Journal: Nat Med

Sorted by: date / impact
Abstract

Colibactin DNA-damage signature indicates mutational impact in colorectal cancer.

Dziubańska-Kusibab PJ, Berger H, Battistini F, Bouwman BAM, ... Aaltonen LA, Meyer TF

The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin associated with certain strains of Escherichia coli, creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics. A survey of somatic mutations at colibactin target sites of several thousand cancer genomes revealed notable enrichment of this motif in colorectal cancers. Moreover, the exact double-strand-break loci corresponded with mutational hot spots in cancer genomes, reminiscent of a trinucleotide signature previously identified in healthy colorectal epithelial cells. The present study provides evidence for the etiological role of colibactin in human cancer.



Nat Med: 31 May 2020; epub ahead of print
Dziubańska-Kusibab PJ, Berger H, Battistini F, Bouwman BAM, ... Aaltonen LA, Meyer TF
Nat Med: 31 May 2020; epub ahead of print | PMID: 32483361
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Abstract

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

Zviran A, Schulman RC, Shah M, Hill STK, ... Altorki NK, Landau DA

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.



Nat Med: 31 May 2020; epub ahead of print
Zviran A, Schulman RC, Shah M, Hill STK, ... Altorki NK, Landau DA
Nat Med: 31 May 2020; epub ahead of print | PMID: 32483360
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Abstract

Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, ... Cahill DP, Sullivan RJ

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.



Nat Med: 31 May 2020; epub ahead of print
Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, ... Cahill DP, Sullivan RJ
Nat Med: 31 May 2020; epub ahead of print | PMID: 32483359
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Abstract

IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies.

Leborgne C, Barbon E, Alexander JM, Hanby H, ... Lacroix-Desmazes S, Mingozzi F

Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans, and block liver transduction and vector readministration; thus, they represent a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied, which often involve immunosuppression and are not efficient in removing pre-existing antibodies. Imlifidase (IdeS) is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients. Here, we studied if IdeS could eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (intravenous Ig) in vitro upon endopeptidase treatment. In mice passively immunized with intravenous Ig, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer. The approach was scaled up to nonhuman primates, a natural host for wild-type AAV. IdeS treatment before AAV vector infusion was safe and resulted in enhanced liver transduction, even in the setting of vector readministration. Finally, IdeS reduced anti-AAV antibody levels from human plasma samples in vitro, including plasma from prospective gene therapy trial participants. These results provide a potential solution to overcome pre-existing antibodies to AAV-based gene therapy.



Nat Med: 31 May 2020; epub ahead of print
Leborgne C, Barbon E, Alexander JM, Hanby H, ... Lacroix-Desmazes S, Mingozzi F
Nat Med: 31 May 2020; epub ahead of print | PMID: 32483358
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Abstract

Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.

Braun DA, Hou Y, Bakouny Z, Ficial M, ... Shukla SA, Choueiri TK

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8 T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8 T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.



Nat Med: 28 May 2020; epub ahead of print
Braun DA, Hou Y, Bakouny Z, Ficial M, ... Shukla SA, Choueiri TK
Nat Med: 28 May 2020; epub ahead of print | PMID: 32472114
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Abstract

Geospatial immune variability illuminates differential evolution of lung adenocarcinoma.

AbdulJabbar K, Raza SEA, Rosenthal R, Jamal-Hanjani M, ... Swanton C, Yuan Y

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.



Nat Med: 26 May 2020; epub ahead of print
AbdulJabbar K, Raza SEA, Rosenthal R, Jamal-Hanjani M, ... Swanton C, Yuan Y
Nat Med: 26 May 2020; epub ahead of print | PMID: 32461698
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Abstract

The effect of LRRK2 loss-of-function variants in humans.

Whiffin N, Armean IM, Kleinman A, Marshall JL, ... Cannon P, MacArthur DG

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson\'s disease, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.



Nat Med: 26 May 2020; epub ahead of print
Whiffin N, Armean IM, Kleinman A, Marshall JL, ... Cannon P, MacArthur DG
Nat Med: 26 May 2020; epub ahead of print | PMID: 32461697
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Abstract

Systemic dysfunction and plasticity of the immune macroenvironment in cancer models.

Allen BM, Hiam KJ, Burnett CE, Venida A, ... Carmi Y, Spitzer MH

Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.



Nat Med: 24 May 2020; epub ahead of print
Allen BM, Hiam KJ, Burnett CE, Venida A, ... Carmi Y, Spitzer MH
Nat Med: 24 May 2020; epub ahead of print | PMID: 32451499
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Abstract

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Roberti MP, Yonekura S, Duong CPM, Picard M, ... Kroemer G, Zitvogel L

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 T cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.



Nat Med: 24 May 2020; epub ahead of print
Roberti MP, Yonekura S, Duong CPM, Picard M, ... Kroemer G, Zitvogel L
Nat Med: 24 May 2020; epub ahead of print | PMID: 32451498
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Abstract

Common germline variants of the human APOE gene modulate melanoma progression and survival.

Ostendorf BN, Bilanovic J, Adaku N, Tafreshian KN, ... Vaughan RD, Tavazoie SF

Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer\'s disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.



Nat Med: 24 May 2020; epub ahead of print
Ostendorf BN, Bilanovic J, Adaku N, Tafreshian KN, ... Vaughan RD, Tavazoie SF
Nat Med: 24 May 2020; epub ahead of print | PMID: 32451497
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Abstract

Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs.

Murugan R, Scally SW, Costa G, Mustafa G, ... Julien JP, Wardemann H

The circumsporozoite protein of the human malaria parasite Plasmodium falciparum (PfCSP) is the main target of antibodies that prevent the infection and disease, as shown in animal models. However, the limited efficacy of the PfCSP-based vaccine RTS,S calls for a better understanding of the mechanisms driving the development of the most potent human PfCSP antibodies and identification of their target epitopes. By characterizing 200 human monoclonal PfCSP antibodies induced by sporozoite immunization, we establish that the most potent antibodies bind around a conserved (N/D)PNANPN(V/A) core. High antibody affinity to the core correlates with protection from parasitemia in mice and evolves around the recognition of NANP motifs. The data suggest that the rational design of a next-generation PfCSP vaccine that elicits high-affinity antibody responses against the core epitope will promote the induction of protective humoral immune responses.



Nat Med: 24 May 2020; epub ahead of print
Murugan R, Scally SW, Costa G, Mustafa G, ... Julien JP, Wardemann H
Nat Med: 24 May 2020; epub ahead of print | PMID: 32451496
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Abstract

BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.

Bockorny B, Semenisty V, Macarulla T, Borazanci E, ... Von Hoff DD, Hidalgo M

Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8 effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.



Nat Med: 24 May 2020; epub ahead of print
Bockorny B, Semenisty V, Macarulla T, Borazanci E, ... Von Hoff DD, Hidalgo M
Nat Med: 24 May 2020; epub ahead of print | PMID: 32451495
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Abstract

Artificial intelligence-enabled rapid diagnosis of patients with COVID-19.

Mei X, Lee HC, Diao KY, Huang M, ... Fayad ZA, Yang Y

For diagnosis of coronavirus disease 2019 (COVID-19), a SARS-CoV-2 virus-specific reverse transcriptase polymerase chain reaction (RT-PCR) test is routinely used. However, this test can take up to 2 d to complete, serial testing may be required to rule out the possibility of false negative results and there is currently a shortage of RT-PCR test kits, underscoring the urgent need for alternative methods for rapid and accurate diagnosis of patients with COVID-19. Chest computed tomography (CT) is a valuable component in the evaluation of patients with suspected SARS-CoV-2 infection. Nevertheless, CT alone may have limited negative predictive value for ruling out SARS-CoV-2 infection, as some patients may have normal radiological findings at early stages of the disease. In this study, we used artificial intelligence (AI) algorithms to integrate chest CT findings with clinical symptoms, exposure history and laboratory testing to rapidly diagnose patients who are positive for COVID-19. Among a total of 905 patients tested by real-time RT-PCR assay and next-generation sequencing RT-PCR, 419 (46.3%) tested positive for SARS-CoV-2. In a test set of 279 patients, the AI system achieved an area under the curve of 0.92 and had equal sensitivity as compared to a senior thoracic radiologist. The AI system also improved the detection of patients who were positive for COVID-19 via RT-PCR who presented with normal CT scans, correctly identifying 17 of 25 (68%) patients, whereas radiologists classified all of these patients as COVID-19 negative. When CT scans and associated clinical history are available, the proposed AI system can help to rapidly diagnose COVID-19 patients.



