Journal: Nat Med

Sorted by: date / impact
Abstract

Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure.

Meran L, Massie I, Campinoti S, Weston AE, ... De Coppi P, Li VSW

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.



Nat Med: 29 Sep 2020; 26:1593-1601
Meran L, Massie I, Campinoti S, Weston AE, ... De Coppi P, Li VSW
Nat Med: 29 Sep 2020; 26:1593-1601 | PMID: 32895569
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease.

Centa JL, Jodelka FM, Hinrich AJ, Johnson TB, ... Rigo F, Hastings ML

CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20-30 years of life. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3), creating a reading frameshift. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.



Nat Med: 30 Aug 2020; 26:1444-1451
Centa JL, Jodelka FM, Hinrich AJ, Johnson TB, ... Rigo F, Hastings ML
Nat Med: 30 Aug 2020; 26:1444-1451 | PMID: 32719489
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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: 30 Jul 2020; 26:1280-1284
Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, ... Cahill DP, Sullivan RJ
Nat Med: 30 Jul 2020; 26:1280-1284 | PMID: 32483359
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Tau molecular diversity contributes to clinical heterogeneity in Alzheimer\'s disease.

Dujardin S, Commins C, Lathuiliere A, Beerepoot P, ... Kennedy ME, Hyman BT

Alzheimer\'s disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with \'typical\' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.



Nat Med: 30 Jul 2020; 26:1256-1263
Dujardin S, Commins C, Lathuiliere A, Beerepoot P, ... Kennedy ME, Hyman BT
Nat Med: 30 Jul 2020; 26:1256-1263 | PMID: 32572268
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Human-computer collaboration for skin cancer recognition.

Tschandl P, Rinner C, Apalla Z, Argenziano G, ... Zalaudek I, Kittler H

The rapid increase in telemedicine coupled with recent advances in diagnostic artificial intelligence (AI) create the imperative to consider the opportunities and risks of inserting AI-based support into new paradigms of care. Here we build on recent achievements in the accuracy of image-based AI for skin cancer diagnosis to address the effects of varied representations of AI-based support across different levels of clinical expertise and multiple clinical workflows. We find that good quality AI-based support of clinical decision-making improves diagnostic accuracy over that of either AI or physicians alone, and that the least experienced clinicians gain the most from AI-based support. We further find that AI-based multiclass probabilities outperformed content-based image retrieval (CBIR) representations of AI in the mobile technology environment, and AI-based support had utility in simulations of second opinions and of telemedicine triage. In addition to demonstrating the potential benefits associated with good quality AI in the hands of non-expert clinicians, we find that faulty AI can mislead the entire spectrum of clinicians, including experts. Lastly, we show that insights derived from AI class-activation maps can inform improvements in human diagnosis. Together, our approach and findings offer a framework for future studies across the spectrum of image-based diagnostics to improve human-computer collaboration in clinical practice.



Nat Med: 30 Jul 2020; 26:1229-1234
Tschandl P, Rinner C, Apalla Z, Argenziano G, ... Zalaudek I, Kittler H
Nat Med: 30 Jul 2020; 26:1229-1234 | PMID: 32572267
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A single-cell landscape of high-grade serous ovarian cancer.

Izar B, Tirosh I, Stover EH, Wakiro I, ... Rotem A, Regev A

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape and provides a resource for the development of novel therapeutic approaches.



Nat Med: 30 Jul 2020; 26:1271-1279
Izar B, Tirosh I, Stover EH, Wakiro I, ... Rotem A, Regev A
Nat Med: 30 Jul 2020; 26:1271-1279 | PMID: 32572264
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis.

Theron G, Limberis J, Venter R, Smith L, ... Warren R, Dheda K

A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host-pathogen interactions.



Nat Med: 30 Aug 2020; 26:1435-1443
Theron G, Limberis J, Venter R, Smith L, ... Warren R, Dheda K
Nat Med: 30 Aug 2020; 26:1435-1443 | PMID: 32601338
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents.

Riether C, Pabst T, Höpner S, Bacher U, ... Leupin N, Ochsenbein AF

Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ( NCT03030612 ). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.



Nat Med: 30 Aug 2020; 26:1459-1467
Riether C, Pabst T, Höpner S, Bacher U, ... Leupin N, Ochsenbein AF
Nat Med: 30 Aug 2020; 26:1459-1467 | PMID: 32601337
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pre-existing immunity to influenza virus hemagglutinin stalk might drive selection for antibody-escape mutant viruses in a human challenge model.

Park JK, Xiao Y, Ramuta MD, Rosas LA, ... Kash JC, Taubenberger JK

The conserved region of influenza hemagglutinin (HA) stalk (or stem) has gained attention as a potent target for universal influenza vaccines. Although the HA stalk region is relatively well conserved, the evolutionarily dynamic nature of influenza viruses raises concerns about the possible emergence of viruses carrying stalk escape mutation(s) under sufficient immune pressure. Here we show that immune pressure on the HA stalk can lead to expansion of escape mutant viruses in study participants challenged with a 2009 H1N1 pandemic influenza virus inoculum containing an A388V polymorphism in the HA stalk (45% wild type and 55% mutant). High level of stalk antibody titers was associated with the selection of the mutant virus both in humans and in vitro. Although the mutant virus showed slightly decreased replication in mice, it was not observed in cell culture, ferrets or human challenge participants. The A388V mutation conferred resistance to some of the potent HA stalk broadly neutralizing monoclonal antibodies (bNAbs). Co-culture of wild-type and mutant viruses in the presence of either a bNAb or human serum resulted in rapid expansion of the mutant. These data shed light on a potential obstacle for the success of HA-stalk-targeting universal influenza vaccines-viral escape from vaccine-induced stalk immunity.



