

Higher ambient temperatures will increase heat stress on workers, leading to impacts upon their individual health and productivity. In particular, research has indicated that higher ambient temperatures can increase the prevalence of urolithiasis. This thesis examines the relationship between ambient heat exposure and urolithiasis among outdoor workers in a shipbuilding company in Guangzhou, China, and makes recommendations for minimising the possible impacts of high ambient temperatures on urolithiasis. A retrospective 1:4 matched case-control study was performed to investigate the association between ambient heat exposure and urolithiasis. Ambient heat exposure was characterised by total exposure time, type of work, department and length of service. The data were obtained from the affiliated hospital of the shipbuilding company under study for the period 2003 to 2010. A conditional logistic regression model was used to estimate the association between heat exposure and urolithiasis. This study found that the odds ratio (OR) of urolithiasis for total exposure time was 1.5 (95% confidence interval (CI): 1.2–1.8). Eight types of work in the shipbuilding company were investigated, including welder, assembler, production security and quality inspector, planing machine operator, spray painter, gas-cutting worker and indoor employee. Five out of eight types of work had significantly higher risks for urolithiasis, and four of the five mainly consisted of outdoors work with ORs of 4.4 (95% CI: 1.7–11.4) for spray painter, 3.8 (95% CI: 1.9–7.2) for welder, 2.7 (95% CI: 1.4–5.0) for production security and quality inspector, and 2.2 (95% CI: 1.1–4.3) for assembler, compared to the reference group (indoor employee). Workers with abnormal blood pressure (hypertension) were more likely to have urolithiasis with an OR of 1.6 (95% CI: 1.0–2.5) compared to those without hypertension. This study contributes to the understanding of the association between ambient heat exposure and urolithiasis among outdoor workers in China. In the context of global climate change, this is particularly important because rising temperatures are expected to increase the prevalence of urolithiasis among outdoor workers, putting greater pressure on productivity, occupational health management and health care systems. The results of this study have clear implications for public health policy and planning, as they indicate that more attention is required to protect outdoor workers from heat-related urolithiasis.

Human Kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients.

Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer, but its application is limited by the lack of suitable target antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly overexpressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201+ KLK4 + cell lines and KLK4 mRNA-transfected monocyte-derived dendritic cells. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Developing a best practice model of refugee maternity care

Background: About one third of refugee and humanitarian entrants to Australia are women age 12—44 years. Pregnant women from refugee backgrounds may have been exposed to a range of medical and psychosocial issues that can impact maternal, fetal and neonatal health. Research question: What are the key elements that characterise a best practice model of maternity care for women from refugee backgrounds? This paper outlines the findings of a project which aimed at developing such a model at a major maternity hospital in Brisbane, Australia. Participants and methods: This multifaceted project included a literature review, consultations with key stakeholders, a chart audit of hospital use by African-born women in 2006 that included their obstetric outcomes, a survey of 23 African-born women who gave birth at the hospital in 2007—08, and a survey of 168 hospital staff members. Results: The maternity chart audit identified complex medical and social histories among the women, including anaemia, female circumcision, hepatitis B, thrombocytopenia, and barriers to access antenatal care. The rates of caesarean sections and obstetric complications increased over time. Women and hospital staff surveys indicated the need for adequate interpreting services, education programs for women regarding antenatal and postnatal care, and professional development for health care staff to enhance cultural responsiveness. Discussion and conclusions: The findings point towards the need for a model of refugee maternity care that comprises continuity of carer, quality interpreter services, educational strategies for both women and healthcare professionals, and the provision of psychosocial support to women from refugee backgrounds.

A six-year descriptive analysis of hospitalisations for ambulatory care sensitive conditions among people born in refugee-source countries

Background: Hospitalisation for ambulatory care sensitive conditions (ACSHs) has become a recognised tool to measure access to primary care. Timely and effective outpatient care is highly relevant to refugee populations given the past exposure to torture and trauma, and poor access to adequate health care in their countries of origin and during flight. Little is known about ACSHs among resettled refugee populations. With the aim of examining the hypothesis that people from refugee backgrounds have higher ACSHs than people born in the country of hospitalisation, this study analysed a six-year state-wide hospital discharge dataset to estimate ACSH rates for residents born in refugee-source countries and compared them with the Australia-born population. Methods: Hospital discharge data between 1 July 1998 and 30 June 2004 from the Victorian Admitted Episodes Dataset were used to assess ACSH rates among residents born in eight refugee-source countries, and compare them with the Australia-born average. Rate ratios and 95% confidence levels were used to illustrate these comparisons. Four categories of ambulatory care sensitive conditions were measured: total, acute, chronic and vaccine-preventable. Country of birth was used as a proxy indicator of refugee status. Results: When compared with the Australia-born population, hospitalisations for total and acute ambulatory care sensitive conditions were lower among refugee-born persons over the six-year period. Chronic and vaccine-preventable ACSHs were largely similar between the two population groups. Conclusion: Contrary to our hypothesis, preventable hospitalisation rates among people born in refugee-source countries were no higher than Australia-born population averages. More research is needed to elucidate whether low rates of preventable hospitalisation indicate better health status, appropriate health habits, timely and effective care-seeking behaviour and outpatient care, or overall low levels of health care-seeking due to other more pressing needs during the initial period of resettlement. It is important to unpack dimensions of health status and health care access in refugee populations through ad-hoc surveys as the refugee population is not a homogenous group despite sharing a common experience of forced displacement and violence-related trauma.