Nat Med: 18 May 2020; epub ahead of print
Mei X, Lee HC, Diao KY, Huang M, ... Fayad ZA, Yang Y
Nat Med: 18 May 2020; epub ahead of print | PMID: 32427924
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Abstract

A deep learning system for differential diagnosis of skin diseases.

Liu Y, Jain A, Eng C, Way DH, ... Dunn RC, Coz D

Skin conditions affect 1.9 billion people. Because of a shortage of dermatologists, most cases are seen instead by general practitioners with lower diagnostic accuracy. We present a deep learning system (DLS) to provide a differential diagnosis of skin conditions using 16,114 de-identified cases (photographs and clinical data) from a teledermatology practice serving 17 sites. The DLS distinguishes between 26 common skin conditions, representing 80% of cases seen in primary care, while also providing a secondary prediction covering 419 skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was non-inferior to six other dermatologists and superior to six primary care physicians (PCPs) and six nurse practitioners (NPs) (top-1 accuracy: 0.66 DLS, 0.63 dermatologists, 0.44 PCPs and 0.40 NPs). These results highlight the potential of the DLS to assist general practitioners in diagnosing skin conditions.



Nat Med: 17 May 2020; epub ahead of print
Liu Y, Jain A, Eng C, Way DH, ... Dunn RC, Coz D
Nat Med: 17 May 2020; epub ahead of print | PMID: 32424212
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Abstract

Predicting conversion to wet age-related macular degeneration using deep learning.

Yim J, Chopra R, Spitz T, Winkens J, ... Keane PA, De Fauw J

Progression to exudative \'wet\' age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression.



Nat Med: 17 May 2020; epub ahead of print
Yim J, Chopra R, Spitz T, Winkens J, ... Keane PA, De Fauw J
Nat Med: 17 May 2020; epub ahead of print | PMID: 32424211
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Abstract

Infection of bat and human intestinal organoids by SARS-CoV-2.

Zhou J, Li C, Liu X, Chiu MC, ... Chen H, Yuen KY

A novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-emerged in humans in Wuhan, China, in December 2019 and has since disseminated globally. As of April 16, 2020, the confirmed case count of coronavirus disease 2019 (COVID-19) had surpassed 2 million. Based on full-genome sequence analysis, SARS-CoV-2 shows high homology to SARS-related coronaviruses identified in horseshoe bats. Here we show the establishment and characterization of expandable intestinal organoids derived from horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium. These bat enteroids are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication. Development of gastrointestinal symptoms in some patients with COVID-19 and detection of viral RNA in fecal specimens suggest that SARS-CoV-2 might cause enteric, in addition to respiratory, infection. Here we demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. Collectively, we established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells. The robust SARS-CoV-2 replication in human intestinal organoids suggests that the human intestinal tract might be a transmission route of SARS-CoV-2.



Nat Med: 12 May 2020; epub ahead of print
Zhou J, Li C, Liu X, Chiu MC, ... Chen H, Yuen KY
Nat Med: 12 May 2020; epub ahead of print | PMID: 32405028
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Abstract

A serological assay to detect SARS-CoV-2 seroconversion in humans.

Amanat F, Stadlbauer D, Strohmeier S, Nguyen THO, ... Simon V, Krammer F

Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.



Nat Med: 11 May 2020; epub ahead of print
Amanat F, Stadlbauer D, Strohmeier S, Nguyen THO, ... Simon V, Krammer F
Nat Med: 11 May 2020; epub ahead of print | PMID: 32398876
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Abstract

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.

Liao M, Liu Y, Yuan J, Wen Y, ... Zhang S, Zhang Z

Respiratory immune characteristics associated with Coronavirus Disease 2019 (COVID-19) severity are currently unclear. We characterized bronchoalveolar lavage fluid immune cells from patients with varying severity of COVID-19 and from healthy people by using single-cell RNA sequencing. Proinflammatory monocyte-derived macrophages were abundant in the bronchoalveolar lavage fluid from patients with severe COVID-9. Moderate cases were characterized by the presence of highly clonally expanded CD8 T cells. This atlas of the bronchoalveolar immune microenvironment suggests potential mechanisms underlying pathogenesis and recovery in COVID-19.



Nat Med: 11 May 2020; epub ahead of print
Liao M, Liu Y, Yuan J, Wen Y, ... Zhang S, Zhang Z
Nat Med: 11 May 2020; epub ahead of print | PMID: 32398875
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Impact:
Abstract

Real-time tracking of self-reported symptoms to predict potential COVID-19.

Menni C, Valdes AM, Freidin MB, Sudre CH, ... Steves CJ, Spector TD

A total of 2,618,862 participants reported their potential symptoms of COVID-19 on a smartphone-based app. Among the 18,401 who had undergone a SARS-CoV-2 test, the proportion of participants who reported loss of smell and taste was higher in those with a positive test result (4,668 of 7,178 individuals; 65.03%) than in those with a negative test result (2,436 of 11,223 participants; 21.71%) (odds ratio = 6.74; 95% confidence interval = 6.31-7.21). A model combining symptoms to predict probable infection was applied to the data from all app users who reported symptoms (805,753) and predicted that 140,312 (17.42%) participants are likely to have COVID-19.



Nat Med: 10 May 2020; epub ahead of print
Menni C, Valdes AM, Freidin MB, Sudre CH, ... Steves CJ, Spector TD
Nat Med: 10 May 2020; epub ahead of print | PMID: 32393804
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Impact:
Abstract

T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers.

Arunachalam PS, Charles TP, Joag V, Bollimpelli VS, ... Amara RR, Pulendran B

Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8 tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector + nAb group, titers <300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4 T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.



Nat Med: 10 May 2020; epub ahead of print
Arunachalam PS, Charles TP, Joag V, Bollimpelli VS, ... Amara RR, Pulendran B
Nat Med: 10 May 2020; epub ahead of print | PMID: 32393800
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Impact:
Abstract

Prediction of mortality from 12-lead electrocardiogram voltage data using a deep neural network.

Raghunath S, Ulloa Cerna AE, Jing L, vanMaanen DP, ... Haggerty CM, Fornwalt BK

The electrocardiogram (ECG) is a widely used medical test, consisting of voltage versus time traces collected from surface recordings over the heart. Here we hypothesized that a deep neural network (DNN) can predict an important future clinical event, 1-year all-cause mortality, from ECG voltage-time traces. By using ECGs collected over a 34-year period in a large regional health system, we trained a DNN with 1,169,662 12-lead resting ECGs obtained from 253,397 patients, in which 99,371 events occurred. The model achieved an area under the curve (AUC) of 0.88 on a held-out test set of 168,914 patients, in which 14,207 events occurred. Even within the large subset of patients (n = 45,285) with ECGs interpreted as \'normal\' by a physician, the performance of the model in predicting 1-year mortality remained high (AUC = 0.85). A blinded survey of cardiologists demonstrated that many of the discriminating features of these normal ECGs were not apparent to expert reviewers. Finally, a Cox proportional-hazard model revealed a hazard ratio of 9.5 (P < 0.005) for the two predicted groups (dead versus alive 1 year after ECG) over a 25-year follow-up period. These results show that deep learning can add substantial prognostic information to the interpretation of 12-lead resting ECGs, even in cases that are interpreted as normal by physicians.



Nat Med: 10 May 2020; epub ahead of print
Raghunath S, Ulloa Cerna AE, Jing L, vanMaanen DP, ... Haggerty CM, Fornwalt BK
Nat Med: 10 May 2020; epub ahead of print | PMID: 32393799
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Impact:
Abstract

Modeling shield immunity to reduce COVID-19 epidemic spread.

Weitz JS, Beckett SJ, Coenen AR, Demory D, ... Shivam S, Zhao CY

The COVID-19 pandemic has precipitated a global crisis, with more than 1,430,000 confirmed cases and more than 85,000 confirmed deaths globally as of 9 April 2020. Mitigation and suppression of new infections have emerged as the two predominant public health control strategies. Both strategies focus on reducing new infections by limiting human-to-human interactions, which could be both socially and economically unsustainable in the long term. We have developed and analyzed an epidemiological intervention model that leverages serological tests to identify and deploy recovered individuals as focal points for sustaining safer interactions via interaction substitution, developing what we term \'shield immunity\' at the population scale. The objective of a shield immunity strategy is to help to sustain the interactions necessary for the functioning of essential goods and services while reducing the probability of transmission. Our shield immunity approach could substantively reduce the length and reduce the overall burden of the current outbreak, and can work synergistically with social distancing. The present model highlights the value of serological testing as part of intervention strategies, in addition to its well-recognized roles in estimating prevalence and in the potential development of plasma-based therapies.



