The Human Oocyte Preservation Experience (HOPE) a phase IV, prospective, multicenter, observational oocyte cryopreservation registry

<p>Abstract</p> <p>Background</p> <p>It has been recommended by the American Society of Clinical Oncology and the American Society of Reproductive Medicine that options to preserve fertility be presented at the outset of treatment for cancer. This recommendation may have arisen, in part, to the increasing survival of patients with cancer and the realization that certain forms of cancer treatment can lead to infertility. One option for these patients, particularly those with ethical or religious objections to freezing embryos is oocyte cryopreservation. However universal acceptance of these procedures has yet to be established, most likely due to a poor history of success and concerns that there has yet to be a comprehensive approach to evaluating these techniques. In light of this, a registry of patients undergoing oocyte cryopreservation, called the HOPE registry, is being implemented.</p> <p>Discussion</p> <p>The intent of the HOPE Registry is to enroll approximately 400 women of reproductive age who will undergo thawing/warming of oocytes and subsequent transfer. Data from the patients enrolled will be collected via a uniform, standardized form and will document important parameters such as demographics, laboratory procedures and outcomes, including following the outcomes of babies born for one year after birth. The results of the registry will be published on a yearly basis.</p> <p>Summary</p> <p>A patient registry has been established in order to systematically document the techniques and outcomes of oocyte cryopreservation procedures. The results will be published in order to provide a widely accessible resource that will allow patients who are considering these procedures validated information in order to make informed decisions as to how their treatment will proceed.</p

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Cognitive engagement in the problem-based learning classroom

The objective of the present study was to examine to what extent autonomy in problem-based learning (PBL) results in cognitive engagement with the topic at hand. To that end, a short self-report instrument was devised and validated. Moreover, it was examined how cognitive engagement develops as a function of the learning process and the extent to which cognitive engagement determines subsequent levels of cognitive engagement during a one-day PBL event. Data were analyzed by means of confirmatory factor analysis, repeated measures ANOVA, and path analysis. The results showed that the new measure of situational cognitive engagement is valid and reliable. Furthermore, the results revealed that students’ cognitive engagement significantly increased as a function of the learning event. Implications of these findings for PBL are discussed

Module-based multiscale simulation of angiogenesis in skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem.</p> <p>Results</p> <p>We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation). Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis.</p> <p>Conclusions</p> <p>This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions.</p

iTRAQ Identification of Candidate Serum Biomarkers Associated with Metastatic Progression of Human Prostate Cancer

A major challenge in the management of patients with prostate cancer is identifying those individuals at risk of developing metastatic disease, as in most cases the disease will remain indolent. We analyzed pooled serum samples from 4 groups of patients (n = 5 samples/group), collected prospectively and actively monitored for a minimum of 5 yrs. Patients groups were (i) histological diagnosis of benign prostatic hyperplasia with no evidence of cancer ‘BPH’, (ii) localised cancer with no evidence of progression, ‘non-progressing’ (iii) localised cancer with evidence of biochemical progression, ‘progressing’, and (iv) bone metastasis at presentation ‘metastatic’. Pooled samples were immuno-depleted of the 14 most highly abundant proteins and analysed using a 4-plex iTRAQ approach. Overall 122 proteins were identified and relatively quantified. Comparisons of progressing versus non-progressing groups identified the significant differential expression of 25 proteins (p<0.001). Comparisons of metastatic versus progressing groups identified the significant differential expression of 23 proteins. Mapping the differentially expressed proteins onto the prostate cancer progression pathway revealed the dysregulated expression of individual proteins, pairs of proteins and ‘panels’ of proteins to be associated with particular stages of disease development and progression. The median immunostaining intensity of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), one of the candidates identified, was significantly higher in osteoblasts in close proximity to metastatic tumour cells compared with osteoblasts in control bone (p = 0.0353, Mann Whitney U). Our proteomic approach has identified leads for potentially useful serum biomarkers associated with the metastatic progression of prostate cancer. The panels identified, including eEF1A1 warrant further investigation and validation

Reprogramming energy metabolism and inducing angiogenesis : co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas

Background: Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior. Methods: The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients’ clinicopathological parameters. Results: Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis. Conclusions: The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.CP received a post-doctoral fellowship (SFRH/BPD/69479/2010) and FM-S received a doctoral fellowship (SFRH/BD/87139/2012) from FCT (Portuguese Foundation for Science and Technology). This work was supported by the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of "Programa Operacional Tematico Factores de Competitividade" (COMPETE) of "Quadro Comunitario de Apoio III" and co-financed by Fundo Comunitario Europeu FEDER, and also by FAPESP 2008/03232-1

Changing atmospheric CO2 concentration was the primary driver of early Cenozoic climate

The Early Eocene Climate Optimum (EECO, which occurred about 51 to 53 million years ago)1, was the warmest interval of the past 65 million years, with mean annual surface air temperature over ten degrees Celsius warmer than during the pre-industrial period2–4. Subsequent global cooling in the middle and late Eocene epoch, especially at high latitudes, eventually led to continental ice sheet development in Antarctica in the early Oligocene epoch (about 33.6 million years ago). However, existing estimates place atmospheric carbon dioxide (CO2) levels during the Eocene at 500–3,000 parts per million5–7, and in the absence of tighter constraints carbon–climate interactions over this interval remain uncertain. Here we use recent analytical and methodological developments8–11 to generate a new high-fidelity record of CO2 concentrations using the boron isotope (δ11Β) composition of well preserved planktonic foraminifera from the Tanzania Drilling Project, revising previous estimates6. Although species-level uncertainties make absolute values difficult to constrain, CO2 concentrations during the EECO were around 1,400 parts per million. The relative decline in CO2 concentration through the Eocene is more robustly constrained at about fifty per cent, with a further decline into the Oligocene12. Provided the latitudinal dependency of sea surface temperature change for a given climate forcing in the Eocene was similar to that of the late Quaternary period13, this CO2 decline was sufficient to drive the well documented high- and low-latitude cooling that occurred through the Eocene14. Once the change in global temperature between the pre-industrial period and the Eocene caused by the action of all known slow feedbacks (apart from those associated with the carbon cycle) is removed2–4, both the EECO and the late Eocene exhibit an equilibrium climate sensitivity relative to the pre-industrial period of 2.1 to 4.6 degrees Celsius per CO2 doubling (66 per cent confidence), which is similar to the canonical range (1.5 to 4.5 degrees Celsius15), indicating that a large fraction of the warmth of the early Eocene greenhouse was driven by increased CO2 concentrations, and that climate sensitivity was relatively constant throughout this period

Wnt signaling in triple-negative breast cancer

Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease

The History, Relevance, and Applications of the Periodic System in Geochemistry

Geochemistry is a discipline in the earth sciences concerned with understanding the chemistry of the Earth and what that chemistry tells us about the processes that control the formation and evolution of Earth materials and the planet itself. The periodic table and the periodic system, as developed by Mendeleev and others in the nineteenth century, are as important in geochemistry as in other areas of chemistry. In fact, systemisation of the myriad of observations that geochemists make is perhaps even more important in this branch of chemistry, given the huge variability in the nature of Earth materials – from the Fe-rich core, through the silicate-dominated mantle and crust, to the volatile-rich ocean and atmosphere. This systemisation started in the eighteenth century, when geochemistry did not yet exist as a separate pursuit in itself. Mineralogy, one of the disciplines that eventually became geochemistry, was central to the discovery of the elements, and nineteenth-century mineralogists played a key role in this endeavour. Early “geochemists” continued this systemisation effort into the twentieth century, particularly highlighted in the career of V.M. Goldschmidt. The focus of the modern discipline of geochemistry has moved well beyond classification, in order to invert the information held in the properties of elements across the periodic table and their distribution across Earth and planetary materials, to learn about the physicochemical processes that shaped the Earth and other planets, on all scales. We illustrate this approach with key examples, those rooted in the patterns inherent in the periodic law as well as those that exploit concepts that only became familiar after Mendeleev, such as stable and radiogenic isotopes