Integrin α6ß4 requires plectin and vimentin for adhesion complex distribution and invasive growth.

Integrin α6ß4 binds plectin to associate with vimentin; however, the biological function remains unclear. Here, we utilized various integrin ß4 mutants and CRISPR-Cas9 editing to investigate this association. Upon laminin binding, integrin α6ß4 distinctly distributed peripherally as well as centrally, proximal to the nucleus. Upon fibronectin addition, integrin α6ß4 was centrally recruited to large focal adhesions (FAs) and enhanced Fak (also known as PTK2) phosphorylation. Integrin ß4 plectin-binding mutants or genetic deletion of plectin inhibited ß4 recruitment to FAs and integrin α6ß4-enhanced cell spreading, migration and three-dimensional invasive growth. Loss of the ß4 signaling domain (but retaining plectin binding) blocked migration and invasiveness but not cell spreading, recruitment to FAs or colony growth. Immunostaining revealed that integrin α6ß4 redistributed vimentin perinuclearly, where it colocalized with plectin and FAs. Depletion of vimentin completely blocked integrin ß4-enhanced invasive growth, Fak phosphorylation and proliferation in three dimensions but not two dimensions. In summary, we demonstrate the essential roles of plectin and vimentin in promoting an invasive phenotype downstream of integrin α6ß4. This article has an associated First Person interview with the first author of the paper.

Frequency of quorum-sensing mutations in Pseudomonas aeruginosa strains isolated from different environments.

Pseudomonas aeruginosa uses quorum sensing (QS) to coordinate the expression of multiple genes necessary for establishing and maintaining infection. It has previously been shown that lasR QS mutations frequently arise in cystic fibrosis (CF) lung infections, however, there has been far less emphasis on determining whether other QS system mutations arise during infection or in other environments. To test this, we utilized 852 publicly available sequenced P. aeruginosa genomes from the Pseudomonas International Consortium Database (IPCD) to study P. aeruginosa QS mutational signatures. To study isolates by source, we focused on a subset of 654 isolates collected from CF, wounds, and non-infection environmental isolates, where we could clearly identify their source. We also worked with a small collection of isolates in vitro to determine the impact of lasR and pqs mutations on isolate phenotypes. We found that lasR mutations are common across all environments and are not specific to infection nor a particular infection type. We also found that the pqs system proteins PqsA, PqsH, PqsL and MexT, a protein of increasing importance to the QS field, are highly variable. Conversely, RsaL, a negative transcriptional regulator of the las system, was found to be highly conserved, suggesting selective pressure to repress las system activity. Overall, our findings suggest that QS mutations in P. aeruginosa are common and not limited to the las system; however, LasR is unique in the frequency of putative loss-of-function mutations.

Norms and equivalences for MoCA-30, MoCA-22, and MMSE in the oldest-old.

BACKGROUND: Cognitive screening is important for the oldest-old (age 90 +). This age group is the fastest growing and has the highest risk of dementia. However, norms and score equivalence for screening tests are lacking for this group. AIMS: To provide norms and score equivalence for commonly used cognitive screening tests for the oldest-old. METHODS: Data on 157 participants of the Center for Healthy Aging Longevity Study aged 90 + were analyzed. First, we derived norms for (1) subtests and cognitive domains of the in-person Montreal Cognitive Assessment having a maximum score of 30 (MoCA-30) and (2) the total MoCA-22 score, obtained from the in-person MoCA-30 by summing the subtests that do not require visual input to a maximum score of 22. These norms were derived from 124 participants with a Mini-Mental State Examination (MMSE) ≥ 27. Second, we derived score equivalences for MMSE to MoCA-30 and MoCA-22, and MoCA-30 to MoCA-22 using equipercentile equating method with log-linear smoothing, based on all 157 participants. RESULTS: MoCA-22 total score norms are: mean = 18.3(standard deviation = 2.2). An MMSE score of 27 is equivalent to a MoCA-30 score of 22 and a MoCA-22 score of 16. DISCUSSION AND CONCLUSIONS: Subtest, domain and MoCA-22 norms will aid in evaluation of the oldest-old who cannot complete the MoCA-30 or are tested over the phone. The equivalences of the three cognitive tests (MMSE, MoCA-30, MoCA-22) in the oldest-old will facilitate continuity of cognitive tracking of individuals tested with different tests over time and comparison of the studies that use different cognitive tests.