Nat Med: 06 May 2020; epub ahead of print
Weitz JS, Beckett SJ, Coenen AR, Demory D, ... Shivam S, Zhao CY
Nat Med: 06 May 2020; epub ahead of print | PMID: 32382154
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Impact:
Abstract

Age and generational patterns of overdose death risk from opioids and other drugs.

Jalal H, Buchanich JM, Sinclair DR, Roberts MS, Burke DS

The ongoing substance misuse epidemic in the United States is complex and dynamic and should be approached as such in the development and evaluation of policy. Drug overdose deaths (largely attributable to opioid misuse) in the United States have grown exponentially for almost four decades, but the mechanisms of this growth are poorly understood. From analysis of 661,565 overdose deaths from 1999 to 2017, we show that the age-specific drug overdose mortality curve for each birth-year cohort rises and falls according to a Gaussian-shaped curve. The ascending portion of each successive birth-year cohort mortality curve is accelerated compared with that of all preceding birth-year cohorts. This acceleration can be attributed to either of two distinct processes: a stable peak age, with an increasing amplitude of mortality rate curves from one birth-year cohort to the next; or a youthward shift in the peak age of the mortality rate curves. The overdose epidemic emerged and increased in amplitude among the 1945-1964 cohort (Baby Boomers), shifted youthward among the 1965-1980 cohort (Generation X), and then resumed the pattern of increasing amplitude in the 1981-1990 Millennials. These shifting age and generational patterns are likely to be driven by socioeconomic factors and drug availability, the understanding of which is important for the development of effective overdose prevention measures.



Nat Med: 03 May 2020; epub ahead of print
Jalal H, Buchanich JM, Sinclair DR, Roberts MS, Burke DS
Nat Med: 03 May 2020; epub ahead of print | PMID: 32367060
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Impact:
Abstract

PrEP rollout in Africa: status and opportunity.

Irungu EM, Baeten JM

Following recommendations by the World Health Organization in 2015, and key clinical trials, countries in sub-Saharan Africa, the region with the highest burden of human immunodeficiency virus (HIV), developed policies that incorporate pre-exposure prophylaxis (PrEP) into national HIV-prevention strategies. By the end of 2019, more than one third of people receiving PrEP globally were in Africa. Crucial understandings gained from early rollout among at-risk populations, such as HIV-serodiscordant couples, adolescent girls and young women, female sex workers, and men who have sex with men, include the importance of strategies for maintaining persistent adherence to PrEP and novel approaches to making PrEP services accessible, simplified and efficient. This Perspective will discuss the current status of these programs and how to further widen their implementation.



Nat Med: 29 Apr 2020; 26:655-664
Irungu EM, Baeten JM
Nat Med: 29 Apr 2020; 26:655-664 | PMID: 32405065
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Impact:
Abstract

Development and validation of serological markers for detecting recent Plasmodium vivax infection.

Longley RJ, White MT, Takashima E, Brewster J, ... Tsuboi T, Mueller I

A major gap in the Plasmodium vivax elimination toolkit is the identification of individuals carrying clinically silent and undetectable liver-stage parasites, called hypnozoites. This study developed a panel of serological exposure markers capable of classifying individuals with recent P. vivax infections who have a high likelihood of harboring hypnozoites. We measured IgG antibody responses to 342 P. vivax proteins in longitudinal clinical cohorts conducted in Thailand and Brazil and identified candidate serological markers of exposure. Candidate markers were validated using samples from year-long observational cohorts conducted in Thailand, Brazil and the Solomon Islands and antibody responses to eight P. vivax proteins classified P. vivax infections in the previous 9 months with 80% sensitivity and specificity. Mathematical models demonstrate that a serological testing and treatment strategy could reduce P. vivax prevalence by 59-69%. These eight antibody responses can serve as a biomarker, identifying individuals who should be targeted with anti-hypnozoite therapy.



Nat Med: 29 Apr 2020; 26:741-749
Longley RJ, White MT, Takashima E, Brewster J, ... Tsuboi T, Mueller I
Nat Med: 29 Apr 2020; 26:741-749 | PMID: 32405064
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Impact:
Abstract

High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade.

Yuen KC, Liu LF, Gupta V, Madireddi S, ... Huseni MA, Mariathasan S

Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade , this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8 T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.



Nat Med: 29 Apr 2020; 26:693-698
Yuen KC, Liu LF, Gupta V, Madireddi S, ... Huseni MA, Mariathasan S
Nat Med: 29 Apr 2020; 26:693-698 | PMID: 32405063
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Impact:
Abstract

Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors.

Schalper KA, Carleton M, Zhou M, Chen T, ... Sanmamed MF, Melero I

Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.



Nat Med: 29 Apr 2020; 26:688-692
Schalper KA, Carleton M, Zhou M, Chen T, ... Sanmamed MF, Melero I
Nat Med: 29 Apr 2020; 26:688-692 | PMID: 32405062
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Impact:
Abstract

A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.

Slyper M, Porter CBM, Ashenberg O, Waldman J, ... Rozenblatt-Rosen O, Regev A

Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption. Here, we have developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We analyzed 216,490 cells and nuclei from 40 samples across 23 specimens spanning eight tumor types of varying tissue and sample characteristics. We evaluated protocols by cell and nucleus quality, recovery rate and cellular composition. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types, but at different proportions. Our work provides guidance for studies in a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.



Nat Med: 29 Apr 2020; 26:792-802
Slyper M, Porter CBM, Ashenberg O, Waldman J, ... Rozenblatt-Rosen O, Regev A
Nat Med: 29 Apr 2020; 26:792-802 | PMID: 32405060
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Impact:
Abstract

Antibody responses to SARS-CoV-2 in patients with COVID-19.

Long QX, Liu BZ, Deng HJ, Wu GC, ... Chen J, Huang AL

We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.



Nat Med: 28 Apr 2020; epub ahead of print
Long QX, Liu BZ, Deng HJ, Wu GC, ... Chen J, Huang AL
Nat Med: 28 Apr 2020; epub ahead of print | PMID: 32350462
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Impact:
Abstract

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Donovan LK, Delaidelli A, Joseph SK, Bielamowicz K, ... Ahmed N, Taylor MD

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.



Nat Med: 26 Apr 2020; epub ahead of print
Donovan LK, Delaidelli A, Joseph SK, Bielamowicz K, ... Ahmed N, Taylor MD
Nat Med: 26 Apr 2020; epub ahead of print | PMID: 32341580
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Impact:
Abstract

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Theruvath J, Sotillo E, Mount CW, Graef CM, ... Monje M, Mackall CL

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. ), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.



Nat Med: 26 Apr 2020; epub ahead of print
Theruvath J, Sotillo E, Mount CW, Graef CM, ... Monje M, Mackall CL
Nat Med: 26 Apr 2020; epub ahead of print | PMID: 32341579
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Impact:
Abstract

Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer.

Lu Y, Xue J, Deng T, Zhou X, ... Li W, Mok T

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.



Nat Med: 26 Apr 2020; epub ahead of print
Lu Y, Xue J, Deng T, Zhou X, ... Li W, Mok T
Nat Med: 26 Apr 2020; epub ahead of print | PMID: 32341578
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Impact:
Abstract

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.

Sungnak W, Huang N, Bécavin C, Berg M, ... Barnes JL,

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells\' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.



Nat Med: 22 Apr 2020; epub ahead of print
Sungnak W, Huang N, Bécavin C, Berg M, ... Barnes JL,
Nat Med: 22 Apr 2020; epub ahead of print | PMID: 32327758
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Impact:
Abstract

Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States.



Data on the detailed clinical progression of COVID-19 in conjunction with epidemiological and virological characteristics are limited. In this case series, we describe the first 12 US patients confirmed to have COVID-19 from 20 January to 5 February 2020, including 4 patients described previously. Respiratory, stool, serum and urine specimens were submitted for SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing, viral culture and whole genome sequencing. Median age was 53 years (range: 21-68); 8 patients were male. Common symptoms at illness onset were cough (n = 8) and fever (n = 7). Patients had mild to moderately severe illness; seven were hospitalized and demonstrated clinical or laboratory signs of worsening during the second week of illness. No patients required mechanical ventilation and all recovered. All had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset. Lowest real-time PCR with reverse transcription cycle threshold values in the upper respiratory tract were often detected in the first week and SARS-CoV-2 was cultured from early respiratory specimens. These data provide insight into the natural history of SARS-CoV-2. Although infectiousness is unclear, highest viral RNA levels were identified in the first week of illness. Clinicians should anticipate that some patients may worsen in the second week of illness.



Nat Med: 22 Apr 2020; epub ahead of print
Nat Med: 22 Apr 2020; epub ahead of print | PMID: 32327757
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Impact:
Abstract

Modelling the COVID-19 epidemic and implementation of population-wide interventions in Italy.

Giordano G, Blanchini F, Bruno R, Colaneri P, ... Di Matteo A, Colaneri M

In Italy, 128,948 confirmed cases and 15,887 deaths of people who tested positive for SARS-CoV-2 were registered as of 5 April 2020. Ending the global SARS-CoV-2 pandemic requires implementation of multiple population-wide strategies, including social distancing, testing and contact tracing. We propose a new model that predicts the course of the epidemic to help plan an effective control strategy. The model considers eight stages of infection: susceptible (S), infected (I), diagnosed (D), ailing (A), recognized (R), threatened (T), healed (H) and extinct (E), collectively termed SIDARTHE. Our SIDARTHE model discriminates between infected individuals depending on whether they have been diagnosed and on the severity of their symptoms. The distinction between diagnosed and non-diagnosed individuals is important because the former are typically isolated and hence less likely to spread the infection. This delineation also helps to explain misperceptions of the case fatality rate and of the epidemic spread. We compare simulation results with real data on the COVID-19 epidemic in Italy, and we model possible scenarios of implementation of countermeasures. Our results demonstrate that restrictive social-distancing measures will need to be combined with widespread testing and contact tracing to end the ongoing COVID-19 pandemic.



Nat Med: 21 Apr 2020; epub ahead of print
Giordano G, Blanchini F, Bruno R, Colaneri P, ... Di Matteo A, Colaneri M
Nat Med: 21 Apr 2020; epub ahead of print | PMID: 32322102
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Impact:
Abstract

Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology.

Kerschbaumer A, Smolen JS, Herkner H, Stefanova T, Chwala E, Aletaha D

Phase 3 trials are the mainstay of drug development across medicine but have often not met expectations set by preceding phase 2 studies. A systematic meta-analysis evaluated all randomized controlled, double-blind trials investigating targeted disease-modifying anti-rheumatic drugs in rheumatoid and psoriatic arthritis. Primary outcomes of American College of Rheumatology (ACR) 20 responses were compared by mixed-model logistic regression, including exploration of potential determinants of efficacy overestimation. In rheumatoid arthritis, phase 2 trial outcomes systematically overestimated subsequent phase 3 results (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.39, 95% confidence interval: 1.25-1.57, P < 0.001). Data for psoriatic arthritis trials were similar, but not statistically significant (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.35, 95% confidence interval: 0.94-1.94, P = 0.09). Differences in inclusion criteria largely explained the observed differences in efficacy findings. Our findings have implications for all stakeholders in new therapeutic development and testing, as well as potential ethical implications.



Nat Med: 19 Apr 2020; epub ahead of print
Kerschbaumer A, Smolen JS, Herkner H, Stefanova T, Chwala E, Aletaha D
Nat Med: 19 Apr 2020; epub ahead of print | PMID: 32313250
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Impact:
Abstract

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017.



A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1-70.8) million) to 6.4% (58.3 (47.6-70.7) million), but is predicted to remain above the World Health Organization\'s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8-38.5) million) in 2000 to 6.0% (55.5 (44.8-67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic.



Nat Med: 19 Apr 2020; epub ahead of print
Nat Med: 19 Apr 2020; epub ahead of print | PMID: 32313249
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Impact:
Abstract

Temporal dynamics in viral shedding and transmissibility of COVID-19.

He X, Lau EHY, Wu P, Deng X, ... Li F, Leung GM

We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector-infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25-69%) of secondary cases were infected during the index cases\' presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.



Nat Med: 14 Apr 2020; epub ahead of print
He X, Lau EHY, Wu P, Deng X, ... Li F, Leung GM
Nat Med: 14 Apr 2020; epub ahead of print | PMID: 32296168
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Impact:
Abstract

Large-scale proteomic analysis of Alzheimer\'s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation.

Johnson ECB, Dammer EB, Duong DM, Ping L, ... Levey AI, Seyfried NT

Our understanding of Alzheimer\'s disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.



Nat Med: 12 Apr 2020; epub ahead of print
Johnson ECB, Dammer EB, Duong DM, Ping L, ... Levey AI, Seyfried NT
Nat Med: 12 Apr 2020; epub ahead of print | PMID: 32284590
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Impact:
Abstract

Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae.

Ernst CM, Braxton JR, Rodriguez-Osorio CA, Zagieboylo AP, ... Cosimi LA, Hung DT

Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae, which are resistant to the antibiotic class of \'last resort\'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. ) sequence type are dominant, endemic and associated with high mortality. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.



Nat Med: 12 Apr 2020; epub ahead of print
Ernst CM, Braxton JR, Rodriguez-Osorio CA, Zagieboylo AP, ... Cosimi LA, Hung DT
Nat Med: 12 Apr 2020; epub ahead of print | PMID: 32284589
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Impact:
Abstract

Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.

Pérez-Guijarro E, Yang HH, Araya RE, El Meskini R, ... Day CP, Merlino G

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.



Nat Med: 12 Apr 2020; epub ahead of print
Pérez-Guijarro E, Yang HH, Araya RE, El Meskini R, ... Day CP, Merlino G
Nat Med: 12 Apr 2020; epub ahead of print | PMID: 32284588
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Impact:
Abstract

Learning from clinical trials of neoadjuvant checkpoint blockade.

Versluis JM, Long GV, Blank CU

Neoadjuvant checkpoint inhibition, in which the therapy is administered before surgery, is a promising new approach to managing bulky but resectable melanoma, and is also being explored in other cancers. This strategy has a high pathologic response rate, which correlates with survival outcomes. The fact that biopsies are routinely available provides a unique opportunity for understanding the responses to therapy and carrying out reverse translation in which these data are used to select therapies in the clinic or in trials that are more likely to improve patient outcomes. In this Perspective, we discuss the rationale for neoadjuvant immunotherapy in resectable solid tumors based on preclinical and human translational data, summarize the results of recent clinical trials and ongoing research, and focus on future directions for enhancing reverse translation.



Nat Med: 08 Apr 2020; epub ahead of print
Versluis JM, Long GV, Blank CU
Nat Med: 08 Apr 2020; epub ahead of print | PMID: 32273608
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Impact:
Abstract

Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers.

Mars N, Koskela JT, Ripatti P, Kiiskinen TTJ, ... Widén E, Ripatti S

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.



Nat Med: 06 Apr 2020; epub ahead of print
Mars N, Koskela JT, Ripatti P, Kiiskinen TTJ, ... Widén E, Ripatti S
Nat Med: 06 Apr 2020; epub ahead of print | PMID: 32273609
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Impact:
Abstract

Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.

Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, ... Voest EE, Haanen JB

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8-55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8PD-1 T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.



Nat Med: 05 Apr 2020; epub ahead of print
Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, ... Voest EE, Haanen JB
Nat Med: 05 Apr 2020; epub ahead of print | PMID: 32251400
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Impact:
Abstract

Respiratory virus shedding in exhaled breath and efficacy of face masks.

Leung NHL, Chu DKW, Shiu EYC, Chan KH, ... Milton DK, Cowling BJ

We identified seasonal human coronaviruses, influenza viruses and rhinoviruses in exhaled breath and coughs of children and adults with acute respiratory illness. Surgical face masks significantly reduced detection of influenza virus RNA in respiratory droplets and coronavirus RNA in aerosols, with a trend toward reduced detection of coronavirus RNA in respiratory droplets. Our results indicate that surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals.



Nat Med: 02 Apr 2020; epub ahead of print
Leung NHL, Chu DKW, Shiu EYC, Chan KH, ... Milton DK, Cowling BJ
Nat Med: 02 Apr 2020; epub ahead of print | PMID: 32371934
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Impact:
Abstract

Therapeutic base editing of human hematopoietic stem cells.

Zeng J, Wu Y, Ren C, Bonanno J, ... Joung JK, Bauer DE

Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. In this study, we purified A3A (N57Q)-BE3 base editor for ribonucleoprotein (RNP) electroporation of human-peripheral-blood-mobilized CD34 hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A erythroid enhancer at +58 with few indels. Fetal hemoglobin (HbF) induction in erythroid progeny after base editing or nuclease editing was similar. A single therapeutic base edit of the BCL11A enhancer prevented sickling and ameliorated globin chain imbalance in erythroid progeny from sickle cell disease and β-thalassemia patient-derived HSPCs, respectively. Moreover, efficient multiplex editing could be achieved with combined disruption of the BCL11A erythroid enhancer and correction of the HBB -28A>G promoter mutation. Finally, base edits could be produced in multilineage-repopulating self-renewing human HSCs with high frequency as assayed in primary and secondary recipient animals resulting in potent HbF induction in vivo. Together, these results demonstrate the potential of RNP base editing of human HSPCs as a feasible alternative to nuclease editing for HSC-targeted therapeutic genome modification.



