<p>Supplementary Figure 2 - PDF file 71K, Construction of biopsy TMA blocks. Four millimeter length of the needle biopsy core (previously delimited by pathologist) is cut out from the original formalin fixed paraffin embedded tissue block. A scalpel blade is used to cut the exceeding wax on the opposite side of the biopsy tissue (opposite side marked in green) in order to reach a final 4 mm x 2 mm x 2 mm checker. These checkers are flipped 90 degrees (long axis of the prostate needle biopsy turns vertical) and placed within a stainless steel mold as a TMA template. The TMA block is completed by re-embedding the checkers by pouring hot wax into the mold. Last step on the right side shows an Hematoxylin and Eosin (H-E)-stained section from a biopsy TMA block (low power)</p>
Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.
<p>Supplementary Figure 2 - PDF file 71K, Construction of biopsy TMA blocks. Four millimeter length of the needle biopsy core (previously delimited by pathologist) is cut out from the original formalin fixed paraffin embedded tissue block. A scalpel blade is used to cut the exceeding wax on the opposite side of the biopsy tissue (opposite side marked in green) in order to reach a final 4 mm x 2 mm x 2 mm checker. These checkers are flipped 90 degrees (long axis of the prostate needle biopsy turns vertical) and placed within a stainless steel mold as a TMA template. The TMA block is completed by re-embedding the checkers by pouring hot wax into the mold. Last step on the right side shows an Hematoxylin and Eosin (H-E)-stained section from a biopsy TMA block (low power)</p>
49 Background: The Cohesin complex plays a critical role in mitotic progression and post-replicative DNA damage repair. It serves to bring together sister chromatids both in metaphase and in homologous recombination repair following ionizing radiation. The complex has also been shown to be phosphorylated in the ATM/BRCA1 pathway. The expression of various proteins in the complex are dysregulated in many cancers: breast, prostate, etc. Interestingly, in breast cancer cell lines, Cohesin is required for MYC activation in response to estrogen. Our study sought to correlate copy number alterations in this pivotal complex with biochemical relapse in prostate cancer patients. Methods: Our cohort consists of 284 patients with D’ Amico-classified intermediate-risk prostate cancer, treated with image-guided radiotherapy (IGRT, N = 143) or radical prostatectomy (RadP, N = 141). Pre-treatment biopsies and prostatectomy samples were analyzed using the Affymetrix Oncoscan array. The Phoenix and AUA criteria was used to define biochemical relapse for RadP and IGRT patients respectively. Results: Copy number alterations of RAD21, SMC1B, and STAG1 were observed in 18% (n = 52), 6.3% (n = 18), and 12% (n = 35) of the cohort respectively. They were predominantly losses in SMC1B, but gains in RAD21 and STAG1. All three genes in the Cohesin complex were associated with increased risk of biochemical relapse: RAD21 on chromosome 8 (HR = 1.93, 95% CI 1.23, 3.02, Wald’s p = 0.004), SMC1B on chromosome 22 (HR = 3.37, 95% CI 1.91, 5.94, Wald’s p < 10 -4 ), and STAG1 on chromosome 3 (HR = 1.74, 95% CI 1.04, 2.89, Wald’s p < 0.05). However, when controlled for percent genome alteration and pre-treatment serum PSA levels, only copy number loss of SMC1B was a significant predictor of biochemical relapse (HR = 2.95, 95% CI 1.62, 5.38, Wald’s p < 10 -3 ). Conclusions: We identified a novel association of copy-number alterations in members of the Cohesin complex with biochemical recurrence following radical prostatectomy or image-guided radiotherapy. This points to the central role of Cohesin in cell-cycle and DNA damage pathways promoting prostate cancer progression.
Powerful, recent advances in technologies to analyze the genome have had a profound impact on the practice of medical genetics, both in the laboratory and in the clinic. Increasing utilization of genome-wide testing such as chromosomal microarray analysis and exome sequencing have lead a shift toward a "genotype-first" approach. Numerous techniques are now available to diagnose a particular syndrome or phenotype, and while traditional techniques remain efficient tools in certain situations, higher-throughput technologies have become the de facto laboratory tool for diagnosis of most conditions. However, selecting the right assay or technology is challenging, and the wrong choice may lead to prolonged time to diagnosis, or even a missed diagnosis. In this review, we will discuss current core technologies for the diagnosis of classic genetic disorders to shed light on the benefits and disadvantages of these strategies, including diagnostic efficiency, variant interpretation, and secondary findings. Finally, we review upcoming technologies posed to impart further changes in the field of genetic diagnostics as we move toward "genome-first" practice.
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