New indicators and indexes for benchmarking university-industry-government innovation in medical and life science clusters: results from the European FP7 Regions of Knowledge HealthTIES project.

BACKGROUND: While the European Union is striving to become the 'Innovation Union', there remains a lack of quantifiable indicators to compare and benchmark regional innovation clusters. To address this issue, a HealthTIES (Healthcare, Technology and Innovation for Economic Success) consortium was funded by the European Union's Regions of Knowledge initiative, research and innovation funding programme FP7. HealthTIES examined whether the health technology innovation cycle was functioning differently in five European regional innovation clusters and proposed regional and joint actions to improve their performance. The clusters included BioCat (Barcelona, Catalonia, Spain), Medical Delta (Leiden, Rotterdam and Delft, South Holland, Netherlands), Oxford and Thames Valley (United Kingdom), Life Science Zürich (Switzerland), and Innova Észak-Alföld (Debrecen, Hungary). METHODS: Appreciation of the 'triple helix' of university-industry-government innovation provided the impetus for the development of two quantifiable innovation indexes and related indicators. The HealthTIES H-index is calculated for disease and technology platforms based on the h-index proposed by Hirsch. The HealthTIES Innovation Index is calculated for regions based on 32 relevant quantitative and discriminative indicators grouped into 12 categories and 3 innovation phases, namely 'Input' (n = 12), 'Innovation System' (n = 9) and 'Output' (n = 11). RESULTS: The HealthTIES regions had developed relatively similar disease and technology platform profiles, yet with distinctive strengths and weaknesses. The regional profiles of the innovation cycle in each of the three phases were surprisingly divergent. Comparative assessments based on the indicators and indexes helped identify and share best practice and inform regional and joint action plans to strengthen the competitiveness of the HealthTIES regions. CONCLUSION: The HealthTIES indicators and indexes provide useful practical tools for the measurement and benchmarking of university-industry-government innovation in European medical and life science clusters. They are validated internally within the HealthTIES consortium and appear to have a degree of external prima facie validity. Potentially, the tools and accompanying analyses can be used beyond the HealthTIES consortium to inform other regional governments, researchers and, possibly, large companies searching for their next location, analyse and benchmark 'triple helix' dynamics within their own networks over time, and to develop integrated public-private and cross-regional research and innovation strategies in Europe and beyond.

Autoantibodies targeting TLR and SMAD pathways define new subgroups in systemic lupus erythematosus.

OBJECTIVES: The molecular targets of the vast majority of autoantibodies in systemic lupus erythematosus (SLE) are unknown. We set out to identify novel autoantibodies in SLE to improve diagnosis and identify subgroups of SLE individuals. METHODS: A baculovirus-insect cell expression system was used to create an advanced protein microarray with 1543 full-length human proteins expressed with a biotin carboxyl carrier protein (BCCP) folding tag, to enrich for correctly folded proteins. Sera from a discovery cohort of UK and US SLE individuals (n = 186) and age/ethnicity matched controls (n = 188) were assayed using the microarray to identify novel autoantibodies. Autoantibodies were validated in a second validation cohort (91 SLE, 92 controls) and a confounding rheumatic disease cohort (n = 92). RESULTS: We confirmed 68 novel proteins as autoantigens in SLE and 11 previous autoantigens in both cohorts (FDR<0.05). Using hierarchical clustering and principal component analysis, we observed four subgroups of SLE individuals associated with four corresponding clusters of functionally linked autoantigens. Two clusters of novel autoantigens revealed distinctive networks of interacting proteins: SMAD2, SMAD5 and proteins linked to TGF-ß signalling; and MyD88 and proteins involved in TLR signalling, apoptosis, NF-κB regulation and lymphocyte development. The autoantibody clusters were associated with different patterns of organ involvement (arthritis, pulmonary, renal and neurological). A panel of 26 autoantibodies, which accounted for four SLE clusters, showed improved diagnostic accuracy compared to conventional antinuclear antibody and anti-dsDNA antibody assays. CONCLUSIONS: These data suggest that the novel SLE autoantibody clusters may be of prognostic utility for predicting organ involvement in SLE patients and for stratifying SLE patients for specific therapies.

A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report.

BACKGROUND: Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula. CASE PRESENTATION: A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16(INK4A), D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators. CONCLUSIONS: In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

Transcranial Endovascular Embolization of Dural Arteriovenous Fistula: A Case Report and Literature Review.

The optimal endovascular management of high-grade dural arterial-venous fistulae (dAVF) can be technically challenging in cases where the involved venous sinus segment is inaccessible through the traditional percutaneous approach. In this report, we describe our experience with the transcranial endovascular approach for the treatment of a high-grade dAVF. We also provide a literature review of other reports of transcranial endovascular dAVF embolization. We propose that transcranial endovascular embolization of high-grade dAVF appears to be safe and effective in cases where the fistula is inaccessible to percutaneous routes alone.

Ischemic Stroke due to Intracranial Embolization of a Pelvic Phlebolith in a Pregnant Patient Successfully Treated by Surgical Embolectomy following Attempted Endovascular Thrombectomy.