Nat Med: 30 Jul 2020; 26:1240-1246
Park JK, Xiao Y, Ramuta MD, Rosas LA, ... Kash JC, Taubenberger JK
Nat Med: 30 Jul 2020; 26:1240-1246 | PMID: 32601336
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.

Alivernini S, MacDonald L, Elmesmari A, Finlay S, ... Otto TD, Kurowska-Stolarska M

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKTREM2 and MerTKLYVE1) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK STM subpopulations could therefore be a potential treatment strategy for RA.



Nat Med: 30 Jul 2020; 26:1295-1306
Alivernini S, MacDonald L, Elmesmari A, Finlay S, ... Otto TD, Kurowska-Stolarska M
Nat Med: 30 Jul 2020; 26:1295-1306 | PMID: 32601335
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice.

Suriben R, Chen M, Higbee J, Oeffinger J, ... Lindhout DA, Allan BB

Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer, and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.



Nat Med: 30 Jul 2020; 26:1264-1270
Suriben R, Chen M, Higbee J, Oeffinger J, ... Lindhout DA, Allan BB
Nat Med: 30 Jul 2020; 26:1264-1270 | PMID: 32661391
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Myocardial infarction accelerates breast cancer via innate immune reprogramming.

Koelwyn GJ, Newman AAC, Afonso MS, van Solingen C, ... Jones LW, Moore KJ

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity or surgery, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6C monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6C monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.



Nat Med: 30 Aug 2020; 26:1452-1458
Koelwyn GJ, Newman AAC, Afonso MS, van Solingen C, ... Jones LW, Moore KJ
Nat Med: 30 Aug 2020; 26:1452-1458 | PMID: 32661390
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.

Ayoub R, Ruddy RM, Cox E, Oyefiade A, ... Morshead CM, Mabbott DJ

We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.



Nat Med: 30 Jul 2020; 26:1285-1294
Ayoub R, Ruddy RM, Cox E, Oyefiade A, ... Morshead CM, Mabbott DJ
Nat Med: 30 Jul 2020; 26:1285-1294 | PMID: 32719487
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Grzymski JJ, Elhanan G, Morales Rosado JA, Smith E, ... Bolze A, Lu JT

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.



Nat Med: 30 Jul 2020; 26:1235-1239
Grzymski JJ, Elhanan G, Morales Rosado JA, Smith E, ... Bolze A, Lu JT
Nat Med: 30 Jul 2020; 26:1235-1239 | PMID: 32719484
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Maternal cannabis use in pregnancy and child neurodevelopmental outcomes.

Corsi DJ, Donelle J, Sucha E, Hawken S, ... Wen SW, Walker M

Cannabis use in pregnancy has increased, and many women continue to use it throughout pregnancy. With the legalization of recreational cannabis in many jurisdictions, there is concern about potentially adverse childhood outcomes related to prenatal exposure. Using the provincial birth registry containing information on cannabis use during pregnancy, we perform a retrospective analysis of all live births in Ontario, Canada, between 1 April 2007 and 31 March 2012. We link pregnancy and birth data to provincial health administrative databases to ascertain child neurodevelopmental outcomes. We use matching techniques to control for confounding and Cox proportional hazards regression models to examine associations between prenatal cannabis use and child neurodevelopment. We find an association between maternal cannabis use in pregnancy and the incidence of autism spectrum disorder in the offspring. The incidence of autism spectrum disorder diagnosis was 4.00 per 1,000 person-years among children with exposure compared to 2.42 among unexposed children, and the fully adjusted hazard ratio was 1.51 (95% confidence interval: 1.17-1.96) in the matched cohort. The incidence of intellectual disability and learning disorders was higher among offspring of mothers who use cannabis in pregnancy, although less statistically robust. We emphasize a cautious interpretation of these findings given the likelihood of residual confounding.



Nat Med: 29 Sep 2020; 26:1536-1540
Corsi DJ, Donelle J, Sucha E, Hawken S, ... Wen SW, Walker M
Nat Med: 29 Sep 2020; 26:1536-1540 | PMID: 32778828
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Bernard E, Nannya Y, Hasserjian RP, Devlin SM, ... Ogawa S, Papaemmanuil E

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.



Nat Med: 29 Sep 2020; 26:1549-1556
Bernard E, Nannya Y, Hasserjian RP, Devlin SM, ... Ogawa S, Papaemmanuil E
Nat Med: 29 Sep 2020; 26:1549-1556 | PMID: 32747829
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Single-cell atlas of colonic CD8 T cells in ulcerative colitis.

Corridoni D, Antanaviciute A, Gupta T, Fawkner-Corbett D, ... Koohy H, Simmons A

Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8 T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8 T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8 T-cell composition, including expanded effector and post-effector terminally differentiated CD8 T cells. While UC-associated CD8 effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8 T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8 T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.



