TCR repertoire divergence reflects micro-environmental immune phenotypes in glioma

Background & significance: Glioblastoma (GBM) remains prognostically dismal, with only modest gains in mean survival time with chemo- and radiotherapy motivating research into reversing its characteristic local and systemic immunosuppression with precision in this high-risk tissue. While whole-repertoire amplification of the TCR repertoire allows unprecedented depth regarding the potentiation of anti-tumor responses, most studies utilize TCRseq for monitoring reactivity to specific tumor antigens, or the identities of particular TCRs as biomarkers. In this study, we have utilized whole-repertoire analysis to describe the relationship between intra-tumoral T cells and peripheral circulation, and leverage mutual information between gene expression and the behavior of the T cell population to characterize glioma-reactive states, driven by the gene expression of the principal resident monocyte population, and perturbable by immunological interventions. Methods & results: From resected tumor tissue and peripheral lymphocytes of low- and high-grade human glioma patients, TCRseq libraries were generated using reverse transcription and nested PCR (iRepertoire 1) of the complementarity-determining region 3 (CDR3) of the TCR-alpha and TCR-beta chains, then sequenced on an Illumina MiSeq. We developed a computational pipeline for mapping TCR cassettes, in silico translation, and sequence error correction from these libraries, enabling sensitive calculation of tumor-infiltrating lymphocyte (TIL) and peripheral TCR diversity (Shannon entropy) 2, as well as the divergence (Jensen-Shannon divergence metric) between the two T cell populations. By integrating amino acid identity and V-J cassette combination, we observed varying levels of divergence between the TIL and peripheral lymphocytes of glioma patients, and changes in this divergence over tumor progression in a PDGF-driven murine model. Correlation of these properties with tumor tissue RNA profiling, by differential gene expression and mutual-information gene ontology, revealed an association between tumor growth and high blood-brain TCR divergence - particularly in amino-acid sequence, suggesting antigen-driven selection - while high expression of inflammatory and certain immune pathway markers computationally attributed to microglia 3 were anti-correlated with divergence. Preliminary murine experiments suggest that TCR divergence can be altered by induction and blockade of cytokine-mediated activation of these pathways. Conclusion: The expression of a subset of microglia-associated genes appears to describe micro-environmental states which are strongly tied to the tumor-specificity of the intra-tumoral TCR repertoire, complementary to the tumor-centric classifications of TCGA. TCRseq-based profiling not only promises to inform tailoring of local and systemic immunotherapy to target the most relevant immunosuppressive mechanisms, but may also provide non-invasive assessment of the intra-tumoral environment for refined diagnosis and monitoring during clinical trials

Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Incorporating progesterone receptor expression into the PREDICT breast prognostic model.

Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10 ) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. [Abstract copyright: Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies