The role of nuclear FGFR1 and FGF2 in pancreatic cancer.

PhDPatients who are diagnosed with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis. One reason for this is the dense stroma that is a characteristic of PDAC, which may preclude drugs from accessing the tumour cells. Pancreatic stellate cells (PSCs) are the key cell responsible for desmoplasia in PDAC and it is becoming clear that they are a promising target for therapy. Over-expression of FGFs and their receptors is a feature of PDAC and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. The aim of my research was 1) to understand the role and function of nuclear FGFR1 and FGF using 2D based assays; 2) to use a physiologically relevant 3D organotypic model to study the effects of blocking nuclear FGFR1 and FGF2 in PSCs; 3) to assess whether this target could provide a novel therapeutic strategy in PDAC. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localised to the nucleus in activated PSCs but not cancer cells. Inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition in vitro, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. Cancer cells co-cultured on top of collagen/Matrigel gels together with PSCs showed marked invasion of both cancer cells and PSCs. However, FGFR inhibition blocked invasion of both PSCs and cancer cells. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion. Thus, for 6 patients with PDAC which is resistant to conventional chemotherapy, targeting the stroma by blocking nuclear FGFR1 and FGF2 in PSCs identifies a novel therapeutic approach

Arduous implementation: Does the Normalisation Process Model explain why it's so difficult to embed decision support technologies for patients in routine clinical practice

Background: decision support technologies (DSTs, also known as decision aids) help patients and professionals take part in collaborative decision-making processes. Trials have shown favorable impacts on patient knowledge, satisfaction, decisional conflict and confidence. However, they have not become routinely embedded in health care settings. Few studies have approached this issue using a theoretical framework. We explained problems of implementing DSTs using the Normalization Process Model, a conceptual model that focuses attention on how complex interventions become routinely embedded in practice.Methods: the Normalization Process Model was used as the basis of conceptual analysis of the outcomes of previous primary research and reviews. Using a virtual working environment we applied the model and its main concepts to examine: the 'workability' of DSTs in professional-patient interactions; how DSTs affect knowledge relations between their users; how DSTs impact on users' skills and performance; and the impact of DSTs on the allocation of organizational resources.Results: conceptual analysis using the Normalization Process Model provided insight on implementation problems for DSTs in routine settings. Current research focuses mainly on the interactional workability of these technologies, but factors related to divisions of labor and health care, and the organizational contexts in which DSTs are used, are poorly described and understood.Conclusion: the model successfully provided a framework for helping to identify factors that promote and inhibit the implementation of DSTs in healthcare and gave us insights into factors influencing the introduction of new technologies into contexts where negotiations are characterized by asymmetries of power and knowledge. Future research and development on the deployment of DSTs needs to take a more holistic approach and give emphasis to the structural conditions and social norms in which these technologies are enacte

Evidence for the generation of juvenile granitic crust during continental extension, Mineral Mountains Batholith, Utah

This is the published version. Copyright 1976 American Geophysical Union. All Rights Reserved.Field, chemical and isotopic data from the Miocene Mineral Mountains batholith in southwest Utah are consistent with the batholith being derived through differentiation of material recently separated from the lithospheric mantle, with little involvement of pre-Oligocene crust. The batholith ranges in composition and texture from diabase and gabbro to high-silica rhyolite and granite and is distinctly calcalkaline in nature. Field evidence for anatexis of intermediate-composition Oligocene crust and magma mixing suggest that fractional melting and mixing were important processes during the evolution of the batholith. Major oxide and rare earth element data for the batholith are consistent with chemical evolution of the magma system being controlled by fractionation of hornblende, plagioclase and sphene (all of which occur in restitic portions of Miocene migmatites exposed in the field area) during partial melting, and mixing between gabbro and granite. Isotopic data indicate a lithospheric mantle source for mafic rocks in the study area and, on the basis of field data and their similarity in isotopic composition, granitic rocks are interpreted to be derived indirectly from the same source during Basin and Range extension. Evolution of the granites is hypothesized to involve a series of partial melting steps, one of which is exposed in the batholith, which refine mantle-derived gabbros into high-silica rocks. Thus the Mineral Mountains batholith represents juvenile granitic material added to the crust during extension. This raises the possibility that extension may be an important granitic crust-forming event. Furthermore, this suggests that pure-shear igneous inflation of the crust by the mantle can be an important mechanism during extensional deformation. Data presented here indicate that fractional melting of young mafic crust may be an important process in the evolution of isotopically homogeneous intrusive suites which span a broad compositional range. Furthermore, the data support the idea that lithospheric mantle in the Great Basin region may be Proterozoic in age

Association of maternal sleep practices with pre‐eclampsia, low birth weight, and stillbirth among Ghanaian women

ObjectiveTo assess sleep practices, and investigate their relationship with maternal and fetal outcomes, among pregnant Ghanaian women.MethodsIn a cross‐sectional study conducted at Korle Bu Teaching Hospital, Accra, Ghana, between June and July 2011, postpartum women were interviewed within 48 hours of delivery about sleep quality and practices during pregnancy. Interviews were coupled with a systematic review of participants’ medical charts for key outcomes including maternal hypertension, pre‐eclampsia, premature delivery, low birth weight, and stillbirth.ResultsMost women reported poor sleep quality during pregnancy. Snoring during pregnancy was independently associated with pre‐eclampsia (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.4–8.5; P = 0.007). The newborns of women who reported supine sleep during pregnancy were at increased risk of low birth weight (OR, 5.0; 95% CI, 1.2–20.2; P = 0.025) and stillbirth (OR, 8.0; 95% CI, 1.5–43.2; P = 0.016). Low birth weight was found to mediate the relationship between supine sleep and stillbirth.ConclusionThe present findings in an African population demonstrate that maternal sleep, a modifiable risk factor, has a significant role in pre‐eclampsia, low birth weight, and subsequently stillbirth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135150/1/ijgo261.pd