S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2.

It is generally accepted that alterations in metabolism are critical for the metastatic process; however, the mechanisms by which these metabolic changes are controlled by the major drivers of the metastatic process remain elusive. Here, we found that S100 calcium-binding protein A4 (S100A4), a major metastasis-promoting protein, confers metabolic plasticity to drive tumor invasion and metastasis of non-small cell lung cancer cells. Investigating how S100A4 regulates metabolism, we found that S100A4 depletion decreases oxygen consumption rates, mitochondrial activity, and ATP production and also shifts cell metabolism to higher glycolytic activity. We further identified that the 49-kDa mitochondrial complex I subunit NADH dehydrogenase (ubiquinone) Fe-S protein 2 (NDUFS2) is regulated in an S100A4-dependent manner and that S100A4 and NDUFS2 exhibit co-occurrence at significant levels in various cancer types as determined by database-driven analysis of genomes in clinical samples using cBioPortal for Cancer Genomics. Importantly, we noted that S100A4 or NDUFS2 silencing inhibits mitochondrial complex I activity, reduces cellular ATP level, decreases invasive capacity in three-dimensional growth, and dramatically decreases metastasis rates as well as tumor growth in vivo Finally, we provide evidence that cells depleted in S100A4 or NDUFS2 shift their metabolism toward glycolysis by up-regulating hexokinase expression and that suppressing S100A4 signaling sensitizes lung cancer cells to glycolysis inhibition. Our findings uncover a novel S100A4 function and highlight its importance in controlling NDUFS2 expression to regulate the plasticity of mitochondrial metabolism and thereby promote the invasive and metastatic capacity in lung cancer.

Building a Cancer Education Program in the Modern Era: Lessons from Stone Soup.

In 2017, the National Cancer Institute (NCI) announced new guidelines for the Cancer Center Support Grant (CCSG) application that requires reporting on education and career development activities in a section entitled, "Cancer Research Career Enhancement and Related Activities" (CRCERA). While these cancer education and training programs previously have been a required part of the CCSG application, the new guidelines require greater rigor in conducting and reporting these endeavors. In this commentary, I give my perspective of how I have built a cancer education program, first as a program director and then as an associate director of cancer education and mentoring, the critical role leadership plays in the process, and how I have recruited contributors to this educational "stone soup."

Spiritually motivated restrictions on animal products have a limited impact on consumption of healthy plant-based foods.

Plant-based diets are considered healthier than many omnivorous diets. However, it is unclear that restriction of animal products necessarily motivates increased consumption of nutrient- and fibre-rich plant-based foods as opposed to energy-dense but nutrient-poor plant-based foods containing refined grains and added sugars and fats. The present study examined FFQ and food record data from ninety-nine individuals in the USA with varying degrees of adherence to the Orthodox Christian tradition of restricting meat, dairy and egg (MDE) products for 48 d prior to Easter to investigate whether restricting MDE products in the absence of explicit nutritional guidance would lead to increased consumption of healthy plant-based foods and greater likelihood of meeting dietary recommendations. Multiple linear regression models assessed changes in major food groups, energy and nutrients in relation to the degree of reduction in MDE consumption. Logistic regression analyses tested the odds of meeting 2015-2020 Dietary Guidelines for Americans on plant-based foods in relation to MDE restriction. Each serving reduction in MDE products was associated with small (approximately 0·1-0·7 serving) increases in legumes, soya products and nuts/seeds (all P values < 0·005). MDE restriction was not associated with higher odds of meeting recommendations on vegetable, fruit or whole-grain intake. Consumption of refined grains and added sugars did not change in relation to MDE restriction but remained above recommended thresholds, on average. These findings demonstrate that a reduction of MDE products for spiritual purposes may result in increases in some nutrient-rich plant-based foods but may not uniformly lead to a healthier dietary composition.

Identifying Vancomycin as an Effective Antibiotic for Killing Borrelia burgdorferi.

Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10 to 20% go on to develop posttreatment Lyme disease syndrome (PTLDS). The nature of PTLDS remains unknown, but currently approved antibiotics for the treatment of Lyme disease do not appear to impact these symptoms after they have developed. We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection. In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary-phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria. We found that peptidoglycan synthesis continues in stationary-phase cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary-phase culture of B. burgdorferi Examination of the action of antibiotics in severe combined immunodeficient (SCID) mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. In contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining the early use of more potent antibiotics on the development of PTLDS may be warranted.

Weight up? Changes in children's anthropometry from time of referral to baseline assessment for paediatric weight management.

OBJECTIVES: To examine children's wait time to access a multidisciplinary, tertiary-level weight management clinic and assess anthropometric changes from time of referral to baseline assessment. METHOD: A retrospective medical record review was completed of children (5 to 17 years) enrolled in a multidisciplinary, tertiary-level paediatric weight management clinic from 2006 to 2015. Children's demographic and anthropometric data from their referral to and baseline assessment at the clinic were retrieved from medical records. Based on changes in body mass index (BMI) z-score from the time of referral to baseline assessment, children were categorized as decreasers (>0.05 unit decrease), increasers (>0.05 unit increase) or stabilizers (-0.05 to 0.05 unit change). The proportion of children with a ≥0.25 unit BMI z-score reduction was calculated. Analysis of variance and chi-squared tests were performed. RESULTS: Children (n=400) were 11.7 ± 2.9 years old at the time of referral, 52.8% (n=211) female, and had an average wait time of 4.5 ± 3.9 months. By 3 and 6 months postreferral, 44.0% (n=176) and 80.8% (n=323), respectively, had attended baseline assessments. Based on BMI z-score change, children were classified as decreasers (n=183; 45.8%), increasers (n=118; 29.5%) or stabilizers (n=99; 24.8%). One-fifth of children (n=86; 21.5%) experienced a BMI z-score reduction ≥0.25 units, a subgroup that was younger, had a higher BMI z-score at referral, and had a longer wait time between referral and baseline assessment (all P<0.05). CONCLUSIONS: Most children who enrolled in paediatric weight management initiated treatment within six months and experienced a modest decrease or stabilization in BMI z-score during their wait time.

Hay fever, asthma, and eczema and early infectious diseases among children in Kilimanjaro, Tanzania.

OBJECTIVES: To investigate the hygiene (or "old friends") hypothesis in a high-infectious disease (ID) environment, rural Kilimanjaro, Tanzania. METHODS: Among a cross-sectional sample of 2- to 7-year-old children, we collected physician-diagnosed hay fever, asthma, and eczema, history of hospitalization, family size, and household environment information via questionnaire; performed active and passive surveillance for ID; and, evaluated total immunoglobulin E (IgE) and biomarkers of inflammation in dried blood spot specimens. We used regression models to describe patterns in allergic diseases. RESULTS: Complete information was available for 280 children: 12.5% had been diagnosed with hay fever; 18.9% with eczema; 2.1% with asthma. There was a positive association between hay fever and eczema diagnoses (π2 : 4.07; P = 0.044); total IgE was positively associated with eczema (ß: 0.24; P = 0.100) and allergic diseases together (ß: 0.26; P = 0.042). ID were common: the incidence of any ID diagnosis was 28 per 100 children per month. Hay fever was inversely associated with household animals (OR: 0.27; P = 0.006), and positively associated with earth housing materials (OR: 1.93; P = 0.079) and hospitalization in infancy with an ID (3.16; P = 0.066); patterns were similar when allergic disease outcomes were considered together. Few associations between these predictors and eczema or asthma alone were apparent. CONCLUSIONS: Allergic diseases were common among children in Kilimanjaro. The inverse association between household animals and allergy is consistent with the hygiene/old friends hypothesis; however, positive associations between allergic diseases and earth housing materials and early hospitalization with ID bear further explanation.

The readiness and motivation interview for families (RMI-Family) managing pediatric obesity: study protocol.

