In vitro metastatic colonization of human ovarian cancer cells to the omentum

Despite the potentially crucial contributions of the omentum in the regulation of ovarian cancer metastatic growth, it remains a poorly understood organ. Due to its anatomic location and structural fragility, the omentum presents inherent challenges to mechanism-based in vivo studies. Thus, the availability of an ex vivo omental model would, in part, address some of these difficulties posed. Here we describe a technique for identifying, isolating and maintaining ex vivo cultures of omenta from immune-compromised and -competent mice. Ex vivo culture conditions were developed that maintain tissue viability, architecture, and function for up to 10 days. Further experiments demonstrate that the ex vivo culture conditions allow for the proliferation of ovarian cancer cells in vitro and support a similar pattern of microscopic lesions after either intraperitoneal injection of ovarian cancer cells or co-culture of ovarian cancer cells with the omentum. In agreement with previous studies from our laboratory, histologic evaluation of these specimens found that ovarian cancer cells, as well as other peritoneal cancer cells, preferentially accumulate in, and colonize, omental areas rich in immune cells. We now recognize that these are specific, functional structures referred to as milky spots. In sum, these are foundational studies of a readily accessible model, which is easily manipulated and can be immediately used to study the dynamic process of omental colonization. It is hoped that investigators will use the data herein as a starting point for refinements and modifications which will enable them to tailor the model to the specific needs of the experimental question(s) they wish to pursue.     

Maternal oestriol levels reflect placental function rather than foetal function

We have examined the relationship between foetal levels of E3 and DHEA-SO4 and the birthweight of the child. Levels of these steroids do not relate to birthweight--although the concentration of DHEA-SO4 was marginally but not significantly higher in infants of lower birthweight. These findings suggest that the placental conversion of foetal precursors, and not the level of the precursors themselves, determines the concentration of E3 in the mother. Measurement of E3 as a clinical test reflects the function of both the foetus and the placenta.     

Hearing and vision impairment and the social networks of older Australians

Two hundred and forty self‐selected community‐based older people were tested for vision and hearing acuity, and reported on their hearing and vision difficulties and social networks. Social network size, proximity and frequency of contacts were used as dependent variables in the analysis of the effects of any sensory loss on social structure. Neither objectively measured sensory loss nor self‐reported sensory difficulties were associated with significant changes to network size, however, people with sensory losses were found to have more intense networks with fewer contacts outside their immediate inner circle.     

The sexual behaviour of young gay men in England and Wales.

Much research has concluded that young gay men are at disproportionately higher risk of HIV infection through unsafe sexual behaviour. This paper is the first report on this particular group in the UK. As part of a larger cohort study, 111 young (less than 21) gay and bisexual men were interviewed about their sexual behaviour, knowledge of AIDS and HIV, particularly safer sexual practices and other factors. Three per cent had not had sex and 13% had not had anal intercourse with a man at the time of interview. Forty-five per cent had sexual experience with a woman and 34% had engaged in vaginal intercourse. The average age at first homosexual experience was just under 15 years and this is higher than other age groups in the cohort. Median number of male partners in the year before interview was 5, with 1 of whom anal intercourse occurred. Sexual repertoire was relatively restricted compared to older men. Condom use was slightly more consistent and levels of knowledge not significantly different. From these findings, the contention that young gay men are at higher risk of HIV infection through risky sexual behaviour is not supported.     

Impact of supplementation with amino acids or their metabolites on muscle wasting in patients with critical illness or other muscle wasting illness: a systematic review

Muscle wasting during critical illness impairs recovery. Dietary strategies to minimise wasting include nutritional supplements, particularly essential amino acids. We reviewed the evidence on enteral supplementation with amino acids or their metabolites in the critically ill and in muscle wasting illness with similarities to critical illness, aiming to assess whether this intervention could limit muscle wasting in vulnerable patient groups. Citation databases, including MEDLINE, Web of Knowledge, EMBASE, the meta‐register of controlled trials and the Cochrane Collaboration library, were searched for articles from 1950 to 2013. Search terms included ‘critical illness’, ‘muscle wasting’, ‘amino acid supplementation’, ‘chronic obstructive pulmonary disease’, ‘chronic heart failure’, ‘sarcopenia’ and ‘disuse atrophy’. Reviews, observational studies, sport nutrition, intravenous supplementation and studies in children were excluded. One hundred and eighty studies were assessed for eligibility and 158 were excluded. Twenty‐two studies were graded according to standardised criteria using the GRADE methodology: four in critical care populations, and 18 from other clinically relevant areas. Methodologies, interventions and outcome measures used were highly heterogeneous and meta‐analysis was not appropriate. Methodology and quality of studies were too varied to draw any firm conclusion. Dietary manipulation with leucine enriched essential amino acids (EAA), β‐hydroxy‐β‐methylbutyrate and creatine warrant further investigation in critical care; EAA has demonstrated improvements in body composition and nutritional status in other groups with muscle wasting illness. High‐quality research is required in critical care before treatment recommendations can be made.     

