Scaffold Translation: Barriers Between Concept and Clinic

Translation of scaffold-based bone tissue engineering (BTE) therapies to clinical use remains, bluntly, a failure. This dearth of translated tissue engineering therapies (including scaffolds) remains despite 25 years of research, research funding totaling hundreds of millions of dollars, over 12,000 papers on BTE and over 2000 papers on BTE scaffolds alone in the past 10 years (PubMed search). Enabling scaffold translation requires first an understanding of the challenges, and second, addressing the complete range of these challenges. There are the obvious technical challenges of designing, manufacturing, and functionalizing scaffolds to fill the Form, Fixation, Function, and Formation needs of bone defect repair. However, these technical solutions should be targeted to specific clinical indications (e.g., mandibular defects, spine fusion, long bone defects, etc.). Further, technical solutions should also address business challenges, including the need to obtain regulatory approval, meet specific market needs, and obtain private investment to develop products, again for specific clinical indications. Finally, these business and technical challenges present a much different model than the typical research paradigm, presenting the field with philosophical challenges in terms of publishing and funding priorities that should be addressed as well. In this article, we review in detail the technical, business, and philosophical barriers of translating scaffolds from Concept to Clinic. We argue that envisioning and engineering scaffolds as modular systems with a sliding scale of complexity offers the best path to addressing these translational challenges.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90495/1/ten-2Eteb-2E2011-2E0251.pd

Memoria, responsabilidad, resistencia. Apuntes sobre ética y política en la ficción de José Saramago

Las tres nociones teóricas que constituyen el dispositivo conceptual de la propuesta aquí presentada, que lleva por título: Memoria, responsabilidad, resistencia (apuntes sobre ética y política en la ficción de José Saramago) y que tienen como eje articulador la marginalidad (desde que opera –benjaminianamente – sobre las relaciones de desigualdad y exclusión), orientan el trabajo heurístico con los textos escogidos como corpus y circunscriben sus alcances y limitaciones. Lo que se pretende en esta nueva etapa –entendida como continuidad de un proceso – es construir una teoría de análisis del discurso saramaguiano desde su intelección ético-política , tomando como referenciales las nociones bajtinianas de «discurso, epistemología, antagonismo, ideología, sujeto y poder». Y para ello, el «recorte» procedimental de las categorías enunciadas sirve como línea transversal de lectura que despliega las significaciones narrativas y las transforma en enunciados de valor y toma de posición. «Memoria» entendida en singular recoge las tesis benjaminianas sobre el «concepto de historia» que operan sobre ese radical campo de estudio que es el «pasado» y recuperan las voces acalladas de los «oprimidos» de la historia, postulando una lectura «a contrapelo » de la historia nacional y global. Situándose, en el caso de las referencialidades saramaguianas, en el contexto que articula la dictadura antes y después de su presencia en el escenario del siglo XX, el trabajo analítico focalizará en los modos de perduración de la memoria y la capacidad pregnante de irrumpir en el presente instaurando nuevos modos discursivos de resistencia. La noción de «responsabilidad» tiene una herencia múltiple en el equipo de investigación pero –sobre todo– conjuga con las tesis de Tzvetan Todorov sobre la ética de las víctimas, adentrándose en el estudio de la «alteridad» como presupuesto indiscutible y con el concepto de eticidad, vinculado a la teoría del reconocimiento desarrollada por Axel Honneth. Por último, la «resistencia» abre hacia una lectura política de la ficción de José Saramago que el procedimiento heurístico y hermenéutico de la investigación, a partir de los enunciados de Foucault y de Said –entre otros– pretende radicalizar. La conjunción tripartita de las nociones destacadas y su dinamicidad dialéctica aseguran la constitución de un referencial teórico que pretende instalar en el aparato crítico sobre la ficción del autor portugués, un dispositivo conceptual a partir del cual dialogar con el pensamiento y la filosofía contemporáne

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

TNM Staging of Neoplasms of the Endocrine Pancreas: Results From a Large International Cohort Study

Background Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. Methods The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. Results Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. Conclusion Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practic

Advancing synoptic cancer reports beyond English: the University of Bern/PathoLink approach.

