A systems approach to clinical oncology: Focus on breast cancer

During the past decade, genomic microarrays have been applied with some success to the molecular profiling of breast tumours, which has resulted in a much more detailed classification scheme as well as in the identification of potential gene signature sets. These gene sets have been applied to both the prognosis and prediction of outcome to treatment and have performed better than the current clinical criteria. One of the main limitations of microarray analysis, however, is that frozen tumour samples are required for the assay. This imposes severe limitations on access to samples and precludes large scale validation studies from being conducted. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), on the other hand, can be used with degraded RNAs derived from formalin-fixed paraffin-embedded (FFPE) tumour samples, the most important and abundant source of clinical material available. More recently, the novel DASL (cDNA-mediated Annealing, Selection, extension and Ligation) assay has been developed as a high throughput gene expression profiling system specifically designed for use with FFPE tumour tissue samples. However, we do not believe that genomics is adequate as a sole prognostic and predictive platform in breast cancer. The key proteins driving oncogenesis, for example, can undergo post-translational modifications; moreover, if we are ever to move individualization of therapy into the practical world of blood-based assays, serum proteomics becomes critical. Proteomic platforms, including tissue micro-arrays (TMA) and protein chip arrays, in conjunction with surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS), have been the technologies most widely applied to the characterization of tumours and serum from breast cancer patients, with still limited but encouraging results. This review will focus on these genomic and proteomic platforms, with an emphasis placed on the utilization of FFPE tumour tissue samples and serum, as they have been applied to the study of breast cancer for the discovery of gene signatures and biomarkers for the early diagnosis, prognosis and prediction of treatment outcome. The ultimate goal is to be able to apply a systems biology approach to the information gleaned from the combination of these techniques in order to select the best treatment strategy, monitor its effectiveness and make changes as rapidly as possible where needed to achieve the optimal therapeutic results for the patient

Wnt signaling in triple negative breast cancer is associated with metastasis

Background Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies. Methods We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease. Results The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases. Conclusion These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways

Spectral Theory for Perturbed Krein Laplacians in Nonsmooth Domains

We study spectral properties for $H_{K,\Omega}$, the Krein--von Neumann extension of the perturbed Laplacian $-\Delta+V$ defined on $C^\infty_0(\Omega)$, where $V$ is measurable, bounded and nonnegative, in a bounded open set $\Omega\subset\mathbb{R}^n$ belonging to a class of nonsmooth domains which contains all convex domains, along with all domains of class $C^{1,r}$, $r>1/2$. In particular, in the aforementioned context we establish the Weyl asymptotic formula #\{j\in\mathbb{N} | \lambda_{K,\Omega,j}\leq\lambda\} = (2\pi)^{-n} v_n |\Omega| \lambda^{n/2}+O\big(\lambda^{(n-(1/2))/2}\big) {as} \lambda\to\infty, where $v_n=\pi^{n/2}/ \Gamma((n/2)+1)$ denotes the volume of the unit ball in $\mathbb{R}^n$, and $\lambda_{K,\Omega,j}$, $j\in\mathbb{N}$, are the non-zero eigenvalues of $H_{K,\Omega}$, listed in increasing order according to their multiplicities. We prove this formula by showing that the perturbed Krein Laplacian (i.e., the Krein--von Neumann extension of $-\Delta+V$ defined on $C^\infty_0(\Omega)$) is spectrally equivalent to the buckling of a clamped plate problem, and using an abstract result of Kozlov from the mid 1980's. Our work builds on that of Grubb in the early 1980's, who has considered similar issues for elliptic operators in smooth domains, and shows that the question posed by Alonso and Simon in 1980 pertaining to the validity of the above Weyl asymptotic formula continues to have an affirmative answer in this nonsmooth setting.Comment: 60 page

Ancillary Therapy and Supportive Care of Chronic Graft-versus-Host Disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. Ancillary Therapy and Supportive Care Working Group Report

