Books Model Behaviors Rosenberg, Mara; Thompson, Erica
American Libraries,
06/2023, Letnik:
54, Številka:
6
Trade Publication Article
Citywide and institution-wide book clubs have long been used to unify communities around literacy. In 2016, staffers at St. Patrick's Episcopal Day School in Washington DC, wondered if a ...book-of-the-month program would do the same for their K-5 division. Could a one-book initiative engage students and enrich their program? They envisioned a club where students, teachers, and caregivers could share a common experience around literature. But it was also important that book selections modeled positive behaviors that align with their school values and fostered conversations around social-emotional learning and equity, diversity, inclusion, and social justice (EDISJ). To bring their community together, they turned to picture books. Picture books are highly effective as schoolwide titles; they are short enough for readers to get through a new title each month but still cover a range of topics written at different levels. The books are read aloud in homerooms and advisories, and many are shared again during chapel services.
Abstract
Comprehensive analysis of cancer genomes in clinical settings holds the promise to inform prognoses and guide the deployment of precise cancer treatments. A major barrier, however, is the ...inaccessibility of adequate metastatic tissue for accurate genomic analysis. The recognition that circulating tumor cells (CTCs) are present in many advanced cancer patients suggests an exciting opportunity to overcome this challenge. For instance, if CTCs could be comprehensively sequenced, it would be possible to obtain an orthogonal sample of the tumor burden_including subsets of transiting cells bound for metastatic colonization_potentially yielding new insights to complement the static sampling of resected or biopsied lesions.
We report an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. We isolated CTCs by magnetic bead purification (Illumina MagSweeper) from the blood of patients with prostate cancer, and integrated a nanowell platform to automatically image and recover candidate single CTCs. We then developed a strategy to qualify individual CTC-derived libraries for DNA sequencing after whole genome amplification, and established an analytical framework for accurate calling of mutations using census-based sequencing and MuTect. Whole exome sequencing was performed on 20 single CTCs, obtained from a patient with advanced prostate cancer. We validated our sequencing process by comparing CTC-derived mutations to mutations found in a lymph node metastasis and nine separate cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in the metastasis or the primary tumor. Moreover, we identified 9 early trunk mutations and 56 metastatic trunk mutations in the non-CTC tumor samples and found 100% and 73% of these, respectively, in CTC exomes. Our work demonstrates the feasibility of CTC sequencing and the ability to confidently call somatic mutations. CTCs may therefore represent a non-invasive window into the mutational landscape of metastatic cancer, and may have utility for genomics in clinical practice.
Citation Format: Viktor A. Adalsteinsson, Jens G. Lohr, Kristian Cibulskis, Atish D. Choudhury, Mara Rosenberg, Peter Cruz-Gordillo, Joshua Francis, ChengZhong Zhang, Alexander K. Shalek, Rahul Satija, John T. Trombetta, Diana Lu, Naren Tallapragada, Narmin T. Tahirova, Sora Kim, Brendan Blumenstiel, Carrie Sougnez, Daniel Auclair, Eliezer M. Van Allen, Mari Nakabayashi, Rosina T. Lis, Gwo-Shu M. Lee, Tiantian Li, Matthew S. Chabot, Mary-Ellen Taplin, Thomas E. Clancy, Massimo Loda, Aviv Regev, Matthew Meyerson, William C. Hahn, Philip W. Kantoff, Todd R. Golub, Gad Getz, Jesse S. Boehm, J Christopher Love. Whole exome sequencing of CTCs as a window into metastatic cancer. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 993. doi:10.1158/1538-7445.AM2014-993
Translating whole exome sequencing (WES) for prospective clinical use may impact the care of cancer patients; however, multiple innovations are necessary for clinical implementation. These include: ...(1) rapid and robust WES from formalin-fixed paraffin embedded (FFPE) tumor tissue, (2) analytical output similar to data from frozen samples, and (3) clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival FFPE tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a “long tail” of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15/16 patients. In one patient, previously undetected findings guided clinical trial enrollment leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine.
