Microarray studies reveal novel genes associated with endocrine resistance in breast cancer

Background Endocrine resistance is a major hurdle in breast cancer management, and determining the underlying factors driving its growth and aggressive behaviour should vastly improve treatment. Methods Microarray technology (BD Atlas Plastic Human 12 K Microarrays; GeneSifter software), verified by PCR, western blotting and immunocytochemisty, was used to identify genes increased in acquired resistant models to tamoxifen (TamR) or faslodex (FasR) as potential predictive/prognostic markers and new therapeutic targets. Results Alongside known breast cancer genes (β-catenin, PEA3, vitronectin, CD44), two novel genes in endocrine resistance were revealed (the latter never previously described in breast cancer): a securin/cell cycle regulator Pituitary Tumour Transforming Gene-1 (PTTG1), and GDNF receptor-alpha 3 (GFRα3) reported to promote cell survival signalling via RET coreceptor. Altered levels of PTTG1, GFRα3, or their associated family members were observed in further endocrine resistant states, including an additional faslodex resistant model that has progressed to a highly-aggressive state (FasR-Lt) and XMCF-7 cells resistant to oestrogen deprivation. PTTG1 and GFRα3 induction were also implicated in limiting response to anti-EGFR agents currently in breast cancer trials, with GFRα3 ligand (artemin) largely overcoming drug response. mRNA studies in clinical disease revealed PTTG1 associated with lymph node spread, high tumour grade and proliferation, while GFRα3 was enriched in ER-negative tumours and those expressing EGFR, profiles implying roles in clinical resistance and aggressive tumour behaviour. Promisingly, PTTG1 or GFRα3 siRNA knockdown promoted cell kill and inhibited proliferation in the resistant models. Conclusion Cumulatively, these data indicate PTTG1 and GFRα3 may provide useful biomarkers, and perhaps clinically relevant therapeutic targets for multiple resistant states

Prioritized Sweeping Neural DynaQ with Multiple Predecessors, and Hippocampal Replays

During sleep and awake rest, the hippocampus replays sequences of place cells that have been activated during prior experiences. These have been interpreted as a memory consolidation process, but recent results suggest a possible interpretation in terms of reinforcement learning. The Dyna reinforcement learning algorithms use off-line replays to improve learning. Under limited replay budget, a prioritized sweeping approach, which requires a model of the transitions to the predecessors, can be used to improve performance. We investigate whether such algorithms can explain the experimentally observed replays. We propose a neural network version of prioritized sweeping Q-learning, for which we developed a growing multiple expert algorithm, able to cope with multiple predecessors. The resulting architecture is able to improve the learning of simulated agents confronted to a navigation task. We predict that, in animals, learning the world model should occur during rest periods, and that the corresponding replays should be shuffled.Comment: Living Machines 2018 (Paris, France

Data Driven Cone Beam CT Motion Management for Radiotherapy Application

The ability to identify respiratory motion is crucial during radiation therapy treatment. In our study we introduced a novel data driven method based on principal component analysis (PCA) to extract a signal related to respiratory motion from cone beam CT projection data. Projection data acquired on cone beam CT devices normally has two motion component information within it, (1) respiratory induced motion and (2) detector rotational induced motion. Our novel approach for extracting a respiratory induced motion signal from projection data was based on computing PCA for different sections of the data set independently, and introducing a technique of combining the extracted signal from each section in a manner to represent the respiratory signal from the entire data set. We tested our method using simulation data set from XCAT software and a real patient data set. The respiratory signal extracted with the XCAT simulation yielded comparable result when compared to the ground truth respiratory signal. Initial results for the real patient data set are encouraging but show need for further refinements

Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials : a consensus study

Background: Current methodological guidelines provide advice about the assessment of sub-group analysis within RCTs, but do not specify explicit criteria for assessment. Our objective was to provide researchers with a set of criteria that will facilitate the grading of evidence for moderators, in systematic reviews. Method: We developed a set of criteria from methodological manuscripts (n = 18) using snowballing technique, and electronic database searches. Criteria were reviewed by an international Delphi panel (n = 21), comprising authors who have published methodological papers in this area, and researchers who have been active in the study of sub-group analysis in RCTs. We used the Research ANd Development/University of California Los Angeles appropriateness method to assess consensus on the quantitative data. Free responses were coded for consensus and disagreement. In a subsequent round additional criteria were extracted from the Cochrane Reviewers’ Handbook, and the process was repeated. Results: The recommendations are that meta-analysts report both confirmatory and exploratory findings for subgroups analysis. Confirmatory findings must only come from studies in which a specific theory/evidence based apriori statement is made. Exploratory findings may be used to inform future/subsequent trials. However, for inclusion in the meta-analysis of moderators, the following additional criteria should be applied to each study: Baseline factors should be measured prior to randomisation, measurement of baseline factors should be of adequate reliability and validity, and a specific test of the interaction between baseline factors and interventions must be presented. Conclusions: There is consensus from a group of 21 international experts that methodological criteria to assess moderators within systematic reviews of RCTs is both timely and necessary. The consensus from the experts resulted in five criteria divided into two groups when synthesising evidence: confirmatory findings to support hypotheses about moderators and exploratory findings to inform future research. These recommendations are discussed in reference to previous recommendations for evaluating and reporting moderator studies

Clinical relevance of "withdrawal therapy" as a form of hormonal manipulation for breast cancer

<p>Abstract</p> <p>Background</p> <p>It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of "withdrawal therapy".</p> <p>Methods</p> <p>Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1) estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years), locally advanced or metastatic breast cancer; (2) disease deemed suitable for treatment by hormonal manipulation; (3) disease assessable by UICC criteria; (4) received "withdrawal" from a prior endocrine agent as a form of therapy; (5) on "withdrawal therapy" for ≥ 6 months unless they progressed prior.</p> <p>Results</p> <p>Seventeen patients with median age of 84.3 (53.7-92.5) had "withdrawal therapy" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10), an aromatase inhibitor (n = 5), megestrol acetate (n = 1) or fulvestrant (n = 1). Ten patients (58.8%) had clinical benefit (CB) (complete response/partial response/stable disease ≥ 6 months) with a median duration of Clinical Benefit (DoCB) of 10+ (7-27) months. Two patients remain on "withdrawal therapy" at the time of analysis.</p> <p>Conclusion</p> <p>"Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients. This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. "Withdrawal" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy.</p

On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

A habituation account of change detection in same/different judgments

We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation

The pathology of familial breast cancer: Immunohistochemistry and molecular analysis

Extensive studies of BRCA1- and BRCA2-associated breast tumours have been carried out in the few years since the identification of these familial breast cancer predisposing genes. The morphological studies suggest that BRCA1 tumours differ from BRCA2 tumours and from sporadic breast cancers. Recent progress in immunohistochemistry and molecular biology techniques has enabled in-depth investigation of molecular pathology of these tumours. Studies to date have investigated issues such as steroid hormone receptor expression, mutation status of tumour suppressor genes TP53 and c-erbB2, and expression profiles of cell cycle proteins p21, p27 and cyclin D(1). Despite relative paucity of data, strong evidence of unique biological characteristics of BRCA1-associated breast cancer is accumulating. BRCA1-associated tumours appear to show an increased frequency of TP53 mutations, frequent p53 protein stabilization and absence of imunoreactivity for steroid hormone receptors. Further studies of larger number of samples of both BRCA1- and BRCA2-associated tumours are necessary to clarify and confirm these observations

Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria.

Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,6'-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,6'-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species