157 research outputs found
Initial lists of AMMA-2050 user-relevant climate metrics
AMMA-2050 (African Monsoon Multi-disciplinary Analysis 2050) will improve understanding of how the West African monsoon will be affected by climate change in the coming decades – and help West African societies prepare and adapt
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Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.
Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer
Identification and Characterization of Optimal Gene Expression Markers for Detection of Breast Cancer Metastasis
Sentinel lymph node (SLN) status is highly predictive of
overall axillary lymph node involvement in breast cancer.
Historically, SLN-positive patients have undergone
axillary lymph node dissection in a second surgery.
Intraoperative SLN analysis could reduce the cost and
complications of a second surgery; however, existing
histopathological methods lack standardization and exhibit
poor sensitivity. Rapid molecular methods may
lead to improved intraoperative diagnosis of SLN metastasis.
In this study,we used a genome-wide gene expression
analysis of breast and other tissues to identify
seven putative markers for detecting breast cancer metastasis.
We assessed the utility of these markers for
identifying clinically actionable metastases in lymph
nodes through reverse transcriptase-polymerase chain
reaction analysis of SLNs from 254 breast cancer patients.
Polymerase chain reaction signals were compared
to pathology on a per-patient basis. The optimal
two-gene combination, mammaglobin and cytokeratin
19, detected clinically actionable metastasis in breast
SLNs with 90% sensitivity and 94% specificity. Application
of stringent criteria for identifying presumptive
hematoxylin- and eosin-positive samples increased sensitivity
and specificity to 91 and 97%, respectively. This
study represents the first comprehensive demonstration
of the utility of gene expression markers for detecting
clinically actionable breast metastases. An intraoperative
molecular assay using these markers has the
potential to significantly reduce second surgeries for
patients undergoing SLN dissection. Originally published Journal of Molecular Diagnostics, Vol. 7, No. 3, Aug 200
Innovation in a crisis: rethinking conferences and scholarship in a pandemic and climate emergency
It is a cliché of self-help advice that there are no problems, only opportunities. The rationale and actions of the BSHS in creating its Global Digital History of Science Festival may be a rare genuine confirmation of this mantra. The global COVID-19 pandemic of 2020 meant that the society's usual annual conference – like everyone else's – had to be cancelled. Once the society decided to go digital, we had a hundred days to organize and deliver our first online festival. In the hope that this will help, inspire and warn colleagues around the world who are also trying to move online, we here detail the considerations, conversations and thinking behind the organizing team's decisions
Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe
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