Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with ...germline mismatch repair (MMR) gene mutations.
Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).
Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered.
Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.
Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven ...mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4 of 15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. Mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93 vs 73%; P=0.028). A strong trend was observed for high-grade dysplasia. Mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low-grade dysplasia (100 vs 76%; P=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.
The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families.
This ...observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing.
Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor-negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups.
MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking.
Reply to J. Moline et al Buchanan, Daniel D; Tan, Yen Y; Walsh, Michael D ...
Journal of clinical oncology,
2014-Jul-20, 2014-07-20, 20140720, Letnik:
32, Številka:
21
Journal Article
Reinforcement learning (RL) has proven its worth in a series of artificial domains, and is beginning to show some successes in real-world scenarios. However, much of the research advances in RL are ...hard to leverage in real-world systems due to a series of assumptions that are rarely satisfied in practice. In this work, we identify and formalize a series of independent challenges that embody the difficulties that must be addressed for RL to be commonly deployed in real-world systems. For each challenge, we define it formally in the context of a Markov Decision Process, analyze the effects of the challenge on state-of-the-art learning algorithms, and present some existing attempts at tackling it. We believe that an approach that addresses our set of proposed challenges would be readily deployable in a large number of real world problems. Our proposed challenges are implemented in a suite of continuous control environments called realworldrl-suite which we propose an as an open-source benchmark.
Abstract
In this article, we consider a class of unfitted finite element methods for scalar elliptic problems. These so‐called CutFEM methods use standard finite element spaces on a fixed unfitted ...triangulation combined with the Nitsche technique and a ghost penalty stabilization. As a model problem we consider the application of such a method to the Poisson interface problem. We introduce and analyze a new class of preconditioners that is based on a subspace decomposition approach. The unfitted finite element space is split into two subspaces, where one subspace is the standard finite element space associated to the background mesh and the second subspace is spanned by all cut basis functions corresponding to nodes on the cut elements. We will show that this splitting is stable, uniformly in the discretization parameter and in the location of the interface in the triangulation. Based on this we introduce an efficient preconditioner that is uniformly spectrally equivalent to the stiffness matrix. Using a similar splitting, it is shown that the same preconditioning approach can also be applied to a fictitious domain CutFEM discretization of the Poisson equation. Results of numerical experiments are included that illustrate optimality of such preconditioners for the Poisson interface problem and the Poisson fictitious domain problem.
We analyze the magnetic field perturbations observed near Jupiter's icy moon Europa by the Galileo spacecraft during the E26 flyby on 3 January 2000. In addition to the expected large‐scale ...signatures of magnetic fieldline draping and induction, the E26 data set contains various prominent structures on length scales much smaller than the moon's radius. By applying a hybrid (kinetic ions and fluid electrons) model of Europa's interaction with the impinging magnetospheric plasma, we demonstrate that these fine structures in the magnetic field are consistent with Galileo's passage through a water vapor plume whose source was located in Europa's orbital trailing, southern hemisphere. Considering the large‐scale asymmetries of Europa's global atmosphere alone is not sufficient to explain the observed magnetic signatures. Combined with the recent identification of a plume during the earlier E12 flyby of Galileo, our results provide strong evidence that plume activity at Europa was a persistent phenomenon during the Galileo era.
Plain Language Summary
Observations by the Hubble Space Telescope have revealed the presence of water vapor plumes at Jupiter's icy moon Europa. However, in contrast to the Enceladus plume, the occurrence of plumes at Europa seems to be a transient phenomenon. The mechanism governing the times and locations of these emissions is still unknown. In addition to telescope observations, magnetic field data collected near Europa can be applied as a tool to search for plumes. Since Europa is located within Jupiter's magnetosphere, the moon is continuously exposed to a flow of magnetized plasma with a relative velocity around 100 km/s. The interaction of this plasma with a plume at Europa will locally deflect the magnetospheric flow, thereby generating characteristic deformations of Jupiter's magnetic field. We have revisited magnetic field observations acquired by the Galileo spacecraft during its E26 flyby of Europa on 3 January 2000. By using a plasma simulation model, we demonstrate that the magnetic perturbations observed near Europa are indicative of a water vapor plume in the moon's trailing hemisphere. The source of this plume was located near the Butterdon Linea at Europa's surface. This finding is highly relevant for the planning of synergistic measurements during the upcoming Europa Clipper mission.
Key Points
Magnetic perturbations seen during Europa flyby E26 consistent with Galileo's passage through a plume in the southern trailing hemisphere
Interaction of the magnetospheric plasma with Europa's global exosphere alone is not sufficient to explain the observed magnetic field
Combined with the detection of a plume during the earlier E12 flyby, this result suggests persistent plume activity during the Galileo era
We consider a standard model for incompressible two-phase flows in which a localized force at the interface describes the effect of surface tension. If a level set (or VOF) method is applied then the ...interface, which is implicitly given by the zero level of the level set function, is in general not aligned with the triangulation that is used in the discretization of the flow problem. This non-alignment causes severe difficulties w.r.t. the discretization of the localized surface tension force and the discretization of the flow variables. In cases with large surface tension forces the pressure has a large jump across the interface. In standard finite element spaces, due to the non-alignment, the functions are continuous across the interface and thus not appropriate for the approximation of the discontinuous pressure. In many simulations these effects cause large oscillations of the velocity close to the interface, so-called spurious velocities. In this paper, for a simplified model problem, we give an analysis that explains why known (standard) methods for discretization of the localized force term and for discretization of the pressure variable often yield large spurious velocities. In the paper S. Groß, A. Reusken, Finite element discretization error analysis of a surface tension force in two-phase incompressible flows, Preprint 262, IGPM, RWTH Aachen, SIAM J. Numer. Anal. (accepted for publication), we introduce a new and accurate method for approximation of the surface tension force. In the present paper, we use the extended finite element space (XFEM), presented in N. Moes, J. Dolbow, T. Belytschko, A finite element method for crack growth without remeshing, Int. J. Numer. Meth. Eng. 46 (1999) 131–150; T. Belytschko, N. Moes, S. Usui, C. Parimi, Arbitrary discontinuities in finite elements, Int. J. Numer. Meth. Eng. 50 (2001) 993–1013, for the discretization of the pressure. We show that the size of spurious velocities is reduced substantially, provided we use both the new treatment of the surface tension force and the extended pressure finite element space.
Injury and loss of podocytes are leading factors of glomerular disease and renal failure. The postmitotic podocyte is the primary glomerular target for toxic, immune, metabolic, and oxidant stress, ...but little is known about how this cell type copes with stress. Recently, autophagy has been identified as a major pathway that delivers damaged proteins and organelles to lysosomes in order to maintain cellular homeostasis. Here we report that podocytes exhibit an unusually high level of constitutive autophagy. Podocyte-specific deletion of autophagy-related 5 (Atg5) led to a glomerulopathy in aging mice that was accompanied by an accumulation of oxidized and ubiquitinated proteins, ER stress, and proteinuria. These changes resulted ultimately in podocyte loss and late-onset glomerulosclerosis. Analysis of pathophysiological conditions indicated that autophagy was substantially increased in glomeruli from mice with induced proteinuria and in glomeruli from patients with acquired proteinuric diseases. Further, mice lacking Atg5 in podocytes exhibited strongly increased susceptibility to models of glomerular disease. These findings highlight the importance of induced autophagy as a key homeostatic mechanism to maintain podocyte integrity. We postulate that constitutive and induced autophagy is a major protective mechanism against podocyte aging and glomerular injury, representing a putative target to ameliorate human glomerular disease and aging-related loss of renal function.
PDF