BACKGROUND: Experts recommend that clinicians assess motivational factors before initiating care for pediatric obesity. Currently, there are no well-established clinical tools available for assessing motivation in youth with obesity or their families. This represents an important gap in knowledge since motivation-related information may shed light on which patients might fail to complete treatment programs. Our study was designed to evaluate the measurement properties and utility of the Readiness and Motivational Interview for Families (RMI-Family), a structured interview that utilizes a motivational interviewing approach to (i) assess motivational factors in youth and their parents, and (ii) examine the degree to which motivation and motivation-related concordance between youth and parents are related to making changes to lifestyle habits for managing obesity in youth. METHODS: From 2016 to 2020, this prospective study will include youth with obesity (body mass index [BMI] ≥97th percentile; 13-17 years old; n = 250) and their parents (n = 250). The study will be conducted at two primary-level, multidisciplinary obesity management clinics based at children's hospitals in Alberta, Canada. Participants will be recruited and enrolled after referral to these clinics, but prior to initiating clinical care. Each youth and their parent will complete the RMI-Family (~1.5 h) at baseline, and 6- and 12-months post-baseline. Individual (i.e., youth or parent) and family-level (i.e., across youth and parent) responses to interview questions will be scored, as will aspects of interview administration (e.g., fidelity to motivational interviewing tenets). The RMI-Family will also be examined for test-retest reliability. Youth data collected at each time point will include demography, anthropometry, lifestyle habits, psychosocial functioning, and health services utilization. Cross-sectional and longitudinal associations between individual and family-level interview scores on the RMI-Family and these clinical measures will be examined. DISCUSSION: As a measurement tool drawing on family-centered care and motivational interviewing, the RMI-Family was designed to increase understanding of the role of motivational factors in pediatric obesity management, allowing healthcare providers and policymakers to manage pediatric obesity more effectively and efficiently. Findings will help to create an innovative, tailored model of health care delivery that uses resources judiciously and is designed to best meet families' needs.

Integrin α6ß4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF).

Integrin α6ß4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6ß4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6ß4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6ß4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and invasion. We found that AREG and EREG were required for autocrine EGFR signaling, as knocking down either ligand inhibited HGF-mediated migration and invasion. We further determined that HGF induced secretion of AREG, which is dependent on integrin-growth factor signaling pathways, including MAPK, PI3K, and PKC. Moreover, matrix metalloproteinase activity and integrin α6ß4 signaling were required for AREG secretion. Blocking EGFR signaling with EGFR-specific antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Finally, we found that EGFR was phosphorylated in response to HGF stimulation that is dependent on EGFR kinase activity; however, c-Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, these data illustrate that integrin α6ß4 stimulates invasion by promoting autocrine EGFR signaling through transcriptional up-regulation of key EGFR family members and by facilitating HGF-stimulated EGFR ligand secretion. These signaling events, in turn, promote pancreatic carcinoma migration and invasion.

Value of Procalcitonin Measurement for Early Evidence of Severe Bacterial Infections in the Pediatric Intensive Care Unit.

OBJECTIVES: To determine whether peak blood procalcitonin (PCT) measured within 48 hours of pediatric intensive care unit (PICU) admission can differentiate severe bacterial infections from sterile inflammation and viral infection and identify potential subgroups of PICU patients for whom PCT may not have clinical utility. STUDY DESIGN: This was a retrospective, observational study of 646 critically ill children who had PCT measured within 48 hours of admission to an urban, academic PICU. Patients were stratified into 6 categories by infection status. We compared test characteristics for peak PCT, C-reactive protein (CRP), white blood cell count (WBC), absolute neutrophil count (ANC), and % immature neutrophils. The area under the receiver operating characteristic curve was determined for each biomarker to discriminate bacterial infection. RESULTS: The area under the receiver operating characteristic curve was similar for PCT (0.73, 95% CI 0.69, 0.77) and CRP (0.75, 95% CI 0.71, 0.79; P = .36), but both outperformed WBC, ANC, and % immature neutrophils (P < .01 for all pairwise comparisons). The combination of PCT and CRP was no better than either PCT or CRP alone. Diagnostic patterns prone to false-positive and false-negative PCT values were identified. CONCLUSIONS: Peak blood PCT measured close to PICU admission was not superior to CRP in differentiating severe bacterial infection from viral illness and sterile inflammation; both PCT and CRP outperformed WBC, ANC, and % immature neutrophils. PCT appeared especially prone to inaccuracies in detecting localized bacterial central nervous system infections or bacterial coinfection in acute viral illness causing respiratory failure.