A 70-mer-oligonucleotide-based microarray (1152 features) that emphasizes stress and immune responses factors was constructed to study transcriptomic responses of the snail
Biomphalaria glabrata to ...different immune challenges. In addition to sequences with relevant putative ID and Gene Ontology (GO) annotation, the array features non-immune factors and unknown
B. glabrata ESTs for functional gene discovery. The transcription profiles of
B. glabrata (3 biological replicates, each a pool of 5 snails) were recorded at 12
h post-wounding, exposure to Gram negative or Gram positive bacteria (
Escherichia coli and
Micrococcus luteus, respectively), or infection with compatible trematode parasites (
Schistosoma mansoni or
Echinostoma paraensei, 20 miracidia/snail), relative to controls, using universal reference RNA. The data were subjected to Significance Analysis for Microarrays (SAM), with a false positive rate (FPR) ≤10%. Wounding yielded a modest differential expression profile (27 up/21 down) with affected features mostly dissimilar from other treatments. Partially overlapping, yet distinct expression profiles were recorded from snails challenged with
E. coli (83 up/20 down) or
M. luteus (120 up/42 down), mostly showing up-regulation of defense and stress-related features. Significantly altered expression of selected immune features indicates that
B. glabrata detects and responds differently to compatible trematodes.
Echinostoma paraensei infection was associated mostly with down-regulation of many (immune-) transcripts (42 up/68 down), whereas
S. mansoni exposure yielded a preponderance of up-regulated features (140 up/23 down), with only few known immune genes affected. These observations may reflect the divergent strategies developed by trematodes during their evolution as specialized pathogens of snails to negate host defense responses. Clearly, the immune defenses of
B. glabrata distinguish and respond differently to various immune challenges.
Objective
Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)–positive ...arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF‐positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.
Methods
Patients with RF‐positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single‐nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF‐positive polyarticular JIA.
Results
As expected, the HLA region was strongly associated with RF‐positive polyarticular JIA (P = 5.51 × 10−31). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF‐negative polyarticular JIA risk loci were associated with RF‐positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF‐positive polyarticular JIA (area under the curve AUC 0.71) better than did the oligoarticular/RF‐negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF‐positive polyarticular JIA was more similar to that of RA patients with age at onset 16–29 years than to that of RA patients with age at onset ≥70 years.
Conclusion
RF‐positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood‐onset presentation of autoantibody‐positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
Older patients with ESRD who receive a kidney transplant (KT) may develop post-KT dementia and Alzheimer's disease (AD) associated with their long-standing kidney disease and/or neurotoxic ...immunosuppressant agents. To investigate this possibility, we studied 40,918 older (aged ≥55 years) KT recipients (January 1, 1999 to December 31, 2011) linked to Medicare claims through the US Renal Data System. We estimated dementia and AD risk (cumulative incidence) and studied factors associated with these sequelae using competing risks models. We estimated the risk of death-censored graft loss and mortality after developing dementia or the AD subtype of dementia, separately, using adjusted Cox proportional hazards models. Older recipients had a 10-year dementia risk ranging from 5.1% for recipients aged 55-60 years to 17.0% for recipients aged ≥75 years; 10-year AD risk ranged from 1.0% to 6.7%, respectively. The strongest predictors for dementia and AD were older recipient age and pretransplant diabetes. The 10-year graft loss risk was 28.8% for those who did not develop dementia and 43.1% for those who did, and the corresponding mortality risks were 55.7% and 89.9%, respectively. Older recipients with dementia had a 1.52-fold (95% confidence interval, 1.39 to 1.68) increased risk of graft loss and a 2.38-fold (95% confidence interval, 2.26 to 2.49) increased risk of mortality. We observed similar results for AD. We conclude that older KT recipients have a high risk of post-KT dementia and AD, and these sequelae associate with a profound effect on patient and graft survival.
Homologous recombination repairs DNA double-strand breaks and must function even on actively transcribed DNA. Because break repair prevents chromosome loss, the completion of repair is expected to ...outweigh the transcription of broken templates. However, the interplay between DNA break repair and transcription processivity is unclear. Here we show that the transcription factor GreA inhibits break repair in Escherichia coli. GreA restarts backtracked RNA polymerase and hence promotes transcription fidelity. We report that removal of GreA results in markedly enhanced break repair via the classic RecBCD-RecA pathway. Using a deep-sequencing method to measure chromosomal exonucleolytic degradation, we demonstrate that the absence of GreA limits RecBCD-mediated resection. Our findings suggest that increased RNA polymerase backtracking promotes break repair by instigating RecA loading by RecBCD, without the influence of canonical Chi signals. The idea that backtracked RNA polymerase can stimulate recombination presents a DNA transaction conundrum: a transcription fidelity factor that compromises genomic integrity.
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