Nat Med: 30 Aug 2020; 26:1480-1490
Corridoni D, Antanaviciute A, Gupta T, Fawkner-Corbett D, ... Koohy H, Simmons A
Nat Med: 30 Aug 2020; 26:1480-1490 | PMID: 32747828
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda.

Uwimana A, Legrand E, Stokes BH, Ndikumana JM, ... Mbituyumuremyi A, Menard D

Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa. Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.



Nat Med: 29 Sep 2020; 26:1602-1608
Uwimana A, Legrand E, Stokes BH, Ndikumana JM, ... Mbituyumuremyi A, Menard D
Nat Med: 29 Sep 2020; 26:1602-1608 | PMID: 32747827
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A combined risk score enhances prediction of type 1 diabetes among susceptible children.

Ferrat LA, Vehik K, Sharp SA, Lernmark Å, ... ,

Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common and is most severe in the very young, in whom it can be life threatening and difficult to treat. Autoantibody surveillance programs effectively prevent most ketoacidosis but require frequent evaluations whose expense limits public health adoption. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.



Nat Med: 30 Jul 2020; 26:1247-1255
Ferrat LA, Vehik K, Sharp SA, Lernmark Å, ... ,
Nat Med: 30 Jul 2020; 26:1247-1255 | PMID: 32770166
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma.

Cader FZ, Hu X, Goh WL, Wienand K, ... Liu XS, Shipp MA

PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4, but not CD8, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to therapy had an increased abundance of activated natural killer cells and a newly identified CD3CD68CD4GrB subset. These studies highlight the roles of recently expanded, clonally diverse CD4 T cells and innate effectors in the efficacy of PD-1 blockade in cHL.



Nat Med: 30 Aug 2020; 26:1468-1479
Cader FZ, Hu X, Goh WL, Wienand K, ... Liu XS, Shipp MA
Nat Med: 30 Aug 2020; 26:1468-1479 | PMID: 32778827
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia.

Luo Y, Eran A, Palmer N, Avillach P, ... Szolovits P, Kohane IS

The promise of precision medicine lies in data diversity. More than the sheer size of biomedical data, it is the layering of multiple data modalities, offering complementary perspectives, that is thought to enable the identification of patient subgroups with shared pathophysiology. In the present study, we use autism to test this notion. By combining healthcare claims, electronic health records, familial whole-exome sequences and neurodevelopmental gene expression patterns, we identified a subgroup of patients with dyslipidemia-associated autism.



Nat Med: 30 Aug 2020; 26:1375-1379
Luo Y, Eran A, Palmer N, Avillach P, ... Szolovits P, Kohane IS
Nat Med: 30 Aug 2020; 26:1375-1379 | PMID: 32778826
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The role of exome sequencing in newborn screening for inborn errors of metabolism.

Adhikari AN, Gallagher RC, Wang Y, Currier RJ, ... Puck JM, Brenner SE

Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs). The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.



Nat Med: 30 Aug 2020; 26:1392-1397
Adhikari AN, Gallagher RC, Wang Y, Currier RJ, ... Puck JM, Brenner SE
Nat Med: 30 Aug 2020; 26:1392-1397 | PMID: 32778825
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Articular cartilage regeneration by activated skeletal stem cells.

Murphy MP, Koepke LS, Lopez MT, Tong X, ... Longaker MT, Chan CKF

Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.



Nat Med: 29 Sep 2020; 26:1583-1592
Murphy MP, Koepke LS, Lopez MT, Tong X, ... Longaker MT, Chan CKF
Nat Med: 29 Sep 2020; 26:1583-1592 | PMID: 32807933
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A digital biomarker of diabetes from smartphone-based vascular signals.

Avram R, Olgin JE, Kuhar P, Hughes JW, ... Aschbacher K, Tison GH

The global burden of diabetes is rapidly increasing, from 451 million people in 2019 to 693 million by 2045. The insidious onset of type 2 diabetes delays diagnosis and increases morbidity. Given the multifactorial vascular effects of diabetes, we hypothesized that smartphone-based photoplethysmography could provide a widely accessible digital biomarker for diabetes. Here we developed a deep neural network (DNN) to detect prevalent diabetes using smartphone-based photoplethysmography from an initial cohort of 53,870 individuals (the \'primary cohort\'), which we then validated in a separate cohort of 7,806 individuals (the \'contemporary cohort\') and a cohort of 181 prospectively enrolled individuals from three clinics (the \'clinic cohort\'). The DNN achieved an area under the curve for prevalent diabetes of 0.766 in the primary cohort (95% confidence interval: 0.750-0.782; sensitivity 75%, specificity 65%) and 0.740 in the contemporary cohort (95% confidence interval: 0.723-0.758; sensitivity 81%, specificity 54%). When the output of the DNN, called the DNN score, was included in a regression analysis alongside age, gender, race/ethnicity and body mass index, the area under the curve was 0.830 and the DNN score remained independently predictive of diabetes. The performance of the DNN in the clinic cohort was similar to that in other validation datasets. There was a significant and positive association between the continuous DNN score and hemoglobin A1c (P ≤ 0.001) among those with hemoglobin A1c data. These findings demonstrate that smartphone-based photoplethysmography provides a readily attainable, non-invasive digital biomarker of prevalent diabetes.



Nat Med: 29 Sep 2020; 26:1576-1582
Avram R, Olgin JE, Kuhar P, Hughes JW, ... Aschbacher K, Tison GH
Nat Med: 29 Sep 2020; 26:1576-1582 | PMID: 32807931
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Wearable-device-measured physical activity and future health risk.

Strain T, Wijndaele K, Dempsey PC, Sharp SJ, ... Wareham N, Brage S

Use of wearable devices that monitor physical activity is projected to increase more than fivefold per half-decade. We investigated how device-based physical activity energy expenditure (PAEE) and different intensity profiles were associated with all-cause mortality. We used a network harmonization approach to map dominant-wrist acceleration to PAEE in 96,476 UK Biobank participants (mean age 62 years, 56% female). We also calculated the fraction of PAEE accumulated from moderate-to-vigorous-intensity physical activity (MVPA). Over the median 3.1-year follow-up period (302,526 person-years), 732 deaths were recorded. Higher PAEE was associated with a lower hazard of all-cause mortality for a constant fraction of MVPA (for example, 21% (95% confidence interval 4-35%) lower hazard for 20 versus 15 kJ kg d PAEE with 10% from MVPA). Similarly, a higher MVPA fraction was associated with a lower hazard when PAEE remained constant (for example, 30% (8-47%) lower hazard when 20% versus 10% of a fixed 15 kJ kg d PAEE volume was from MVPA). Our results show that higher volumes of PAEE are associated with reduced mortality rates, and achieving the same volume through higher-intensity activity is associated with greater reductions than through lower-intensity activity. The linkage of device-measured activity to energy expenditure creates a framework for using wearables for personalized prevention.



Nat Med: 30 Aug 2020; 26:1385-1391
Strain T, Wijndaele K, Dempsey PC, Sharp SJ, ... Wareham N, Brage S
Nat Med: 30 Aug 2020; 26:1385-1391 | PMID: 32807930
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.

Carter MJ, Fish M, Jennings A, Doores KJ, ... Tibby SM, Shankar-Hari M

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-multisystem inflammatory syndrome in children (MIS-C)-which comprises multiorgan dysfunction and systemic inflammation. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4CCR7 T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness and appears distinct from Kawasaki disease.



Nat Med: 17 Aug 2020; epub ahead of print
Carter MJ, Fish M, Jennings A, Doores KJ, ... Tibby SM, Shankar-Hari M
Nat Med: 17 Aug 2020; epub ahead of print | PMID: 32812012
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A population-based phenome-wide association study of cardiac and aortic structure and function.

Bai W, Suzuki H, Huang J, Francis C, ... Matthews PM, Rueckert D

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart-brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.



Nat Med: 29 Sep 2020; 26:1654-1662
Bai W, Suzuki H, Huang J, Francis C, ... Matthews PM, Rueckert D
Nat Med: 29 Sep 2020; 26:1654-1662 | PMID: 32839619
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo.

Maldini CR, Claiborne DT, Okawa K, Chen T, ... Riley JL, Allen TM

An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4 T cell loss after the discontinuation of antiretroviral therapy. Through iterative improvements to the CAR T cell product, we developed Dual-CAR T cells that simultaneously expressed both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains. Dual-CAR T cells exhibited expansion kinetics that exceeded 4-1BB-, CD28- and third-generation costimulated CAR T cells, elicited effector functions equivalent to CD28-costimulated CAR T cells and prevented HIV-induced CD4 T cell loss despite persistent viremia. Moreover, when Dual-CAR T cells were protected from HIV infection through expression of the C34-CXCR4 fusion inhibitor, these cells significantly reduced acute-phase viremia, as well as accelerated HIV suppression in the presence of antiretroviral therapy and reduced tissue viral burden. Collectively, these studies demonstrate the enhanced therapeutic potency of a novel Dual-CAR T cell product with the potential to effectively treat HIV infection.



Nat Med: 30 Aug 2020; epub ahead of print
Maldini CR, Claiborne DT, Okawa K, Chen T, ... Riley JL, Allen TM
Nat Med: 30 Aug 2020; epub ahead of print | PMID: 32868878
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters.

Tostanoski LH, Wegmann F, Martinot AJ, Loos C, ... Zahn R, Barouch DH

Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters and nonhuman primates have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.



Nat Med: 02 Sep 2020; epub ahead of print
Tostanoski LH, Wegmann F, Martinot AJ, Loos C, ... Zahn R, Barouch DH
Nat Med: 02 Sep 2020; epub ahead of print | PMID: 32884153
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Recommendations for measuring HIV reservoir size in cure-directed clinical trials.

Abdel-Mohsen M, Richman D, Siliciano RF, Nussenzweig MC, ... Montaner LJ,

Therapeutic strategies are being clinically tested either to eradicate latent HIV reservoirs or to achieve virologic control in the absence of antiretroviral therapy. Attaining this goal will require a consensus on how best to measure the numbers of persistently infected cells with the potential to cause viral rebound after antiretroviral-therapy cessation in assessing the results of cure-directed strategies in vivo. Current measurements assess various aspects of the HIV provirus and its functionality and produce divergent results. Here, we provide recommendations from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements should be prioritized in HIV-cure-directed clinical trials.



Nat Med: 30 Aug 2020; 26:1339-1350
Abdel-Mohsen M, Richman D, Siliciano RF, Nussenzweig MC, ... Montaner LJ,
Nat Med: 30 Aug 2020; 26:1339-1350 | PMID: 32895573
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genomic copy number predicts esophageal cancer years before transformation.

Killcoyne S, Gregson E, Wedge DC, Woodcock DJ, ... Gerstung M, Fitzgerald RC

Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett\'s esophagus as an exemplar. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett\'s esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.



Nat Med: 06 Sep 2020; epub ahead of print
Killcoyne S, Gregson E, Wedge DC, Woodcock DJ, ... Gerstung M, Fitzgerald RC
Nat Med: 06 Sep 2020; epub ahead of print | PMID: 32895572
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial.

Motzer RJ, Robbins PB, Powles T, Albiges L, ... Donahue AC, Choueiri TK

We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886; NCT02684006), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC.



Nat Med: 06 Sep 2020; epub ahead of print
Motzer RJ, Robbins PB, Powles T, Albiges L, ... Donahue AC, Choueiri TK
Nat Med: 06 Sep 2020; epub ahead of print | PMID: 32895571
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Polygenic architecture informs potential vulnerability to drug-induced liver injury.

Koido M, Kawakami E, Fukumura J, Noguchi Y, ... Shinozawa T, Takebe T

Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who are at risk. In this study, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed \'polygenicity-in-a-dish\' strategy might potentially inform designs of safer, more efficient and robust clinical trials.



Nat Med: 29 Sep 2020; 26:1541-1548
Koido M, Kawakami E, Fukumura J, Noguchi Y, ... Shinozawa T, Takebe T
Nat Med: 29 Sep 2020; 26:1541-1548 | PMID: 32895570
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension.

Cruz Rivera S, Liu X, Chan AW, Denniston AK, ... ,

The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human-AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.



Nat Med: 30 Aug 2020; 26:1351-1363
Cruz Rivera S, Liu X, Chan AW, Denniston AK, ... ,
Nat Med: 30 Aug 2020; 26:1351-1363 | PMID: 32908284
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Reporting guidelines for clinical trial reports for interventions involving artificial intelligence: the CONSORT-AI extension.

Liu X, Cruz Rivera S, Moher D, Calvert MJ, Denniston AK

The CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human-AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.



Nat Med: 30 Aug 2020; 26:1364-1374
Liu X, Cruz Rivera S, Moher D, Calvert MJ, Denniston AK
Nat Med: 30 Aug 2020; 26:1364-1374 | PMID: 32908283
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Insulin dose optimization using an automated artificial intelligence-based decision support system in youths with type 1 diabetes.

Nimri R, Battelino T, Laffel LM, Slover RH, ... Phillip M,

Despite the increasing adoption of insulin pumps and continuous glucose monitoring devices, most people with type 1 diabetes do not achieve their glycemic goals. This could be related to a lack of expertise or inadequate time for clinicians to analyze complex sensor-augmented pump data. We tested whether frequent insulin dose adjustments guided by an automated artificial intelligence-based decision support system (AI-DSS) is as effective and safe as those guided by physicians in controlling glucose levels. ADVICE4U was a six-month, multicenter, multinational, parallel, randomized controlled, non-inferiority trial in 108 participants with type 1 diabetes, aged 10-21 years and using insulin pump therapy (ClinicalTrials.gov no. NCT03003806). Participants were randomized 1:1 to receive remote insulin dose adjustment every three weeks guided by either an AI-DSS, (AI-DSS arm, n = 54) or by physicians (physician arm, n = 54). The results for the primary efficacy measure-the percentage of time spent within the target glucose range (70-180 mg dl (3.9-10.0 mmol l))-in the AI-DSS arm were statistically non-inferior to those in the physician arm (50.2 ± 11.1% versus 51.6 ± 11.3%, respectively, P < 1 × 10). The percentage of readings below 54 mg dl (<3.0 mmol l) within the AI-DSS arm was statistically non-inferior to that in the physician arm (1.3 ± 1.4% versus 1.0 ± 0.9%, respectively, P < 0.0001). Three severe adverse events related to diabetes (two severe hypoglycemia, one diabetic ketoacidosis) were reported in the physician arm and none in the AI-DSS arm. In conclusion, use of an automated decision support tool for optimizing insulin pump settings was non-inferior to intensive insulin titration provided by physicians from specialized academic diabetes centers.



Nat Med: 30 Aug 2020; 26:1380-1384
Nimri R, Battelino T, Laffel LM, Slover RH, ... Phillip M,
Nat Med: 30 Aug 2020; 26:1380-1384 | PMID: 32908282
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Seasonal coronavirus protective immunity is short-lasting.

Edridge AWD, Kaczorowska J, Hoste ACR, Bakker M, ... Deijs M, van der Hoek L

A key unsolved question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of acquired immunity. Insights from infections with the four seasonal human coronaviruses might reveal common characteristics applicable to all human coronaviruses. We monitored healthy individuals for more than 35 years and determined that reinfection with the same seasonal coronavirus occurred frequently at 12 months after infection.