Salivary but not blood cortisol excretion is associated with metabolic biomarkers in healthy young women.

OBJECTIVES: Elevated and suppressed concentrations of cortisol have been linked with less favorable metabolic biomarkers, such as elevated lipids and glycosylated hemoglobin (HbA1c). Based on recent work reporting that some individuals secrete more cortisol into saliva (high saliva-to-blood cortisol ratio; high secretors) than others after correcting for blood cortisol concentrations, our objectives were to examine (1) whether lipids and glycosylated hemoglobin varied across cortisol and salivary secretor status; and (2) if blood and saliva provide the same results with respect to metabolic markers. METHODS: Matched saliva and dried blood spot (DBS) specimens collected once a week for four weeks (N = 48 healthy women, 192 specimens) were assayed for cortisol. Fasting blood specimens collected once from each woman were quantified for cholesterol (total, HDL, LDL), triglycerides and HbA1c. RESULTS: Low salivary cortisol secretors showed significantly higher triglyceride and HbA1c compared to high-secretors (P<0.05; t-test). The only significant correlation with mean blood or salivary cortisol concentration was a negative correlation between salivary cortisol and HbA1c (P = 0.021, r = -0.333). CONCLUSIONS: Triglycerides, HDL, and especially HbA1c were associated with salivary cortisol secretor status but not with DBS cortisol concentrations. These results suggest that blood and saliva cortisol measures might provide different health outcome information, and that salivary cortisol secretor status may provide additional information on health status. Am. J. Hum. Biol. 28:539-544, 2016. © 2016 Wiley Periodicals, Inc.

Adherence to complementary feeding recommendations for infants and implications for public health.

OBJECTIVE: The current study investigates (i) the extent to which breast-feeding and non-breast-feeding mothers follow the Canadian Nutrition for Healthy Term Infants (NHTI) recommendations; (ii) the first complementary foods given and the differences by breast-feeding status; (iii) whether any breast-feeding is associated with earlier introduction to complementary foods relative to non-breast-feeding, after controlling for potentially confounding factors; and (iv) the need for improvements in timing and resources of interventions by examining breast-feeding rates over time and information sources used by mothers. DESIGN: Longitudinal data from the Kingston, Frontenac, and Lennox & Addington (KFL&A) Infant Feeding Survey were used. Mothers completed a survey at the end of their hospital stay and were interviewed by telephone at 2, 4, 6 and 12 months thereafter. SETTING: The study took place in the KFL&A region of Ontario, Canada. SUBJECTS: The sample consisted of 325 mothers who gave birth to a live infant of at least 36 weeks' gestation and a birth weight of at least 1500 g at Kingston General Hospital between January and July of 2008. RESULTS: Four in five mothers introduced complementary foods prior to 6 months. Mothers not breast-feeding at 6 months introduced water, juice, infant cereals, fruit and vegetables, and foods not recommended by Canada's Food Guide sooner than breast-feeding mothers. Breast-feeding mothers were more likely to introduce milks appropriately, but had low adherence to giving their infants vitamin D supplements. CONCLUSIONS: To support adherence to NHTI recommendations, interventions should be conducted during early infancy and deliver consistent, evidence-based recommendations.

Description and cohort characterization of the Longevity Study: learning from our elders.

The purpose of this article is to describe the Longevity Study: Learning From Our Elders, a research program on healthy aging that began in 2007 at the Center for Healthy Aging at Banner Sun Health Research Institute. As of June 2015, 1139 participants (age range of 50-110 years) completed baseline assessments with the majority living in the Sun Cities retirement communities northwest of Phoenix, Arizona but expanding throughout the state. The registry includes over 830 currently active participants with 450 aged 80 years and older, 188 aged 90 and older, and 27 centenarians. Data from in-person interviews at the Center for Healthy Aging in Sun City or in the participants' residences which includes sociodemographic, medical, cognitive, physical and psychosocial variables have been collected since the study's inception. This paper outlines some of the key demographic and clinical characteristics of the Longevity Study, its progress, and future directions. It also reflects on how exceptional aging individuals function psychosocially, cognitively and physically, particularly among individuals aged 85 and older.