Synoptic reporting (SR) increases completeness and improves the understanding of pathology reports for tumours as compared to the more traditional “narrative” style. Furthermore, it is an important step towards higher levels of structured data capture [1]. SR is defined by a set of required data elements (RDE) specific for each tumour type and a characteristic paired format of RDE and response. The College of American Pathologists (CAP) requires accredited pathology laboratories to report many cancer types in a synoptic format and for this purpose publishes a comprehensive set of protocols [2]. More recently, the International Collaboration for Cancer Reporting (ICCR)—sponsored amongst others by the European Society of Pathology—has started to publish synoptic protocols with the aim to “produce internationally standardised and evidence-based datasets for the pathology reporting of cance

Open source clinical science for emerging infections

International audienc

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy

The multiplicity fraction in 202 open clusters from Gaia

In this study, we estimate the fraction of binaries with high mass ratios for 202 open clusters in the extended solar neighbourhood (closer than 1.5 kpc from the Sun). This is one of the largest homogeneous catalogues of multiplicity fractions in open clusters to date, including the unresolved and total (close-binary) multiplicity fractions of main-sequence systems with mass ratio larger than $0.6_{-0.15}^{+0.05}$. The unresolved multiplicity fractions are estimated applying a flexible mixture model to the observed Gaia colour-magnitude diagrams of the open clusters. Then we use custom Gaia simulations to account for the resolved systems and derive the total multiplicity fractions. The studied open clusters have ages between 6.6 Myr and 3.0 Gyr and total high-mass-ratio multiplicity fractions between 6% and 80%, with a median of 18%. The multiplicity fractions increase with the mass of the primary star, as expected. The average multiplicity fraction per cluster displays an overall decreasing trend with the open cluster age up to ages about 100 Myr, above which the trend increases. Our simulations show that most of this trend is caused by complex selection effects (introduced by the mass dependence of the multiplicity fraction and the magnitude limit of our sample). Furthermore, the multiplicity fraction is not significantly correlated with the clusters' position in the Galaxy. The spread in multiplicity fraction decreases significantly with the number of cluster members (used as a proxy for cluster mass). We also find that the multiplicity fraction decreases with metallicity, in line with recent studies using field stars.Comment: 17 pages, 13 figures, resubmitted to A&A following referee comment

Role of front-line bevacizumab in advanced ovarian cancer: the OSCAR study

Objective Two randomized phase III trials demonstrated the efficacy and safety of combining bevacizumab with front-line carboplatin/paclitaxel for advanced ovarian cancer. The OSCAR (NCT01863693) study assessed the impact of front-line bevacizumab-containing therapy on safety and oncologic outcomes in patients with advanced ovarian cancer in the UK. Methods Between May 2013 and April 2015, patients with high-risk stage IIIB–IV advanced ovarian cancer received bevacizumab (7.5 or 15 mg/kg every 3 weeks, typically for ≤12 months, per UK clinical practice) combined with front-line chemotherapy, with bevacizumab continued as maintenance therapy. Co-primary endpoints were progression-free survival and safety (NCI-CTCAE v4.0). Patients were evaluated per standard practice/physician’s discretion. Results A total of 299 patients received bevacizumab-containing therapy. The median age was 64 years (range 31–83); 80 patients (27%) were aged ≥70 years. Surgical interventions were primary debulking in 21%, interval debulking in 36%, and none in 43%. Most patients (93%) received bevacizumab 7.5 mg/kg with carboplatin/paclitaxel. Median duration of bevacizumab was 10.5 months(range <0.1–41.4); bevacizumab and chemotherapy were given in combination for a median of three cycles (range 1–10). Median progression-free survival was 15.4 (95% CI 14.5 to 16.9) months. Subgroup analyses according to prior surgery showed median progression-free survival of 20.8, 16.1, and 13.6 months in patients with primary debulking, interval debulking, and no surgery, respectively. Median progression-free survival was 16.1 vs 14.8 months in patients aged <70 versus ≥70 years, respectively. The 1-year overall survival rate was 94%. Grade 3/4 adverse events occurred in 54% of patients, the most common being hypertension (16%) and neutropenia (5%). Thirty-five patients (12%) discontinued bevacizumab for toxicity (most often for proteinuria (2%)). Conclusions Median progression-free survival in this study was similar to that in the high-risk subgroup of the ICON7 phase III trial. Median progression-free survival was shortest in patients who did not undergo surgery