AbstractThe Ancillary Therapy and Supportive Care Working Group had 3 goals: (1) to establish guidelines for ancillary therapy and supportive care in chronic graft-versus-host disease (GVHD), including treatment for symptoms and recommendations for patient education, preventive measures, and appropriate follow-up; (2) to provide guidelines for the prevention and management of infections and other common complications of treatment for chronic GVHD; and (3) to highlight the areas with the greatest need for clinical research. The definition of “ancillary therapy and supportive care” embraces the most frequent immunosuppressive or anti-inflammatory interventions used with topical intent and any other interventions directed at organ-specific control of symptoms or complications resulting from GVHD and its therapy. Also included in the definition are educational, preventive, and psychosocial interventions with this same objective. Recommendations are organized according to the strength and quality of evidence supporting them and cover the most commonly involved organs, including the skin, mouth, female genital tract, eyes, gastrointestinal tract, and lungs. Recommendations are provided for prevention of infections, osteoporosis, and steroid myopathy and management of neurocognitive and psychosocial adverse effects related to chronic GVHD. Optimal care of patients with chronic GVHD often requires a multidisciplinary approach

Effects of Heterogeneous and Clustered Contact Patterns on Infectious Disease Dynamics

The spread of infectious diseases fundamentally depends on the pattern of contacts between individuals. Although studies of contact networks have shown that heterogeneity in the number of contacts and the duration of contacts can have far-reaching epidemiological consequences, models often assume that contacts are chosen at random and thereby ignore the sociological, temporal and/or spatial clustering of contacts. Here we investigate the simultaneous effects of heterogeneous and clustered contact patterns on epidemic dynamics. To model population structure, we generalize the configuration model which has a tunable degree distribution (number of contacts per node) and level of clustering (number of three cliques). To model epidemic dynamics for this class of random graph, we derive a tractable, low-dimensional system of ordinary differential equations that accounts for the effects of network structure on the course of the epidemic. We find that the interaction between clustering and the degree distribution is complex. Clustering always slows an epidemic, but simultaneously increasing clustering and the variance of the degree distribution can increase final epidemic size. We also show that bond percolation-based approximations can be highly biased if one incorrectly assumes that infectious periods are homogeneous, and the magnitude of this bias increases with the amount of clustering in the network. We apply this approach to model the high clustering of contacts within households, using contact parameters estimated from survey data of social interactions, and we identify conditions under which network models that do not account for household structure will be biased

The Effect of a DNA Repair Gene on Cellular Invasiveness: Xrcc3 Over-Expression in Breast Cancer Cells

Over-expression of DNA repair genes has been associated with resistance to radiation and DNA-damage induced by chemotherapeutic agents such as cisplatin. More recently, based on the analysis of genome expression profiling, it was proposed that over-expression of DNA repair genes enhances the invasive behaviour of tumour cells. In this study we present experimental evidence utilizing functional assays to test this hypothesis. We assessed the effect of the DNA repair proteins known as X-ray complementing protein 3 (XRCC3) and RAD51, to the invasive behavior of the MCF-7 luminal epithelial-like and BT20 basal-like triple negative human breast cancer cell lines. We report that stable or transient over-expression of XRCC3 but not RAD51 increased invasiveness in both cell lines in vitro. Moreover, XRCC3 over-expressing MCF-7 cells also showed a higher tumorigenesis in vivo and this phenotype was associated with increased activity of the metalloproteinase MMP-9 and the expression of known modulators of cell-cell adhesion and metastasis such as CD44, ID-1, DDR1 and TFF1. Our results suggest that in addition to its' role in facilitating repair of DNA damage, XRCC3 affects invasiveness of breast cancer cell lines and the expression of genes associated with cell adhesion and invasion

Inconvenient glow: Cliometrics and the "golden age" of capitalism

This paper aims to criticize the recent cliometrics literature on the so-called "golden age" of capitalism. The works of Nicholas Crafts, Gianni Toniolo, and Barry Eichengreen are reconstructed in order to reveal the main characteristics of this research program. Its narrow quantitative focus, its reliance on theoretical propositions borrowed from neoclassical economics, and its auspicious interpretation of the postwar reconstruction are the main focus of the criticism presented. Finally, the cliometricians' attempt to historicize the "golden age" and de-historicize the following decades is related to the ideological understanding of the recent decades as a period of "great moderation."