The Therapeutic Implications of Plasticity of the Cancer Stem Cell Phenotype

The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer

Impact of source data on the interpretation of contrast-enhanced magnetic resonance angiography of the lower limbs

Background The primary purpose of this study is to examine whether use of source data is effective in increasing the number of arterial segments that can be interpreted from maximum intensity projections of lower limb MR angiograms. Correlation between sites of arterial disease and venous contamination was also measured. Interpretation of source data is performed routinely by radiologists, but the value of this has not been well studied with randomized studies. Results The proportion of segments visible above the knee was 87% using maximal intensity projection alone (MIP) and 88% when the MIP was combined with source data. The proportions were 67% for MIP and 72% for MIP plus source data below the knee. There was substantial agreement between presence of arterial disease and venous contamination in the calf and thigh. Conclusion The use of source data increases the number of assessable segments, but not individuals, by a statistically significant but small amount (1.2%, p <0.05). This study supports the association between arterial disease and venous contamination

Packages of Care for Dementia in Low- and Middle-Income Countries

In the fifth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Martin Prince and colleagues discuss the treatment of dementia

Part-time hospitalisation and stigma experiences: a study in contemporary psychiatric hospitals

Background: Because numerous studies have revealed the negative consequences of stigmatisation, this study explores the determinants of stigma experiences. In particular, it examines whether or not part-time hospitalisation in contemporary psychiatric hospitals is associated with less stigma experiences than full-time hospitalisation. Methods: Survey data on 378 clients of 42 wards from 8 psychiatric hospitals are used to compare full-time clients, part-time clients and clients receiving part-time care as aftercare on three dimensions of stigma experiences, while controlling for symptoms, diagnosis and clients' background characteristics. Results: The results reveal that part-time clients without previous full-time hospitalisation report less social rejection than clients who receive full-time hospitalisation. In contrast, clients receiving part-time treatment as aftercare do not differ significantly from full-time clients concerning social rejection. No significant results for the other stigma dimensions were found. Conclusion: Concerning social rejection, immediate part-time hospitalisation could be recommended as a means of destigmatisation for clients of contemporary psychiatric hospitals

The effect on mental health of a large scale psychosocial intervention for survivors of mass violence: A quasi-experimental study in Rwanda

Background: War has serious and prolonged mental health consequences. It is argued that post-emergency mental health interventions should not only focus on psychological factors but also address the social environment. No controlled trials of such interventions exist. We studied the effect on mental health of a large scale p

Integrated Management and Visualization of Electronic Tag Data with Tagbase

Electronic tags have been used widely for more than a decade in studies of diverse marine species. However, despite significant investment in tagging programs and hardware, data management aspects have received insufficient attention, leaving researchers without a comprehensive toolset to manage their data easily. The growing volume of these data holdings, the large diversity of tag types and data formats, and the general lack of data management resources are not only complicating integration and synthesis of electronic tagging data in support of resource management applications but potentially threatening the integrity and longer-term access to these valuable datasets. To address this critical gap, Tagbase has been developed as a well-rounded, yet accessible data management solution for electronic tagging applications. It is based on a unified relational model that accommodates a suite of manufacturer tag data formats in addition to deployment metadata and reprocessed geopositions. Tagbase includes an integrated set of tools for importing tag datasets into the system effortlessly, and provides reporting utilities to interactively view standard outputs in graphical and tabular form. Data from the system can also be easily exported or dynamically coupled to GIS and other analysis packages. Tagbase is scalable and has been ported to a range of database management systems to support the needs of the tagging community, from individual investigators to large scale tagging programs. Tagbase represents a mature initiative with users at several institutions involved in marine electronic tagging research

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

Efficient tumour formation by single human melanoma cells

A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells ( 0.1 - 0.0001%) form tumours when transplanted into non- obese diabetic/ severe combined immunodeficiency ( NOD/ SCID) mice. However, the extent to which NOD/ SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/ SCID interleukin- 2 receptor gamma chain null (Il2rg(-/-)) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single- cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.Howard Hughes Medical Institute ; Allen H. Blondy Research Fellowship ; Lewis and Lillian Becker ; University of Michigan Comprehensive Cancer Center ; National Institutes of Health [CA46592]; University of Michigan Flow Cytometry Core Facility ; N. McAnsh and the University of Michigan Cancer Centre Histology Core ; National Institute of Diabetes, Digestive, and Kidney Diseases [NIH5P60- DK20572]; Michigan Diabetes Research and Training Center ; Spanish Ministry of Education ; Marie Curie Outgoing International Fellowship from the European Commission ; Australian National Health and Medical Research Council ; Human Frontiers Science Program and Australia PostThis work was supported by the Howard Hughes Medical Institute and by the Allen H. Blondy Research Fellowship. The University of Michigan Melanoma Bank was supported by a gift from Lewis and Lillian Becker. Flow cytometry was partly supported by the University of Michigan Comprehensive Cancer Center grant from the National Institutes of Health CA46592. We thank: D. Adams, M. White and the University of Michigan Flow Cytometry Core Facility for support; N. McAnsh and the University of Michigan Cancer Centre Histology Core for histological studies; G. K. Smyth for assistance with statistics; and Z. Azizan for support with tissue collection. Antibody production was supported in part by the National Institute of Diabetes, Digestive, and Kidney Diseases, grant NIH5P60- DK20572 to the Michigan Diabetes Research and Training Center. Some antibodies were provided by Caltag or by eBioscience to screen for cancer stem- cell markers. Human primary melanocyte cultures were provided by M. Soengas. Human mesenchymal stem cells were provided by Z. Wang and P. Krebsbach. E. Q. was supported by the Spanish Ministry of Education and the Marie Curie Outgoing International Fellowship from the European Commission. M. S. was supported by the Australian National Health and Medical Research Council, the Human Frontiers Science Program and Australia Post.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62970/1/nature07567.pd

Pleasure in decision-making situations

BACKGROUND: This study explores the role of pleasure in decision making. RESULTS: In Experiment 1, 12 subjects were presented with a questionnaire containing 46 items taken from the literature. Twenty-three items described a situation where a decision should be made and ended with a suggested solution. The other items served as filler items. The subjects were requested not to make a decision but to rate the pleasure or displeasure they experienced when reading the situation described in the item. The subjects' ratings were then compared to the decisions on the same situations made by the other subjects of the studies published by other workers. The ratings of pleasure/displeasure given by our subjects correlated significantly with the choices published by other authors. This result satisfies a necessary condition for pleasure to be the key of the decision making process in theoretical situations. In Experiment 2, a new group of 12 subjects rated their experience of pleasure/displeasure when reading various versions of 50 situations taken from daily life where an ethical decision had to be made (Questionnaire I) including 200 items. This was followed by a multiple-choice test with the 50 situations (Questionnaire II) using the same 200 items and offering the various behaviors. Subjects tended to choose ethical and unethical responses corresponding to their highest pleasure rating within each problem. In all cases the subjects' behavior was higher than chance level, and thus, followed the trend to maximize pleasure. In Experiment 3, 12 subjects reading 50 mathematical short problems followed by correct and incorrect versions of the answer to the problem (Questionnaire III), including 200 items. This was followed by a multiple-choice mathematical test with the 50 problems (Questionnaire IV) using the same 200 items and offering the correct and incorrect answers. In questionnaire IV, subjects tended to choose correct as well as incorrect responses corresponding to their highest hedonic rating within each problem. In all cases the subjects' behavior was higher than chance level, and thus, followed the trend to maximize pleasure. CONCLUSIONS: The results of the three experiments support the hypothesis according to which decisions are made in the hedonic dimension of conscious experience