Dietetic confidence working with clients with depression/anxiety is associated with client-focused practic and advocacy skills

Confidence in a professional role is a key element in the successful transition to competent practice. New graduate dietitians report that whilst they are confident about their general dietetic ability, they are not as confident when working with clients experiencing depression and anxiety. This study aimed to develop and validate a scale which measured confidence about working with clients with depression/anxiety. The 21-item Dietetics Collaborative Practice Scale was developed using research about dietetic practice in mental health, coping self-efficacy literature and collaboration with industry experts. A convenience sample of 189 Australian dietitians completed the questionnaire. Exploratory factor analysis suggests that dietetic confidence is best represented by a two dimensional solution consisting of (a) Client –focused practice (CFP, 50.8% variance) and (b) Advocacy for self and client care (ASC, 9.7% variance). The alpha coefficient of both dimensions (CFP ɑ=0.95, ASC ɑ=0.84) demonstrated the internal consistency of components. Combined, these two components account for 60.5% of variance. The scale components were not related to years of practice or working with mental health clients but were significantly related to overall dietetic confidence (ODC). Correlation coefficients between ODC and CFP were 0.501 (p<0.01), ODC and ASC were correlated at 0.465 (p<0.01) and CFP and number of years as a dietitian were weakly correlated at 0.24 (p<0.05). Results have implications for dietetic training and professional development. Client focus and advocacy for self and client appear to be important factors in overall confidence as a dietitian.

Meeting the Food Needs of Queensland’s Culturally and Linguistically Diverse (CALD) Aged Population: A Review of the Literature

This report summarises research undertaken by Queensland University of Technology, Brisbane, in partnership with Diversicare, on ‘Meeting the cultural food needs of Queensland’s Culturally and Linguistically Diverse (CALD) aged’. An earlier literature review[6] summarised the state of the evidence in relation to Australia’s CALD aged population and their less than optimal usage of Home and Community Care services (HACC), in particular, food services. This report builds on the information presented in the literature review aiming to explore the current provision of food services to CALD clients and the barriers and enablers to this service provision in Queensland.

The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure

Critically ill patients receiving extracorporeal membrane oxygenation (ECMO) are often noted to have increased sedation requirements. However, data related to sedation in this complex group of patients is limited. The aim of our study was to characterise the sedation requirements in adult patients receiving ECMO for cardiorespiratory failure. A retrospective chart review was performed to collect sedation data for 30 consecutive patients who received venovenous or venoarterial ECMO between April 2009 and March 2011. To test for a difference in doses over time we used a regression model. The dose of midazolam received on ECMO support increased by an average of 18 mg per day (95% confidence interval 8, 29 mg, P=0.001), while the dose of morphine increased by 29 mg per day (95% confidence interval 4, 53 mg, P=0.021) The venovenous group received a daily midazolam dose that was 157 mg higher than the venoarterial group (95% confidence interval 53, 261 mg, P=0.005). We did not observe any significant increase in fentanyl doses over time (95% confidence interval 1269, 4337 µg, P=0.94). There is a significant increase in dose requirement for morphine and midazolam during ECMO. Patients on venovenous ECMO received higher sedative doses as compared to patients on venoarterial ECMO. Future research should focus on mechanisms behind these changes and also identify drugs that are most suitable for sedation during ECMO.

Overdue choices : how information and role in decision-making influence women's preferences for induction for prolonged pregnancy

Background: Enabling women to make informed decisions is a crucial component of consumer-focused maternity care. Current evidence suggests that health care practitioners’ communication of care options may not facilitate patient involvement in decision-making. The aim of this study was to investigate the effect of specific variations in health caregiver communication on women’s preferences for induction of labor for prolonged pregnancy. Methods: A convenience sample of 595 female participants read a hypothetical scenario in which an obstetrician discusses induction of labor with a pregnant woman. Information provided on induction and the degree of encouragement for the woman’s involvement in decision-making was manipulated to create four experimental conditions. Participants indicated preference with respect to induction, their perceptions of the quality of information received, and other potential moderating factors. Results: Participants who received information that was directive in favor of medical intervention were significantly more likely to prefer induction than those given nondirective information. No effect of level of involvement in decision-making was found. Participants’ general trust in doctors moderated the relationship between health caregiver communication and preferences for induction, such that the influence of information provided on preferences for induction differed across levels of involvement in decision-making for women with a low trust in doctors, but not for those with high trust. Many women were not aware of the level of information required to make an informed decision. Conclusions: Our findings highlight the potential value of strategies such as patient decision aids and health care professional education to improve the quality of information available to women and their capacity for informed decision-making during pregnancy and birth. (BIRTH 39:3 September 2012)