Nat Med: 30 Mar 2020; 26:535-541
Zeng J, Wu Y, Ren C, Bonanno J, ... Joung JK, Bauer DE
Nat Med: 30 Mar 2020; 26:535-541 | PMID: 32284612
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Impact:
Abstract

CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption.

Harper J, Gordon S, Chan CN, Wang H, ... Estes JD, Paiardini M

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4 T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4 T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8 T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.



Nat Med: 30 Mar 2020; 26:519-528
Harper J, Gordon S, Chan CN, Wang H, ... Estes JD, Paiardini M
Nat Med: 30 Mar 2020; 26:519-528 | PMID: 32284611
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Impact:
Abstract

A randomized proof-of-mechanism trial applying the \'fast-fail\' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.

Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, ... Gao K, Potter WZ

The National Institute of Mental Health (NIMH) \'fast-fail\' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the \'fast-fail\' approach.



Nat Med: 29 Mar 2020; epub ahead of print
Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, ... Gao K, Potter WZ
Nat Med: 29 Mar 2020; epub ahead of print | PMID: 32231295
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Impact:
Abstract

Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.

Basolo A, Hohenadel M, Ang QY, Piaggi P, ... Turnbaugh PJ, Krakoff J

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest.



Nat Med: 22 Mar 2020; epub ahead of print
Basolo A, Hohenadel M, Ang QY, Piaggi P, ... Turnbaugh PJ, Krakoff J
Nat Med: 22 Mar 2020; epub ahead of print | PMID: 32235930
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Impact:
Abstract

Safety and immunogenicity of Ad26 and MVA vaccines in acutely treated HIV and effect on viral rebound after antiretroviral therapy interruption.

Colby DJ, Sarnecki M, Barouch DH, Tipsuk S, ... Tomaka FL, Ananworanich J

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).



Nat Med: 22 Mar 2020; epub ahead of print
Colby DJ, Sarnecki M, Barouch DH, Tipsuk S, ... Tomaka FL, Ananworanich J
Nat Med: 22 Mar 2020; epub ahead of print | PMID: 32235883
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Impact:
Abstract

Integrated single-cell analysis of multicellular immune dynamics during hyperacute HIV-1 infection.

Kazer SW, Aicher TP, Muema DM, Carroll SL, ... Walker BD, Shalek AK

Cellular immunity is critical for controlling intracellular pathogens, but individual cellular dynamics and cell-cell cooperativity in evolving human immune responses remain poorly understood. Single-cell RNA-sequencing (scRNA-seq) represents a powerful tool for dissecting complex multicellular behaviors in health and disease and nominating testable therapeutic targets. Its application to longitudinal samples could afford an opportunity to uncover cellular factors associated with the evolution of disease progression without potentially confounding inter-individual variability. Here, we present an experimental and computational methodology that uses scRNA-seq to characterize dynamic cellular programs and their molecular drivers, and apply it to HIV infection. By performing scRNA-seq on peripheral blood mononuclear cells from four untreated individuals before and longitudinally during acute infection, we were powered within each to discover gene response modules that vary by time and cell subset. Beyond previously unappreciated individual- and cell-type-specific interferon-stimulated gene upregulation, we describe temporally aligned gene expression responses obscured in bulk analyses, including those involved in proinflammatory T cell differentiation, prolonged monocyte major histocompatibility complex II upregulation and persistent natural killer (NK) cell cytolytic killing. We further identify response features arising in the first weeks of infection, for example proliferating natural killer cells, which potentially may associate with future viral control. Overall, our approach provides a unified framework for characterizing multiple dynamic cellular responses and their coordination.



Nat Med: 22 Mar 2020; epub ahead of print
Kazer SW, Aicher TP, Muema DM, Carroll SL, ... Walker BD, Shalek AK
Nat Med: 22 Mar 2020; epub ahead of print | PMID: 32251406
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Impact:
Abstract

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan.

Sakaue S, Kanai M, Karjalainen J, Akiyama M, ... Kamatani Y, Okada Y

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (n = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], P = 3.9 × 10) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (P = 9.5 × 10 for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.



Nat Med: 22 Mar 2020; epub ahead of print
Sakaue S, Kanai M, Karjalainen J, Akiyama M, ... Kamatani Y, Okada Y
Nat Med: 22 Mar 2020; epub ahead of print | PMID: 32251405
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Impact:
Abstract

A neuroimaging biomarker for striatal dysfunction in schizophrenia.

Li A, Zalesky A, Yue W, Howes O, ... Jiang T, Liu B

Mounting evidence suggests that function and connectivity of the striatum is disrupted in schizophrenia. We have developed a new hypothesis-driven neuroimaging biomarker for schizophrenia identification, prognosis and subtyping based on functional striatal abnormalities (FSA). FSA scores provide a personalized index of striatal dysfunction, ranging from normal to highly pathological. Using inter-site cross-validation on functional magnetic resonance images acquired from seven independent scanners (n = 1,100), FSA distinguished individuals with schizophrenia from healthy controls with an accuracy exceeding 80% (sensitivity, 79.3%; specificity, 81.5%). In two longitudinal cohorts, inter-individual variation in baseline FSA scores was significantly associated with antipsychotic treatment response. FSA revealed a spectrum of severity in striatal dysfunction across neuropsychiatric disorders, where dysfunction was most severe in schizophrenia, milder in bipolar disorder, and indistinguishable from healthy individuals in depression, obsessive-compulsive disorder and attention-deficit hyperactivity disorder. Loci of striatal hyperactivity recapitulated the spatial distribution of dopaminergic function and the expression profiles of polygenic risk for schizophrenia. In conclusion, we have developed a new biomarker to index striatal dysfunction and established its utility in predicting antipsychotic treatment response, clinical stratification and elucidating striatal dysfunction in neuropsychiatric disorders.



Nat Med: 22 Mar 2020; epub ahead of print
Li A, Zalesky A, Yue W, Howes O, ... Jiang T, Liu B
Nat Med: 22 Mar 2020; epub ahead of print | PMID: 32251404
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Impact:
Abstract

Improving prevention strategies for cardiometabolic disease.

Sattar N, Gill JMR, Alazawi W

There is a growing burden of cardiometabolic disease in many parts of the world. Despite some progress in its prevention, more can be done to tackle risks of its development in the community and in different specialty clinics. Currently, the identification and management of those at elevated risk of developing cardiovascular disease or diabetes or with conditions such as fatty liver disease remains fragmented and is not linked to constructive lifestyle advice. In this Perspective, we argue for a more consistent weight-management approach, alongside a holistic assessment of the risk for developing cardiometabolic diseases, offering patients a range of simple or more-intensive evidence-based lifestyle options in an empathetic manner, with encouragement for repeated attempts and a willingness to embrace failure.



Nat Med: 08 Mar 2020; epub ahead of print
Sattar N, Gill JMR, Alazawi W
Nat Med: 08 Mar 2020; epub ahead of print | PMID: 32152584
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Impact:
Abstract

Early prediction of circulatory failure in the intensive care unit using machine learning.

Hyland SL, Faltys M, Hüser M, Lyu X, ... Rätsch G, Merz TM

Intensive-care clinicians are presented with large quantities of measurements from multiple monitoring systems. The limited ability of humans to process complex information hinders early recognition of patient deterioration, and high numbers of monitoring alarms lead to alarm fatigue. We used machine learning to develop an early-warning system that integrates measurements from multiple organ systems using a high-resolution database with 240 patient-years of data. It predicts 90% of circulatory-failure events in the test set, with 82% identified more than 2 h in advance, resulting in an area under the receiver operating characteristic curve of 0.94 and an area under the precision-recall curve of 0.63. On average, the system raises 0.05 alarms per patient and hour. The model was externally validated in an independent patient cohort. Our model provides early identification of patients at risk for circulatory failure with a much lower false-alarm rate than conventional threshold-based systems.



Nat Med: 08 Mar 2020; epub ahead of print
Hyland SL, Faltys M, Hüser M, Lyu X, ... Rätsch G, Merz TM
Nat Med: 08 Mar 2020; epub ahead of print | PMID: 32152583
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Impact:
Abstract

Deep learning models for electrocardiograms are susceptible to adversarial attack.

