The effects of a competitive exclusion product and two probiotics on Salmonella colonization and nutrient digestibility in broiler chickens

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The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation

Proteolysis mediated by matrix metalloproteinases (MMPs) and serine proteinases is associated with cancer invasion and metastasis. Activation of latent proMMPs, and especially the proforms of the type IV collagen degrading gelatinases A and B (proMMP-2 and proMMP-9), is thought to be a critical step in this process. We have recently found that human tumour-associated trypsin-2 is a potent activator of proMMP-9 and it also activates proMMP-2 in vitro. Trypsinogen, MMP-2, and MMP-9 are expressed in ovarian cancer. To elucidate the function of trypsin in vivo, we studied whether high concentrations of trypsinogen-1, trypsinogen-2, their α1-proteinase inhibitor (API) complexes, and tumour-associated trypsin inhibitor (TATI) are associated with proMMP-2 and proMMP-9 activation in ovarian tumour cyst fluids. Zymography and immunofluorometric analysis of 61 cyst fluids showed a significant association between high trypsin concentrations and the activation of MMP-9 (P= 0.003–0.05). In contrast, the trypsin concentrations were inversely associated with the activation of MMP-2 (P= 0.01–0.02). Immunohistochemical analysis of ovarian tumour tissue demonstrated expression of trypsinogen-2 and TATI in the secretory epithelium. MMP-2 was detected both in stromal and epithelial cells whereas MMP-9 was detected in neutrophils and macrophage-like cells in stromal and epithelial areas. These results suggest that trypsin may play a role in the regulation of the MMP-dependent proteolysis associated with invasion and metastasis of ovarian cancer. © 2001 Cancer Research Campaign www.bjcancer.co

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Cohort Profile: The Finnish Gestational Diabetes (FinnGeDi) Study

publishedVersionPeer reviewe

Factors associated with dropout during recruitment and follow-up periods of a mHealth-based randomized controlled trial for Mobile.Net to encourage treatment adherence for people with serious mental health problems

Background: Clinical trials are the gold standard of evidence-based practice. Still many papers inadequately report methodology in randomized controlled trials (RCTs), particularly for mHealth interventions for people with serious mental health problems. To ensure robust enough evidence, it is important to understand which study phases are the most vulnerable in the field of mental health care. Objective: We mapped the recruitment and the trial follow-up periods of participants to provide a picture of the dropout predictors from a mHealth-based trial. As an example, we used a mHealth-based multicenter RCT, titled “Mobile.Net,” targeted at people with serious mental health problems. Methods: Recruitment and follow-up processes of the Mobile.Net trial were monitored and analyzed. Recruitment outcomes were recorded as screened, eligible, consent not asked, refused, and enrolled. Patient engagement was recorded as follow-up outcomes: (1) attrition during short message service (SMS) text message intervention and (2) attrition during the 12-month follow-up period. Multiple regression analysis was used to identify which demographic factors were related to recruitment and retention. Results: We recruited 1139 patients during a 15-month period. Of 11,530 people screened, 36.31% (n=4186) were eligible. This eligible group tended to be significantly younger (mean 39.2, SD 13.2 years, P<.001) and more often women (2103/4181, 50.30%) than those who were not eligible (age: mean 43.7, SD 14.6 years; women: 3633/6514, 55.78%). At the point when potential participants were asked to give consent, a further 2278 refused. Those who refused were a little older (mean 40.2, SD 13.9 years) than those who agreed to participate (mean 38.3, SD 12.5 years; t1842=3.2, P<.001). We measured the outcomes after 12 months of the SMS text message intervention. Attrition from the SMS text message intervention was 4.8% (27/563). The patient dropout rate after 12 months was 0.36% (4/1123), as discovered from the register data. In all, 3.12% (35/1123) of the participants withdrew from the trial. However, dropout rates from the patient survey (either by paper or telephone interview) were 52.45% (589/1123) and 27.8% (155/558), respectively. Almost all participants (536/563, 95.2%) tolerated the intervention, but those who discontinued were more often women (21/27, 78%; P=.009). Finally, participants’ age (P<.001), gender (P<.001), vocational education (P=.04), and employment status (P<.001) seemed to predict their risk of dropping out from the postal survey. Conclusions: Patient recruitment and engagement in the 12-month follow-up conducted with a postal survey were the most vulnerable phases in the SMS text message-based trial. People with serious mental health problems may need extra support during the recruitment process and in engaging them in SMS text message-based trials to ensure robust enough evidence for mental health care

A selective cyclic integrin antagonist blocks the integrin receptors α(v)β(3 )and α(v)β(5 )and inhibits retinal pigment epithelium cell attachment, migration and invasion