Asthma and Asthma Severity among African American Adults in the Jackson Heart Study

The aims of this study were to investigate the baseline prevalence of and risk factors associated with asthma, classify asthma severity, and describe medication use in a population-based sample of African American men and women 21 to 84 years of age from the Jackson Heart Study (JHS). Participants provided responses to respiratory and medical history questions and a medication inventory and underwent spirometry and other clinical examinations. These data were used to examine the extent to which novel and traditional risk factors were associated with asthma. Of the 4,098 participants included in this analysis, 9.4% reported lifetime asthma (5.7% current, 3.7% former), and current asthma was higher in women (6.8%) than in men (3.8%). An additional 9.8% reported an attack of wheeze with shortness of breath or non-doctor confirmed asthma (i.e., “probable” asthma). The mean forced expiratory volume in 1 second (FEV₁)% predicted was lower in those reporting current asthma (women: 83.7 ± 18.0; men: 75.2 ± 16.8) compared to those not reporting asthma (women: 95.6 ± 16.7; men: 91.7 ± 16.0). Current and probable asthma was associated with lower serum cortisol levels and hypertension medication use, along with traditional risk factors (i.e., lower socio-economic status, higher global stress scores, obesity, and fair to poor perceived general health). Severe asthma was low among participants reporting current (9.8%), former (3.3%), and probable (4.9%) asthma. Asthma medication use was reported by nearly 60% of the participants reporting current asthma. Asthma in African American adults is associated with decreased serum cortisol, hypertension medication use, and considerable lung function impairment compared to those who did not report asthma. The prevalence of asthma in the JHS is lower than state and national estimates, although the estimates are not directly comparable. Furthermore, asthma is drastically underdiagnosed in this population.     

Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase

Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50=13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50=220 nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro.     

Societal interactions in ovarian cancer metastasis: a quorum-sensing hypothesis

The biochemical and biological mechanisms metastatic cancer cells use to function as communities and thwart internal and external growth control mechanisms remain undefined. In this work, we present the hypothesis that cancer cells may use a Quorum-Sensing mechanism to regulate multicellular functions and control steps in metastatic colonization. Quorum sensing is a bacterial cell-cell communication process used to track increasing cell-population density and, in response to changes in cell number, coordinate gene expression and behavior on a community-wide scale. Important parallels between the behavior of societies of bacterial cells and societies of malignant cancer cells exist in the bacterial literature. Of relevance to metastasis is the finding that pathogenic bacteria use quorum sensing to determine when their population numbers are high enough to collectively form biofilms in or on host organisms. Biofilms are complex, heterogeneous communities of bacterial cells encased within an extracellular matrix attached to a solid surface. Biofilms exacerbate disease and are refractory to a battery of therapies. We suggest that the quorum-sensing-controlled bacterial biofilm formation process closely parallels the steps in metastatic colonization. Cells migrate toward/on target surfaces (organ-specific homing), show cell-cell and cell-matrix interactions (tumor cell-stromal cell crosstalk), remain subclinical until they can mount an effective attack (dormancy), form complex structures with channels for nutrient flow (vascularized lesions), and contain resistant cells which can cause disease recurrence (persistors). Using ovarian cancer as an example, we present data supporting the connection between metastatic colonization and quorum sensing and discuss the implications for understanding and controlling metastasis formation.

Comparing response options for the International Outcome Inventory for Hearing Aids (IOI-HA) and for Alternative Interventions (IOI-AI) daily-use items

Abstract Objective: This study investigated how clients quantify use of hearing rehabilitation. Comparisons focused on the daily-use item of the International Outcome Inventory for Hearing Aids (IOI-HA), and for Alternative Interventions (IOI-AI). Design: Adults with hearing impairment completed the original versions of the IOI-HA and the IOI-AI daily-use item which has five numerical response options (e.g. 1-4 hours/day) and a modified version with five word response options (e.g. 'Sometimes'). Respondents completed both IOI versions immediately after intervention completion and three months later. Study sample: In total, 64 people who had obtained hearing aids completed both IOI-HA versions and 27 people who had participated in communication programs completed both IOI-AI versions. Results: Participants reported higher scores on the modified (word) daily-use item than on the original (number) daily-use item. Participants who completed the IOI-AI did so significantly more than participants who completed the IOI-HA. This was true both after intervention completion and three months later. Conclusion: This study showed that comparisons between IOI-HA and IOI-AI daily-use item scores should be made with caution. Word daily-use response options are recommended for the IOI-AI (i.e. Never; Rarely; Sometimes; Often; and Almost always).