Han X, Hu Y, Foschini L, Chinitz L, Jankelson L, Ranganath R

Electrocardiogram (ECG) acquisition is increasingly widespread in medical and commercial devices, necessitating the development of automated interpretation strategies. Recently, deep neural networks have been used to automatically analyze ECG tracings and outperform physicians in detecting certain rhythm irregularities. However, deep learning classifiers are susceptible to adversarial examples, which are created from raw data to fool the classifier such that it assigns the example to the wrong class, but which are undetectable to the human eye. Adversarial examples have also been created for medical-related tasks. However, traditional attack methods to create adversarial examples do not extend directly to ECG signals, as such methods introduce square-wave artefacts that are not physiologically plausible. Here we develop a method to construct smoothed adversarial examples for ECG tracings that are invisible to human expert evaluation and show that a deep learning model for arrhythmia detection from single-lead ECG is vulnerable to this type of attack. Moreover, we provide a general technique for collating and perturbing known adversarial examples to create multiple new ones. The susceptibility of deep learning ECG algorithms to adversarial misclassification implies that care should be taken when evaluating these models on ECGs that may have been altered, particularly when incentives for causing misclassification exist.



Nat Med: 08 Mar 2020; epub ahead of print
Han X, Hu Y, Foschini L, Chinitz L, Jankelson L, Ranganath R
Nat Med: 08 Mar 2020; epub ahead of print | PMID: 32152582
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Impact:
Abstract

STAR particles for enhanced topical drug and vaccine delivery.

Tadros AR, Romanyuk A, Miller IC, Santiago A, ... Kwong GA, Prausnitz MR

Drug delivery to the skin is highly constrained by the stratum corneum barrier layer. Here, we developed star-shaped particles, termed STAR particles, to dramatically increase skin permeability. STAR particles are millimeter-scale particles made of aluminum oxide or stainless steel with micron-scale projections designed to create microscopic pores across the stratum corneum. After gentle topical application for 10 s to porcine skin ex vivo, delivery of dermatological drugs and macromolecules, including those that cannot be given topically, was increased by 1 to 2 orders of magnitude. In mice treated with topical 5-fluorouracil, use of STAR particles increased the efficacy of the drug in suppressing the growth of subcutaneous melanoma tumors and prolonging survival. Moreover, topical delivery of tetanus toxoid vaccine to mice using STAR particles generated immune responses that were at least as strong as delivery of the vaccine by intramuscular injection, albeit at a higher dose for topical than intramuscular vaccine administration. STAR particles were well tolerated and effective at creating micropores when applied to the skin of human participants. Use of STAR particles provides a simple, low-cost and well-tolerated method for increasing drug and vaccine delivery to the skin and could widen the range of compounds that can be topically administered.



Nat Med: 08 Mar 2020; epub ahead of print
Tadros AR, Romanyuk A, Miller IC, Santiago A, ... Kwong GA, Prausnitz MR
Nat Med: 08 Mar 2020; epub ahead of print | PMID: 32152581
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Impact:
Abstract

Joint international consensus statement for ending stigma of obesity.

Rubino F, Puhl RM, Cummings DE, Eckel RH, ... Torres AJ, Dixon JB

People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.



Nat Med: 03 Mar 2020; epub ahead of print
Rubino F, Puhl RM, Cummings DE, Eckel RH, ... Torres AJ, Dixon JB
Nat Med: 03 Mar 2020; epub ahead of print | PMID: 32127716
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Impact:
Abstract

Diagnostic value of plasma phosphorylated tau181 in Alzheimer\'s disease and frontotemporal lobar degeneration.

Thijssen EH, La Joie R, Wolf A, Strom A, ... Boxer AL,

With the potential development of new disease-modifying Alzheimer\'s disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.



Nat Med: 01 Mar 2020; epub ahead of print
Thijssen EH, La Joie R, Wolf A, Strom A, ... Boxer AL,
Nat Med: 01 Mar 2020; epub ahead of print | PMID: 32123386
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Impact:
Abstract

Plasma P-tau181 in Alzheimer\'s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer\'s dementia.

Janelidze S, Mattsson N, Palmqvist S, Smith R, ... Dage JL, Hansson O

Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer\'s disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials.



Nat Med: 01 Mar 2020; epub ahead of print
Janelidze S, Mattsson N, Palmqvist S, Smith R, ... Dage JL, Hansson O
Nat Med: 01 Mar 2020; epub ahead of print | PMID: 32123385
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Impact:
Abstract

A maternal serum metabolite ratio predicts fetal growth restriction at term.

Sovio U, Goulding N, McBride N, Cook E, ... Lawlor DA, Smith GCS

Fetal growth restriction (FGR) is the major single cause of stillbirth and is also associated with neonatal morbidity and mortality, impaired health and educational achievement in childhood and with a range of diseases in later life. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) metabolomics on maternal serum at 12, 20 and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the Pregnancy Outcome Prediction (POP) study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1) and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5α-androstan-3α,17α-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker, the soluble fms-like tyrosine kinase 1:placental growth factor (sFLT1:PlGF) ratio (AUC 0.78 versus 0.64, P = 0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford (BiB), conducted in Bradford, UK (P = 0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor.



Nat Med: 28 Feb 2020; 26:348-353
Sovio U, Goulding N, McBride N, Cook E, ... Lawlor DA, Smith GCS
Nat Med: 28 Feb 2020; 26:348-353 | PMID: 32161413
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Impact:
Abstract

A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer\'s disease.

Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, ... McDade E,

Development of tau-based therapies for Alzheimer\'s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer\'s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.



Nat Med: 28 Feb 2020; 26:398-407
Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, ... McDade E,
Nat Med: 28 Feb 2020; 26:398-407 | PMID: 32161412
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Impact:
Abstract

Skin-interfaced biosensors for advanced wireless physiological monitoring in neonatal and pediatric intensive-care units.

Chung HU, Rwei AY, Hourlier-Fargette A, Xu S, ... Lee JY, Rogers JA

Standard clinical care in neonatal and pediatric intensive-care units (NICUs and PICUs, respectively) involves continuous monitoring of vital signs with hard-wired devices that adhere to the skin and, in certain instances, can involve catheter-based pressure sensors inserted into the arteries. These systems entail risks of causing iatrogenic skin injuries, complicating clinical care and impeding skin-to-skin contact between parent and child. Here we present a wireless, non-invasive technology that not only offers measurement equivalency to existing clinical standards for heart rate, respiration rate, temperature and blood oxygenation, but also provides a range of important additional features, as supported by data from pilot clinical studies in both the NICU and PICU. These new modalities include tracking movements and body orientation, quantifying the physiological benefits of skin-to-skin care, capturing acoustic signatures of cardiac activity, recording vocal biomarkers associated with tonality and temporal characteristics of crying and monitoring a reliable surrogate for systolic blood pressure. These platforms have the potential to substantially enhance the quality of neonatal and pediatric critical care.



Nat Med: 28 Feb 2020; 26:418-429
Chung HU, Rwei AY, Hourlier-Fargette A, Xu S, ... Lee JY, Rogers JA
Nat Med: 28 Feb 2020; 26:418-429 | PMID: 32161411
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Impact:
Abstract

Multiplexed single-cell morphometry for hematopathology diagnostics.

Tsai AG, Glass DR, Juntilla M, Hartmann FJ, ... Ohgami RS, Bendall SC

The diagnosis of lymphomas and leukemias requires hematopathologists to integrate microscopically visible cellular morphology with antibody-identified cell surface molecule expression. To merge these into one high-throughput, highly multiplexed, single-cell assay, we quantify cell morphological features by their underlying, antibody-measurable molecular components, which empowers mass cytometers to \'see\' like pathologists. When applied to 71 diverse clinical samples, single-cell morphometric profiling reveals robust and distinct patterns of \'morphometric\' markers for each major cell type. Individually, lamin B1 highlights acute leukemias, lamin A/C helps distinguish normal from neoplastic mature T cells, and VAMP-7 recapitulates light-cytometric side scatter. Combined with machine learning, morphometric markers form intuitive visualizations of normal and neoplastic cellular distribution and differentiation. When recalibrated for myelomonocytic blast enumeration, this approach is superior to flow cytometry and comparable to expert microscopy, bypassing years of specialized training. The contextualization of traditional surface markers on independent morphometric frameworks permits more sensitive and automated diagnosis of complex hematopoietic diseases.



Nat Med: 28 Feb 2020; 26:408-417
Tsai AG, Glass DR, Juntilla M, Hartmann FJ, ... Ohgami RS, Bendall SC
Nat Med: 28 Feb 2020; 26:408-417 | PMID: 32161403
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Impact:
Abstract

Broad immune activation underlies shared set point signatures for vaccine responsiveness in healthy individuals and disease activity in patients with lupus.

Kotliarov Y, Sparks R, Martins AJ, Mulè MP, ... Moir S, Tsang JS

Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations. Identifying such baseline predictors of immune responses and their biological basis is of broad interest, given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. These same signatures evaluated at clinical quiescence are correlated with disease activity in patients with systemic lupus erythematosus with plasmablast-associated flares. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-type I IFN-T/B lymphocyte network. Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activity.



Nat Med: 23 Feb 2020; epub ahead of print
Kotliarov Y, Sparks R, Martins AJ, Mulè MP, ... Moir S, Tsang JS
Nat Med: 23 Feb 2020; epub ahead of print | PMID: 32094927
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Impact:
Abstract

Viable bacterial colonization is highly limited in the human intestine in utero.

Rackaityte E, Halkias J, Fukui EM, Mendoza VF, ... Burt TD, Lynch SV

Mucosal immunity develops in the human fetal intestine by 11-14 weeks of gestation, yet whether viable microbes exist in utero and interact with the intestinal immune system is unknown. Bacteria-like morphology was identified in pockets of human fetal meconium at mid-gestation by scanning electron microscopy (n = 4), and a sparse bacterial signal was detected by 16S rRNA sequencing (n = 40 of 50) compared to environmental controls (n = 87). Eighteen taxa were enriched in fetal meconium, with Micrococcaceae (n = 9) and Lactobacillus (n = 6) the most abundant. Fetal intestines dominated by Micrococcaceae exhibited distinct patterns of T cell composition and epithelial transcription. Fetal Micrococcus luteus, isolated only in the presence of monocytes, grew on placental hormones, remained viable within antigen presenting cells, limited inflammation ex vivo and possessed genomic features linked with survival in the fetus. Thus, viable bacteria are highly limited in the fetal intestine at mid-gestation, although strains with immunomodulatory capacity are detected in subsets of specimens.



Nat Med: 23 Feb 2020; epub ahead of print
Rackaityte E, Halkias J, Fukui EM, Mendoza VF, ... Burt TD, Lynch SV
Nat Med: 23 Feb 2020; epub ahead of print | PMID: 32094926
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Impact:
Abstract

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR.

Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, Nanda A, ... Stanga PE, MacLaren RE

Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.



Nat Med: 23 Feb 2020; epub ahead of print
Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, Nanda A, ... Stanga PE, MacLaren RE
Nat Med: 23 Feb 2020; epub ahead of print | PMID: 32094925
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Impact:
Abstract

TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma.

Ennishi D, Healy S, Bashashati A, Saberi S, ... Scott DW, Steidl C

Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and \'eat-me\' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.



Nat Med: 23 Feb 2020; epub ahead of print
Ennishi D, Healy S, Bashashati A, Saberi S, ... Scott DW, Steidl C
Nat Med: 23 Feb 2020; epub ahead of print | PMID: 32094924
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Impact:
Abstract

A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics.

Langenberg MCC, Hoogerwerf MA, Koopman JPR, Janse JJ, ... Visser LG, Roestenberg M

Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas. Novel medicines and vaccines are urgently needed. An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4 T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.



Nat Med: 16 Feb 2020; epub ahead of print
Langenberg MCC, Hoogerwerf MA, Koopman JPR, Janse JJ, ... Visser LG, Roestenberg M
Nat Med: 16 Feb 2020; epub ahead of print | PMID: 32066978
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Impact:
Abstract

Engineered immunogen binding to alum adjuvant enhances humoral immunity.

Moyer TJ, Kato Y, Abraham W, Chang JYH, ... Crotty S, Irvine DJ

Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.



Nat Med: 16 Feb 2020; epub ahead of print
Moyer TJ, Kato Y, Abraham W, Chang JYH, ... Crotty S, Irvine DJ
Nat Med: 16 Feb 2020; epub ahead of print | PMID: 32066977
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Impact:
Abstract

Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

Ordonez AA, Wang H, Magombedze G, Ruiz-Bedoya CA, ... Ivaturi VD, Jain SK

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study using dynamic [C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.



Nat Med: 16 Feb 2020; epub ahead of print
Ordonez AA, Wang H, Magombedze G, Ruiz-Bedoya CA, ... Ivaturi VD, Jain SK
Nat Med: 16 Feb 2020; epub ahead of print | PMID: 32066976
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Impact:
Abstract

Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota.

Nagao-Kitamoto H, Leslie JL, Kitamoto S, Jin C, ... Young VB, Kamada N

The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.



Nat Med: 16 Feb 2020; epub ahead of print
Nagao-Kitamoto H, Leslie JL, Kitamoto S, Jin C, ... Young VB, Kamada N
Nat Med: 16 Feb 2020; epub ahead of print | PMID: 32066975
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Impact:
Abstract

An immune-cell signature of bacterial sepsis.

Reyes M, Filbin MR, Bhattacharyya RP, Billman K, ... Goldberg MB, Hacohen N

Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14 monocyte state that is expanded in people with sepsis and validated its power in distinguishing these individuals from controls using public transcriptomic data from subjects with different disease etiologies and from multiple geographic locations (18 cohorts, n = 1,467 subjects). We identified a panel of surface markers for isolation and quantification of the monocyte state and characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single-cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis.



Nat Med: 16 Feb 2020; epub ahead of print
Reyes M, Filbin MR, Bhattacharyya RP, Billman K, ... Goldberg MB, Hacohen N
Nat Med: 16 Feb 2020; epub ahead of print | PMID: 32066974
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Impact:
Abstract

Effect of salt substitution on community-wide blood pressure and hypertension incidence.

Bernabe-Ortiz A, Sal Y Rosas VG, Ponce-Lucero V, Cárdenas MK, ... Gilman RH, Miranda JJ

Replacement of regular salt with potassium-enriched substitutes reduces blood pressure in controlled situations, mainly among people with hypertension. We report on a population-wide implementation of this strategy in a stepped-wedge cluster randomized trial (NCT01960972). The regular salt in enrolled households was retrieved and replaced, free of charge, with a combination of 75% NaCl and 25% KCl. A total of 2,376 participants were enrolled in 6 villages in Tumbes, Peru. The fully adjusted intention-to-treat analysis showed an average reduction of 1.29 mm Hg (95% confidence interval (95% CI) (-2.17, -0.41)) in systolic and 0.76 mm Hg (95% CI (-1.39, -0.13)) in diastolic blood pressure. Among participants without hypertension at baseline, in the time- and cluster-adjusted model, the use of the salt substitute was associated with a 51% (95% CI (29%, 66%)) reduced risk of developing hypertension compared with the control group. In 24-h urine samples, there was no evidence of differences in sodium levels (mean difference 0.01; 95% CI (0.25, -0.23)), but potassium levels were higher at the end of the study than at baseline (mean difference 0.63; 95% CI (0.78, 0.47)). Our results support a case for implementing a pragmatic, population-wide, salt-substitution strategy for reducing blood pressure and hypertension incidence.



Nat Med: 16 Feb 2020; epub ahead of print
Bernabe-Ortiz A, Sal Y Rosas VG, Ponce-Lucero V, Cárdenas MK, ... Gilman RH, Miranda JJ
Nat Med: 16 Feb 2020; epub ahead of print | PMID: 32066973
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Impact:
Abstract

Potent Zika and dengue cross-neutralizing antibodies induced by Zika vaccination in a dengue-experienced donor.

Dussupt V, Sankhala RS, Gromowski GD, Donofrio G, ... Joyce MG, Krebs SJ

Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. ). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV) in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas.



Nat Med: 02 Feb 2020; epub ahead of print
Dussupt V, Sankhala RS, Gromowski GD, Donofrio G, ... Joyce MG, Krebs SJ
Nat Med: 02 Feb 2020; epub ahead of print | PMID: 32015557
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Impact:
Abstract

Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity.

Niessl J, Baxter AE, Mendoza P, Jankovic M, ... Nussenzweig MC, Kaufmann DE

Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir. Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy. However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8 T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption. Increased CD4 T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.



Nat Med: 02 Feb 2020; epub ahead of print
Niessl J, Baxter AE, Mendoza P, Jankovic M, ... Nussenzweig MC, Kaufmann DE
Nat Med: 02 Feb 2020; epub ahead of print | PMID: 32015556
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Impact:
Abstract

Single-cell genomic approaches for developing the next generation of immunotherapies.