Alcohol-Related Facebook Activity Predicts Alcohol Use Patterns in College Students.

The purpose of this study was to determine if a brief 10-item alcohol-related Facebook® activity (ARFA) questionnaire would predict alcohol use patterns in college students (N = 146). During a single laboratory session, participants first privately logged on to their Facebook® profiles while they completed the ARFA measure, which queries past 30 day postings related to alcohol use and intoxication. Participants were then asked to complete five additional questionnaires: three measures of alcohol use (the Alcohol Use Disorders Identification Test [AUDIT], the Timeline Follow-Back [TLFB], and the Personal Drinking Habits Questionnaire [PDHQ]), the Barratt Impulsiveness Scale (BIS-11), and the Marlowe-Crowne Social Desirability Scale (MC-SDS). Regression analyses revealed that total ARFA scores were significant predictors of recent drinking behaviors, as assessed by the AUDIT, TLFB, and PDHQ measures. Moreover, impulsivity (BIS-11) and social desirability (MC-SDS) did not predict recent drinking behaviors when ARFA total scores were included in the regressions. The findings suggest that social media activity measured via the ARFA scale may be useful as a research tool for identifying risky alcohol use.

Clinical significance of the integrin α6ß4 in human malignancies.

Integrin α6ß4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6ß4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK, and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor-promoting transcription factors such as the NFATs and NF-κB. Expression of integrin α6ß4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6ß4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6ß4 that contribute to tumor progression.

Improving regional and rural cancer services in Western Australia.

OBJECTIVE: This paper examines health reform which has been designed to improve cancer services across Western Australia. SETTING: Western Australia is a large state divided into nine regions each with differing demographics. The diversity of the state and the distribution of the population over a large area of land create significant challenge in ensuring equality in service delivery. DESIGN: A comparison was conducted looking at cancer services in Western Australia pre-2005 and service delivery in 2014. A review of the partnership initiatives and programs provides a clear discussion on the need for coordination of care between service providers. MAIN OUTCOME: The approach undertaken in Western Australia has seen an increase in the delivery of cancer services closer to the patient's home as well as greater involvement of primary care professionals in cancer care. This work has resulted in demonstrated improvements in patient care and support. CONCLUSION: Services for cancer patients need to be accessible closer to home with distance being an appreciable barrier to treatment access.A statewide approach needs to be developed to ensure all people have equitable access to service delivery.

Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer.

Upregulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models using immunohistochemistry, immunofluorescent staining and confocal microscopy. Cell secretion was evaluated by ELISA and antibody arrays. Proliferation, migration and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC coculture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in 'normalization' of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and antiangiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the antiangiogenic activity noted with knockdown of FASN included: downregulation of VEGF(189), upregulation of antiangiogenic isoform VEGF(165b) and a decrease in expression and activity of matrix metalloproteinase-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor-2 and its downstream signaling and decreased proliferation, migration and tubulogenesis of ECs as compared with control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC.

Successful hunting increases testosterone and cortisol in a subsistence population.

Controversy over the adaptive significance of male hunting in subsistence societies hinges on the relative importance of familial provisioning and mate-quality signalling. This paper examines the proximate and ultimate motivations of hunting behaviour from a neuroendocrine perspective, using salivary testosterone and cortisol data collected before, during and after hunting focal follows from 31 Tsimane hunters aged 18-82 years. Despite circadian declines in hormone levels, testosterone and cortisol of Tsimane hunters increased at the time of a kill, and remained high as successful hunters returned home. Previous studies of hormonal changes during competitions find that high-stakes and success in the presence of relevant audiences result in increased neuroendocrine arousal. If men hunt primarily to provision their families, then an additional audience would not be expected to impact testosterone or cortisol, nor would the size of the animal killed. However, if signalling male quality by 'showing off' was a larger relative driver of men's hunting behaviour, one would expect greater hormonal response in cases where men returned with large sharable kills, especially in the presence of community members. Consistent with provisioning models of male hunting motivation, neither kill size nor encountering an audience of villagers while returning from hunting was associated with hormonal changes for successful hunters.