Desmoplakin (DP) is a key component of cellular adhesion junctions known as desmosomes; however, recent investigations have revealed a novel location for DP in junctions separate from desmosomes termed complexus adherens junctions. These junctions are found at contact sites between endothelial cells that line capillaries. Few studies have focused on the function of DP in de novo capillary formation (vasculogenesis) and branching (angiogenesis) during tumorigenesis, embryonic development, cardiovascular development or wound healing. Only recently have investigations begun to determine the effect the loss of DP has on capillaries during embryogenesis (i.e. in DP–/– mice). Evidence shows that the loss of desmoplakin in vivo results in leaky capillaries and/or capillary malformation. Consequently, the goal of this study was to determine the function of DP in complexus adherens junctions during capillary formation. To accomplish this goal, we used siRNA technology to knock down desmoplakin expression in endothelial cells before they were induced to form microvascular tubes on matrigel. DP siRNA treated cells sent out filopodia and came in close contact with each other when plated onto matrigel; however, in most cases they failed to form tubes as compared with control endothelial cells. Interestingly, after siRNA degradation, endothelial cells were then capable of forming microvascular tubes. In depth analyses into the function of DP in capillary formation were not previously possible because the tools and experimental approaches only recently have become available (i.e. siRNA). Consequently, fully understanding the role of desmoplakin in capillary formation may lead to a novel approach for inhibiting vasculo- and angiogenesis in tumor formation.
Genetic Counselors are increasingly becoming involved in organizing and facilitating support groups for couples who have terminated a pregnancy because of an abnormal fetal diagnosis. This paper discusses recurrent themes which have emerged in the FATE (Feelings After the Termination Experience) support group which was founded in New Jersey in 1990. By becoming familiar with the issues we have observed in our support group, genetic counselors should be better able to understand and empathize with their patients who make the decision to terminate a much wanted pregnancy. They may also feel better prepared to become involved in organizing and facilitating such support groups.
e20062 Background: The increasing incidence and poor outcome associated with MPM demand identification of effective treatment options. Promising results have been reported with immunotherapy (IO) in a small proportion of MPM patients (p). MMR deficiency (dMMR) has been well described in several malignancies and was recently approved as a tumor biomarker for IO with anti-PD-1 checkpoint inhibitor. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM p. Methods: Tumors of 159 MPM p from Vall d´Hebron University Hospital and October 12th University Hospital diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR when any MMR protein expression was negative and MMR intact when all MMR proteins were positively expressed. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: P characteristics: median age: 69 years (29-88 years), males: 71%, performance status (PS) 1:69%, asbestos exposure: 52%, stage III at diagnosis: 42%, epithelial subtype: 65%, systemic treatment 81% (57% chemotherapy with cisplatin plus pemetrexed in first line), 50% received second line and 28% third line. MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8m). In a multivariate model factors associated to improved mOS were PS 0 vs PS2 (13 v 2 m, HR 12.8, p < 0.01), neutrophil-lymphocyte ratio (NLR) < 5 (18 v 9 m in NLR ≥5,HR 1.5, p < 0.05) and epitheliod vs sarcomatoid histology (18 vs 4 m HR 4.7, p < 0.01). Thirteen p received IO with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1m). Conclusions: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate novel predictive biomarkers benefit from IO in MPM.
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