Nat Med: 13 Sep 2020; epub ahead of print
Edridge AWD, Kaczorowska J, Hoste ACR, Bakker M, ... Deijs M, van der Hoek L
Nat Med: 13 Sep 2020; epub ahead of print | PMID: 32929268
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle.

Wang W, Vilella F, Alama P, Moreno I, ... Simon C, Quake SR

In a human menstrual cycle the endometrium undergoes remodeling, shedding and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, our understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single-cell resolution across the menstrual cycle, resolving cellular heterogeneity in multiple dimensions. We profiled the behavior of seven endometrial cell types, including a previously uncharacterized ciliated cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that the human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with a widespread decidualization feature in the stromal fibroblasts. Our study provides a high-resolution molecular and cellular characterization of human endometrial transformation across the menstrual cycle, providing insights into this essential physiological process.



Nat Med: 29 Sep 2020; 26:1644-1653
Wang W, Vilella F, Alama P, Moreno I, ... Simon C, Quake SR
Nat Med: 29 Sep 2020; 26:1644-1653 | PMID: 32929266
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study.

Bloor AJC, Patel A, Griffin JE, Gilleece MH, ... Slukvin I, Rasko JEJ

The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases, including steroid-resistant acute graft versus host disease (SR-aGvHD). However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 10 cells per kg body weight, to a maximum of 1 × 10 cells per infusion (cohort A), or 2 × 10 cells per kg body weight, to a maximum dose of 2 × 10 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.



Nat Med: 13 Sep 2020; epub ahead of print
Bloor AJC, Patel A, Griffin JE, Gilleece MH, ... Slukvin I, Rasko JEJ
Nat Med: 13 Sep 2020; epub ahead of print | PMID: 32929265
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study.

Liu STH, Lin HM, Baine I, Wajnberg A, ... Aberg JA, Bouvier NM

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease with few effective treatments. Convalescent plasma, donated by persons who have recovered from COVID-19, is the acellular component of blood that contains antibodies, including those that specifically recognize SARS-CoV-2. These antibodies, when transfused into patients infected with SARS-CoV-2, are thought to exert an antiviral effect, suppressing virus replication before patients have mounted their own humoral immune responses. Virus-specific antibodies from recovered persons are often the first available therapy for an emerging infectious disease, a stopgap treatment while new antivirals and vaccines are being developed. This retrospective, propensity score-matched case-control study assessed the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at The Mount Sinai Hospital in New York City. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score-matched controls who were hospitalized with COVID-19 (adjusted odds ratio (OR), 0.86; 95% confidence interval (CI), 0.75-0.98; chi-square test P value = 0.025). Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13-0.89; chi-square test P = 0.027). Convalescent plasma is potentially effective against COVID-19, but adequately powered, randomized controlled trials are needed.



Nat Med: 14 Sep 2020; epub ahead of print
Liu STH, Lin HM, Baine I, Wajnberg A, ... Aberg JA, Bouvier NM
Nat Med: 14 Sep 2020; epub ahead of print | PMID: 32934372
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clustering and superspreading potential of SARS-CoV-2 infections in Hong Kong.

Adam DC, Wu P, Wong JY, Lau EHY, ... Leung GM, Cowling BJ

Superspreading events (SSEs) have characterized previous epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. For SARS-CoV-2, the degree to which SSEs are involved in transmission remains unclear, but there is growing evidence that SSEs might be a typical feature of COVID-19. Using contact tracing data from 1,038 SARS-CoV-2 cases confirmed between 23 January and 28 April 2020 in Hong Kong, we identified and characterized all local clusters of infection. We identified 4-7 SSEs across 51 clusters (n = 309 cases) and estimated that 19% (95% confidence interval, 15-24%) of cases seeded 80% of all local transmission. Transmission in social settings was associated with more secondary cases than households when controlling for age (P = 0.002). Decreasing the delay between symptom onset and case confirmation did not result in fewer secondary cases (P = 0.98), although the odds that an individual being quarantined as a contact interrupted transmission was 14.4 (95% CI, 1.9-107.2). Public health authorities should focus on rapidly tracing and quarantining contacts, along with implementing restrictions targeting social settings to reduce the risk of SSEs and suppress SARS-CoV-2 transmission.



Nat Med: 16 Sep 2020; epub ahead of print
Adam DC, Wu P, Wong JY, Lau EHY, ... Leung GM, Cowling BJ
Nat Med: 16 Sep 2020; epub ahead of print | PMID: 32943787
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.

Khan TA, Revah O, Gordon A, Yoon SJ, ... Dolmetsch RE, Paşca SP

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.



Nat Med: 27 Sep 2020; epub ahead of print
Khan TA, Revah O, Gordon A, Yoon SJ, ... Dolmetsch RE, Paşca SP
Nat Med: 27 Sep 2020; epub ahead of print | PMID: 32989314
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Global maps of travel time to healthcare facilities.

Weiss DJ, Nelson A, Vargas-Ruiz CA, Gligorić K, ... Bhatt S, Gething PW

Access to healthcare is a requirement for human well-being that is constrained, in part, by the allocation of healthcare resources relative to the geographically dispersed human population. Quantifying access to care globally is challenging due to the absence of a comprehensive database of healthcare facilities. We harness major data collection efforts underway by OpenStreetMap, Google Maps and academic researchers to compile the most complete collection of facility locations to date. Leveraging the geographically variable strengths of our facility datasets, we use an established methodology to characterize travel time to healthcare facilities in unprecedented detail. We produce maps of travel time with and without access to motorized transport, thus characterizing travel time to healthcare for populations distributed across the wealth spectrum. We find that just 8.9% of the global population (646 million people) cannot reach healthcare within one hour if they have access to motorized transport, and that 43.3% (3.16 billion people) cannot reach a healthcare facility by foot within one hour. Our maps highlight an additional vulnerability faced by poorer individuals in remote areas and can help to estimate whether individuals will seek healthcare when it is needed, as well as providing an evidence base for efficiently distributing limited healthcare and transportation resources to underserved populations both now and in the future.



Nat Med: 27 Sep 2020; epub ahead of print
Weiss DJ, Nelson A, Vargas-Ruiz CA, Gligorić K, ... Bhatt S, Gething PW
Nat Med: 27 Sep 2020; epub ahead of print | PMID: 32989313
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Crowding and the shape of COVID-19 epidemics.

Rader B, Scarpino SV, Nande A, Hill AL, ... Pybus OG, Kraemer MUG

The coronavirus disease 2019 (COVID-19) pandemic is straining public health systems worldwide, and major non-pharmaceutical interventions have been implemented to slow its spread. During the initial phase of the outbreak, dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was primarily determined by human mobility from Wuhan, China. Yet empirical evidence on the effect of key geographic factors on local epidemic transmission is lacking. In this study, we analyzed highly resolved spatial variables in cities, together with case count data, to investigate the role of climate, urbanization and variation in interventions. We show that the degree to which cases of COVID-19 are compressed into a short period of time (peakedness of the epidemic) is strongly shaped by population aggregation and heterogeneity, such that epidemics in crowded cities are more spread over time, and crowded cities have larger total attack rates than less populated cities. Observed differences in the peakedness of epidemics are consistent with a meta-population model of COVID-19 that explicitly accounts for spatial hierarchies. We paired our estimates with globally comprehensive data on human mobility and predict that crowded cities worldwide could experience more prolonged epidemics.



Nat Med: 04 Oct 2020; epub ahead of print
Rader B, Scarpino SV, Nande A, Hill AL, ... Pybus OG, Kraemer MUG
Nat Med: 04 Oct 2020; epub ahead of print | PMID: 33020651
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer.

Wong M, Mayoh C, Lau LMS, Khuong-Quang DA, ... Ekert PG, Cowley MJ

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.



Nat Med: 04 Oct 2020; epub ahead of print
Wong M, Mayoh C, Lau LMS, Khuong-Quang DA, ... Ekert PG, Cowley MJ
Nat Med: 04 Oct 2020; epub ahead of print | PMID: 33020650
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Nakamura Y, Taniguchi H, Ikeda M, Bando H, ... Odegaard JI, Yoshino T

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.



Nat Med: 04 Oct 2020; epub ahead of print
Nakamura Y, Taniguchi H, Ikeda M, Bando H, ... Odegaard JI, Yoshino T
Nat Med: 04 Oct 2020; epub ahead of print | PMID: 33020649
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i.

Dummer R, Lebbé C, Atkinson V, Mandalà M, ... Gasal E, Long GV

Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients\' outcomes. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n = 36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg of spartalizumab every 4 weeks plus 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. Part 2 characterized changes in PD-L1 levels and CD8 cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3 months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell-inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.



Nat Med: 29 Sep 2020; 26:1557-1563
Dummer R, Lebbé C, Atkinson V, Mandalà M, ... Gasal E, Long GV
Nat Med: 29 Sep 2020; 26:1557-1563 | PMID: 33020648
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial.

Shah NN, Johnson BD, Schneider D, Zhu F, ... Orentas R, Hari P

Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies. Despite impressive outcomes, relapse with CD19 disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB-CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10-2.5 × 10 cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10 cells per kg was chosen for expansion. Grade 3-4 cytokine release syndrome occurred in one (5%) patient, and grade 3-4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10 cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.



Nat Med: 29 Sep 2020; 26:1569-1575
Shah NN, Johnson BD, Schneider D, Zhu F, ... Orentas R, Hari P
Nat Med: 29 Sep 2020; 26:1569-1575 | PMID: 33020647
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial.

Algazi AP, Othus M, Daud AI, Lo RS, ... Grossmann KF, Ribas A

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF in melanoma. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAF melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.



Nat Med: 29 Sep 2020; 26:1564-1568
Algazi AP, Othus M, Daud AI, Lo RS, ... Grossmann KF, Ribas A
Nat Med: 29 Sep 2020; 26:1564-1568 | PMID: 33020646
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Targeting the HIF2-VEGF axis in renal cell carcinoma.

Choueiri TK, Kaelin WG

Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.



Nat Med: 29 Sep 2020; 26:1519-1530
Choueiri TK, Kaelin WG
Nat Med: 29 Sep 2020; 26:1519-1530 | PMID: 33020645
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.

Deng Q, Han G, Puebla-Osorio N, Ma MCJ, ... Wang L, Green MR

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.



Nat Med: 04 Oct 2020; epub ahead of print
Deng Q, Han G, Puebla-Osorio N, Ma MCJ, ... Wang L, Green MR
Nat Med: 04 Oct 2020; epub ahead of print | PMID: 33020644
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.

van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, ... van Rhijn BW, van der Heijden MS

Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma and colorectal cancer. In NABUCCO (ClinicalTrials.gov: NCT03387761), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8 presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8 T cell activity.



Nat Med: 11 Oct 2020; epub ahead of print
van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, ... van Rhijn BW, van der Heijden MS
Nat Med: 11 Oct 2020; epub ahead of print | PMID: 33046870
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.

Gao J, Navai N, Alhalabi O, Siefker-Radtke A, ... Goswami S, Sharma P

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.



Nat Med: 11 Oct 2020; epub ahead of print
Gao J, Navai N, Alhalabi O, Siefker-Radtke A, ... Goswami S, Sharma P
Nat Med: 11 Oct 2020; epub ahead of print | PMID: 33046869
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis.

Heczey A, Courtney AN, Montalbano A, Robinson S, ... Dotti G, Metelitsa LS

Vα24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean ± s.d., 94.7 ± 3.8%) and treated patients with 3 × 10 CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.



Nat Med: 11 Oct 2020; epub ahead of print
Heczey A, Courtney AN, Montalbano A, Robinson S, ... Dotti G, Metelitsa LS
Nat Med: 11 Oct 2020; epub ahead of print | PMID: 33046868
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Magnitude, demographics and dynamics of the effect of the first wave of the COVID-19 pandemic on all-cause mortality in 21 industrialized countries.

Kontis V, Bennett JE, Rashid T, Parks RM, ... Mathers CD, Ezzati M

The Coronavirus Disease 2019 (COVID-19) pandemic has changed many social, economic, environmental and healthcare determinants of health. We applied an ensemble of 16 Bayesian models to vital statistics data to estimate the all-cause mortality effect of the pandemic for 21 industrialized countries. From mid-February through May 2020, 206,000 (95% credible interval, 178,100-231,000) more people died in these countries than would have had the pandemic not occurred. The number of excess deaths, excess deaths per 100,000 people and relative increase in deaths were similar between men and women in most countries. England and Wales and Spain experienced the largest effect: ~100 excess deaths per 100,000 people, equivalent to a 37% (30-44%) relative increase in England and Wales and 38% (31-45%) in Spain. Bulgaria, New Zealand, Slovakia, Australia, Czechia, Hungary, Poland, Norway, Denmark and Finland experienced mortality changes that ranged from possible small declines to increases of 5% or less in either sex. The heterogeneous mortality effects of the COVID-19 pandemic reflect differences in how well countries have managed the pandemic and the resilience and preparedness of the health and social care system.



Nat Med: 13 Oct 2020; epub ahead of print
Kontis V, Bennett JE, Rashid T, Parks RM, ... Mathers CD, Ezzati M
Nat Med: 13 Oct 2020; epub ahead of print | PMID: 33057181
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings.

Gupta RK, Calderwood CJ, Yavlinsky A, Krutikov M, ... Noursadeghi M, Abubakar I

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.



Nat Med: 18 Oct 2020; epub ahead of print
Gupta RK, Calderwood CJ, Yavlinsky A, Krutikov M, ... Noursadeghi M, Abubakar I
Nat Med: 18 Oct 2020; epub ahead of print | PMID: 33077958
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.

Cerezo-Wallis D, Contreras-Alcalde M, Troulé K, Catena X, ... Olmeda D, Soengas MS

An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8 T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.



Nat Med: 18 Oct 2020; epub ahead of print
Cerezo-Wallis D, Contreras-Alcalde M, Troulé K, Catena X, ... Olmeda D, Soengas MS
Nat Med: 18 Oct 2020; epub ahead of print | PMID: 33077955
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Jin SC, Dong W, Kundishora AJ, Panchagnula S, ... Lifton RP, Kahle KT

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.



Nat Med: 18 Oct 2020; epub ahead of print
Jin SC, Dong W, Kundishora AJ, Panchagnula S, ... Lifton RP, Kahle KT
Nat Med: 18 Oct 2020; epub ahead of print | PMID: 33077954
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A global survey of potential acceptance of a COVID-19 vaccine.

Lazarus JV, Ratzan SC, Palayew A, Gostin LO, ... Kimball S, El-Mohandes A

Several coronavirus disease 2019 (COVID-19) vaccines are currently in human trials. In June 2020, we surveyed 13,426 people in 19 countries to determine potential acceptance rates and factors influencing acceptance of a COVID-19 vaccine. Of these, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine, and 61.4% reported that they would accept their employer\'s recommendation to do so. Differences in acceptance rates ranged from almost 90% (in China) to less than 55% (in Russia). Respondents reporting higher levels of trust in information from government sources were more likely to accept a vaccine and take their employer\'s advice to do so.



Nat Med: 19 Oct 2020; epub ahead of print
Lazarus JV, Ratzan SC, Palayew A, Gostin LO, ... Kimball S, El-Mohandes A
Nat Med: 19 Oct 2020; epub ahead of print | PMID: 33082575
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.