Yofe I, Dahan R, Amit I

Recent progress in single-cell genomics urges its application in drug development, particularly of cancer immunotherapies. Current immunotherapy pipelines are focused on functional outcome and simple cellular and molecular readouts. A thorough mechanistic understanding of the cells and pathways targeted by immunotherapy agents is lacking, which limits the success rate of clinical trials. A large leap forward can be made if the immunotherapy target cells and pathways are characterized at high resolution before and after treatment, in clinical cohorts and model systems. This will enable rapid development of effective immunotherapies and data-driven design of synergistic drug combinations. In this Perspective, we discuss how emerging single-cell genomic technologies can serve as an engine for target identification and drug development.



Nat Med: 02 Feb 2020; epub ahead of print
Yofe I, Dahan R, Amit I
Nat Med: 02 Feb 2020; epub ahead of print | PMID: 32015555
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Impact:
Abstract

Peripheral CD8 T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma.

Fairfax BP, Taylor CA, Watson RA, Nassiri I, ... Payne M, Middleton MR

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8 T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8 transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8 T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8 clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.



Nat Med: 30 Jan 2020; 26:193-199
Fairfax BP, Taylor CA, Watson RA, Nassiri I, ... Payne M, Middleton MR
Nat Med: 30 Jan 2020; 26:193-199 | PMID: 32042196
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Impact:
Abstract

The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research.

Painter CA, Jain E, Tomson BN, Dunphy M, ... Golub TR, Wagle N

Despite rare cancers accounting for 25% of adult tumors, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.



Nat Med: 30 Jan 2020; 26:181-187
Painter CA, Jain E, Tomson BN, Dunphy M, ... Golub TR, Wagle N
Nat Med: 30 Jan 2020; 26:181-187 | PMID: 32042194
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Impact:
Abstract

Cancer prognosis with shallow tumor RNA sequencing.

Milanez-Almeida P, Martins AJ, Germain RN, Tsang JS

Disrupted molecular pathways are often robustly associated with disease outcome in cancer. Although biologically informative transcriptional pathways can be revealed by RNA sequencing (RNA-seq) at up to hundreds of folds reduction in conventionally used coverage, it remains unknown how low-depth sequencing datasets perform in the challenging context of developing transcriptional signatures to predict clinical outcomes. Here we assessed the possibility of cancer prognosis with shallow tumor RNA-seq, which would potentially enable cost-effective assessment of much larger numbers of samples for deeper biological and predictive insights. By statistically modeling the relative risk of an adverse outcome for thousands of subjects in The Cancer Genome Atlas, we present evidence that subsampled tumor RNA-seq data with a few hundred thousand reads per sample provide sufficient information for outcome prediction in several types of cancer. Analysis of predictive models revealed robust contributions from pathways known to be associated with outcomes. Our findings indicate that predictive models of outcomes in cancer may be developed with dramatically increases in sample numbers at low cost, thus potentially enabling the development of more realistic predictive models that incorporate diverse variables and their interactions. This strategy could also be used, for example, in longitudinal analysis of multiple regions of a tumor alongside treatment for quantitative modeling and prediction of outcome in personalized oncology.



Nat Med: 30 Jan 2020; 26:188-192
Milanez-Almeida P, Martins AJ, Germain RN, Tsang JS
Nat Med: 30 Jan 2020; 26:188-192 | PMID: 32042193
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Impact:
Abstract

Using human genetics to understand the disease impacts of testosterone in men and women.

Ruth KS, Day FR, Tyrrell J, Thompson DJ, ... Frayling TM, Perry JRB

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.



Nat Med: 30 Jan 2020; 26:252-258
Ruth KS, Day FR, Tyrrell J, Thompson DJ, ... Frayling TM, Perry JRB
Nat Med: 30 Jan 2020; 26:252-258 | PMID: 32042192
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Impact:
Abstract

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Laughney AM, Hu J, Campbell NR, Bakhoum SF, ... Pe\'er D, Massagué J

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.



Nat Med: 30 Jan 2020; 26:259-269
Laughney AM, Hu J, Campbell NR, Bakhoum SF, ... Pe'er D, Massagué J
Nat Med: 30 Jan 2020; 26:259-269 | PMID: 32042191
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Impact:
Abstract

Lentiviral gene therapy for X-linked chronic granulomatous disease.

Kohn DB, Booth C, Kang EM, Pai SY, ... Thrasher AJ,

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34 hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.



Nat Med: 26 Jan 2020; epub ahead of print
Kohn DB, Booth C, Kang EM, Pai SY, ... Thrasher AJ,
Nat Med: 26 Jan 2020; epub ahead of print | PMID: 31988463
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Impact:
Abstract

Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy.

Moretti A, Fonteyne L, Giesert F, Hoppmann P, ... Wurst W, Kupatt C

Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. ) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.



Nat Med: 26 Jan 2020; epub ahead of print
Moretti A, Fonteyne L, Giesert F, Hoppmann P, ... Wurst W, Kupatt C
Nat Med: 26 Jan 2020; epub ahead of print | PMID: 31988462
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Impact:
Abstract

iPSC modeling of young-onset Parkinson\'s disease reveals a molecular signature of disease and novel therapeutic candidates.

Laperle AH, Sances S, Yucer N, Dardov VJ, ... Tagliati M, Svendsen CN

Young-onset Parkinson\'s disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson\'s disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson\'s disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.



Nat Med: 26 Jan 2020; epub ahead of print
Laperle AH, Sances S, Yucer N, Dardov VJ, ... Tagliati M, Svendsen CN
Nat Med: 26 Jan 2020; epub ahead of print | PMID: 31988461
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Impact:
Abstract

Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.

Brudno JN, Lam N, Vanasse D, Shen YW, ... Gress RE, Kochenderfer JN

Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.



Nat Med: 19 Jan 2020; epub ahead of print
Brudno JN, Lam N, Vanasse D, Shen YW, ... Gress RE, Kochenderfer JN
Nat Med: 19 Jan 2020; epub ahead of print | PMID: 31959992
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Abstract

A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance.

Chivukula RR, Montoro DT, Leung HM, Yang J, ... Alkuraya FS, Sabatini DM

Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.



Nat Med: 19 Jan 2020; epub ahead of print
Chivukula RR, Montoro DT, Leung HM, Yang J, ... Alkuraya FS, Sabatini DM
Nat Med: 19 Jan 2020; epub ahead of print | PMID: 31959991
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Abstract

Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report.

Kim D, Kobayashi T, Voisin B, Jo JH, ... Freeman AF, Nagao K

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4 T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.



Nat Med: 19 Jan 2020; epub ahead of print
Kim D, Kobayashi T, Voisin B, Jo JH, ... Freeman AF, Nagao K
Nat Med: 19 Jan 2020; epub ahead of print | PMID: 31959990
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Abstract

Fecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure.

Hayden HS, Eng A, Pope CE, Brittnacher MJ, ... Miller SI, Hoffman LR

Most infants with cystic fibrosis (CF) have pancreatic exocrine insufficiency that results in nutrient malabsorption and requires oral pancreatic enzyme replacement. Newborn screening for CF has enabled earlier diagnosis, nutritional intervention and enzyme replacement for these infants, allowing most infants with CF to achieve their weight goals by 12 months of age. Nevertheless, most infants with CF continue to have poor linear growth during their first year of life. Although this early linear growth failure is associated with worse long-term respiratory function and survival, the determinants of body length in infants with CF have not been defined. Several characteristics of the CF gastrointestinal (GI) tract, including inflammation, maldigestion and malabsorption, may promote intestinal dysbiosis. As GI microbiome activities are known to affect endocrine functions, the intestinal microbiome of infants with CF may also impact growth. We identified an early, progressive fecal dysbiosis that distinguished infants with CF and low length from infants with CF and normal length. This dysbiosis included altered abundances of taxa that perform functions that are important for GI health, nutrient harvest and growth hormone signaling, including decreased abundance of Bacteroidetes and increased abundance of Proteobacteria. Thus, the GI microbiota represent a potential therapeutic target for the correction of low linear growth in infants with CF.



Nat Med: 19 Jan 2020; epub ahead of print
Hayden HS, Eng A, Pope CE, Brittnacher MJ, ... Miller SI, Hoffman LR
Nat Med: 19 Jan 2020; epub ahead of print | PMID: 31959989
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Abstract

Visualization of AMPA receptors in living human brain with positron emission tomography.

Miyazaki T, Nakajima W, Hatano M, Shibata Y, ... Uchida H, Takahashi T

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with C ([C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [C]K-2 in the brain; secondary outcome: adverse events of [C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.



Nat Med: 19 Jan 2020; epub ahead of print
Miyazaki T, Nakajima W, Hatano M, Shibata Y, ... Uchida H, Takahashi T
Nat Med: 19 Jan 2020; epub ahead of print | PMID: 31959988
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This program is still in alpha version.