Leonardo Tozzi, Xue Zhang, Adam Pines, Alisa M Olmsted, Emily S Zhai, Esther T Anene, Megan Chesnut, Bailey Holt-Gosselin, Sarah Chang, Patrick C Stetz, Carolina A Ramirez, Laura M Hack, Mayuresh S Korgaonkar, Max Wintermark, Ian H Gotlib, Jun Ma, Leanne M Williams <<<

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry. <<<

Biological aging of human organ systems reflects the interplay of age, chronic disease, lifestyle and genetic risk. Using longitudinal brain imaging and physiological phenotypes from the UK Biobank, we establish normative models of biological age for three brain and seven body systems. Here we find that an organ's biological age selectively influences the aging of other organ systems, revealing a multiorgan aging network. We report organ age profiles for 16 chronic diseases, where advanced biological aging extends from the organ of primary disease to multiple systems. Advanced body age associates with several lifestyle and environmental factors, leukocyte telomere lengths and mortality risk, and predicts survival time (area under the curve of 0.77) and premature death (area under the curve of 0.86). Our work reveals the multisystem nature of human aging in health and chronic disease. It may enable early identification of individuals at increased risk of aging-related morbidity and inform new strategies to potentially limit organ-specific aging in such individuals. <<<

Yanshuo Chu, Enyu Dai, Yating Li, Guangchun Han, Guangsheng Pei, Davis R Ingram, Krupa Thakkar, Jiang-Jiang Qin, Minghao Dang, Xiuning Le, Can Hu, Qing Deng, Ansam Sinjab, Pravesh Gupta, Ruiping Wang, Dapeng Hao, Fuduan Peng, Xinmiao Yan, Yunhe Liu, Shumei Song, Shaojun Zhang, John V Heymach, Alexandre Reuben, Yasir Y Elamin, Melissa P Pizzi, Yang Lu, Rossana Lazcano, Jian Hu, Mingyao Li, Michael Curran, Andrew Futreal, Anirban Maitra, Amir A Jazaeri, Jaffer A Ajani, Charles Swanton, Xiang-Dong Cheng, Hussein A Abbas, Maura Gillison, Krishna Bhat, Alexander J Lazar, Michael Green, Kevin Litchfield, Humam Kadara, Cassian Yee, Linghua Wang <<<

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, T, characterized by heat shock gene expression. T cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8 cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of T cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery. <<<

Bin Fu, Jiaoyang Liao, Shuanghong Chen, Wei Li, Qiudao Wang, Jian Hu, Fei Yang, Shenlin Hsiao, Yanhong Jiang, Liren Wang, Fangping Chen, Yuanjin Zhang, Xin Wang, Dali Li, Mingyao Liu, Yuxuan Wu <<<

Gene editing to disrupt the GATA1-binding site at the +58 BCL11A erythroid enhancer could induce γ-globin expression, which is a promising therapeutic strategy to alleviate β-hemoglobinopathy caused by HBB gene mutation. In the present study, we report the preliminary results of an ongoing phase 1/2 trial (NCT04211480) evaluating safety and efficacy of gene editing therapy in children with blood transfusion-dependent β-thalassemia (TDT). We transplanted BCL11A enhancer-edited, autologous, hematopoietic stem and progenitor cells into two children, one carrying the β/β genotype, classified as the most severe type of TDT. Primary endpoints included engraftment, overall survival and incidence of adverse events (AEs). Both patients were clinically well with multilineage engraftment, and all AEs to date were considered unrelated to gene editing and resolved after treatment. Secondary endpoints included achieving transfusion independence, editing rate in bone marrow cells and change in hemoglobin (Hb) concentration. Both patients achieved transfusion independence for >18 months after treatment, and their Hb increased from 8.2 and 10.8 g dl at screening to 15.0 and 14.0 g dl at the last visit, respectively, with 85.46% and 89.48% editing persistence in bone marrow cells. Exploratory analysis of single-cell transcriptome and indel patterns in edited peripheral blood mononuclear cells showed no notable side effects of the therapy. <<<

Marion Thibaudin, Jean-David Fumet, Benoist Chibaudel, Jaafar Bennouna, Christophe Borg, Jerome Martin-Babau, Romain Cohen, Marianne Fonck, Julien Taieb, Emeric Limagne, Julie Blanc, Elise Ballot, Léa Hampe, Marjorie Bon, Susy Daumoine, Morgane Peroz, Hugo Mananet, Valentin Derangère, Romain Boidot, Henri-Alexandre Michaud, Caroline Laheurte, Olivier Adotevi, Aurélie Bertaut, Caroline Truntzer, François Ghiringhelli <<<

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 . <<<

Aniruddh P Patel, Minxian Wang, Yunfeng Ruan, Satoshi Koyama, Shoa L Clarke, Xiong Yang, Catherine Tcheandjieu, Saaket Agrawal, Akl C Fahed, Patrick T Ellinor, Genes & Health Research Team; the Million Veteran Program, Philip S Tsao, Yan V Sun, Kelly Cho, Peter W F Wilson, Themistocles L Assimes, David A van Heel, Adam S Butterworth, Krishna G Aragam, Pradeep Natarajan, Amit V Khera <<<

Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPS, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPS strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPS was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPS demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPS for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction. <<<

Chao Xie, Shitong Xiang, Chun Shen, Xuerui Peng, Jujiao Kang, Yuzhu Li, Wei Cheng, Shiqi He, Marina Bobou, M John Broulidakis, Betteke Maria van Noort, Zuo Zhang, Lauren Robinson, Nilakshi Vaidya, Jeanne Winterer, Yuning Zhang, Sinead King, Tobias Banaschewski, Gareth J Barker, Arun L W Bokde, Uli Bromberg, Christian Büchel, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Hervé Lemaître, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H Fröhner, Ulrike Schmidt, Julia Sinclair, Michael N Smolka, Argyris Stringaris, Henrik Walter, Robert Whelan, Sylvane Desrivières, Barbara J Sahakian, Trevor W Robbins, Gunter Schumann, Tianye Jia, Jianfeng Feng, IMAGEN Consortium, STRATIFY/ESTRA Consortium, ZIB Consortium <<<

Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the Stratify Project). In conclusion, we identify a reproducible and general neural basis underlying symptoms of multiple mental health disorders, bridging multidimensional evidence from behavioral, neuroimaging and genetic substrates. These findings may help to develop new therapeutic interventions for psychiatric comorbidities. <<<

Jessica Roelands, Peter J K Kuppen, Eiman I Ahmed, Raghvendra Mall, Tariq Masoodi, Parul Singh, Gianni Monaco, Christophe Raynaud, Noel F C C de Miranda, Luigi Ferraro, Tatiana C Carneiro-Lobo, Najeeb Syed, Arun Rawat, Amany Awad, Julie Decock, William Mifsud, Lance D Miller, Shimaa Sherif, Mahmoud G Mohamed, Darawan Rinchai, Marc Van den Eynde, Rosalyn W Sayaman, Elad Ziv, Francois Bertucci, Mahir Abdulla Petkar, Stephan Lorenz, Lisa Sara Mathew, Kun Wang, Selvasankar Murugesan, Damien Chaussabel, Alexander L Vahrmeijer, Ena Wang, Anna Ceccarelli, Khalid A Fakhro, Gabriele Zoppoli, Alberto Ballestrero, Rob A E M Tollenaar, Francesco M Marincola, Jérôme Galon, Souhaila Al Khodor, Michele Ceccarelli, Wouter Hendrickx, Davide Bedognetti <<<

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches. <<<

Federico Comitani, Joshua O Nash, Sarah Cohen-Gogo, Astra I Chang, Timmy T Wen, Anant Maheshwari, Bipasha Goyal, Earvin S Tio, Kevin Tabatabaei, Chelsea Mayoh, Regis Zhao, Ben Ho, Ledia Brunga, John E G Lawrence, Petra Balogh, Adrienne M Flanagan, Sarah Teichmann, Annie Huang, Vijay Ramaswamy, Johann Hitzler, Jonathan D Wasserman, Rebecca A Gladdy, Brendan C Dickson, Uri Tabori, Mark J Cowley, Sam Behjati, David Malkin, Anita Villani, Meredith S Irwin, Adam Shlien <<<

The causes of pediatric cancers' distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types. <<<

Zongli Zheng, Matthew Liebers, Boryana Zhelyazkova, Yi Cao, Divya Panditi, Kerry D Lynch, Juxiang Chen, Hayley E Robinson, Hyo Sup Shim, Juliann Chmielecki, William Pao, Jeffrey A Engelman, A John Iafrate, Long Phi Le <<<

We describe a rapid target enrichment method for next-generation sequencing, termed anchored multiplex PCR (AMP), that is compatible with low nucleic acid input from formalin-fixed paraffin-embedded (FFPE) specimens. AMP is effective in detecting gene rearrangements (without prior knowledge of the fusion partners), single nucleotide variants, insertions, deletions and copy number changes. Validation of a gene rearrangement panel using 319 FFPE samples showed 100% sensitivity (95% confidence limit: 96.5-100%) and 100% specificity (95% confidence limit: 99.3-100%) compared with reference assays. On the basis of our experience with performing AMP on 986 clinical FFPE samples, we show its potential as both a robust clinical assay and a powerful discovery tool, which we used to identify new therapeutically important gene fusions: ARHGEF2-NTRK1 and CHTOP-NTRK1 in glioblastoma, MSN-ROS1, TRIM4-BRAF, VAMP2-NRG1, TPM3-NTRK1 and RUFY2-RET in lung cancer, FGFR2-CREB5 in cholangiocarcinoma and PPL-NTRK1 in thyroid carcinoma. AMP is a scalable and efficient next-generation sequencing target enrichment method for research and clinical applications. <<<

Single-cell atlases promise to provide a 'missing link' between genes, diseases and therapies. By identifying the specific cell types, states, programs and contexts where disease-implicated genes act, we will understand the mechanisms of disease at the cellular and tissue levels and can use this understanding to develop powerful disease diagnostics; identify promising new drug targets; predict their efficacy, toxicity and resistance mechanisms; and empower new kinds of therapies, from cancer therapies to regenerative medicine. Here, we lay out a vision for the potential of cell atlases to impact the future of medicine, and describe how advances over the past decade have begun to realize this potential in common complex diseases, infectious diseases (including COVID-19), rare diseases and cancer. <<<

Nazli Dizman, Luis Meza, Paulo Bergerot, Marice Alcantara, Tanya Dorff, Yung Lyou, Paul Frankel, Yujie Cui, Valerie Mira, Marian Llamas, Joann Hsu, Zeynep Zengin, Nicholas Salgia, Sabrina Salgia, Jasnoor Malhotra, Neal Chawla, Alex Chehrazi-Raffle, Ramya Muddasani, John Gillece, Lauren Reining, Jeff Trent, Motomichi Takahashi, Kentaro Oka, Seiya Higashi, Marcin Kortylewski, Sarah K Highlander, Sumanta K Pal <<<

Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab-ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab-ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05-0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab-ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments. <<<

Oliver Lester Saldanha, Philip Quirke, Nicholas P West, Jacqueline A James, Maurice B Loughrey, Heike I Grabsch, Manuel Salto-Tellez, Elizabeth Alwers, Didem Cifci, Narmin Ghaffari Laleh, Tobias Seibel, Richard Gray, Gordon G A Hutchins, Hermann Brenner, Marko van Treeck, Tanwei Yuan, Titus J Brinker, Jenny Chang-Claude, Firas Khader, Andreas Schuppert, Tom Luedde, Christian Trautwein, Hannah Sophie Muti, Sebastian Foersch, Michael Hoffmeister, Daniel Truhn, Jakob Nikolas Kather <<<

Artificial intelligence (AI) can predict the presence of molecular alterations directly from routine histopathology slides. However, training robust AI systems requires large datasets for which data collection faces practical, ethical and legal obstacles. These obstacles could be overcome with swarm learning (SL), in which partners jointly train AI models while avoiding data transfer and monopolistic data governance. Here, we demonstrate the successful use of SL in large, multicentric datasets of gigapixel histopathology images from over 5,000 patients. We show that AI models trained using SL can predict BRAF mutational status and microsatellite instability directly from hematoxylin and eosin (H&E)-stained pathology slides of colorectal cancer. We trained AI models on three patient cohorts from Northern Ireland, Germany and the United States, and validated the prediction performance in two independent datasets from the United Kingdom. Our data show that SL-trained AI models outperform most locally trained models, and perform on par with models that are trained on the merged datasets. In addition, we show that SL-based AI models are data efficient. In the future, SL can be used to train distributed AI models for any histopathology image analysis task, eliminating the need for data transfer. <<<