BACKGROUND: Proliferative vitreoretinopathy (PVR) is a leading cause of blindness after failed retinal reattachment surgery. PVR is characterized by the proliferation, migration and contraction of retinal pigmented epithelial cells (RPE), and these cellular responses are influenced by the expression and function of integrin receptors. The effect of a cyclic integrin antagonist containing the amino acid sequence Arg-Gly-Asp-D-Phe-Val (RGDfV), specific for the integrin receptors α(v)β(3 )and α(v)β(5), was investigated on basic fibroblast growth factor (bFGF), platelet derived growth factor-BB (PDGF-BB), and serum induced human RPE proliferation, migration, invasion and attachment to the extracellular matrix. Furthermore, the effects of bFGF and PDGF-BB regulated expression of integrins α(v)β(3 )and α(v)β(5 )on RPE cells was examined. METHODS: The effect of a cyclic integrin antagonist and a control peptide (0.01 μg/ml to 300 μg/ml) was investigated on serum or cytokine (bFGF or PDGF-BB pretreatment) induced human fetal RPE cell proliferation by H(3)-thymidine uptake. The effect of the cyclic integrin antagonist on RPE cell attachment onto different extracellular matrices (laminin, collagen IV, fibronectin), RPE cell invasion stimulated by PDGF-BB or serum, and migration stimulated by PDGF-BB, vascular endothelial growth factor (VEGF) or serum was explored. PDGF-BB and bFGF modulation of the integrin receptors α(v)β(3 )and α(v)β(5 )was evaluated by flow cytometry. RESULTS: The integrin antagonist did not inhibit DNA synthesis stimulated by serum, bFGF, or PDGF-BB treatment. RPE attachment onto fibronectin was inhibited in a concentration range of 1–10 μg/ml (p < 0.05). Attachment of the RPE cells onto collagen IV and laminin was inhibited in a range of 3–10 μg/ml (p < 0.05). Serum and PDGF-BB stimulated migration was inhibited by the cyclic integrin antagonist in a concentration range of 1–10 μg/ml (p < 0.05). Furthermore, the cyclic integrin antagonist inhibited PDGF-BB stimulated RPE cell invasion through fibronectin (3μg/ml: 66% inhibition, p < 0.001). In each of these experiments, the control peptides had no significant effects. PDGF-BB and bFGF pretreatment of RPE cells increased the expression of integrin receptors α(v)β(3 )(bFGF: 1.9 fold, PDGF-BB: 2.3 fold) and α(v)β(5 )(bFGF: 2.9 fold, PDGF-BB: 1.5 fold). CONCLUSION: A selective inhibition of the integrin receptors α(v)β(3 )and α(v)β(5 )through a cyclic integrin antagonist is able to inhibit RPE cell attachment, migration and invasion. Since these steps are of importance for the progression of PVR, a cyclic integrin antagonist should be further evaluated for the treatment of this disease

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo

Dementia Wristband Report

This research project explored the use of new wearable and mobile technologies to support independent living and social interactions in the community for people living with dementia and their carers, more safely and for longer. The three key aims of the project were to: • Assess the potential acceptability, and usability of a mobile phone App and wearable wristband solution • Test the use of the technological in the everyday life contexts • Evaluate the usability and utility of a mobile phone App and digital wristband to reduce social isolation and improve health outcomes The research project had two stages: Stage 1 - Acceptability, utility and usability of the devices This stage of the project focused on developing initial understandings of the ways in which the proposed technological solutions work and potentially meet the needs of people living with dementia and their carers. This was achieved through: - Technology testing by the project team members. This gave the team a better understanding of the device used in the project. - Interviews with people with dementia and their carers, and with health and social care professionals. The interviews explored whether participants were receptive to, and what they thought about, the proposed solutions. Any concerns they had about the tracking technology in general or about the technology used in the project were also examined. Stage 2: Real world testing of the wristbands and smartphone App Research participant’s trialled the technology, as part of their everyday lives, for up to three months. During this period the research team worked closely with them to provide training and technological support and used a multi-method data collection focused on semi-structured interviews and observation to capture their experiences of using the technology. The participants living with dementia and their carers were given the opportunity to choose the technology that best suits them, either a wristbands or a smartphone application. Key findings In summary, through the interviews and focus groups and real world technology testing the research team and SME partners found there are issues around: - the use of technology for people living with dementia and their carers – for some people it was seen as a real benefit, others did not want to engage with the technology or have others know where they were. - education, information and support for people living with dementia and their carers to use new technologies; even when delivered via familiar technologies this can be challenging and needs support and time - support for family/other carers who are key to the support of mobile and wearable technologies. - support for people who do not have a local or remote family carer who can support the use of new technologies needs to be considered. - current GPS technologies not being accurate as a stand alone way of finding someone who may be lost or needing support. - safeguarding – which needs to take an holistic approach and include more traditional and ‘paper based’ safeguarding systems such as the Herbert protocol, - emerging and new technologies, which are developing constantly but a national approach is still missing; - the challenges for unpaid carers and people living with dementia to around exploring options around new technologies and deciding what are the best/cost effective options for their situations. - wearable and mobile technologies which can support people to be more independent in the community, but the technologies need to be: introduced early; affordable and be more easily supported by family and professional care givers as appropriate