A historical analysis of herpes simplex virus promoter activation in vivo reveals distinct populations of latently infected neurones

Herpes simplex virus type 1 (HSV-1) has the capacity to establish a life-long latent infection in sensory neurones and also to periodically reactivate from these cells. Since mutant viruses defective for immediate-early (IE) expression retain the capacity for latency establishment it is widely assumed that latency is the consequence of a block in IE gene expression. However, it is not clear whether viral gene expression can precede latency establishment following wild-type virus infection. In order to address this question we have utilized a reporter mouse model system to facilitate a historical analysis of viral promoter activation in vivo. This system utilizes recombinant viruses expressing Cre recombinase under the control of different viral promoters and the Cre reporter mouse strain ROSA26R. In this model, viral promoter-driven Cre recombinase mediates a permanent genetic change, resulting in reporter gene activation and permanent marking of latently infected cells. The analyses of HSV-1 recombinants containing human cytomegalovirus major immediate-early, ICP0, gC or latency-associated transcript promoters linked to Cre recombinase in this system have revealed the existence of a population of neurones that have experienced IE promoter activation prior to the establishment of latency

(Un)twisted: talking back to media representations of eating disorders

In 2014-15, there were several news reports about a rise in the diagnoses and treatment of eating disorders (EDs), as attributed to the use of image-driven social media. Such coverage can be situated within a long history of concern in which those diagnosed with an ED are constructed as ‘especially vulnerable’ to the power of media images – a subjectivity which is pathologised and devalued precisely through its association with femininity. The most incisive objections to EDs being presented as a response to the ‘weight’ of media representation have come from Abigail Bray (2005) in her work on how anorexia is constructed as a reading as well as an eating disorder. Indeed, there is a whole history of empirical work in Feminist Media Studies and Girlhood Studies which has challenged the pernicious construction of female subjectivity as ‘excessively’ invested in, and ‘damaged’ by, the consumption of mass mediated forms. Yet the media consumption practices of those with experience of an ED have not been subject to similar feminist re-evaluation – an omission which this research seeks to address. In exploring the results of 17 semi-structured interviews with people who have experience of an ED discussing their encounters with media representations of EDs (material that is often co-opted into debates about the ‘toxic’ nature of media culture in this regard), this article seeks to intervene in how such imagined media consumption practices are often defined. In seeking to speak back to historically pathologising constructions, the article seeks to explore the qualitative responses in the context of more ‘every day’ understandings of media engagement, thus working against the gendered othering which has persistently occurred

Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion

Keeping the Faith: African American Faith Leaders’ Perspectives and Recommendations for Reducing Racial Disparities in HIV/AIDS Infection

In Philadelphia, 66% of new HIV infections are among African Americans and 2% of African Americans are living with HIV. The city of Philadelphia has among the largest numbers of faith institutions of any city in the country. Although faith-based institutions play an important role in the African American community, their response to the AIDS epidemic has historically been lacking. We convened 38 of Philadelphia’s most influential African American faith leaders for in-depth interviews and focus groups examining the role of faith-based institutions in HIV prevention. Participants were asked to comment on barriers to engaging faith-based leaders in HIV prevention and were asked to provide normative recommendations for how African American faith institutions can enhance HIV/AIDS prevention and reduce racial disparities in HIV infection. Many faith leaders cited lack of knowledge about Philadelphia’s racial disparities in HIV infection as a common reason for not previously engaging in HIV programs; others noted their congregations’ existing HIV prevention and outreach programs and shared lessons learned. Barriers to engaging the faith community in HIV prevention included: concerns about tacitly endorsing extramarital sex by promoting condom use, lack of educational information appropriate for a faith-based audience, and fear of losing congregants and revenue as a result of discussing human sexuality and HIV/AIDS from the pulpit. However, many leaders expressed a moral imperative to respond to the AIDS epidemic, and believed clergy should play a greater role in HIV prevention. Many participants noted that controversy surrounding homosexuality has historically divided the faith community and prohibited an appropriate response to the epidemic; many expressed interest in balancing traditional theology with practical public health approaches to HIV prevention. Leaders suggested the faith community should: promote HIV testing, including during or after worship services and in clinical settings; integrate HIV/AIDS topics into health messaging and sermons; couch HIV/AIDS in social justice, human rights and public health language rather than in sexual risk behavior terms; embrace diverse approaches to HIV prevention in their houses of worship; conduct community outreach and host educational sessions for youth; and collaborate on a citywide, interfaith HIV testing and prevention campaign to combat stigma and raise awareness about the African American epidemic. Many African American faith-based leaders are poised to address racial disparities in HIV infection. HIV prevention campaigns should integrate leaders’ recommendations for tailoring HIV prevention for a faith-based audience

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences