Fusion of Protein Aggregates Facilitates Asymmetric Damage Segregation

Asymmetric segregation of damaged proteins at cell division generates a cell that retains damage and a clean cell that supports population survival. In cells that divide asymmetrically, such as Saccharomyces cerevisiae, segregation of damaged proteins is achieved by retention and active transport. We have previously shown that in the symmetrically dividing Schizosaccharomyces pombe there is a transition between symmetric and asymmetric segregation of damaged proteins. Yet how this transition and generation of damage-free cells are achieved remained unknown. Here, by combining in vivo imaging of Hsp104-associated aggregates, a form of damage, with mathematical modeling, we find that fusion of protein aggregates facilitates asymmetric segregation. Our model predicts that, after stress, the increased number of aggregates fuse into a single large unit, which is inherited asymmetrically by one daughter cell, whereas the other one is born clean. We experimentally confirmed that fusion increases segregation asymmetry, for a range of stresses, and identified Hsp16 as a fusion factor. Our work shows that fusion of protein aggregates promotes the formation of damage-free cells. Fusion of cellular factors may represent a general mechanism for their asymmetric segregation at division

SFRP4 drives invasion in gastric cancer and is an early predictor of recurrence.

OBJECTIVE: Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence. DESIGN: Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection. RESULTS: Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed PredictR. CONCLUSIONS: This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection

Epstein-Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting

A web-based 3D visualisation and assessment system for urban precinct scenario modelling

Recent years have seen an increasing number of spatial tools and technologies for enabling better decision-making in the urban environment. They have largely arisen because of the need for cities to be more efficiently planned to accommodate growing populations while mitigating urban sprawl, and also because of innovations in rendering data in 3D being well suited for visualising the urban built environment. In this paper we review a number of systems that are better known and more commonly used in the field of urban planning. We then introduce Envision Scenario Planner (ESP), a web-based 3D precinct geodesign, visualisation and assessment tool, developed using Agile and Co-design methods. We provide a comprehensive account of the tool, beginning with a discussion of its design and development process and concluding with an example use case and a discussion of the lessons learned in its development

Primary cutaneous CD4/CD56 hematodermic neoplasm (blastic NK-cell lymphoma): a report of five cases

This is a publisher's version of an article published in Haematologica 2006 published by European Hematology Association. This version is reproduced with permission from European Hematology Association. http://www.haematologica.org/CD4/CD56hematodermic neoplasm (WHO- EORTC) or blastic NK-cell lymphoma (WHO) is a rare aggressive CD4+CD56+lin- skin-tropic lymphoma of putative early-plasmacytoid dendritic cell origin. We present five cases to highlight the need for greater awareness of this entity amongst pathologists such that aggressive treatment be considered given the generally poor prognosis

Early relapses after adjuvant chemotherapy suggests primary chemoresistance in diffuse gastric cancer

<div><p>Background</p><p>Survival from gastric cancer remains poor, particularly in Western populations. Previous pre-clinical and subgroup analyses of clinical trials have suggested differing benefits from fluoropyrimidine-based chemotherapeutics for diffuse and intestinal gastric cancer. This analysis examines patterns of relapse with and without adjuvant chemotherapy after curative resection for gastric cancer in these subtypes to explore the Lauren classification as a predictive marker of benefit for fluoropyrimidine-based adjuvant chemotherapy.</p><p>Patients and methods</p><p>Gastric cancer patients enrolled in an ongoing tissue banking study were analysed, 164 patients who would currently be considered for adjuvant therapy after curative resection were included in the analysis. Patients who did and did not receive adjuvant chemotherapy were compared. The primary end point was relapse free survival.</p><p>Results</p><p>Approximately 50% of patients received adjuvant chemotherapy, the majority receiving a fluoropyrimidine-based regimen. The comparison of Kaplan-Meier curves for patients who did and did not receive adjuvant chemotherapy are different between patients with intestinal and diffuse gastric cancer, and suggest that there may be a benefit in intestinal gastric cancer. The hazard ratio for adjuvant chemotherapy for intestinal gastric cancer was 0.56, (95% CI 0.27–1.17), suggesting a trend towards benefit that was lacking in diffuse gastric cancer patients (1.26, 95% CI 0.70–2.38). The patterns of relapse after adjuvant chemotherapy also differed between diffuse and intestinal gastric cancer. More than 50% of diffuse gastric cancer patients who received adjuvant chemotherapy relapsed within 12 months of surgery despite similar surgical parameters.</p><p>Conclusions</p><p>Lauren classification is prognostic in gastric cancer. This analysis adds further evidence that it may also be predictive of benefit for fluoropyrimidine-based chemotherapeutics, with lower chemosensitivity seen in diffuse gastric cancer. Treating diffuse and intestinal gastric cancer as separate entities, with identification of efficacious treatments for diffuse gastric cancer will help in improving outcomes from gastric cancer.</p></div