An unusual case of ischemic stroke due to calcified cerebral embolus occurring in a pregnant patient during the peripartum period is reported. The source of the embolus was suspected to be a pelvic phlebolith in origin which paradoxically embolized via a patent foramen ovale to the supraclinoid right internal carotid artery. To our knowledge, this is the first reported case of calcified cerebral embolus attributed to paradoxical embolism of a pelvic phlebolith, and we theorize that introduction of the phlebolith into the venous system may have occurred as a consequence of vascular remodeling due to pregnancy-related hemodynamic changes. Clinicians should be aware of this potential source of calcified cerebral emboli in patients with a patent foramen ovale during pregnancy. Our patient ultimately achieved an excellent outcome with surgical endarterectomy and embolectomy following an unsuccessful attempt at mechanical thrombectomy.

An innovative method of data analysis: Using art as a lens through which to view pharmacy undergraduate students' learning and assessment practices.

BACKGROUND: It has been argued in the literature that pharmacy is a unique integration of art and science. This paper addresses the art aspect of this and draws on the existence of multiple philosophies, theories and belief systems and describes the methodological process of use fine art (paintings) as a lens through which to view thematic data about a 'scientific' concept; a method which appears to be unique in the literature. OBJECTIVES: To explore pharmacy students' assessment practices and any influence on their learning practices. To explore how feedback influences pharmacy students' learning practices. To determine whether the affective dimension impacts on pharmacy students' learning. To evaluate whether fine can art be used as a lens to make sense of thematic data. METHODS: Data collection took the form of individual semi-structured interviews and was underpinned by an interpretivist qualitative approach. Analysis of data involved exploring the themes relating to assessment. Initially, thematic analysis of the data was carried out using an inductive approach and mind-mapping then Pierre Bonnard's art was used as a 'lens' through which to view the themes. RESULTS: Eighteen pharmacy students in one UK School of Pharmacy were interviewed. Themes relating to assessment practices which are discussed in this paper and compared to Pierre Bonnard's paintings are: conceptions of assessment (compared with Coffee), the impact of the nature of assessment on learning practices (compared with Dining Room in the Country), feedback (compared with Nude in a Mirror), strategies used in assessment practices (compared with The French Window), the affective dimension of assessment (compared with Red Roos at Le Cannet) and assessment constrains free-thinking (compared with The White Interior). CONCLUSIONS: Using Bonnard's art in analysis has provided an additional way of extending the analysis of participant's assessment practices. Aligning with Bonnard's technique of foregrounding the unexpected or diverting attention away from the obvious has allowed illumination of these practices and previously un-noticed aspects of pharmacy students' learning practices. There were a number of new insights gained from using this approach as well limitations. By attending to a different perspective that art brings, we have been able to see how assessment practices link to learning as pharmacy students.

Intramedullary PNET of the spine: long-term survival after combined modality therapy and subsequent relapse.

Primitive neuroectodermal tumors (PNET) originating within the spinal cord are extraordinarily rare. We report a female who presented at age 21 with diffuse involvement of the lower spinal cord. After biopsy and successful treatment with radiation and chemotherapy, she recurred 10 years later with disease in her cerebellum. She was reinduced with chemotherapy and subsequently received high-dose chemotherapy with autologous stem cell support. She is alive and free of disease 11 years after her initial presentation. This represents the longest survival ever documented for a primary spinal PNET.

Using Artifacts and Qualitative Methodology to Explore Pharmacy Students' Learning Practices.

Objective. To explore the use of artifacts and material objects in accessing what learning means to pharmacy students, what their learning practices are, and their assumptions about what it means to master the pharmacy curriculum. Methods. Data collection was qualitative and took the form of individual semi-structured interviews with students in a Master of Pharmacy program. Participants were asked to select three artifacts (a photograph, an object, a song, a picture, or something else) that represented what learning as a pharmacy student meant to them and bring them to the interview. The interviews were conducted using both the abstracts and a semi-structured interview plan constructed as a mind map. Flexibility was applied to changing the sequence of themes, and additional probing questions were asked. Data were analyzed thematically using mind mapping and, subsequently, theoretical constructs were applied to make sense of the analysis. Results. Nineteen interviews were conducted. Findings were grouped into five distinct themes: study practices or strategies adopted, rituals associated with learning and studying, pharmacy knowledge, motivation for learning, and ways of learning. Each of these identified themes was summarized and illustrations from the data given. The affective dimensions of learning were a strong emergent theme throughout the data. Conclusion. The use of artifacts in the research process afforded in-depth insight into the specific study practices adopted by a group of pharmacy students. Qualitative methods can be useful in surfacing students' learning practices and difficulties faced in their negotiation of the pharmacy curriculum.

Mutational analysis of the von Willebrand factor gene in type 1 von Willebrand disease using conformation sensitive gel electrophoresis: a comparison of fluorescent and manual techniques.

Two versions of conformation sensitive gel electrophoresis, fluorescent (F-CSGE) and manual (M-CSGE) techniques, were compared for mutation analysis of the von Willebrand factor gene. 56 PCRs were used to amplify all 52 exons of the gene in seven type 1 von Willebrand disease cases, plus a healthy control. One hundred and ninety-two samples were analyzed on each F-CSGE gel, compared with 40 on M-CSGE. 125 amplicons revealed bandshifts using F-CSGE, but only 101 by M-CSGE. Five mutations were detected by both techniques. F-CSGE detected 45 different polymorphisms whereas M-CSGE detected only 39. F-CSGE is high-throughput and more sensitive than M-CSGE.

Mutational analysis of 206 families with cavernous malformations.

OBJECT: A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene. METHODS: The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded. CONCLUSIONS: All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.